Elevated HDL-C May be Risk Factor for Fracture in Older Adults

Elevated levels of high-density lipoprotein cholesterol (HDL-C) may lead to increased risk of fracture in healthy older adults independent of a range of conventional risk factors, according to findings of a post-hoc analysis from the ASPREE clinical trial.

Specifically, in a large cohort of community dwelling adults aged ≥70 years, fully adjusted models found that for each 1-standard deviation (SD) increment in HDL-C level, fracture risk rose by 14%. Further, the risk among study participants in the highest quintile of HDL-C was 33% greater than for those in the lowest.

The brief report was published online January 18, 2023, in JAMA Cardiology.

The investigators, from several large Australian universities, cite research demonstrating elevated levels of HDL-C in persons with osteoporosis as well as preclinical studies describing reduced bone mineral density in the setting of high HDL-C levels, purportedly related to reduced osteoblast number and function. Other studies of the relationship, they say, have been inconclusive. The authors stress that clarity around a potential link is increasingly important to reduce morbidity and mortality as the global population ages.

Led by John J. McNeil, MBBS, PhD, professor, epidemiology & preventive medicine at Monash University in Melbourne, the research team says its findings contribute to the accumulating evidence of “unfavorable effects” now associated with high HDL-C levels. Other recent studies “have reported that moderate (60-80mg/dL) and high (>80mg/dL) levels of HDL-C are associated with adverse cardiovascular outcomes in high-risk populations.”

McNeil and colleagues conducted a post-hoc analysis of data from adults participating in the ASPREE (Aspirin in Reducing Events in the Elderly ) study and the ASPREE-Fracture substudy. ASPREE participants from Australia (n = 16,703) were aged ≥70 years and those from the US (n = 2,411) aged ≥65 years and were recruited between March 2010 and December 2014. All were judged free of cardiovascular disease (CVD), dementia, physical disability, and chronic illness at baseline. The ASPREE-Fracture substudy collected data on fractures reported after randomization from Australian participants only.

Researchers assessed associations between HDL-C level and traumatic and minimal trauma fractures. All fractures were confirmed by medical imaging and adjudicated by an expert review panel.

FINDINGS

The investigators report that among 16 262 participants who had a plasma HDL-C measurement at baseline (55% women), 1659 experienced at least 1 fracture during a median follow up of 4 years.

In a model fully adjusted for potential confounding variables, each 1-SD increment in HDL-C level was associated with a 14% higher risk for fractures (HR 1.14, 95% CI 1.08-1.2). When McNeil and colleagues analyzed HDL-C in quintiles, compared with participants in Q1, participants in Q5 had a 33% higher risk of fracture (HR, 1.33; 95% CI, 1.14-1.54). The associations between HDL-C level and fractures were linear for both men and women, according to the study.

In analyses stratified by sex and limited to only minimal trauma fractures and participants not taking osteoporosis medications, the results remained consistent. The researchers observed no association between non-HDL-C levels and fractures.

More research needed

Writing in an accompanying editorial John T. Wilkins, MD, MS, assistant professor of medicine (cardiology)/preventive medicine at Northwestern University Feinberg School of Medicine, and Anand Rohatgi, MD, MSCS, professor of medicine at University of Texas Southwestern Medical Center noted that despite the significant associations between HDL-C and risk of fracture identified, analytic models could have been adjusted for a range of more detailed measures.

They point out also, “There was no assessment of whether HDL cholesterol improved discrimination reclassification, or any other validated measures of risk prediction performance." Without additional investigation unanswered questions remain about whether or not elevated HDL-C could serve as a biomarker to assess fracture risk, the editorialists add.

“With respect to fracture risk, future questions include whether HDL particle concentration or functional measures confer similar or differential risk information, whether these associations vary by sex, Black race, diabetes and kidney function status, and whether therapies that decrease fracture risk have an effect on lipoprotein metabolism, independent of consequent changes in lifestyle,” they concluded.

Reference: Hussain SA, Ebeling PR, Barker AL, et al. Association of plasma high-density lipoprotein cholesterol level with risk of fractures in healthy older adults. JAMA Cardiol. Published online January 18, 2023. doi:10.1001/jamacardio.2022.5124