How innovations are changing our management of osteoporosis

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

by M. L . Brandi ,

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 ( 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.


1. Johnell O, Kanis JA, Johansson H, et al. Predictive value of BMD for hip and other fractures. J Bone Miner Res. 2005;20:1185-1194.
2. Consensus Development Conference. Diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med. 1993;94:646-650.
3. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis and Therapy. JAMA. 2001;285:785-795.
4. Kanis JA; WHO Scientific Group on the Assessment of Osteoporosis at Primary Health Care Level. Technical Report. WHO Press; 2008.
5. Sornay-Rendu E, Munoz F, Garnero P, et al. Identification of osteopenic women at high risk of fracture: the OFELY Study. J Bone Miner Res. 2002;20: 1929-1943.
6. Sarkar S, Mitlab B, Wong M, et al. Relationships between bone mineral density and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res. 2002;17:1-10.
7. Currey JD. Bones: structure and mechanics. Princeton, NJ: Princeton University Press; 1982:1-436.
8. Villanueva AR, Jaworski ZFG, Hitt O, et al. Cellular-level bone resorption in chronic renal failure and primary hyperparathyroidism. A tetracycline-based evaluation. Calcif Tissue Res. 1970;5:288-304.
9. Meunier P, Aaron J, Edouard C, Vignon G. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. A quantitative study of 84 iliac bone biopsies. Clin Orthop. 1971;80:147-154.
10. Frost HM. Skeletal histomorphometry and biotechnology in 2001. J Histotechnol. 2001;24:89-93.
11. Alexander JM, Bab I, Fish S, et al. Human parathyroid hormone 1-34 reverses bone loss in ovariectomized mice. J Bone Miner Res. 2001;16:1665-1673.
12. Chappard D, Retailleau-Gaborit N, Legrand E, et al. Comparison insight bone measurements by histomorphometry and microCT. J Bone Miner Res. 2005; 20:1177-1184.
13. Genant HK, Jiang Y. Advanced imaging assessment of bone quality. Ann N Y Acad Sci. 2006;1068:410-428.
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.