High-Density Lipoprotein Cholesterol and Risk of Fractures in Healthy Older Adults

High-density lipoprotein cholesterol (HDL-C), sometimes known as “good cholesterol,” carries cholesterol from the blood to the liver. HDL particles grow larger as they take on more cholesterol and phospholipid molecules from cells and other lipoproteins and transport these molecules to the liver, adrenals, ovaries, and testes for the synthesis of steroid hormones.¹ HDL is removed from circulation by HDL receptors.¹ 

An inverse relationship exists between HDL-C and heart disease. HDL-C is a well-known risk marker for heart disease and is included in heart disease risk factor equations to estimate atherosclerotic cardiovascular disease (ASCVD).^2-3 High concentrations of HDL (over 60 mg/dL) have protective value against ASCVD whereas low concentrations of HDL (below 40 mg/dL for men or below 50 mg/dL for women) increase the risk for ASCVD.^2-3

HDL-C has been linked by association studies to heart failure, dementia, diabetes, and kidney disease.⁴ In a recent cohort study, which was a post-hoc analysis of the Aspirin in Reducing Events in the Elderly (ASPREE) clinical trial and the ASPREE-Fracture substudy, 16,262 participants with HDL-C measurements at baseline were studied for patient-reported fractures.⁵ The participants were mostly healthy women (55%) and men (45%) of mean age 75 years. A total of 1659 participants experienced at least 1 fracture over 4 years of follow-up.⁵ Each standard deviation resulted in a 14% higher risk of fracture (hazard ratio [HR]: 1.14; 95% CI: 1.08-1.20). The association was linear for both men and women. This association was maintained after researchers adjusted for traumatic fractures, lack of osteoporosis medications, non-smokers, non-alcohol drinkers, participants who did 30-minutes per day of outside exercise, and statin use. There was no association with non–HDL-C levels and fractures.

Another study called the Cardiovascular Health Study (CHS) found lipids and lipoproteins were associated with 755 incident hip fractures among women (1.19 fractures per 100 participant years [95% CI, 1.04, 1.35]) and 197 among men (0.67 fractures per 100 participant years [95% CI, 0.41, 1.10]) over an average 13.5 (SD 7.1) years of follow-up. 

“HDL-C and LDL-C levels had statistically significant non-linear U-shaped relationships with hip fracture risk (HDL-C, P = .009; LDL-C, P = .02),” researchers said. 

Their evidence supports the findings from the ASPREE substudy.⁶ Of note, the ASPREE substudy enrolled primarily White patients, and the CHS study enrolled a larger proportion of Black patients.  

So, what should clinicians do with this data? Association studies are limited by the confounding factors.  In the case of HDL-C, heavy alcohol intake, renal function, sex, and diabetes need to be taken into consideration. The mechanism of this interaction has not been delineated. For both studies, the associated increases are modest. Based on these limitations, there remains a need for a prospective, randomized clinical trials to confirm whether HDL-C causes bone fractures in older adults. 

References:

1. Deng S, Xu Y, Zheng L. HDL Structure. Adv Exp Med Biol. 2022;1377:1–11. doi:10.1007/978-981-19-1592-5_1
2. Rahilly-Tierney CR, Spiro A, Vokonas P, Gaziano JM. Relation between high-density lipoprotein cholesterol and survival to age 85 years in men (from the VA normative aging study). Am J Cardiol 2011;107(8):117. doi:10.1016/j.amjcard.2010.12.015. 
3. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma insulin, and cardiovascular disease: subgroup analysis from the Department of Veterans Affairs high-density lipoprotein intervention trial (VA-HIT). Arch Int Med. 2002:162 (22):2597–604. doi:10.1001/archinte.162.22.2597. 
4. Wilkins J, Rohatgi A. Higher high-density lipoprotein cholesterol—good omen, bad omen, or not an omen at all. JAMA. Published online January 18, 2023. doi:10.1001/jamacardio.2022.5143
5. Hussain SM, Ebeling PR, Barker AL, Berlin LJ, Tonkin AM, McNeil JJ. Association of plasma high-density lipoprotein cholesterol level with risk of fractures in health older adults. JAMA Cardiol. Published online January 18, 2023. doi:10.1001/jamacardio.2022.5124
6. Barzilay JI, Buzkova P, Kuller LH, et al. The Association of Lipids and Lipoproteins with Hip Fracture Risk: The Cardiovascular Health Study. Am J Med. 2022 Sep;135(9):1101-1108.e1. doi:10.1016/j.amjmed.2022.05.024.