Bone loss

Osteoporosis has traditionally been a disease affecting women past the age of menopause. However, studies have established that osteoporosis is also common amongst HIV-positive men of all ages, as well as in some younger HIV-positive women.

According to one estimate, bone loss may be up to three times more common overall among people with HIV than in the general population.1 Many of the traditional risk factors for osteoporosis, such as low testosterone levels, low body weight, smoking, and drinking alcohol, are also more common in the HIV-positive population and likely contribute to increased prevalence of osteoporosis and osteopenia.

Antiretroviral therapy (ART) is another factor that has been associated with bone loss. A systematic review of cross-sectional studies identified the thymidine analogue reverse transcriptase inhibitors AZT (zidovudine, Retrovir) and d4T (stavudine, Zerit) and the protease inhibitor class as risk factors for decreased bone mineral density (BMD), a marker used to track changes in bone.2

Researchers are still in the process of sorting out the extent to which HIV disease itself, antiretroviral therapy, inflammation and other possible factors contribute to bone loss. Study findings are described in more detail in Osteoporosis and osteopenia in the chapter A to Z of illnesses.

ART effect

The ANRS 121 substudy looked at bone mineral density (BMD) change at the hip and lumbar spine, using dual-energy X-ray absorptiometry (DEXA), in 71 ART-naive patients (median CD4 cell count 219 cells/mm3) randomised into one of three study arms: a boosted protease inhibitor (PI/r) plus a non-nucleoside reverse transcriptase inhibitor (NNRTI); a PI/r plus 2 nucleoside reverse transcriptase inhibitors (NRTIs); or an NNRTI plus NRTIs regimen. Measurements were taken at baseline and at 48 weeks.3

At baseline, 31% had osteopenia and 3% had osteoporosis. At week 48, there was significant BMD loss at the spine and hip in the two PI-containing arms as compared to the NNRTI and NRTIs arm. Investigators suggest monitoring BMD in those on prolonged ART.

A prospective, randomised substudy of the SMART study enrolled over 200 participants into the prospective, randomised, international SMART Body Composition substudy. (The SMART study was designed to compare continuous antiretroviral therapy with CD4 cell-guided treatment interruptions.) Those in the body composition substudy had their BMD assessed using DEXA and quantitative CT scans of the hip and spine at baseline and then once yearly for a mean follow-up time of 2.4 years.4

Those on the study arm with continuous ART received ART for 93% of the follow-up period. On average, they lost between 0.4% and 2.4% of BMD, depending on the site measured. The decline by year was 0.8% (hip), 0.4% (spine DXA), and 2.4% (spine qCT).

In the intermittent therapy arm, ART was received 37% of the time, with the majority of time off treatment occurring in the first year of follow-up. BMD remained stable or increased in those who were part of the intermittent therapy arm during the first year, when most were off therapy. After year one, BMD decreased at a rate similar to that seen in the continuous therapy group. SMART study researchers noted that rate of BMD loss seen in this population of men in their mid-forties was similar to that seen in postmenopausal women age 55 to 75 years.

In the SMART substudy, investigators reported that in the continuous ART study arm, cumulative use of d4T or AZT was associated with loss in spine BMD, consistent with other studies. Cumulative use of boosted lopinavir was associated with BMD loss at the spine and hip.

In Study 613, over 100 ART-naive participants were randomised to receive either efavirenz (Sustiva /Stocrin) or boosted lopinavir (Kaletra). Both arms also started with AZT and 3TC. Those on the boosted lopinavir arm who had undetectable viral load at 24 weeks had AZT and 3TC removed from their regimen.5

Each arm saw similar decreases in BMD over 96 weeks, including those who were in the Kaletra monotherapy arm, suggesting that AZT with 3TC did not have an additive effect on total bone mineral density. Those with lower baseline CD4 T-cell count, non-black race, and higher baseline glucose demonstrated an up to 5% decrease in BMD, but there were not significant differences between the study arms and BMD loss was not related to markers of tumour necrosis factor-alpha activity.

ACTG 5202 was a large controlled clinical trial whose participants were randomised to receive tenofovir/FTC (Truvada) or abacavir/3TC (Kivexa), plus ritonavir-boosted atazanavir (Reyataz) or efavirenz (Sustiva).

At 96 weeks, BMD loss was significantly greater with Truvada than with Kivexa (-1.3 vs -3.0% for lumbar spine; -2.6 vs -3.9% for hip). BMD loss was also significantly greater with atazanavir/ritonavir than with efavirenz as measured at the lumbar spine only (-1.7% vs -3.2%).

With all four regimens, BMD declined sharply soon after starting treatment. After roughly one year, BMD then rose and stabilised at a level below baseline. With Truvada, another decline began near week 144, while with Kivexa BMD was still increasing by week 192.6

While evidence linking ART to bone loss grows, so does the confusion around which anti-HIV drugs may be responsible for the condition. In both the SMART substudy and Study 613, neither trial could identify specific anti-HIV drugs responsible. With a growing push for early and lifelong HIV treatment, bone loss may become a more pressing clinical issue for people with HIV and their doctors as might fracture risk.

This very point was investigated in the French ANRS CO8 APROCO-COPILOTE study that looked at the incidence of fractures in an analysis of nearly 1300 patients who initiated protease inhibitor-based ART between 1997 and 199 with a median follow-up time of seven years. The incidence of fractures in this group was no greater than that found in the general French population.7

Countering bone loss

The question remains, how can bone mineral density be preserved? A small study looked at the efficacy of giving a single 5mg dose of intravenous zoledronate to treat HIV-associated osteopenia and osteoporosis.8

Following an infusion of zoledronate or placebo, participants were followed for a year. Supplements of daily calcium and vitamin D were taken by all. Lumbar spine and hip bone measurements were taken at baseline, six months, and one year.

In this small study of ART-experienced individuals, with a median CD4 cell count of 461 cells/mm3 and viral load less than 400 copies ml, a single dose of zoledronate seemed to be well tolerated and effective. Body mass index, body fat percentage, and physical activity levels did not differ between arms or at different points in time. At one year, there were significant bone density improvements in individuals receiving zoledronate versus those who did not.

References

  1. Brown T, Qaqish RD Antiretroviral therapy and the prevalence of osteopenia and osteoporosis: a meta-analytic review. AIDS 20 (17): 2165-2174, 2006
  2. Fausto A et al. Potential predictive factors of osteoporosis in HIV-positive subjects. Bone 38: 893-897, 2006
  3. Duvivier C et al. Greater decrease in bone mineral density with protease inhibitor regimens compared with nonnucleoside reverse transcriptase inhibitor regimens in HIV-1 infected naïve patients. AIDS 23(7): 817-824, 2009
  4. Grund B et al. Continuous antiretroviral therapy decreases bone mineral density. AIDS 23:1519–1529, 2009
  5. Brown TT et al. Loss of bone mineral density after antiretroviral therapy initiation, independent of antiretroviral regimen. J Acquir Immune Defic Syndr 51(5): 554-561, 2009
  6. McComsey G et al. Bone and limb fat outcomes of ACTG A5224s, a substudy of ACTG A5202: a prospective, randomized, partially blinded phase III trial of ABC/3TC or TDF/FTC with EFV or ATV/r for initial treatment of HIV-1 infection. Seventeenth Conference on Retroviruses and Opportunistic Infections, abstract 106LB, San Francisco, 2010
  7. Collin F et al. Ten-year incidence and risk-factors of bone fractures in a cohort of treated HIV-1-infected adults. AIDS 23(8): 1021-1023, 2009
  8. Huang J et al. A double-blinded, randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis. AIDS 23(1): 52–57, 2009