Optimizing bone health in people living with HIV: insights from a network meta-analysis of randomized controlled trials.

Background: With life expectancy for people living with HIV (PLWH) approaching that of the general population, age-related conditions like osteoporosis are increasingly common. Both HIV infection and long-term antiretroviral therapy (ART), particularly tenofovir disoproxil fumarate (TDF), are associated with early-onset osteoporosis. Bisphosphonates are commonly used for treatment, but the optimal strategy for improving bone health in PLWH remains unclear.

Methods: We conducted a network meta-analysis (NMA) with component analysis of randomized controlled trials (RCTs) identified from Medline, EMBASE, Cochrane CENTRAL, Scopus, Web of Science and CINAHL EBSCO databases, from inception to December 1, 2024. The study included RCTs comparing zoledronate, alendronate, calcium and vitamin D, and their combinations in PLWH with osteoporosis. The primary outcomes were changes in lumbar spine and total hip bone mineral density (LS-BMD and TH-BMD). Secondary outcomes included changes in bone turnover markers (BTMs)-C-terminal telopeptide of type 1 collagen (CTx) and osteocalcin (OC)-as well as major adverse events associated with anti-osteoporosis medication (AOMs). Data were analyzed using a component NMA approach to compare treatment strategies. The study was prospectively registered on PROSPERO: CRD42023475160.

Findings: A total of 11 RCTs involving 816 participants were included. In mixed PLWH populations, zoledronate-based regimens significantly improved LS-BMD [weighted mean difference (wMD): 0.0821-0.0985 g/cm; certainty of evidence (CoE): very low to low] and TH-BMD (wMD: 0.0372-0.0606 g/cm; CoE: low to moderate), with the highest treatment rankings (SUCRA: LS-BMD = 93.2%, TH-BMD = 87.4%). Alendronate-based regimens showed significant reductions in CTx (wMD: -0.3347 ng/ml; CoE: very low) and ranked highest for reducing CTx (SUCRA = 95.7%) but did not significantly improve BMD. No substantial differences were found in changes in OC or the incidence of major adverse events related to AOMs. Component NMA confirmed that intravenous zoledronic acid provided significant incremental benefits across both BMDs and BTMs. Sensitivity analyses by ART status revealed that in ART-experienced patients, zoledronate with calcium and higher-dose vitamin D ranked highest for LS-BMD (SUCRA = 94.4%) and zoledronate with calcium and standard-dose vitamin D for TH-BMD (SUCRA = 87.2%). However, in ART-naïve patients, no treatment demonstrated superiority, with comparable effects across three interventions.

Interpretation: While zoledronate-based treatments appear to offer the greatest improvements in bone mineral density in both mixed PLWH populations and ART-experienced PLWH, their effectiveness in ART-naïve populations remains uncertain. The limited evidence and substantial heterogeneity between populations highlight the need for additional trials, particularly in ART-naïve individuals, to establish definitive treatment strategies.

Funding: This research was funded by the National Science and Technology Council through grant number NSTC 113-2314-B-006-090, as well as by the National Cheng Kung University Hospital under grant number NCKUH-11303051 and NCKUH-11404024.