Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research
TL;DR: This newer evidence suggests that AFFs are stress or insufficiency fractures, and studies with radiographic review consistently report significant associations between A FFs and BP use, although the strength and magnitude of effect vary.
Abstract: Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. © 2010 American Society for Bone and Mineral Research.
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TL;DR: The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteiporosis Foundation in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF.
Abstract: The Clinician’s Guide to Prevention and Treatment of Osteoporosis was developed by an expert committee of the National Osteoporosis Foundation (NOF) in collaboration with a multispecialty council of medical experts in the field of bone health convened by NOF. Readers are urged to consult current prescribing information on any drug, device, or procedure discussed in this publication.
2,926 citations
TL;DR: There has been a paradigm shift in the prevention and treatment of osteoporosis and fractures, and the focus now is on preventing fragility fractures and their negative effects.
Abstract: See related commentary by Kanis, page [1829][1]
Since the publication of the Osteoporosis Canada guidelines in 2002, there has been a paradigm shift in the prevention and treatment of osteoporosis and fractures. [1][2],[2][3] The focus now is on preventing fragility fractures and their negative
1,691 citations
TL;DR: Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -2.5 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk.
Abstract: Key Clinical Points Postmenopausal Osteoporosis Fractures and osteoporosis are common, particularly among older women, and hip fractures can be devastating Treatment is generally recommended in postmenopausal women who have a bone mineral density T score of -25 or less, a history of spine or hip fracture, or a Fracture Risk Assessment Tool (FRAX) score indicating increased fracture risk Bisphosphonates (generic) and denosumab reduce the risk of hip, nonvertebral, and vertebral fractures; bisphosphonates are commonly used as first-line treatment in women who do not have contraindications Teriparatide reduces the risk of nonvertebral and vertebral fractures Osteonecrosis of the jaw and atypical femur fractures have been reported with treatment but are rare The benefit-to-risk ratio for osteoporosis treatment is strongly positive for most women with osteoporosis Because benefits are retained after discontinuation of alendronate or zoledronic acid, drug holidays after 5 years of alendronate therapy or 3 years of zoledronic acid therapy may be considered for patients at lower risk for fracture
1,047 citations
TL;DR: Increasing awareness among doctors, which, in turn, facilitates increase awareness of the normal populace, will be effective in preventing this epidemic of osteoporosis.
Abstract: Osteoporosis -related to various factors including menopause and aging- is the most common chronic metabolic bone disease, which is characterized by increased bone fragility. Although it is seen in all age groups, gender, and races, it is more common in Caucasians (white race), older people, and women. With an aging population and longer life span, osteoporosis is increasingly becoming a global epidemic. Currently, it has been estimated that more than 200 million people are suffering from osteoporosis. According to recent statistics from the International Osteoporosis Foundation, worldwide, 1 in 3 women over the age of 50 years and 1 in 5 men will experience osteoporotic fractures in their lifetime. Every fracture is a sign of another impending one. Osteoporosis has no clinical manifestations until there is a fracture. Fractures cause important morbidity; in men, in particular, they can cause mortality. Moreover, osteoporosis results in a decreased quality of life, increased disability-adjusted life span, and big financial burden to health insurance systems of countries that are responsible for the care of such patients. With an early diagnosis of this disease before fractures occur and by assessing the bone mineral density and with early treatment, osteoporosis can be prevented. Therefore, increasing awareness among doctors, which, in turn, facilitates increase awareness of the normal populace, will be effective in preventing this epidemic.
1,040 citations
TL;DR: The discovery and development of the bisphosphonates (BPs) as a major class of drugs for the treatment of bone diseases has been a fascinating story, and a paradigm of a successful journey from 'bench to bedside'.
905 citations
References
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TL;DR: Among women with low bone mass and existing vertebral fractures, alendronate is well tolerated and substantially reduces the frequency of morphometric and clinical vertebra fractures, as well as other clinical fractures.
3,730 citations
TL;DR: Daily treatment with alendronate progressively increases the bone mass in the spine, hip, and total body and reduces the incidence of vertebral fractures, the progression of vertebra deformities, and height loss in postmenopausal women with osteoporosis.
Abstract: Background Postmenopausal osteoporosis is a serious health problem, and additional treatments are needed. Methods We studied the effects of oral alendronate, an aminobisphosphonate, on bone mineral density and the incidence of fractures and height loss in 994 women with postmenopausal osteoporosis. The women were treated with placebo or alendronate (5 or 10 mg daily for three years, or 20 mg for two years followed by 5 mg for one year); all the women received 500 mg of calcium daily. Bone mineral density was measured by dual-energy x-ray absorptiometry. The occurrence of new vertebral fractures and the progression of vertebral deformities were determined by an analysis of digitized radiographs, and loss of height was determined by sequential height measurements. Results The women receiving alendronate had significant, progressive increases in bone mineral density at all skeletal sites, whereas those receiving placebo had decreases in bone mineral density. At three years, the mean (±SE) differences in bone...
2,150 citations
TL;DR: This report summarizes the findings and recommendations of the task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder.
Abstract: ONJ has been increasingly suspected to be a potential complication of bisphosphonate therapy in recent years. Thus, the ASBMR leadership appointed a multidisciplinary task force to address key questions related to case definition, epidemiology, risk factors, diagnostic imaging, clinical management, and future areas for research related to the disorder. This report summarizes the findings and recommendations of the task force. Introduction: The increasing recognition that use of bisphosphonates may be associated with osteonecrosis of the jaw (ONJ) led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address a number of key questions related to this disorder. Materials and Methods: A multidisciplinary expert group reviewed all pertinent published data on bisphos- phonate-associated ONJ. Food and Drug Administration drug adverse event reports were also reviewed. Results and Conclusions: A case definition was developed so that subsequent studies could report on the same condition. The task force defined ONJ as the presence of exposed bone in the maxillofacial region that did not heal within 8 wk after identification by a health care provider. Based on review of both published and unpublished data, the risk of ONJ associated with oral bisphosphonate therapy for osteoporosis seems to be low, estimated between 1 in 10,000 and <1 in 100,000 patient-treatment years. However, the task force recognized that information on incidence of ONJ is rapidly evolving and that the true incidence may be higher. The risk of ONJ in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1-10 per 100 patients (depending on duration of therapy). In the future, improved diagnostic imaging modalities, such as optical coherence tomography or MRI combined with contrast agents and the manipulation of image planes, may identify patients at preclinical or early stages of the disease. Management is largely supportive. A research agenda aimed at filling the considerable gaps in knowledge regarding this disorder was also outlined. J Bone Miner Res 2007;22:1479-1491. Published online on July 19, 2007; doi: 10.1359/JBMR.0707ONJ
1,517 citations
"Atypical subtrochanteric and diaphy..." refers background in this paper
...comminution 71 Thickened cortices; transverse orientation; medial spike; single observer, no Kappa 6 (1) 3 (50) NA Crude OR 5....
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...One patient had ONJ and 27 (13.4...
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...In the past decade, however, osteonecrosis of the jaw (ONJ)((1)) and atypical femoral fractures (AFFs)((2)) have emerged as potential complications of BP and, more recently, denosumab therapy (http://www....
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...In contrast to ONJ, which came to attention in patients receiving high‐dose BP therapy for malignancy, most though not all patients with AFFs were receiving the lower doses of BPs typically used to treat osteoporosis or osteopenia....
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...%) had AFFs (transverse or oblique orientation, focal cortical thickening of the lateral cortex, without malignancy or radiation of the fracture site), five had bilateral findings, and two had ONJ....
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TL;DR: It is found that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells.
Abstract: Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.
1,478 citations
"Atypical subtrochanteric and diaphy..." refers background in this paper
...Stress fractures heal by targeted remodeling of the injured site through a process of osteocyte apoptosis, which signals for repair through elevated production of receptor activator of NF‐kB ligand (RANKL),((71,72)) osteoclastic resorption to remove the damage, and then osteoblastic formation to replace resorbed bone....
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TL;DR: The findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures, and the need for increased awareness and monitoring.
Abstract: Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.
1,344 citations