A new study has shown that administering zoledronate intravenously appears to be a safe and effective strategy for treating bone loss in HIV-positive people. Researchers reported in the January 2nd 2009 edition of AIDS that a small United States cohort of HIV-positive men and women who received a single intravenous 5mg dose of zoledronate experienced a greater improvement in bone density than a control cohort that was given a placebo.
An oral formulation of a similar drug is already being administered to HIV-positive people who have experienced bone loss. However, that treatment is associated with gastrointestinal side effects. A more tolerable alternative may be particularly useful for people taking antiretroviral therapy because of the challenges associated with adhering to complex antiretroviral regimens, some of which also cause gastrointestinal problems.
For reasons that are not well understood, HIV-positive people appear to be at increased risk of thinning of the bones. In severe cases, bone fractures are more likely to occur. Because some HIV-positive people see reverses in bone loss without treatment, there is uncertainty about whether treatment is warranted under all circumstances.
Bone loss can be measured with a type of X-ray that indicates bone mineral density (BMD). The World Health Organization’s diagnostic criteria for osteopaenia and osteoporosis are based on BMD scores: a person with a BMD score in the range of 1 to less than 2.5 standard deviations below average has osteopaenia, and person with a BMD score of 2.5 or more standard deviations below average has osteoporosis.
The study published in AIDS found that people receiving zoledronate had an overall bone-density increase of 3.7 ± 4.1% (mean ± SD) at the lumbar spine twelve months after treatment, while the increase for people receiving placebo was only 0.7 ± 3.1% (p = 0.04). Zoledronate recipients also had a significantly greater increase in bone density at the hip: 3.2 ± 2.2% versus -1.8 ± 9.3% (p = 0.016). Lumbar-spine BMD scores in the zoledronate group peaked at six months, while hip BMD scores rose from the six-month to twelve-month mark.
Further evidence of the efficacy of zoledronate was found in changes in biomarkers of bone metabolism within the first two weeks of treatment. The treatment arm experienced significantly greater reductions than the control arm in N-telopeptides and C-telopeptides (two by-products of bone breakdown) indicating a slower breakdown rate (N-telopeptides: F = 3.04, p = 0.03; C-telopeptides: F = 2.70, p = 0.048). A third biomarker of bone metabolism, osteocalcin, showed no changes during the twelve-month monitoring period.
The trial was double-blinded and randomised, with 15 HIV-positive people assigned to the treatment arm and 15 to the control arm. Enrolment criteria included having a lumbar-spine or hip BMD score of -3.5 standard deviations to -1.5 standard deviations below average; a CD4 cell count of at least 100 cells/mm3; and a viral load not exceeding 5000 copies/ml. Seven study participants received a high dose of vitamin D in a single treatment to restore low vitamin D levels before the baseline evaluation was performed. For the duration of the study, everyone took daily calcium and vitamin D supplements.
Nutrition and physical-activity assessments were performed at baseline and at six and twelve months. No relationship was found between changes in calcium levels and bone density scores. Body mass index, body-fat percentage and physical-activity levels did not differ between arms or at different points in time, an indication that none of these factors were responsible for the changes observed in the treatment arm. Likewise, outcomes did not appear to be related to CD4 cell count or to viral-load level.
The study protocol called for participants to take a low dose of acetaminophen before undergoing the infusion in order to reduce the likelihood of a reaction occurring. No participants experienced infusion reactions, although one person developed uveitis, which was treated successfully with topical steroids. Uveitis, a type of eye inflammation, is known to be a potential side effect of zoledronate.
The study enrolled 27 men and three women, and thus does not clarify possible differences between men’s and women’s responses to treatment. While the researchers conclude that zoledronate is a suitable therapy for bone loss, they note that problematic gaps remain in the knowledge base. They call for “larger and longer studies . . . to evaluate women, the persistence of benefits in bone density after treatment, and potential long-term clinical benefits such as reduction in fracture rates.”
Huang J et al. A double-blinded, randomized controlled trial of zoledronate therapy for HIV-associated osteopenia and osteoporosis. AIDS 23: 52–57, 2009.