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

Abstract

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.

Tenofovir Causes Bone Loss via Decreased Bone Formation and Increased Bone Resorption, Which Can Be Counteracted by Dipyridamole in Mice

“…In a study of rats, a relatively short exposure to stavudine (nucleoside reverse transcriptase inhibitors) monotherapy and TDF significantly decreased femoral BMD; this translated to decreased bone strength. (36) This finding is similar to our finding that, even in the absence of HIV infection, tenofovir diminished BMD and trabecular bone. In this same rat study, Conradie and colleagues also observed that treatment with both stavudine and TDF resulted in significant marrow adiposity and suggested that osteoblast numbers may be depleted.…”

“…In a study of rats, a relatively short exposure to stavudine (nucleoside reverse transcriptase inhibitors) monotherapy and TDF significantly decreased femoral BMD; this translated to decreased bone strength . This finding is similar to our finding that, even in the absence of HIV infection, tenofovir diminished BMD and trabecular bone.…”

The anti-HIV drug abacavir stimulates β-catenin activity in osteoblast lineage cells

“…( 36 , 37 ) However, data from preclinical models have been more mixed. For example, both Conradie et al ( 38 ) and Matuszewsaka et al ( 23 ) noted bone loss with TDF treatment in rats, but neither detected elevated bone resorption marker levels. The reason for this discrepancy is unknown but has been noted in the clinic as well, with direct tissue assessments of bone biopsies from PLWH initiating TDF-based cART showing increased osteoclast surfaces with no corresponding change in CTX levels.…”

<p>Antiretroviral Therapy-Associated Metabolic Complications: Review of the Recent Studies</p>

“…The safety and efficacy of antiretroviral drugs have been monitored, as has the metabolic alteration during the treatment period tested in preclinical trial studies. 13 – 16 Conradie et al 13 examined the effects of ART on bone metabolism and lipodystrophy in rats. Stavudine (6.2 mg/kg), tenofovir DF (26.6 mg/kg), lopinavir/ritonavir (70.8 mg/kg), and water (1.5 mL) were subjected orally to 40 male rats for 9 weeks.…”