Effects of Long-Term Low-Molecular-Weight Heparin on Fractures and Bone Density in Non-Pregnant Adults: A Systematic Review With Meta-Analysis

Abstract

Background: Adults who require long-term anticoagulation with low-molecular-weight heparin (LMWH) such as cancer patients or the elderly may be at increased risk of fractures.

Objective: To determine the effects of LMWH therapy of at least 3 months' duration on fractures and bone mineral density (BMD) in non-pregnant adult populations.

Methods: We systematically reviewed electronic databases (e.g., MEDLINE, EMBASE), conferences and bibliographies until June 2015 and included comparative studies in non-pregnant adult populations that examined the effects of LMWH (≥3 months) on fractures and BMD. We synthesized evidence qualitatively and used random-effects meta-analysis to quantify the effect of LMWH on fractures.

Results: Sixteen articles reporting 14 studies were included: 10 clinical trials (n = 4865 participants) and four observational cohort studies (3 prospective, n = 221; 1 retrospective, n = 30). BMD and fractures were secondary outcomes in the majority of trials, while they were primary outcomes in the majority of observational studies. In participants with venous thromboembolism and underlying cardiovascular disease or cancer (5 RCTs, n = 2280), LMWH for 3-6 months did not increase the relative risk of all fractures at 6-12 months compared to unfractionated heparin, oral vitamin K antagonists or placebo [pooled risk ratio (RR) = 0.58, 95 % CI: 0.23-1.43; I(2) = 12.5 %]. No statistically significant increase in the risk of fractures at 6-12 months was found for cancer patients (RR = 1.08, 95 % CI: 0.31-3.75; I(2) = 4.4 %). Based on the data from two prospective cohort studies (n = 166), LMWH for 3-24 months decreased mean BMD by 2.8-4.8 % (depending on the BMD site) compared to mean BMD decreases of 1.2-2.5 % with oral vitamin K antagonists.

Conclusions: LMWH for 3-6 months may not increase the risk of fractures, but longer exposure for up to 24 months may adversely affect BMD. Clinicians should consider monitoring BMD in adults on long-term LMWH who are at increased risk of bone loss or fracture.

Keywords: bone; bone density; fractures; heparin, low-molecular-weight; systematic review.

Figure 1.

PRISMA flow diagram; n denotes the total number of citations. LMWH denotes low-molecular-weight heparin; UFH denotes unfractionated heparin.

Figure 2.

a Forest plot: The effect of long-term low-molecular-weight heparin vs. control on all fractures in non-pregnant participants. LMWH denotes low-molecular-weight heparin. Control: unfractionated heparin, oral vitamin K antagonist or placebo; RR denotes risk ratio; RR < 1 favors LMWH; RR >1 favors control treatment. b Forest plot: Long-term low-molecular-weight heparin vs. control in cancer patients. LMWH denotes low-molecular-weight heparin. Control: oral vitamin K antagonist or placebo; RR denotes risk ratio; RR < 1 favors LMWH; RR >1 favors control treatment. c Forest plot: Long-term low-molecular- weight heparin vs. oral vitamin K antagonists in non-pregnant participants. LMWH denotes low-molecular-weight heparin. Control: oral vitamin K antagonists (i.e., acenocoumarol/warfarin); RR denotes risk ratio; RR < 1 favors LMWH; RR >1 favors control treatment.