Changes in Bone Turnover and Bone Loss in HIV-Infected Patients Changing Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine

Abstract

BackgroundThose receiving tenofovir/emtricitabine (TDF-FTC) had greater bone loss compared with abacavir/lamivudine (ABC-3TC) in a randomized simplification trial (STEAL study). Previous studies associated increased bone turnover and bone loss with initiation of antiretroviral treatment, however it is unclear whether change in bone mineral density (BMD) was a result of specific drugs, from immune reconstitution or from suppression of HIV replication. This analysis determined predictors of BMD change in the hip and spine by dual-energy x-ray absorptiometry in virologically suppressed participants through week 96.Methodology/Principal FindingsBone turnover markers (BTMs) tested were: formation [bone alkaline phosphatase, procollagen type 1 N-terminal propeptide (P1NP)]; resorption (C-terminal cross-linking telopeptide of type 1 collagen [CTx]); and bone cytokine-signalling (osteoprotegerin, RANK ligand). Independent predictors of BMD change were determined using forward, stepwise, linear regression. BTM changes and fracture risk (FRAX®) at week 96 were compared by t-test. Baseline characteristics (n = 301) were: 98% male, mean age 45 years, current protease-inhibitor (PI) 23%, tenofovir/abacavir-naïve 52%. Independent baseline predictors of greater hip and spine bone loss were TDF-FTC randomisation (p≤0.013), lower fat mass (p-trend≤0.009), lower P1NP (p = 0.015), and higher hip T score/spine BMD (p-trend≤0.006). Baseline PI use was associated with greater spine bone loss (p = 0.004). TDF-FTC increased P1NP and CTx through Wk96 (p<0.01). Early changes in BTM did not predict bone loss at week 96. No significant between-group difference was found in fracture risk.Conclusions/SignificanceTenofovir/emtricitabine treatment, lower bone formation and lower fat mass predicted subsequent bone loss. There was no association between TDF-FTC and fracture risk.

Efficacy, safety, bone and metabolic effects of HIV nucleoside reverse transcriptase inhibitor BMS-986001 (AI467003): a phase 2b randomised, controlled, partly blinded trial

“…[52·2%]) and CD4+ T-cell count less than 200 cells/mm 3 Baseline demographics and disease characteristics were similar across study arms ( Table 1); median age was 31 years, two-thirds of subjects were male, and almost half were Black/African-American.…”

“…1,2 Despite the widespread use of NRTIs in first-line treatment regimens, they are associated with toxicities, which can lead to long-term complications. These can include decreased bone mineral density (BMD), 3 lipoatrophy, 4,5 anaemia, pancreatitis, 6,7 and hypersensitivity reaction. 8 Several NRTIs, including didanosine, stavudine (d4T), and zidovudine, are not used routinely due to toxicities associated with mitochondrial (mt) dysfunction, namely peripheral neuropathy, 9,10 lipoatrophy, 4,5 hepatic steatosis 11 , and metabolic acidosis 12,13 .…”

HIV infection and osteoporosis

“…15 Prospective studies of HIV-infected individuals initiating ART have shown a bone loss of between 2 and 6% in the hip and spine during the first 1-2 years of treatment. [16][17][18][19][20][21][22][23] Tenofovir-containing regimens have consistently been shown to be associated with the greatest bone loss, [20][21][22][23] and in one study the use of PIs was associated with greater bone loss in the spine, 18 although this finding has not been universal. ARTinduced bone loss is accompanied by increases in biochemical markers of bone resorption and formation, implicating increased bone turnover as the mechanism of bone loss.…”

Bone turnover markers in HIV-infected women on tenofovir-based antiretroviral therapy

“…13 Resulting cellular stress perturbs deoxyribonucleic (DNA) synthesis by altering gene expression that is involved in signalling osteoblast activity resulting in decreased bone formation. 13,14 Despite studies 3,5,7 performed on the relationship between TDF-use and bone…”

“…These include bone resorption markers such as C-terminal telopeptide (CTx) and bone formation markers such as procollagen type 1 N-terminal propeptide (P1NP), bone-specific ALP (BALP) osteocalcin and ALP. 5,6,7,8 Furthermore, increased bone turnover, after initiation of TDF therapy, was characterised by elevated serum concentrations of parathyroid hormone (PTH).9 However, elevated serum concentrations of PTH were more profound in patients with vitamin D (VitD) deficiency. 10,11,12 Tenofovir disoproxil fumarate undergoes initial di-ester hydrolysis in plasma to tenofovir (TFV).…”