Higher HDL levels may be associated with increased fracture risk for older adults independent of other risk factors, according to a post hoc analysis of the ASPREE study.

“Our findings add to growing evidence of unfavorable impacts linked to high HDL levels,” Sultana Monira Hussain, MBBS, PhD, MPH, a senior research fellow at Monash University School of Public Health and Preventive Medicine in Melbourne, Victoria, Australia, told Healio. “It shows that HDL, commonly known as ‘good cholesterol,’ in high levels is not as good as we previously thought. Rather, it is associated with several adverse outcomes such as fractures.”

ASPREE fracture data

Sultana Monira Hussain

Hussain and colleagues analyzed data from adults participating in the ASPREE study and the ASPREE-Fracture substudy. Participants from Australia (n = 16,703) were aged 70 years or older; participants from the U.S. (n = 2,411) were aged 65 years or older; all were free of CVD, dementia, physical disability and chronic illness at baseline. The ASPREE-Fracture substudy collected data on fractures reported after randomization from Australian participants. Researchers assessed HDL and traumatic and minimal trauma fractures, confirmed by medical imaging and adjudicated by an expert review panel.

The findings were published in JAMA Cardiology.

Among 16,262 participants who had a plasma HDL measurement at baseline (55% women), 1,659 experienced at least one fracture during a median of 4 years.

In a fully adjusted model, each one standard deviation increment in HDL level was associated with a 14% higher risk for fractures (HR = 1.14; 95% CI, 1.08-1.2). Results persisted in analyses stratified by sex and limited to only minimal trauma fractures and participants not taking osteoporosis medications. Researchers did not observe an association between non-HDL levels and fractures.

“HDL particles are complexes of lipids and apolipoproteins with diverse structures and biological activities,” Hussain told Healio. “Having high levels of HDL does not mean that the HDL particles are functional. Therefore, in the future, researchers should aim to examine the role of other aspects of HDL structure and functionality in the pathogenesis of chronic diseases in older populations.”

Data leave ‘unanswered questions’

John T. Wilkins

In a related 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 the study demonstrated significant associations between HDL level and fracture risk; however, models were not adjusted for detailed measures of exercise or physical activity, triglycerides or any other lipids, including other HDL compositional measures such as HDL particle concentration or apolipoprotein A-I levels.

“There was no assessment of whether HDL cholesterol improved discrimination reclassification, or any other validated measures of risk prediction performance,” Wilkins and Rohatgi wrote. “Taken together, this study alone leaves several unanswered questions as to whether high HDL cholesterol could be a useful biomarker to detect fracture risk.”

Wilkins and Rohatgi wrote that extreme high HDL may reflect dysfunctional biology, rare adverse genetic variants, some component of heavy alcohol use, and/or a unique metabolic substrate in specific populations.

“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 wrote.