This article is more than 5 years old. Information may no longer be current.
Are osteoporosis medications associated with improved mortality rates?
Click Here to Manage Email Alerts
Click here to read the Cover Story, ‘Pathbreaking’ osteoporosis therapy offers new option, but treatment challenges remain
Where there is smoke, there is usually fire.
Bisphosphonates work in the same pathway as statins, inhibiting protein prenylation and disrupting the function of key regulatory proteins, thereby interfering with intracellular signaling and reducing osteoclast activity. The question is whether that process is happening only in bone cells or in other tissues too.
Randomized controlled trials with zoledronate — including one recently conducted in women with osteopenia with 6 years of follow-up — seem to suggest that bisphosphonates are associated with improved health outcomes overall, including mortality (Reid IR, et al. N Engl J Med. 2018; doi:10.1056/NEJMoa1808082). Research also suggests that zoledronate attenuates the accumulation of DNA damage in mesenchymal stem cells and protects their function.
There are numerous other studies — many of them observational — where, in retrospect, you find that bisphosphonate users experience a survival benefit vs. people not prescribed the therapy. Some studies are more impressive than others. The nonbelievers could say those studies were potentially confounded by the reasons those people were prescribed the drugs, and certain populations are healthier. What we desperately need are controlled studies to answer that critique.
We have the zoledronate studies, plausible mechanisms and lots of observational studies that, yes, can be criticized. But why ignore a signal that is as strong as this? The plea would be, don’t overlook the signal just because a meta-analysis shows there is nothing happening. Use this as a reason to take the knowledge further by conducting the appropriate studies that can show us what might be going on. This is a finding that could actually alter health care, if it were positive. People would begin using these drugs rather differently than we do at the moment, and it would strengthen the case for using zoledronic acid vs. something else.
The data on bisphosphonates suggest there is a story here, and it is an exciting one. A mortality benefit is an unexpected property of these drugs, and it may turn out to be really important.
Graham Russell, PhD, DM(Oxon), MD, FRCP, FRCPath, FMedSci, FRS, is emeritus professor of musculoskeletal pharmacology at the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences at the University of Oxford, and the Mellanby Centre for Bone Research at the University of Sheffield, U.K. Disclosure: Russell reports no relevant financial disclosures.
counter
There are suggestive but not conclusive data that there is a mortality benefit with bisphosphonate therapy, and that data will be hard to obtain.
Data from both randomized controlled trials and cohort studies suggest that bisphosphonate therapy may be associated with an improved mortality risk. A couple of meta-analyses also suggested about a 10% reduction in mortality risk for patients prescribed bisphosphonate therapy. Several cohort studies all demonstrated a significant reduction in mortality risk with bisphosphonate therapy. However, there are criticisms pertinent to analyses of both cohort and randomized controlled studies in this area.
The criticism of randomized controlled trials is that people have to be very healthy to get into the study, so the mortality rate is generally much lower vs. cohort studies. Such a study may not include the people for whom you could observe an effect — or one may just not be able to see an effect because the mortality rate is so low.
In cohort studies that have much wider entry criteria and, thus, higher mortality rates, there are potentially unmeasured biases that one cannot adjust for. Additionally, there is always the possibility that people who are given bisphosphonates are healthier and better positioned to do well with therapy. A recent cohort study attempted to control for all these factors, comparing nitrogen bisphosphonates with a weak non-nitrogen bisphosphonate and still found a mortality benefit for the nitrogen bisphosphonates (Bliuc D, et al. Osteoporosis Int. 2019;doi:10.1007/s00198-018-4806-0). However, unmeasured biases may still persist.
The greatest evidence from the randomized controlled trials would really be with zoledronic acid. One study of hip fracture patients demonstrated a 28% reduction in mortality (Lyles KW, et al. N Engl J Med. 2007;doi:10.1056/NEJMoa074941), and another study in women with osteopenia suggested a mortality benefit, although it did not reach statistical significance (Reid IR, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1808082). However, a third randomized controlled trial, also with zoledronic acid, did not show any evidence of reduction in mortality risk.
There is some suggestion that a possible mortality benefit could be related to the nonbone effects of bisphosphonates, including possible effects on cancer, the vasculature and the immune system; however, the clinical data are not conclusive and the mechanisms, as yet, not understood. But the data are tantalizing.
I’m not sure we will get conclusive data from randomized controlled trials, unless the inclusion criteria are very wide. It may be that this effect is picked up either when the mortality rate is higher or whether the follow-up is long enough. Until there is a study with osteoporosis therapies where mortality is the primary outcome, we may never know for sure.
Jacqueline Center, MBBS, PhD, is a senior staff specialist and deputy director of the department of endocrinology at St. Vincent’s Hospital, professor and senior research fellow with the Garvan Institute of Medical Research in Sydney and a conjoint professor at the University of New South Wales Australia School of Medicine. Disclosure: Center reports she has received honoraria from Amgen and Teva.