Long-term effect of zoledronate on bone health in HIV-positive men

A group of drugs called bisphosphonates has been used for the past two decades to improve bone density and reduce the risk of fractures. These drugs were initially designed for and tested largely in women.

One bisphosphonate is zoledronate. This drug can be given once a year via intravenous infusion over a period of 15 minutes. In clinical trials in HIV-negative people, zoledronate has been found to prevent hip and spine fractures in postmenopausal women who have osteoporosis. It can increase bone density in men and reduces the risk of subsequent death in people who have fractured their hips, a debilitating situation.

Zoledronate is meant to be taken once a year. However, emerging data suggests that less frequent dosing might be safe, effective and cheaper.

As HIV-positive people are at increased risk for thinning bones, bisphosphonates need to be tested in this population. So researchers in New Zealand conducted a study of zoledronate in men and found that two annual doses of this drug have prolonged and significant benefit on bone mineral density.

Study details

Researchers enrolled 43 HIV-positive men who were taking anti-HIV therapy (ART) and had reduced bone mineral density. The men were randomly assigned to one of the following interventions:

• 21 men – zoledronate 4 mg given as a 15-minute intravenous infusion once yearly for two consecutive years. The 4 mg dose of zoledronate was used because at the time of the study the now-standard 5 mg formulation was not available.
• 22 men – fake zoledronate (placebo) also given by intravenous infusion once yearly for two consecutive years

All participants received a daily supplement of 400 mg of calcium and 50,000 IU of vitamin D₃ once monthly.

DEXA scans were used to assess bone mineral density every six months for the first two years of the study. After the first two years, most participants entered an extension of the study, where they were monitored for up to six years and DEXA scans were less frequent.

No participant had any significant dysfunction of the following organs/glands (which could affect bone health):

• kidneys
• liver
• thyroid gland

Also, none of the men were using corticosteroids during the study, which can thin bones.

The average profile of participants when they entered the study was as follows:

• age – 49 years
• weight – 75 kg (165 lbs)
• length of time HIV positive – 8 years
• CD4+ count – 550 cells
• proportion with a viral load less than 50 copies/ml – 80%
• duration of ART – 2 years
• total daily intake of calcium – 900 mg

Results – Turnover and density

Bone tissue may feel thick and hard but, at the level of the cell, bones are very dynamic, as small parts of bones are always in the process of being absorbed so that they can be repaired. This process of tearing down and repair is called bone turnover.

In the present study, researchers analysed blood samples, assessing the levels of chemical signals associated with bone turnover. They found an imbalance in chemical signals favouring the absorption of bone in all participants. However, among participants who received zoledronate, bone turnover rates fell significantly compared to placebo. This difference continued for six years.

The impact of zoledronate on bone mineral density was significant and also lasted for six years. For example, the bone density among zoledronate users was greater in the following locations compared to placebo:

• spine: +4%
• hip: +2%
• entire skeleton: +3%

Results – Vitamin D

At the start of the study, participants had less-than-ideal levels of vitamin D in their blood. Indeed, about 25% of them were severely deficient. Despite supplementation in all participants averaging 1,700 IU of vitamin D/day (50,000 IU/month), bone density among placebo users did not significantly increase during the study.

Fractures

Two participants who were taking placebo experienced fractures, one in the backbone and the other in the upper arm bone.

Exposure to tenofovir

Use of tenofovir (Viread, and in Truvada, Atripla and Complera) has been linked to decreased bone density in some studies. In the present study, seven people taking zoledronate and four taking placebo were also taking tenofovir-containing regimens. However, exposure to tenofovir did not affect the study’s results.

Dropouts and deaths

The number of participants who were in the study for six years was as follows:

• zoledronate – 17 men
• placebo – 14 men

Overall, about 28% of participants prematurely left the study, mostly because they emigrated from New Zealand.

Two participants who received zoledronate died, one from lung cancer and the other’s cause of death was not known (Mark Bolland, MD, written communication). These deaths were not related to the study drug.

Safety

Bisphosphonates given by intravenous infusion can sometimes cause temporary side effects—usually a flu-like syndrome that clears within two days but may last up to a week after the infusion. Two participants developed symptoms of a flu-like syndrome after zoledronate infusion, including high fever and muscle and bone pain, and as a result withdrew from the study.

Key points

1. Just two doses of zoledronate given once a year for two consecutive years were able to have a long-term, favourable and significant impact on bone mineral density compared to placebo among men taking ART.

2. The effect of zoledronate on bone mineral density in this study is of a similar degree as that seen in HIV-negative men and women who also used the following drugs:

• alendronate 10 mg daily
• alendronate 70 mg once weekly
• zoledronate 5 mg once yearly for two consecutive years

The New Zealand researchers have also conducted a five-year study observing the impact of a single dose of zoledronate among HIV-negative women. In that study, favourable changes in bone density occurred and were similar to those seen in the present study of HIV-positive men.

3. As zoledronate has to be given just once a year, it may offer better adherence than drugs that have to be taken daily or weekly.

4. Another apparent advantage of zoledronate is that with just an annual dose for two consecutive years, bone mineral density increases significantly and is maintained for up to six years. When other drugs used to increase bone mineral density are discontinued, bones quickly become thinner, as is the case with the following drugs:

• estrogen
• denosumab
• ondanacatib
• teriparatide

5. The present New Zealand study was randomized and placebo controlled, and participants were monitored for up to six years, therefore its findings are robust. Disadvantages of the study were the relatively number of small participants and the dropout rate. As most dropouts were due to emigration, this appeared to be randomly and equally distributed between the study’s two groups, so it was not likely to have a major impact on the results.

6. Participants in the New Zealand study had mildly thin bones—no osteoporosis—so the findings may not apply to other HIV-positive people with more severe bone loss.

7. Larger studies are needed to explore the long-term effect of one or two doses of zoledronate in HIV-positive men and women.

— Sean R. Hosein

REFERENCES:

1. Bolland MJ, Grey A, Horne AM, 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. 2012; in press.
2. Reid IR, Gamble GD, Mesenbrink P, et al. Characterization of and risk factors for the acute-phase response after zoledronic acid. Journal of Clinical Endocrinology & Metabolism. 2010 Sep;95(9):4380-7.