Prospective evaluation of bone markers, parathormone and 1,25-(OH)2 vitamin D in HIV-positive patients after the initiation of tenofovir/emtricitabine with atazanavir/ritonavir or efavirenz

Abstract

BackgroundIncreased risk of fractures and osteoporosis have been associated with the use of antiretroviral drugs. There is a paucity of prospective evaluations of bone markers after the initiation of drugs currently recommended to treat HIV infection and results on the evolution of these markers are conflicting. Lastly, the effect of tenofovir on 1,25-(OH)2 vitamin D is uncertain.MethodsWe performed a prospective study on the evolution of bone markers, parathormone and 1,25-(OH)2 vitamin D before and after standard antiretroviral regimens. This was a sub-study of a trial conducted in antiretroviral-naïve patients randomized to tenofovir + emtricitabine in combination with either atazanavir/ritonavir (ATV/r) or efavirenz (EFV). Follow-up lasted 48 weeks. The following bone markers were analyzed: C-terminal cross-laps (CTx), osteocalcin (OC), osteoprotegerin (OPG), and receptor activator of nuclear factor κB ligand (RANKL). Mixed-factorial analysis of variance with random-coefficient general linear model was used to compare their trends over time and linear multivariable regression was performed with a backward selection method to assess predictors of their variations from baseline to week 48. Trends of parathormone and 1,25-(OH)2 vitamin D were also evaluated.ResultsSeventy-five patients were studied: 33 received EFV and 42 ATV/r. Significant increases were found for all markers except for RANKL. There was a significant direct association between CTx and OC increases. Multivariable analysis showed that higher glomerular filtration rate (estimated through cystatin C clearance) predicted greater OPG increase, while older age, higher HIV RNA at baseline and use of ATV/r predicted greater CTx increase. A significant increase of parathormone accompanied the evolution of the study markers. 1,25-(OH)2 vitamin D remained stable, though a seasonality variation was demonstrated.ConclusionsThese data demonstrate CTx increase (bone resorption marker) corresponding to OC increase (bone formation marker) early upon HAART initiation. Moreover, predictors of bone marker increases have been suggested, possibly indicating that a stricter monitoring of bone health and pro-active interventions are needed in older patients, those with higher HIV RNA, prescribed ATV/r rather than EFV, and with decreased renal function at baseline. Further studies are needed to clarify the mechanisms responsible for up-regulation of bone turnover markers, as well as to understand if and what markers are best correlated or predictive of pathological fractures.

Tenofovir Alafenamide Versus Tenofovir Disoproxil Fumarate in the First Protease Inhibitor–Based Single-Tablet Regimen for Initial HIV-1 Therapy

“…6,28 Initiation of ART increases bone turnover: TDF-containing regimens lead to greater changes in bone turnover markers and greater BMD declines than regimens without TDF. 23,24,[29][30][31][32][33] In this study, declines in hip and spine BMD over 48 weeks were smaller in the TAF group than in the TDF group; the BMD findings were supported by significantly less change in markers of bone turnover in the TAF group. The magnitude of BMD declines in the TAF group is among the lowest seen when naive participants have been evaluated by dual-energy x-ray absorptiometry.…”

Longitudinal increase in vitamin D binding protein levels after initiation of tenofovir/lamivudine/efavirenz among individuals with HIV

“…The authors observed an increase in key osteoclast stimulating inflammatory cytokines [tumor necrosis factor-alpha (TNF-α) and receptor activator of nuclear factor kappa-B ligand (RANKL)] and hypothesized that inflammation driven largely by reconstituting T cells may be responsible for the observed increase in bone resorption [33]. However, the sample size of this study was limited and other studies have also reported decreases in TNF-α and RANKL levels after initiation of ART regimens with and without TDF [9,34]. Therefore further research is necessary to fully understand how these inter-related mechanisms of renal dysfunction, alterations in DBP and vitamin D metabolism, and the changing inflammatory and immunologic milieu intersect in TDF-associated bone loss.…”

Increased bone resorption during tenofovir plus lopinavir/ritonavir therapy in Chinese individuals with HIV

“…Tenofovir disoproxil fumarate (TDF) has been consistently associated with a 1–2% greater decline in BMD compared to other nucleoside reverse transcriptase inhibitors when used in combination with other ARTs [6,14–16]. The mechanism of TDF’s effect on the skeleton remains uncertain, and may be related to direct effects on bone cells, or indirect effects due to secondary hyperparathyroidism and disruption of calcium-phosphate homeostasis resulting in inadequate bone mineralization [17–20]. Protease inhibitor (PI)-containing regimens have been shown to be associated with greater bone loss than non-PI containing regimens in some [16,21,22] but not all studies [8].…”