CROI 2014: Vitamin D and Rosuvastatin Improve Bone Loss in People with HIV

A combination of high-dose vitamin D and calcium may help reduce bone loss after starting antiretroviral therapy (ART), according to a presentation at the Conference on Retroviruses and Opportunistic Infections (CROI 2014) last month in Boston. A related study found that rosuvastatin increased hip bone mineral density in HIV positive people on ART, though insulin resistance worsened.

Vitamin D and Calcium

Edgar Overton from the University of Alabama and colleagues conducted a randomized study (ACTG A5280) to evaluate the effect of high-dose vitamin D plus calcium supplements on bone mineral density (BMD) in HIV positive people taking and ART regimen of efavirenz, tenofovir, and emtricitabine (the drugs in Atripla).

ART initiation -- particularly using tenofovir-containing regimens -- is associated with a 2% to 5% loss in bone density, the researchers noted as background. Vitamin D deficiency is common among people with HIV, and efavirenz has been linked to decreased vitamin D levels.

This 48-week prospective study included 165 participants. Most (90%) were men, the median age was 33 years, and the population was racially/ethnically diverse (37% white, 33% black, 25% Hispanic). Most had undetectable HIV viral load (<50 copies/mL). Self-reported vitamin D intake at baseline was low on average (about 130 IU/day).

Participants were randomly assigned to receive high-dose vitamin D3 (4000 IU daily) plus calcium carbonate 1000 mg daily, or else placebo. The primary endpoint was percentage change in total hip bone mineral density over 48 weeks according to DEXA scans. Data were stratified by baseline 25(OH) vitamin D level.

Results

• In an intent-to-treat analysis at week 48, participants receiving vitamin D and calcium had significantly less decline in hip BMD than those receiving placebo (median -1.46% vs -3.19%).
• BMD loss at the lumbar spine was similarly reduced in the vitamin D/calcium group (-1.41% vs -2.91%), but this difference did not reach statistical significance.
• Markers of bone formation and breakdown (P1NP and CTX) rose in both arms, but did so less in the vitamin D/calcium group, indicating reduced bone turnover.
• Vitamin D and calcium supplementation was generally well-tolerated.
• 3 participants discontinued the study due to adverse events, 1 in the vitamin D/calcium arm and 2 in the placebo arm.
• Similar proportions reported grade 3 or 4 adverse events in both arms (22% vs 23%, respectively).

"Vitamin D/calcium supplementation mitigated the loss of BMD seen with initiation of efavirenz/emtricitabine/tenofovir, particularly at the total hip, which is the site of greatest concern for fragility fracture," the researchers concluded. "Future research will evaluate the potential of this safe, low-cost preventive measure to attenuate bone loss associated with other ART regimens."

They noted that this group started the study with low vitamin D intake, and it is not clear whether supplementation would provide further benefit for people already getting adequate amounts.

Rosuvastatin

Grace McComsey from Case Western Reserve University and colleagues looked at the effect of statin therapy on bone mineral density in HIV positive people on ART.

Many people with HIV use statins to manage elevated blood cholesterol, as a measure to reduce cardiovascular risk. These drugs are also known to have an anti-inflammatory effect and to increase expression of bone morphogenetic protein 2, which promotes bone formation. However, little is known about the effects of statins on bone density in HIV positive people, and there have been conflicting reports on whether statins increase the risk of diabetes.

The Stopping Atherosclerosis and Treating Unhealthy bone with Rosuvastatin in HIV (SATURN-HIV) study was a randomized, placebo-controlled trial to evaluate the effect of statins on markers of cardiovascular risk and bone health in people with HIV.

The study enrolled 147 participants on stable ART with HIV RNA <1000 copies/mL, LDL ("bad") cholesterol levels below <130 mg/dL, and evidence of immune activation (either CD8+CD38+HLA-DR+ cells >19% or high sensitivity C-reactive protein >2 mg/L). They did not have cardiovascular disease, diabetes, or a history of fragility bone fractures at baseline.

Most participants (78%) were men, about 70% were black, and the median age was 47 years. The median CD4 cell count was approximately 600 cells/mm³ and about 80% had undetectable viral load. About half were taking protease inhibitors and 89% were taking tenofovir. At baseline, 23% had evidence of osteopenia at the hip and 22% at the spine.

Participants were randomly assigned to take 10 mg rosuvastatin or placebo. The primary bone endpoint was changes in total hip BMD according to DEXA. Data were stratified by protease inhibitor use and presence or absence of osteopenia at baseline (bone loss with a lumbar spine or total hip T-score < -1).

Results

• At week 48, participants taking rosuvastatin had a significant increase in total hip BMD (mean +0.6%), while the placebo group saw a decrease (-0.6%).
• Changes in bone density at the trochanter or ball of the hip joint were also significantly more favorable in the rosuvastatin arm (+0.9% vs -0.7%).
• Changes in spine density, however, were statistically similar in both groups.
• Larger increases in hip BMD were independently associated with lower baseline levels of soluble tumor necrosis factor-receptor I, as well as greater increases in this biomarker, but not with other inflammation or T-cell activation markers.
• Within the rosuvastatin group, mean increases in fasting glucose, insulin, and HOMA-IR -- indicating greater insulin resistance -- were 5%, 52%, and 72%, respectively, significantly greater than changes seen in the placebo group (3%, 6%, and 15%, respectively).
• Only 1 person in placebo group developed overt diabetes.

"Rosuvastatin therapy increased total hip and trochanter BMD in HIV-infected subjects on ART, regardless of baseline bone density and concomitant [protease inhibitor] therapy," the researchers concluded.

However, they cautioned, "Markers of insulin resistance worsened significantly after statin therapy."

4/9/14

References

ET Overton, ES Chan, TT Brown, et al. High-Dose Vitamin D and Calcium Attenuates Bone Loss With ART Initiation: Results From ACTG A5280. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 133.

GA McComsey, Y Jiang, KM Erlandson, et al. Rosuvastatin Improves Hip Bone Mineral Density But Worsens Insulin Resistance. 21st Conference on Retroviruses and Opportunistic Infections (CROI 2014). Boston, March 3-6, 2014. Abstract 134.