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Bone quality in the treatment of osteoporosis: new approaches, new techniques, and new answers

Editorial

• How innovations are changing our management of osteoporosis
  Comment l’innovation transforme la prise en charge de l’ostéoporose
  M. L. Brandi, Italy

Themed articles

• Osteoporosis: a disease of bone formation
  P. J. Marie, France
• Long-term antifracture efficacy and safety of antiosteoporotic treatments: the hidden part of the iceberg
  J. B. Díaz-López and J. B. Cannata-Andía, Spain
• Adherence to antiosteoporotic treatment: a question of tolerability, mode of administration, or merely good patient dialogue?
  E. C. Fung and T. D. Spector, United Kingdom
• FRAX®, a new tool for assessing fracture risk: clinical applications and
  intervention thresholds
  J. A. Kanis, A. Odén, H. Johansson, F. Borgström,
  O. Ström, and E. V. McCloskey, United Kingdom
• Absolute risk reduction to compare efficacy of antiosteoporotic treatments in the absence of head-to-head trials
  B. Cortet, France

Controversal Question

• Is BMD measurement still useful with the advent of the FRAX® fracture
  risk assessment tool?
  M. Chandran, Singapore – F. S. Hough, South Africa – J. K. Lee, Malaysia -
  W. Lems, The Netherlands – R. Nuti, C. Caffarelli, and S. Gonnelli, Italy -
  M. E. Simões, Portugal – G. Skarantavos, Greece – S. Waikakul,
  Thailand – C. Horváth, Hungary

PROTELOS

• Broad antifracture efficacy coupled with unique benefits on bone: Protelos, the logical response to osteoporosis
  P. Halbout, France

Interview

• National implementation of the ESCEO guidance and its consequences
  J.-Y. Reginster, Belgium

Focus

• Osteoporosis in men
  J. D. Ringe, Germany

Update

• Fracture healing and antiosteoporotic treatments
  G. P. Lyritis, Greece

A Touch of France

• The Big Blue: a touch of French underwater medicine
  C. Régnier, France
• France, a pioneer of underwater archaeology
  D. Camus, France

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Maria Luisa BRANDI
MD, PhD
Metabolic Bone Unit
Department of Internal Medicine
University Hospital of Careggi
Viale Pieraccini 6
50139 Florence, ITALY

Bone mineral density (BMD) was, for a long time, the only parameter that could be used for the diagnosis of osteoporosis in daily practice.¹ However, after the first definition of osteoporosis was proposed in 1993,² it was realized that other factors beside bone mass influence bone strength, particularly bone microarchitecture and clinical risks. Not surprisingly, in 2001, the revised definition of osteoporosis shifted the emphasis to changes in bone quality³ and, in 2008, the World Health Organization (WHO) released recommendations for the assessment of fragility fracture risk using clinical risk factors, with or without BMD.⁴ Even though bone mineral density is the single most important contributor to bone strength, qualitative factors also play a significant role.^5,6 These include, in a hierarchical size distribution, the properties of organic and mineral materials, the degree of mineralization, turnover, and the manner in which bone mass is distributed in space, known as bone microarchitecture and macroarchitecture.

While many of the parameters that have been developed to describe structural bone properties can easily be assessed in vitro by histomorphometry, nondestructive and noninvasive techniques for use in vivo are at the forefront of radiological research in osteoporosis. A variety of innovative modalities, ranging from plain x-ray– and DXA (dual-energy x-ray absorptiometry)–based hip structural analysis to computed tomography and magnetic resonance imaging, have been developed to assess bone structure, both at the micro and macro levels.

A second area of innovation is the WHO FRAX® fracture risk assessment algorithm, a simple, practical Web tool that integrates clinical information in a quantitative manner to predict a 10-year probability of major osteoporotic fracture for both women and men for a range of different countries.

Advanced imaging for the material and structural basis of bone strength

The strength of bone and its fragility are the result of its material composition and structure.⁷ Bone histomorphometry was developed in the 1950s by pioneer workers to explore various metabolic bone diseases.^8-10 The microscopic technique was done on 2-D sections and, even though several mathematical formulations have been proposed to extrapolate 2-D measurements to the third, special dimension, the results are discordant.^11,12

Today, structural information about bone can be provided by noninvasive and/or nondestructive imaging techniques that include computed tomography (CT), particularly volumetric quantitative CT (vQCT), high-resolution CT (hrCT), micro-CT (mi- cro–computed tomography), high-resolution magnetic resonance imaging (hrMRI), and micro-MRI (micro–magnetic resonance imaging). vQCT, hrCT, and hrMRI are generally applicable in vivo, while micro-CT and micro-MRI are principally used in vitro.¹³

Bone geometry is a relevant determinant of bone strength and fragility that can be evaluated using an automated DXAbased analysis of x-ray attenuation profiles, also known as hip structural analysis (HSA). This is easily derived from routine DXA scans that are elaborated by software provided by the manufacturers. This method has provided novel information on the correlation between hip geometry and risk of hip fracture,^14,15 even though the contribution of hip geometry to the risk of hip fracture cannot be delineated using HSA independent of area BMD.

The only way to measure true volumetric density is through vQCT, a well-established method for assessing bone fragility and for monitoring BMD.¹⁶ As a volumetric measurement, vQCT can determine the bone mineral content of the entire bone or specific subregions, with a separate analysis of the trabecular and cortical compartments.¹⁷ The technique makes certain measurements possible, such as cross-sectional area and hip axis length, with derivation of the cross-sectional moment of inertia. Today, vQCT results can be applied to the analysis of finite elements,¹⁸ making it possible to identify the mechanisms of action of compounds whose effects are not apparent using DXA measurements.¹⁹

Standard quantative computed tomography techniques generate a spatial resolution of the order of 1 mm3 and are thus inadequate for detailed cortical and trabecular measurements. High-resolution imaging with multislice spiral CT (hrCT) provides a better depiction of trabecular and cortical morphology.²⁰ hrCT can provide information that correlates to vertebral fracture risk,²¹ offering information distinct from that of a BMD measurement.²² A high-resolution peripheral QCT (hr-pQCT) system is available for the assessment of trabecular and cortical geometry at the distal radius and tibia.^23,24 Muscle cross-sectional area can be assessed as well as the apparent density of muscles (pure muscle, fat) can be quantified using peripheral quantative computed tomography.

Finite element analysis (FEA) was applied in solid mechanics to evaluate the behavior of complex and heterogeneous structures, like bone tissue, in response to applied loads. In FEA, the structure is decomposed into elements defined by reference points or nodes, which predict strength without using direct mechanical testing.^25,26 When data from prospective studies of fracture risk become available, the prediction of fracture risk will be enhanced by the use of FEA.

Micro-CT analysis was developed to perform in vitro evaluation of small bone samples. This technique, using high radiation doses, makes it possible to visualize individual trabeculae, endosteal and periosteal surfaces, and cortical porosity.^27,28 Only recently have in vivo micro-CT scanners (XtremeCT) become commercially available, providing quantitative and qualitative assessment of the distal part of the radius or tibia.

Magnetic resonance microscopy, which encompasses hrMRI and micro-MR, has received considerable attention as a potential technique to clinically evaluate bone fragility. Magnetic resonance imaging (MRI), whose availability is widespread, can provide three-dimensional images of bone tissue using nonionizing radiation. This advantage is counterbalanced by the high cost of the equipment, by the interference of metallic implants, and by the complexity of its interpretation. In combination with FEA, hrMRI offers high-quality interpretation of the trabecular bone microarchitecture and mechanical properties of bone tissue.²⁹

Nanoindentation, a technique widely applied in materials science, is capable of describing micromechanical properties, including hardness and elastic modulus, of material surfaces.^30,31 The majority of studies have evaluated cortical bone, while relatively few studies have been devoted to trabecular bone.^32,33 Correlations between these properties and bone mineral content may be evaluated using quantitative backscattered scanning electron microscopy in the future.³⁴

FRAX®and its application in patient management

FRAX®³⁵ is a fracture risk assessment tool that was developed under the aegis of the World Health Organization by John Kanis and a group of epidemiologists. It was published in 2008, after being impatiently awaited for years,^36,37 and is now universally accessible free of charge on the Internet (www.shef.ac.uk/FRAX). Kanis and coworkers studied 12 international, population-based cohorts, analyzing risk factors and their predictive values in about 60 000 individuals. The FRAX® algorithms give the 10-year probability of hip fracture and the 10-year probability of a major osteoporotic fracture (hip, shoulder, forearm, or clinical spine fracture, but not radiological spine fracture without symptoms). The fracture risk variables are entered on the Web site. Femoral neck BMD can additionally be entered as a T-score. The obvious application of FRAX® is for the assessment of individuals to identify those who would be candidates for pharmacological intervention, and it has been widely used since the launch of the Web site. There are also challenges to be faced in the assessment of pharmacological agents for drug registration and in health economics.

The introduction of the FRAX® tool is expected to influence the assessment of patients. Until now, treatments were made based on the presence or absence of fractures and of a T-score of 2.5 SD or lower. Even though these criteria are applied by agencies responsible for drug reimbursement and are included in all the clinical guidelines, they leave out sev- eral conditions encountered in clinical practice. It is relevant to recognize that FRAX® estimates fracture risk without changing the definition of osteoporosis, which is defined by T-score. Similarly, the Framingham Risk Index did not change the definition of hypertension.

In the UK, guidance for the identification of patients with a high fragility fracture risk has been based on an opportunistic case-finding strategy, where the presence of clinical risk factors associated with fracture makes the physician aware of the possibility of osteoporosis, with a consequent evaluation of BMD, followed by the treatment prescription needed.³⁸ A similar approach has been used in several European countries³⁹ and in the USA.⁴⁰

The FRAX® tool is easy to use, but it has limitations. First, several risk factors can be indicated only as present or absent (ie, glucocorticoid therapy and previous fracture), without taking into account the time of exposure to a given fracture risk or the number of events that are expression of risk. Moreover, only femoral neck BMD is taken into account by FRAX®, an area where precision errors are more frequent and which means the exclusion of other areas, such as the lumbar spine, that are more frequently involved at younger ages. In addition, there are several risk factors, such as bone turnover, risk of falls, and previous pharmacological interventions, that are not incorporated into the assessment algorithms.

The goal of quantitative fracture-risk prediction is to determine the threshold fracture probability at which intervention becomes cost-effective. Cost-effectiveness cutoffs vary with age.⁴¹ The FRAX® tool may help provide evidence of the fragility fracture risk in younger subjects, who are often in the osteopenic range and who represent 40% of all patients with fragility fractures.

Given the worldwide variability of the reimbursement for antifracture drugs, it is not surprising to see different positions in the determination of treatment thresholds based on FRAX®.^42-44 In summary, the cutoffs published up to now are only suggestions, and they are going to be changed based on findings from ongoing studies. Future efforts should aim to offer a platform for future homogeneity in the choice of treatment thresholds in osteoporosis.

Since 2006, the Committee for Medicinal Products for Human Use has been revising guidelines on the evaluation of drugs in the treatment of osteoporosis, and emphasis is now given to patients at risk of fracture.⁴⁵ The few analyses conducted up to now on phase 3 clinical studies have shown that patients identified on the basis of clinical risk factors with FRAX® do respond to pharmacological interventions, even when BMD was not used to characterize risk.^46,47

All this renewed interest in osteoporosis, especially by general practitioners, is going to be good for the field. As happened for cardiovascular disorders, the opportunity of using an easy model to evaluate risk for the medical community will unearth novel possibilities for intervention in an area that it is not getting enough attention from governments, physicians, or patients.

_ This work was supported by an unrestricted grant to the author from FIRMO Fondazione Raffaella Becagli.

References

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14. Nelson DA, Barondess DA, Hendrix SL, Beck TJ. Cross-sectional geometry, bone strength, and bone mass in the proximal femur in black and white postmenopausal women. J Bone Miner Res. 2000;15:1992-1997.
15. Rivadeneira F, Zillikens MC, De Laet CE, et al. Femoral neck BMD is a strong predictor of hip fracture susceptibility in elderly men and women because it detects cortical bone instability: the Rotterdam Study. J Bone Miner Res. 2007; 22:1781-1790.
16. Genant HK, Engelke K, Fuerst T, et al. Noninvasive assessment of bone mineral and structure: state of the art. J Bone Miner Res. 1996;11:706-730.
17. Karig Y, Engelke K, Fuchs C, Kalender WA. An anatomic coordinate system of the femoral neck for highly reproducible BMD measurements using 3D QCT. Comput Med Imaging Graph. 2005;29:533-541.
18. Crawford RP, Cann CE, Keaveny TM. Finite element models predict in vitro vertebral body compressive strength better than quantitative computed tomography. Bone. 2003;33:744-750.
19. Black DM, Greenspan SL, Ensrud KE, et al. The effects of parathyroid hormone and alendronate alone or in combination in postmenopausal osteoporosis. N Engl J Med. 2003;349:1207-1215.
20. Timm W, Graeff C, Villar J, et al. In vivo assessment of trabecular bone structure in human vertebrae using high resolution computed tomography. J Bone Miner Res. 2005;20(suppl 1):S336.
21. Ito M, Ikeda K, Nishiguchi M, et al. Multidetector row CT imaging of vertebral microstructure for evaluation of fracture risk. J BoneMiner Res. 2005;20:1828-1836.
22. Graeff C, Timm W, Nickelsen TN, et al. Monitoring teriparatide-associated changes in vertebral microstructure by high-resolution CT in vivo: results from the EUROFORS study. J Bone Miner Res. 2007;22:1426-1433.
23. Boutroy S, Bouxsein ML, Munoz F, Delmas PD. In vivo assessment of trabecular bone microarchitecture by high-resolution peripheral quantitative computed tomography. J Clin Endocrinol Metab. 2005;90:6508-6515.
24. Khosla S, Melton LJ III, Achenbach SJ, et al. Hormonal and biochemical determinants of trabecular microstructure at the ultradistal radius in women and men. J Clin Endocrinol Metab. 2005;91:885-891.
25. Morgan EF, Bouxsein ML. Use of finite element analysis to assess bone strength. IBMS BoneKEy. 2005;2:8-19.
26. Boutroy S, Van Rietbergen B, Sornay-Rendu E, et al. Finite element analyses based on in vivo hr-pQCT images of the distal radius is associated with wrist fracture in postmenopausal women. J Bone Miner Res. 2008;23:392-399.
27. Jiang Y, Zhao J, Liao EY, et al. Application of micro-CT assessment of 3-D bone microstructure in preclinical and clinical studies. J Bone Miner Metab. 2005; (23 suppl):122-131.
28. Wachter NJ, Augat P, Krischak GD, Mentzel M, Kinzl L, Claes L. Prediction of cortical bone porosity in vitro by microcomputed tomography. Calcif Tissue Int. 2001;68:38-42.
29. Newitt DC, Majumdar S, van Rietbergen B, et al. In vivo assessment of architecture and micro-finite element analysis derived indices of mechanical properties of trabecular bone in the radius. Osteoporos Int. 2002;13:6-17.
30. Oliver WC, Pharr GM. Measurement of hardness and elastic modulus by instrumental indentation: Advances in understanding and refinements in methodology. J Mater Res. 2004;19:3-20.
31. VanLandingham MR. Review of instrumented indentation. J Res Natl Inst Stand Technol. 2003;10:249-265.
32. Hoffler CE, Moore KE, Kozloff K, et al. Heterogeneity of bone lamellar-level elastic moduli. Bone. 2000;26:603-609.
33. Norman J, Shapter JG, Short K, et al. Micromechanical properties of human trabecular bone: A hierarchical investigation using nanoindentation. J Biomed Mater Res. 2008;87A:196-202.
34. Gupta HS, Schratter S, Tesch W, et al. Two different correlations between nanoindentation modulus and mineral content in the bone-cartilage interface. J Struct Biol. 2005;149:138-148.
35. Kanis JA, Johnell O, Oden A, et al. FRAX® and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
36. Black DM, Steinbuch M, Palermo L, et al. An assessment tool for predicting fracture risk in postmenopausal women. Osteoporos Int. 2001;12:519-528.
37. Roux C, Briot K, Horlait S, et al. Assessment of non-vertebral fracture risk in postmenopausal women. Ann Rheum Dis. 2007;66:931-935.
38. Royal College of Physicians. Osteoporosis: clinical guidelines for the prevention and treatment. London, UK: Royal College of Physicians; 1999.
39. European Community. Report on osteoporosis in the European Community. Strasbourg, France: EC; 1998.
40. National Osteoporosis Foundation (NOF). Physician’s guide to prevention and treatment of osteoporosis. Washington, DC: National Osteoporosis Foundation; 2003.
41. Kanis JA, Borgstrom F, Zethraeus N, et al. Intervention thresholds for osteoporosis in the UK. Bone. 2005;36:22-32.
42. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al. Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int. 2008;19:437-447.
43. Dawson-Hughes B, Tosteson ANA, Melton LJ III, et al. Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA. Osteoporos Int. 2008;19:449-458.
44. Kanis JA, McCloskey EV, Johansson H, et al; National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX®—assessment and intervention thresholds for the UK. Osteoporos Int. 2008;19:1395- 1408.
45. Committee for Medicinal Products for Human Use(CHMP). Guideline on the evaluation of medicinal products in the treatment of primary osteoporosis. Ref CPMP/EWP/552/95Rev2. London, UK: CHMP; 2006.
46. McCloskey E, Johansson H, Oden A, et al. Efficacy of clodronate on fracture risk in women selected by 10-year fracture probability. Osteoporos Int. 2009;20: 811-817.
47. Kanis JA, Johansson H, Oden A, McCloskey EV. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX®. Bone. 2009;44:1049-1054.

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Bernard CORTET, MD, PhD
Département Universitaire
de Rhumatologie
Université de Lille 2
Lille, FRANCE

The last 15 years have seen considerable development in the therapeutic arsenal available for the treatment of osteoporosis. While this is good news, it also implies that therapeutic choices prescribers are required to make are not always easy. Analyzing the major pivotal studies reported in the literature is of great help when faced with these choices. However, the level of proof is not the same for all available molecules, especially as regards prevention of nonvertebral fractures as a whole and hip fractures in particular. Nevertheless, there are several efficient treatments for the prevention of vertebral fractures, nonvertebral fractures as a whole, and hip fractures in particular. Where several possible treatments seem to be efficient, a choice needs to be made. Besides tolerance to antiosteoporotic treatments, which is generally satisfactory, and the practical aspects of administration, other tools need to be employed. Molecules cannot be compared directly since there are no randomized studies in which their efficacies are directly compared. Nor is it possible to consider the reduction in relative risk, since doing so would lead to an error in interpretation as the inclusion criteria for the various studies are not strictly identical. On the other hand, a review of the data from the major pivotal studies shows that the reduction in relative risk depends on the severity of osteoporosis. Thus, when that type of analysis was possible, it was shown that the reduction in relative risk was greater when osteoporosis was less severe. It would be appropriate, therefore, in these conditions, to take into account the improvement in absolute fracture risk (defined as the difference between fracture risk in placebo and treatment groups). This parameter varies widely from one molecule to the next, even though all of the drugs at our disposal have proven antifracture efficacy (for vertebral fractures, in any case), which justified their being granted full market approval. This parameter can also be used to calculate the number needed to treat to prevent a fracture event, defined as the inverse of the reduction in absolute fracture risk, an asset to practitioners for translating clinical trial results into benefits for patients.

Within the last 15 years, substantial progress has been made in the understanding and treatment of osteoporosis. With the considerable development of the therapeutic arsenal at their disposal, practitioners now find themselves having to choose from among the many different molecules available. The choices they are faced with are not easy, since all of the available molecules have been granted full market approval and have, by definition, demonstrat- ed their usefulness. One of the problems stems from the fact that, as far as osteoporosis is concerned, no head-to-head trials have ever been carried out to evaluate antifracture efficacy. In practice, the practitioner must make a choice, and this will depend on the antifracture efficacy of the molecule for all types of fractures, since this may differ from one molecule to the next. In intertrial comparisons of antifracture efficacy with respect to a placebo group, relative risk is generally taken into account. This approach is open to criticism in that the reduction in relative riskmay depend on the severity of the disease in the selected population. In other words, quite frequently, the reduction in relative risk is found to be greater in less severe cases of osteoporosis. More generally, the lack of strict similarity across trial populations is a serious criticism of this approach. Within the last few years, as observed in other domains and particularly cardiovascular pathology, absolute risk reduction has emerged as a factor to be taken into account. In some situations, for instance, it can serve as the basis for deciding which antiosteoporotic treatment to administer.

Given the broad scope of this topic, we will restrict our discussion to postmenopausal osteoporosis. In doing so, we can suppose that the diagnosis of osteoporosis is established. In other words, initial testing would have already been carried out to eliminate malignant and benign bone fragility diseases other than osteoporosis (osteomalacia, primary hyperparathyroidism). Similarly, in this paper, we will only address the drug treatment of osteoporosis, even though it is clear that nondrug aspects of therapy must be taken into account, regardless of the drug used. Likewise, we will not be considering vitamin D, which is widely used in the treatment of osteoporosis, but in more of a supplementary role (in association with another antiosteoporotic treatment) than as a treatment in its own right.

In the first part of this paper, we will explore the antifracture effects of various treatments, expressed in terms of reduction in relative fracture risk. In the second part, we will examine the concept of absolute risk, and the reduction of the latter during antiosteoporotic treatment. Lastly, we will consider the corollary of absolute fracture risk, ie, the number needed to treat (NNT) to prevent a fracture event. The antifracture efficacy of various antiosteoporotic treatments was the subject of a recent update,1 the main results of which are summarized in Table I.¹

Antiosteoporotic drugs are generally classified into three groups, according to their mechanism of action: bone resorption inhibitors, bone anabolic agents, and uncoupling agents. Bone resorption inhibiting drugs include drugs used in menopausal hormone treatment, selective estrogen receptor modulators (SERMs), and bisphosphonates. We will not consider menopausal hormone replacement therapy (HRT) in this paper for two reasons: firstly, the WHI (Women’s Health Initiative) study has clearly demonstrated that its benefit/tolerance ratio is poor; and, secondly, given the wide range of therapeutic solutions available today, it is now very rare to prescribe HRT as part of the treatment of osteoporosis. Where bone-forming drugs are concerned, we will focus particular attention on teriparatide. Lastly, strontiumranelate is the only uncoupling agent at our disposal.

Bone resorption inhibitors

_ Selective estrogen receptor modulators (SERMs)
The only SERMcurrently available is raloxifene. Although basedoxifene and lazofoxifene have recently been granted market approval in Europe, they are not yet available to prescribers in the major European countries.

Raloxifene was examined in MORE (Multiple Outcomes of Raloxifene Evaluation).² At the end of 3 years of treatment, a reduction in vertebral fracture risk was found in a population of osteoporotic women defined as such according to densitometric criteria and/or the presence of at least one vertebral fracture compared with a placebo group. However, fracture risk reduction varied according to the initial data. Thus, risk reduction was 55% in women without vertebral fractures at inclusion (relative risk [RR], 0.45; 95% confidence interval [CI], 0.29-0.71). On the other hand, in women who had at least one vertebral fracture at inclusion, risk reduction was lower (30%; RR, 0.70; 95% CI, 0.56-0.86). The study was extended for a further year, with the double-blind procedure being maintained. During the fourth year, a 50%reduction in fracture risk was observed in women who had no initial vertebral fractures, as opposed to a 38%reduction in women with a preva- lent vertebral fracture.³ However, efficacy was not demonstrated either in preventing nonvertebral fractures as a whole or hip fractures in particular. Through the MORE study, raloxifene was shown to be effective in preventing breast cancer, but its efficacy varied according to the type of cancer and duration of follow-up (–70%).⁴ It was found to be effective only in cancers in which estrogen receptors were present. The initial findings on the prevention of cardiovascular morbidity were not confirmed by the RUTH (Raloxifene Use for The Heart) study.⁵ On the other hand, unlike estrogens, raloxifene has not been demonstrated to have harmful cardiovascular effects.

Table I. European guidelines for the diagnosis and management of osteoporosis in postmenopausal women.

_ Bisphosphonates
Bisphosphonates—structural analogues of pyrophosphates— are powerful inhibitors of bone resorption. Etidronate will not be considered in this review, on account of its modest efficacy.

_ Alendronate
Alendronate was the first available bisphosphonate to demonstrate antifracture efficacy. Thus, in FIT-1 (Fracture Intervention Trial 1), which evaluated patients with at least one vertebral fracture at inclusion, a significant reduction in the risk of vertebral fractures (–47%), wrist fractures (–50%), and hip fractures (–51%) was observed.6 However, the efficacy of the treatment was not demonstrated when nonvertebral fractures were considered globally. In the FIT-2 study,⁷ alendronate was only found to be effective in preventing morphometric vertebral fractures. The study population, however, was not osteoporotic. On average, at inclusion, the women had osteopenia and, in most cases, without a prevalent fracture. In a subanalysis of the trial, it was demonstrated that when women with densitometric osteoporosis (T-score <–2.5) were considered, alendronate was also effective in preventing wrist and hip fractures. However, as was the case in the FIT-1 trial (and in the subpopulation of women with densitometric osteoporosis), alendronate was not found to be effective in preventing nonvertebral fractures as a whole.

_ Risedronate
Risedronate has also proven its efficacy in preventing vertebral fractures. After being administered for 3 years, it was found to reduce vertebral fracture risk by between 41% and 49%, depending on the authors.^8,9 It has also been shown to be effective in preventing nonvertebral fractures. However, findings concerning its efficacy vary according to different studies. Thus, the reduction in nonvertebral fracture risk was significant in one of the two pivotal studies (–36%).⁸ In the other pivotal study conducted in Europe, the reduction was not significant (–33%).⁹ In a specific study on the efficacy of risedronate in preventing hip fractures,¹⁰ the authors reported a global 30% reduction in fracture risk. However, the efficacy of the drug was most apparent in women aged 70 to 79 years old, in whom femoral neck bone density had substantially declined (T-score <–3, and presence of at least one hip-fracture risk factor). Under these conditions, a 40% reduction in hip fracture risk was observed after 3 years of treatment. A comparative meta-analysis of alendronate and risedronate was performed to evaluate their efficacy in preventing nonvertebral fractures, given the results observed in the pivotal studies.¹¹ The meta-analysis showed that both molecules were effective: RR values for alendronate and risedronate were 0.86 (0.76-0.97) and 0.81 (0.71-0.92), respectively.

_ Ibandronate
Ibandronate has also proved to be effective in preventing vertebral fractures, with a 62% risk reduction after 3 years of treatment.¹² Its efficacy in preventing nonvertebral fractures was not demonstrated in BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe), which involved a population of women at risk of vertebral fracture. On the other hand, in a post hoc analysis of women with severe osteoporosis in the population (T-score <–3 or T-score <–2.5 plus a history of bone fragility fractures in the 5 years preceding their inclusion in the study), a 69% reduction in nonvertebral fracture risk was observed in the former case and a 60% reduction in the latter.

_ Zoledronate
It was recently demonstrated that zoledronic acid could reduce vertebral fracture risk by 70% (95% CI, 62% to 76%) in patients with osteoporosis, defined either in densitometric terms or by the presence of at least one vertebral fracture. In the same study, the drug was found to be effective in preventing both nonvertebral fractures (–25%) (95% CI, 13% to 36%) and hip fractures (–41%) (95% CI, 17% to 58%).¹³ In a study involving a population of men and women with recent hip fractures, zoledronate was found to reduce the risk of clinical fractures by 35%(RR, 0.65; 95%CI, 0.50-0.84).¹⁴ In the same study, the drug was also shown to be effective in preventing clinical vertebral fractures (–46%) (95% CI, 8% to 28%). Lastly, in a secondary analysis of their data, the authors also found the treatment to be effective in reducing the death rate (–28%; RR, 0.72 [0.56-0.93]).

_ Optimal bisphosphonate treatment duration
This is a difficult question to answer insofar as the pivotal studies were conducted over a period of 3 years. A 5-year study was conducted on the efficacy of risedronate (an extension of the VERT MN [Vertebral Efficacy with Risedronate Therapy, Multinational] study for a further 2 years), but the study is methodologically subject to criticism. In that study,¹⁵ the authors showed that the efficacy of treatment: (i) remained unchanged during the 5th year when compared to the previous years, but (ii) declined significantly during the 5th year when compared to the results observed in the placebo group. Lastly, a follow-up study of the effect of alendronate on bone mineral density (BMD) was published in 2004,¹⁶ the maximum treatment duration of which was 10 years. In that study, group sizes were small, and, over such a long period of time, the double-blind procedure was not maintained. Nonetheless, the authors¹⁶ were able to demonstrate that the evolution in nonvertebral fracture risk between the 1st and the 3rd year and the 6th and the 10th years was identical, suggesting that efficacy did not decline over time. However, the methodology can be criticized, and it is difficult to draw definitive conclusions.

Bone formation stimulants

_ Parathyroid hormone
The leading drug in this category is teriparatide, which is the 1-34 fragment of parathyroid hormone. At a dose of 20 ìg/ day, teriparatide has been shown to be capable of reducing vertebral fracture risk by 65% (after 18 months of treatment, on average) when compared with the results observed in a placebo group. At the end of that period, an equally significant reduction in nonvertebral fracture risk (–53%) was also demonstrated. Moreover, its vertebral antifracture efficacy seemed to be more pronounced in women who had at least two vertebral fractures at inclusion, and it is for this reason that teriparatide is generally indicated for the treatment of the most severe osteoporosis. Parathyroid hormone (1-84) has also been evaluated.¹⁷ After 18 months of treatment, a 60% reduction in vertebral fracture risk was observed, but without a significant effect on nonvertebral fracture risk.

_ Strontium ranelate
Strontium ranelate has an original mode of action in that it stimulates bone formation while at the same time inhibiting bone resorption. This has been demonstrated in vitro as well as in vivo by measuring changes in bone-remodeling markers and analyzing bone biopsies. Strontium ranelate has been the subject of a vast development program comprising two pivotal studies: namely, the SOTI (Spinal Osteoporosis Therapeutic Intervention) study,¹⁸ which sought to evaluate the efficacy of strontium ranelate in preventing vertebral fractures; and the TROPOS (TReatment Of Peripheral OSteoporosis) study, whose main purpose was to evaluate the efficacy of the molecule on nonvertebral fractures.¹⁹ In the SOTI study, after four years of strontium ranelate treatment, a 33% reduction in vertebral fracture risk was observed when compared with the results observed in the placebo group.²⁰ The 5-year data from the TROPOS study have recently been published.²¹ In that study, the authors observed a significant reduction in nonvertebral fracture risk (–15%). The reduction was somewhat higher (–18%) when major nonvertebral fractures alone were considered. A significant reduction (43%) in hip fracture risk was also observed in patients with low bone densities (T-score <–2.4 at the spine and femoral neck). Strontium ranelate was also found to be effective in patients over 80 years old, in whom a global reduction of 30% in both vertebral and nonvertebral fracture risk was observed.²² Lastly, in a very recent study,²³ strontium ranelate was shown to be effective in osteopenic women, regardless of whether they had vertebral fractures at inclusion or not.

Toward a more judicious approach: absolute fracture risk reduction

Globally, these various data show that there are currently several antiosteoporotic molecules with proven therapeutic value. In practice, the question is how does one know which of these molecules is the most relevant for a given patient. The previously mentioned therapeutic trials, in focusing on relative risk only, cannot always provide an answer. Indeed, as mentioned earlier, not all of the molecules were found to be effective in preventing nonvertebral and hip fractures. However, some of the molecules mentioned earlier have clearly been shown to be capable of reducing both vertebral and nonvertebral fracture risks. For practical purposes and to assist prescribers with their choices, appropriate tools are needed. Unfortunately, in the field of osteoporosis, there are no comparative studies on the antifracture efficacy of the various treatments. And given the sizes of the populations required for such studies and the cost of the latter, there is little likelihood that such studies will be undertaken.

Furthermore, it is not possible to compare the reduction in relative risk across different studies. Indeed, the criteria for inclusion in the studies seeking to evaluate the efficacy of a given molecule were quite variable. In some of them, patients with at least one vertebral fracture were included. In others, only patients with densitometric osteoporosis were included. And in other studies, both of these criteria were taken into account. In practice, therefore, other tools are needed to help determine the benefits patients can expect in a given situation. As is the practice in other medical disciplines, the evaluation of absolute risk—and consequently the reduction thereof with treatment—is an important factor to take into consideration.

The evaluation of absolute fracture risk is now possible on an individual basis, thanks to the FRAX® tool.²⁴ More specifically in therapeutic terms, besides what has been previously mentioned, the use of relative risk presents at least two drawbacks. In clinical practice, by definition, there are no placebo groups. The reduction in relative risk observed in certain conditions is therefore of little relevance. Moreover, by definition, the concept of relative risk does not take account of the frequency of the event that one wishes to predict (in our case, the fracture). Taking into consideration relative risk alone to guide therapeutic choices could lead to the treatment of populations in which fracture risk is very low, as illustrated in the article by P. Alonso-Coello.²⁵ Another approach consists of considering the reduction in absolute fracture risk, defined as fracture incidence in the placebo group minus fracture incidence in the treatment group.²⁶ The reduction in absolute risk can also be used to calculate the number needed to treat to prevent the occurrence of the event being considered (in this case, the fracture). This is defined as the inverse of the reduction in absolute risk (expressed as a raw value and not as a percentage). Figure 1 shows the reductions in absolute vertebral fracture risk expressed as percentages for the major clinical trials mentioned in the first part of this paper.

Obviously, this is not a comparative study of the various antiosteoporotic treatments, but this approach underscores the fact that the improvement in absolute risk is very variable from one molecule to the next, for both vertebral and nonvertebral fractures. For vertebral fractures, the reduction in absolute risk varies from 5% for ibandronate to 12% for strontium ranelate.

By definition, the reduction in absolute fracture risk takes account of the fracture risk in the placebo group, which varies widely across different studies. A high incidence of fractures in the placebo group reflects the relevance of the population targeted for assessing the efficacy of the treatment in a clinical trial. Once again, this risk is highest with strontium ranelate and risedronate in the VERT MN study. These results should also be compared with the reduction in absolute risk, which is highest with strontium ranelate as well as with risedronate in the VERT MN study (Figure 1).

Figure 1. Effects of antiosteoporotic treatments on the risk of vertebral fracture (absolute risk reduction).

Figure 2. Effects of antiosteoporotic treatments on the risk of hip fracture (absolute risk reduction)

As regards the reduction in absolute hip fracture risk, less data is available in the literature. A summary of this data is shown in Figure 2. While, by definition, the reduction in absolute hip fracture risk with ibandronate is nil, it is identical and low (–1%) with zoledronate, risedronate, and alendronate. It is most pronounced with strontium ranelate (a 2% reduction in absolute hip fracture risk).

From reduction in absolute fracture risk to number needed to treat to prevent a fracture event As mentioned earlier, the NNT to prevent a fracture event is defined as the inverse of the reduction in absolute fracture risk. This approach has been adopted by several authors²⁷ within the framework of the major therapeutic trials to eval- uate the efficacy of the various treatments. A recent report²⁸ reviews the therapeutic modalities for the prevention and treatment of osteoporosis. One of the interesting things about this report is that it provides NNT values for the studies referred to in the first part of this paper. As an example, it is classically reported that HRT—which was not mentioned previously given the fact that the reasons for not prescribing HRT are numerous—is the only treatment whose antifracture efficacy has been established in the general population. This is true, but aside from the poor benefit/risk ratio of HRT, it is certainly not useful to treat all women with HRT to prevent hip and vertebral fractures. Indeed, for the latter two conditions, the NNTs are 216 and 225, respectively.

As regards the other drugs and following the order in the first part of this paper, the results are as follows: for raloxifene, through the MORE study and taking into consideration the population as a whole, the NNT is 29. Where the bisphosphonates are concerned, the results depend on the molecule. Thus, for alendronate within the framework of the FIT-1 study (patients with at least one vertebral fracture at inclusion), the NNT is 37 for vertebral fractures, 91 for hip fractures, and 53 for wrist fractures. In the FIT-2 study, a post hoc analysis was immediately performed on patients with a T-score <–2.5.When all clinical fractures were taken into consideration, the NNT was 15. For clinical vertebral fractures, the NNT was 34. For risedronate in the VERT NA (Vertebral Efficacy with Risedronate Therapy, North America) study, the NNT to prevent vertebral fracture was 20. In the VERT MN study, it was 10. One explanation for this is that vertebral fracture risk in the placebo group was much higher in the VERT MN study than in the VERT NA study (29%and 16%, respectively). In the previously mentioned HIP (Hip Intervention Program), the NNT was 91. In the BONE study evaluating the efficacy of ibandronate, the NNT for the prevention of vertebral fracture was 20.

The most recent bisphosphonate to receive market approval, ie, zoledronate (HORIZON PFT [Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial]) has an NNT of 13 for vertebral fractures, 91 for hip fractures, and 37 for nonvertebral fractures. These marked differences are not always comparable with the reduction in relative risk. For example, the reduction in hip fracture risk in the HORIZON PFT study was 41%, while the reduction in nonvertebral fracture risk was markedly lower (–25%). In the HORIZON RCT (Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Randomized Controlled Trial), the NNT to prevent a clinical fracture was 19. This increased to 48 when clinical vertebral fractures alone were taken into consideration. When all nonvertebral fractures were taken into account, the NNT was 32. As mentioned earlier, in the HORIZON RCT study, a 28% reduction in mortality was observed, corresponding to an NNT of 27.

For strontium ranelate, the NNT (SOTI study) to prevent the occurrence of a vertebral fracture was 9,18 and 59 (TROPOS study) to prevent a peripheral fracture.19 In the latter study, the NNT to prevent a hip fracture in women at high risk of fracture at the upper end of the femur was 48.

Conclusion

Studies on osteoporosis are always conducted versus a placebo group. Currently, several antiosteoporotic drugs exist with different mechanisms of action and modalities of administration. These molecules have all demonstrated their usefulness in preventing the occurrence of vertebral fractures, and to a lesser degree—but this is highly dependent on the molecule in question—nonvertebral fractures in general and hip fractures in particular. Taking into consideration the reduction in relative fracture risk alone to guide prescribers’ choices is not sufficient. However, no comparative studies have been conducted with the main goal of evaluating antifracture efficacy. It is known that the populations selected for inclusion in the pivotal studies were quite different. Given these conditions, taking the reduction in absolute fracture risk into consideration seems appropriate.

As mentioned earlier, the reduction in absolute fracture risk varies from one molecule to the next. It is also possible, using this parameter, to calculate the NNT to prevent a fracture event, thus translating the results of clinical trials into current medical practice. These parameters deserve to be taken into consideration as tools to allow a fair and complete comparison of the efficacy of the antiosteoporotic treatment. _

References

1. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;19:399-428.
2. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial multiple outcomes of raloxifene evaluation (MORE) investigators. JAMA. 1999;382:637-645.
3. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results froma randomized clinical trial. J Clin EndocrinolMet. 2002;87:3609-3617.
4. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of breast cancer in postmenopausal women: results from the MORE randomized trial. Multiple Outcomes of Raloxifene Evaluation. JAMA. 1999;281:2189-2197.
5. Barret-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular events and breast cancer in postmenopausal women. N Engl J Med. 2006; 355:125-137.
6. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures. Fracture Intervention Trial research group. Lancet. 1996;348:1535-1541.
7. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280:2077-2082.
8. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy with Risedronate Therapy (VERT) study group. JAMA. 1999;282:1344-1352.
9. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) study group. Osteoporos Int. 2000;11:83-91.
10. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip fracture in elderly women. Hip Intervention Program study group. N Engl J Med. 2001;344:333-340.
11. Boonen S, Laan RF, Barton IP, Watts NB. Effect of osteoporosis treatments on risk of non-vertebral fractures: review and meta-analysis of intention-to-treat studies. Osteoporos Int. 2005;16:1291-1298.
12. Chesnut III CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19:1241-1249.
13. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-1822.
14. Lyles KW, Colon-Emeric CS, Magaziner JS, et al. The HORIZON recurrent fracture trial zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.
15. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone. 2003;32:120-126.
16. Bone HG, Hosking D, Devogelaer JP, et al. Ten years’ experience with alendronate for osteoporosis in postmenopausal women. N Engl J Med. 2004;350: 1189-1199.
17. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal women with osteoporosis. A randomized trial. Ann Intern Med. 2007;146:326-339.
18. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.
19. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: treatment of peripheral osteoporosis (TROPOS) study. J Clin Endocrinol Metab. 2005;90:2816-2822.
20. Meunier PJ, Roux C, Ortolani S, et al. Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int. 2009;20:1663-1673.
21. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of nonvertebral and vertebral fractures in postmenopausal osteoporosis. Results of a five-year, randomized, placebo-controlled trial. Arthritis Rheum. 2008;58:1687-1695.
22. Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and onvertebral fractures in women eighty years of age and older. J Bone Miner Res. 2006;21:1113-1120.
23. Seeman E, Devogelaer JP, Lorenc R, et al. Strontium ranelate reduces the risk of vertebral fractures in patients with osteopenia. J Bone Miner Res. 2008;23: 433-438.
24. Kanis JA, Oden A, Johansson H, Borgström F, Ström O, McCloskey E. FRAX® and its applications to clinical practice. Bone. 2009;44:734-743.
25. Alonso-Coello P, Lopez Garcia-Franco A, Guyatt G, Moynihan R. Drugs for preosteoporosis: prevention or disease mongering? BMJ. 2008;336:126-129.
26. Replogle WH, Johnson WD. Interpretation of absolute measures of disease risk in comparative research. Fam Med. 2007;39:432-435.
27. Nuovo J, Melnikow J, Chang D. Reporting number needed to treat and absolute risk reduction in randomized controlled trials. JAMA. 2002;287:2813-2814.
28. MacLaughlin EJ, Raehl C. ASHP therapeutic position statement on the prevention and treatment of osteoporosis in adults. Am J Health Syst Pharm. 2008; 65:343-357.

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Johann D. RINGE, MD
West German Osteoporosis
Center (WCO) and Department
of General Internal Medicine
Klinikum Leverkusen
University of Cologne
GERMANY

Osteoporosis in men is today recognized worldwide as an important and growing public health problem. Although osteoporosis is less prevalent in men, 30% of all hip fractures occur in males and the prevalence of vertebral fractures—half of that in women—is still substantial. Loss of trabecular bone in aging men is associated with changes in the insulinlike growth factor 1 (IGF-1) regulation system leading to trabecular thinning, rather than the reduced trabecular connectivity seen in women after the menopause. Cortical bone loss in men, however, starts later in life and is associated with a decrease in physical activity and bioavailability of both sex hormones. Alendronate was the first bisphosphonate to be approved for the treatment of male osteoporosis based on consistently positive effects on bone mineral density (BMD) and vertebral fractures from two independent studies in men on a daily dosage of 10 mg. Just two years ago, risedronate followed suit with its once weekly dosage and, recently, 5 mg zoledronic acid IV once yearly and teriparatide—as the first osteoanabolic agent for men—were approved. Up till now, etidronate and ibandronate have been insufficiently studied in men. Pilot study data show that the lumbar spine and total hip BMD increases seen with strontium ranelate are consistent with those found previously in postmenopausal women. A randomized, placebo-controlled trial testing this innovative dual-action drug in a purely male population has been set up to confirm these preliminary results and will soon be finished.

The rather exclusive focus on postmenopausal osteoporosis in the past has undoubtedly led to an underreporting of osteoporosis in men. Fifteen years ago, it was shown that 29% of men and 56% of women, if they are currently 60 years old and receive no preventive measures, will experience fractures during their remaining lifetime.¹ Only in the past decade has attention been focused upon the increasingly important problem of osteoporosis in men.^2-4 Efforts devoted to the issue have been successful. There is today a much better understanding of the disorder, and effective diagnostic, preventive, and therapeutic strategies have been developed.⁵ Today, osteoporosis in men is recognized as an important public health problem and has developed into a very active research issue. Male-female differences have been revealed that in turn have had positive effects on our understanding of bone biology in general. Drugs that have been developed primarily for the treatment of postmenopausal osteoporosis have been studied and approved for male osteoporosis with a typical delay of several years.

The magnitude of the problem

Although osteoporosis is less prevalent in men, it has been estimated that 30% of all hip fractures occur in males and that one in eight men older than 50 years will experience an osteoporotic fracture.^3,4 Moreover, studies have shown that the mortality rate after fracture in men is higher compared with that in women.^6,7 The reported prevalence is further increasing due to the increasing life expectancy of men, measuring bone mineral density more frequently in men with back pain, and probably due to general changes in nutrition and lifestyle with a negative impact on calciummetabolismand the skeleton.^5,8 In our outpatient department today, already 20% of patients presenting for diagnosis and treatment of osteoporosis are men. Nevertheless, the disease remains largely underdiagnosed and undertreated.^9,10

_ Epidemiology of fractures
The incidence of fractures is bimodal in both sexes with peaks of fracture incidence in adolescence and young adulthood, lower rates in middle age, and dramatic increases thereafter. Figure 1 clearly shows that men have a higher “juvenile peak”, possibly due to a higher risk of traumatic impacts. The sharp increase in later life in men is as dramatic as in women, but occurs about 10 years later in life.¹¹ In younger men, long bone fractures are more common, whereas vertebral and hip fractures predominate in the elderly, where skeletal fragility, frailty, and falls are major factors.¹² The age-adjusted incidence of hip fractures in men is one third to one half that of women. There is less information concerning vertebral fracture rates in men. According to data from the European Prospective Osteoporosis Study (EPOS), the age-adjusted incidence in men seems to be rather high, reaching 50% of that in women.¹³

_ Pathogenesis of male osteoporosis
According to results of longitudinal studies, bone loss accelerates in men after the age of 70 and rapid bone loss is more common with deficient testosterone and estradiol levels.^14,15 In contrast to women developing reduced trabecular connectivity due to a loss of trabeculae, men show trabecular thinning secondary to reduced osteoblastic formation.^16,17 The better preservation of spongy bone microstructure may explain their 50% lower lifetime risk of fractures.¹ The loss of trabecular bone in men starts after reaching peak bone mass in association with changes in the insulinlike growth factor 1 (IGF-1) regulation system. Cortical bone loss, however, starts later in life and is associated with decreasing physical activity and bioavailability of both sex hormones, causing increased bone remodeling. Up to 85% is lost after age 50.¹⁸ As important differences between men and women, it was always stated that men lose less bone than women from the endosteal envelope and that they gain more bone on the periosteal envelope with advancing age. Recent evidence challenges these observations and further research is requested.^19-21 Data from the MINOS study on 796 elderly men showed that low muscle mass in men is associated with narrower bones, thinner cortices, and a consequent decreased bending strength.¹²

Figure 1. Average annual fracture incidence.

The cause of osteoporosis in men is much more heterogeneous than in women; 50% to 60% of men with osteoporosis are diagnosed as secondary cases, ie, the disease is associated with one or more relevant medical conditions, medications, or lifestyle factors that may result in bone loss and reduced bone strength.^2,3,22 The reported pattern of identified risk factors in men varies largely between centers due to differences in the respective patient sources.²³ In our own earlier study on 500 unselectedmen, we found that 52%had primary idiopathic and 48% secondary osteoporosis.^2,8 Among the latter, we identified a subgroup of monoetiological (n=124) and another of polyetiological origin (n=116). In Table I, the frequency of risk factors in these 240 males is shown in terms of mono- and polyetiological subgroups. It becomes obvious that some factors are “strong” pathogenetic risks, which lead to secondary osteoporosis on their own (for example, numbers 1, 4, 5, 11, and 21 in Table I), while other “weak” risk fac- tors only cause osteoporosis when in combination (for example, numbers 2,3,6,7,8, and 10 in Table I). In an important fraction of osteoporotic men, hypercalciuria can be detected as an underlying disorder.24 In our study, we found this risk factor in 34 patients (Table I). Interestingly, idiopathic hypercalciuria is an uncommon risk factor in osteoporotic women.

Diagnosis of osteoporosis in men

There are important sexual differences in skeletal biology that may influence bone density measurement. In particular, bone size is larger in men. For diagnostic purposes, gender differences are addressed by the use of sex-specific T-scores, but this practice remains controversial.¹⁶ Epidemiologic data suggest that for any given absolute bone mineral density (BMD) value at the spine or hip, the risk of fracture is similar among women and men of the same age.^25-27 Since the prevalence of degenerative changes in men at the lumbar spine with increasing age is very high, measurements of bone mineral density at the femoral neck or total hip are preferable to spinal assessments. The average BMD in men who fracture a hip, however, is higher than in women, suggesting that other factors such as bone microarchitecture or trauma may contribute to fractures more in men than in women.¹⁶ Until safety data are available to confidently link fracture risk to BMD measurements in men, the use of male-specific reference ranges has to be adopted.⁵ Today in most guidelines, bone densitometry is recommended inmen aged 70 or older or earlier in men with major risk factors for osteoporotic fractures. That means male patients should be assessed routinely for risk factors for osteoporosis and for clinical symptoms of secondary osteoporosis.

Additional examinations to obtain a definite diagnosis of osteoporosis are not very different from the procedures used in women. When proving a BMD z-score below –2.0 (2 SD below the age-related mean), a clinical examination and further laboratory testing for secondary osteoporosis is indicated.²⁸In our osteoporosis center, we use a 25-question questionnaire as a first source of information. The answers are verified by taking a thorough personal history of the patient, with an evaluation of possible underlying diseases, medications, risk factors of lifestyle, and finally a physical examination. The results are a basis to judge the extent of additional blood and urine examinations and any further diagnostic program.² Since hypogonadism is often difficult to detect on the basis of a patient’s history and physical examination, measurement of total testosterone and sex hormone–binding globulin (SHBG) is recommended in all men with osteoporosis.¹⁶ 25-Hydroxyvitamin D should be measured in patients reporting little exposure to sunshine and/or with low-normal serum calcium, hypocalciuria, or increased parathyroid hormone. There are only limited data relating markers of bone turnover to fracture risk in men.²⁹ Because they show high biological variability, routine use of these markers cannot be recommended. They may, however, be useful in men with no apparent cause of osteoporosis and in men with very low BMD for detecting low levels of bone formation.

Table I. Risk factors in men with secondary osteoporosis.

Prevention of osteopenia and fractures in men

Measures to avoid bone loss and associated fractures in men are similar to those in women. In early life, a combination of good nutrition, regular exercise, and a healthy lifestyle should aim to produce a high peak bone mass. Reducing modifiable individual risk factors of diet and lifestyle, including alcohol, nicotine, and physical inactivity, remain important throughout life.³⁰

For men with one or more diseases or medical conditions associated with a high risk of developing secondary osteoporosis (Table I), early detection and counteracting measures are important. Examples include a reduction of glucocorticoid dosage if possible, substitution of androgen in hypogonadism, thiazides in idiopathic hypercalciuria, or early surgical treatment of primary hyperparathyroidism.^2,30

In the elderly at risk of falls (eg, reduced muscle strength, poor balance, frailty, and history of previous falls), attempts to increase strength and balance or the use of a hip protector may be beneficial. Due to positive effects on muscle mass and function, vitamin D supplementation of at least 800 IU per day reduces the risk of falls.^31,32 There are still conflicting data on the benefits of calciumand vitamin D in osteoporosis, butmore recent meta-analyses favor beneficial effects on falls and fractures.^33,34 Table II summarizes general recommendations for the prevention of bone loss and osteoporotic fractures in men.

Table II. General measures for prevention of bone loss and osteoporotic fractures in men.

_ The therapeutic dilemma of male osteoporosis
Even today, not all drugs available for women with postmenopausal osteoporosis are also approved treatments for osteoporosis in men. This is due to the fact that data from earlier trials on mixed female-male populations have not been accepted and that the requested randomized controlled studies on purely male cohorts are always smaller and often contain insufficient fracture reduction evidence.

Earlier drugs were approved for osteoporosis in general, without separate trials in men being asked for (eg, calcium, fluoride, calcitonin, and alfacalcidol). These are still available for treating osteoporosis in men in some countries. Starting with the bisphosphonates, health authorities only approved new substances for postmenopausal osteoporosis, arguing that the respective phase 3 trials had been performed in this population. Furthermore, it was suggested that significant differences in bone biologymight exist between the sexes, with consequent clinically relevant differences in therapeutic response.

Accordingly, nowadays the approval for using a new drug in men follows after several years’ delay in general or never, if the respective pharmaceutical company considers a new independent study in men as being too expensive given the limited time of their patent protection. This is a severe therapeutic disadvantage for men with osteoporosis. To prescribe innovative drugs to men with established osteoporosis “off label” is often difficult because insurers tend to be reluctant to reimburse the costs in many countries. Interestingly, so far for all drugs studied in men, similar therapeutic results to those seen in women in terms of BMD, bone turnover markers, and fracture-reducing potency have been reported, disproving the argument that relevant basic differences exist in the bone biology of the female and male skeleton.³⁰

Osteoporosis therapy in men

_ Causative therapy in secondary osteoporosis
Since about 50% of men are diagnosed as having secondary osteoporosis, an etiologically tailored treatment is more important in male than in postmenopausal osteoporosis. In hypogonadal men with secondary osteoporosis, androgen replacement therapy is effective.^35-37 We recommend a combination with calcium and vitamin D and found that subcutaneous or transdermal testosterone therapy, especially in advanced osteoporosis, is not sufficient per se to significantly improve BMD.² A combination with another bone turnover– modifying substance is very often mandatory. Contraindications for androgen use (lipid pattern, prostatic cancer risk) have to be taken into consideration.

Other examples of a causative therapy have been mentioned above under prevention. In glucocorticoid-induced osteoporosis, a premature reduction in corticoids may increase the risk of osteoporosis, since an insufficient immunosuppressive effect will favor further loss of bone tissue by proinflammatory cytokines.38 Furthermore, insufficient disease control is associated with less mobility. For the majority of secondary osteoporoses (see Table I), no causative therapies are available, ie, therapeutic strategy is the same as that for idiopathic osteoporosis.

_ Treatment of idiopathic osteoporosis
In men with secondary osteoporosis without options for etiology- related treatment and in all primary or idiopathic cases of osteoporosis, an individually tailored therapeutic strategy has to be planned. A prerequisite for devising this long-term strategy is information about the history and present situation of the respective patient (Table III). Since osteoporosis is a chronic disease requiring long-term therapy, it is important to inform the patient very carefully about the type of osteoporosis, its severity, modifiable risk factors, future fracture risk, the chance of alleviating pain, and the therapeutic mechanisms of available medications and their possible side effects. Only then can good compliance and adherence be expected.

Table III. Data for devising an optimal osteoporosis treatment strategy in men.

Figure 2 gives an overview of the options for an individually tailored treatment regimen in men with idiopathic or primary osteoporosis. With the exception of estrogen and raloxifene, the same specific drugs can be adopted in men as in women. But there are differences in the evidence of fracture reducing potency and in the approval status in different countries. As mentioned before, calcitonin, alfacalcidol, and fluoride are older substances without exclusions inmale osteoporosis and are often listed as second-line treatments. All bisphosphonates, strontium ranelate, and teriparatide are first-line treatments in postmenopausal osteoporosis, but only alendronate, risedronate, zoledronic acid, and teriparatide are also approved in men.³⁰

_ Calcitonin, fluoride, and alfacalcidol
There are only older case reports or small studies for these treatments in male osteoporosis. In a double-blind, placebocontrolled study testing the physiological osteoclast inhibitor calcitonin, 28 men received either 200 IU salmon calcitonin via nasal spray plus 500 mg calcium per day or placebo via nasal spray plus calcium. A significant lumbar spine BMD increase of 7.1% in the calcitonin group vs 2.4% in the controls was found in parallel with a higher decrease in bone resorption markers with calcitonin.³⁹

In a prospective controlled 3-year trial in 60 men with primary osteoporosis, we found a significantly lower vertebral fracture rate with low-dose intermittent fluoride therapy when compared with controls receiving only calcium plus vitamin D.⁴⁰ Further relevant studies with fluoride in men were not undertaken mainly due to the low cost of the substance and the lack of patent protection.

Only recently, it was shown that treatment with the active D-hormone analogue alfacalcidol plus calcium is superior to plain vitamin D plus calcium in male osteoporosis.⁴¹

_ Bisphosphonates
There are only two small uncontrolled studies using the typical intermittent cyclical therapeutic regimen with etidronate in men with osteoporosis that show significant effects on BMD, but no fracture results.^42,43

Alendronate was shown to be effective for the treatment of male osteoporosis and was the first bisphosphonate to be approved for this indication.⁴⁴ The positive evidence was mainly based on two large trials. The first trial was a two-year multicenter randomized placebo-controlled US study on 241 men with primary osteoporosis or secondary osteoporosis due to hypogonadism.⁴⁵ In the second trial, an open prospective controlled study by our group, 134 men with only idiopathic osteoporosis were treated over 3 years.⁴⁶ Both studies proved that the therapeutic results on BMD and fracture incidence with 10 mg alendronate daily are consistent with the effects known for postmenopausal osteoporosis. Although similar effects on BMD and significant decreases in bone turnover markers could be demonstrated with alendronate 70 mg once weekly, this dosage was never approved for male osteoporosis.⁴⁷

Figure 2. Therapeutic osteoporosis strategies in men.

The first evidence that risedronate is also effective in men came from a large subgroup of male patients with glucocorticoid- induced osteoporosis.⁴⁸ We were the first to investigate the therapeutic efficacy of risedronate in a purely male population (n=316) with primary and secondary osteoporosis.⁴⁹ Patients were randomized to risedronate or controls, stratified by the presence of prevalent vertebral fractures at baseline. All patients in the bisphosphonate treatment arm received 5 mg risedronate plus 1000 mg calcium and 800 IU vitamin D daily. Patients in the control group received 1 ìg alfacalcidol plus 500 mg calcium daily if they had prevalent vertebral fractures and 1000 IU plain vitamin D plus 800 mg calcium per day if they did not. After 12 and 24 months, we found significantly higher increases in lumbar spine and total hip BMD with risedronate compared with the combined controls. The relative risk reduction of patients with new vertebral fractures with risedronate was 60%after the first and 61% after the second year of intervention.⁵⁰

Figure 3. Effect of year-long osteoporosis therapy on BMD.

Risedronate 35 mg per week was studied in an international randomized placebo-controlled study. Some 192 patients received once weekly risedronate and 93, placebo. All patients received additional supplementation of 1000 mg calcium and 400-500 IU vitamin D.⁵¹ After 2 years, there was a significant increase in lumbar spine BMD of 5.8% in the risedronate group versus 1.2% in controls. Concerning all new fracture events documented as adverse events, there was a positive trend in favor of risedronate, but no significant difference (7.7% placebo vs 4.9% risedronate). Risedronate 35 mg once weekly was the second bisphosphonate to be approved for the treatment of men at high fracture risk, and its fracture reducing potency was recently underlined by a meta-analysis.⁵² There are no relevant studies on pamidronate and ibandronate in men. Zoledronic acid 5 mg once yearly by infusion, however, was approved recently for male osteoporosis. In a subset of 508 men from the Health Outcomes and Reduced Incidence with Zoledronic Acid ONce yearly (HORIZON) recurrent fracture trial, significant increases in total hip BMD and a reduction in the rate of new clinical fractures could be demonstrated.^53,54 A large purely male study comparing once yearly zoledronic acid versus placebo is currently being performed.

_ Teriparatide and strontium ranelate
There are two trials that have studied the osteoanabolic effect of parathyroid hormone (PTH) in men with osteoporosis. The first one was a small pilot study (n=23) with daily injections of 400 IU teriparatide (rhPTH[1-34]) in 10 patients and placebo injections in 13.⁵⁵ After 18months, average lumbar spine BMD had increased 13.5% in the PTH group and was unchanged in the placebo group (P<0.001). This mean rate of gain in BMD was consistent with the rate seen in the pivotal fracture trial in postmenopausal osteoporosis. A larger international trial of 437 men with osteoporosis (20 ìg or 40 ìg rhPTH daily or subcutaneous placebo) over 11 months plus 18 months’ follow-up found similar effects on BMD and a significantly lower rate of vertebral fractures for the pooled PTH groups.^56,57

With strontium ranelate in postmenopausal osteoporosis, significant effects on all fracture types over the whole age range fromearly postmenopausal to advanced age could be demonstrated. In the open-label, controlled, prospective CASIMO (Comparing Alendronate and Strontium ranelate In Male Osteoporosis) trial, we randomly included 152 men (mean age 59.8 years) with prevalent vertebral fractures and T-score values of lower than –3.0 SD at lumbar spine and lower than –2.5 SD at total hip. Patients of group A (n=76) received 2 g strontium ranelate plus 800 IU vitamin D and 1200 mg calcium per day. The 76 men of group B were treated with alendronate 70 mg once weekly and the same daily amounts of vitamin D and calcium.58 After 12 months, the average lumbar spine–bone mineral density (LS-BMD) increase was 5.8% and 4.5% in the strontium ranelate and alendronate patients, respectively. The corresponding mean changes at total hip amounted to 3.5% and 2.7%.

These increases were significantly higher for the strontium ranelate–treated patients compared with alendronate, at both sites (Figure 3), and were consistent with the respective average 12 month increases from the pivotal fracture studies with strontium ranelate in postmenopausal osteoporosis.⁵⁹ Interestingly, there was a significantly steeper reduction in back pain in strontium ranelate–treated patients.

We concluded from the CASIMO trial that strontium ranelate is at least as potent if not superior in men with established osteoporosis as alendronate, which has received approval for this indication. A multicenter international trial with strontium ranelate in men is due to finish soon.

Conclusion

Although the causes of osteoporosis are more heterogeneous in men than they are in women (about 50% of cases in men are diagnosed as secondary cases), the options for prevention and basic therapy of osteoporosis are the same as those in postmenopausal women. Initially, modifying and counteracting existing negative risk factors, especially those relating to diet, physical exercise, and calcium and vitamin D supplementation, is recommended. The current treatments available for male osteoporosis are alendronate, risedronate, and zoledronate, but strontium ranelate has good potential with some promising results. More news about strontium ranelate will shortly be available after the completion of an ongoing international multicenter study. _

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Who has not thrilled to a seafaring tale of newfound passages and far-flung landfalls, pirates and plunder, mutiny and marooning, or to the Raft of the Medusa and the “Convergence of the Twain”? But what of the hapless, silenced by the sea? Are their tales to remain forever untold, their spirits drifting mute like flotsam on the boundless main? Long inaccessible, hidden away in Davy Jones’s locker, the imprint of humankind in the silence of the depths is now being deciphered by marine archaeologists. Theirs is a discipline that long struggled to establish itself, hampered by the difficulties of reaching underwater sites and by captious dry land archaeologists contending that the sea bears no trace of the past, has no memory. Yet submerged sites, oftentimes the aftermath of shipwrecks or seismic events, are time capsules of human interaction with seas, lakes, and rivers. With its 11 million square kilometers of territorial waters and maritime borders with 30 countries, France not surprisingly was the first country to invest in underwater archaeology. In 1966, André Malraux, the then French Minister of Culture, created the Department for Underwater and Undersea Archaeological Research in Marseilles, which, with the aid of its 30-meter boat L’Archéonaute, has since mapped over 900 sites in its mission to protect and preserve France’s underwater cultural heritage.

Taking the plunge

Working underwater is hazardous and complex. Diving equipment is burdensome— breathing apparatus, isothermal combination, flippers, diving weights, buoyancy compensator—comfort relative, and the breathing of compressed air means that a diver is less efficient than when working on dry land. Beyond a depth of 10 meters, tissue nitrogen uptake forces a diver to limit time spent underwater or to undergo gradual decompression, either by resurfacing in successive stages or by using a decompression chamber. Strict observance of safety rules is therefore key to successful underwater exploration of archaeological sites.

_ Famous early discoveries
Remarkable finds in the 1900s spurred archaeologists’ interest in shipwrecks. Two cargoes of Greek artworks were discovered a few years apart: in the Aegean Sea at Antikythera (including a large 4th century BC bronze statue of Hermes), and then off the coast of Tunisia near Mahdia.

A team of divers handling a 2-ton, eight-sided calcite block with the utmost care, as the slightest slip could have severe consequences.

A 2nd-century bronze statue of Hermes, the messenger of the Gods in Greek mythology, found during underwater excavations at Mahdia, Tunisia.

The Mary Rose, an English Tudor warship built in Portsmouth (1509-1510),
is the only 16th-century warship on display anywhere in the world.

These exceptional finds prompted the Italian authorities to undertake excavations near Rome on the bed of Lake Nemi, which since the 15th century had been known to be the last resting place of two ships built for the Roman Emperor Caligula in the first century AD. From 1928 to 1932, the lake was drained and the wrecks, which had already been plundered, were studied scientifically for the first time. One ship served as a temple dedicated to Diana, the goddess of the hunt; the second was a floating palace, with heated, mosaic floors and baths, inspired, it is believed, by Caligula’s fascination with the opulent lifestyles of the Hellenistic rulers of Syracuse and Ptolemaic Egypt.

The Mary Rose is the only 16th century warship on display anywhere in the world. One of the first warships able to fire a full broadside of cannons and the pride of the English fleet, she was built for Henry VIII in 1509-1510 and was manned by a crew of 200 sailors, 185 soldiers, and 30 gunners. After serving for over thirty years, she sank in the Solent during an engagement with the French fleet in July 1545, not it seems because of enemy fire. It would appear that in firing from the port side first and then turning sharply to fire from starboard, the Mary Rose heeled and water flooded in through the open gunports. Her plight was worsened because the upper decks were crowded with soldiers in full armor, thus raising the ship’s center of gravity, and she capsized. The wreck was rediscovered nearly three centuries later, but the location was subsequently forgotten and new searches begun in the 1960s culminated with the lifting of the Mary Rose in 1982.

In August 1628, on her maiden voyage from Stockholm, the Swedish warship Vasa ran straight into a violent storm and foundered before it could even leave the harbor, in full view of thousands of Stockholmers eager to see the great ship set sail. After much searching through the archives, Anders Franzen relocated the Vasa in the 1950s, at a depth of 32 meters in a busy shipping lane just outside Stockholm harbor. Exceptionally well preserved because of the low salinity of the Baltic Sea, the Vasa was recovered in 1961 and is now housed in a purpose-built museum in Stockholm, where it offers a fascinating insight into life aboard a 17th century warship.

_ The Mediterranean
Marseilles has played a key role in the history of archaeological diving. Studies by Jacques-Yves Cousteau of the wreck of the Grand Congloué in the Harbor of Marseilles in the 1950s are regarded as a world first. The divers used scuba equipment, developed by Cousteau, and a suction dredge to clean the site. The expedition’s archaeologist, Fernand Benoît, remained aboard the support ship Calypso, while the divers, albeit untrained in archaeology, searched the wreck and recovered artifacts. Not being a diver, Benoît was unable to observe first hand the positions of the wrecks, and this led to thirty years of controversy regarding the dating of one thousand Roman amphoras and a large cargo of black, glazed dishware and Greco-Roman amphoras. Only later was it realized that the cargoes were actually from two superimposed wrecks of vessels that had sunk almost a century apart.

In the 2nd century BC, when Rome had conquered the wineand pottery-producing regions of Latium and Campania, there was extensive trading between Italy, Gaul, and the Iberian Peninsula. As Michel L’Hour, the Director of the Department for Underwater and Undersea Archaeological Research (DRASSM) in Marseilles, points out, “one third of the ancient shipwrecks currently inventoried in the Mediterranean bear witness to this huge trade and together account for some 13 000 pieces of dishware and double that number of amphoras”.

The stern of the warship Vasa. Vasa, which was built in 1628, was lost on its maiden voyage before it could leave Stockholm harbor, after running into a violent storm.

Further evidence of this trade emerged during the excavation of a shipwreck off the harbor of Madrague de Giens, near Hyères, in what is considered the first scientific underwater excavation conducted in France (1972 to 1982). This 1st century BC sailboat (40 meters long, 9 m wide; approximately 400 tons) was carrying wine from Italy in thousands of amphoras of the Dressel 1B type, as well as hundreds of black, glazed vases.

Paleolithic cave painting of a stag from the Cosquer Cave, near Marseille, France.

The hand of time. An image of a hand found in sector 205 of the Cosquer Cave.

The Mediterranean also boasts the cave with the oldest cave paintings in the world: the Cosquer Cave, located near Cap Morgiou, not far from Marseille in France. The cave, named after Henri Cosquer, the professional diver who discovered it in 1985, is the only underwater cave with Paleolithic cave paintings in the world. The entrance to the cave is located 37 m below sea level because of changes in the relative altitudes of land and sea since prehistoric times. During the peak of the last major glaciation era approximately 20 000 years ago, the Würm period, the shoreline of the Mediterranean would have been several kilometers away. It contains paintings from two distinct Upper Paleolithic eras. The first set comprises 65 hand stencil paintings, which date back approximately 27 000 years (Gravettian epoch), while the second set consists of 177 animal drawings, which date back 19 000 years (Solutrean epoch). Both land animals, such as bison and horses, and marine animals, like seals and penguins, are represented in the latter set. Interestingly, ancient stencil hand paintings, which are all of adult hands in the Cosquer Cave, have been found throughout the world, from Australia to Africa and from Asia to the Americas.

_ The English Channel and the Atlantic
Long discounted because of its depressions and dangerous currents, the English Channel and the Atlantic off the French coast became of focus of great interest in the 1980s. When archaeologists from DRASSM were called in to work on a wreck discovered five miles from Ploumanac’h, they found that it contained an astonishing cargo of lead ingots covered with inscriptions in Latin characters. Epigraphic study of the 271 ingots showed that the shipwreck was ancient. Michel L’Hour explains that:

In 1994, a Breton diver discovered the La Natière site off Saint Malo. An initial survey revealed an extensive site, almost 50 meters from East to West and from North to South. As the excavations advanced, the archaeologists found four shipwrecks and Michel L’Hour qualified the site as “one of the most attractive in the world. A veritable underwater Pompeii. The sites were unchanged since the time of the sinking”. After eight years of work, two shipwrecks were identified. La Dauphine was a large royal frigate that disappeared on 10 December, 1704, when returning with a captured English ship, The Dragon. It was remarkably well preserved, with objects from daily life aboard, such as Norman and German pottery, arms, pewter pots, swords, sabers, pistols, and a surgeon’s instrument case. And at the La Natière II site, there was the wreck of L’Aimable Grenot, a privateer frigate lost at sea on 6 May, 1749, with its cargo of Breton cloth to be sold at Cadiz. In 1692, at the height of the War of the League of Augsburg, when Europe was opposed to French ambitions, Louis XIV sought to help his cousin King James II of England regain his throne, which he had lost to William III of Orange. Louis offered to make his fleet and men available, under Vice Admiral de Tourville. After initial success off Barfleur on 29 May, when Tourville defeated an Anglo-Dutch fleet, English ships destroyed three of the largest French vessels in Cherbourg Harbor and, a few days later, burnt twelve French ships anchored in Hougue Bay. This defeat sounded the death knell for the ambitions of Louis XIV and James II to invade England.

Portrait of Le Comte de Tourville, Vice Admiral and Marshal of France.

In 1985, a Norman diver reported these wrecks and the local French authorities called on the expertise of DRASSM, with a view to setting up a maritime museum on Tatihou Island. From 1990 to 1995, Michel L’Hour and Elisabeth Veyrat codirected the excavations at a depth of 4 to 9 meters. Some 5000 hours of underwater work revealed five wrecks from Admiral Tourville’s fleet and enriched our knowledge of shipbuilding, weaponry, and life aboard royal ships during the reign of Louis XIV, a pivotal period in the evolution of ship hull design.

_ The high seas
Shipwrecks in shallow water suffer the ravages of time, erosion, and human activity, but those resting at greater depths are magically preserved and are most commonly discovered while drilling for oil. In 1985, while exploring Gabonese territorial waters, the company Elf Gabon discovered an archaeological site at a depth of twelve meters. The French authorities lost no time in dispatching a team from DRASSM, led by Michel L’Hour and Luc Long. With logistic backup from Elf Gabon, an exhaustive three-month study of the site identified the Mauritius, a three-masted Dutch vessel (40 to 45 meters long) built in 1601-1602 for the Dutch East India Company. In addition to cannon, instruments from a surgeon’s trunk, a bronze bell, and white and blue porcelain, the archaeologists discovered 140 tons of pepper and 20 000 zinc disks, a cargo that gives us a glimpse of 17th century trade between Asia and Europe.

On 24 May, 1997, an autonomous underwater vehicle was exploring the coastal waters of the Sultanate of Brunei for TotalFinaElf, when piles of dishes and jars suddenly appeared in its light beams. Excavations overseen by DRASSM lasted three months and involved a multidisciplinary team 172 strong (archaeologists, caterers, divers, artists, experts in gas mixtures, physicians specialized in diving accidents), 70 of whom were French. Two submarines—Jules and Jim—fitted with three 450-watt projectors and several cameras, enabled the archaeologists to work in excellent conditions at a site that had probably never been plundered because of its distance (22 nautical miles) from the coast. Every day, the Royal Brunei Navy ferried the team from the shore to a barge anchored near the site. Another land-based team received over 13 200 objects retrieved from the sea, which they sorted, restored, drew, photographed (20 000 digital photos), and inventoried on a daily basis. These sunken treasures of Brunei, it was established, were lost in the South China Sea during a commercial voyage of a vessel (22 meters long and 8 meters wide) probably dating from the late 15th or early 16th century.

Bust of Julius Caesar found in the Rhone.

French underwater archaeologists have made many remarkable finds over the first few decades of scientific exploration of the ocean depths, and will no doubt in the future uncover many more of the three million or more wrecks and hundreds of submerged rock art sites, cities, and monuments that the United Nations Educational, Scientific, and Cultural Organization (UNESCO) estimates remain undiscovered around the world.

_ An exceptional discovery: the bust of Caesar at Arles
Luc Long, curator at DRASSM, has for twenty years been exploring the bed of the Rhone River, a task complicated by poor visibility and strong currents. For a decade, he and his team have been diving at Arles, where they have discovered hundreds of amphoras and pottery that bears witness to a booming river trade in Roman times. In September 2007, Long and his team recovered a veritable treasure trove of marble sculptures (Neptune, Asclepius), architectural fragments, magnificent bronzes (including a gold-plated Victory), and a 40 cm-high white marble bust of Julius Caesar, which he believes was sculpted from real life. If so, it is one of the most important historical discoveries in France since the 1960s. “That it was found here is not surprising,” says Long, “as Caesar founded Arles in 46 BC. After his assassination, the bust may have been thrown in the Rhone by partisans of Pompey.”

_ Alexandria: metamorphosis, preservation, and rebirth
In 1912, the French engineer Gaston Jondet was the first to publish maps of underwater ruins at Alexandria, discovered during work to enlarge the western port. In 1990, the French archaeologist Jean-Yves Empereur created the Centre d’Études Alexandrines.

The port of Alexandria in Egypt with the remains of its famous Lighthouse.

A representation of the Lighthouse of Alexandria, one of the Seven Wonders
of the Ancient World, by Hermann Thiersch (early 20th century).

Soon after, the center was asked by the Egyptian Antiquities Department to study the waters around the Citadel of Qaitbay. Between 1994 and 1996, in the sector where Jondet conducted his first explorations, Jean-Yves Empereur’s team from the Centre d’Études Alexandrines (CEAlex) drew up a digital map of over 3000 pieces of stonework (some weighing 75 tons) of archaeological interest, spread over 2 hectares under only 8meters of water. These blocks of granite, statues, columns of different shapes, capitals, and parts of obelisks are probably vestiges of one of the SevenWonders of the Ancient World, the Lighthouse of Alexandria. Early on the morning of October 4, 1995, archaeologists from CEAlex pulled a 12-ton granite torso over 4 meters high from the seabed and, using further finds of the crown, head, and legs, pieced together a 12-meter statue that used to stand guard at the main door to the lighthouse. This statue was of Ptolemy II, the king of Ptolemaic Egypt, during whose reign (283 to 246 BC) was completed the fabled Lighthouse that for centuries guided ships into Alexandria, one of the greatest ports of the ancient world. Ongoing topographic studies and the architectural inventory are currently being directed by Isabelle Hairy of CEAlex.

Remains of a statue of Ptolemy II found at Alexandria, Egypt.

A riddle at the bottom of the Mediterranean Sea found during underwater exploration of the Lighthouse of Alexandria.

Kamel Abul Saadat was the first diver to explore the port of Alexandria in 1960. A few years later, the archaeologist Honor Frost and the geologist Vladimir Nesteroff, working for UNESCO, confirmed vestiges of the palaces of Alexander and Ptolemy and located, at the site of the current 15th century Citadel of Qaitbay, the ruins of the famous Lighthouse of Alexandria, which was destroyed by earthquakes. The French architect Jacques Rougerie recently won an international competition to design an Underwater ArchaeologyMuseumin Alexandria, to be built near the site of the famous Library of Alexandria. Rougerie, a specialist in architecture for extreme environments, such as sea and space, has designed a futuristic, partially submerged museum where visitors will be able to walk through an undersea tunnel to discover the heritage of the Bay of Alexandria in situ.

_ The mystery of the Lapérouse Expedition
As he mounted the scaffold on 21 January, 1793, Louis XVI is reputed to have called out “Have we any news of Monsieur Lapérouse?”. Apocryphal or not, his inquiry reflects the fascination of the time engendered by the mysterious fate five years before of the explorer Lapérouse and his two ships, La Boussole and L’Astrolabe (The Compass and The Sextant), which disappeared with all hands in the Solomon Islands, east of Papua New Guinea.

In appointing Jean-Baptiste Lapérouse to lead an expedition around the world, Louis XVI hoped to complete the mapping of the planet, establish new trading posts, open up new sea routes, and enrich scientific knowledge and collections. The expedition’s two frigates, La Boussole and L’Astrolabe, left Brest in August 1785 with 220 men aboard. For nigh on three years, they sailed the high seas to Easter Island, the Sandwich Islands, the Philippines, Brazil, Chile, and Japan before vanishing one day in 1788 in a violent Pacific storm after calling at Botany Bay, Australia.

Louis XVI and Captain Lapérouse.
The picture, by Nicolas André (1754-1837), shows Louis XVI giving Captain Lapérouse instructions for his round-the-world journey of discovery in the presence of the Marquis de Castries, minister of the French Navy, on June 29, 1785.

Some forty years later in September 1827, Peter Dillon, a South Seas trader, shed the first light on the fate of Lapérouse and his men when he happened upon the wreckage of the expedition north of Vanuatu. He recovered the bell of L’Astrolabe and the bronze muzzle-loading cannon, but there was no trace of La Boussole. Dillon later recounted in his Narrative and Successful Result of a Voyage in the South Seas, to Ascertain the Actual Fate of la Pérouse’s Expedition how local inhabitants had told him that both ships had been thrown onto reefs by a tempest, that some survivors had later built a boat from the wreckage and sailed away, and that two survivors had remained on the island, but had since died.

It was not until well over a century and a half later that new evidence emerged. In the mid-1980s, the two wrecks were identified—L’Astrolabe had foundered on rocks not far from La Boussole, which had run aground on the reefs of Vanikoro. Numerous objects were brought to the surface, land-based digs revealed a camp of the survivors, and the skeleton of an unknown member of Lapérouse’s crew was recovered. These findings came more than two centuries too late to satisfy Louis XVI’s eleventh-hour curiosity, but, as the last pieces of the jigsaw fall into place, we can now affirm: “Yes, we do have news of Monsieur Lapérouse.” _

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Philippe HALBOUT, PhD
Servier International
Paris, FRANCE

Osteoporosis is a common insidious disease seen typically in middleaged and elderly women due to the postmenopausal fall in estrogen levels. The combination of progressive bone loss and decreased bone quality increases the risk of vertebral, nonvertebral, and hip fracture, causing major morbidity and mortality. In spite of this apparent simple picture, treatment confronts clinicians with three major challenges: first, drugs against osteoporosis have been around for 40 years, but few have proved effective in preventing fractures at all sites; second, the increase in fracture risk in postmenopausal women with osteoporosis is due to a variety of risk factors, whose combination results in a great number of different profiles, obliging clinicians to select a drug that is effective for their patient’s particular profile; third, solid evidence of long-term efficacy is required when treating a chronic disease such as osteoporosis. As an antiosteoporotic agent with a unique mode of action, Protelos (strontium ranelate) is the first drug to meet these challenges. It has a unique mode of action, by means of which it increases bone formation and reduces bone resorption, thus rebalancing bone turnover in favor of bone formation. Protelos builds strong new bone in osteoporotic women, providing protection against vertebral, nonvertebral, and hip fractures. Protelos has been shown to be effective across a variety of profiles: from the youngest to the oldest patients, and from those with osteopenia to those with the most severe osteoporosis. The 2008 European Guidance acknowledged Protelos as the treatment with the most robust evidence of comprehensive antifracture efficacy and, hence, as an unequivocal first-line choice in the treatment of postmenopausal osteoporosis.

Osteoporosis is a devastating disease that induces progressive bone loss and bone fragility in postmenopausal women, thereby increasing fracture risk in a silent fashion. However, in spite of this apparently simple picture, treatment confronts clinicians with three challenges: first, drugs against osteoporosis have been around for 40 years, but few have proved effective in preventing fractures at all sites; second, the increase in fracture risk in postmenopausal women with osteoporosis is due to a variety of risk factors, whose combination results in a great number of different profiles, obliging clinicians to select a drug that is effective for their patient’s particular profile; third, evidence of long-term efficacy is required when treating a chronic disease such as osteoporosis. Very few treatments have proved effective against fractures at all sites, irrespective of patient profile, and in the long term. This article reviews the extent to which Protelos satisfies these three criteria (Figure 1).

Figure 1. Three key criteria for the treatment of osteoporosis.

Protelos: comprehensive efficacy against vertebral, nonvertebral, and hip fracture

Treatments of osteoporosis are generally assessed by their ability to prevent two types of fracture: vertebral fractures (the most common type) and hip fractures (the most serious type in terms of morbidity and mortality, especially in the elderly). Surprisingly, few treatments among the armamentarium available to clinicians have proved effective against both vertebral and hip fractures.

Two pivotal efficacy trials, both multinational, randomized, double-blind, and placebo-controlled have confirmed the efficacy of Protelos on each fracture type in a total of 6740 postmenopausal women, all of whom received concomitant calcium/vitamin D supplementation at a dose tailored to the degree of deficiency (calcium 500/1000 mg, vitamin D₃ 400/800 IU).

The efficacy of Protelos against vertebral fracture was assessed in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial in 1649 postmenopausal women aged ≥_50 years with ≥_1 vertebral fracture(s) and lumbar spine bone mineral density (BMD) ≤0.840 g/cm2 (Hologic: www.hologic.com). Protelos decreased new vertebral fracture risk by 49% after only 1 year (relative risk [RR], 0.51; 95% confidence interval [CI], 0.36-0.74; P<0.001). Clinical vertebral fractures, defined as vertebral fracture coupled with back pain and/or height loss ≥_1 cm, fell by 52% also as early as the first year of treatment (RR, 0.48; 95% CI, 0.29-0.80; P=0.003). Reductions in vertebral and clinical vertebral fractures at 3 years (41%; RR, 0.59; 95%CI, 0.48-0.73, and 38%; RR, 0.62; 95% CI, 0.47-0.83, respectively; both P<0.001) further confirmed the long-termefficacy of Protelos (Figure 2).¹

The second study, TReatment Of Peripheral Osteoporosis Study (TROPOS), assessed the efficacy of Protelos against nonvertebral and hip fractures in 5091postmenopausal women with femoral neck BMD equivalent to a T-score below –2.5 SD (centralized normative data analysis: Dr D. O. Slosman, Geneva, Switzerland) and age ≥_74 years or 70 to 74 years with an additional fracture risk factor. At 3 years, Protelos decreased the risk of nonvertebral fractures by 16% (RR, 0.84; 95% CI, 0.702-0.995; P<0.05) and the risk of major nonvertebral fractures (hip, wrist, pelvis, sacrum, ribs-sternum, clavicle, and humerus) by 19% (RR, 0.81; 95% CI, 0.66-0.98; P<0.05).2 Special attention was paid to the effect of Protelos on hip fractures, because of their devastating consequences in terms of morbidity and mortality. In the subgroup of patients at highest hip fracture risk, ie, those aged ≥_74 years with femoral neck T score ≤–2.4 SD, Protelos decreased the risk of hip fractures by 36% (RR, 0.64; 95% CI, 0.412-0.667; P=0.046) over 3 years (Figure 3). At the same time, TROPOS confirmed the SOTI data by showing that Protelos decreased the risk of new vertebral fractures over 1 and 3 years by 45%(RR, 0.55; 95% CI, 0.39-0.77; P<0.001) and 39% (RR, 0.61; 95% CI, 0.51-0.73; P<0.001), respectively, versus placebo.

Figure 2. The effects of Protelos on the risk of vertebral fracture in women with postmenopausal osteoporosis in the SOTI study.

Figure 3. Significant decreases in the relative risks of nonvertebral, major nonvertebral, and hip fractures with Protelos vs placebo in the TROPOS study.

Protelos is thus effective against osteoporotic fractures at all major sites in postmenopausal women,3 regardless of disease severity, as recently acknowledged in the European Guidance for the Treatment and Management of Osteoporosis in Postmenopausal Women (Table I).⁴

Table I. Protelos is the only treatment to have demonstrated its efficacy on vertebral, nonvertebral, and hip fractures, whatever the severity of osteoporosis.

_ Absolute risk reduction (ARR) and number needed to treat (NNT): two key parameters in interpreting clinical studies
A head-to-head clinical trial comparing the antifracture efficacy between two drugs is undoubtedly the ideal option; but, this would require a huge number of patients and long-term follow-up. However, at least two other options are available. The first is to use surrogatemarkers of fracture risk (eg, BMD, bone quality analysis, and bone markers).⁵ Unfortunately, these are not sufficiently accurate or fracture-predictive to be useful. The second is to analyze the clinical studies in depth and consider every parameter that reflects efficacy. Relative risk reduction (RRR) is clearly a major parameter, but absolute risk reduction (ARR) and number needed to treat (NNT, the reciprocal of ARR) are also important and should not be overlooked,6 all the more so as they both are directly applicable to clinical practice. ARR reflects the real risk of osteoporotic patients that a clinician has to treat (there is no placebo group in the waiting room), while NNT readily translates into patient terms. SOTI and TROPOS show very low NNTs for Protelos: only 9 patients need to be treated in order to prevent 1 vertebral fracture and 48 to prevent 1 hip fracture, over 3 years.^1,2 Protelos outperforms other treatments in terms of both ARR and NNT.

Protelos is effective across a broad range of patient profiles

Hitherto, osteoporosis and osteopenia have been determined based solely on bone mineral density. Osteoporosis and osteopenia are defined by T-scores <–2.5 SD and between –1 SD and –2.5 SD, respectively. However, fracture risk does not depend on BMD alone, but also on other risk factors, including prevalent fractures, age, steroid treatment, smoking, alcohol intake, maternal fracture history, and low body mass index (BMI), thereby creating a range of fracture risk profiles. An ideal treatment should be risk profile–independent. The first indication that Protelos would meet this requirement by preventing osteoporotic fractures independently of risk factors came in 2006,⁷ well before the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX®) began to quantify the contribution of such risk factors to fracture prediction.⁴

_ Risk factors
BMD remains the main fracture risk factor and the basis for diagnosis. Independently of other risk factors, Protelos de- creases vertebral fracture risk by 39% (RR, 0.61; 95% CI, 0.53-0.70; P<0.001) in osteoporotic women with hip/lumbar spine T-score ≤–2.5 SD.⁷ It is also the only treatment to reduce vertebral fracture risk in osteopenic women (hip/lumbar spine T-score between –1 and –2.5 SD) by a margin as high as 72% (RR, 0.28; 95% CI, 0.07-0.99; P=0.045).⁸ Efficacy is independent of the number of prevalent fractures: in osteoporotic women with no, one, or two prevalent fractures, Protelos reduced vertebral fracture risk by 48% (RR, 0.52; 95% CI, 0.40-0.67; P<0.001), 45% (RR, 0.55; 95% CI, 0.41-0.74; P<0.001), and 33% (RR, 0.67; 95% CI, 0.55-0.81; P<0.001), respectively.⁷ Similarly, in osteopenic women with and without prevalent fractures, Protelos decreased vertebral fracture risk by 38% (RR, 0.62; 95% CI, 0.44-0.88; P=0.008), and 59% (RR, 0.41; 95% CI, 0.17-0.99; P=0.039).⁸

Bone markers, which allow estimation of the level of bone remodeling in postmenopausal women, are sometimes used to confirm the diagnosis of osteoporosis. Even though the relationship between bone markers and fracture risk has not been established, a treatment that works whatever the level of bone markers can only bolster clinician confidence. In the pooled SOTI and TROPOS populations, Protelos decreased vertebral fracture risk by a significant 31% to 42% (nonsignificant difference) across all ranges of the bone formation marker bALP (bone alkaline phosphatase). Similar decreases, from 37% to 47%, were achieved across all ranges of the bone resorption marker sCTX (serum cross-linked C-telopeptides of type I collagen). The two markers can be combined to differentiate patients into low- and high-turnover groups. Protelos decreased vertebral fracture risk by 33% (RR, 0.67; 95% CI, 0.47-0.95; P=0.023) and 49% (RR, 0.51; 95% CI, 0.37-0.70; P<0.001) in low- and high-turnover women, respectively.⁹

Finally the efficacy of Protelos has been shown to be independent of family history of osteoporosis, body mass index, and smoking.⁷

_ Young patients with severe osteoporosis
Osteoporosis is one of the most common disorders in young postmenopausal women. Bone loss, due to a dramatic increase in bone turnover, can be rapid in the first decade after the fall in estrogens. This explains why treatment needs to be initiated early if it is to maximize its effect and prevent more devastating consequences. In postmenopausal women aged 50-65 years, Protelos reduced vertebral fracture risk by 47% (RR, 0.53; 95% CI, 0.33-0.85; P=0.006) over 3 years10 and this effect was found to be sustained over a further year, as shown by a 40% reduction in vertebral fracture risk at 4 years (RR, 0.60; 95% CI, 0.39-0.92; P=0.017).¹¹ Efficacy was also independent of age in the pooled SOTI and TROPOS populations: 3-year vertebral fracture risk fell by 37% in women <70 years (RR, 0.63; 95% CI, 0.46-0.85; P=0.003) and by 42% in those aged 70-80 years (RR, 0.58; 95% CI, 0.48- 0.68; P<0.001).⁷

_ Elderly and frail patients
Women over the age of 80 are particularly prone to fractures due to the frequent combination of risk factors in that age group. These women represent about 8% of the postmenopausal population, but account for over 30% of fragility fractures and over 60% of hip fractures. These have particularly debilitating sequelae in terms of delayed fracture healing, functional impairment, loss of autonomy, as well as increased consumption of nursing homes resources, financial cost, and mortality.

In patients over 80, Protelos reduced vertebral fracture risk by 59% (RR, 0.41; 95% CI, 0.22-0.75; P=0.002), clinical fractures by 37% (RR, 0.63; 95% CI, 0.44-0.91; P=0.012), and nonvertebral fractures by 41% (RR, 0.59; 95% CI, 0.37- 0.95; P=0.027) after 1 year, and by 32% (RR, 0.68; 95% CI, 0.50-0.92; P=0.013), 22% (RR, 0.78; 95% CI, 0.61-0.99; P=0.040), and 31% (RR, 0.69; 95% CI, 0.52-0.92; P=0.011) after 3 years.¹² Protelos is the only treatment to have shown long-term efficacy in the elderly, with decreases of 31% in vertebral fracture risk (RR, 0.69; 95% CI, 0.52-0.92; P=0.010) and 26% in nonvertebral fracture risk (RR, 0.74; 95% CI, 0.57-0.95; P=0.019) over 5 years.¹³

The concept of frailty takes into account a variety of health status factors in addition to age, including decreased strength, tiredness, involuntary weight loss, slowness, and inactivity.¹⁴ Frail osteoporotic women are more vulnerable when exposed to stressors and more likely not only to fall, but to fracture as a result. In frail patients from the SOTI and TROPOS populations, Protelos decreased vertebral fractured risk by 58% (RR, 0.41; 95% CI, 0.23-0.73; P=0.002) and overall osteoporotic fracture risk by 28% (RR, 0.72; 95% CI, 0.49-1.04; P=0.08) after 3 years.¹⁵

Thus, Protelos is similarly effective in reducing the risk of vertebral and nonvertebral fractures in young and elderly postmenopausal women and in the frail elderly, suggesting that the earlier it is introduced after menopause onset, the greater the anticipated benefit.

Protelos: the only antiosteoporotic treatment with long-term antifracture efficacy proven beyond 3 years

_ Protelos: proven antifracture efficacy beyond 3 years
Only treatments with proven long-term efficacy can hope to be effective in treating a lifelong disease such as osteoporosis. Despite this obvious requirement, there are long-term fracture data for few, if any, treatments. At best, they tend to be BMD data and/or fracture data in open studies or calculated as an annual incidence, rather than in terms of efficacy over time. Protelos is alone in having proven antifracture efficacy beyond 3 years, as shown by the findings fromTROPOS, which evidenced efficacy sustained over 5 years, and even as much as 8 years in an open-label extension study in a subgroup of SOTI and TROPOS patients.

Figure 4. The efficacy of Protelos is sustained over 8 years on (A) vertebral and (B) nonvertebral fractures, as demonstrated by the similar incidence of fractures over the first and last 3 years of follow-up.

_ Protelos: unique in being effective over 5 years
Proof of the efficacy of Protelos was afforded by TROPOS, a randomized, double-blind, multicenter, placebo-controlled study with preplanned analysis over 5 years in the intentionto- treat population (n=2714).

During that period, Protelos reduced nonvertebral fracture risk by 15% (RR, 0.85; 95% CI, 0.73-0.99; P=0.032) and the risk of new major nonvertebral osteoporotic fracture by 18% (RR, 0.82; 95% CI, 0.69-0.98; P=0.025) versus placebo.

In a high-risk subgroup (n=1128; ≥74 years and lumbar/ femoral neck T-score ≤–2.4 SD), Protelos reduced hip fracture risk by 43% versus placebo over 5 years (RR, 0.57; 95% CI, 0.33-0.97; P=0.036)¹⁶ and vertebral fracture risk by 24% (RR, 0.76; 95% CI, 0.65-0.88; P<0.001). Overall, Protelos reduced the risk of osteoporotic fracture by 20% versus placebo independently of location (RR, 0.20; 95% CI, 0.71-0.90; P<0.001). Only 21 patients needed to be treated with Protelos to prevent 1 new osteoporotic fracture; safety was similar to that over 3 years, with mostly mild and transient side effects. Rates of venous thromboembolism were comparable to those on placebo (2.7% vs 2.1%; odds ratio 1.30).

_ Confirmation of Protelos efficacy extended to 8 years
Having been treated for 5 years in SOTI or TROPOS, an 893-patient subgroup was included in a 3-year open-label extension study. For ethical reasons, it was decided to stop treating patients with placebo as the fracture risk was too high. Longer-term efficacy was assessed by comparing cumulative fracture incidence over the first and last 3-year periods in the 8-year follow-up.

The cumulative incidence of new vertebral fractures over the 3-year extension was 13.7% compared with 11.5% in the first 3 years. In TROPOS patients, the respective figures for new nonvertebral fractures were 12%and 9.6%. Thus, Protelos, in contrast to any other treatment, remains effective over the very long term (Figure 4) as well as safe and well tolerated.¹⁷

Protelos and bone architecture

_ Protelos improves bone architecture
Treatment strategy used to focus on decreasing bone resorption, but this strategy had limitations: strong downregulation of bone resorption hindered repair of normal stress-induced microcracks, while there is an inevitable decrease in bone formation induced by antiresorptive treatment due to the coupling between osteoblast and osteoclast activity. Protelos is currently alone among antiosteoporotic agents in decreasing bone resorption while increasing bone formation. The net balance is the creation of new bone. Benefits on bone were first shown in bone biopsies from SOTI and TROPOS patients. Treatment for 3 years resulted in bone microarchitecture benefits, as evidenced by increased cortical bone thickness of 18%(P=0.008) and trabecular number by 14%(P=0.05), while decreasing trabecular separation by 16% (P=0.004). These improvements were associated with a change in bone structure from “rod-like” on placebo to “plate-like” on Protelos (Figure 5, page 64).¹⁸

These benefits of Protelos in terms of bone architecture result from increased osteoblast activity, shown by increases in mineral apposition rate (+9%; P=0.019) and osteoblast sur- face (+38%; P=0.047), and a 10% trend toward a decrease in osteoclast surface. Bone biopsy analysis at 5 years revealed no abnormalities in structure or mineralization.¹⁹

Figure 5. Protelos improves bone microarchitecture at the cortical and trabecular sites in postmenopausal women with osteoporosis.

Figure 6. Comparison of the changes in cortical thickness and the ratio of bone volume to total volume for Protelos and alendronate.

_ Protelos is more effective than bisphosphonates in improving microarchitecture
A recent head-to-head randomized, double-dummy, double- blind study in osteoporotic women used high-resolutionperipheral quantitative computed tomography (HR-pQCT, Scanco Medical) to compare the effect on bone microarchitecture for 1 year of treatment with Protelos versus alendronate. Cortical thickness increased by 5.3% (P<0.001) and the trabecular bone volume/total volume ratio by 2.0% (P=0.002) on Protelos; the changes in each parameter were already significant at 3 months (P=0.012 and P=0.042, respectively; Figure 6). No improvement occurred in the alendronate group, confirming that this latter type of treatment is not able to build new bone.²⁰

_ Protelos improves hip architecture
Impact on hip geometry after treatment for 5 years was studied in 483 TROPOS patients (Protelos, n=251; placebo, n=231) using the dual-energy x-ray absorptiometry (DXA)-derived hip structure analysis (HSA) program, devised by Thomas Beck and incorporated in Hologic densitometers. The program includes cross-sectional area (CSA), section modulus, cortical thickness, and buckling ratio. Protelos increased cortical thickness—the main determinant of hip fracture risk—at the femoral neck, intertrochanteric region, and proximal shaft (+5.2±9.8% vs –3.6±7.9%, P<0.001 vs placebo). This improvement in bone microarchitecture resulted in improved bending strength, with an increase in sectionmodulus of +8.6± 14.3% vs –2.3±11.6% on placebo (P<0.001; Figure 7).²¹

Thus three studies by different teams using different techniques confirm the benefits of Protelos on bone architecture. Not only does Protelos increase cortical thickness, the main determinant of hip fracture risk, as early as after 3 months’ treatment, but it also rapidly improves hip geometry, as evidenced at three different sites. Protelos also rapidly improves trabecular bone, the main component involved in vertebral fractures. Protelos therefore improves the two main components of bone strength, thus ensuring optimal prevention of osteoporotic fractures in postmenopausal women.

Protelos: unique dual mode of action

The experimental evidence accumulated for the dual mode of action of Protelos, notably on osteoblasts, osteoclasts, and bone architecture, has been reviewed elsewhere (Figure 8).²² An intensive effort is underway to elucidate the molecular basis of its innovative mode of action. Studies in various models have shown that Protelos has a direct effect on both osteoblasts and osteoclasts by increasing osteoblast replication, differentiation, and activity,^23-26 while simultaneously downregulating osteoclast differentiation and activity.^26-29 A recent Australian study also shows that Protelos promotes osteocyte differentiation into osteoblasts.³⁰

Protelos modulates the level of two major factors closely involved in regulating osteoclastogenesis by osteoblasts. Osteoprotegerin (OPG) and receptor activator nuclear factor-êB ligand (RANKL) are both expressed by osteoblasts. The OPG/ RANKL ratio governs osteoclastogenesis: a low ratio promotes osteoclastogenesis, a high ratio downregulates it. Two studies in human osteoblasts have shown Protelos to increase mRNA expression of OPG, while simultaneously decreasing mRNA expression of RANKL. This is highly predictive of subsequent downregulation of osteoclastogenesis.^30,31 In the same studies, Protelos increased the replication and differentiation of human osteoblasts, which are similarly highly predictive of subsequent enhancement of bone formation. This was the first evidence to show that Protelos modulates both bone formation and bone resorption by acting directly on human osteoblasts, suggesting that osteoblasts play a key role in the drug’s mechanism of action.

Figure 7. Protelos improves hip geometry and bone strength compared with the placebo group.

Figure 8. Protelos increases bone formation through an increase in osteoblast replication, differentiation, and activity.

A remarkable mouse model of severe osteoporosis and spontaneous fracture recently confirmed the link between the benefits of Protelos on bone architecture and osteoporotic fracture prevention. Protelos decreased the number of new fractures by 60% vs controls after 9 weeks. Spontaneous fracture prevention was related to a net improvement in both trabecular and cortical microarchitecture.³²

Bone marker monitoring in clinical trials has consistently confirmed the dual mode of action revealed in the in vitro studies. In women receiving Protelos in both SOTI and TROPOS, bALP (a marker of bone formation) independently increased, while sCTX (a marker of bone resorption) decreased. These effects were detected as early as after 3 months of treatment (bALP, +8.1%; P<0.001; and sCTX, –12.2%; P<0.001) and were sustained over 3 years.¹ These trials thus confirmed the clinical benefits of the dual mode of action of Protelos: new bone formation, improved bone quality, greater bone strength, and lower fracture risk.

Conclusion

Protelos has proved its efficacy against vertebral, nonvertebral, and hip fractures. This treatment is the only one to have also proven its efficacy across a wide spectrum of patient profiles. In addition, Protelos is the only treatment to have proven its efficacy over 5 years, which is sustained for up to 8 years. Furthermore, this long-term efficacy was associated with very good safety and tolerability. These unique benefits are explained by the ability of Protelos to build new, strong bone, thanks to its unique dual mode of action. The benefits on the microarchitecture have been proven consistently, with improvement in both cortical and trabecular bone (the main determinants of hip and vertebral fractures, respectively). Protelos has all the characteristics of a major treatment and must be considered a first-line treatment in the armamentarium of clinicians concerned with the treatment of osteoporosis. _

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9. Collette J, Bruyère O, Kaufman JM, et al. Vertebral anti-fracture efficacy of strontium ranelate according to pre-treatment bone turnover. Osteoporos Int. 2009 May 13. Epub ahead of print.
10. Roux C, Fechtenbaum J, Kolta S, Isaia G, Andia JB, Devogelaer JP. Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis. Ann Rheum Dis. 2008;67:1736-1738.
11. Devogelaer J, Fechtenbaum J, Kolta S, et al. Strontium ranelate demonstrates efficacy over 3 and 4 years against vertebral fracture in young postmenopausal women (50-65 years) with severe osteoporosis. Osteoporos Int. 2008;19: S14-S15.
12. Seeman E, Vellas B, Benhamou C, et al. Strontium ranelate reduces the risk of vertebral and nonvertebral fractures in women eighty years of age and older. J Bone Miner Res. 2006;21:1113-1120.
13. Seeman E, Vellas B, Benhamou CL, et al. Sustained 5-year vertebral and non-vertebral fracture risk reduction with strontium ranelate in elderly women with osteoporosis. Osteoporos Int. 2006;18. OC39. Abstract.
14. Fried LP, Tangen CM, Walston J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci. 2001;56:M146-M156.
15. Vellas B, Seeman E, Boonen S, et al. Strontium ranelate over 5 years reduces nonvertebral fractures in women age >80 and is cost saving. J Nutr Health Aging. 2009;13:S425. Abstract.
16. Reginster J, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate treatment on the risk of non-vertebral and vertebral fractures in postmenopausal osteoporosis: results of a 5-year, randomized, placebo-controlled trial. Arthritis Rheumat. 2008;58:1687-1695.
17. Reginster JY, Bruyère O, Sawicki A, Roces-Varela A, Fardellone P, Roberts A, Devogelaer JP. Long-term treatment of postmenopausal osteoporosis with strontium ranelate: results at 8 years. Bone. 2009;45:1059-1064.
18. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and muCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.
19. Boivin G, Farlay D, Khebbab MT, Jaurand X, Delmas PD, Meunier PJ. In osteoporotic women treated with strontium ranelate, strontium is located in bone formed during treatment with a maintained degree of mineralization. Osteoporosis Int. 2009 Jul 14. Epub ahead of print.
20. Rizzoli R, Felsenberg D, Laroche M, et al. Superiority of strontium ranelate as compared to alendronate on microstructural determinants of bone strength at the distal tibia in women with postmenopausal osteoporosis. Ann Rheum Dis. 2009;68(suppl 3):669. Abstract SAT0388.
21. Briot K, Benhamou L, Roux C. Effect of strontium ranelate on hip structural geometry. Ann Rheum Dis. 2009;68(suppl 3):665. Abstract SAT0375.
22. Marie PJ, Ammann P, Boivin G, et al. Mechanisms of action and therapeutic potential of strontium in bone. Calcif Tissue Int. 2001;69:121-129.
23. Canalis E, Hott M, Deloffre P, et al. The divalent strontium salt S12911 enhances bone cell replication and bone formation in vitro. Bone. 1996;18:517-523.
24. Choudhary S, Halbout P, Alander C, et al. Strontium ranelate promotes osteoblastic differentiation and mineralization of murine bone marrow stromal cells: involvement of prostaglandins. J Bone Miner Res. 2007;22:1002-1010.
25. Zhu LL, Zaidi S, Peng Y, et al. Induction of a program gene expression during osteoblast differentiation with strontium ranelate. Biochem Biophys Res Commun. 2007;355:307-311.
26. Bonnelye E, Chabadel A, Saltel F, et al. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone. 2008;42:129-138.
27. Baron R, Tsouderos Y. In vitro effects of S12911-2 on osteoclast function and bone marrow macrophage differentiation. Eur J Pharmacol. 2002;450:11-17.
28. Takahashi N, Sasaki T, Tsouderos Y, et al. S 12911-2 inhibits osteoclastic bone resorption in vitro. J Bone Miner Res. 2003;18:1082-1087.
29. Wattel A, Hurtel-Lemaire A, Godin C, Mentaverri R, Kamel S, Brazier M. Strontium ranelate decreases in vitro human osteoclastic differentiation. Bone. 2005; 36:S400-S401. P585. Abstract.
30. Atkins GJ, Welldon KJ, Halbout P, Findlay DM. Strontium ranelate treatment of human primary osteoblasts promotes an osteocyte-like phenotype while eliciting an osteoprotegerin response. Osteoporos Int. 2009;20:653-664.
31. Brennan TC, Rybchyn MS, Green W, Atwa S, Conigrave AD, Mason RS. Osteoblasts play key roles in the mechanism of action of strontium ranelate. Br J Pharmacol. 2009;157:1291-1300.
32. Geoffroy V, Marty C, Lalande A, et al. Strontium ranelate reduces new vertebral fractures in a severe osteoporotic mice model with spontaneous fractures by improving bone microarchitecture. Calcif Tissue Int. 2006;78:S38. Abstract P003.

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George P. LYRITIS
MD, PhD
University of Athens
Laboratory for the Research
of Musculoskeletal System
KAT Hospital, Athens
GREECE

Fracture healing is an extremely important biological process that is necessary for the survival of the animal. Fracture healing failure is associated with serious impairment of the locomotor systemas well as a decline in quality of life. Postfracture deformities after poor reduction of the fractured extremity, eg, leg shortening or angulations, are associated with serious functional incapacity. Fracture healing should ideally fully return bone strength to its prefracture state. Fracture healing is a unique biological event that takes a considerably long period of time to complete. A short phase of endochondral external callus formation is followed by a prolonged remodeling period. There is a danger of nonunion and possible refracture occurring during the endochondral callus formation phase. As fractures are more common in people with osteoporosis who may already be undergoing long-term treatment with antiosteoporotic medication, it is of great clinical importance to know whether these drugs have a positive or negative effect on the biological process of fracture repair. Surprisingly, the existing literature, especially clinical studies, is limited. Prospective trials in patients receiving antiosteoporotic medications prior to and/or after a fracture would be helpful, especially for orthopedic surgeons, and would aid their care of osteoporotic patients before and following fracture. In this review, the existing knowledge is presented with an emphasis on the practical issues related to the clinical applications in orthopedic surgery.

Fracture healing: a three-step process

Fracture healing is an important biological process that is necessary for the survival of the injured animal.¹ Bone is a unique tissue and its repair process of great biological importance, as it aims to fully restore lamellar bone to its original condition thereby regaining initial bone strength.² Fracture is usually understood as being the complete disruption of a long bone after a fall, but many people ignore the fact that trabecular bones, especially in osteopenic patients, may suffer microfractures, which are automatically restored by minicallus formation,³ as shown in Figure 1 (page 80). Repair of a fractured long bone typically progresses in three consequent stages.

_ Stage 1 (inflammatory phase)
This follows immediately after fracture and is associated with the activation of wound healing pathways usually observed after a soft tissue injury (bleeding, development of a hematoma with macrophages and other inflammatory cells) and the gradual development of capillary clotting.⁴ Several cytokines and growth factors, including transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF), facilitate the recruitment of additional inflammatory cells and the invasion of multipotent mesenchymal stem cells from the periosteum and the bone marrow. During this stage, a primitive callus develops, reducing uncontrolled mobility at the fracture site.⁴ The inflammatory stage of fracture healing is fast and lasts up to a week after fracture.

Figure 1. Trabecular microfractures.

_ Stage 2 (reparative phase)
This phase starts within the first days of the inflammatory one and continues for several weeks. A gradually developing hard callus is formed—usually around the fracture site—that imitates a large internal splint around the fractured bone. The formation of the external callus is stimulated by instability at the fracture site. Micromotion enhances callus maturation and its transformation froma cartilaginous to a harder osseous model, while local strains become gradually smaller.² The simultaneous removal from the injured area of avascular dead bone and the production of fresh bone occur during the reparative phase, with the action of cartilage and differentiated osteoblasts coming directly from precursor cells (intramembranous ossification).Within the fracture gap and at its periphery, abundant cartilage formation occurs in a manner similar to the endochondral ossification observed at the growth plate. Chondrocyte proliferation and differentiation are stimulated by the expression of growth factors including TGF-β2, platelet-derived growth factor (PDGF), insulinlike growth factor 1 (IGF-1), and some bone morphogenetic proteins (BMPs), ie, BMP-2, –4, –5, and –6).⁵ The reparative external callus, which is typically composed of woven bone, now connects the fragment ends, offering limited mechanical strength at the fracture site. The first two stages of fracture healing (inflammatory and reparative) and external callus formation are considered mechanisms necessary for the survival of the injured animal, which after a reasonable consolidation of the fracture can partially return to its usual activities. Of course, this solution by no means offers bone strength equal to that in the prefracture period, and the possibility of a refracture is still high. The full restoration of the initial mechanical condition occurs after a prolonged period of time through the well-known mechanism of bone remodeling. During the callus remodeling phase, woven bone is gradually replaced by lamellar bone, according to the laws of the mechanostat that Frost described many years ago.^2,3

_ Stage 3 (remodeling phase)
This is a nonemergency phase and can be considered as a gradual adaptation of the fractured bone to the usual strains of everyday life. As a paradigm for the adaptive biological mechanism of fracture remodeling, we have taken the story of the restoration of the walls of the Acropolis of Athens6 following the destruction of the city during the PersianWars and their urgent rebuilding with the ruins of the walls destroyed by the Persians (Figure 2).

_ Does osteoporosis affect fracture healing?
Fractures in the osteoporotic elderly are more frequently associated with complications and invalidity during the period of rehabilitation.⁷ Experimental studies on the effect of osteoporosis on fracture repair in the ovariectomized rat model have shown delayed fracture healing⁸ and a diminution of the mechanical strength of bone after the completion of the healing process. The final outcome is the union of the fracture; nonunion is very uncommon. On the other hand, there is only anecdotal evidence that osteoporosis may delay fracture healing in humans.⁹ Taking into consideration that bone modeling and fracture healing have similar mechanisms and that osteoblastic modeling is usually suppressed in advanced age and in osteoporotic patients, it seems normal that fracture repair in elderly people should take longer.¹⁰ In the corticosteroid-induced osteoporosis animal model, fracture healing was found to be delayed.¹¹ In conclusion, there is still a question mark over whether postmenopausal and senile osteoporosis affects fracture healing in humans. Nevertheless, mechanical and biological factors involved in the healing process of bone are influenced by age and osteoporosis, in the way estrogen deficiency has a biological effect on bone.¹²

_ Does high bone turnover affect fracture healing?
It is well known that posttraumatic osteopenia is the result of high bone turnover and that fracture healing is associated with increased biochemical bone markers, especially those of bone resorption.¹³ Women who have recently sustained fracture have higher levels of bone markers, in particular serum tartrate-resistant acid phosphatase 5b (S-TRACP-5b) and urine osteocalcin. Even two years after fracture, biochemical formation and resorption markers such as serum bone alkaline phosphatase and serum collagen C-telopeptide (S-CTX) are elevated, compared to prefracture period levels.¹³ Scintigraphy also demonstrates hot areas at fracture sites, presumably a result of existing long-term high bone turnover at the fracture site. This is a possible explanation as to why a history of preexisting fracture is an indicator of high risk for a new fracture.¹⁴

Figure 2. An ancient Greek metaphor for the inflammatory, reparative, and remodeling phases of fracture healing.

Pharmaceutical treatment of osteoporosis and its effect on fracture healing

Fractures are common in osteoporotic patients. According to epidemiologic studies, the incidence of fractures of long bones exponentially increases with age, representing a major cause of morbidity and mortality in elderly people.¹⁵ While antiosteoporotic therapies significantly lower the risk of a fracture, almost half of elderly people experience a new fracture in their lifetime.¹⁶ Fracture healing in patients already being treated is therefore a problem of clinical importance. The effect of osteoporotic therapies on fracture healing has been studied experimentally, but the existing clinical studies are rather limited. Osteoporosis treatments are nowadays classified into three groups: anticatabolic, anabolic,¹⁷ and dual action (anabolic and anticatabolic, mainly represented by strontium ranelate) categories. Each group of antiosteoporotic therapy has different mechanisms of action on bone cells, but it is true that most of them also influence other bone cells, either directly or indirectly, via the coupling phenomenon.¹⁸ Based on the characteristics of fracture repair and the type of fixation, an antiosteoporotic drug may be chosen to accelerate fracture healing, to assist the recovery of the patient, or to avoid any fracture complications. An evaluation of the complication rates after fracture fixation of the proximal femur shows that patients with suspected osteoporosis have an increased rate of refracture or fixation failure.¹⁹ While preclinical studies support the fact that pharmacological agents can augment fracture union,²⁰ it is not clear if this translates into clinical benefit and offers patients with osteoporosis or at high risk of delayed union a better chance of fracture healing.²¹ To ensure that antiosteoporotic agents have a beneficial effect on fracture healing (especially for diaphyseal and metaphyseal fractures of long bones), biomechanical, histologic, and radiographic differences must be shown between individual patients and nontreated injured persons.¹⁸ This means that prospective clinical studies should be designed to demonstrate a positive medicinal effect.

_ Preclinical evaluation of the effect of osteoporosis therapies
A reduced capacity in osteoporosis to heal a fracture has been shown in several animal models. Experimental data show a 40% reduction in the cross-sectional area of fracture callus as well as a 23% reduction in bone mineral density (BMD) in healing ovariectomized rat femoral fractures.²² Mechanical properties of callus are impaired, and the fixation stability of the implants deteriorates dramatically.²³ Some drugs, in particular corticosteroids, decrease the healing process remarkably.¹¹ It would be of great interest to know the effect of osteoporosis therapies on the fracture healing process. For convenience, both preclinical and clinical data will be presented.

_ Clinical studies and experience of the effect of bisphosphonate treatment on fracture healing
Bisphosphonates have a marked inhibitory effect on osteoclasts and bone resorption, especially in the case of high bone turnover conditions. The effect of bisphosphonates on fracture healing depends on the type of substance as well as the duration and the prefracture administration dosage. In a canine model of closed, transverse radial fracture treated with alendronate, increased callus formation was found, due to slower callus formation, and no inhibition of bone formation or decrease of callus strength was observed.²⁴ A larger callus with increased bone mineral content was also found in a sheep animal fracture model treated with pamidronate, but again no effect on the mechanical properties of the callus was detected.²⁵ Incadronate given to growing rats with a femoral shaft fracture, which also produced a larger callus, increased stiff- ness and ultimate load of the callus, too.²⁶ A similar effect (larger callus and increased torsional mechanical strength) was also found after the administration of ibandronate in ovariectomized rat.²⁷ Zoledronic acid administered in rats that sustained a closed femoral fracture and that were examined using different methods (nanoindentation,²⁸ histology,²⁹ and biomechanical³⁰ after local application of zoledronic acid) suffered no delay of callus formation and no effect on the mechanical properties of the callus. By the absence of interference with mechanical status, one can speculate that in animal models, different bisphosphonates do no practical harm to the fracture healing outcome, but delay endochondral ossification.³¹

Figure 3. The healing process in a subtrochanteric fracture.

There is a surprising lack of evidence and prospective clinical studies on fracture healing in patients treated with bisphosphonates, especially over a long period of time. One year of alendronate treatment did not alter fracture healing at the distal radius in a small group of postmenopausal osteoporotic women.³² In another small group of patients, one in 9 patients treated with alendronate who had sustained a fracture had a problem with fracture healing.³³ All these 9 patients were found to have histological evidence of severe depression of bone formation. It was speculated from this small amount of evidence that alendronate treatment in osteoporotic patients who had sustained a fracture of the appendicular skeleton does not delay fracture union.³⁴ As it is possible that bisphosphonate treatment may suppress bone turnover and promote microfracture accumulation, it is questionable whether this type of treatment can also facilitate the development of stress fractures.³⁵ Bone microdamage is critical in the understanding of bone quality. Assessment of microdamage is technically difficult, especially in humans. The clinical impact of microdamage accumulation, potentially induced by bone drugs, has been demonstrated in experimental studies, but is still controversial in humans. In clinical practice, orthopedic surgeons with concerns about the depression of bone turnover during the period of fracture healing may wish to stop bisphosphonates in order to avoid impairment of the bone healing process. But on the other hand, initiating antiosteoporotic treatment in untreated people who have suffered a fracture could prevent consequent macrofracture.³⁶

_ Atypical subtrochanteric fractures and bisphosphonates
During the last few years, a series of case reports have drawn our attention to an unusual type of subtrochanteric or diaphyseal femoral fracture,^37-41 especially in alendronate patients. The high number of reported cases in a short period of time suggests that many similar fractures were treated previously by orthopedic surgeons, who either did not notice the association with alendronate treatment or never reported it. All these fracture have some common clinical and radiological features. The majority of the patients received alendronate for a long period of time, some of them had atypical pain in the broken thighmonths before femoral fracture, and someof them were taking additional drugs, commonly corticosteroids.⁴¹ Radiologically, all these fractures are surprisingly almost identical to unusually thick femoral cortices with a transverse fracture line and a cortical peak at the medial distal femoral fragment. Because of the longstanding preexisting femoral pain, some patients were examined and, in the prefracture radiograph, there was a suspicion of a stress fracture of the medial cortex (Figure 3). Scintigraphy in some prefracture cases also revealed a hot spot at the site of the future fracture.⁴⁰ The biggest retrospective controlled study of the atypical fractures³⁷ reports a long prefracture period with alendronate. As this category of fractures is a new scientific finding, more epidemiologic³⁹ and laboratory studies are needed. Suppressed (frozen) bone turnover could be speculated, but high levels of active osteoclasts were detected in one case with bone biopsy at the fracture site.⁴⁰

_ Effect of PTH (1-34) and strontium ranelate on fracture healing
The amino terminal active form of human parathyroid hormone (PTH [1-34], teriparatide) has an anabolic effect on both cortical and trabecular bone. Animal studies on fracture healing suggest that PTH signaling improves the biomechanical properties of fracture callus and accelerates callus formation, endochondral ossification, and bone remodeling.^42,43 Based on these data, PTH (1-34) is likely to be a potent agent for enhancing fracture healing in patients with poor fracture healing potential, such as those with osteoporosis, prolonged steroid use, or recalcitrant nonunion.⁴³ It is also recognized that daily PTH administration is an effective therapy for increasing BMD and preventing fractures in both male and female osteoporosis patients. More recently, a growing body of evidence supports the conclusion that PTH would also be an effective anabolic therapy for the enhancement of bone repair following fracture.⁴² Treatment with PTH results in significant increases in BMD, production of bone matrix proteins, new bone formation, and increased mechanical strength, indicating that PTH can enhance and accelerate normal fracture healing.

Several animal studies have demonstrated that PTH therapy consisting of daily subcutaneous injections during bone repair leads to increased callus volumes and a more rapid return of bone strength. Although no human clinical trial data are yet available, the role of PTH and of teriparatide in fracture healing is currently under investigation. The magnitude of the increase in the animal group treated with teriparatide was found to be two times higher than at the nonosteotomy site.⁴² It is difficult to extrapolate a positive effect to humans, as there is no evidence in humans suffering recent fracture and because the doses administered to animals are several times higher than the human dosage (20 ìg/day). Theoretically, its anabolic effect on bone formation could explain the significant decrease in vertebral fractures observed in clinical studies.

Strontium ranelate was found to stimulate bone formation and inhibit bone resorption.⁴⁴ This dual-action (formation and resorption) medication can also be considered as a possible therapeutic agent for accelerating fracture healing and increasing itsmechanical properties. In an intact, closed femoral fracture male rat model, healing was studied radiologically and histologically. Both studies showed an increase in effect with time.⁴⁵ Local application of strontium salts in implants used in fracture fixation has been suggested for fracture repair promotion.⁴⁶ Prospective studies in humans are necessary to show this healing acceleration also occurs in man.¹⁸ Recently, it was reported that strontium ranelate as well as teriparatide can increase the callus volume in a closed femoral fracture experimental rat model, while callus torsional strength is improved by strontium alone.⁴⁷ However, further studies are necessary to confirm these encouraging results in humans.

_ Effects of estrogen, raloxifene, and vitamin D and its analogues on fracture healing
The effect of estrogens and raloxifene on fracture healing was studied in the ovariectomized closed tibial fracture rat model. It was found that both medications improve fracture healing histologically and mechanically.⁴⁸ Apart from the animal study, there is no evidence for the clinical use of estrogens and raloxifene in fracture healing in humans, especially over a prolonged period of time.

Several animal studies have shown that vitamin D3 treatment promotes both fracture healing and mechanical strength in the callus.⁴⁹ However, no adequate studies on the role of vitamin D and calcium treatment in fracture healing are currently available in humans. One study focused on the healing process in osteoporotic/osteopenic fractures and investigated the potential of an oral calcium and vitamin D3 supplement at mitigating some of the problems associated with the osteoporotic fracture healing process, such as delayed or insufficient healing.⁵⁰

The increase in BMD in the fracture region was interpreted as a positive impact by vitamin D3 and calcium on the fracture healing process, thanks to a higher concentration in the cellular environment of these agents. The supplement potentially facilitates osteoblasts in building Ca2+ and producing callus via an increase in the rate of osteoblast/osteoclast turnover from osteogenic cells. Despite a high concentration of calcium in the animal study, the callus had little bending strength, so it is therefore possible that although vitamin D3 and calcium increase the calcium concentration in the fracture area, it still yields brittle bone.More investigation is necessary, but it seems likely that osteoporotic women might benefit from oral calcium plus vitamin D3 supplementation during the fracture healing process.

Calcitonin is found to promote the cartilaginous phase of fracture healing.⁵¹ However, examination of the innervation of callus reveals an extensive distribution of sensory fibers containing calcitonin gene–related peptide (CGRP), a neuropeptide with potent vasodilatory actions. In a rabbit animal model with a defect of the mandible, there was a positive correlation between the expression and activity of CGRP and nitric oxide synthase (NOS) and fracture healing. It has therefore been speculated that CGRP may promote fracture healing via the regulation of the expression and activity of NOS.⁵²

New strategies for the evaluation of antiosteoporotic treatments are needed

Therapeutic strategies for the prevention and treatment of the nontraumatic fractures, especially those of the appendicular skeleton, must seriously consider the importance of the high incidence of fracture healing delay or failure in the elderly, especially, as well as the increased incidence of refracture after a fracture. Both the disturbance of fracture healing as well as the possibility of fracture reoccurrence at the site of the mechanically immature callus are important for osteoporotic patients, especially those of advanced age. Antiosteoporosis medication enhances the healing process in general, but it is surprising that there is a lack of evidence in prospective clin- ical studies to support this notion. New studies must be designed and performed with better quality methodology¹⁸ to prove the efficacy and safety of antiosteoporotic medication in humans. The extrapolation of positive findings found in experimental studies to human biology is, in many aspects, unsafe. Dosing in experimental studies is different to that in humans, the duration of the fracture process in animals is shorter, and the side effects of drugs in humans and animals are different. Another important point is that prospective clinical studies in osteoporotic patients in the fracture repair or rehabilitation period would be helpful for the orthopedic surgeons who have to look after osteoporotic patients before and following fracture. It is well known that a history of fracture is a major risk factor for future bone injury.¹⁴ Patients with recent trauma remain under orthopedic observation and care for a considerably long period of time (up to 2 years) and may possibly undergo orthopedic intervention to remove implants. Orthopedic surgeons should therefore get seriously involved with osteoporosis and metabolic bone diseases, in general. _

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37. Lenart BA, Neviaser AS, Lyman S, et al. Association of low-energy femoral fractures with prolonged bisphosphonate use: a case control study. Osteoporos Int. 2009;20:1457-1458.
38. Sayed-Noor AS, Sjödén GO. Subtrochanteric displaced insufficiency fracture after long-term alendronate therapy-a case report. Acta Orthop. 2008;79: 565-567.
39. Abrahamsen B, Eiken P, Eastell R. Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate. A registered-based national cohort. J Bone Miner Res. 2009;24:1095-1102.
40. Sayed-Noor AS, Sjödén GO. Case reports: Two femoral insufficiency fractures after long-termalendronate therapy. Clin Orthop Relat Res. 2009;467:1921-1926.
41. Somford MP, Draijer FW, Thomassen BJ, Chavassieux PM, Boivin G, Papapoulos SE. Bilateral fractures of the femur diaphysis in a patient with rheumatoid arthritis on long-term treatment with alendronate: clues to the mechanism of increased bone fragility. J Bone Miner Res. 2009;24:1736-1740.
42. Nozaka K, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Shimada Y. Intermittent administration of human parathyroid hormone enhances bone formation and union at the site of cancellous bone osteotomy in normal and ovariectomized rats. Bone. 2008;42:90-97.
43. Cipriano CA, Issack PS, Shindle L, Werner CM, Helfet DL, Lane JM. Recent advances toward the clinical application of PTH (1-34) in fracture healing. HSS J. 2009;5:149-153.
44. Rizzoli R. A new treatment for post-menopausal osteoporosis: strontiumranelate. J Endocrinol Invest. 2005;28(suppl 8):50-57.
45. Cebosoy O, Tutar E, Kose KC, Baltaci Y, Bagci C. Effect of strontium ranelate on fracture healing in rat tibia. Joint Bone Spine. 2007;74:590-593.
46. Wong KL, Liu WC, Pan HB, et al. Mechanical properties and in vitro response of strontium-containing hydroxyapatite/polyetheretherketone composites. Biomaterials. 2009;30:3810-3817.
47. Habermann B, Olender G, Eberhardt C, Augat P, Kurth AA. Strontium ranelate and teriparatide (PTH 1-34) enhance fracture healing in osteoporotic Sprague- Dawley rats. J Bone Miner Res. 2008;23(suppl 1):S206.
48. Stuermer EK, Sehmisch S, Rack T, et al. Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracturehealing model at the tibia in rat. Langenbecks Arch Surg. 2008 Dec 2. Epub ahead of print.
49. Delgado-Martinez AD, Martinez ME, Carrascal MT, Rodriguez-Avial M, Munuera I. Effect of 25-OH-vitamin D on fracture healing in elderly rats. J Orthop Res. 1998;16:650-653.
50. Doetsch AM, Faber J, Lynnerup N,Watzen I, Bliddal H, Danneskiold-Samsoe B. The effect of calcium and vitamin D3 supplementation on the healing of the proximal humerus fracture: A randomized placebo-controlled study. Calcif Tissue Int. 2004;75:183-188.
51. Lyritis GP, Boscainos PJ. Calcitonin effects on cartilage and fracture healing. J Musculoskel Neuron Interact. 2001;2:137-142.
52. Li Y, Tan Y, Zhang G, Yang B, Zhang J. Effects of calcitonin Gene-Related Peptide on the expression and activity of Nitric Oxide Synthase during mandibular bone healing in rabbits: An Experimental study. J Oral Maxillofac Surg. 2009; 67:273-279.

Keywords: antiosteoporotic treatment; fracture healing; bone remodeling; bisphosphonate; strontium ranelate

1. M. Chandran, Singapore

Manju CHANDRAN, MD, FACP, FACE, CCD
Consultant Endocrinologist, Director
Osteoporosis and Bone Metabolism Unit
Singapore General Hospital
SINGAPORE
(e-mail: manju.chandran@sgh.com.sg)

Though estimating relative risks and lifetime risk of fractures is of value in evaluating the burden of osteoporosis in populations and the effects of intervention strategies, they are less relevant with regard to individual risk assessment. The FRAX® tool computes the 10-year probability of fractures from clinical risk factors with or without the measurement of femoral neck bone mineral density (BMD).

In conclusion, even in this current era of fracture risk assessment using FRAX®, measurement of BMD still plays a very important role in the diagnosis of osteoporosis for fracture prediction (in which case it’s value can be enhanced by combining it with other clinical risk factors) and for the follow-up and management of treated patients.Where facilities for BMD testing are limited, consideration should be given to the judicious and selective use of this important tool, so as to optimally deploy resources and appropriately identify individuals above or below an intervention threshold. _

References

1. Schott AM, Ganne C, Hans D, et al.Which screening strategy using BMD measurements would be most cost effective for hip fracture prevention in elderly women? A decision analysis based on a Markov model. Osteoporos Int. 2007;18; 143-151.
2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: technical report series 843. Geneva, Switzerland: WHO; 1994.
3. Hochbery MC, Ross PD, Black D, et al; Fracture Intervention Trial Research Group. Larger increases in bone mineral density during alendronate therapy are associated with a lower risk of new vertebral fractures in women with postmenopausal osteoporosis. Arthritis Rheum. 1999;42:1246-1254.
4. Bruyere O, Roux C, Detilleux J, et al. Relationship between bone mineral density changes and fracture risk reduction in patients treated with strontium ranelate. J Clin Endocrinol Metab. 2007;92:3076-3081.
5. Bruyere O, Roux C, Badurski J, et al. Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate. Curr Med Res Opin. 2007;23:3041-3045.
6. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures inmen and women. Osteoporos Int. 2007:18:1033-1046.

2. F. S. Hough, South Africa

Stephen HOUGH, MBChB, Hons BSc,
MMed, FCP(SA), MD
Professor of Medicine and Endocrinology
Division of Endocrinology, Department
of Medicine, Stellenbosch University
Tygerberg, 7505, Western Cape
SOUTH AFRICA
(e-mail: fsh@sun.ac.za)

Will the addition of BMD measurements improve identification of those at risk of osteoporotic fractures?

Osteoporosis is a complex syndrome which is best managed when CRFs, a history of prior fracture, and BMD measurements are combined to optimize treatment. The need to determine the importance of different CRFs in a community and to establish local intervention thresholds is emphasized. _

References

1. Kanis JA, Johnell O, Oden A, et al. FRAXTM and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
2. Chen P, Krege JH, Adachi JD, et al. Vertebral fracture status and the World Health Organization risk factors for predicting osteoporotic fracture risk. J Bone Miner Res. 2009;24:495-502.
3. Kanis JA, Oden A, Johnell O, et al. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007;18:1033-1046.
4. Kendler DL, Adachi JD, Josse RG, Slosman DO. Monitoring strontium ranelate therapy in patients with osteoporosis. Osteoporos Int. 2009;20:1101-1106.

3. J. K. Lee, Malaysia

Joon Kiong LEE, MBBS (Mal), FRCS (Edin),
M.S.ORTHO. (Mal), A.M. (Mal)
Orthopaedic and Traumatology
No.923A, Jalan 17/38
46400 Petaling Jaya, Selangor
MALAYSIA
(e-mail: osteoporosis_jklee@yahoo.com)

Osteoporosis is defined in terms of bone mineral density (BMD) and microarchitectural deterioration of bone tissue. BMD measurement can be used in untreated individuals as a diagnostic tool. Dual-energy x-ray absorptiometry (DXA) is the most widely used bone densitometric technique in measuring BMD. It can be used to assess bone mineral content of the whole skeleton as well as of specific sites, including thosemost vulnerable to fracture.¹ In 1994, an expert panel of the World Health Organization (WHO) recommended thresholds for BMD in women to define osteoporosis.² A relatively high Z-score (lower than –2.0) also indicates the possibility of secondary causes.

The use of clinical risk factors together with BMD improves sensitivity of fracture prediction without adverse effects on specificity and provides a mechanism for the effective and efficient delivery of health care to individuals at high risk and the avoidance of unnecessary treatment to others.⁶ There are other clinical uses of BMD measurement which are not possible and cannot be replaced with FRAX®. Therefore, themeasurement of BMD, wherever it is available and accessible, is still very important in managing our patients with osteoporosis. _

References

1. Genant HK, Engelke K, Fuerst T, et al. Noninvasive assessment of bone mineral and structure: state of the art. J Bone Miner Res. 1996;11:707-730.
2. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Technical report series 843. Geneva, Switzerland: World Health Organization; 1994.
3. Marshall D, Johnell O, Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ. 1996;312: 1254-1259.
4. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008;19:399-428.
5. Pickney CS, Arnason JA. Correlation between patient recall of bone densitometry results and subsequent treatment adherence. Osteoporos Int. 2005;16: 1156-1160.
6. Graham J, Ahn C, Hai N, et al. Effect of bone density on vertebral strength and stiffness after percutaneous vertebroplasty. Spine. 2007;32:E505-E511.

4. W. Lems, The Netherlands

Willem F. LEMS, MD, PhD
Rheumatologist, Professor
Department of Rheumatology, 3A61
VU Medical Center, Postbox 7057
1007 MB Amsterdam, THE NETHERLANDS
(e-mail: wf.lems@vumc.nl)

Bone mineral density (BMD) measurement is advocated in elderly patients with clinical risk factors for osteoporotic fractures, such as low body mass index, familiar osteoporosis, the use of glucocorticoids, etc. Usually, in the work-up of patients with (possible) osteoporosis, a dual-energy x-ray absorptiometry (DXA) scan of the lumbar spine and the hips is performed. Suppose that a 61-yearold woman with a height of 165 cm and a body weight of 59 kg—without other obvious causes of (secondary) osteoporosis— has T-scores of –1.8 for the lumbar spine and of –2.6 for the hips. Should you treat her with antiosteoporotic drugs or not? Because the T-score of the hips is lower than –2.5, the diagnostic threshold for osteoporosis, many of our colleagues would start antiosteoporotic treatment, but is that realistic? What is her fracture risk and what is the risk reduction that can be expected, based on the literature? For the first question, the FRAX® scoring system¹ is very helpful: for this patient, the 10-year probability of having a major fracture is 9.9% and her 10-year hip fracture risk is 2.8%. A lot of our colleagues and several patients are probably hesitating about whether their preliminary treatment decision based on low BMD is correct.

1. Measuring BMD gives additional information about future fracture risk, making the risk score more precise. That can easily be seen in the model: low T-scores are associated with slightly higher fracture risk scores for major fractures and for hip fractures, etc.
2. With a DXA measurement at baseline, the possibility of performing repeated measurements after some years to evaluate the effect of (drug) treatment in the individual patient remains;
3. Since modern DXA machines are also equipped with lateral vertebral assessment (LVA), it is possible to perform additional morphometry of vertebrae height in the thoracolumbar spine; and
4. A low BMD measurement can confirm a diagnosis of osteoporosis, which might be important in patients with a high trauma fracture. In contrast, a finding of normal BMD in a patient with a vertebral or nonvertebral fracture may induce hesitation about whether or not antiosteoporotic treatment is indicated. _

References

1. FRAX®: http:www.shef.ac.uk.FRAX/index.htm
2. Watts NB, Ettinger B, LeBoffMS. FRAX facts. J BoneMiner Res. 2009;24:975-979.
3. Kanis JA, McCloskey EV, Johansson H, Ström O, Borgström F, Oden A; National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX. Osteoporos Int. 2008;19:1395-1408.

5. R. Nuti, C. Caffarelli, and S. Gonnelli , Italy

Ranuccio NUTI, MD
Carla CAFFARELLI
Stefano GONNELLI, MD
Professor, Department of Internal Medicine
Endocrine-Metabolic Science and Biochemistry
University of Siena, Policlinico Le Scotte
Viale Bracci 2, 53100 Siena, ITALY
(e-mail: nutir@unisi.it)

For at least two decades, bone mineral density (BMD) has formed the cornerstone not only for the diagnosis of osteoporosis, but also for the assessment of fracture risk and the monitoring of treatment. However, although the risk of fractures approximately doubles for each SD reduction in BMD, there is a growing conviction that assessment with BMD alone captures a minority of the fracture risk. In fact, half or more osteoporosis-related fractures occur in patients with T-scores better than –2.5, which are in the osteopenic or normal range.

In conclusion, the use of FRAX® with BMD increases the performance characteristics of fracture risk assessment compared with the use of CRFs alone. Further studies are needed to define the cost-effectiveness of such a strategy, which on the one hand requires more resources, but on the other improves the budget impact by limiting treatment only to highrisk patients. _

References

1. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
2. Johansson H, Kanis JA, Oden A, Johnell O, McCloskey E. BMD, clinical risk factors and their combination for hip fracture prevention. Osteoporos Int. 2009; 20:1675-1682.
3. Kanis JA, Oden A, Johansson H, Borgström F, Ström O, McCloskey E. FRAX® and its applications to clinical practice. Bone. 2009;44:734-743.
4. McCloskey EV, Johansson H, Oden A, et al. Ten-year fracture probability identifies women who will benefit from clodronate therapy—additional results from a double-blind, placebo-controlled randomised study. Osteoporos Int. 2009;20:811-817.
5. Kanis JA, Johansson H, Oden A, McCloskey EV. Bazedoxifene reduces vertebral and clinical fractures in postmenopausal women at high risk assessed with FRAX®. Bone. 2009;44:1049-1054.

6. M. E. Simões, Portugal

Maria Eugénia C. SIMÕES, MD
Rheumatologist, Osteo-Metabolic Disease Unit
Portuguese Institute of Rheumatology
Apartado 13051, 1050 Lisboa
PORTUGAL
(e-mail: eugenia.simoes@netcabo.pt)

In the last 15 years, our medical rationale for evaluating fracture risk has been bone mineral density (BMD)–based. According to the dual-energy x-ray absorptiometry (DXA) operational definition of osteoporosis, we tended to classify, and therefore to treat, individuals with T-scores lower than –2.5 as osteoporotic and consequently at high risk of fracture. After a while, this approach was demonstrated to be inefficient and inappropriate; a great part of the population classified as being osteopenic would miss out on treatment if medical thinking was based uniquely on DXA. In fact, we now know, thanks to the results of epidemiological studies like the National Osteoporosis Risk Assessment (NORA) study,¹ that in a real population, the majority of fractures develop in individuals classified as osteopenic (partially because this is the real state of the majority of the fracture population).

But, as with other subjects in medicine, not everything is purely black or white…there is a “twilight” zone. Because FRAX® is not perfect, there are some factors that are underweighted by this tool: falls, number of fractures, magnitude and duration of smoking and drinking, vitamin D status, bone remodeling, and vertebral osteoporosis…. And it is for these twilight zone cases that measuring BMD can be useful; for those individuals considered at intermediate risk when calculating FRAX®, for all cases of secondary osteoporosis (this is one area that FRAX® underestimates), probably for everyone above 65 years of age, and whenever the clinician believes that reassessing fracture risk could be useful. In addition, monitoring BMD during osteoporosis treatment is considered a valuable process according the majority of guidelines. We must always remember that there is no guideline, guidance, or tool that should overrule good clinical judgement! _

References

1. Chesnut CH III. Osteoporosis, an underdiagnosed disease. JAMA. 2001;286: 2865-2866.
2. Kanis JA, Johnnel O, Oden A, et al. Risk of hip fracture according to the World Health Organization criteria for osteopenia and osteoporosis. Bone. 2000;27: 585-590.
3. Gennant H, Cooper C, Poor G, Reid I. Interim report and recommendations of a World Health Organization task force on osteoporosis. Osteoporos Int. 1999; 10:259-264.
4. Kanis JA, Borgström F, De Laet C, et al. Assessment of fracture risk. Osteoporos Int. 2005;16:581-589.
5. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al. Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporos Int. 2008; 19:437-447.

7. G. Skarantavos, Greece

Grigoris N. SKARANTAVOS, MD
Rheumatologist Director
1st Orthopedic Clinic University of Athens
Attikon General University Hospital
Haidari, Rimini 1, 12462 GREECE
(e-mail: skarant@hol.gr)

The World Health Organization (WHO) Consensus Conference defines osteoporosis as a condition of bone deterioration in which individuals have “a bone mineral density (BMD) that lies 2.5 standard deviations or more below the average value for young healthy women,”¹ and the Surgeon General’s report adds to this definition increased risk of fracture.² BMD, while associated with fracture risk, is not fully predictive of who will experience a low impact fracture. Large epidemiological studies have shown that BMD accounts for only H60% of the fracture risk³ and have suggested that other “bone quality” parameters may account for why two individuals with similar lifestyles and equivalent BMDs may have different fragility fracture histories. Although measurable decreases in BMD in untreated patients have been associated with increased risk of fragility fracture, areal BMD changes account for less than half of the improvement in fracture risk seen in osteoporotic patients treated with anticatabolic and anabolic agents.⁴

In clinical practice, areal BMD can only be useful in determining if a patient is healthy, osteopenic, or osteoporotic at first visit according to the WHO criteria, but does not answer questions about the patient’s fracture risk and treatment decisions. The FRAX® model is an aid to enhance patient assessment by the integration of clinical risk factors alone and/or in combination with BMD.⁶ Other tools, such as determination of bone turnover, can provide physicians with further valuable information for treatment, when available. _

References

1. World Health Organization. Prevention and management of osteoporosis. WHO technical report series 921. Geneva, Switzerland: World Health Organization; 2003.
2. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285: 785-795.
3. Siris ES, Brenneman SK, Miller PD, et al. Predictive value of low BMD for 1-year fracture outcomes is similar for postmenopausal women ages 50-64 and 65 and Older: results from the National Osteoporosis Risk Assessment (NORA). J Bone Miner Res. 2004;19:1215-1220.
4. Hillier TA, Stone KL, Bauer DC, et al. Evaluating the value of repeat bone mineral density measurement and prediction of fractures in older women: the study of osteoporotic fractures. Arch Intern Med. 2007;167:155-160.
5. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey EV. FRAX™ and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
6. Kanis JA, Oden A, Johansson H, Borgström F, Ström O, McCloskey EV. FRAX® and its applications to clinical practice. Bone. 2009:44:734-743.

8. S. Waikakul, Thailand

Saranatra WAIKAKUL, BSc, MD,
FRCOST, FIMS
Professor, 59/2 Soi Charoenjai
Ekamai Road, Wattana
Bangkok 10110, THAILAND
(e-mail: sisvk@mahidol.ac.th)

Identification of population at risk is the most important step in the management of osteoporosis,¹ and bone mineral density (BMD) is just one tool that has been used for the diagnosis of osteoporosis and fracture prediction in the last decade. However, BMD alone might not be a good fracture predictor, as low energy fractures can be found quite often in osteopenia patients with BMDs between –1.5 and –2.5. Furthermore, BMD does not directly determine bone architecture and bone strength, which are the most important factors effecting bone fragility.² Recently, Kanis JA et al presented an algorithm of their fracture risk assessment tool (FRAX®) for the prediction of fracture in men and women with the use of clinical risk factors (CRFs) for fracture with and without the use of femoral neck bone mineral density.³ The clinical risk factors include age (between 40 and 90 years), sex, weight, height, previous fracture in adult life, parent with fractured hip, current smoking, glucocorticoid administration, rheumatoid arthritis, secondary osteoporosis, and consumption of 3 or more units of alcohol per day.

Bone mineral density is not included in the clinical risk factors. However, BMD is still an important investigation point for the diagnosis and planning the management of osteoporosis. In sensitivity analyses, the positive predictive value and number needed to treat were always better for the combination of BMD with CRFs than for either BMD or CRFs alone, across all ages studied (50 to 70 years).⁴ When using FRAX® in a relatively young population—50 to 55 years old— the probability of fracture doses not change much, whether BMD is used or not. On the other hand, in an older population aged between 80 to 85 years old, low BMD can increase the probability of fracture by more than 7%, which may affect the clinical outcome.⁵ In patients who have premenopausal or secondary osteoporosis, BMD is a useful tool for decision making about treatment and follow-up. With the recent development of bone turnover markers, better monitoring of bone physiology can be carried out during medical treatment of osteoporosis in short-term follow-up.⁶ When the osteoporotic patient information from these three independent tools—clinical risk factors, bone turnover markers, and BMD—is coevaluated, a more accurate probability of fracture in a particular patient can be predicted. For now, BMD is still being used in clinical practice. Patients who have low BMD, ie, T-score <–2.5, usually have lower quality of life than comparable patients with osteopenia and a BMD >–2.5. Most of the research into the management of osteoporosis use pain, BMD, and bone turnovermarkers as outcomemeasurements. Thus, BMD is still a useful tool in the management of osteoporosis._

References

1. Borgström F, Kanis JA. Health economics of osteoporosis. Best Pract Res Clin Endocrinol Metab. 2008;22:885-900.
2. Griffith JF, Genant HK. Bone mass and architecture determination: state of the art. Best Pract Res Clin Endocrinol Metab. 2008;22:737-764.
3. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey E. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19:385-397.
4. Kanis JA, Torgerson D, van Staa T, Watts NB, Yoshimura N. The use of clinical risk factors enhances the performance of BMD in the prediction of hip and osteoporotic fractures in men and women. Osteoporos Int. 2007;18:1033-1046.
5. Fujiwara S, Nakamura T, Orimo H, Kanis JA. Development and application of a Japanese model of the WHO fracture risk assessment tool (FRAX™). Osteoporos Int. 2008;19:429-435.
6. Reginster JY, Collette J, Neuprez A, Zegels B, Deroisy R, Bruyere O. Role of biochemical markers of bone turnover as prognostic indicator of successful osteoporosis therapy. Bone. 2008;42:832-836.

9. C. Horváth, Hungary

Csaba HORVÁTH, MD, PhD, DSc
1st Department of Medicine
Semmelweis University, Koranyi 2/a
H-1083 Budapest, HUNGARY
(e-mail: horcsa@bel1.sote.hu)

Osteoporosis is a collective name for diseases with different pathomechanisms, but with a common clinical output: fragility fracture. Bone fragility is predominantly determined by mineral content, but other bone properties also contribute toward ensuring mechanical competence. The collagen network, microstructure of bone tissue, trabecular network, and size and macrostructure of bones are accepted as important, while the role of elasticity, the osteocyte network (vectorially governing bone turnover), and other contributors to bone quality are only recently becoming clear. As most of these factors cannot be evaluated in daily practice, the link between pathophysiological knowledge and patient management remains a point of controversy. Little is known about the relation of bone properties to widely used clinical risk factors (CRFs), while bonemineral density (BMD) hasmore or less of an impact on bone quality.

In summary, the advent of FRAX® does not mean the end of BMD. In fact, wider use of BMD and nonmass bone testing methods could help FRAX® provide a more precise risk assessment. _
References
1. Kanis JA, Johnell O, Oden A, Johansson H, McCloskey EV. FRAX® and the assessment of fracture probability in men and women from the UK. Osteoporosis Int. 2008;19:385-397.
2. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al. Cost-effective osteoporosis treatment thresholds: the United States perspective. Osteoporosis Int. 2008; 19:437-447.
3. Roux C, Thomas T. Optimal use of FRAX®. Joint Bone Spine. 2009;76:1-3. Editorial.
4. Kanis JA, Johnell O, Oden A, de Laet C, de Terlizzi F. Ten-year probabilities of clinical vertebral fractures according to phalangeal quantitative ultrasound. Osteoporosis Int. 2005;16:1065-1070.

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John A. KANIS, MD
Anders ODÉN, PhD
Helena JOHANSSON
Fredrik BORGSTRÖM, PhD
Oskar STRÖM, PhD
Eugene V. MCCLOSKEY, MD
University of Sheffield Medical
School, Sheffield
UNITED KINGDOM

FRAX® (http://www.shef.ac.uk/FRAX) is a web-based tool, developed by the World Health Organization (WHO) Collaborating Centre for Metabolic Bone Diseases, University of Sheffield (UK), that provides models for assessing fracture probability in men and women. These models, developed from studies in population-based cohorts in Europe, North America, Asia, and Australia, have been extensively validated in additional population-based cohorts with over a million patient years of observation. The algorithms in FRAX® integrate several well-validated clinical risk factors (CRFs)—age, body mass index, and dichotomized variables (eg, prior fracture, smoking, glucocorticoid use, rheumatoid arthritis), with or without bone mineral density (BMD). The models use Poisson regression to derive hazard functions of death and fracture that provide output as 10-year probabilities (hip fracture and major osteoporotic fracture of hip, spine, humerus, or forearm). Models are calibrated to specific countries where the epidemiology of fracture is known. This review addresses the translational practicalities of developing practice guidelines that apply the FRAX® tool at its intended primary-care level. The main applications are to identify patients requiring pharmacological intervention (CRFs alone suffice in some cases) and BMD testing. The practice guidelines that have incorporated FRAX® have set intervention thresholds that vary between countries, since considerations are not only clinical, but also economic. As for the FRAX® tool itself, it remains a work in progress that can only grow in strength, accuracy, and relevance as new databases on multiple other CRFs become available to enrich its algorithms.

Fracture is the main clinical outcome for osteoporosis patients. The ability to accurately predict the risk of fracture in a patient is highly useful for clinicians in order to select the most appropriate treatment and management interventions. Bone mineral density (BMD) is considered as a major determinant of bone strength, and assessment of BMD at the femoral neck using dual-energy x-ray absorptiometry (DXA) is often performed to diagnose osteoporosis. The usual expression of BMD is as a T-score, which represents the number of standard deviations (SDs) by which the BMD of a patient differs from the mean BMD in young, healthy individuals. A patient has a clinical diagnosis of osteoporosis when their T-score is 2.5 SD or more below that of the young adult mean (T score ≤–2.5 SD).¹ Although a T-score ≤–2.5 SD has been shown to accurately predict fracture risk in up to half of women aged over 50 years,² the risk of fractures in osteoporosis is also dependent on many other factors in addition to BMD. Indeed, many patients reported to be at low fracture risk according to their BMD assessment will still go on to experience fractures. Conversely, not all patients with a T-score ≤–2.5 SD will inevitably develop fractures. Treatment intervention thresholds based on only BMD therefore lack sensitivity and estimation of future fracture risk can be improved when other risk factors are taken into consideration.

The use of additional factors in fracture risk assessment is also advantageous in cases where BMD cannot be determined and in helping to decide the necessity of BMD assessments when health-care resources are limited.TheWorldHealth Organization (WHO) has developed statistical models that integrate information from BMD assessments and clinical risk factors for fracture to predict future fracture risk.^1,3 These models can now be used clinically as the FRAX® tool (http: //www.shef.ac.uk/FRAX), which is a computer-based program that calculates the 10-year probability of major osteoporotic fracture (hip, spine, humerus, or wrist) and the 10-year probability of hip fracture for a patient.

The selection of the clinical risk factors used in FRAX® is based on a succession of meta-analyses that aimed to identify factors that are independently associated with osteoporotic fracture risk.¹ These meta-analyses used the primary data obtained from 12 prospective cohort studies and comprised individual participant data from almost 60 000 men and women.^4-18 The use of primary data in the analyses allows the prognostic importance of each risk factor to be determined in a multivariable context, thereby also allowing interactions between risk factors to be analyzed. Ultimately, this improves the accuracy of the statistical models aimed at predicting fracture risk. It should also be noted that the risk of publication bias is absent with the use of primary data. The dichotomous risk factors identified from the meta-analyses included prior fragility fracture, parental history of hip fracture, current smoker, oral glucocorticoids, rheumatoid arthritis, and alcohol consumption greater than 3 units per day. In addition, body mass index (BMI) was identified as a continuous variable associated with fracture risk. All of these variables showed low to moderate heterogeneity between the different population cohorts and all fulfilled the criteria of being risk factors that were “reversible”, with the appropriate interventions. Each variable was investigated for interactions with sex, age, and BMD, as well as for interactions with the variable itself. With the exception of BMI, all variables were associated with fracture risk independently of BMD.

Figure 1. UK FRAX® tool chart.

On the basis of the risk factors identified in these metaanalyses, four statistical models were constructed with the aim of predicting the probability of future fractures.1 These four models comprised the probability of hip fractures and the probability of other osteoporotic fractures, both with and withoutmeasurements for BMD. In eachmodel, fracture was computed as a continuous hazard function using Poisson regression. All significant interactions of risk factors that were observed in the initial meta-analyses were entered into the model. In turn, any of these interactions that were found to be no longer significant for hip fracture and other osteoporotic fractures within the framework of the statistical models were omitted. In addition to the risk factors identified in the metaanalyses, provision was also made in the models for secondary causes of osteoporosis that have been consistently reported to be associated with a significant increase in fracture risk. These included untreated hypogonadism in men and women, inflammatory bowel disease, prolonged immobility, organ transplantation, type 1 diabetes, and thyroid disorders.¹

There is some uncertainty regarding the independence of these factors from BMD, but a conservative judgment was made that fracture risk was linked to a low BMD. However, in the absence of any measurements for BMD, the risk ratio for these other secondary causes was assumed to be similar to that of rheumatoid arthritis. The development of these statistical models forms the basis of the FRAX® tool. In the clinical setting, patient risk factors are easily obtained and can be input into the FRAX® Web site to give the probability of hip and other major osteoporotic fractures (Figure 1). Femoral neck BMD may be entered in addition as a T-score or as an absolute value.

It is important to note that besides clinical risk factors, the risk of fracture also varies with geographical location throughout the world.¹⁹ In order to calibrate the FRAX® models according to global region, algorithms have been developed based on average 10-year hip fracture probability according to epidemiological data for index countries. Global regions have been categorized according to hip fracture risk as follows:
(a) Very high risk (eg, Denmark, Iceland, Norway, Sweden, USA).
(b) High risk (eg, Australia, Austria, Canada, Finland, Germany, Greece, Hungary, Italy, Kuwait, Netherlands, Portugal, Singapore, Switzerland, Taiwan, UK).
(c) Moderate risk (eg, Argentina, China, France, Hungary, Hong Kong, Japan, Spain).
(d) Low risk (eg, Cameroon, Chile, Korea, Turkey, Venezuela). Currently, FRAX® algorithms have been developed for Austria, China, Germany, France, Italy, Japan, Spain, Sweden, Switzerland, Turkey, the United Kingdom, and the USA. Therefore, in situations where there is no FRAX® algorithm specific to a particular country, a representative country should be chosen that is similar in terms of fracture risk.

Since its launch, the FRAX® tool has been extensively used and its Web site receives an average of 55 000 hits each day. One of the clear uses of FRAX® is the evaluation of the need for treatment intervention among osteoporosis patients in order to minimalize the future risk of fractures. Despite its advantages, FRAX® does have some limitations, which must be borne in mind along when using it in the clinic. Furthermore, the development of algorithms that predict the future risk of osteoporotic fractures needs to be accommodated by the construction of new clinical guidelines. The remainder of this review focuses on the applications and constraints of FRAX® and also on the new challenges that this tool has brought to clinical guidelines for the management osteoporosis patients.

Evaluation of patients for fracture risk

The clinical guidelines for the management of osteoporosis in most countries are currently based on an opportunistic approach where certain clinical risk factors for fracture suggest the possible diagnosis of osteoporosis.^20-26 The presence of these risk factors in a given patient is an indication for BMD assessment using DXA. Following this, treatment intervention is considered for patients with BMD values that are within the range of osteoporosis, as defined by the WHO (ie, T-score ≤–2.5 SD).¹ Treatment is also recommended for women with a previous history of osteoporotic fracture, without necessarily the need for BMD assessment. With these clinical guidelines, the threshold for treatment intervention is largely dependent on the value of a patient’s BMD.¹ However, several of the risk factors that indicate the need for BMD assessment do in themselves contribute independently to fracture risk.27 For example, at age 80 years, the 10-year probability of hip fracture is around 12% in women with a T-score of –2.5 SD, whereas, at age 50 years, the probability is only 2% for the women with the same T-score (Figure 2).^28,29 Similarly, the 10-year probability for any major osteoporotic fracture (hip, forearm, shoulder, or clinical spine fracture) in women with a T-score of -2.5 SD ranges from 11% at the age of 50 years to 26% at the age of 80 years.²⁹ These observations demonstrate that the age of a patient has a marked impact on the risk of osteoporotic fracture and that fracture risk can be more accurately assessed from age and BMD than by BMD alone. Similar observations were also noted for the other clinical risk factors identified for use in the FRAX® model that all have an impact independent from BMD on the future risk of fracture (Figure 3, page 36). The incorporation of these factors into the FRAX tool provides a means by which the future probability of fracture for patients can be predicted with more accuracy than with the use of BMD assessments alone.

Figure 2. Probability of hip fracture in Swedish women.

Limitations of FRAX®in clinical evaluations

FRAX® has been primarily designed for use in most countries by primary-care physicians, who have relatively little expert knowledge in the management of patients with osteoporosis.

Figure 3. Effect of clinical risk factors on osteoporotic fracture risk.

However, the FRAX® tool is not a substitute for a detailed clinical evaluation and physicians must be aware of its limitations when they interpret results in the clinic. Many of the risk factors used in FRAX®, such as cigarette smoking, alcohol consumption, and use of glucocorticoids, are dose dependent.^30-32 For these, FRAX® uses risk ratios based on an average dose. Similarly, the risk of fracture increases with the number of prior fractures,^33,34 and a previous vertebral fracture is a particularly strong risk factor. Due to a lack of substantial clinical data, the clinician should also be aware that several risk factors for fracture have not been included in the FRAX® algorithm. These include factors such as biochemical markers of bone turnover, risk of falls, and previous pharmacological treatment. In the clinic, this information may also need to be taken into account if necessary.

The FRAX® tool allows the entry of several secondary causes of osteoporosis as risk factors for fracture. With respect to these secondary risk factors, the current evidence is unclear regarding the proportion of risk that they carry compared with BMD. Because of this, it is conservatively assumed that they all mediate fracture risk as a result of low BMD and that they are all left unweighted when entered into FRAX®.³⁵ Another secondary cause of osteoporosis is rheumatoid arthritis. However, it has been established that rheumatoid arthritis carries a fracture risk independent to that provided by BMD,³⁶ and this factor is therefore weighted accordingly in FRAX®. As mentioned above, when no BMD data is entered, the other secondary risk factors for osteoporosis are presumed to increase fracture risk in a manner similar to that of patients with rheumatoid arthritis.

Due to the large amount of clinical data currently available for BMD at the femoral neck, FRAX® is only compatible with BMD measurements from this site. The risk of fracture associated with BMD measurements from the femoral neck is the same in men and women at any given age.³⁷ One convenience of this is that, in accordance with current recommendations, the T-score can be obtained from a single reference standard, the National Health and Nutrition Examination Survey (NHANES) database for female Caucasians aged 20-29 years.^1,38 However, it is important to consider that a range of other bone assessments also provide pertinent information concerning fracture risk.¹ These include biochemical indices of bone turnover,³⁹ quantitative ultrasound or computed tomography assessments,^40,41 and BMD measurements from other parts of the skeleton.⁴² Although the data from these assessments is too sparse for a meta-analysis of fracture risk that could be used in FRAX®, they should be incorporated into future risk-assessment tools when more clinical information becomes available.

Figure 4. Algorithm for the assessment and management of individuals at risk of fracture.

In summary, the present model of FRAX® is able to enhance the assessment of osteoporosis patients through the integration of clinical risk factors with or without BMD measurements. Nevertheless, clinicians should not consider the FRAX® tool as the ultimate means of assessing patients, but rather as a basis of assessment which will improve as more clinical data regarding osteoporotic fracture risk becomes available.

Modifications to clinical guidelines to accommodate FRAX®

The advent of fracture risk prediction algorithms such as FRAX® requires some adjustments to current clinical practice guidelines in terms of thresholds for BMD assessment and treatment intervention. In the United Kingdom, some changes have been introduced by the National Osteoporosis Guideline Group (NOGG), and previous opportunistic strategies to identify cases of osteoporosis are now incorporating a probability- based assessment of patients.⁴³ The clinical risk factors for fracture that are now included in the NOGG guidelines are the same as those used in FRAX® with the addition of a BMI less than 19 kg/m2.

The general procedure for managing a patient presenting to the clinic is illustrated in Figure 4.¹ Patient management starts with an initial assessment of fracture probability based on age, sex, BMI, and clinical risk factors. The NOGG management strategy classifies patients as being at high, medium, or low risk of future fractures. With the use of the FRAX® tool, this categorization of patients is based on 10-year probabilities of osteoporotic fracture for women aged 50 to 80 years (Table I). In patients considered to be at high risk of future fracture, treatment is recommended, irrespective of BMD. For example, as with previous guidelines,^20-26 the NOGG considers that women aged over 50 years with previous fractures should have treatment interventions without having to have BMD assessment.⁴³ Based on the FRAX® model, the treatment intervention threshold in the UK has been set to the equivalent to that of the 10-year probability of future fracture in women over the age of 50 years with prior osteoporotic fracture, but whose BMD is unknown. As can be seen in Figure 5, this treatment intervention threshold increases progressively with age. This is because age is an important independent determinant of fracture risk, and this was not accounted for in the source guidelines. Compared with women of equivalent fracture risk, treatment interventions in men are largely similar in their efficacy,⁴⁴ and therefore the same intervention threshold applies to men. It is also important to note that, if the resources are available, many clinicians would also perform a BMD test to gain additional information, such as a baseline measure to evaluate response to treatment. In patients considered to be at low risk (Figure 4), the probability of future fracture risk will be so low that a decision not to treat can be made without BMD assessments. An example of such a patient may be a woman at menopause with average BMI (24 kg/m2) with weak or no clinical risk factors, according to the Royal College of Physicians and European guidelines.^20-25 The FRAX® 10-year probabilities of amajor fracture and hip fracture that exclude such women are shown in Table I for women with an average BMI.

Table I. Range of probabilities for BMD testing.

Figure 5. Management chart for osteoporosis.

The proportion of patients considered to be at intermediate risk (Figure 4) will vary between different countries and depends partly on available resources. It is in this group of patients that a BMD evaluation could be potentially useful in order to further assess future risk of fracture. The NOGG has included 10-year probabilities of future fractures that represent upper and lower thresholds for BMD assessment across a range of different ages over 50 years (Figure 5). Patients above the upper probability threshold are recommended for treatment intervention regardless of their BMD. This threshold prevents a patient classified as being at high risk on the basis of clinical risk factors being reclassified as low risk due to information gleaned from BMD assessments.10 For patients below the lower assessment threshold, neither treatment nor BMD evaluation is considered necessary. This threshold has been seen set to exclude a requirement for BMD testing in patients who have minimal risk of future fractures. In the United Kingdom, the upper assessment threshold has been arbitrarily set at 1.2 times the intervention threshold and determines the number of patients who would be eligible for BMD testing.⁴⁵ Excluding patients with a previous history of osteoporotic fracture, these assessment thresholds imply that, depending on their age, 15% to 30% of patients should undergo BMD assessment.⁴³ Assessing this proportion of the population presenting at the clinic makes the most of the predictive power of BMD measurements, especially with respect to hip fracture.¹⁰

In the light of these recommendations for treatment intervention and BMD assessment, the NOGG has summarized the following proposals for patient management:⁴³

1. Postmenopausal women with a previous history of osteoporotic fracture should be considered for treatment. BMD measurement may sometimes be appropriate for these patients, particularly in younger postmenopausal women. Men with a history of osteoporotic fracture should be referred for BMD assessment.

2. Men aged 50 years or more and all postmenopausal women with aWHO risk factoror a BMI <19 kg/m² should have their future probability of fracture evaluated using the FRAX® tool without measurement of BMD.

3. Individuals with probabilities of a major osteoporotic fracture below the lower assessment threshold shown in Figure 5 can be reassured. A further evaluation using FRAX® is recommended in 5 years or less, depending on the clinical context.

4. Individuals with probabilities of a major osteoporotic fracture above the upper assessment threshold given in Figure 5 or with probabilities of a hip fracture above the upper limit in Table I can be treated without BMD testing.

5. Individuals with probabilities of a major osteoporotic fracture within the limits of the assessment thresholds given in Figure 5 and with probabilities of a hip fracture below the upper limit in Table I should have a BMD test, and probabilities for future fracture risk should be recalculated with FRAX®. If the recalculated probabilities exceed the treatment threshold, treatment intervention should be considered.Where probabilities fall below the treatment threshold, a further assessment is recommended in 5 years or less, depending on the clinical context.

If the clinician has no access to computer facilities, the above guidelines can be broadly followed using simplified paper charts that summarize management decisions on the basis of clinical risk factors and age.⁴⁶

The integration of a probability-based assessment of future fracture risk using FRAX® is currently being introduced into clinical guidelines for other countries.^47-51 The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) guidelines now apply the same treatment intervention and assessment thresholds (Figure 5).⁵² However, one difference of the ESCEO guidelines is that BMD measurements are recommended for all patients with future fracture probabilities above the lower assessment threshold. The Japanese Society for Bone and Mineral Research defines a diagnosis of osteoporosis requiring treatment as a BMD less than 70% of the young adult mean (YAM) and less than 80% of the YAM for patients with previous fracture.⁴⁵ In order to integrate the FRAX® algorithm into Japanese guidelines, T-score equivalents to 70% and 80% of YAM BMD for Japanese people were used.⁵³

Using the NHANES III reference for BMD at the femoral neck in Caucasian women aged 20-29 years, these T-scores were –2.7 SD and –1.8 SD, respectively.⁵⁴ With these data, the treatment intervention thresholds based on 10-year probabilities of future fractures were highly concordant with the intervention thresholds developed for the UK and Europe (Figure 5).

Conclusions

The development of the FRAX® tool enables physicians working in primary health care to calculate the future risk of osteoporotic fractures in patients through the integration of a range of clinical risk factors with or without BMD measurements. This improves the sensitivity of future fracture risk assessments based on BMD measurements alone. The incorporation of the FRAX® tool into practice guidelines around the world provides an updated means of categorizing patients requiring treatment for osteoporosis and/or BMD assessments. Nevertheless, the FRAX® tool should not replace detailed clinical evaluation, and additional clinical factors that are not currently included in the FRAX® models may need to be considered by the physician, if necessary. In this regard, FRAX® is an evolving body of work that will be constantly updated to improve its outreach and relevance as new data on epidemiology and clinical risk factors are available.

_

References

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Pierre J. MARIE, PhD
Inserm U606 and
University of Paris Diderot
Lariboisière Hospital
Paris, FRANCE

by P. J . Marie, France

Bone remodeling, a process by which bone resorption by osteoclasts is followed by bone formation by osteoblasts, is an essential physiological process regulating bone mass and strength. During growth, bone formation exceeds bone resorption, resulting in bone expansion. In the young adult, bone resorption is balanced by bone formation, resulting in maintenance of bone mass. The cellular mechanisms underlying the age-related alterations in bone resorption and formation are now better known. With aging, bone formation decreases due to reduction in osteoblast number, activity, and life span, whereas bone resorption increases as a result of sex hormone deprivation. These two mechanisms contribute to the decreased bone mass and increased risk of fractures seen in the aging population. Current effective antiresorbing drugs reduce bone remodeling in osteoporotic subjects. An ideal way to prevent age-related bone loss would be not only to reduce bone resorption, but also to promote bone formation. There is therefore an important need to develop therapeutic strategies capable of promoting bone formation in osteoporotic subjects. Current research efforts are focusing on strategies to target signaling pathways that positively control bone formation and bone mass. This may lead to the development of novel therapeutic approaches that promote osteoblastogenesis to counteract the defective bone formation and bone loss related to aging.

The skeleton is a unique tissue providing support and mineral balance for the organism. It is formed during growth and is maintained during adult life by continual renewal of the matrix, a process called bone remodeling. Bone remodeling is ensured by two cell types: osteoclasts, which resorb the calcified bone matrix, and osteoblasts, which are responsible for new bone matrix synthesis. During growth, bone formation exceeds bone resorption, resulting in bone expansion. In the young adult, bone resorption is balanced by bone formation, resulting in maintenance of bone mass. With aging and after the menopause, an imbalance in bone resorption relative to formation results in negative bone balance at the tissue level. This may lead to osteoporosis, a common skeletal disease characterized by reduced bone mass, deterioration of bone microarchitecture, and increased susceptibility to fractures.¹ The causes of increased bone resorption relative to bone formation in women after the menopause are now better known (Figure 1). Estrogen deficiency in perimenopausal women (and to a lesser extent, the decline in testosterone levels in men) results in accelerated bone remodeling with bone resorption exceeding bone formation. This leads to an increased number of bone remodeling units, perforation of trabeculae, endocortical erosion (responsible for trabecular disconnection), alteration of trabecular microarchitecture, and reduced bone strength.^2,3 Several mechanisms are involved in the acceleration of the bone remodeling occurring in estrogen deficiency, including increased cytokine production by monocytes, lymphocytes, and osteoblast/stromal cells in the bone microenvironment, as well as an increased receptor activated nuclear factor-êB ligand (RANKL)/osteoprote-gerin ratio that determines osteoclast differentiation.^2,3 Although the increased bone resorption activity associated with the menopause is related to increased bone formation due to the coupling phenomenon, bone formation remains insufficient to compensate for the increased bone resorbing activity (Figure 1). This is a key issue when considering the prevention and treatment of age-related bone loss, since once trabeculae are perforated, it is almost impossible to replace the missing trabeculae within the bone marrow and to rebuild appropriate connections with other trabeculae.

Figure 1. Age-related alteration in bone mass.

Age-related defective bone formation

Bone formation is a complex process involving the commitment of osteoprogenitor cells, their differentiation into preosteoblasts, and mature osteoblasts, whose function it is to synthesize bone matrix that becomes progressively mineralized. Osteoblast commitment, differentiation, and function are all governed by several transcription factors, resulting in the expression of phenotypic genes and the acquisition of the osteoblast phenotype.⁴ The sequence of osteogenic differentiation is characterized by the expression of alkaline phosphatase and the synthesis and deposition of type I collagen and bone matrix proteins, followed by the onset of mineralization. At the end of bone formation, most osteoblasts become flattened lining cells, some become osteocytes, and others undergo apoptosis. A fraction of osteoblasts also die by apoptosis, a process that directly affects osteoblast life span and the duration of the bone formation phase.⁵ It has been established from animal models and human metabolic bone diseases that bone formation is more dependent on osteoblast number, which can be expanded, than on osteoblast activity, which is physiologically limited.⁶

Aging is associated with decreased bone formation relative to bone resorption (Figure 1). There are two major causes that underlie the relative, age-related alteration in bone formation. As mentioned above, bone resorption increases as a result of hormone deprivation in the perimenopausal years. The coupling mechanism during bone remodeling results in increased bone formation, as reflected, for example, by the increase in bone remodeling markers occurring at menopause.³ However, the increased bone formation cannot compensate for the increased resorption, and this imbalance results in bone loss after menopause. Several mechanisms can be involved in the defective bone formation relative to bone resorption in estrogen deficiency. First, the osteoblast capacity of forming bone is limited, as evaluated by the mineral apposition rate, and this limited capacity to form bone matrix by osteoblasts is not increased in estrogen deficiency. Second, although the proliferative capacity of osteoblastic cells is increased by estrogen deficiency,^7,8 most probably in response to the local release of growth factors from bone, this is not sufficient to compensate for the increase in bone resorption. A third mechanism underlying the relative lack of bone formation in estrogen deficiency is the alteration of osteoblast life span.⁵ Estrogens prevent osteoblast apoptosis, and estrogen deficiency results in increased osteoblast apoptosis that leads to a decrease in the duration of the bone formation phase. The decreased osteoblast life span does not allow bone to compensate for the increased bone resorbing activity of osteoclasts.

Figure 2. Main mechanisms involved in age-related defective bone formation.

Age-related bone loss is associated with a second phenomenon, characterized by a slow, continuous decrease in bone forming activity, independent of sex hormone deficiency (Figure 1). This decreased bone forming activity that occurs with aging was first documented in humans as the decline in the amount of bone formed by osteoblasts in each remodeling unit.⁹ Although this slow decrease in bone matrix formed does not lead to perforation of trabeculae, the effect results in thinning of the bone trabeculae, increased trabecular separation, and decreased cortical thickness with age.³ This is an important and underestimated mechanism that contributes to the deterioration of bone microarchitecture and strength associated with fractures in osteoporotic subjects.^10,11

_ Cellular causes of age-related decrease in bone formation
The development of appropriate therapeutic strategies in osteoporosis requires a better understanding of the mechanisms underlying defective bone formation occurring with aging and the menopause. Multiple mechanisms are believed to contribute to the age-related decline in bone formation (Figure 2). It is well known that mesenchymal stromal cells within the bone marrow are able to differentiate into osteoblasts or adipocytes under stimulation by hormonal or local factors, a process called cell plasticity. It has been found that the decreased osteoblastogenesis that occurs with aging may result from preferential differentiation of mesenchymal stromal cells into adipocytes, as a result of increased lipid oxidation causing oxidative stress and activation of the transcription factor peroxisome proliferator-activated receptor gamma 2 (PPAR-γ2) that governs adipocyte differentiation.¹² Pharmacological inactivation of PPAR-γ2 was consistently found to increase osteoblast differentiation and bone formation in mice.¹³

A second mechanism that might contribute to defective bone formation with aging is a decrease in the preosteoblastic cell proliferative capacity.¹⁴ This decrease in cell proliferative capacity is likely to contribute to the age-related decline in osteoblast number in humans.¹⁵ Another important possible mechanism is the age-related intrinsic decrease in osteoblast function, possibly related to local decreases in the production of anabolic factors such as insulin-like growth factor 1 (IGF-1) or transforming growth factor β (TGF-β).¹⁶ Another like- ly causative mechanism is the decreased maximal life span and accelerated senescence of bone marrow stromal cells with aging. This phenomenon may be linked to the age-related increase in oxidative stress in bone¹² or to the increased local cytokine production occurring in bone after the menopause.³ All these pathogenic mechanisms may concur to decrease osteoblast number and function and contribute to age-related decline in bone formation relative to bone resorption (Figure 2).

Besides these intrinsic causes, several exogenous factors may be involved in defective age-related osteoblastogenesis. One well-known extrinsic factor that may alter osteoblast differentiation is the progressive decline in physical activity in aged subjects. Decreased mechanical strain is known to reduce osteogenic differentiation and to increase adipogenic differentiation of mesenchymal stromal cells, presumably by changes in the local production of growth factors and Wnt signaling.^17,18 Thus, it is likely that the reduced physical activity that occurs with age reduces bone formation. Other important exogenous factors that may contribute to defective osteoblastogenesis in the aging population include insufficient protein intake,¹⁹ excess alcohol and tobacco consumption, as well as medications, such as long-term glucocorticoid treatment.²⁰ It is thus likely that the alterations in osteoblastogenesis and the resulting decline in bone formation that occurs with aging result from multiple intrinsic and extrinsic causes.

Promoting bone formation: an enduring therapeutic challenge in osteoporosis

Given the fact that estrogen deficiency results in excessive bone resorption relative to bone formation, pharmacological compounds that decrease bone resorption are efficient at treating osteoporosis.³ Bisphosphonates are known to act by reducing bone remodeling (both resorption and formation), which leads to the prevention of bone loss and to a reduction in fracture incidence in osteoporosis. Denosumab, a fully human monoclonal antibody to RANKL that blocks its binding to receptor activated nuclear factor-êB and hence osteoclast differentiation, was recently shown to strongly reduce the risk of fractures in women with osteoporosis.21 Although efficient at decreasing bone remodeling activity, the long-term effects of bisphosphonates or denosumab on bone properties remain unknown.

Since age-related bone loss is associated with insufficient bone formation relative to bone resorption, a major advance in the therapeutic field would be to promote bone formation while reducing bone resorption. In this context, strontium ranelate was found to act by dissociating bone resorption and bone formation in vitro. A number of studies have shown that strontium ranelate activates osteoblast replication, differentiation, activity, and survival and reduces osteoclast function and survival.²² Accordingly, this drug was found to increase the mineral apposition rate, to improve trabecular microarchitecture, and to reduce fracture risk in osteoporotic subjects.^23-25 This compound thus offers an ideal way of favoring bone formation without increasing bone resorption in age-related bone loss.

An enduring challenge in the prevention or treatment of agerelated bone loss is whether one should prevent or protect the age-related decrease in bone formation. Up to now, the number of anabolic agents that promote osteoblastogenesis has been very limited. Nature has provided us with some physiological tools to promote bone formation. For example, bone morphogenetic proteins (BMPs) are natural anabolic molecules that physiologically promote osteoblast differentiation in vitro and in vivo.²⁵ However, BMPs can only be used as therapeutic agents for local bone repair because of their short half-life and possible side effects on nonskeletal stem cell development. Other natural skeletal growth factors such as IGF-1 or TGF-β have been shown to promote bone formation and reduce bone loss in experimental models of osteoporosis.^26,27 However, these growth factors cannot be used easily in clinics because of their possible modulation of bone resorption as well as side effects. Two decades ago, fluoride, a mitogenic agent for osteoblastic cells, was tested in osteoporosis. Unfortunately, although fluoride is effective in increasing osteoblast replication in osteoporosis,²⁸ osteoblast function is altered with fluoride treatment, which failed to improve bone strength.²⁹ Finally, some statins have been shown to promote bone formation in experimental studies in animals.³⁰ However, there is still no evidence for a clear anabolic effect on bone for these agents in humans.

A major step forward was the finding that, in contrast to continuous treatment, intermittent parathyroid hormone (PTH) increases bone formation in osteoporotic patients.³¹ At the cellular level, PTH acts on osteoblasts by activating protein kinase A (PKA), which phosphorylates the osteoblast transcription factor Runx2, which in turn upregulates the expression of osteoblast genes. Additionally, intermittent PTH activates extracellular signal-regulated kinase 1/2 (ERK1/2), mitogen-activated protein kinase (MAPK), and phosphoinositide 3-kinase signaling, which upregulate osteoblast proliferation, differentiation, and survival (Figure 3, page 14). Furthermore, IGF-1, TGF-β, and fibroblast growth factor expression is upregulated by intermittent PTH, resulting in increased osteogenesis.³² All these mechanisms contribute to increase the recruitment of osteoblast progenitors and to decrease osteoblast apoptosis, resulting in increased bone formation relative to bone resorption.

At the tissue level, the increased bone formation induced by PTH (1-34) or (1-84) results in increased trabecular bone mass and cortical thickness, leading to a marked reduction in fracture risk in osteoporotic patients.^31,33 This finding emphasizes the point that anabolic treatments may be more effective than antiresorbing drugs in the maintenance of bone quality and quantity in osteoporosis. Although the development of intermittent PTH as an anabolic agent is a major advance in the treatment of osteoporosis, this treatment has some limitations linked to its short half-life and cost. Alternatively, the use of an oral calcilytic molecule that blocks the parathyroid cell calcium receptor, thus stimulating the endogenous release of PTH, may prove to be useful for promoting bone formation in osteopenic disorders.³⁴

Figure 3. Main signaling pathways involved in the anabolic effect of PTH on bone.

_ Therapeutic perspectives in promoting bone formation
As emphasized above, there is still a need to develop efficient and safe drugs that are able to promote bone formation in osteoporosis. One possibility is to target theWnt/β-catenin signaling pathway that was found to upregulate osteoblastogenesis, postnatal bone formation, and bone mass in animals and humans.^35-37 How does Wnt signaling control bone formation? It was found that activation of the canonical Wnt/β-catenin pathway promotes osteoblastic cell proliferation and differentiation and reduces adipogenic differentiation from mesenchymal stromal cells through modulation of Runx2 and PPAR-γ2. Additionally,Wnt signaling promotes osteoblast survival (Figure 4). These effects, in addition toexisting crosstalks betweenWnt, BMP-2, and PTH signaling, contribute to the positive effects ofWnt signaling on osteoblastogenesis and bone mass.^35-37 Interestingly, mechanical loading upregulates Wnt signaling and prevents adipogenic differentiation in mesenchymal stem cells.³⁸ Moreover, attenuation of Wnt/β-catenin signaling contributes to age-related bone loss in mice,³⁹ suggesting that the combination of reduced β-catenin signaling and mechanical stimulation may be involved in age-related decline of bone formation in humans.

Figure 4. The canonical Wnt signaling pathway and control of bone formation.

Recent data have challenged the role of low-density lipoprotein receptor–related protein 5 (LRP-5) in the control of bone formation. Yadav et al⁴⁰ showed that LRP-5 may not play a major role in osteoblast function, but rather that bone mass is regulated by a β-catenin- and Wnt-independent effect of LRP-5 deletion on serotonin secretion from the gut. If confirmed, this discovery may lead to novel therapeutic approaches aimed at antagonizing serotonin synthesis in the gut and/or serotonin action on osteoblasts. Nevertheless, the fact remains that Wnt signaling in the bone microenvironment is likely to play a role in the control of bone mass.⁴¹ The important role of Wnt signaling in the control of bone mass suggests that this pathway may be a potential therapeutic target in osteoporosis. According to this concept, activation of canonical Wnt signaling using glycogen synthase kinase 3 inhibitors were shown to promote bone formation and to prevent bone loss in aged or ovariectomized osteopenic mice.^42,43 However, the therapeutic use of Wnt signaling agonists in clinical settings is limited due to the potential activation of cancer cells. Future research is needed to determine whether pharmacological inhibition of natural antagonists of Wnt signaling, such as Frizzled or Dkk1, results in safe activation of Wnt signaling in bone. Alternatively, noncanonical Wnt signaling, which has been shown to promote bone formation,⁴⁴ may be another target for developing new anabolic therapeutic approaches in osteopenic disorders.

Figure 5. Mode of action of sclerostin on osteoblastogenesis.

Recent studies have opened a new area of translational research based on the clinical observation that the loss of function of sclerostin, the product of the SOST gene, results in increased bone mass.^45,46 Sclerostin is produced by osteocytes and is a potent inhibitor of bone formation. It does this by antagonizing LRP-5 receptor signaling,Wnt signaling, and bone formation (Figure 5). Interestingly, sclerostin expression is negatively regulated by loading⁴⁷ and PTH,⁴⁸ suggesting that it may be a physiological modulator of bone formation. These findings led to the exciting concept that targeting sclerostin may lead to increased bone formation and bone mass in vivo. Indeed, targeted deletion of the sclerostin gene results in increased bone formation and bone strength in mice.⁴⁹ More interestingly, a sclerostin antibody treatment was shown to increase bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis.⁵⁰ This raises the hope that this novel therapeutic strategy may result in increased bone formation and bone mass in age-related osteopenic disorders.

Conclusion and perspectives

The available data indicate that aging is associated with impaired bone formation relative to bone resorption, indicating that osteoporosis is (also) a disease of bone formation. This has important implications for developing novel, efficient, anabolic therapeutic strategies in age-related bone loss.

Up to now, a limited number of molecules, including teriparatide and, to a lesser extent, strontium ranelate, have been shown to activate bone formation in clinical studies. Ongoing investigations are currently focused on targeting the Wnt signaling pathway that governs osteoblastogenesis and bone formation. It is hoped that this approach will lead to the development of safe anabolic agents that are able to promote bone formation in age-related osteopenic disorders. _

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