Among the most important concerns regarding the

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1 140 Osteoporosis An Update Stephen Honig, M.D., M.Sc., and Gregory Chang, M.D. Abstract The past year has been a dynamic one for clinicians and researchers with an interest in osteoporosis. This update will focus on the issue of the relationship between bisphosphonate treatment and atypical femoral fractures, highlight the advances in imaging techniques that are increasingly being studied as adjuncts to bone density testing, and explore recent evidence that suggests that osteoporosis medications may be linked to an increase in life expectancy. Since the first case reports describing unusual femur fractures in long term users of bisphosphonates began to appear, there has been great interest in identifying why and whether this class of drug can cause these atypical fractures. There have been a significant number of large studies that seem to suggest that these fractures do occur with an increased frequency among subjects who have used bisphosphonates over an extended period of time, but that these events are relatively rare. The occurrence of these fractures have helped to fashion new treatment regimens with periods of drug holidays often recommended to people with lower short-term and intermediate-term fracture risk. It is important to remind the reader that bisphosphonates prevent many typical hip and vertebral compression fractures, particularly in the higher risk elderly patient and that a rational balance be struck Stephen Honig, M.D., M.Sc., is a Clinical Associate Professor of Medicine at New York University School of Medicine, and Director, Osteoporosis Center, NYU Hospital for Joint Diseases, NYU Langone Medical Center, New York, New York. Gregory Chang, M.D., is an Assistant Professor of Radiology at the New York University School of Medicine, Quantitative Multinuclear Musculoskeletal Imaging Group, NYU Langone Medical Center, New York, New York. Correspondence: Stephen Honig, M.D., NYU Hospital for Joint Diseases, 301 East 17th Street, New York, New York 10003; stephen.honig@nyumc.org. so that those in need of continued osteoporosis treatment receive it. Advances in imaging, such as high resolution MRI and peripheral micro CT scanners, are allowing investigators to non-invasively assess bone microarchitecture and bone stiffness of individuals as a means of trying to more accurately define those subjects who might be at increased risk of fracture and who might benefit from bone strengthening medication. Finally, this update will briefly review the emerging data that suggests that anti-resorptive medication may extend life expectancy beyond that which can be expected solely by reducing the incidence of future fractures. Among the most important concerns regarding the treatment of osteoporosis is defining the risk and benefits of long term use of bisphosphonates. Alendronate received FDA approval for the treatment of postmenopausal osteoporosis in 1995 and quickly became the most widely used drug for this condition. In 2005, the first case report describing patients with low energy proximal femur or femoral shaft fractures who had been long-term users of alendronate was published. 1 This type of fracture which has a characteristic radiographic appearance has subsequently been labeled as an atypical femur or subtrochanteric fracture. Since that initial publication, there have been a significant number of case reports linking bisphosphonate use and the development of these atypical fractures. In 2009, the American Society of Bone and Mineral Research convened a task force to review data linking atypical fractures and bisphosphonate use. The task force was asked to recommend a provisional case definition and to define the imaging modalities that would enhance the identification and characterization of the disorder. 2 The task force developed a working definition of these fractures by describing both the major and minor features of these fractures (Table 1). The major features define the classical radiographic findings of the atypical femur fractures (Fig. 1). Unfortunately, many of Honig S, Chang G. Osteoporosis: an update. Bull NYU Hosp Jt Dis. 2012;70(3):140-4.

2 141 Table 1 Major and Minor Features of Atypical Fractures (ASBMR) Major Features of Atypical Fractures Location-subtrochanteric and shaft regions of femur Transverse or oblique orientation Minimal or no associated trauma Medial spike when fracture is complete Absence of comminution Minor Features of Atypical Fractures Cortical thickening Periosteal reaction of lateral cortex Prodromal pain Bilaterality and delayed healing Concomitant drugs-bisphosphonates, steroids, PPIs the studies that have had access to data describing long-term bisphosphonate use and atypical fracture incidence have not included examination of the actual radiographs of patients with a history of femur fractures and have relied instead on discharge diagnosis codes to estimate the incidence of bisphosphonate related fractures. A large Danish registry study involving almost 40,000 alendronate users and over 158,000 nonusers and which did not have access to radiographs to identify the features of atypical fractures was not able to show a definitive association between alendronate and atypical femur fractures. 3 Similarly, an United Statesbased study involving femur fractures including those with a subtrochanteric location among patients with up to 8 years of bisphosphonate use failed to show an increase in any type of femur fracture with long term alendronate or risedronate use. 4 In contrast, a Canadian study involving over 200,000 women aged 68 or older who used bisphosphonates for longer than 5 years were found to have double the risk of atypical fractures compared to those who were transient users defined as less than 100 days of drug use. 5 In that study, there were only 716 women (0.35%) identified as having had an atypical fracture. The largest observational study with radiologic review was a Swedish report that reviewed all fractures among women age 55 or older that occurred in Sweden in This large study identified 12,777 femur fractures of which 1351 were characterized as either subtrochanteric or femoral shaft fractures. After X-ray and clinical review, 912 of these fractures were deemed not relevant for comparison leaving 322 fractures that were judged to be either atypical or typical femoral fractures. There were 59 patients with radiographic findings characteristic of atypical fractures. Seventyeight percent of these patients were bisphosphonate users compared to 263 controls with typical subtrochanteric fractures with a 10% rate of bisphosphonate use. 6 A major weakness of this study was that drug use data was available for only 3 years so that identifying patients with longer term bisphosphonate use was not possible. Another recent study that attempted to define the incidence of atypical femoral fractures and bisphosphonate use was a Swiss report that details the experience of a single university hospital where 477 patients with subtrochanteric or femoral shaft fractures were identified from 1999 to Among this group, 39 patients had atypical fractures; 82.1% were bisphosphonate users, and 438 patients were classified as classic fractures (6.4% were bisphosphonate users). In this study, atypical fractures were associated with bisphosphonate use, and the risk of these fractures increased with duration of use; but as with other population based studies, the absolute number of atypical femoral fractures was very small. 7 A B Figure 1 A, Complete atypical fracture with major features (see Table 1) and B, stress fracture with cortical thickening and periosteal reaction of lateral cortex.

3 142 In summary, it appears that atypical fractures, while not common, are related to long-term bisphosphonate use (3 or more years) and that the risk of these fractures decreases rapidly after stopping the use of these drugs. The fractures have a characteristic X-ray appearance and healing takes an extended period of time, aspects that distinguish these fractures from typical subtrochanteric and shaft fractures. Surgical treatment for complete fractures is recommended, but the optimal approach for an incomplete or stress fracture is not yet clear. Osteoporosis: Advances in Imaging Bone strength is determined by its material composition, structure, geometry, and microarchitecture. 8 Bone density testing with dual-energy X-ray absorptiometry (DEXA) allows assessment of areal bone density, which reflects the amount of calcium (bone mineral composition) represented in an area of bone (bone mass), but it does not discriminate between cortical and cancellous bone compartments nor does it permit assessment of bone microarchitecture. Over the past few years, noninvasive assessment of bone architecture has become possible by the use of high-resolution peripheral quantitative CT scanners and with the development of high-resolution magnetic resonance imaging (MR) techniques. 9,10 It is hoped that these new imaging modalities can provide insights into the relationship between bone microarchitecture and bone strength. Several recent studies have shown the value of these techniques in demonstrating bone microarchitectural changes in osteoporosis 11 and in response to treatment with bone strengthening medication. 12 Additionally, high-resolution CT and MR images have been shown to be suitable for generation of microfinite element models to estimate properties of bone, including bone stiffness, which is correlated with the ability of bone to resist fracture. 13 We have been using high resolution MRI as a complementary tool to traditional DEXA scans in the hope that we can gain some insights into why some individuals suffer fragility fractures despite having better bone mineral density scores than some women who have never fractured a bone (Fig. 2). Other investigators have found that impaired trabecular microarchitecture among individuals without a DEXA based diagnosis of osteoporosis appear to be at increased fracture risk. 14 Identifying individuals with structural deterioration of bone may help us make more informed treatment decisions particularly in the younger postmenopausal with a low bone density on DEXA scanning, but no history of fragility fracture. We are also hopeful that these high resolution imaging techniques will help better define the structural effects of bone strengthening medications on bone microarchitecture and bone strength. Ultra high-resolution MR and peripheral micro CT images are capable of showing trabecular number and both trabecular and cortical thickness, components of bone structure thought to correlate directly with bone strength. While these modalities are presently used for investigational and research purposes, we are hopeful that the information that is being gained from these tools will prove clinically useful in the near future. Bisphosphonate Use and Life Expectancy Over the past decade, there have been several different reports raising the issue that osteoporosis drug treatments may extend life expectancy among users of these drugs beyond that which is expected by reducing subsequent fracture risk. Cree and colleagues identified post hip fracture osteoporosis drug treatment and its association with mortality in a group of 449 patients 65 years or older who had sustained a hip fracture in 1996 and 1997 and whose medical histories were analyzed in Twenty-three percent of the hip fracture patients received some osteoporosis treatment (mainly a bisphosphonate) with most treatment started only after the fracture had occurred. While the rates of subsequent distal forearm and hip fractures were the same in the treated and untreated groups, the mortality rates were significantly lower in the treated group. 15 While this was a retrospective study, the results suggested the need for further investigation into the effects of bisphosphonates and life expectancy. In the Horizon Hip Fracture Study, Lyles and colleagues followed a group of patients who received zoledronic acid or placebo A B Figure 2 High resolution 7T MRI. A, A 35-year-old, premenopausal woman with lowest T score of -1.5 and 10 fragility fractures. B, A 56-year-old, postmenopausal woman with lowest T score of -3.3 and no fractures.

4 143 within 90 days after surgical repair of a hip fracture. The group who received zoledronic acid had a 35% reduction in subsequent fractures over a median follow up of 1.9 years, and a 28% reduction in deaths from any cause. 16 In a retrospective study, the same group analyzed the causes of death seen in the Horizon trial and suggested that only 8% of the death benefit seen among those who received zoledronic acid could be explained by a reduction in subsequent fractures. They postulated that this drug may have had a positive effect on cardiovascular events and pneumonia. 17 In a meta-analysis involving 1,400 deaths among nearly 40,000 subjects who had used a variety of osteoporosis medications including non-bisphosphonates, there was a 10% reduction in mortality among those subjects who were using such drugs. 18 A prospective Australian study, involving 1,233 women and 819 men aged 60 and older followed in the Dubbo Osteoporosis Epidemiology Study, analyzed the effect of osteoporosis treatment on mortality risk and also found a significant reduction in mortality among women using bisphosphonates whether or not they had sustained a fracture while taking these drugs. 19 The above studies suggest, but of course do not conclusively prove, that bisphosphonates may have a salutary effect on life expectancy particularly in older women. Why this might be true is not clear although there has been great interest in the effects of bisphosphonates on vascular tissue and atherosclerosis. 20 Additionally, there is animal research data linking decreased aortic calcification in rats receiving bisphosphonates in a pro-atherogenic warfarin-vitamin D model. 21 Clinically, a recent large study from Taiwan compared a group of patients who received bisphosphonates after a vertebral or hip fracture to a group who did not receive such treatment after these fractures and found that the former had a significantly lower incidence of stroke during a 2-year follow-up period. The hazard ratios (HR) for an ischemic stroke among bisphosphonate users was 0.81 (CI = ), and for a subarachnoid or intracerebral hemorrhage, the HR was 0.53 (CI = ) compared to non-users. These studies support the limited observational data suggesting that bisphosphonates may be vascular and cardioprotective particularly in the elderly. Such findings, of course, need to be confirmed in randomized prospective trials. Conclusions This update in osteoporosis highlighted three different subject areas that are stimulating interest in metabolic bone research. The finding that longer term bisphosphonate use may result in atypical femur fractures has significantly changed the prescribing practices of clinicians who care for patients with osteoporosis or increased fracture susceptibility. It is important to emphasize that bisphosphonates reduce the incidence of fragility fractures, and that the small risk of atypical fractures should not deter recommending their use in higher fracture risk patients particularly older patients with a history of such fractures. The data suggesting that these drugs may improve life expectancy needs to be proven in larger randomized studies, and if confirmed, this information will likely push back against the forces questioning the risk benefit ratio of bisphosphonate use. Finally, the experiences with new imaging modalities may provide critical information linking bone architecture and fracture risk and may provide some additional guidance for clinicians deciding on when to recommend starting a patient on osteoporosis treatment. Disclosure Statement None of the authors have a financial or proprietary interest in the subject matter or materials discussed, including, but not limited to, employment, consultancies, stock ownership, honoraria, and paid expert testimony. References 1. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab Mar;90(3): Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal femoral fractures; report of a task force of the American Society for Mineral Research. J Bone Miner Res Nov;25(11): Abrahamsen B, Eiken P, Eastell R. 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5 144 cal and trabecular microarchitecture, biomechanics and bone turnover. J Bone Miner Res Dec;25(12): Rajapaske CS, Magland JF, Wald MJ, et al. Computational biomechanics of the distal tibia from high-resolutions MR and micro-ct images. Bone Sep;47(3): Kijowski R, Tuite M, Kruger D, et al. Evaluation of trabecular microarchitecture in nonosteoporotic postmenopausal women with and without fracture. J Bone Miner Res Jul;27(7): Cree MW, Juby AG, Carriere KC. Mortality and morbidity associated with osteoporosis drug treatment following hip fracture. Osteoporos Int Sep;14(9): Lyles KW, Colon-Emeric CS, Magaziner J, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med Nov 1;357(18): Colon-Emeric CS, Mesenbrink P, Lyles KW, et al. Potential mediators of the mortality reduction with zoledronic acid after hip fracture. J Bone Miner Res Jan;25(1): Bolland MJ, Grey AB, Gamble GD, Reid IR. Effect of osteoporosis treatment on mortality: a meta-analysis. J Clin Endocrinol Metab Mar;95(3): Center JR, Bliuc D, Nguyen N, et al. Osteoporosis medication and reduced mortality risk in elderly women and men. J Clin Endocrinol Metab Apr;96(4): Bevilacqua M, Dominguez LJ, Rosini S, Bargagallo M. Bisphosphonates and atherosclerosis: why? Lupus. 2005;14(9): Price PA, Faus SA, Williamson MK. Bisphosphonates alendronate and ibandronate inhibit artery calcification at doses comparable to those that inhibit bone resorption. Arterioscler Thromb Vasc Biol May;21(5):