A Direct Comparison of the Effects of the Antiretroviral Drugs Stavudine, Tenofovir and the Combination Lopinavir/Ritonavir on Bone Metabolism in a Rat Model.

Antiretroviral (ARV) treatment may induce metabolic complications in HIV patients on long-term therapy that can affect bone health. In this study, the effects of the ARVs Stavudine (d4T), Tenofovir (TDF) and Lopinavir/ritonavir (LPV/r) on bone metabolism and lipodystrophy were directly compared in rats to negate the consequences of HIV-associated confounding factors. Healthy 12-14-week-old male Wistar rats (n = 40) were divided into four treatment groups and received an oral animal equivalent dose of either Stavudine (6.2 mg/kg/day), TDF (26.6 mg/kg/day), LPV/r (70.8 mg/kg/day) or water (Control 1.5 mL water/day) for a period of 9 weeks. Whole-body DXA measurements, a biomechanical three-point breaking test and histomorphometric analysis were performed on the femurs and tibias at the end of the treatment period. Stavudine monotherapy was found to be associated with decreased femoral bone mineral density that translated into reduced bone strength, whereas histomorphometric analysis demonstrated that Stavudine induces an imbalance in bone metabolism at tissue level, evident in higher resorption (eroded surfaces, osteoclast surfaces and osteoclast number) and lower formation parameters (osteoblast surfaces and osteoid surfaces). This was less clear in the rats treated with either TDF or LPV/r. Furthermore, both Stavudine and TDF treatment resulted in significant bone marrow adiposity, although no significant redistribution of body fat was noted in the treated rats compared to controls. The data from this study suggest that in the absence of HIV-associated factors, LPV/r is less detrimental to bone metabolism compared to Stavudine and TDF.

Thiazolidinedione-induced lipid droplet formation during osteogenic differentiation.

Chronic administration of the insulin-sensitising drugs, thiazolidinediones (TZDs), results in low bone mineral density and 'fatty bones'. This is thought to be due, at least in part, to aberrant differentiation of progenitor mesenchymal stem cells (MSCs) away from osteogenesis towards adipogenesis. This study directly compared the effects of rosiglitazone, pioglitazone, and netoglitazone treatment on osteogenesis and adipogenesis in MSCs derived from subcutaneous (SC) or visceral (PV) white adipose tissue. MSCs were isolated from adipose tissue depots of male Wistar rats and characterised using flow cytometry. The effects of TZD treatment on osteogenic and adipogenic differentiation were assessed histologically (day 14) and by quantitative PCR analysis (Pparγ2 (Pparg2), Ap2 (Fabp4), Adipsin (Adps), Msx2, Collagen I (Col1a1), and Alp) on days 0, 7, and 10. Uniquely, lipid droplet formation and mineralisation were found to occur concurrently in response to TZD treatment during osteogenesis. Compared with SC MSCs, PV MSCs were more prone to lipid accumulation under controlled osteogenic and adipogenic differentiation conditions. This study demonstrated that the extent of lipid accumulation is dependent on the nature of the Ppar ligand and that SC and PV MSCs respond differently to in vitro TZD treatment, suggesting that metabolic status can contribute to the adverse effects associated with TZD treatment.