Use of bisphosphonates and raloxifene and risk of deep venous thromboembolism and pulmonary embolism

Prior studies have associated raloxifene and strontium ranelate with deep venous thromboembolism and pulmonary embolism. In a cohort study, we observed an increased risk also with the bisphosphonates. However, the increase was present already before the start of bisphosphonates pointing at an effect of the underlying condition. We seek to study the association between use of drugs against osteoporosis and risk of deep venous thromboembolism (DVT) and pulmonary embolism (PE). Nationwide register-based cohort study from Denmark with all users of bisphosphonates and other drugs against osteoporosis between 1996 and 2006 (n = 103,562) as cases and three age- and gender-matched controls from the general population (n = 310,683). Before start of a drug against osteoporosis, an increased risk of DVT/PE was present in the crude analysis for alendronate, etidronate, and risedronate. However, upon adjustment, this increase in risk disappeared. Before start of raloxifene, a decreased risk of DVT/PE was present (odds ratio (OR) = 0.53, 95% confidence interval (CI), 0.39-0.71). After start of a drug, alendronate (HR = 1.20, 95% CI, 1.00-1.43), clodronate (HR = 4.06, 95% CI, 1.47-11.2), and etidronate (HR = 1-37, 95% CI, 1.23-1.51) were all associated with an increased risk of DVT/PE, while raloxifene was only borderline, significantly associated with risk of DVT/PE (HR = 1.64, 95% CI, 0.97-2.77). No dose-reponse relationship was present except for alendronate, where the risk was inversely associated with dose, i.e., the risk of DVT/PE decreased with increasing average daily dose. The HR for DVT/PE was higher with clodronate and etidronate than with alendronate. Alendronate and raloxifene carried the same risk for DVT/PE. Bisphosphonates seem associated with an increased risk of DVT/PE. However, the association does not seem to be causal.