HORIZON-RFT showed that yearly zoledronic acid reduced the risk of subsequent clinical fractures after hip fracture by 35%, with comparable reductions in all fracture types, and across multiple subgroups of patients. BMD was significantly improved, as were quality-of-life measures related to pain and mobility.7 Fracture reduction benefits were seen in both community dwelling and institutionalized patients, and were also seen in those with baseline BMD above –2.5. Surprisingly, although mortality was included as a safety endpoint in the study, a significant 28% reduction in mortality was also observed in the treated patients; this was the first time a mortality benefit had been documented with an osteoporosis treatment.
Following the publication of the HORIZON-RFT trial results, additional studies have replicated the positive mortality findings among hip-fracture patients. In a cohort of 209 patients with hip fracture, treatment with oral bisphosphonate was associated with a significantly lower mortality, (6% reduction per month of treatment), even after adjusting for multiple confounders.8
Also consistent with the findings on lower mortality in treated patients, oral bisphosphonate use was associated with a 27% reduction in mortality among frail, institutionalized older adults in Australia.9 Thus, it appears that the antifracture efficacy of bisphosphonates is substantial in hip-fracture patients despite their competing comorbidities and lower life expectancies, and that measurable reductions in mortality are seen with oral and IV bisphosphonate treatment in this group.
Potential Mechanisms for Mortality Reduction
Because osteoporotic fractures themselves are associated with morbidity and mortality, it would seem logical that the lower rate of secondary fractures would explain the mortality reduction observed in HORIZON-RFT and subsequent studies. However, analyses of these data have shown that only 8% of the mortality reduction can be explained by prevention of secondary fractures.10 Potential mechanisms for the remaining mortality benefit remain controversial, but several intriguing hypotheses have been formulated.
It was noted in HORIZON-RFT that, while intervention and control patients had similar rates of common acute illnesses such as pneumonia or cardiovascular events, the risk of dying from these acute events was lower across most categories of illness in those patients who had received zoledronic acid. This pattern is consistent with a mechanism termed hormesis. In hormesis, an acute stressor (such as the acute phase reaction precipitated by intravenous bisphosphonate) renders an organism better able to withstand subsequent stressors. However, since the mortality benefit of bisphosphonates also appears to extend to oral agents, which have very short serum half-lives and no appreciable acute phase response, it is unclear how hormesis could be produced.
