Atypical forearm fractures associated with long-term use of bisphosphonate

Recent reports on atypical femoral fracture have raised concerns about the long-term use of bisphosphonate. More recent case series focus specifically on the subtrochanteric fractures. But, there is relatively rarity and unawareness of atypical fracture in upper extremity. We report forearm fracture in two women receiving long-term bisphosphonate therapy. First woman presented with pain in the forearm and both thighs and radiographs showed incomplete fractures in a proximal ulnar shaft and bilateral femoral shaft. The other woman had a fracture in the radial shaft. This report suggests atypical fractures associated long-term use of bisphosphonate could occur in bones other than femur. More study is required to identify the magnitude of clinical features of this emerging concern.     

Atypical femur fracture in an adolescent boy treated with bisphosphonates for X-linked osteoporosis based on PLS3 mutation

Long-term use of bisphosphonates has raised concerns about the association with Atypical Femur Fractures (AFFs) that have been reported mainly in postmenopausal women. We report a case of an 18-year-old patient with juvenile osteoporosis based on X-linked osteoporosis due to a PLS3 mutation who developed a low trauma femoral fracture after seven years of intravenous and two years of oral bisphosphonate use, fulfilling the revised ASBMR diagnostic criteria of an AFF. The occurrence of AFFs has not been described previously in children or adolescents. The underlying monogenetic bone disease in our case strengthens the possibility of a genetic predisposition at least in some cases of AFF. We cannot exclude that a transverse fracture of the tibia that also occurred after a minor trauma at age 16 might be part of the same spectrum of atypical fractures related to the use of bisphosphonates. In retrospect our patient experienced prodromal pain prior to both the tibia and the femur fracture. Case reports of atypical fractures in children with a monogenetic bone disease such as Osteogenesis Imperfecta (OI) or juvenile osteoporosis are important to consider in the discussion about optimal duration of bisphosphonate therapy in growing children.In conclusion, this case report 1) highlights that AFFs also occur in adolescents treated with bisphosphonates during childhood and pain in weight-bearing bones can point towards this diagnosis 2) supports other reports suggesting that low trauma fractures of other long bones besides the femur may be related to long-term use of bisphosphonates 3) strengthens the concept of an underlying genetic predisposition in some cases of AFF, now for the first time reported in X-linked osteoporosis due to a mutation in PLS3 and 4) should be considered in decisions about the duration of bisphosphonate therapy in children with congenital bone disorders.     

Treatment of femoral fracture nonunion after long-term bisphosphonate use

Bisphosphonates are a class of drugs that prevent bone loss by decreasing bone resorption. They represent a major treatment for osteoporosis and other metabolic bone diseases. Recent reports suggest that a potential complication of long-term bisphosphonate therapy may be atypical insufficiency fractures of the femur. Concern exists about delayed union after fracture stabilization in patients taking bisphosphonates.This article describes 2 patients on long-term bisphosphonate therapy treated for atypical femur fractures that failed to heal with intramedullary nailing. Both patients' fractures occurred after at least 4.5 years of bisphosphonate use and displayed classic findings of bisphosphonate fractures reported in the literature, including a subtrochanteric location, presentation after minimal trauma, transverse fracture, no comminution, and cortical beaking. The original fractures were treated at other institutions with intramedullary nails. Subsequently, both patients presented with pain and atrophic nonunion of their fractures. Evaluation included a computed tomography scan of the fracture and a metabolic workup. The patients discontinued bisphosphonate therapy. They were treated with nail removal and definitive plating to achieve compression across the fracture site. Both fractures went on to heal after this treatment with no further complications.The literature currently recommends treating bisphosphonate fractures with an intramedullary nail. Perhaps initial treatment of these fractures should be similar to an atrophic nonunion, involving compression plating to obtain bone-on-bone contact and promote healing. This would address the biologic and mechanical etiologies of the bisphosphonate fracture.     

Stress fracture of the ulna associated with bisphosphonate therapy and use of walking aid

We report a case of a stress fracture of the ulna secondary to long-term bisphosphonate therapy and walking cane. Physicians need to have a high index of suspicion of stress fractures occurring in patients complaining of chronic upper limb pain if they are on bisphosphonate therapy and are using walking aids. Stress fractures of the upper extremities are rare and are usually associated with athletes; however, a few recent case reports have shown an association between stress fractures of the upper extremities and the use of walking aids. The association between increased incidence of upper extremity stress fractures and the use of both bisphosphonates and walking aids in patients has not been well studied, with only one previously reported case. Here, we report a case of a complete stress fracture of the ulna in a 77-year-old female, premorbidly ambulant with walking cane, on long-term bisphosphonates without any pre-existing medical conditions which could result in secondary causes of bone loss. Investigations did not reveal any causes of pathological fracture. This fracture is attributed to the use of long-term bisphosphonate therapy in conjunction with the use of a walking cane. This case highlights the importance of entertaining the possibility of such fractures occurring in any patient who is on bisphosphonate therapy presenting with stress fractures of the upper extremity.     

A rare case of a bisphosphonate-induced peri-prosthetic femoral fracture

An 81-year-old woman presented with a fracture in the left femur. She had well-fixed bilateral hip replacements and had received long-term bisphosphonate treatment. Prolonged bisphosphonate use has been recently linked with atypical subtrochanteric and diaphyseal femoral fractures. While the current definition of an atypical fracture of the femur excludes peri-prosthetic fractures, this case suggests that they do occur and should be considered in patients with severe osteopenia. Union of the fracture followed cessation of bisphosphonates and treatment with teriparatide. Thus, this case calls into question whether prophylactic intramedullary nailing is sufficient alone to treat early or completed atypical femoral fractures.     

Evolution of bisphosphonate-related atypical fracture retrospectively observed with DXA scanning

We present a case of a 61-year-old female with history of long-term bisphosphonate therapy for osteoporosis initially diagnosed by screening dual-energy X-ray absorptiometry (DXA). After 4 years of treatment with bisphosphonates, the patient presented to primary care with left hip pain. Diagnostic hip radiographs were interpreted as normal, and she continued to take bisphosphonates. Two months later, she experienced a complete transverse subtrochanteric left femur fracture after minimal trauma. The patient underwent open reduction and internal fixation. Review of the patient's postoperative films revealed lateral subtrochanteric cortical beaking at the fracture. This type of "atypical" fracture has been reported to be a result of chronic bisphosphonate-associated fractures with high specificity. In addition, the right femur also showed cortical beaking with a horizontal linear lucency in an identical location, suggesting an impending fracture. Longitudinal review of the both diagnostic radiographs as well as DXA images shows a stepwise development of these subtrochanteric abnormalities in both femurs. A current hypothesis regarding the pathophysiology of bisphosphonate-associated fracture is that the medication inhibits bone turnover and repair of microscopic trauma. A cycle of defective repair and continual microtrauma compounded over time gradually weakens the bone and creates an architectural conduit for transverse or "atypical" fracture. Standard practice is not to use DXA as a diagnostic "image." We present this case to show that a common location and classic appearance of subtrochanteric bisphosphonate-associated fractures may be clearly visualized on absorptiometry images long before fracture. This observation is important because the majority of patients taking bisphosphonate therapy also receive regular DXA imaging. Because of the chronicity of standard bone-density monitoring for these patients throughout their treatment regimen, DXA may find a role for early detection of cortical abnormalities.     

Low-energy fractures of the humeral shaft and bisphosphonate use

Atypical fractures of the femur have been reported to occur in patients on long-term treatment with bisphosphonates; however, causality has not been proven, and it is not known whether similar fractures may occur in other long bones. We addressed this issue by examining the relationship between humeral shaft fractures and bisphosphonate use. We identified all patients aged ≥50 years consecutively admitted to a single center with a new fracture of the humerus. All individual radiographs were examined and fracture site was classified. A case-control study was undertaken in patients with humeral shaft fractures, and controls were sex- and age-matched patients with proximal humeral fractures in a 1:4 ratio. Patients with shaft fractures and radiographic characteristics similar to those of atypical femoral fractures were compared with those with ordinary shaft fractures. The association between "atypical" fractures and bisphosphonate or glucocorticoid use was examined. A total of 198 patients had a low-energy fracture of the humerus; 20 of these patients had a shaft fracture (10%). These 20 patients (cases) were matched with 80 patients with proximal fractures (controls). Bisphosphonates were used by 5% of cases and by 6.3% of controls (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.09-6.85); glucocorticoids were used by 10% of cases and 8.8% of controls (OR, 1.15; 95% CI, 0.23-5.83). There was no difference in cortical thickness between cases and controls and bisphosphonate or glucocorticoid users and nonusers. Four of the 20 patients with shaft fractures had "atypical" radiographic features, with significantly increased cortical thickness, but none of these had ever been treated with bisphosphonates or glucocorticoids. Our results show that low-energy fractures of the humeral shaft with "atypical" radiographic characteristics are infrequent and are not associated with the use of bisphosphonates or glucocorticoids.     

Atypical femoral fractures are a separate entity,characterized by highly specific radiographic features. A comparison of 59 cases and 218 controls

BackgroundEstimations of the risk of bisphosphonate associated atypical femoral fractures vary between different population-based studies, from considerable to neglectable. A possible explanation for these discrepancies could be different definitions of atypical fractures. We aimed to identify specific radiographic fracture characteristics associated with bisphosphonate use.MethodsIn a previous nationwide study, 59 atypical and 218 ordinary fractures were diagnosed. The atypical fractures were defined by their stress-type fracture pattern. All fractures were now re-assessed by a physician in training, without information about bisphosphonate use. The fracture angle (0–180°) was measured. Presence of local lateral cortical thickening (a callus reaction), more than 2 fragments, or a medial spike was noted. The reader then made a judgment whether the fracture appeared as an atypical fracture based on the ASBMR criteria.ResultsFrequency distribution analysis of the fracture angle showed a distinct subgroup, comprising 25% of all 277 fractures, with a mean of 89 and SD of 10°. Forty-two of 57 patients in this subgroup used bisphosphonates, whereas only 27 of 213 others did (specificity 0.93; 95% CI 0.88–0.96). Presence of a callus reaction had also a high specificity for bisphosphonate use (0.96; 95% CI 0.92–0.98). The ASBMR criteria had a lower specificity, increasing the number of atypical fractures without bisphosphonate use from 13 to 31. This led to a decrease in age-adjusted relative risk associated with bisphosphonate use from 47 (95% CI 26–87) to 19 (95% CI 12–29).InterpretationStress fractures of the femoral shaft are a specific entity, which is easily diagnosed on radiographs and strongly related to bisphosphonate use. Differences in diagnostic criteria may partially explain the large differences in relative risk between different population-based studies.     

Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report

Summary

This paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case?Ccontrol studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven.

Introduction

A Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians.

Methods

A PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed.

Results

Several clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these ??atypical?? fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case?Ccontrol studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks.

Conclusions

Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk?Cbenefit ratio still remains favourable for use of bisphosphonates to prevent fractures.     

Mechanical property and tissue mineral density differences among severely suppressed bone turnover (SSBT) patients, osteoporotic patients, and normal subjects

Pathogenesis of atypical fractures in patients on long term bisphosphonate therapy is poorly understood, and the type, the manner in which they occur and the fracture sites are quite different from the usual osteoporotic fractures. We hypothesized that the tissue-level mechanical properties and mean degree of mineralization of the iliac bone would differ among 1) patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy, 2) age-matched, treatment-na?ve osteoporotic patients with vertebral fracture, 3) age-matched normals and 4) young normals. Large differences in tissue-level mechanical properties and/or mineralization among these groups could help explain the underlying mechanism(s) for the occurrence of typical osteoporotic and the atypical femoral shaft fractures. Elastic modulus, contact hardness, plastic deformation resistance, and tissue mineral densities of cortical and trabecular bone regions of 55 iliac bone biopsies--12 SSBT patients (SSBT; aged 49-77), 11 age-matched untreated osteoporotic patients with vertebral fracture (Osteoporotic), 12 age-matched subjects without bone fracture (Age-Matched Normal), and 20 younger subjects without bone fracture (Young Normal)--were measured using nanoindentation and quantitative backscattered electron microscopy. For cortical bone nanoindentation properties, only plastic deformation resistance was different among the groups (p<0.05), with greater resistance to plastic deformation in the SSBT group compared to all other groups. For trabecular bone, all nanoindentation properties and mineral density of the trabecular bone were different among the groups (p<0.05). The SSBT group had greater plastic deformation resistance and harder trabecular bone compared to the other three groups, stiffer bone compared to the Osteoporotic and Young Normal groups, and a trend of higher mineral density compared to the Age-Matched Normal and Osteoporotic groups. Lower heterogeneity of modulus and contact hardness for cortical bone of the SSBT and trabecular bone of the Osteoporotic fracture groups, respectively, compared to the non-fractured groups, may contribute to fracture susceptibility due to lowered ability to prevent crack propagation. We tentatively conclude that, in addition to extremely low bone formation rate, atypical fractures in SSBT and/or long-term bisphosphonate treatment may be associated with greater mean plastic deformation resistance properties and less heterogeneous elastic properties of the bone.     

Assessment of Bone Microarchitecture in Postmenopausal Women on Long‐Term Bisphosphonate Therapy With Atypical Fractures of the Femur

Reports of atypical femoral fractures (AFFs) in patients receiving long‐ term bisphosphonate therapy have raised concerns regarding the genesis of this rare event. Using high‐resolution peripheral quantitative computed tomography (HR‐pQCT), we conducted a study to evaluate bone microarchitecture in patients who had suffered an AFF during long‐term bisphosphonate treatment. The aim of our study was to evaluate if bone microarchitecture assessment could help explain the pathophysiology of these fractures. We compared bone volumetric density and microarchitectural parameters measured by HR‐pQCT in the radius and tibia in 20 patients with AFFs with 35 postmenopausal women who had also received long‐term bisphosphonate treatment but had not experienced AFFs, and with 54 treatment‐naive postmenopausal women. Control groups were similar in age, body mass index (BMI), and bone mineral density (BMD). Mean age of the 20 patients with AFFs was 71 years, mean lumbar spine T‐score was ?2.2, and mean femoral neck T‐score was ?2. Mean time on bisphosphonate treatment was 10.9 years (range, 5–20 years). None of the patients had other conditions associated with AFFs such as rheumatoid arthritis, diabetes or glucocorticoid use. There were no statistically significant differences in any of the parameters measured by HR‐pQCT between postmenopausal women with or without treatment history and with or without history of atypical fractures. We could not find any distinctive microarchitecture features in the peripheral skeleton of women who had suffered an atypical fracture of the femur while receiving bisphosphonate treatment. This suggests that risk of developing an atypical fracture is not related to bone microarchitecture deterioration. Our results indicate that there may be other individual factors predisposing to atypical fractures in patients treated with bisphosphonates, and that those are independent of bone microarchitecture. In the future, identification of those factors could help prevent and understand the complex physiopathology of these rare events. © 2014 American Society for Bone and Mineral Research.     

Diaphyseal Femur Fractures in Osteogenesis Imperfecta: Characteristics and Relationship With Bisphosphonate Treatment

Several recent case reports have suggested that bisphosphonate treatment in individuals with osteogenesis imperfecta (OI) is causally related to atypical femur fractures. However, it is not known whether atypical femur fractures are actually more frequent in patients who have received bisphosphonates. In the present study, we retrospectively analyzed 166 femur fractures in 119 children with a diagnosis of OI that had not undergone intramedullary rodding procedures. A total of 130 fractures in 90 patients occurred in femurs with preexisting deformities (age at fracture between 1 month and 19.9 years; 43 girls). Because deformities are a typical cause of fracture in OI, deformed femurs were excluded from the analysis of atypical fractures. However, it was noted that in deformed femurs a transverse fracture pattern (one of the criteria of atypical fractures) was associated with a moderate to severe OI phenotype and not related to bisphosphonate treatment. Of the 36 fractures that occurred in nondeformed femurs (30 individuals; age at fracture between 1 month and 17.4 years; 13 girls), 11 (in nine children) occurred during bisphosphonate treatment. Three of these fractures (27%) resembled atypical femur fractures. Among the 25 femur fractures (23 patients) that occurred in the absence of prior bisphosphonate treatment, 8 (22%) resembled atypical femur fractures. Logistic regression analysis showed that bisphosphonate treatment history was not associated with the occurrence of atypical fractures. In contrast, the presence of moderate to severe OI (defined as any OI type other than OI type I) was strongly associated with atypical femur fractures. Thus, we observed an atypical appearance in about a quarter of nondeformed femur fractures that occurred in children with OI. Such atypical femur fractures seemed to be related to the severity of OI rather than to bisphosphonate treatment history. © 2016 American Society for Bone and Mineral Research.     

Recurrent Proximal Femur Fractures in a Teenager With Osteogenesis Imperfecta on Continuous Bisphosphonate Therapy: Are We Overtreating?

Long‐term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long‐term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair‐dependent. The case of this girl raises questions about the long‐term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low‐frequency, low‐dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case‐by‐case basis. © 2016 American Society for Bone and Mineral Research.     

Atypical Subtrochanteric and Femoral Shaft Fractures and Possible Association with Bisphosphonates

Several case series and multiple individual case reports suggest that some subtrochanteric and femoral shaft fractures might occur in patients who have been treated with long-term bisphosphonates. Several unique clinical and radiographic features are emerging: prodromal thigh pain prior to the fracture, complete absence of trauma precipitating the fracture, and bilateral fractures in some patients. Radiographic features include presence of stress reaction, transverse or short oblique fractures, and thick femoral cortices. The overall incidence of subtrochanteric and shaft fractures combined is below 30 per 100,000 person-years, so this type of fracture is much less common than proximal femur (hip) fracture. Furthermore, the unique “atypical” fracture type is a subset of all subtrochanteric and femoral shaft fractures. The putative mechanism is unknown, and more research is needed to identify distinctive characteristics and the pathophysiology of these atypical fractures. There is no rationale to withhold bisphosphonate therapy from patients with osteoporosis, although continued use of bisphosphonate therapy beyond a treatment period of 3 to 5 years should be re-evaluated annually.     

Clinical presentation and pathological features of atypical subtrochanteric fracture after bisphosphonate treatment

In recent years, there have been increasing reports of fractures associated with long-term bisphosphonate treatment. Clinical presentation should be examined carefully because fractures after long-term bisphosphonate treatment present typical symptoms and radiological and pathological findings. The unique clinical features of such fractures include prodromal thigh pain and complete absence of trauma. The radiological features include stress reaction of the thickened cortex and transverse or short oblique fractures on plain-film radiography and bone marrow edema on magnetic resonance imaging. Careful surveillance and early preventive internal surgical fixation must be considered by both orthopedic and non-orthopedic physicians. In this study, we reviewed recent articles on atypical subtrochanteric fractures after long-term bisphosphonate treatment. We also present the case of a 72-year-old woman with this type of a fracture who had been using a bisphosphonate for 2?years. The findings at presentation and pathological features of the fracture are discussed, including those of imaging studies, and the treatment administered is described.     

Surgical outcome of intramedullary nailing in patients with complete atypical femoral fracture: A multicenter retrospective study

BackgroundManagement of atypical femoral fracture on bisphosphonate therapy still remains controversy and is reported high rate of complications. The aim of this study was to evaluate the outcome of intramedullary nailing in patients with atypical femoral fracture who took bisphosphonate more than one year through the multicenter retrospective study.MethodsWe gathered 75 atypical femoral fractures from seven institutions between 2009 and 2014. Among them 46 atypical femoral fractures which met the inclusion criteria was evaluated in this study. The average age was 70.1 years (53–80) and the average duration of bisphosphonate use was 5.1 years (1–15 years). Medical records and radiographs were reviewed to determine time to union, union rate, need for revision surgery, restoration of ambulatory function, and complications.ResultsTwenty-nine (63%) fractures healed within 6 months without complications. The average time to union except two non-union was 24.9 weeks (11–48 weeks). Two patients (4.3%) underwent revision surgery for non-union and there was no implant failure. Thirty-seven (80.4%) patients achieved their pre-fracture ambulatory function at the final follow up.ConclusionsAlthough the incidence of delayed bone healing is high in atypical femoral fracture on bisphosphonate therapy even treated with intramedullary nailing, the incidence of revision surgery and implant failure was relatively lower than those of extramedullary devices.     

Atypical subtrochanteric and diaphyseal femoral fractures: Report of a task force of the american society for bone and mineral Research

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.     

Tibial stress reaction presenting as bilateral shin pain in a man taking denosumab for giant cell tumor of the bone

Prolonged bisphosphonate use has been associated with increased risk of atypical femoral fractures. Very few cases of atypical femoral fractures have been reported with denosumab. We report a case of bilateral tibial stress reactions in a 60-year-old man with no history of osteoporosis who was on prolonged high-dose denosumab for the treatment of giant cell tumor of bone. He presented with a 3-month history of pain in his bilateral shins worsening with activity and improving with rest. Although initial radiographs were unremarkable, he was found to have changes consistent with a stress reaction on magnetic resonance imaging of the distal tibia. To our knowledge, bilateral tibial stress reactions have not been previously reported with anti-resorptive therapies (neither bisphosphonates nor denosumab). Our case is intriguing in terms of the development of stress reactions as a precursor to stress fractures which may also relate to atypical fractures. Our case suggests a possible association between denosumab use and stress reactions. Of note the indication for denosumab in our case was for the treatment of giant cell tumor of bone where the Food and Drug Administration (FDA) approved dose is substantially higher than the FDA approved dose for osteoporosis treatment. Although rare, clinicians should consider the possibility of stress fractures in patients on anti-resorptive medications such as denosumab, especially when a patient presents with new onset thigh pain, hip pain or pain over an area affecting the long bones. Evaluation by imaging of affected areas should be pursued to enable early detection and intervention, as well as prevention of morbidity and associated ongoing risk to the patient.     

Incidence and demography of femur fractures with and without atypical features

The case definition, community incidence, and characteristics of atypical femoral shaft fractures (FSFs) are poorly understood. This retrospective study utilized electronic medical records and radiograph review among women ≥50 years of age and men ≥65 years of age from January 1996 to June 2009 at Kaiser Permanente Northwest to describe the incidence rates and characteristics of subgroups of femur fractures. Fractures were categorized based on the American Society for Bone and Mineral Research (ASBMR) as atypical fracture major features (AFMs) (low force, shaft location, transverse or short oblique, noncomminuted) and AFMs with additional minor radiograph features (AFMms) (beaking, cortical thickening, or stress fracture). There were 5034 fractures in the study. The incidence rates of FSFs (without atypical features) and AFMs appeared flat (cumulative incidence: 18.2 per 100,000 person‐years, 95% CI = 16.0–20.7; 5.9 per 100,000 person‐years, 95% CI = 4.6–7.4; respectively) with 1,271,575 person‐years observed. The proportion of AFMs that were AFMms increased over time. Thirty percent of AFMs had any dispensing of a bisphosphonate prior to the fracture, compared to 15.8% of the non‐atypical FSFs. Years of oral glucocorticosteroid dispensing appeared highest in AFM and AFMm fractures. Those with AFMs only were older and had a lower frequency of bisphosphonate dispensing compared to those with AFMms. We conclude that rates of FSFs, with and without atypia, were low and stable over 13.5 years. Patients with only AFMs appear to be different from those with AFMms; it may be that only the latter group is atypical. There appear to be multiple associated risk factors for AFMm fractures. © 2012 American Society for Bone and Mineral Research.     

What do we know about atypical femoral fractures? Insights and enigmas

Although the existence of atypical femoral fractures is well established and bisphosphonate therapy is thought to be a major risk factor, the underlying mechanisms are poorly understood. Epidemiological data show that atypical femoral fractures account for only a small proportion of diaphyseal subtrochanteric femoral fractures, being about 100 times less common than proximal femoral fractures. Consequently, the existence of atypical femoral fractures does not call into question the extremely favorable risk/benefit ratio of bisphosphonate therapy in patients with osteoporosis. Clearly, the number of fractures prevented by bisphosphonate therapy far exceeds the number of atypical femoral fractures potentially related to bisphosphonates.