Risk factors for development of atypical femoral fractures in patients on long-term oral bisphosphonate therapy

Bisphosphonates (BPs) are the first-line therapy for osteoporosis. In recent years, atypical femoral fractures (AFF) have been described in patients on BPs therapy. However, the relationship between BPs and AFF remains to be clarified. We evaluated clinical and hormonal characteristics of AFF patients, in order to determine AFF risk factors. We studied 11 females with AFF and 58 females with typical femoral fractures (TFF), admitted to our Department for surgical repair between January 2008 and December 2011. All AFF patients received BPs therapy for 6 to 13 yrs, whereas 36.2% (p < 0.0001) of TFF patients received BPs for shorter period (TFF, 6.1 ± 1.8 yr vs. AFF, 8.6 ± 1.9 yr, p < 0.0001). A higher prevalence of hypocalcemia was observed in AFF patients compared with TFF (p < 0.02), with significantly (p < 0.05) lower corrected calcium levels in AFF patients. By contrast a reduced prevalence of elevated PTH levels (p < 0.05) was found in AFF patients. No significant difference in prevalence of vitamin D defect was observed between the two groups. Younger age (p < 0.004), higher BMI (> 30 kg/m2, p < 0.03) and early menopausal age (p < 0.05) were observed in AFF patients. At time of fracture, prevalence of osteopenia/osteoporosis and levels of bone turnover markers were significantly (p < 0.01) lower in AFF compared with TFF patients. By multivariate analysis hypocalcemia, obesity, and younger age (< 70 yr) were confirmed to be independent predictors of AFF; elevated PTH level was the predominant independent protective factor (p < 0.004). In conclusion, our data indicate that clinical characteristics and metabolic factors may favor the development of AFF in BP treated patients. We identified hypocalcemia due to latent hypoparathyroidism as primary risk factor for AFF; age, obesity, early menopause, and BMD may also influence the development of AFF. An adequate clinical and metabolic assessment is suggested to prevent the development of AFF in BP treated patients.