Antiresorptive drugs, such as amino-bisphosphonates and denosumab (Dmab), have dominated osteoporosis therapies for over 20 years. Since osteoporosis is a chronic disease, antifracture therapy could continue for the rest of a patient's life. Phase III clinical trials for antiresorptive drugs assessed relatively small patient populations for short durations and excluded up to 80% of patients who might seek osteoporosis therapy in clinical practice. Postmarketing reports based upon millions of patient-years and long-term (>5 years) clinical administration have associated some previously unknown, rare adverse events with antiresorptive use including osteonecrosis of the jaw (ONJ) and atypical femur fractures (AFFs). In the osteoporosis patient population, who receive much lower doses of bisphosphonate (BP) or Dmab, the incidence of ONJ is estimated at 0.001% to 0.01%, which is only slightly higher than that seen in the general population. AFFs are insufficiency or fissure transverse fractures originating on the lateral cortex of the subtrochanteric or diaphyseal region of the femur becoming oblique as they progress medially when complete. Incidence rates of AFF range from 1.8/100,000 per year with a 2-year BP exposure to 113/100,000 per year with BP exposure from 8 to 9.9 years. Most recent pathogenic hypotheses of these rare events will be discussed.
Keywords: atypical femur fracture; bisphosphonates; denosumab; osteonecrosis of the jaw.