- Category: Bone Loss/Osteoporosis
- Published on Tuesday, 10 April 2012 00:00
- Written by Gregory Fowler
The effects of 2 annual doses of zoledronate persist for at least 5 years in HIV positive men on antiretroviral therapy (ART), according to a New Zealand study published in the March 14, 2012, advance online edition of the Journal of Clinical Endocrinology & Metabolism.
Low bone mineral density (BMD) is common among HIV positive men, and recent studies suggest that rates of fragility fracture are also increased, especially among older individuals. A poster presented at the Conference on Retroviruses and Opportunistic Infections (CROI 2012) in March found that 66% of HIV positive study participants had low BMD.
Reasons for bone loss (osteopenia or more severe osteoporosis) among people with HIV may include chronic HIV infection itself, related inflammation or metabolic changes, side effects of antiretroviral drugs, or a combination of factors.
Zoledronate (zoledronic acid; brand names include Aclasta, Reclast, and Zometa) is a potent bisphosphonate that is administered annually by intravenous (IV) infusion for the treatment of osteoporosis and prevention of fractures. It is often used as an alternative to oral bisphosphonates such as alendronate (Fosamax), which are typically taken once-weekly and can cause side effects including upset stomach and ulceration of the esophagus. While the optimal dosing of zoledronate has yet to be determined, annual administration has been shown to be a well-tolerated and effective therapy for HIV-associated bone loss.
In the current study, Mark Bolland from the University of Auckland and colleagues enrolled 43 HIV positive men; 21 were randomly assigned to receive 4 mg IV doses of zoledronate once annually for 2 years, while 22 were assigned to the placebo arm.
The average age was 49 years and the men had been HIV positive for an average of 8 years. All participants were on combination ART, with similar medication regimens in the 2 arms. Participants did not have significant renal, hepatic, or concurrent major systemic illness, and they were not using bisphosphonates or glucocorticoids at study entry. The average CD4 cell count at baseline was about 540 cells/mm3 and most (about 80%) had undetectable viral load. At baseline they had T-scores below -0.5 at the lumbar spine or total hip, indicating mildly low BMD but not osteoporosis.
In 2007 Bolland's team reported that annual administration of 4 mg zoledronate for 2 years was a potent and effective therapy for prevention or treatment of bone loss in HIV positive men, leading to increases in BMD and decreases in markers of bone formation and resorption. In this analysis, they evaluated the duration of these effects in a 4-year extension of the original 2-year study; 14 people in the zoledronate arm and 17 in the placebo arm completed all 6 years of follow-up.
- Between years 2 and 6, levels of serum osteocalcin -- a protein marker of bone turnover -- remained 41% lower, on average, in the zoledronate group than in the placebo group.
- Levels of serum CTX (beta-C-terminal telopeptide of type I collagen) -- a marker of bone resorption -- were 52% lower, on average, in the zoledronate group.
- At year 6 (that is, 5 years after the second infusion), serum osteocalcin remained 38% lower and serum CTX remained 49% lower in the zoledronate group.
Between years 2 and 6, average BMD was higher in the zoledronate group than in the placebo arm at all sites measured using dual-energy x-ray absorptiometry (DEXA):
- Lumbar spine: 3.7% higher;
- Total hip: 2.3% higher;
- Total body: 2.5% higher.
- At year 6, BMD at all sites remained higher in the zoledronate group than in the placebo arm (3.5%, 3.4%, and 1.6% higher, respectively).
- Assessing the impact of baseline vitamin D status, there were no significant differences between the groups in mean 25-hydroxyvitamin D (250HD) levels or proportion of individuals with 250HD below 20 ng/mg, and baseline 25OHD did not independently predict changes in BMD.
- 2 study participants, both in the placebo arm, sustained fractures during follow-up.
- None of the participants experienced adverse side effects attributed to zoledronate during the extension study.
In summary, the researchers wrote, "the effects of 2 annual 4-mg doses of zoledronate on bone turnover and BMD in men persist for at least 5 years after the second dose. Additional randomized trials are justified to explore the anti-fracture efficacy of dosing schedules of zoledronate given less frequently than is currently recommended."
Although this study was small and had some limitations -- for example, 28% of participants did not complete the 6-year follow-up -- the authors concluded that the narrow confidence intervals around the changes in bone turnover and BMD suggest that their results are robust. "There was no evidence in the sensitivity analysis that the missing data affected the study findings, although this might be limited by the small study size," they wrote.
Another consideration is that the study included individuals with mildly low BMD, and it is not known if these results may be applicable to those with lower BMD and higher fracture risk. Likewise, the study included men on ART with well-controlled HIV infection, and the conclusions may not be generalizable to other groups. Finally, only 7 of 17 men in the zoledronate group and 4 of 14 in the placebo group were taking tenofovir (Viread, also in the Truvada, Atripla, and Complera coformulations), which has been linked to bone loss in some studies.
This study raises some important clinical considerations:
- For HIV positive men with high fracture risk, infrequent zoledronate dosing would offer the benefit of not adding to a patient’s "pill burden."
- There would be less concern about poor adherence with infrequent IV zoledronate than with osteoporosis medications that require more frequent dosing and possible gastrointestinal side effects.
- Compared with zoledronate’s long-term effects, discontinuation of other osteoporosis agents (such as denosumab or odanacatib) can lead to a rapid increase in bone turnover and reduction in BMD.
"A key question is whether the effects of zoledronate observed on the surrogate endpoints of bone turnover and BMD will translate into reductions in clinical endpoint fractures," the authors concluded. "This question will be answered definitively only by a carefully designed prospective clinical trial."
M Bolland, A Grey, A Horn, et al. Effects of Intravenous Zoledronate on Bone Turnover and Bone Density Persist for at Least Five Years in HIV-Infected Men. Journal of Clinical Endocrinology & Metabolism 97(6). March 14, 2012 (Epub ahead of June 2012 print edition).