BackgroundHIV 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.MethodsWe 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.FindingsOf 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.InterpretationThere 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.FundingEuropean Developing Country Clinical Trials Partnership.