The research team, led by Xuelei Liang and corresponding author Fujie Zhang, enrolled 223 virologically suppressed men living with HIV who had low bone mineral density while taking TDF-based antiretroviral therapy. All participants were relatively young and free of chronic hepatitis B co-infection, a deliberate design choice that allowed the investigators to isolate the skeletal effects of treatment strategy from the confounding influence of hepatitis B, which itself mandates tenofovir use in most guidelines. The participants were allocated into four groups reflecting real-world clinical decisions: 48 men continued their existing TDF regimen, 37 remained on TDF but received a single intravenous infusion of 5 milligrams of zoledronic acid, a potent bisphosphonate, at the start of the study, 70 switched to a fixed-dose combination of bictegravir, emtricitabine, and tenofovir alafenamide, and 68 switched to a two-drug regimen of dolutegravir and lamivudine that eliminates tenofovir entirely.

The study’s primary endpoints were the absolute changes in bone mineral density from baseline to week 48 at three anatomically and clinically distinct sites: the femoral neck, the total hip, and the lumbar spine. These sites were measured with dual-energy X-ray absorptiometry, the standard technique for quantifying bone density, and the researchers used analysis of covariance with multivariable adjustment to compare outcomes between groups. Crucially, they bolstered their statistical confidence with 2,000 bootstrap resamples, generating bias-corrected and accelerated confidence intervals that are robust to the non-normal distributions common in clinical bone data. A total of 189 participants completed the full 48-week follow-up, and the team also ran sensitivity analyses using 20 imputed datasets under the intention-to-treat principle to guard against bias from missing data.

The findings were striking in their consistency. Men who simply continued TDF experienced persistent bone loss across all three measured sites over the 48 weeks, with median changes of approximately minus 0.01 grams per square centimeter at the femoral neck and total hip and minus 0.02 grams per square centimeter at the lumbar spine. While these absolute declines may appear modest, they represent a continued trajectory of skeletal demineralization in men who already had low bone density at baseline, a population in whom every fraction of a percentage point of bone mineral density carries meaningful implications for future fracture risk.

In contrast, all three intervention strategies produced significantly greater bone mineral density gains than continuing TDF, with the differences reaching statistical significance at every site. The magnitude of recovery was most clearly illustrated at the lumbar spine, where the adjusted mean differences relative to the TDF group were 0.09 grams per square centimeter for the TDF-plus-zoledronic-acid group, 0.07 grams per square centimeter for those switching to bictegravir, emtricitabine, and tenofovir alafenamide, and 0.11 grams per square centimeter for those switching to dolutegravir and lamivudine, all with confidence intervals excluding zero and p-values at or below 0.001. Perhaps the most clinically consequential finding was that no significant pairwise differences emerged among the three intervention regimens themselves, suggesting that switching drugs and adding an antiresorptive agent delivered broadly comparable skeletal benefits over one year.

Beneath these density measurements, the study tracked bone turnover markers, the biochemical fingerprints of skeletal remodeling. The researchers measured beta-C-terminal telopeptide of type 1 collagen, known as beta-CTX, a marker of bone resorption, and procollagen type 1 N-terminal propeptide, or P1NP, a marker of bone formation. Men who continued TDF showed significant increases in both markers from baseline, a pattern consistent with accelerated bone turnover, in which osteoclast-driven resorption outpaces osteoblast-driven formation and net bone is lost. This biochemical signature helps explain the density declines seen on dual-energy X-ray absorptiometry and aligns with the known mechanism of tenofovir disoproxil fumarate, whose active metabolite can impair mitochondrial function and differentiation of osteoblasts, the bone-forming cells, while also promoting osteoclast activity.

The zoledronic acid group displayed a distinctly different turnover profile. Co-administration of the bisphosphonate with TDF produced the greatest percentage reduction in P1NP compared with both switch groups, with both comparisons reaching p-values below 0.001, and also suppressed beta-CTX more strongly than the dolutegravir and lamivudine switch strategy. Zoledronic acid works by binding to hydroxyapatite crystals in bone and, once internalized by osteoclasts during resorption, disrupting their farnesyl pyrophosphate synthase pathway and triggering osteoclast apoptosis. The result is a deep and sustained braking of the entire remodeling cycle, which the marker data captured vividly. By contrast, the switch strategies allowed turnover markers to normalize more gradually as the offending tenofovir prodrug was withdrawn, permitting the remodeling system to rebalance without pharmacological suppression.

The multiple imputation sensitivity analyses yielded findings consistent with the primary per-protocol results, strengthening the internal validity of the study. The investigators also note that the work was supported by Capital’s Funds for Health Improvement and Research and by a program establishing longitudinal follow-up infrastructure for the hospital’s cohort of people living with HIV, and that the study was approved by the hospital’s ethics committee with all participants providing written informed consent. The research was conducted according to the Declaration of Helsinki, and the authors declare no competing interests.

The clinical implications are substantial. Tenofovir alafenamide achieves high intracellular concentrations of the active tenofovir diphosphate in lymphocytes while producing markedly lower plasma tenofovir exposure, which is thought to spare bone and kidneys, and the dolutegravir and lamivudine two-drug regimen goes further by removing tenofovir altogether. This study suggests that in men with low bone density on TDF, either approach can reverse the skeletal trajectory within a year, and that for patients who must remain on TDF for other reasons, a single dose of zoledronic acid offers an effective parallel strategy. The findings support individualized bone management, in which clinicians weigh hepatitis B status, renal function, fracture risk, drug cost, and patient preference when deciding whether to switch regimens or add bone-protective therapy.

Important caveats temper the enthusiasm. The cohort consisted exclusively of relatively young men without chronic hepatitis B co-infection, so the results cannot be directly extrapolated to women, older patients, or those co-infected with hepatitis B, for whom tenofovir remains essential. As a prospective observational cohort rather than a randomized trial, the study cannot fully exclude residual confounding, although the multivariable adjustment and bootstrap-based inference mitigate this concern. The 48-week horizon captures early recovery but not long-term fracture outcomes, and the comparable efficacy of the three strategies means the choice among them will likely hinge on factors beyond bone, including tolerability, drug interactions, and access. Even so, the study delivers a clear and encouraging message: bone lost to tenofovir disoproxil fumarate is not necessarily lost forever, and clinicians now have evidence-backed pathways, whether through regimen switching or targeted bisphosphonate therapy, to help their patients rebuild it.

Subject of Research: Bone mineral density recovery in men with HIV after switching from TDF-based antiretroviral therapy

Article Title: Bone health trajectories following regimen optimization in male people living with HIV receiving TDF: a prospective, observational, cohort study

Article References: Liang, X., Yang, D., Zhang, H., Zhao, H., Wang, Y., Yu, F., Guo, M., Yang, X., Yan, C., & Zhang, F. (2026). Bone health trajectories following regimen optimization in male people living with HIV receiving TDF: a prospective, observational, cohort study. BMC Infectious Diseases. https://doi.org/10.1186/s12879-026-14623-6

Image Credits: AI Generated

DOI: 10.1186/s12879-026-14623-6

Keywords: HIV, bone mineral density, tenofovir disoproxil fumarate, tenofovir alafenamide, zoledronic acid, bone turnover markers, antiretroviral therapy, osteoporosis, dolutegravir, bisphosphonates, cohort study, BMC Infectious Diseases