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Effects of Intravenous Zoledronate on Bone Turnover and Bone Density Persist for at Least Five Years in HIV-Infected Men
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J Clin Endocrin Metab. First published ahead of print March 14, 2012
Mark J. Bolland, Andrew Grey, Anne M. Horne, Simon E. Briggs,
Mark G. Thomas, Rod B. Ellis-Pegler, Greg D. Gamble, and Ian R. Reid
Departments of Medicine (M.J.B., A.G., A.M.H., G.D.G., I.R.R.) and Molecular Medicine and Pathology (M.G.T., R.B.E.-P.), University of Auckland, Private Bag 92 019, Auckland 1142, New Zealand; and Department of Infectious Diseases (S.E.B., M.G.T., R.B.E.-P.), Auckland Hospital, Private Bag 92 024, Auckland 1142, New Zealand
"In summary, the effects of two annual 4-mg doses of zoledronate on bone turnover and BMD in men persist for at least 5 yr after the second dose. Additional randomized trials are justified to explore the antifracture efficacy of dosing schedules of zoledronate given less frequently than is currently recommended.
In this study, the effects of two annual doses of 4 mg iv zoledronate on bone turnover and BMD in men lasted at least 5 yr after the second dose. Markers of bone formation and resorption showed sustained and stable suppression, and BMD remained stable between 1 and 5 yr after the second dose of zoledronate. The results are consistent with another clinical trial from our group that showed sustained, stable suppression of bone turnover and increased BMD 5 yr after a single dose of 5 mg zoledronate in postmenopausal women (submitted for publication). Taken together, the results extend findings from previous studies from our group and others that have also reported duration of effects of zoledronate in various population groups lasting at least 2-3 yr (5- 8, 11). These results are also consistent with the extension of the original phase 3 Horizon study. Results from that study show that after 3 yr after three annual doses of zoledronate, femoral neck BMD decreased slightly and bone turnover increased slightly in older postmenopausal women (12). Our findings complement and extend the findings of the Horizon extension by reporting the effects of a different dose and duration of treatment, in a different population group, in a placebo-controlled study design, with a substantially longer duration of follow-up after discontinuation of zoledronate.
A key question is whether the effects of zoledronate observed on the surrogate endpoints of bone turnover and BMD will translate into reductions in the clinical endpoint of fractures. That question will be answered definitively only by a carefully designed prospective clinical trial. However, there are several lines of evidence that suggest that fracture prevention is likely. The changes in bone turnover and BMD 5 yr after the second dose of 4 mg zoledronate in this study are similar to those observed in men with osteoporosis after 2 yr of annual 5 mg zoledronate (1), weekly 70 mg alendronate (1), or 10 mg daily alendronate (13). In the latter study, daily alendronate reduced the incidence of morphometric vertebral fractures by 90%....
The study cohort was HIV-infected men treated with HAART whose HIV infection was well controlled, so the conclusions may not be generalizable to other groups, although the results were similar to results from studies of men with osteoporosis (1, 13). The congruent findings from a 5-yr trial of a single dose of zoledronate in postmenopausal women suggest that the current results are broadly applicable (manuscript submitted). Nevertheless, both studies have included only individuals with mildly low BMD, and the results may not apply to individuals with lower BMD and higher risk of fracture."
Abstract
Context: In HIV-infected men, the antiresorptive effects of zoledronate persist for at least 2 yr after the second annual dose.
Objective: Our objective was to determine the duration of action of zoledronate in men.
Design and Setting: This was 4-yr extension of a 2-yr, double-blind, randomized, placebo-controlled trial at an academic research center.
Participants: Participants included 43 HIV-infected men with bone mineral density (BMD) T score below -0.5, 35 of whom entered the extension study.
Intervention: Intervention was annual administration of 4 mg iv zoledronate or placebo at baseline and 1 yr and no intervention subsequently.
Main Outcome Measures: We evaluated changes in the bone turnover markers, serum osteocalcin and serum C-telopeptide (CTx), and changes in BMD at the lumbar spine, total hip, and total body.
Results: There was no time x treatment interaction between 1 and 5 yr after the second zoledronate dose for osteocalcin or CTx (P > 0.4) or any BMD site (P > 0.7). Between 1 and 5 yr after the second dose, on average, osteocalcin was 41% lower (95% confidence interval = 19-62%; P < 0.001), CTx 52% lower (33-71%; P < 0.001), lumbar spine BMD 3.7% greater (0.3-7.0%; P = 0.03), total hip BMD 2.3% greater (0.3-4.3%; P = 0.02), and total body BMD 2.5% greater (0.8-4.1%; P = 0.004) in the zoledronate group than the placebo group. Five years after the second dose, the between-groups differences were 38% (13-62%) for osteocalcin, 49% (20-77%) for CTx, 3.5% (0.7-6.7%) for lumbar spine BMD, 3.4% (1.4-5.4%) for total hip BMD, and 1.6% (0.2-3.1%) for total body BMD.
Conclusion: The effects of two annual 4-mg doses of zoledronate in men persist for at least 5 yr after the second dose. Larger trials assessing the antifracture efficacy of less frequent dosing of zoledronate are justified.
Zeledronate is a potent bisphosphonate that, when administered annually by iv infusion, increases bone mineral density (BMD) in men and women with osteoporosis (1, 2); prevents vertebral, nonvertebral, and hip fractures in women with osteoporosis (2); and prevents fractures and reduces mortality in people with a previous hip fracture (3). The optimal frequency of zoledronate dosing is yet to be determined. Previously, we reported that two annual 4-mg doses of zoledronate in HIV-infected men led to increases in BMD and decreases in markers of bone formation and resorption that persisted for 2 yr after the second dose of zoledronate (4, 5). After a single 5-mg dose of zoledronate in postmenopausal women with osteopenia, there were increases in BMD and decreases in markers of bone formation and resorption that persisted for at least 3 yr (6-8). In a post hoc analysis of the phase 3 trial of zoledronate, women receiving one dose of zoledronate had a 32% reduction in all clinical fractures after 3 yr compared with women receiving one dose of placebo (9). These findings suggest that the effects of zoledronate persist well beyond 12 months and that it could be administered less frequently than annually.
Here we report the findings from an extension of our 2-yr, randomized, placebo-controlled trial of annual 4 mg iv zoledronate in HIV-infected men (4). We studied participants for an additional 4 yr after completion of the trial, without administration of additional antiresorptive medication. Thus, we investigated the persistence of effects of zoledronate on markers of bone turnover and BMD in men for 5 yr after the second of two doses of zoledronate.
Discussion
In this study, the effects of two annual doses of 4 mg iv zoledronate on bone turnover and BMD in men lasted at least 5 yr after the second dose. Markers of bone formation and resorption showed sustained and stable suppression, and BMD remained stable between 1 and 5 yr after the second dose of zoledronate. The results are consistent with another clinical trial from our group that showed sustained, stable suppression of bone turnover and increased BMD 5 yr after a single dose of 5 mg zoledronate in postmenopausal women (submitted for publication). Taken together, the results extend findings from previous studies from our group and others that have also reported duration of effects of zoledronate in various population groups lasting at least 2-3 yr (5- 8, 11). These results are also consistent with the extension of the original phase 3 Horizon study. Results from that study show that after 3 yr after three annual doses of zoledronate, femoral neck BMD decreased slightly and bone turnover increased slightly in older postmenopausal women (12). Our findings complement and extend the findings of the Horizon extension by reporting the effects of a different dose and duration of treatment, in a different population group, in a placebo-controlled study design, with a substantially longer duration of follow-up after discontinuation of zoledronate.
A key question is whether the effects of zoledronate observed on the surrogate endpoints of bone turnover and BMD will translate into reductions in the clinical endpoint of fractures. That question will be answered definitively only by a carefully designed prospective clinical trial. However, there are several lines of evidence that suggest that fracture prevention is likely. The changes in bone turnover and BMD 5 yr after the second dose of 4 mg zoledronate in this study are similar to those observed in men with osteoporosis after 2 yr of annual 5 mg zoledronate (1), weekly 70 mg alendronate (1), or 10 mg daily alendronate (13). In the latter study, daily alendronate reduced the incidence of morphometric vertebral fractures by 90% (13). In postmenopausal women, the changes in bone turnover and BMD 5 yr after a single dose of 5 mg zoledronate (submitted for publication) are similar to those observed in studies of 3-4 yr treatment with risedronate (14), alendronate (15), and annual administration of iv zoledronate (2, 3) that reported prevention of osteoporotic fractures with these agents. Finally, in a 3-yr trial of annual 5 mg zoledronate, women who received only one dose of zoledronate had a 32% reduction in all clinical fractures compared with women who received only one dose of placebo (9). These data provide a strong rationale for investigating alternative treatment regimens of zoledronate, including both lower doses and less frequent dosing intervals. If effective, such regimens might offer substantial cost savings and reduce concern regarding long-term safety.
Some important clinical issues arise from the prolonged effects of zoledronate. First, for men with HIV and high fracture risk, the current data suggest that infrequent dosing with zoledronate may be an effective therapy, with the benefit of not adding to daily oral medication regimens. Second, there should be less concern about poor compliance than with some other osteoporosis agents. For example, after discontinuation of denosumab or odanacatib, there is a rapid increase in bone turnover and a rapid reduction in BMD to baseline levels (16, 17). Similarly, discontinuation of estrogen and teriparatide leads to a rapid decrease in BMD (18-20).
The current study has some limitations. It is a small study, although the narrow confidence intervals around the changes in bone turnover and BMD suggest that the findings are robust. Although there were no statistically significant baseline differences between the groups, the study did not have power to detect small differences in these variables. Twenty-eight percent of individuals enrolled in the study did not complete the 6-yr follow-up, although the majority of those lost to follow-up emigrated overseas so are likely to be missing at random rather than for reasons related to their treatment allocation. There was no evidence from the sensitivity analyses that the missing data affected the study findings, although this might be limited by the small study size. The study cohort was HIV-infected men treated with HAART whose HIV infection was well controlled, so the conclusions may not be generalizable to other groups, although the results were similar to results from studies of men with osteoporosis (1, 13). The congruent findings from a 5-yr trial of a single dose of zoledronate in postmenopausal women suggest that the current results are broadly applicable (manuscript submitted). Nevertheless, both studies have included only individuals with mildly low BMD, and the results may not apply to individuals with lower BMD and higher risk of fracture.
In summary, the effects of two annual 4-mg doses of zoledronate on bone turnover and BMD in men persist for at least 5 yr after the second dose. Additional randomized trials are justified to explore the antifracture efficacy of dosing schedules of zoledronate given less frequently than is currently recommended.
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