HIV-positive people taking rosuvastatin for 48 weeks had significantly greater gains in bone mineral density than people taking placebo, according to results of a 150-person trial.1 Statins are used to treat high cholesterol in people with and without HIV, but this is the first comparative trial to show that statins have a positive impact on bone density in people with HIV.
HIV-positive people have higher rates of heart disease than people without HIV.2 Because statins lower "bad" low-density lipoprotein (LDL) cholesterol, they could help prevent heart disease in HIV-positive people. A recent study found that -- besides lowering LDL cholesterol -- a statin also cut the number and size of coronary artery plaques (fatty build-ups) in people with HIV (see the preceding article in this issue of HIV Treatment Alerts).3 That could be another way statins prevent heart disease in HIV-positive people.
Like heart disease, osteoporosis (low bone mineral density, Figure 1) has become more common in people with HIV as they grow older. Some studies of older people with HIV suggest that statins have a positive impact on bone mineral density and body composition, but research has not firmly established these benefits. To address those questions, US researchers planned a trial to compare daily rosuvastatin with placebo (a dummy pill) in HIV-positive adults.
How the Study Worked
The trial involved HIV-positive adults invited to join the study between March 2011 and August 2012. The researchers randomly assigned half of them to take 10 mg of rosuvastatin daily and half to take placebo, an inactive pill made to look like rosuvastatin. The prime use of rosuvastatin and all statins is to lower LDL cholesterol and thus prevent heart disease. Neither study participants nor study investigators knew which people got rosuvastatin and which got placebo. This is the strongest trial design for determining the impact of a treatment in a given group of people.
All study participants were at least 18 years old, were taking antiretroviral therapy for at least 6 months, and had a viral load below 1000 copies. Everyone had a "bad" LDL cholesterol at or below 130 mg/dL, which is a healthy LDL level. Everyone also had certain signals of inflammation or immune-cell activation.
No one had an active or ongoing inflammatory condition (except HIV infection), and no one had an earlier fracture suggesting low bone mineral density or an earlier heart attack. No one was taking bone therapy drugs, cancer chemotherapy, steroids, or more than 81 mg of aspirin daily (the low dose taken to prevent heart disease).
When people entered the study and 48 weeks later, they had a DXA scan of their whole body, their lower spine, and their left hip. Researchers used initial DXA findings to see who had osteopenia (low bone density) or osteoporosis (very low bone density) and to measure limb fat, trunk fat, and lean mass. The researchers defined lean mass as DXA-measured mass not including fat or bone. They also measured blood markers of inflammation and immune-cell activation.
The main goals were to measure changes in bone mineral density, fat, and lean mass from study entry to week 48 and to compare changes in people taking rosuvastatin and people taking placebo. The research team used accepted statistical methods to make these comparisons.
This analysis of changes in bone mineral density, fat, and lean mass after 48 weeks was a planned part of the SATURN-HIV trial, which is also testing the impact of rosuvastatin on cholesterol, inflammation, and activation of immune system cells.4-7
What the Study Found
The researchers randomly assigned 72 people to take rosuvastatin and 75 to take placebo. The study group had a median age of 47 years, about three quarters were men, and about 70% were black. When the study began, median CD4 count stood at 613, and 78% of participants had an undetectable viral load. Almost one quarter of participants had osteopenia or osteoporosis when the study started.
After 48 weeks of treatment, average hip bone mineral density rose 0.6% in people taking rosuvastatin and fell 0.6% in people taking placebo (Figure 2). The difference between groups was statistically significant, meaning chance cannot explain the difference. At the trochanter (the top of the thigh bone), average bone mineral density rose 0.9% in the rosuvastatin group and fell 0.7% in the placebo group (Figure 2). This difference between rosuvastatin and placebo was also statistically significant. Average bone mineral density in the lower spine changed little through 48 weeks in either group.
The researchers then performed a statistical analysis that assessed the potential impact of age, race, sex, and smoking on hip bone mineral density. (Older age, white rate, female sex, and smoking can contribute to lower bone density.) In this analysis, the estimated average difference in hip bone mineral density between the rosuvastatin group and the placebo group was almost 1% (0.92%).
Leg lean mass increased significantly by 1.5% in the rosuvastatin group, and there was a trend toward increased total lean mass with rosuvastatin (+0.8%). Changes in total, leg, or arm lean mass did not differ significantly between people taking rosuvastatin and people taking placebo. Total body fat, trunk fat, and limb fat did not change significantly during 48 weeks of treatment with rosuvastatin. And fat changes did not differ significantly between people taking rosuvastatin and people taking placebo.
What the Results Mean for You
This well-planned trial of rosuvastatin versus placebo in people with HIV found that 48 weeks of statin therapy increased hip and trochanter bone mineral density, while bone density fell at those sites in HIV-positive people taking placebo (a dummy pill). Clinicians prescribe statins to lower dangerously high cholesterol. The relatively small gains in bone mineral density seen with rosuvastatin in this trial do not support use of statins for bone health alone. But the study suggests that HIV-positive people taking a statin to lower cholesterol could get the added benefit of small gains in bone mineral density -- which is better than the continuing loss of bone density seen among people not taking statin.
The trial also showed that people taking rosuvastatin for 48 weeks gained total lean mass and leg lean mass. Fat mass also increased slightly but not significantly in people taking rosuvastatin. These findings suggest that statins may contribute to improved body composition in people with HIV.
Falling bone mineral density is a well-recognized problem in people with HIV infection. Bone density drops with age, and people responding well to antiretroviral therapy are now living as long or almost as long as people in the general population. HIV-positive people also have high rates of other risk factors for osteopenia and osteoporosis:
- Hepatitis C virus infection
- Low weight
- Physical inactivity
- Diet low in calcium
People with low bone density run a higher risk of fractures (broken bones), and several studies of HIV groups found higher fracture rates in people with HIV than in those without HIV.8-11 Therefore, finding ways to slow or reverse bone loss has become a priority in people with HIV. Combined analysis of eight studies in the general population found that statins protect against fractures.12 But statins did not lower fracture rates in a separate study of people with HIV13 or in a placebo-controlled trial including almost 18,000 men over 50 and women over 60 in the general population.14 The researchers who conducted the rosuvastatin study observed that larger and longer studies are needed to tell whether statin therapy helps people with HIV avoid fractures.
Statins can cause muscle pain in a few people. One person in this study stopped rosuvastatin because of muscle pain that required hospital admission; 2 people assigned to placebo dropped out of the study because of muscle pain.
US HIV care guidelines recommend statin therapy for HIV-positive adults with (1) high LDL cholesterol (at or above 190 mg/dL) or (2) high LDL cholesterol plus triglycerides between 200 and 500 mg/dL.15 Guidelines for bone health in people with HIV say providers should use FRAX (without DXA) to assess fracture risk in (1) all HIV-positive men 40 to 49 years old, and (2) all HIV-positive premenopausal women at least 40 years old.16 These guidelines recommend DXA scans for HIV-positive men 50 and older, postmenopausal women, people who have had a fragility fracture, people taking glucocorticoids (steroid hormones), and people with a high risk of falls.
- Erlandson KM, Jiang Y, Debanne SM, McComsey GA. Effects of randomized rosuvastatin compared with placebo on bone and body composition among HIV-infected adults. AIDS. 2015;29:175-182.
- Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med. 2012;13:453-468.
- Lo J, Lu MT, Ihenachor EJ, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015;2:e52-e63.
- Eckard AR, Jiang Y, Debanne SM, Funderburg NT, McComsey GA. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. J Infect Dis. 2014;209:1156-1164.
- Funderburg NT, Jiang Y, Debanne SM, et al. Rosuvastatin treatment reduces markers of monocyte activation in HIV-infected subjects on antiretroviral therapy. Clin Infect Dis. 2014;58:588-595.
- Erlandson KM, O'Riordan M, Labbato D, McComsey GA. Relationships between inflammation, immune activation, and bone health among HIV-infected adults on stable antiretroviral therapy. J Acquir Immune Defic Syndr. 2014;65:290-298.
- Longenecker CT, Funderburg NT, Jiang Y, et al. Markers of inflammation and CD8 T-cell activation, but not monocyte activation, are associated with subclinical carotid artery disease in HIV-infected individuals. HIV Med. 2013;14:385-390.
- Prieto-Alhambra D, Güerri-Fernández R, De Vries F, et al. HIV infection and its association with an excess risk of clinical fractures: a nationwide case-control study. J Acquir Immune Defic Syndr. 2014;66:90-95.
- Hansen AB, Gerstoft J, Kronborg G, et al. Incidence of low and high-energy fractures in persons with and without HIV infection: a Danish population-based cohort study. AIDS. 2012;26:285-293.
- Peters BS, Perry M, Wierzbicki AS, et al. A cross-sectional randomised study of fracture risk in people with HIV infection in the PROBONO 1 study. PLoS One. 2013;8:e78048.
- Womack JA, Goulet JL, Gibert C, et al. Increased risk of fragility fractures among HIV infected compared to uninfected male veterans. PLoS One. 2011;6:e17217.
- Bauer DC, Mundy GR, Jamal SA, et al. Use of statins and fracture: results of 4 prospective studies and cumulative meta-analysis of observational studies and controlled trials. Arch Intern Med. 2004;164:146-152.
- Overton ET, Kitch D, Benson CA, et al. Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death. Clin Infect Dis. 2013;56:1471-1479.
- Peña JM, Aspberg S, MacFadyen J, Glynn RJ, Solomon DH, Ridker PM. Statin therapy and risk of fracture: results from the JUPITER randomized clinical trial. JAMA Intern Med. 2015;175:171-177.
- US Department of Health and Human Services Health Resources and Services Administration. Guide for HIV/AIDS Clinical Care. April 2014.
- Brown TT, Hoy J, Borderi M, et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. Published online January 21, 2015.