Immediate ART in START linked to greater bone loss over three years

15th EACS graphicMark Mascolini,

People randomised to begin antiretroviral therapy (ART) immediately in the international START trial had steeper declines in bone mineral density (BMD) than people randomised to delayed therapy. [1]

Hip BMD kept falling through three years of follow-up in the immediate ART group, but dwindling spine BMD stabilised after 1 year.

Waning BMD with ART remains a concern in HIV care, especially among people with other risk factors for osteoporosis and fracture. An international team that offered recommendations for managing bone disease with HIV noted that BMD drops 2% to 6% in the first two years of ART, depending on the antiretrovirals used. [2]

START randomised more than 4600 antiretroviral-naive people with a CD4 count above 500 cells/mm3 to begin ART immediately or to wait until the CD4 count dropped to 350 cells/mm3 or AIDS developed [3]. The bone substudy focused on 193 people randomised to early ART and 204 randomised to deferred ART. All participants had hip and spine BMD determined by DXA scan at baseline then every year. Follow-up ended in May 2015, when START results were unblinded.

The bone substudy group had a median age of 32 years (IQR: 26 to 41), very young for an antiretroviral trial. While 26% of participants were women (only 13% of whom had reached menopause), 32% were Asian, 24% Latino/Hispanic, 20% white, and 19% black. Median known HIV duration measured only 0.7 years (IQR 0.3 to 2.8), median CD4 count stood at 641, and median viral load at 4.2 log10 copies/mL (about 16,000 copies). Only 19% of the study group currently smoked. Median body mass index lay in the high normal range at 24 kg/m2 (IQR 21 to 27). A little more than one third of the group (38.3%) had low BMD at the baseline visit (T score at or below –1 at spine, total hip, or femoral neck), and 3.3% had osteoporosis.

The early ART group used tenofovir during 79% of follow-up, compared with 15% in the deferred group. Respective proportions of follow-up time on efavirenz were 65% and 11%, and on protease inhibitors 19% and 3%. Among treated people, more than 80% in both study arms used tenofovir. Decline from baseline in total spine BMD was significantly greater in the early ART group than the deferred ART group at 12 months (about 2% versus less than 1%, p <0.001) and at 36 months (more than 2% versus less than 1%, p = 0.001). Decline from baseline in total spine BMD was also greater in the early group at 12 months (about 2% versus less than 1%, p <0.001) and 36 months (more than 3% versus 2%, nearly significant at p = 0.06).

Through an average follow-up of 2.2 years, estimated average difference in total spine BMD was 1.6% lower in the early ART group (95% confidence interval [CI] –2.2% to –1.0%, p <0.001). At that point, estimated average difference in total hip BMD was 1.5% lower in the early ART group (95% CI –2.3% to –0.8%, p <0.001). When START statisticians limited the analysis to people actually on ART and off ART, estimated mean difference in total spine BMD became 2.2% lower in the early ART group (95% CI –2.8% to –1.6%, p <0.001) and estimated mean difference for total hip BMD became 2.1% lower in the early group (95% CI –2.8% to –1.4%, p <0.001).

During follow-up, osteoporosis developed at a nonsignificantly greater rate in the immediate ART arm of this young study group (1.72 versus 0.90 per 100 person-years, p=0.27). Incidence of any fracture was similar in the two groups (0.81 and 0.71 per 100 person-years, p=0.45), while incidence of minimal-trauma fracture was nonsignificantly lower in the early ART group (0.18 versus 0.32 per 100 person-years, p=0.11).

The START team concluded that people randomised to immediate ART had greater BMD loss at both the hip and spine. Spine BMD dropped steeply in the first year of ART then stabilised, while hip BMD loss continued through three years of follow-up.


The likelihood of greater reductions in BMD from earlier use of ART was expected, based on results of the earlier SMART study.

The results from the START sub-study emphasise the importance of indivudalising HIV management, especially for people at higher risk of bone disease.



  1. Hoy JF et al. Effects of immediate versus deferred initiation of antiretroviral therapy on bone mineral density: a substudy of the INSIGHT strategic timing of antiretroviral therapy (START) study. 15th European AIDS Conference, October 21-24, 2015, Barcelona. Abstract ADRLH-62.
  2. Brown TT et al. Recommendations for evaluation and management of bone disease in HIV. Clin Infect Dis. 2015;60:1242-1251.
  3. The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795-807.

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