Controversal question: What is the goal of antiosteoporotic therapy: improve bone health or only prevent fractures?



What is the goal of antiosteoporotic therapy: improve bone health or only prevent fractures?
1. B.-H. Albergaria, Brazil


Ben-Hur ALBERGARIA, MD
Osteoporosis Diagnosis and
Research Center (CEDOES)
Federal University of Espirito Santo
Joao da Silva Abreu 78
Praia do Canto, Vitória
Espirito Santo, 29055 450
BRAZIL
(e-mail: benhur.gaz@terra.com.br)

Osteoporosis is a major public health concern in adults over age 55, resulting in billions of euros/dollars in costs. Over the past 20 years, antiresorptive drugs have been the treatment of choice for osteoporosis. Most of these drugs are derived from the bisphosphonate molecule. Large, placebo-controlled trials generally show that these drugs can indeed increase bone mineral density (BMD) and reduce the risk of vertebral, hip, and other nonvertebral fractures in women with osteoporosis—at least in the short run. The main potential problem is that anticatabolic drugs not only directly—and unnaturally—inhibit osteoclastic bone resorption, they also indirectly inhibit the flip side of the bonebuilding coin, osteoblastic bone formation. What does this mean for bone health in the long term? This is a crucial question, because there is no such thing as short-term treatment with these drugs.

Bone remodeling is a physiological process that replaces old bone with new and preserves the mechanical integrity of the skeleton. During aging, an increase in the rate of remodeling is observed, together with incomplete filling of individual bone remodeling units by osteoblasts, resulting in bone loss and increased risk of fractures. Most treatments for osteoporosis act predominantly by inhibiting the osteoclasts, hence decreasing bone resorption. While clinical trials, generally performed over 3 years, have shown these drugs to be effective in reducing fractures, concerns have been expressed about the potential for long-term suppression of bone remodeling to produce adverse effects on bone strength and fracture risk. Recent reports of atypical fractures in patients receiving bisphosphonates, the most commonly used treatment for osteoporosis, have attracted much attention in this respect.

During the past few years, remarkable advances in molecular biology and genetics have led to deeper understanding of the bone remodeling cycle and the implications with regard to this biologic process for the concept of bone quality. Bone quality is difficult to define and includes aspects such as toughness, strength, resistance to failure, load-bearing capacity, etc. More recent definitions include a number of aspects that are part of a single concept that includes bone intrinsic material properties, bone remodeling, bone microarchitecture, and bone mass.1

This has led to the definition of new therapeutic targets. New drugs have or are being developed, which reduce the risk of fracture in patients with osteoporosis and, at the same time, seek to improve structural and material parameters of bone quality. This ultimately translates into enhanced bone health and long-term efficacy and safety.

Strontium ranelate (SR) is a novel antiosteoporotic agent approved for the treatment of postmenopausal osteoporosis that appears to be going in the right direction. In contrast to other available treatments for osteoporosis, SR induces antiresorption and bone-forming effects. SR reduces bone resorption by decreasing osteoclast differentiation and activity, and stimulates bone formation by increasing replication of preosteoblast cells, leading to increased matrix synthesis. It is suggested that strontium ranelate exerts its dual mechanism of action, at least in part, through the calcium-sensing receptor (CaSR), thereby activating osteoblastic cell replication, and by reducing osteoclastogenesis and bone resorption through the modulation of the RANKL/OPG ratio (= receptor activator of nuclear factor-kappaB ligand/ostopreotegerin ratio).1-3

Preclinical studies have shown that this dual effect results in increased bone mass and improves bone microarchitecture and strength.4 In clinical trials, strontium ranelate reduces vertebral fractures in women with osteopenia, osteoporosis, and severe osteoporosis. Reduction in nonvertebral and hip fractures has been documented in elderly subjects with low femoral density. Histomorphometry and microcomputed tomography (mCT) of bone biopsies from these osteoporotic patients have also highlighted the capacity of SR to promote bone quality and improve bone microarchitecture and strength.5-7

In summary, we are now looking to drugs that are real bone health builders and not only bone hardeners. _

References
1. Seeman E, Delmas PD. Bone quality—the material and structural basis of bone strength and fragility. N Engl J Med. 2006;354:2250-2261.
2. Fonseca JE. Rebalancing bone turnover in favour of formation with strontium ranelate: implications for bone strength. Rheumatology. 2008;47:iv17-iv19.
3. Marie P. Strontium ranelate: a dual mode of action rebalancing bone turnover in favour of bone formation. Curr Opin Rheumatol. 2006;18:S11-S15.
4. Ammann P, Shen V, Robin B,Mauras Y, Bonjour JP, Rizzoli R. Strontiumranelate improves bone resistance by increasing bone mass and improving architecture in intact female rats. J Bone Miner Res. 2004;19:2012-2020.
5. 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(5):459-468.
6. 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. Clin Endocrinol Metab. 2005;90:2816-2822.
7. ArlotME, Jiang Y, Genant HK, et al. Histomorphometric and CT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.

2. A. Çetin, Turkey


Alp ÇETIN, MD
Hacettepe University Medical School
Department of Physical Medicine
and Rehabilitation
Z Kati, 06100 Ankara
TURKEY
(e-mail: acetin@hacettepe.edu.tr)

Antiosteoporotic therapy seeks to prevent fragility fractures and improve bone quality. While the effects of available antifracture treatments on fracture risk have been relatively well established, the effect of many of them on bone quality is relatively unknown. Current agents used in the treatment of osteoporosis are classified either as antiresorptive or bone-forming agents. Thus, their mechanism of action involves only one of the aspects of bone remodeling.

Antiresorptive drugs, particularly bisphosphonates, reduce bone turnover, resulting in an increase in bone mineralization and homogeneity of mineralization. It is suggested that most of the change in bone mineral density induced by antiresorptive agents is a consequence of the increase in mineralization.1 Aging also increases bone mineralization, like antiresorptive therapy, which seems contradictory. Greater mineralization seems to be beneficial, at least up to a certain extent, since excessive mineralization may result in poor bone quality. There is concern that prolonged therapy with bisphosphonates leads to oversuppression of bone remodeling and overmineralization of bone. This results in impaired ability to repair microfractures and increased bone fragility.2 Increased rates of microfractures have been reported in dogs treated with high doses of bisphosphonates.3 Although this finding does not appear to be common among postmenopausal women with osteoporosis treated with bisphosphonates, increased numbers of cases with atypical subtrochanteric femur fractures have been reported under bisphosphonate therapy.4 Awaited data on the material properties of bone and data on the prevention of fractures after long-term bisphosphonate therapy should help clarify this issue. Bone-forming agents, such as parathyroid hormone, reduce fracture risk by stimulating the formation of new bone and increasing bone turnover in favor of bone formation, thus increasing bone mass and improving bone architectural properties, and by reducing fracture rates. Parathyroid hormone also influences bonemineralization, leading to decreased mean mineralization of bone and increased heterogeneity of mineralization.1

Strontium ranelate has been shown to be effective in reducing the risk of vertebral and nonvertebral fractures, including hip, in postmenopausal women with osteoporosis. In contrast to other available treatments for osteoporosis, strontium ranelate induces a dual effect on bone resorption and formation: it increases bone formation and reduces bone resorption, thereby rebalancing bone remodeling in favor of bone formation. In addition to its effect on fracture reduction, strontium ranelate has also been shown to improve bone quality. Bone biopsies obtained from both the SOTI (Spinal Osteoporosis Therapeutic Intervention) and TROPOS (Treatment Of Peripheral OSteoporosis) studies have shown that patients treated with strontium ranelate have a significant increase in trabeculae number, a significant decrease in trabecular separation, and a significant increase in cortical thickness when compared with placebo.5

Although antiresorptive agents such as bisphosphonates also increase mean bone volume and preserve trabecular microarchitecture, they have no effect on cortical bone. On the other hand, bone-forming agents such as strontium ranelate and parathyroid hormone improve trabecular microarchitecture and increase cortical thickness. While strontium ranelate has a positive effect on bone quality, mean bone mineralization remains unchanged, regardless of dosage and duration of treatment.6

In conclusion, the aim of antiosteoporotic therapy should be not only to prevent fractures, but also to improve bone quality. With its unique dualmode of action, strontiumranelate both improves bone health and prevents fractures, and should be considered as a first-choice treatment in the prevention of osteoporotic fractures. _

References
1. Davison KS, Siminoski K, Adachi JD, et al. The effects of antifracture therapies on the components of bone strength: assessment of fracture risk today and in the future. Semin Arthritis Rheum. 2006;36:10-21.
2. Drake MT, Clarke BL, Khosla S. Bisphosphonates mechanism of action and role in clinical practice. Mayo Clin Proc. 2008;83:1032-1045.
3. Chapurlat RD, Arlot M, Burt-Pichat B, et al. Microcrack frequency and bone remodeling in postmenopausal osteoporotic women on long-term bisphosphonates: a bone biopsy study. J Bone Miner Res. 2007;22:1502-1509.
4. Solomon DH, Rekedal L, Cadarette SM. Osteoporosis treatment and adverse events. Curr Opin Rheumatol. 2009;21:363-368.
5. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.
6. Cortet B. Effects of bone anabolic agents on bone ultrastructure. Osteoporos Int. 2009;20:1097-1100.

3. F. Cons-Molina, Mexico


Fidencio CONS-MOLINA, MD
Medical Director
Centro de Investigación
en Artritis y Osteoporosis
Calzada de las Américas # 430
colonia Cuauhtémoc sur
Mexicali BC, México 21200
MEXICO
(e-mail: fidenciocons@prodigy.net.mx)

The goal of any treatment for osteoporosis is to improve bone strength, thereby decreasing fracture risk. In the past several years, a number of therapies have been developed that are effective in achieving this goal, but do not treat bone loss. These therapies, eg, the bisphosphonates, largely target bone remodeling and increase bone mass by significantly suppressing bone resorption and also bone formation, resulting in an overall suppression of bone turnover.

Another approach has been to stimulate bone formation and decrease bone resorption, resulting in an overall stimulation of bone turnover, by using anabolic agents such as parathyroid hormone, fluoride, and, recently, strontium ranelate.

These two diametrically opposed ways of treating osteoporosis (the antiresorptive and the anabolic approaches) have been shown to significantly decrease the risk of fracture by improving the mechanical properties of bone.

Antiresorptive treatment avoids the elimination of bone that should be reabsorbed chiefly because it is no longer functional (ie, bone that is not deformed as usual by mechanical usage, because of the presence of microcracks), though they may protect some mechanically useful elements, too. Among these agents, bisphosphonates have recently been associated with atypical femoral shaft fractures in long-term treated patients, which could be a consequence of excessive overall bone remodeling suppression.1

In addition, bisphosphonates seem to improve some littleknown aspects of the mechanical quality of bone tissue. In some cases, the positive effects eventually produced on bone architecture could be optimized, provided that the drug has a positive interaction with the bone’s mechanostat, and the mechanical stimulation of that system is maintained through adequate control of the patient’s physical activity. The impact of the positive effects of some of these treatments on bone strength does not necessarily correlate with the relatively small improvements (if any) in densitometric bone mass.

The fact that current antiresorptive therapeutic agents produce only modest increases in bone mineral density would appear to stress the need for anabolic strategies, in order to produce larger increases in bone mass and strength. One such strategy is intermittent treatment with anabolic agents such as parathyroid hormone (PTH) and sodium fluoride.

Anabolic treatments enhance bone mass chiefly by inducing peritrabecular apposition, with small evidence (if any) of improvement in bone architectural design. Some of these agents may even deteriorate the mechanical quality of bone material because of crystal contamination (fluoride) or excessive haversianization (PTH).2

Strontium ranelate, for its part, possesses a novel and unique dual mode of action, which rebalances bone turnover in favor of bone formation. It activates the calcium-sensing receptor, and increases the expression of osteoprotegerin, while decreasing RANKL (receptor activator of nuclear factor-kappaB ligand) expression by the osteoblast. In addition, micro-CT analysis of bone biopsies from strontium ranelate–treated patients has evidenced an improvement in intrinsic bone tissue quality, as shown by an increase in trabecular number, a decrease in trabecular separation, a lower structure model index, and an increase in cortical thickness.3

Our growing knowledge of the cellular and molecular pathways involved in the maintenance of bone homeostasis and of the disturbances in these pathways caused by osteoporosis has permitted better understanding of the mechanisms through which antiosteoporotic agents work, and opens up perspectives for the development of ever-more effective therapeutic options. _

Reference
1. Schneider JP. Bisphosphonates and low-impact femoral fractures: current evidence on alendronate-fracture risk. Geriatrics. 2009;64(1):18-23.
2. Roldan E, Ferreti JL. How Do Anti-Osteoporotic Agents Prevent Fractures? Abstracts from the Round Table Held at the XVIth Annual Meeting of the Argentine Association of Osteology and Mineral Metabolism (AAOMM), City of Bahia Blanca, October 29, 1999. Bone. 2000;26(4):393–396.
3. Hamdy NAT. Strontium ranelate improves bone microarchitecture in osteoporosis. Rheumatology. 2009;48(suppl 4):iv9-iv13.

4. T. J. de Villiers, South Africa


Tobie J. DE VILLIERS,
MBChB, Mmed (O&G), MRCOG, FCOG(SA)
Consultant Gynaecologist
Panorama MediClinic and Dept O&G
Stellenbosch University
Cape Town
SOUTH AFRICA
(e-mail: tobie@iafrica.com)

The primary aim of osteoporosis therapy is the prevention of fragility fractures in patients at increased risk of fracture. The ability of a drug to significantly reduce fracture risk is judged by comparison versus placebo over a 3-year period. Such randomized placebo controlled trials have become the golden standard of regulatory approval and prescriber and consumer acceptance. Although this approach was acceptable in the initial registration of new modalities in bone therapeutics, it can be questioned presently for various reasons.

The ethics of conducting placebo-controlled trials are challenged in view of the availability of several approved antifracture agents. This may have a negative impact on the procedure for registration of any new agents. Also, agents registered under the present rules can be questioned regarding the effects on bone health over periods longer than 3 years.

The longest placebo-controlled antifracture data available are for alendronate (4 years) and strontium ranelate (5 years). Even here where the data exceed the compulsory 3 years, interpretation of data beyond 3 years is fraught with statistical pitfalls.1 Thus, smaller numbers in both the placebo and treated groups compound covariates that influence fracture outcomes in not being equally distributed in the remaining population. Also, the removal of subjects from the study after fractures usually involves more patients from the placebo group, which may leave patients at lower risk of fracture in the placebo group. It is unlikely that any antifracture study will extend the placebo arm beyond 5 years. Typically, studies longer than 5 years drop the placebo group and compare fracture incidence over periods of time to detect a trend of sustained efficacy.2 The numbers involved in these extension studies become small and the ability to detect changes in efficacy is compromised.

Why is it important to know the effect of drugs on bone health for periods longer than 3 to 5 years? Clinicians are treating patients for longer than 5 years in view of lack of evidence as to the optimal duration of treatment. Patients are being treated from a younger age because of increased osteoporosis awareness and wider availability of diagnostic tools such as dual x-ray absorptiometry (DXA) and integrated risk factor tools. In the UK, the lower price of generic alendronate has liberalized intervention thresholds. All these factors, combined with an ever-increasing life expectancy, increase the likelihood that patients will be exposed to antifracture drugs for periods exceeding 5 years.

The possibility of sustained long-term suppression of bone turnover causing poor bone health has been raised by recent observations. Alendronate-induced osteonecrosis of the jaw is an example of a possible negative influence on bone health by a drug with proven fracture efficacy when given over longer periods of time at higher dosages. Atypical low-trauma subtrochanteric fractures have likewise been implicated as the result of long-term effects of bisphosphonates, although this has not been proven.

It is clear that long-term bone heath in patients on antifracture therapy is of cardinal importance. Available diagnostic tools for this purpose are limited. Biochemical markers of bone turnover, DXA, and ultrasound have limited application. Transiliac bone biopsies yield more information, but are limited by technical and practical considerations.

It is thus with great interest that the study of bone microstructure and changes induced by drugs over time as recorded by high-resolution peripheral computed tomography (HR-pQCT) on the radius and tibia is followed.3 This in vivo technique is noninvasive and produces brilliant images of the trabecular and cortical structures. The technique is presently being limited by cost, availability, restriction to peripheral sites, and limited validation of the outcomes measured. It is the opinion of the author that development of HR-pQCT and other techniques will lead to new insights into the effect of drugs on longterm bone health. This will complement knowledge of antifracture efficacy in determining not only the choice of drug, but also the duration of treatment in osteoporosis based on bone health. _

References
1. Seeman E, et al. Five years treatment with strontium ranelate reduces vertebral
and nonvertebral fracture and increases the number and quality of remaining lifeyears
in women over 80 years. Bone. (2010),DOI1016/J.BONE2009.12.006.
2. Reginster J-Y, Sawicki A, Roces-Varela A. Strontium ranelate: 8 years efficacy on
vertebral and nonvertebral fractures in postmenopausal osteoporotic women.
Osteoporos Int. 2008;19(suppl 1):S131-1S32.
3. Vico L et al. High-resolution pQCT analysis at the distal radius and tibia discriminates
patients with recent wrist and femoral neck fractures. J Bone Miner Res. 2008;23:1741-1750.

5. J. Laíns, Portugal


Jorge LAÍNS,
MD
Centro de Reabilitaçao do Centro
Hospital Rovisco Pais
Rua da Fonte
3060-644 Cantanhede
PORTUGAL
(e-mail: jorgelains@sapo.pt)

In 2000, he National Institutes of Health (NIH) Consensus Development Conference Statement defined osteoporosis as:

a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength reflects the integration of two main features: bone density and bone quality. Bone quality refers to architecture, turnover, damage accumulation (eg, microfractures) and mineralization.1

Osteoporosis is a disease, and not part of the natural process of aging, although age and gender are independent fracture risk factors. “Bone health” is a dynamic process, involving the concept of homeostasis, and should be considered over the entire lifespan.1 The health of any living tissue is dependent on its metabolism/turnover, which allows the tissue to maintain its properties and functions, ie, its youth. Bone is continuously remodeled by the bone multicellular unit (BMU), dissolving areas of microfractures and/or dysfunctional bone and filling it with new and “healthy” bone. In osteoporosis there is a disruption of bone remodeling, leading to microarchitectural damage, namely, disruption of, and reduction in, trabeculae connections. Bone needs to permanently repair the microfractures that occur in its midst. In this connection, it is believed that the age of the mineral crystal may play a role on bone strength. Research suggests that older bone is more brittle and that bone remodeling plays an important role in bone strength, replacing older with newer bone, which is more elastic and mechanically resistant.2

At first glance, this definition of osteoporosis implies that the goal of any antiosteoporotic treatment is to decrease fracture risk by increasing bone resistance. However, bone resistance is dependent on its health and quality, and bone quality is dependent on its architecture, degree, and age of mineralization, and the accumulation of damage. In turn, all of these depend on turnover and the possibility of maintaining the youth of all the components of bone tissue.2

All antiosteoporotic drugs act on bone turnover, on the activation frequency of the BMU, either by inhibiting resorption (estrogens, bisphosphonates, calcitonin, and raloxifene), or by stimulating formation (parathormone [rhPTH 1-84] and its fragment [rhPTH 1-34]), or by a simultaneous dual action resulting in stimulation of bone formation and inhibition of bone resorption (strontium ranelate).3 Most probably, these drugs act not only on bone mineral density (BMD), but also on bone quality. Again most probably, it is not a coincidence that osteonecrosis of the jaw and a particular type of fractures in the shaft of the femur are reported with (prolonged) use of antiresorptives, perhaps in relation with the inhibition of bone turnover, leading to the so-called “frozen bone.” In contrast, drugs promoting bone formation are proven to ameliorate microarchitecture.2 Interestingly, to my knowledge, there is no published article or research mentioning any negative interference with bone health with strontium ranelate.

To conclude, when considering treatment with an antiosteoporotic drug, we should take into account both bone safety and bone health, and not only the prevention of fractures. _

References
1. NIH Consensus Statement Online. Osteoporosis prevention, diagnosis, and therapy. 2000 March 27-29; [cited 2010, 03, 30]; 17(1):1-36.
2. Ott S. Osteoporosis and Bone Physiology. http://courses.washington.edu/ bonephys/phystrength.html [cited 2010, 04, 01]
3. Geusens PP, Roux CH, Reid DM, et al. Drug insight: choosing a drug treatment strategy for women with osteoporosis—an evidence-based clinical perspective. Nat Clin Pract Rheumatol. 2008;4(5):240-248.

6. N. Taechakraichana, Thailand


Nimit TAECHAKRAICHANA,MD
Department of Obstetric and Gynecology
Faculty of Medicine
Chulalongkorn University
Bangkok, 10330
THAILAND
(e-mail: nimit2009@gmail.com)

Bone is a specialized connective tissue endowed with three functions: mechanical, protective, and metabolic. Bone development and function are dictated by the activity of the osteoblasts and osteoclasts. These include growth, modeling, repair, and remodeling. Bone remodeling is a renewal process geared to removing damage in order to maintain bone strength. This cellular machinery is effective during the period of adolescence, but fails with advancing age as the remodeling balance grows negative. The crucial window for bone accrual during the third decade of life and the critical transition of postmenopausal bone loss are key determinants of skeletal mass in the elderly. However, bone strength—the maximal load that can be applied before a fracture occurs—is also influenced by factors other than bone mass. For instance,1 sex differences in bone width with greater periosteal bone formation in boys and higher endocortical apposition in girls result in a wider bone in boys, conferring greater resistance to bending. Bone tissue quality, which is related to the degree of bone mineralization and the characteristics of bone matrix also exerts important role in determining bone strength.

The triad of antiosteoporotic therapy includes: (i) enhancing peak bone mass during adulthood; (ii) preventing bone loss after menopause; and (iii) preventing falls in the elderly. Most antiosteoporotic medications used in advanced age to prevent bone loss can be categorized into three main groups: antiresorptives, bone-formative agents, and “the others.” Most of the available antiosteoporotic drugs, particularly the bisphosphonates, have been shown to exert their antifracture efficacy by retarding osteoclast maturation and inhibiting the cascade of resorbing activities. Bone-formative agents, which are fewer in number, play a greater role in osteoblastic bone formation, in particular intermittent parathyroid hormone (PTH).

Strontium ranelate, a recently developed agent, claims a dual action on bone resorption and bone formation.2 Vitamin K2 is a key coenzyme critical for the maturation of osteocalcin,3 which seems to play a crucial role in osseous and nonosseous systems.

Fractures have devastating consequences in terms of physical, economic, and psychosocial outcomes. One of the major goals of antiosteoporotic therapy is to prevent fractures in order to minimize morbidity and maximize quality of life. However, bone health is an issue that goes far beyond the quantifiable repercussion of fractures, since bone functions are multiple. In addition to antifracture efficacy, long-termsafety should be taken into account when considering antiosteoporotic therapy. The risk-benefit ratios of the short- and long-term safety and efficacy outcomes of each treatment option should be thoroughly examined. This would include the cardiovascular and cancer risks in elderly users of hormone replacement therapy,4 the long-term risk of cerebrovascular accident in raloxifene users at high cardiovascular risk,5 the unresolved issue of osteonecrosis of the jaw in patients using high-dose intravenous bisphosphonates, and the frozen bone debate around the long-term use of bisphosphonates.6 _

References
1. Seeman E. Physiology of aging: pathogenesis of osteoporosis. J Appl Physiol. 2003;95:2142-2151.
2. Ammann P. Strontium ranelate: a physiological approach for an improved bone quality. Bone. 2006;38:S15-S18.
3. Plaza SM, Lamson DW. Vitamin K2 in bone metabolism and osteoporosis. Altern Med Rev. 2005;10:24-35.
4. Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women. JAMA. 2002; 288:321-333.
5. Barrett-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. Silverman SL, Maricic M. Recent developments in bisphosphonate therapy. Semin Arthritis Rheum. 2007;37:1-12.

7. D. O’Gradaigh, Ireland


Donncha O’GRADAIGH,MB, PHD, MRCPI
Waterford Regional Hospital
Dunmore Road, Waterford
IRELAND
(e-mail: donncha.ogradaigh@hse.ie)

“The doctor has been taught to be interested
not in health, but in disease.
What the public is taught is that health
is the cure for disease.”

Ashley Montagu

Osteoporosis is the paradigm of impaired bone health, as it is a condition of reduced bone mass and impaired bone architecture caused by perturbed bone physiology (bone remodeling), resulting in bone fragility and fracture. Several classes of antiosteoporotic treatment are available, and their effectson thedeterminantsof bone strength differ—hence the potential conflict raised in this question.

A bone that fractures in a low-trauma injury is “fragile.” Can we recognize, and therefore treat, impaired bone health prior to this first fracture? Our most reliable single tool is the measurement of areal bone mineral density (BMD) in the hip and spine. However, the majority of those who fracture have a normal or only modestly impaired BMD.

Bone architecture is assessed on bone biopsy or high-resolution imaging, which is certainly not applicable clinically. Data suggest that BMD loss may explain only 20% to 30% of the microarchitectural deterioration seen in an osteoporotic population with prevalent fractures. Clinical risk factors can predict the risk of fracture independently of BMD measurements, and the presence of these BMD-independent risk factors correlates with the deterioration in measures of bone microarchitecture. Finally, bone turnover markers also support more accurate prediction of fracture than BMD alone. The purpose of having thus identified impaired bone health is to prevent fragility fractures. While it is logical to assume that improving bone health will do so, this may be a fallacy—an improvement in bone health is a means to an end, not an end in itself. This does not preclude the argument that a treatment that best restores bone health should be the preferred choice when fracture risk reduction is comparable.

Each of the existing treatment options alter one or more determinants of bone strength: (i) tissue properties, such as hardness, maximal strength; (ii) bone architecture such as trabecular number, thickness and connectivity, cortical porosity, trabecularization, and transformation between plate and rodlike trabecular structures; and (iii) dynamic measures such as mineral apposition rate, activation frequency, and resorption surfaces.

Interpretation of these comparative data is complex—for instance, while raloxifene has the most pronounced effects on tissue quality, as assessed by nanoindentation, teriparatide reduces tissue hardness in trabecular bone, but has the greatest effect on bone volume. Bisphosphonates increase stiffness, but not hardness, and do not alter bone volume significantly. The significance of these findings can only be interpreted in regard to the clinical utility of these treatment options, ie, in their ability to protect a patient from fracture.

Strontium ranelate is notable in adjusting bone formation and bone resorption in a way that most closely resembles preosteoporotic bone health, with desirable effects on trabecular and cortical bone and without adverse effects on tissue quality such as stiffness. This allows a restoration of bone quality, mineral properties, and, most crucially normal bone remodeling.

To paraphrase the architect Leon Battista Alberti, this treatment can “adjust all the parts proportionally so as not to impair the harmony of the whole,” achieving the combined, not conflicting goals of reduced bone fragility through optimizing every aspect of bone health. _

8. P. Sambrook, Australia


Philip SAMBROOK,
MBBS, MD, FRACP, LLB
Professor, Sydney Medical School
University of Sydney
Level 4, Building 35
Royal North Shore Hospital
St Leonards, Sydney 2065
AUSTRALIA
(e-mail: sambrook@med.usyd.edu.au)

The principal functions of the skeleton are mechanical support, maintenance of calcium homeostasis, and hematopoiesis in the bone marrow. These functions can be disturbed in a variety of metabolic bone diseases of which osteoporosis is the commonest. Metabolic bone disease is a rather loose term that encompasses diseases of bone in which abnormal bone remodeling results in a reduced volume of mineralized bone and/or abnormal bone architecture. These processes in turn usually give rise to an increased risk of fracture. For this reason, the most important complication of osteoporosis is often considered to be fracture, although other manifestations can have significant effects on patient quality of life.

Osteoporotic fractures result from a combination of decreased bone strength and increased incidence of falls. Bone mineral density (BMD), because it is easy to measure and has an excellent precision, was initially the favored end point in most clinical trials and remains the best noninvasive assessment of bone strength available in routine clinical practice. Prevention of fractures subsequently became the more relevant end point for clinical trials with a view to satisfying regulatory authorities about the efficacy of a particular drug.

However, it is now recognized that bone strength (and hence fracture risk) depends on many properties including the shape and size of the bone as well as the strength of the material inside. Material strength is influenced by architectural abnormalities and microdamage as well as BMD. Assessment of these other end points (often referred to as “bone quality” in the past), is now considered a more appropriate reflection of overall bone health. Architectural abnormalities occur particularly in the trabeculae of vertebral bodies. A loss of trabecular connectivity (density of connections between trabeculae) especially with horizontal loss, results in increased loads on remaining trabeculae resulting in a weakened structure. Loss of trabecular connectivity has been demonstrated in individuals with vertebral crush fractures compared with controls, even when matched for bone volume. Prior fracture, an independent risk factor for further fracture, may reflect these existing architectural abnormalities. Measurement of microarchitecture is possible in the research setting,1,2 but is more problematic in clinical practice. Nevertheless, it is now considered an important end point in all recent major trials of antiosteoporotic therapies.

Biochemical bone markers have also been used as intermediate end points in most recent major studies of antiosteoporotic therapies. Bone resorption markers, in particular, may add an independent, predictive value to the assessment of bone loss and fracture risk. There are also potential advantages in monitoring antiosteoporotic treatment in the short term in addition to bone densitometry, to more quickly identify nonresponders to therapy, or noncompliance.

To summarize, while the clinical goal of antiosteoporotic therapy is to prevent fractures, understanding the mechanism of action of such benefit to the skeleton is enhanced when measures of bone health that include not just BMD, but also bone turnover and microarchitecture are included in trial endpoints. _

References
1. Borah B, Dufresne TE, Ritman EL, et al. Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone. 2006;39: 345-352.
2. Arlot ME, Jiang Y, Genant HK, et al. Histomorphometric and microCT analysis of bone biopsies from postmenopausal osteoporotic women treated with strontium ranelate. J Bone Miner Res. 2008;23:215-222.