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


BACKGROUND
We seek to study the association between use of drugs against osteoporosis and risk of deep venous thromboembolism (DVT) and pulmonary embolism (PE).


METHODS
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).


RESULTS
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-response 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.


CONCLUSIONS
Bisphosphonates seem associated with an increased risk of DVT/PE. However, the association does not seem to be causal.
Department of Endocrinology and Metabolism C, Aarhus University Hospital, Tage Hansens Gade 2, 8000 Arhus C, Denmark. p-vest@post4.tele.dk
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Vestergaard
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Schwartz
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Pinholt
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Rejnmark
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Mosekilde
D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents / Q000008:administration & dosage / Q000009:adverse effects*; D003718:Denmark / Q000453:epidemiology; D004164:Diphosphonates / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009942:Organometallic Compounds / Q000009:adverse effects; D010024:Osteoporosis / Q000188:drug therapy / Q000453:epidemiology; D011655:Pulmonary Embolism / Q000139:chemically induced* / Q000453:epidemiology; D020849:Raloxifene Hydrochloride / Q000009:adverse effects*; D013876:Thiophenes / Q000009:adverse effects; D054556:Venous Thromboembolism / Q000139:chemically induced* / Q000453:epidemiology
D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D009942:Organometallic Compounds; D013876:Thiophenes; C081587:strontium ranelate; D020849:Raloxifene Hydrochloride