Observational studies—just telling us what we want to hear or telling us where we need to look?

The association of osteoporosis with cardiovascular disease and increased mortality has been recognized for many years. Over the last decade, increased mortality after specific fractures has also been documented, though whether this represents a causal link or just reflects the frailty and comorbidities of those who fracture, is unresolved. The osteoporosis–mortality connection took on a much greater significance after a randomized controlled trial of zoledronate in patients with recent hip fracture demonstrated a 28% reduction in all‐cause mortality and a 35% reduction in numbers of clinical fractures associated with randomization to zoledronate. Because not everybody who fractures dies, the reduction in fracture incidence could not account for the substantial reduction in mortality, opening up the possibility that zoledronate had some direct effect on mortality. A direct effect of bisphosphonates on cardiovascular mortality is an attractive explanation for the rapid onset of this effect and its magnitude, so there has been a significant effort to explore possible mechanisms for a cardioprotective effect of bisphosphonates, and seek further evidence for it. In the elderly, calcification of arteries is very common, and bisphosphonates bind avidly to calcium. Thus, they are targeted to the vasculature, where they are postulated to influence T cell and macrophage function, and to reduce levels of inflammatory cytokines. The inhibition of farnesyl pyrophosphate synthase (in the mevalonate pathway) by bisphosphonates, leads to a reduction in prenylated RhoA, which in turn will increase tissue levels of nitric oxide. This would be expected to decrease monocyte adhesion, platelet aggregation, and vascular smooth muscle cell proliferation, and to cause vasodilation. Thus, a cardioprotective of bisphosphonates is biologically plausible. This possibility is further explored in the carefully conducted observational study of Wolfe and colleagues in this issue of the Journal of Bone and Mineral Research. They accessed data on 19,281 adults with rheumatoid arthritis enrolled in a longitudinal study recruited from rheumatology practices in the United States. Patients completed 6‐monthly questionnaires relating to medication use and health status. Myocardial infarctions (MIs) were confirmed by a central adjudicator. Among the 5689 patients who were treated with bisphosphonates at some time during the study period, the risk of MI while on bisphosphonate compared towhen not on bisphosphonatewas 0.56 (95%CI 0.37, 0.86, p< 0.01), after adjustment for multiple confounders. This approach, of focusing the analysis on the bisphosphonate‐ treated patients, and comparing event rates in their periods on and off treatment, is an innovative way to overcome the many significant differences between the bisphosphonate‐treated subjects and the others in the cohort. Although this overcomes the problem of residual confounding between subjects, it might create a separate set of difficulties. Are patients with increasing angina or other acute medical problems more likely to discontinue their oral bisphosphonates, either because osteoporosis management seems a lesser priority at that time, or because of the possibility that the bisphosphonates may have been contributing to the chest pain? The long residence time of bisphosphonates in calcified tissue (skeletal or vascular) makes this approach less suitable with these drugs. Reassuringly, similar results emerge from this within‐patient analysis to those found when users and nonusers are compared with the broader cohort. These findings appear to agree with the findings of the Lyles’ trial in suggesting that bisphosphonates are cardioprotective. In the presence of a reasonable biological explanation for these findings, should we be embracing bisphosphonates with even greater enthusiasm in the elderly at risk of both osteoporosis and cardiovascular disease? Possibly not, since the full picture is not quite so straightforward. Following the Lyles article, the same authors published very detailed analyses of themortality effects in that study and could not demonstrate that the mortality benefit was attributable to an effect on any single organ system. The incidence of common conditions was not different between the treatment groups, but beneficial trends in mortality were seen for cardiac, respiratory, and neoplastic diseases. Thus, we have the puzzling situation of zoledronate‐treated patients appearing to be more robust in the face of whatever pathology afflicts them, and