Clinical Context

High-density lipoprotein cholesterol (HDL-C) has traditionally been known as the "good" cholesterol, as older studies have found that elevated levels of HDL-C are associated with lower rates of cardiovascular (CV) events; however, medications such as niacin, estrogen, and cholesterol ester transfer protein inhibitors, which raise HDL-C, have not been associated with better CV outcomes, and more recent studies have suggested a positive relationship between HDL-C and CV risk.

Liu and colleagues performed one such study, and their results were published in the May 18, 2022 issue of JAMA Cardiology.^[1] They used 2 large databases of health information on adults, the UK Biobank and Emory Cardiovascular Biobank, to find adults with known coronary artery disease (CAD) and compare outcomes of these individuals based on HDL-C levels ≤ 80 mg/dL or > 80 mg/dL.

Overall, there was a U-shaped relationship between HDL-C and the risk for death in adjusted analyses, with a near 2-fold increase in mortality among adults with HDL-C > 80 mg mg/dL compared with the control group. Very high HDL-C was also associated with a significant 71% increase in the risk for CV death specifically. Men with very high HDL-C seemed particularly at higher risk for mortality compared with women.

Perhaps even more surprising, some research has linked high HDL-C with higher risks for osteoporosis and fracture. The current study by Hussain and colleagues explores this subject further.

Study Synopsis and Perspective

High levels of HDL-C in older adults are associated with a higher risk of sustaining a fracture than in older adults with lower HDL-C levels, a new study suggests.

"Two animal studies showing that HDL-C reduces bone mineral density by reducing osteoblast number and function provide a plausible explanation for why high HDL-C may increase the risk of fractures," Monira Hussain, MBBS, MPH, PhD, of Monash University in Melbourne, Australia, told theheart.org | Medscape Cardiology. "So, it was not surprising when our analyses provided evidence that amongst those in the highest quintile of HDL-C (> 74 mg/dL) there was a [33%] increased risk of fractures."

After adjustment, one standard deviation increment in HDL-C level was associated with a 14% higher risk for fracture during a 4-year follow-up.

Based on this and other studies, Hussain said, "I believe that the finding of a very high HDL-C [should] alert clinicians to a higher risk of mortality, fractures, and possibly other threats to their patient's health."

The study was published online January 18 in JAMA Cardiology.^[2]

For this report, the researchers conducted a post-hoc analysis of data from the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial^[3] and the ASPREE-Fracture substudy.^[4]

ASPREE was a double-blind, randomized, placebo-controlled primary prevention trial of aspirin. Participants were 16,703 community-dwelling Australians and 2411 individuals from the United States with a mean age of 75 ± 4 years without evident cardiovascular disease (CVD), dementia, physical disability, or life-limiting chronic illness.

The ASPREE-Fracture substudy collected data on fractures reported postrandomization from the Australian participants. Fractures were confirmed by imaging and adjudicated by an expert panel and included both traumatic and minimal trauma fractures.

Of the 16,262 participants who had a plasma HDL-C measurement at baseline (55% women), 1659 (10.2%) experienced at least 1 fracture over a median of 4 years. This included 711 minimal trauma fractures (eg, falls from standing height) and 948 other trauma fractures, mainly falls on stairs, ladders, or stools.

Higher rates of fractures occurred in the highest quintile of HDL-C level where the mean level was 89 mg/dL. At baseline, participants in that quintile had a lower body mass index (BMI), a high prevalence of current/former smoking and current alcohol use, 12 years or longer of school, more physical activity, and higher use of antiosteoporosis medication. They also had less chronic kidney disease, diabetes, prefrailty/frailty, or treatment with lipid-lowering drugs.

In a fully adjusted model, each standard deviation increment in HDL-C level was associated with a 14% higher risk for fractures (HR 1.14). When analyzed in quintiles (Q), compared with participants in Q1, persons in Q5 had a 33% higher risk for fracture (HR 1.33).

Prevalence rates were similar between the sexes. The increase in fracture risk appeared to be independent of traditional risk factors for fractures, including age, sex, physical activity, alcohol use, frailty, BMI, smoking status, diabetes, chronic kidney disease, use of lipid-lowering or anti-osteoporosis drugs, and education, the authors noted.

The results persisted in sensitivity analyses in restricted subgroups of interest and in stratified analyses, including, for example, only minimal fractures; participants not taking anti-osteoporosis drugs or statins; never smokers; nondrinkers; and participants engaging in minimal physical activity (walking < 30 min/d).

No association was observed between non--HDL-C levels and fractures.

The authors concluded that the study, "provides robust evidence that higher levels of HDL-C are associated with incident fractures in both male and female individuals, independent of conventional risk factors."

Commenting on the study fortheheart.org | Medscape Cardiology, Marilyn Tan, MD, clinic chief of the Endocrine Clinic and clinical associate professor of medicine at Stanford University School of Medicine, Stanford, California, said, "I certainly would not recommend anyone do anything to actively lower their HDL levels. HDL levels are largely determined by genetics, diet, and lifestyle, with some effects from certain medications/supplements. Studies have demonstrated that moderately higher HDL levels may be protective for atherosclerosis."

In the current study, she said, "Causation has not been proven, and importantly there is no evidence that reducing HDL levels reduces fracture risk. Also, this association between raised HDL levels and fracture risk has not been demonstrated consistently in other studies."

Furthermore, she noted, the preclinical trials on which the authors based their hypothesis (ie, an association between HDL-C and a reduction in the number and function of osteoblasts) "has not been demonstrated widely in human subjects."

"We have a large armamentarium of FDA-approved treatments for osteoporosis that have been clinically proven to reduce facture risk very significantly, and these are the tools [in addition to lifestyle changes] we should use to reduce fracture risk," Tan concluded.

John Wilkins, MD, of Northwestern University Feinberg School of Medicine in Chicago, Illinois, and Anand Rohatgi, MD, MSCS, of The University of Texas Southwestern Medical Center in Dallas, Texas, also pointed out some limitations of the study in a related editorial.^[5]

They noted the inclusion of predominantly healthy adults with a mean age of 75 ± 4 years, a population that could yield different findings from middle-aged cohorts with chronic illnesses, as well as a lack of clarity regarding the possible role of alcohol intake among the study participants.

Furthermore, the editorialists wrote, although significant associations were shown in this study, "models were not adjusted for detailed measures of exercise/activity, triglycerides, or any other lipids, including other HDL compositional measures such as [high-density lipoprotein particle number (HDL-P)] or [apolipoprotein AI (ApoA-I)] levels. There was no assessment of whether HDL-C improved discrimination, reclassification, or any other validated measures of risk prediction performance.

"Taken together," they concluded, "this study alone leaves several unanswered questions as to whether high HDL-C could be a useful biomarker to detect fracture risk."

No commercial funding was disclosed. The authors reported no relevant financial relationships.

Clinical Implications

• A previous study by Liu and colleagues of adults with CAD found a U-shaped relationship between HDL-C and the risk for death in adjusted analyses, with a near 2-fold increase in mortality among adults with HDL-C > 80 mg mg/dL compared with the control group. Very high HDL-C was also associated with a significant 71% increase in the risk for CV death specifically. Men with very high HDL-C seemed particularly at higher risk for mortality compared with women.
• The current study by Hussain and colleagues demonstrates a linear positive relationship between HDL-C levels and the risk for fracture among older women and men. Subgroup analyses based on fracture type, statin and anti-osteoporosis drug use, and physical activity level failed to alter the main study conclusions.
• Implications for the healthcare team: The healthcare team should not assume that high levels of HDL-C are salutary for older adults.

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