Higher HDL-C Levels Associated with Increased Fracture Risk in Older Adults

Sultana Monira Hussain, MBBS, PhD

Higher levels of high-density lipoprotein cholesterol (HDL-C) may be associated with increased fracture risk in healthy older adults, according to a new study.

The findings indicate the increase in fracture risk appeared independent of traditional risk factors for fractures, including age, sex, physical activity, alcohol use, frailty status and use of lipid-lowering or antiosteoporosis medications.

“These findings highlight another potential concern with high HDL-C levels and another likely adverse effect of the drugs that substantially increases plasma HDL-C levels,” wrote corresponding author Sultana Monira Hussain, MBBS, PhD, School of Public Health and Preventive Medicine, Monash University. “Further research is needed to determine the pathophysiological explanation for these findings.”

The aging population continues to grow globally, and fracture rates are increasing as a result, despite the availability of antiosteoporosis medications. Minimal trauma fractures are shown to affect 25% of men and 44% of women aged 60 years and older. Recently, a meta-analysis of 12 cross-sectional and case-control studies suggested the level of HDL-C was elevated in patients with osteoporosis.

Preclinical studies report that HDL-C reduces bone mineral density by stimulating molecular mechanisms that reduce osteoblast number and function. Based on these findings, a potential relationship may exist between HDL-C level and an increased risk of fractures, although results are inconclusive.

In this post-hoc analysis, data from the Aspirin in Reducing Events in the Elderly (ASPREE) study (16,703 Australians aged ≥70 years and 2,411 US participants ≥ 65 years) and the ASPREE-Fracture (Australians only) substudy were used to examine the associations between plasma HDL-C level and incident fractures.

The ASPREE study recruited community-dwelling older adults with no evident cardiovascular disease, dementia, physical disability, or chronic illness expected to limit survival to less than 5 years between March 2010 and December 2014. The ASPREE-Fracture substudy collected data on incident fractures occurring post randomization were collected during the annual visits and at telephone contacts every 6 months. Each reported fracture was confirmed by clinical notes, discharge summaries, and medical imaging reports and classified by cause and site.

Investigators used cox regression to calculate the hazard ratios (HRs) and 95% confidence intervals (CIs) from the time of randomization to the first fracture occurring during the ASPREE follow-up period. HDL-C and non-HDL-C levels were treated as continuous variables and analyzed according to quintiles (Q1, lowest 20%; Q5, highest 20%).

A total of 16,262 participants who had plasma HDL-C measurements at baseline were included in the study (8945 female participants [55%]). Of this population, there were 711 minimal trauma fractures and 948 other trauma fractures over a median of 4.0 years.

The full-adjusted model revealed the associations between HDL-C level and fractures. Each 1-SD increment in HDL-C level was associated with a 14% higher risk of fracture during the follow-up period (HR, 1.14; 95% CI, 1.08 - 1.20).

When HDL-C was analyzed in quintiles, participants in Q5 had a 33% higher risk of fracture than those in Q1 (HR, 1.33; 95% CI, 1.14 - 1.54). Investigators saw no association between non-HDL-C values and fractures, and results remained similar when these analyses were stratified by sex. The observed results persisted in sensitivity analyses in restricted subgroups of interest and stratified analyses (based on statin use).

Investigators note the findings add to the growing evidence of unfavorable effects linked to HDL-C levels. In addition to an increased fracture risk, high levels of HDL-C have been associated with adverse cardiovascular outcomes in high-risk populations.

The brief report, “Association of Plasma High-Density Lipoprotein Cholesterol Level with Risk of Fractures in Healthy Older Adults,” was published in JAMA Cardiology.