Single dose drug inhibits ART-induced bone loss

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A single dose of the drug zoledronic acid was found to inhibit the bone loss that is common in HIV-infected patients and that is increased during the first two years of treatment with antiretroviral therapy (ART). Bone loss also leads to a higher rate of fracture in HIV-infected individuals.

Study co=authors were Dr Ighovwerha Ofotokun, associate professor of medicine (infectious diseases) at Emory University School of Medicine and Dr M Neale Weitzmann, associate professor of medicine (endocrinology) at Emory School of Medicine and the Atlanta Veterans Affairs Medical Centre.

Researchers studied HIV positive individuals, ages 30 to 50 years, who did not have osteoporosis, had no history of immunological disease other than HIV, had serum vitamin D and calcium levels within the normal range, and normal CBC and blood chemistry profiles.

The study excluded patients who had osteoporosis, those with planned or recent invasive dental procedures, active peptic ulcer disease or recent history of GI bleed, and pregnant or breastfeeding women.

Outcome measures included a marker of bone loss (CTx), and osteocalcin, a marker of bone formation. A bone marrow density scan was used to measure osteopenia and osteoporosis. The study also measured tolerability and safety.

The researchers assessed 343 individuals for eligibility, and 63 were selected and randomised to receive either ART and placebo, or ART and zoledronic acid. Treatment with zoledronic acid was associated with a 73% and a 65% reduction in bone loss relative to placebo at 12 weeks and 24 weeks respectively, an effect that lasted throughout the 48 weeks of the study.

Enhanced bone loss was seen in almost all participants in the placebo arm of the study, while no participant in the treatment arm had an appreciable rise in bone loss. Participants in the placebo arm had a compensatory increase in bone formation, which was an expected result, but bone formation was flat in the treatment arm.

Treatment with zoledronic acid was associated with an 8% increase in lumbar spine bone marrow density at 12 weeks relative to the placebo arm, with an 11% increase at 24 and 48 weeks. Bone loss was higher in men compared to women in the placebo arm, and the protection against bone loss was higher in men than in women in the treatment arm.

Treatment did not impact the rate of viral suppression or immunologic response. “We are encouraged that our protocol was able to prevent bone loss in HIV patients on ART therapy,” says Ofotokun. “These effects occurred early and last through 48 weeks, which is the period when ART-induced bone loss is most intense. This could be an opportunity for effective prophylaxis for preventing bone loss.”

Ofotokun notes this was a small sample size conducted at a single site, with a mostly male, African-American population, and a short duration of 48 weeks. The researchers hope to conduct a larger multicenter study to confirm their findings.

The clinical trial in humans was based on positive results of a 2015 study in mice. In that paper, Weitzmann, Ofotokun, and their colleagues described bone loss similar to that observed in humans following the reconstitution of the T cell population in immune-compromised mice (similar to T-cell expansion following ART). Their findings suggested that the bone loss associated with ART might be caused by inflammatory responses resulting from recovery of the immune system, rather than by the antiretroviral drugs themselves.

In the mouse study, a single injection of zoledronic acid was able to prevent bone loss without impairing the rebuilding of the immune system.

Abstract
HIV enhances bone loss, and close to 2/3 of HIV patients are osteopenic and 15% osteoporotic, leading to 2-9 fold higher fracture prevalence in the aging HIV population. Antiretroviral therapy (ART) further worsens this loss, inducing an additional 2-6% loss in bone mineral density (BMD), mostly within the first 48 weeks, providing a window for prophylaxis with long-acting antiresorptives such as zoledronic acid (ZA).
We randomized non-osteoporotic, viremic ART-naïve adult HIV-patients initiating ART with atazanavir/ritonavir+tenofovir/emtricitabine to a single ZA (5mg) vs. placebo (PL) infusion in a double-blinded placebo controlled phase 2 trial. Laboratory and safety measures, plasma bone turnover markers including C-terminal telopeptide of collagen (CTx), a sensitive marker of bone resorption, and BMD were performed at weeks 0, 12, 24, and 48. Repeated-measures analyses using mixed linear models were used to estimate and compare study endpoints.
Of the 63 subjects enrolled, 84% were black, 16% white, and 21% women with a mean age of 39.6 years. Treatment with ZA was associated with a 74% reduction in bone resorption relative to PL at 12 weeks [CTx: 0.08 ng/ml (ZA) vs. 0.31 ng/ml (PL), p<0.001; mean difference= -0.23 ng/ml (95% CI: -0.31, -0.14)] with 65% and 56% relative reduction at 24 and 48 weeks respectively. ZA led to an 8% increase in lumbar spine BMD at 12 weeks relative to PL [1.305 g/cm2 vs. 1.204 g/cm2, p=0.003; mean difference=0.101 g/cm2 (95% CI: 0.035, 0.168)], with a greater increase of 11% at 24 and 48 weeks. Of note, BMD at the lumbar spine increased 1.9% (95% CI: 0.39, 4.22) from baseline to 48 weeks in the ZA arm but decreased 4.4% (95% CI: 2.63, 6.24) in the PL arm. Lumbar spine T- and Z-scores were significantly higher in patients receiving ZA vs. PL at weeks 12, 24, and 48 (all p<0.05). Significant trends were also observed at the hip and femoral neck. The rate of virologic suppression and mean CD4 T cell increase over 48 weeks were similar between the arms. ZA was well tolerated without major side effects.
In this single center proof-of-concept study, a single infusion of ZA at the time of ART initiation prevented ART-induced bone resorption and bone loss at key fracture-prone anatomical sites. These effects were observed as early as 12 weeks and persisted through 48 weeks, the period when ART-induced bone loss is most intense. Replication of these results in a confirmatory multicenter randomized clinical trial is warranted.

Abstract
HIV infection causes bone loss. We previously reported that immunosuppression-mediated B-cell production of receptor activator of NF-κB ligand (RANKL) coupled with decline in osteoprotegerin correlate with decreased bone mineral density (BMD) in untreated HIV infection. Paradoxically, antiretroviral therapy (ART) worsens bone loss although existing data suggest that such loss is largely independent of specific antiretroviral regimen. This led us to hypothesize that skeletal deterioration following HIV disease reversal with ART may be related to T-cell repopulation and/or immune reconstitution. Here we transplant T cells into immunocompromised mice to mimic ART-induced T-cell expansion. T-cell reconstitution elicits RANKL and TNFα production by B cells and/or T cells, accompanied by enhanced bone resorption and BMD loss. Reconstitution of TNFα- or RANKL-null T-cells and pharmacological TNFα antagonist all protect cortical, but not trabecular bone, revealing complex effects of T-cell reconstitution on bone turnover. These findings suggest T-cell repopulation and/or immune reconstitution as putative mechanisms for bone loss following ART initiation.

Emory University Woodruff Health Sciences material
CROI 2016 abstract
Nature Communications abstract


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