Bone mineral density linked to inflammatory markers in HIV positive people who are ART naïve

Gareth Hardy, HIV i-Base

In the July edition of AIDS, Corrilynn Hileman and colleagues at Case Western Reserve University in Cleveland, Ohio investigated changes in bone mineral density (BMD) in treatment-naive subjects who remained off treatment for over 48 weeks and the association of BMD with other factors in order to throw light on the reported higher prevalence of osteoporosis and fracture in HIV positive people. [1]

This was a prospective, matched cohort study performed on ART-naive, HIV positive people and HIV negative controls matched for age (within 3 years), sex and race. The effects of HIV, inflammation and vitamin D concentration were assessed on BMD over 48 weeks. Dual-energy X-ray absorptiometry (DXA) of the spine and left hip was performed at baseline and at 48 weeks. In order to assess their possible relationships with BMD, plasma levels of the following inflammatory markers were also determined: high-sensitivity C-reactive protein (hsCRP); interleukin-6 (IL-6); soluble tumor necrosis factor-alpha receptors-I and -II (sTNFR-I and II); soluble vascular cell adhesion molecule-1 (sVCAM-1); soluble intercellular adhesion molecule-1 (sICAM-1); and 25-hydroxy vitamin D (25[OH]D).

At baseline, no differences were observed between the 40 HIV positive individuals and the 37 HIV negative controls in terms of age, race, sex, BMI, alcohol use or family history of hip fracture. There were more smokers and HCV positive people in the HIV positive group. Mean duration of HIV infection was 4 years (1.1-12.4 years). Median CD4 count was 625 (533 – 844), nadir CD4 was 520 (542 – 618) and median viral load was 4,638 (783 – 20,600). All participants remained treatment naive throughout the study. Higher levels of some inflammatory markers were found in the HIV positive subjects: IL-6; sTNFR-II; sVCAM-1; sICAM-1 (p <0.01 for all). No differences were seen in hsCRP, sTNFR-I or 25[OH]D. There was also no difference in BMD between the groups at baseline, although there was a trend towards lower BMD at the femoral neck in the HIV-infected group (adjusted mean 1.074 vs 1.145 g/square cm for HIV positive participants versus controls; p = 0.054). BMD measured at the total hip, femoral neck, trochanter and spine was not associated with HIV status, inflammatory markers or 25[OH]D at baseline and the proportion of participants with osteopenia or osteoporosis was not different between HIV positive and control groups.

At 48 weeks, there was a significant percentage reduction in BMD at the total hip and trochanter for the HIV positive group (median absolute change in BMD [IQR] at total hip -0.005 (0.026 – 0.008 g/square cm, p = 0.023 within the group; trochanter -0.013 (-0.03 – 0.003), p = 0.002). BMD did not significantly change at any site in the control group. Despite this, the change in BMD did not reach statistical significance between the groups.

However, the HIV positive group was 2.8 times more likely to suffer loss of BMD at the trochanter site (73% vs 49% for HIV positive and control group respectively; OR 2.8, 95% confidence interval 1.1-7.2, p = 0.034). Adjustment for age, race, sex, BMI, smoking and HCV did not affect this risk. However, adjustment for IL-6, sTNFR-II, sVCAM-1 and sICAM-1 reduced the odds ratio for HIV status by 10% with the addition of each marker. With all 4 markers in the model, HIV status no longer independently predicted bone loss at the trochanter, suggesting that inflammation is an important mechanistic intermediary in the cause of bone loss in people with HIV.

Progression from normal bone to osteopenia or from osteopenia to osteoporosis occurred in 20.5% of HIV positive individuals compared with 5.6% of controls (p = 0.089). For HIV positive people, higher baseline IL-6 (OR 1.1, 95% confidence interval 1-1.2, p = 0.036) and Caucasian race (OR 17.4, 95% confidence interval 2.1-142, p = 0.008) were independently associated with bone loss. No association was found between reduction in BMD and baseline levels of the other inflammatory markers, 25[OH]D, viral load, CD4 count or CD4 nadir.

This study lends further evidence to the literature reducing the potential for a direct role of low vitamin D levels in loss of BMD in HIV infection, as also suggested by Sherwood et al [2] and El-Maouche et al [3].

Instead, the results indicate that inflammatory markers may play a direct role in bone mineral loss and that IL-6 levels at baseline are associated with progression to osteopenia or osteoporosis in HIV positive people. However, the authors also note that the sample size was not large enough to measure statistically significant differences between HIV positive and control groups for BMD. Furthermore, the 48-week limit of the study may have further hindered the detection of differences in BMD change between groups, although it is not feasible for sufficient study numbers of HIV positive people to remain ART naive for longer periods than this.


  1. Corrilynn HO et al. Is bone loss linked to chronic inflammation in antiretroviral-naïve HIV-infected adults? A 48-week matched cohort study. AIDS (2014), 28: 1759-1767. (PDF)
  2. Sherwood JE et al. Vitamin D deficiency and its association with bone low mineral density, HIV-related factors, hospitalization, and death in a predominantly black HIV-infected cohort. Clin Infect Dis (2012), 55: 1727-1736
  3. El-Maouche D et al. Vitamin D deficiency and its relation to bone mineral density and liver fibrosis in HIV-HCV coinfection. Antivir Ther (2013), 18: 237-242 (PDF)

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