Bisphosphonates May Act to Reduce Mortality through Vascular Mechanisms

Bisphosphonates are used as a treatment for osteoporosis. Like most pharmaceutical therapies for age-related disease, they have a set of unpleasant side-effects, but a couple of studies have found evidence for long-term bisphosphonate use to reduce mortality in older individuals. In one case the effect was quite large, a dramatic decrease in mortality versus the expected rates. I think there remains some skepticism about an effect of that size resulting from commonly used medications, versus it being an accident of the data or the study group or some other correlated but unrecorded difference, at least until further studies with larger patient groups take place.

What might the mechanism be, however? Past work suggests that bisphosphonates have some beneficial effect on stem cell activity, which might be a viable explanation, given better evidence in patients. The paper here is focused instead on cardiovascular issues, such as (a) the calcification of blood vessels that contributes to hypertension, and (b) the development of atherosclerosis, in which fatty plaques form to narrow and weaken blood vessels, ultimately causing death when one of these weak points ruptures. These are prominent issues in aging, and given strong evidence for bisphosphonates to produce benefits on this front, it would be a plausible mechanism for reduced mortality. The open access review paper here walks through the current evidence for this hypothesis.

In the past, osteoporosis and atherosclerosis were considered as separate entities with a similar increasing prevalence with aging. Recently, studies have outlined that patients with low bone mineral density (BMD) are at significantly greater risk of developing cardiovascular disease (CVD) as well as unexpected cardiovascular events, more severe coronary atherosclerosis and vascular calcification. In addition, it is known that postmenopausal women with osteoporosis have an increased risk of developing cardiovascular events and that the increased risk is proportional to the severity of osteoporosis. These data have also suggested a possible influence of drugs affecting bone metabolism on lipid and atherosclerosis mechanisms, or that drugs effective on the atherosclerosis process could also be efficacious in fracture prevention.

An initial interesting theory was that CVD and osteoporosis were linked by a common denominator, such as serum lipid profile, which could act in parallel on both vascular and bone cells. However, an interesting observational study showed that in a multiple regression analysis, lipid profile did not predict osteoporosis or fracture risk, whereas aortic calcification severity significantly explained BMD at the hip. On the other hand, low BMD at the distal radius was found to be associated with increased risk of stroke and CVD mortality.

The common finding of simultaneous vascular calcification and osteoporosis in individual patients suggests that local tissue factors could have a crucial role in the regulation of mineralization and cell differentiation. Cardiovascular calcification was conventionally viewed as an inevitable consequence of aging, but some landmark studies have demonstrated that it is a highly regulated process of mineralization which involves cellular and molecular signaling processes similar to those found in normal osteogenesis. The similarity of the molecular mechanisms in osteogenesis and vascular calcification has led to the knowledge that atherosclerotic calcification is an actively regulated process, not a passive mineralization.

The growing evidence that atherosclerosis and osteoporosis share several pathophysiologic mechanisms reinforces the interest in pharmacologic agents which could inhibit bone loss and also provide benefits in terms of slowing the progression of atherosclerosis. At present, only bisphosphonates (BPs), currently considered the drug of choice for the prevention and treatment of osteoporosis, could have this potential.

The interest in the relationships between BPs and atherosclerosis has recently shown a further increase after the publication of the results of the HORIZON study which reported a 28% reduction in mortality in hip fracture patients treated with an annual i.v. dose of zoledronic acid. In another study, it was revealed that patients who received BP therapy for osteoporotic fracture had a lower hazard of myocardial infarction during the 2-year follow-up period with respect to controls. Moreover, two recent studies have reported that oral BPs reduce mortality in osteoporotic patients and that the reduction in mortality could be mainly due to cardiovascular and cerebrovascular deaths.

To sum up, the BPs seem to have the potential of influencing atherosclerosis and calcium homeostasis at the level of vascular walls with several possible mechanisms which may differ according to the type, potency, dosage and administration route of BPs. However, until the present time, it is not yet clear which of these above-mentioned mechanisms may be the most important in humans and additional studies are needed to specifically address the mechanism by which BPs use could influence cardiovascular morbidity and mortality.

Link: https://doi.org/10.2147/CIA.S138002


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