Table 1.

The main findings of contemporary studies on the potential adverse effects of antiretroviral therapy on bone mineral density in patients living with HIV/AIDS.

Study (Reference)	Study Design	Number of Patients	Assessed Skeletal Site	Main Results on ART-Induced BMD Alterations
Moore A. et al. [25]	Case–control study	male, n = 221 NRTI, n = 42 PI, n = 147	Total body, LV	Low total body BMD was associated with low body weight prior to commencing cART, while low lumbar BMD was associated with increased lactate concentrations.
Carr A. et al. [26]	Cross-sectional study	n = 105 male, n = 75 NNRTI, n = 47	LV, PF, FN	Low BMD was associated with using a PI-based cART regimen. Age, sex, race, and smoking were not associated with skeletal outcomes.
Knobel H. et al. [27]	Cross-sectional study	n = 80 male, n = 58 PI, n = 37	LV, PF	Low BMD was noted in PLWHIV, but without a significant association with any of the specific cART regimens.
Bruera D. et al. [16]	Case–control study	n = 142 male, n = 113 PI, n = 42 non-PI, n = 36	Total body, LV, PF	Low BMD at all assessed skeletal sites was noted in PLWHIV, irrespective of the cART regimen used.
Fernandez-Rivera J. et al. [28]	Prospective study	n = 89 PI, n = 32 NNRTI, n = 15	LV, FN	Low BMD was associated with PI-based cART, low plasma albumin level, and male sex. Bone loss did not substantially progress after 1 year of continued therapy.
Amiel C. et al. [29]	Cross-sectional study	n = 148 PI, n = 49 non-PI, n = 51	LV, FN	Low BMD was noted in PLWHIV, predominantly related to the low body weight, irrespective of the cART regimen used.
Garcia Aparicio A. et al. [30]	Cross-sectional study	n = 30 PI, n = 17	LV, PF, FN	The use of PI-based cART regimens was not associated with BMD alterations, while vitamin D deficiency and hypogonadism contributed to bone loss in the included individuals.
Brown T. et al. [23]	Meta-analysis	n = 884 ART, n = 824 PI, n = 791	LV, PF	Use of cART and especially the use of PI-based cART regimens were associated with low BMD.
Arnsten J. et al. [31]	Cross-sectional study	n = 328 ART, n = 285 PI, n = 242	LV, FN	Low BMD at both analyzed skeletal sites was associated with HIV infection after adjusting for age, weight, race, testosterone level, and prednisone and illicit drug use, irrespective of the cART regimen.
Madeddu G. et al. [32]	Longitudinal study	n = 67 ART, n = 62 PI, n = 27	LV, PF	Low BMD was associated with cART use in PLWHIV. Bone alterations may persist over time and further worsen with accelerated turnover, particularly in patients receiving PI-based cART regimens.
Stellbrink H. et al. [33]	Multicenter longitudinal study	n = 328 TDF, n = 193	LV, PF	More prominent bone alterations were noted in patients treated with tenofovir–emtricitabine than in patients treated with abacavir–lamivudine.
McComsey G. et al. [34]	Randomized control trial	n = 328 male, n = 228	LV, PF	Patients treated with TDF-FTC had significantly lower BMD compared to patients treated with ABC-3TC. Patients treated with ATV/r had lower lumbar BMD but not femoral BMD in comparison to EFV-treated individuals.
Baranek B. et al. [35]	Meta-analysis	Total number of individuals not reported	LV, PF	TDF caused more substantial BMD loss compared to other ART regimens. The effect was less prominent if used for pre-exposure prophylaxis than as a treatment for PLWHIV.
Mills A. et al. [36]	Randomized control trial	n = 1448 TDF, n = 477 TAF, n = 959	LV, PF	Switching to a TAF-containing regimen from the TDF-based regimen was non-inferior for the maintenance of viral suppression and led to improved BMD and renal function.
Pozniak A. et al. [37]	Randomized control trial	n = 242	LV, PF	After switching to a TAF-based cART regimen, proteinuria, proximal renal tubular function, and BMD significantly improved over 48 weeks compared to individuals initially on TDF-based cART.
Hill A. et al. [38]	Meta-analysis	n = 811,134, male, n = 6732	LV, PF	TDF boosted with ritonavir or cobicistat was associated with higher risks of skeletal alterations and lower HIV RNA suppression rates when compared with TAF. In contrast, when ritonavir and cobicistat were not used, there were no efficacy differences between TAF and TDF, and marginal differences were noted in drug safety.
Walmsley S. et al. [39]	Randomized control trial	n = 34, female, n = 34	LV	The trend was noted toward increased lumbar BMD after a switch from a TDF-based cART regimen to a TAF-based cART regimen in perimenopausal and early postmenopausal WLWHIV.

Abbreviations: LV—lumbar vertebrae; PF—proximal femur; FN—femoral neck; cART—combined antiretroviral therapy; BMD—bone mineral density; PLWHIV—people living with HIV/AIDS; WLWHIV—women living with HIV/AIDS; NRTI—nucleoside analogue reverse transcriptase inhibitor; NNRTI—non-nucleoside reverse transcriptase inhibitor; PI—proteinase inhibitor; TDF-FTC—tenofovir disoproxil fumarate emtricitabine; ABC-3TC—abacavir–lamivudine; ATV/r—atazanavir–ritonavir; EFV—efavirenz; TDF—tenofovir disoproxil fumarate; TAF—tenofovir alafenamide.