Evidence for the cardiovascular effects of osteoporosis treatments in randomized trials of post-menopausal women: A systematic review and Bayesian network meta-analysis

Osteoporosis medications have been reported to have beneficial and harmful cardiovascular effects. Much of this evidence stems from single reports and as such, a comprehensive examination of the evidence is needed. We conducted a network meta-analysis (NMA) of cardiovascular adverse event (CAE) data from randomized trials of osteoporosis medications in postmenopausal women. Trials were identified from recent NMAs of osteoporosis treatment for fracture reduction with an updated literature search (December 2020). Included studies were randomized, included over 100 participants, and reported skeletal primary outcomes. We investigated three-point major adverse cardiovascular events (MACE3), four- (MACE4) and five-point MACE (MACE5), as well as myocardial infarction (MI) and stroke. Data were synthesized in a random-effects network meta-analysis using Bayesian modelling. Probabilistic ranking of treatment safety was performed. Relative to placebo, point estimates for the odds ratios (OR) with 95 % credible intervals (CrI) were also generated. We identified 75 trials (n = 136,940 women), of which 27 (68,699 women, nine arms) reported CAEs. In women randomized to placebo, the overall event rate for the MACE3 outcome was 2.58 % compared with 1.99 % in those randomized to all other active comparators. Probabilistic ranking found abaloparatide, oral bisphosphonates, teriparatide, and menopausal hormone therapy were less likely to have increased risk of CAEs than placebo, while romosozumab ranked more likely to have increased risk of CAEs than placebo for all outcomes. Compared with placebo, abaloparatide (one trial, n = 1642) was associated with a reduced odds for MACE3 (OR = 0·31; 95%CrI: 0·06 to 0·99), MACE4 (0·28; 0·06 to 0·88) and MACE5 (0·25; 0·06 to 0·79). When all PTH analogues were grouped together, magnitude and direction of effects were consistent but no longer statistically significant. We did not find pooled direct and indirect evidence that osteoporosis treatments significantly increased the risk of adverse cardiovascular events relative to placebo. (PROSPERO: CRD42020178702).