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.

Bone mineral density and osteoporosis in heart transplanted patients: A single‐center retrospective study at Skåne University Hospital in Lund 1988‐2016

“…A common side effect of immunosuppressive therapies is osteoporosis, which is characterized as a skeletal disorder with impaired bone strength, measured in bone mineral density (BMD), and increased risk of bone fractures . Osteoporosis may also be a consequence of various factors that are associated with the heart failure itself prior to HT, such as immobilization, impaired renal function, nutritional deficiency, as well as heart failure medications . Not only does osteoporosis cause increased morbidity, but it is also associated with increased mortality rates …”

Effects of drugs on bone metabolism in a cohort of individuals with traumatic spinal cord injury

“…In two prospective cohort studies, low-molecular-weight heparin treatment for 3-24 months was shown to decrease mean BMD by 2.8-4.8% compared to mean BMD decreases of 1.2-2.5% with oral vitamin K antagonists, such as warfarin [30] Steroids: Steroid exposure results in an increased fracture risk by as much as 75% within the first 3 months after initiation of therapy. Steroids ultimately decrease bone mass by decreasing the production of new osteoblast precursors while also causing premature apoptosis of both mature osteoblasts and osteoclasts [31] SSRI selective serotonin reuptake inhibitors, SNRI Serotonin and norepinephrine reuptake inhibitors, TCA tricyclic antidepressants immobilization, the loss of positive central and peripheral neural influences to the sub-lesional bone, the loss of essential anabolic factors, the administration of catabolic factors at the time of injury, and the subsequent use of commonly prescribed pharmacologic agents may all play a role [6].…”

Extensive Deep Venous Thrombosis in a Young Male Patient as the First Manifestation of a Rare Venous Anomaly – Inferior Vena Cava Duplication: Case Report

“…Studies assessing the potential complications, efficacy and safety of prolonged LMWH use were designed in diff erent populations, such as cancer patients, pregnancy, and other [25][26][27][28][29][30][31][32][33][34] . Th ose studies addressed the possible side eff ects of extended LMWH use, such as bleeding and thrombocytopenia, and showed a low risk of major bleeding, rare heparin-induced thrombocytopenia, and infrequent allergic and skin reactions [25][26][27][28][29][30][31][32][33][34] .…”

“…Th ose studies addressed the possible side eff ects of extended LMWH use, such as bleeding and thrombocytopenia, and showed a low risk of major bleeding, rare heparin-induced thrombocytopenia, and infrequent allergic and skin reactions [25][26][27][28][29][30][31][32][33][34] . Transient elevations of aminotransferases may occur 34 , while an increased risk of fractures and osteoporosis is less clear [32][33][34] . For example, a systematic review and meta-analysis showed that the use of LMWH for 3-6 months did not increase the risk of fractures compared to unfractionated heparin or oral vitamin K antagonists (VKA), but longer exposure for up to 24 months was associated with a decrease in bone mineral density 33 .…”

“…Transient elevations of aminotransferases may occur 34 , while an increased risk of fractures and osteoporosis is less clear [32][33][34] . For example, a systematic review and meta-analysis showed that the use of LMWH for 3-6 months did not increase the risk of fractures compared to unfractionated heparin or oral vitamin K antagonists (VKA), but longer exposure for up to 24 months was associated with a decrease in bone mineral density 33 . Another concern was patient compliance with daily subcutaneous administration of LMWH.…”