Nancy A Melville

September 19, 2017

DENVER — The prevalence of vertebral fractures is significantly increased in HIV-positive patients, regardless of age or gender, according to a systemic review and meta-analysis, while other new research presented here at the American Society for Bone and Mineral Research (ASBMR) 2017 Annual Meeting shows increased bone loss associated with HIV infection.

"We found that HIV-positive subjects are at higher risk of vertebral fractures when compared with HIV-negative subjects," Melissa Premaor, MD, PhD, of the Federal University of Santa Maria, Brazil, first author of the systemic review, told Medscape Medical News.

"Clinicians should be aware of this information, and the necessity of a spine X-ray in these subjects should be discussed with the health providers," said Dr Premaor.

While antiretroviral therapy (ART) has allowed for substantial improvement in survival with HIV, comorbidities are emerging that wouldn't otherwise be expected in a middle-aged population, including effects on the skeleton. However, studies documenting the risk of vertebral fractures have been inconsistent in design and outcomes.

"Unprecedented" Rates of Fractures in Men in Their 40s and 50s

To better understand the effects, Dr Premaor and colleagues conducted a systemic review and meta-analysis of randomized controlled trials, cohort, cross-sectional, and other studies evaluating either morphometric or clinical vertebral fractures in patients who were HIV-positive, with or without treatment with ART.

The analysis showed that out of 26 studies included in the review, the odds ratio (OR) for vertebral fractures in HIV-positive patients compared with HIV-negative patients was 2.3 (95% CI, 1.37–3.85).

In 14 studies involving 10,593 HIV-positive (ages 31 to 72), the prevalence of all vertebral fractures was 12.7%, with the prevalence of clinical vertebral fractures at 3.9% and the prevalence of morphometric vertebral fracture at 21.1%.

A meta-regression analysis showed no association between age or gender in the prevalence of vertebral fracture, and importantly, the age range was from 40 to 58.

The total incidence of vertebral fracture per 1000 persons per year was 0.8 (95% CI, 0.4–1.8).

The higher fracture rates seen with HIV could be the result of either the HIV virus itself or the medications used to treat it, Dr Premaor speculated.

"It's probably both," she said. "The early antiretrovirals, such as tenofovir, have a deleterious effect on bone.

"In addition, some of these subjects have vitamin D deficiency, hypogonadism, and other risk factors for fractures, and the HIV itself might play a role. And we could not rule out unknown mechanisms."

In commenting on the study, Steven R Cummings, MD, professor of medicine, epidemiology, and biostatistics, emeritus, at the University of California, San Francisco, said the findings are important — and surprising.

"We have very little data on how much risk there is for fracture in people with HIV," he told Medscape Medical News. "We know they have an increased risk of hip fractures, and this study shows there is also an increased risk of vertebral fractures."

The prevalence rate of fractures observed in people with HIV is remarkable, he added.

"To see a prevalence rate of morphometric fractures that is that high is unprecedented in that age group — you don't see those rates except in women over the age of 65," he stressed.

"And the fact that the majority of the subjects are men is even more striking. This level of risk, if it is accurate, would certainly make it worthwhile for men in their 40s and 50s with HIV to get an X-ray of their spine."

Dr Cummings noted, however, that the incidence rate of just 0.8 (per 1000 patient-years) appears inconsistent with the higher prevalence rates.

"We believe the quality of the reporting of the incidence of vertebral fracture was not as good, and we believe it is likely" a great underestimate, Dr Premaor responded.

Effects of HIV Infection on Bone Health

Additional research presented at the meeting further describes the effects of HIV on bone health.

In one cross-sectional study in Thailand comparing the bone-mineral density (BMD) of HIV-infected patients with those not infected, from 2016 to 2017, the unadjusted BMD in HIV-infected men was significantly lower than uninfected men at all sites and remained 5.8% lower at the total hip after adjustment for body mass index (BMI) and age.

The study included 201 male and 122 female HIV-infected patients, with 82% treated with tenofovir for a median of 7.6 years, and showed the prevalence of T scores at the total hip below -1.0 was 36% in HIV-infected men compared with 21% in the uninfected controls (P = .01). At the femoral neck, the corresponding rates were 62% in the HIV-infected males compared with 45% in controls (P = .01).

Among women, the prevalence of T scores below -1.0 was also significantly higher in HIV-infected patients at the femoral neck (74% vs 54%; P = .01), while Z scores were lower among infected women at all sites.

The prevalence of osteoporosis was greater in HIV-infected men compared with uninfected men, while infected vs not infected women showed only a trend of increased risk for osteoporosis that was not statistically significant.

"Aging ART-treated HIV-infected patients had lower bone-mineral density. Thus, careful monitoring and treatment of low BMD in these patients should not be overlooked to prevent further reduction in BMD and future fractures," the authors indicate.

Prudent to Ensure That HIV-Infected Patients Have Adequate Vitamin D Levels

A third study offered insights on still another piece of the HIV–bone loss puzzle, showing no link between vitamin D supplementation and improvements in bone loss.

With previous evidence suggesting lower total 25-hydroxy vitamin D (25-OHD) levels to be associated with greater bone loss at the distal radius in HIV-infected postmenopausal women, researchers at Columbia University Medical Center randomized 81 HIV-infected women to receive either moderate vitamin D3 supplementation (3000 IU) or low (1000 IU) supplementation in a double-blind study.

The women had an average age of 56, 43% were African American, and 57% were Hispanic.

While measures of 25-OHD increased to higher levels in the moderate-supplementation group compared with low-supplement group at 6 months (33.1 vs 27.8 ng/mL, P = .03) and 12 months (30.2 vs 24.3 ng/mL, P = .007), there were no significant changes between the groups in terms of areal or volumetric BMD or bone-turnover markers in unadjusted or adjusted analyses. Patients also showed no differences in parathyroid (PTH) levels.

Regression analyses showed patients with lower baseline 25-OHD levels in the moderate-vitamin D group did have greater increases in areal BMD at the femoral neck (= .04) and ultradistal radius (= .04) at 12 months; however, no other improvements were seen.

"Vitamin D supplementation at 3000 IU daily increased mean total 25-OHD levels to > 30 ng/mL in HIV-positive postmenopausal women but did not result in increases in BMD or suppression of bone-turnover markers compared with 1000 IU daily," the authors note.

First author Michael Yin, MD, an associate professor of medicine in the division of infectious diseases at Columbia University Medical Center, in New York, said the findings were somewhat unexpected.

"It was surprising, given our previous findings that women with low vitamin D levels had higher rates of bone loss," he told Medscape Medical News.

"However, it could be that lower vitamin D levels are a marker for other conditions or risk factors associated with higher bone turnover and bone loss in this population, rather than a causal factor."

Other possibilities are the differences between the low and high doses of vitamin D were not large enough or that the study wasn't adequately powered, he said. But the findings nevertheless add to needed research on the issue.

"In general, the take-home message for clinicians is that we need more evidence to be certain of the effects of vitamin D on bone health in HIV-infected patients," Dr Yin said.

"However, until such evidence becomes available, it is prudent to ensure that HIV-infected patients have adequate serum levels of vitamin D. Finally, it may take higher doses than typically recommended to achieve serum levels of 20 to 30 ng/mL in HIV-infected patients on ART."

The studies' authors had no relevant financial relationships.

American Society of Bone and Mineral Research Annual Meeting. September 10 and 11, 2017, Denver, Colorado. Abstracts 1128, SU0280, and SU0282.

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