Bone loss in SMART study
Mark Mascolini, for NATAP.org
People randomised to continuous antiretroviral therapy in the SMART trial lost more bone mineral density (BMD) than those randomised to intermittent therapy, according to results of a SMART substudy analysis. 
After 2.8 years of follow-up in the overall 5472-person study group, 10 people on continuous antiretrovirals had grade 4 fractures, compared with 2 in the intermittent-therapy arm. The findings are surprising in light of recent cohort studies that saw no link between antiretroviral therapy (except perhaps tenofovir) and declining BMD in men  or women . Also confounding expectation, the substudy did not correlate steady tenofovir use with waning BMD.
The SMART substudy used yearly DEXA scans to measure hip and spine BMD and quantitative computed tomography (QCT) to measure trabecular density in the spine. Among 98 substudy participants on continuous antiretroviral therapy and 116 on intermittent therapy, median age stood at 43 and 45 years, 25% and 15% were women, 51% and 41% smoked, and 5% and 3% used steroids. Median CD4 counts were similar in the two groups (525 on continuous therapy and 590 on intermittent therapy), and nadir CD4 counts were similar (268 and 235). About 40% in each group had low initial BMD by DEXA t-scores, and about 4% in each group already had DEXA-defined osteoporosis.
Compared with people taking intermittent antiretroviral therapy, those on steady treatment had significantly greater drops in femur BMD (0.9% per year), spine by QCT (2.9% per year), and spine by DEXA (0.4% per year). Estimated BMD change differences between the two groups (continuous therapy BMD minus interrupted therapy BMD) reflected significantly more BMD loss in the continuous-therapy group:
- 1.4% in femur (95% confidence interval [CI] 0.5 to 2.3, p=0.002)
- 2.9% in spine by QCT (95% CI 0.7 to 5.1, p=0.01)
- 1.2% in spine by DEXA (95% CI 0.02 to 2.3, p=0.05)
In the treatment-interruption group, BMD remained stable in the first year of follow-up then began falling roughly in parallel with the drop in the continuous-therapy group. The investigators suggest that “this pattern is consistent with the increased antiretroviral therapy use after year 1 in the treatment-interruption group. “Higher viral loads during the first year did not appear to contribute to bone loss in the interruption group”.
Treatment with lopinavir/ritonavir, with abacavir, and with the two thymidine nucleoside analogues, stavudine and zidovudine, correlated with lower spine density by DEXA or QCT. Nevirapine use correlated with greater spine density by DEXA. Tenofovir did not affect BMD in the SMART analysis, though some studies of adults and children tied tenofovir to bone loss. [4-6]
The models used to make these associations considered race, gender, race-by-gender interaction, age, smoking (ever and time-updated current smoking status), history of alcohol abuse, body mass index (baseline and time-updated change), and baseline BMD. Alone among all these traditional risk factors, lower body mass index correlated with decreasing hip BMD.
Among all SMART participants, 10 of 2753 in the steady-therapy group and 2 of 2720 in the treatment-interruption group had a grade 4 fracture. Those numbers translated into rates of 0.13 per 100 person-years in the steady-therapy group versus 0.03 per 100 person-years in the intermittent group.
The SMART team did not speculate on why tenofovir did not threaten bones in their study group, as it has in others. They caution that SMART was not designed to assess the effects of individual drugs on bone density and that the trial did not dictate which drugs participants should take. The researchers list moderate sample size and follow-up as limitations of their BMD analysis.
The SMART investigators stress that these findings do not support intermittent antiretroviral therapy since overall trial results show a higher risk AIDS and death from AIDS and non-AIDS diseases in the intermittent-therapy arm. 
While several studies have generally documented significantly higher rates of osteopenia and osteoporosis in HIV-positive compared to HIV-negative groups, this is the first large study to report a negative effect of treatment, without a link to specific drugs or classes.
These findings highlight the importance of prospective studies of bone health in HIV-positive patients – increasingly important as the HIV-population ages – especially as the main finding of SMART still strongly supported the use of continuous treatment.
A sub-study from the GSK COL100758 study looking at either 100mg or 200mg boosting doses of ritonavir with 1400mg fosamprenavir plus abacavir/FTC (all once-daily) included results on BMD. Patients in both arms experienced reductions of -1.05% in total BMD and of -2.99 and -2.22 in L-spine BMD (in the 100mg and 200mg arms respectively). 
- Grund B, Carr A. Continuous antiretroviral therapy (ART) decreases bone mineral density: results from the SMART study. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-2312a.
- Arnsten JH, Freeman R, Howard AA, et al. Decreased bone mineral density and increased fracture risk in aging men with or at risk for HIV infection. AIDS. 2007;21:617-623.
- Arnsten JH, Freeman R, Howard AA, et al. HIV infection and bone mineral density in middle-aged women. Clin Infect Dis. 2006;42:1014-1020.
- Jacobson DL, Spiegelman D, Knox TK, Wilson IB. Evolution and predictors of change in total bone mineral density over time in HIV-infected men and women in the Nutrition for Healthy Living Study. J Acquir Immune Defic Syndr. 2008 Oct 3. Epub ahead of print.
- Purdy JB, Gafni RI, Reynolds JC, Zeichner S, Hazra R. Decreased bone mineral density with off-label use of tenofovir in children and adolescents infected with human immunodeficiency virus. J Pediatr. 2008;152:582-584.
- Jones S, Restrepo D, Kasowitz A, et al. Risk factors for decreased bone density and effects of HIV on bone in the elderly. Osteoporos Int. 2008;19:913-918.
- The Strategies for Management of Antiretroviral Therapy (SMART) Study Group. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355:2283-2296.
- Wohl D et al. Limb and trunk fat changes by total body DEXA after 96 weeks of treatment with once-daily (QD) fosamprenavir (FPV) boosted with either 100 mg or 200 mg of ritonavir (/r) plus abacavir (ABC)/lamivudine(3TC): COL100758. 48th ICAAC, 25-28 October 2008. Washington. Abstract H-2302.