Jörg Schilcher

Bisphosphonate use and atypical fractures of the femoral shaft.

BACKGROUND Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use. METHODS In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. RESULTS The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). CONCLUSIONS These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.).

Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate

Background Recent case reports have identified an association between long-term bisphosphonate treatment and stress fractures of the femoral shaft. The risk of such fractures in bisphosphonate users has not been determined. Methods We identified women over 55 years of age with the specific fracture pattern by searching the operation registry of the hospitals in 2 healthcare districts. Prevalence of bisphosphonate treatment was provided by a Swedish national registry covering all drugs delivered to all individuals since 2005. Results The number of women on bisphosphonate treatment was 3,087. Of these, 5 had femoral stress fractures. They had been taking bisphosphonates for 3.5 to 8.5 years. The incidence density for a patient on bisphosphonate was 1/1,000 per year (95% CI: 0.3–2). In the remaining 88,869 women who were not taking bisphosphonates, there were 3 stress fractures. Thus, their risk (without correction for inhomogeneity in age distribution) was 46 times less (95% CI: 11–200). Interpretation These results are rough estimations based on a comparatively small material. Still, a treatment-associated incidence density of 1/1,000 is acceptable, considering that bisphosphonate treatment is likely to reduce the incidence density of any fracture by 15/1,000 according to a large randomized trial ().

Risk of Atypical Femoral Fracture during and after Bisphosphonate Use

This letter indicates that there is long-lasting skeletal accumulation of bisphosphonate, and ongoing use appears to be the dominant risk factor for rare fractures.

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

BACKGROUND Estimations 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. METHODS In 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. RESULTS Frequency 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). INTERPRETATION Stress 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.

Risk of atypical femoral fracture during and after bisphosphonate use : Full report of a nationwide study

Background and purpose — Use of bisphosphonates in women is associated with higher risk of atypical femoral fractures. The risk in terms of timing of use and type of bisphosphonate, and in men, remains unclear. Patients and methods — We reviewed radiographs of 5,342 Swedish women and men aged 55 years or more who had had a fracture of the femoral shaft in the 3-year period 2008–2010 (97% of those eligible), and found 172 patients with atypical fractures (93% of them women). We obtained data on medication and comorbidity. The risk of atypical fracture associated with bisphosphonate use was estimated in a nationwide cohort analysis. In addition, we performed a case-control analysis with comparison to 952 patients with ordinary shaft fractures. A short report of the findings has recently been presented (Schilcher et al. 2014a). Here we provide full details. Results — The age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39–79) in women and 54 (CI: 15–192) in men. In bisphosphonate users, women had a 3-fold higher risk than men (RR = 3.1, CI: 1.1–8.4). Alendronate users had higher risk than risedronate users (RR = 1.9, CI: 1.1–3.3). The RR after 4 years or more of use reached 126 (CI: 55–288), with a corresponding absolute risk of 11 (CI: 7–14) fractures per 10,000 person-years of use. The risk decreased by 70% per year since last use. Interpretation — Women have a higher risk of atypical femoral fracture than men. The type of bisphosphonate used may affect risk estimates and the risk decreases rapidly after cessation.

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.

Atypical fracture of the femur in a patient using denosumab – a case report

A woman born in 1930 was diagnosed with osteoporosis in 2000, and was started on treatment with alendronate. Her lumbar T-score in 2010 was –3.0. In 2008, she had a displaced atypical fracture of her left femur, which healed uneventfully after intramedullary nailing (Figure 1). No radiographs of her contralateral femur were obtained. She continued taking alendronate until it was stopped in September 2010. In February 2011, she received a single zoledronate infusion. No bisphosphonate was given after that, due to reduced kidney function. She received a first injection of denosumab in April 2012 and then every 6 months, with the last and fourth injection in October 2013.

Histology of an undisplaced femoral fatigue fracture in association with bisphosphonate treatment. Frozen bone with remodelling at the crack.

A 57-year-old woman stumbled over her carpet, almost fell, and tried to sit down on the floor, when she heard a crack and sustained a transverse diaphyseal fracture of her left femur. The fracture had been preceded by thigh pain for a couple of months, but this was thought to be caused by spinal stenosis, for which she had been operated twice. She had been diagnosed with seronegative rheumatoid arthritis 10 years before the fracture and had initially undergone different pharmacologcal treatments, all of which except cortisone had been terminated. The diagnosis was repeatedly doubted, but cortisone gave symptomatic relief and was therefore continued at 5 mg/day with intermittent high-dose treatment (25 mg/day) during exacerbations. Apart from prednisolone, no anti-rheumatic drugs had been given during the previous 6 years. The patient had been given alendronate (70 mg/week) in 2001, followed by risedronate (35 mg/week) from 2002 until the fracture in 2009. The patient had also been taking 20–40 mg omeprazol a day since 2000. The fracture had a typical fatigue fracture appearance (Neviaser et al. 2008), and was operated on with intramedullary nailing. Because of a history of pain on weight bearing also in her contralateral thigh, new radiographs were taken and showed a non-displaced stress fracture of the subtrochanteric region (Figure 1). This fracture was also treated with intramedullary nailing. Figure 1. Right femur. Arrow indicates undisplaced fatigue fracture. Surgery (second operation) After the nail had been inserted, the non-displaced fracture was exposed. It could be seen as a dark line the size of a hair on the bone surface, surrounded by a barely visible protrusion of the bone. A 12 × 15-mm specimen including the fracture was excised, with the patients informed consent. The procedure was approved by the Regional Ethics Committee. Both fractures healed uneventfully and mineralized callus was seen at the biopsy site after 5 months.

Atypical Femoral Fractures, Bisphosphonates, and Mechanical Stress

Atypical fractures are stress fractures occurring in the femoral shaft and closely related to bisphosphonate use. We here discuss their radiographic definition and different putative etiologies, apart from mechanical stress. Long time reduction of skeletal remodeling because of bisphosphonate use is thought to allow time for the bone to deteriorate mechanically, resulting in reduced toughness. However, the risk of atypical fracture diminishes rapidly after cessation of treatment, which suggests more acute effects of bisphosphonate use. Microdamage normally accumulates at areas of high stress. Possibly, ongoing bisphosphonate use reduces the ability to resorb and replace areas of microdamage by targeted remodeling. This could lead to crack propagation beyond a point of no return, ending in macroscopic stress fracture.

Epidemiology, Radiology and Histology of Atypical Femoral Fractures : Development of understanding

“The beginning of knowledge is the discovery of something we do not understand.” – Frank Herbert