Impact of high-dose vitamin D and calcium carbonate supplementation on bone density in adolescents living with HIV: a randomised, placebo-controlled trial.

BACKGROUND: HIV has adverse impact on skeletal development in children despite antiretroviral therapy (ART). We investigated the effect of high-dose (20 000 IU) weekly vitamin D3 and daily calcium carbonate (500 mg) supplementation for 48 weeks on bone density and muscle strength and power among peripubertal individuals (11-19 years) with perinatally acquired HIV. METHODS: We conducted an individually randomised, double-blind, placebo-controlled trial. Individuals taking ART for at least 6 months who had a defined caregiver, and knew their HIV status (in those aged >12 years) were recruited from HIV clinics in Harare, Zimbabwe and Lusaka, Zambia. The primary outcome was total body less-head bone mineral density (TBLH-BMD) Z score and secondary outcome was lumbar spine bone mineral apparent density (LS-BMAD) Z score (both measured by dual-energy x-ray absorptiometry). Linear regression was used to compare arms adjusting for country and baseline value of the measure. Pre-specified subgroup analyses by country, age-group, sex, pubertal stage, calcium intake, tenofovir disproxil fumarate use, and baseline vitamin D insufficiency (defined as 25[OH]D <75 nmol/L), and a post-hoc subgroup analysis by viral suppression, were performed. A Participant Advisory Board that included adolescents with HIV, their guardians, and health providers guided study conduct. The trial is registered with the Pan African Clinical Trials Registry, PACTR20200989766029. FINDINGS: Of 842 participants (median age 15 years [IQR 13-17], 448 [53%] female and 394 [47%] male) enrolled between Feb 4 to Nov 23, 2021, 639 (76%) were vitamin D insufficient. At 48 weeks, outcomes were available for 751 (89%) participants. There was no difference by arm in TBLH-BMD Z score (intervention vs control: mean -1·53 [SD 1·18] vs -1·56 [1·12], adjusted mean difference -0·04 [95% CI -0·01 to 0·09]) or in LS-BMAD Z score (intervention vs control: -0·64 [1·17] vs -0·71 [SD 1·16], adjusted mean difference -0·05 [95% CI -0·01 to 0·12]). However, among participants with vitamin D insufficiency at baseline, there was a significantly higher LS-BMAD Z score (adjusted mean difference 0·09 [95% CI 0·02 to 0·16], pinteraction=0·025) in the intervention arm than in the control arm. The corresponding adjusted mean difference in TBLH-BMD Z score was 0·06 (0·00-0·11), pinteraction=0·15. There was no statistical evidence of interaction in other subgroups. No drug-related severe adverse events were observed. INTERPRETATION: There was no difference in bone density between arms overall, but among those with vitamin D insufficiency the intervention improved bone density. High-dose vitamin D3 and calcium supplementation, a safe and cheap intervention, during adolescence might promote bone accrual and mineralisation in those with vitamin D insufficiency, which could increase peak bone mass. FUNDING: European Developing Country Clinical Trials Partnership.