In the HIV population, bone loss is greater among women

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Bone mineral density declines twice as quickly among HIV-positive women than HIV-positive men, according researchers at the University of Colorado, University of Texas Health Sciences Centre; Houston, University of California-Los Angeles; McGill University; Montreal; Hospital Beatriz Ângelo; Loures, Portugal; University of Alberta; Edmonton; Johns Hopkins University; Baltimore and the University of Modena and Reggio Emilia; Modena, Italy.

The study led by Kristine M Erlandson, at the University of Colorado is the largest ever analysis of long-term changes in bone mineral density (BMD) in HIV-positive people, over three-quarters of whom had an undetectable viral load at baseline. Several other modifiable risk factors were also associated with reductions in BMD, including hepatitis C virus infection (HCV), treatment with tenofovir (TDF), low vitamin D levels and lack of physical exercise.

“In a large cohort of HIV-infected men and women on long-term ART (antiretroviral therapy), BMD at both the femoral neck and lumbar spine, a significant predictor of fracture risk, declined twice as quickly among HIV-infected women compared to men, even after adjusting for other covariates,” write the authors. “Notably, the majority of our study population were less than 50 years old, and only 15% of female participants were menopausal at baseline and 24% during follow-up. Thus, with ageing and menopause, the rate of BMD decline among HIV-infected women is expected to be even more pronounced, as suggested by our sex*time differences.”

Declines in BMD during the first three years after starting ART are well described in the medical literature. However, rates of further bone loss and its risk factors are less clear. Investigators from the Modena Metabolic Clinic therefore designed a study involving 839 women and 1759 men taking long-term ART. BMD was measured every six to 12 months using dual-energy X-ray absorptiometry (DXA) scans for up to ten years. The investigators calculated annual rates of BMD decline in the hip (femoral neck) and lumbar spine and the factors associated with this. Their statistical models included demographics and HIV-related factors. A final model added an interaction between sex and duration of therapy (sex*time).

Participants had a minimum of two DXA scans (median five) during a median of five years of follow-up. All the participants were white, 82% were aged under 50 years, and 76% had an undetectable viral load at baseline. Approximately a third (30% of women and 27% of men) had co-infection with HCV. On entry to the study, 7% of men had low testosterone and 15% of women were post-menopausal, with a quarter of women categorised as post-menopausal at any time during follow-up.

Baseline mean BMD for the entire cohort was 1.138 for total body, 0.833 at the femoral neck and 1.055 at the lumbar spine.

In the initial analysis, BMD in the femoral neck declined significantly more among women than men (-0.0353, p < 0.0001), but there was no sex difference in changes to BMD in the lumbar spine. Lower femoral neck BMD was also associated with longer exposure to tenofovir, increasing age, lack of physical activity, low testosterone or post-menopausal status, vitamin D insufficiency and co-infection with HCV. Protective factors included longer duration of treatment with an integrase inhibitor and higher body mass index (BMI).

When the investigators introduced a sex*time interaction into the model, annual changes in BMD were significantly greater among women than men at both the femoral neck (-0.00897 vs -0.00422, < 0.001) and lumbar spine (-0.0127 vs +0.00765, p < 0.001).

“In the largest and longest study of BMD changes among HIV-infected men and women to date, we have found nearly double the rate of BMD decline among HIV-infected women compared to men,” comment the investigators. “Our results highlight BMD losses among women, independent of menopause, effects that require future consideration in ART selection.”

They also note that several modifiable risk factors were associated with bone loss and that bone loss could potentially be slowed by, where appropriate, HCV therapy, vitamin D supplements, choice of HIV therapy and physical exercise.

“Low BMD is one of several risk factors for fracture,” conclude the researchers. “Therefore, the interventions likely to have the greatest impact in this ageing population are those that both attenuate BMD losses and minimise fracture risk through reduced falls.”

Abstract
Background: Initial declines in bone mineral density (BMD) following antiretroviral therapy (ART) initiation in HIV are well described, but data on long-term changes and risk factors for decline, particularly among women, are limited.
Methods: HIV-infected men and women in the Modena Metabolic Clinic underwent dual-energy X-ray absorptiometry (DXA) scans every 6-12 months for up to 10 years (median 4.6 years). Mixed effect regression model in combined and sex-stratified models determined annual rates of decline and clinical factors associated with BMD. Models included demographics, HIV-specific factors, and bone-specific factors; a final model added a sex*time interaction term.
Results: 839 women and 1759 men contributed ≥2 DXA scans. The majority (82%) were ≤ 50 years old; 49% had HIV-1 RNA <50 copies/mL at baseline; 15% of women were post-menopausal and 7% of men had hypogonadism; 30% and 27%, respectively, had hepatitis C virus co-infection. The adjusted slopes in BMD among women and men were significantly different at both the femoral neck (women -0.00897 versus men -0.00422 g/cm2/year; p<0.001) and L-spine (women -0.0127 versus men -0.00763 g/cm2/year; p<0.001). Modifiable risks associated with BMD decline included ART exposure (greater decline with tenofovir disoproxil fumarate, less decline with integrase strand transfer inhibitor therapy), HCV, physical activity, and vitamin D insufficiency.
Conclusions: Among HIV-infected individuals, bone density at the femoral neck, a significant predictor of fracture risk, declined twice as quickly among women compared to men. Female sex was independently associated with both lower femoral neck and lumbar BMD over time in adjusted models.

Authors
Erlandson KM, Lake JE, Sim M, Falutz J, Prado CM, Domingues da Silva AR, Brown TT, Guaraldi G

Aidsmap material
Journal of Acquired Immune Deficiency Syndrome abstract


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