Unexpected Benefits of Bisphosphonates after Hip Fracture

Significant treatment by disease interactions were observed in HORIZON-RFT for arrhythmias and pneumonia, with fewer treated patients dying of these illnesses.¹⁰

These findings raise the possibility that bisphosphonates may impact these illnesses through their documented immune system or antiinflammatory effects. Further work needs to be done to untangle these findings.

Practical and Safety Considerations for Bisphosphonate Use in Hip-Fracture Patients

Because of the higher burden of comorbidities in hip-fracture patients compared with postmenopausal osteoporosis populations, the concern for drug safety is heightened. In addition, there are logistical implications for initiating bisphosphonates in frail patients who may be transitioning between healthcare settings. The following section will consider fracture healing, vitamin D deficiency, renal safety, and the timing of infusion. We will discuss whether some patients are “too frail” to receive secondary fracture prevention after hip fracture.

Animal studies have suggested that bisphosphonates given in the acute fracture period might have an adverse impact on healing due to their suppression of bone turnover and therefore remodeling; the few human studies available have reported conflicting results, with oral bisphosphonates enhancing callus formation in Colles’ fractures, but doubling the risk of delayed healing of humeral fractures.^11,12 HORIZON-RFT was therefore designed to prospectively identify and centrally adjudicate all potential cases of delayed hip-fracture healing. Similarly, potential cases of hip avascular necrosis were adjudicated as a potential harmful effect of giving zoledronic acid in the post-fracture period; femoral neck fractures may damage the single artery to the femoral head and precipitate a process similar to that hypothesized to lead to osteonecrosis of the jaw. While the rates of these complications in the HORIZON-RFT study were generally low, there was no difference in delayed fracture healing or avascular necrosis in those receiving zoledronic acid or placebo, regardless of the timing of infusion in relation to the hip-fracture repair.¹³ Thus, it appears that fracture healing complications are not a concern with bisphosphonates in hip-fracture populations.

The prevalence of vitamin D insufficiency has been reported to exceed 60% in hip-fracture patients.¹⁴ This is a concern in initiating bisphosphonates, particularly intravenous formulations, because of the risk of precipitating clinically significant hypocalcemia.¹⁵ This risk may be especially problematic in older patients with concomitant renal impairment and secondary hyperparathyroidism. Measurement of 25(OH) vitamin D levels is recommended after fragility fracture, but results are often not immediately available, and then further delay accrues if the patient requires repletion prior to initiation of bisphosphonate. After initial experience in HORIZON-RFT demonstrated that most patients were vitamin D insufficient, and that waiting for 25(OH) vitamin D levels to return before proceeding with the protocol was not practical, the approach taken was to provide repletion dose for everyone with a single dose of approximately 100,000 IU vitamin D one week prior to the zoledronic acid infusion. The precise dose used and whether the supplement was D2 or D3 varied slightly across countries based on availability.