Bisphosphonate-associated Atypical Femoral Fractures Research Articles

Characteristic features and surgical outcome in bisphosphonate-associated atypical femoral fracture: A retrospective observational study

Background: Bisphosphonate-associated atypical femoral fracture (AFF) is a rare and serious ‎condition with poorly understood characteristics and management. ‎Objectives: To evaluate the characteristic features and outcomes of AFF in a two-center cohort ‎study.‎Methods: In a retrospective survey, medical profiles of 22 AFF patients, who have used ‎alendronate for > 12 months, were reviewed. The demographic characteristics such as age, ‎gender, and BMI, the clinical features including symptoms, symptom duration, radiologic ‎characteristics including fracture site, the severity of the fracture, and contralateral involvement, ‎surgical characteristics including the type of surgery union period and postoperative ‎complications such as fixation failure, and union problems were extracted from the patients’ ‎profiles.‎Results: The study population included 4 males and 18 females with a mean age ‎of ‎70.6±11.9 ‎‏ ‏years. ‎‏The mechanism ‎of fracture was falling down‎ in 21 (95.5% ) patients. The ‎mean duration of ‎‏bisphosphonate consumption was ‎‏‎3.8±2 ‎‏‎ years. Prodromal symptoms (pain and ‎limping) were recorded in 12 (54.55%) ‎‏patients. ‎‏The fracture was in the femoral shaft in 15 ‎‎(68.2%) and in the subtrochanteric‎‏‎ in 7 (‎‏‏‎31.8%) patients. ‎‏The fixation device was ‎‏the ‎intramedullary nail in 18 (81.8%) and plate in 4 (18.2%) patients. ‎‏The mean union period was ‎‏‎8.3±2.8 ‎months. Union complications (delayed or ‎‏nonunion) occurred in 6 (27.3%) patients. ‎Fixation failed in 5 (22.7%) patients (3 nails and 2 ‎‏plate fixation).‎‏Conclusions: AFF is associated with a prolonged union. ‎‏The intramedullary nail provides a more ‎secure fixation. Prodromal symptoms could be used for earlier detection of patients. ‎‏

Knowledge and Needs of Resident Physicians Regarding Osteoporosis: A Nationwide Survey of Residents.

ABSTRACTLarge‐scale studies have not addressed the knowledge level of US resident physicians regarding osteoporosis management. We gauged the knowledge level of family medicine, internal medicine, and obstetrics and gynecology resident physicians regarding osteoporosis management. In 2019, we sent an anonymous survey via e‐mail to all program directors of Accreditation Council for Graduate Medical Education–accredited residency programs in family medicine, internal medicine, and obstetrics and gynecology for distribution to resident physicians. Knowledge items assessed osteoporosis screening, diagnosis, and treatment. We received responses from 182 family medicine, 275 internal medicine, and 122 obstetrics and gynecology programs. Of 582 resident physician respondents, 31% were family medicine residents, 47% were internal medicine residents, and 21% were obstetrics and gynecology residents. Although 77% of respondents correctly selected the T‐score threshold for the diagnosis of osteoporosis among persons aged 50 years and older (−2.5), only 20% of respondents correctly identified minimal‐trauma hip fracture as being diagnostic of osteoporosis. One‐third of respondents correctly identified which medications were demonstrated in clinical trials to decrease hip fracture risk. Fifteen percent of respondents correctly identified that denosumab and alendronate are associated with osteonecrosis of the jaw; and 40% of respondents correctly identified that decline in bone density is more rapid after discontinuation of denosumab than after discontinuation of bisphosphonates. Less than half of resident physicians knew that bisphosphonate‐associated atypical femoral fractures are duration‐dependent. One‐quarter of respondents felt not at all prepared to manage osteoporosis. In this nationwide survey of resident physicians, knowledge regarding osteoporosis diagnosis and treatment was poor, with a striking lack of knowledge regarding the two most serious adverse effects of osteoporosis pharmacotherapy (osteonecrosis of the jaw and atypical femoral fractures). The undertreatment of osteoporosis is unlikely to improve without increased education of resident physicians. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture

Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n = 51) with population-based controls (n = 4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n = 324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p < 5 × 10−8 was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p < 5.7 × 10−6). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

Incidence and medical management of bisphosphonate-associated atypical femoral fractures in a major trauma centre: a retrospective observational study

BackgroundAtypical femoral fractures (AFFs) are rare events associated with increased duration of bisphosphonate exposure. Recommended management of AFFs include cessation of bisphosphonates and imaging of the contralateral femur. The aims of this study were to identify the local incidence of AFFs in bisphosphonate users and to audit the medical management of AFFs against published recommendations.MethodsA retrospective analysis of the admissions database for a major trauma centre identified all femoral fractures (3150) in a five-year period (July 2009 to June 2014). Electronic health records and radiographs were reviewed using the 2013 American Society for Bone and Mineral Research (ASBMR) diagnostic criteria for AFF to establish the number of cases. To estimate incidence, the total number of bisphosphonate users was derived from primary care prescription and secondary care day-case records. Medical management of cases with AFF on bisphosphonates was audited against guidance from ASBMR and Medicines & Healthcare Products Regulatory Agency.Results10 out of 3150 femoral fractures met criteria for AFF; 7 of these patients had a history of exposure to bisphosphonates (6 oral, 1 intravenous). There were 19.1 AFFs per 100,000 years of bisphosphonate use in our region. Bisphosphonates were stopped and the contralateral femur imaged in only 2 of the 7 patients treated with bisphosphonates.ConclusionOur local incidence is in line with published figures; however, this is the first published evidence suggesting that medical management and identification of AFF may be suboptimal. Managing these patients remains challenging due to their rarity and possible lack of awareness.

Clinical features of atypical femur fracture

ObjectivesWe aim to elucidate the clinical outcomes of bisphosphonate-associated atypical femoral fracture and the clinical results depending on the bisphosphonate therapy period. MethodsTwenty cases involving 15 patients who had been diagnosed with atypical femoral facture between 2004 and 2014 and who had been followed up for at least 12 months were retrospectively analyzed. The control group was composed of 15 typical femoral facture patients. We used plain radiography and physical examinations to determine the period of time required for fracture healing as well as complication occurrence. We investigated the bisphosphonate administration status and duration and the names of its components, bilateral fracture occurrence status, the period of time required for bone union, and reoperation or bone graft status due to nonunion. ResultsRevision surgery involving a bone graft was performed due to nonunion in 1 out of 15 cases. Except in one revision case, the duration of the union was 11.9 months on average in 14 cases of atypical fracture patients, and 4.3 months on average in the control group. This difference was statistically significant (p < 0.05). The bisphosphonate administration duration was positively correlated with the union period (p < 0.05). In contrast, there was no statistically significant correlation between the bisphosphonate administration duration and the incidence of bilateral atypical fractures (p > 0.05). ConclusionsAtypical femoral fractures required more time for bone union than typical ones and prolonged bisphosphonate administration led to a longer period of time required for bone union.

Identification of Risk Factors for Bisphosphonate-Associated Atypical Femoral Fractures and Osteonecrosis of the Jaw in a Pharmacovigilance Database.

Atypical femoral fractures (AFs) and osteonecrosis of the jaw (ONJ) are well-known adverse drug reactions (ADRs) associated with bisphosphonates. To prevent these ADRs and to aid in the search for pathogenic mechanisms, knowledge of risk factors can be helpful. To identify risk factors for bisphosphonate-related ONJ and AF. In this case-control study of reports of bisphosphonate-related ADRs from February 16, 1984, to October 16, 2013, in the Swedish national database of ADRs, we compared characteristics for cases of ONJ (n = 167) and AF (n = 55) with all other bisphosphonate-related ADRs (n = 565) with regard to demographic variables, clinical characteristics, and concomitant drug treatments. We adjusted for multiple comparisons with Bonferroni correction. Time to onset of ADRs differed statistically significantly between cases of AF and controls (2156 vs 111 days). For ONJ versus controls, differences were statistically significant for time to onset (1240 vs 111 days), intravenous administration (40% vs 20%), dental procedures (49% vs 0.2%) and prostheses (5% vs 0%), cancer disease (44% vs 12%), multiple myeloma (21% vs 1%), rheumatoid arthritis (14% vs 5%), and treatment with antineoplastic agents and oxycodone. These results lend further evidence to previously identified risk factors for ONJ-that is, intravenous bisphosphonate administration; invasive dental procedures and dental prostheses; cancer disease, in particular multiple myeloma; and possibly, long-term bisphosphonate treatment. A putative further risk factor is rheumatoid arthritis. Only long-term bisphosphonate treatment was more common among AF cases. The lack of overlap of risk factors between ONJ and AF suggests different pathogenic mechanisms.

Atypical Vancouver Type-C Periprosthetic Fracture Complicated by Nonunion

In recent years, atypical femoral fractures (AFFs) associated with bisphosphonate use have increasingly been reported, but current definitions limit their diagnosis to native femora. Atypical periprosthetic fractures are rare. We present a case of a Vancouver type-C periprosthetic fracture that was recognized as an AFF following nonunion. Bisphosphonate-associated AFFs can present as periprosthetic fractures. Delayed recognition of the role of bisphosphonates in a periprosthetic fracture may lead to a worse outcome, including a delay in diagnosis, delayed union, and failure of fixation.

Treating Atypical Femoral Fractures Related to Bisphosphonates.

Doctors widely prescribe osteoclast-inhibiting bisphosphonate drugs to treat osteoporosis, but long-term bisphosphonate use has been linked to an increased risk of atypical subtrochanteric femoral fractures. According to an updated task force report from the American Society for Bone and Mineral Research, the features that distinguish these atypical subtrochanteric fractures include transverse orientation, general lack of comminution, and localized cortical thickening at the fracture site. In addition, the prolonged healing times of these fractures challenge orthopaedists to obtain strong and stable fixation that outlasts the extended period required for fracture union. Intramedullary nailing is often used to treat these fractures, but related characteristics such as canal narrowing can make this fixation approach unfeasible. This month’s “Case Connections” looks at various techniques for repairing bisphosphonate-associated atypical femoral fractures. In the January 14, 2015, JBJS Case Connecto r , Yuasa et al. reported on the case of a sixty-nine-year-old woman who, one month prior to scheduled right hip arthroplasty to treat osteoarthritis, presented with severe right thigh pain after a low-trauma fall. History-taking revealed four-plus years of treatment with alendronate (Fosamax), and radiographs showed a noncomminuted transverse subtrochanteric fracture below an arthritic hip joint. During a single operation, the patient underwent cementless total hip arthroplasty using a modular stem/neck, followed by fracture reduction and fixation using a cable-and-plate system (Fig. 1). The patient was switched from alendronate to a …

Bisphosphonate-associated atypical femoral fractures and one-year mortality

Dear Editor, It is well known that osteoporotic fractures (OF) of the hip are associated with increased mortality, in particular immediately after the fracture (1). Although several theories have been proposed, the cause of the increase is not fully understood. In the past few years there have been an increasing number of reports of femoral fractures associated with bisphosphonate use (2). The pattern of these fractures differs from the typical OFs, and hence they are referred to as atypical fractures (AF). One of the differences between the two is the fact that OFs are secondary to a disease, while AFs is the result of an adverse drug reaction (ADR). However, both affect patients with osteoporosis, and the end result is fracture of the same bone (femur). Whether or not AFs are associated with a similar increase in mortality as OFs is unknown. We aimed to investigate this question. The Medical Products Agency (MPA) is the Swedish regulatory authority registering spontaneous reports of ADRs from health care professionals. We reviewed all reports of AF received by the MPA, from January 2006 through September 2013, associated with use of oral bisphosphonates or once-yearly intravenous zoledronic acid, prescribed with osteoporosis as the indication. Reports not fulfilling diagnostic criteria for AF were excluded (3). Diagnostic accuracy (3) was confirmed in all patients consenting to have their medical records and radiographs reviewed. The one-year mortality rate was determined by using data from the national population register of the Swedish tax authority. For all cases, survival or mortality was determined at least one year after the fracture. A total of 48 reports had been received from January 2006 through September 2013. Forty-four reports (2 men, 42 women) fulfilled the diagnostic criteria for AF (3). Twenty-seven patients consented to complete a structured interview about their medical history and drug therapies, and to have their medical records and radiographs reviewed. Diagnostic accuracy (3) could be confirmed in each case. Data on co-morbidities were collected based on either interviews and medical records, or on information from case narratives. The mean age of the 44 patients at the time of the AF was 73 years. During the mean follow-up time (from fracture to determination of mortality) of four years, five (all women) of the included 44 patients had died (11.4%), of which one (2.3%) had done so within one year after the fracture. Like patients who experience OFs, the great majority of the patients in the current study were women. Based on the results of a previously published Swedish nation-wide study, the one-year mortality rate among women aged 70–75 years who experience a hip fracture has been estimated to be 9.6% (4). In comparison, based on the results of the present study, the one-year mortality rate following AF of the hip appears significantly lower (2.4% for the 42 women). As frequencies of co-morbidities were similar (cardiovascular disease 21.4% versus 28.6%; obstructive lung disease/pneumonia 14.3% versus 5.0%; diabetes 4.8% versus 5.0%; cancer 7.1% versus 8.3%; psychiatric disease 4.8% versus 12.5%), the difference in mortality rate is unlikely to be explained by differences in patient characteristics. In conclusion, although AF is often associated with delayed healing (3), our results reveal no evidence of a high mortality rate. In this respect, AF appears less hazardous compared to OF, which should be of importance when assessing the benefit risk ratio of bisphosphonate therapy. Since both AF and OF affect the same category of patients and the same bone, it is reasonable to assume that the higher mortality rate associated with OF is not entirely due to the fracture (5), but rather the overall systemic effects of the disease, and possibly genetic factors.

Bisphosphonate-associated atypical femoral fracture, effect of teriparatide

Bisphosphonate-associated atypical femoral fracture, effect of teriparatide

Histology of 8 atypical femoral fractures

Background and purpose — The pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues.Patients and methods — Between 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology.Results — Incomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 µm. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption.Interpretation — Atypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival.

Vitamin D and atypical femoral fractures

Dear Editors, There have been recent reports of atypical femoral fractures occurring in patients treated with bisphosphonates [1]. While the primary hypothesis has centered on the oversuppression of bone turnover, there have been suggestions that vitamin D deficiency might also be an important risk factor [1, 2]. Thus far, only one series has examined the association between vitamin D levels and atypical femoral fractures [2]. In the study by Girgis et al., serum 25-hydroxyvitamin D (25OHD) of less than 16 ng/mL was associated with an increased the risk of atypical subtrochanteric fractures (OR03.2). While it is plausible that vitamin D deficiency may play a role in the pathogenesis of these fractures since it is associated with impaired calcium absorption, compensatory hyperparathyroidism, and increased bone resorption, it was not an evident risk factor in our clinical experience. In our case series, which was one of the first published series describing this phenomenon [3], there were 16 women, age 52 to 91 years and of Asian ethnicity, who had a serum 25OHD level ascertained at the time of presentation between May 2004 and March 2010. They were compared to age-, ethnicity-, and sex-matched controls with low-energy osteoporotic femoral neck or pertrochanteric fractures admitted during the same period of time. Vitamin D deficiency was defined as 25OHD <20 ng/mL. Baseline characteristics were similar between cases and controls. The median 25OHD was 26.2 ng/mL in cases vs 19.0 ng/mL in controls (p00.0127), consistent with a greater use of calcium (81.3 vs 37.5 %, p00.004) and vitamin D (68.8 vs 34.4 %, p0 0.024) supplementation in cases vs. controls. Only 3 out of 16 cases (18.75 %) were vitamin D deficient, while 17 out of 32 controls (53.13 %) were vitamin D deficient (p0 0.031). The odds ratio for vitamin D deficiency in cases vs controls was 0.20 (95 % CI 0.03, 0.97). The main limitation of this analysis was the measurement of 25OHD at the time of presentation rather than at the initiation of and during bisphosphonate therapy. Nevertheless, our study indicated that vitamin D status was significantly better in cases vs controls at the time of fracture, suggesting that vitamin D status might be a less important factor than previously thought in the development of bisphosphonate-associated atypical femoral fractures.