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Long-Term Exposure to Low-Molecular-Weight Heparins May Put Patients at Risk for Bone Fractures

December 30, 2021

In men and non-pregnant women requiring at least three months of anticoagulation therapy, three- to six-months' use of low-molecular-weight heparin (LMWH) may not increase the risk of fractures, though longer exposure can adversely affect bone mineral density (BMD) in patients with cancer or underlying cardiovascular disease, according to a study published in the Journal of General Internal Medicine.

"This is the most comprehensive systematic review and meta-analysis in this area to date and highlights the need to study the bone effects of LMWH and other anticoagulation medications," Angela M. Cheung, MD, PhD, the senior author of the study, told ASH Clinical News. Most previous research on bone-density loss and risk of fractures associated with LMWH focused on pregnant women, she added.

Olga Gajic-Veljanoski, MD, PhD, of the Osteoporosis Program at the University Health Network/Toronto Rehabilitation Institute/Mount Sinai Hospital in Toronto, Canada, and colleagues analyzed 16 articles from electronic databases (MEDLINE, EMBASE, the Cochrane Library, and Cochrane Controlled Clinical Trials Register), conferences, and bibliographies through 2015.

Dr. Gajic-Veljanoski and co-authors identified clinical trials and observational studies (retrospective and prospective cohort and case-controlled studies) of non-pregnant adults that assessed the effects of long-term LMWH treatment (≥3 months) on fractures or BMD. The following were excluded from the study:

  • Reviews, letters, and commentaries without original data
  • Descriptive (case series/reports) or cross-sectional observational studies
  • Studies that did not report on bone outcomes
  • Studies that reported short-term exposure to LMWH or long-term exposure to unfractionated heparin (UFH) only

Sixteen articles were identified, and 14 studies were included in the systematic review: 10 clinical trials that included 4,865 patients (one was a crossover trial, while the others were parallel-group, randomized, controlled trials) and four observational cohort studies that included 251 patients, three of which were prospective (n=221) and one that was retrospective (n=30). BMD and fractures were primary outcomes in the majority of the observational studies and secondary endpoints in the majority of trials.

The majority of patients in the clinical trials were older than 60 years, male, and had a prior venous thromboembolism (VTE) resulting from underlying cardiovascular, renal, or malignant disease; in the cohort studies, most patients were younger and more heterogeneous in age (range = 30-67 years).

Among these studies, long-term LMWH was compared with:

  • Long-term UFH in 3 trials and 1 cohort study
  • Vitamin K antagonists (VKA) in 3 trials and 2 cohort studies
  • Short-term LMWH in 1 cohort study
  • Compression therapy in 1 trial
  • Placebo in 3 trials
  • No treatment in 1 cohort study

Most of the studies analyzed LMWH use for a duration of three to six months, up to 24 months, though one cohort study compared long- and short-term LMWH treatment (6-48 months vs. <4 months). Eight articles reported findings on fractures: seven describing six trials that included 4,320 patients and one describing a prospective, cohort study of 80 patients.

Dr. Gajic-Veljanoski and co-authors found that, in the 2,280 patients with VTE and underlying cardiovascular disease or cancer, short-term use of LMWH (3-6 months) did not increase the relative risk of fractures at a six- to 12-month follow-up compared with UFH, oral VKA, or placebo (pooled risk ratio [RR] = 0.58; 95% CI 0.23-1.34). In addition, they did not observe a statistically significant increase in the risk of fractures at six to 12 months in cancer patients (RR=1.08; 95% CI 0.31-3.75).

BMD was assessed in five clinical trials that included 545 patients and in all four cohort studies (n=251). Based on observational data, use of LMWH for three to 24 months decreased mean BMD by 2.8 percent to 4.8 percent (depending on the BMD site); oral VKA treatment, however, decreased mean BMD by 1.2 percent to 2.5 percent. "Based on the current literature, LMWH does not seem to have a strong detrimental effect on bone," the authors observed. Though LMWH is not recognized as a major modifying factor for fracture in standardized fracture-risk assessment tools, "the potential for a greater than three percent decrease in BMD may be clinically important in some adult populations on LMWH."

"We recommend that clinicians be aware of the data and take preventive measures (such as ensuring adequate calcium and vitamin D intake) and consider monitoring BMD in patients on long-term LMWH who are at increased risk for bone loss or fractures," said Dr. Cheung. "Since patients on this therapy often have other comorbidities (older age, cancer, and certain other medications) that predispose them to increased bone loss or fractures, our study highlights the need to pay close attention to this population in terms of bone health."

Limitations of the study include the potential for selection bias, small number of available studies, detection bias with fractures (as they were not collected as primary outcome, only as adverse events or secondary outcomes) and the variability of outcomes assessment among the studies, thus "the effect of LMWH on BMD can be distorted in either direction," the authors wrote.

"The lack of solid evidence on the long-term effects of LMWH on bone in non-pregnant adults suggests a need for future prospective studies," concluded Dr. Gajic-Veljanoski and colleagues.


Gajic-Veljanoski O, Phua CW, Shah PS, Cheung AM. Effects of long-term low-molecular-weight heparin on factures and bone density in non-pregnant adults: a systemic review with meta-analysis. J Gen Intern Med. 2016 February 19. [Epub ahead of print]


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