Background/Purpose: Tenofovir is an anti-retroviral agent commonly used to treat human immunodeficiency virus (HIV)-infected patients as part of the drug regimen known as highly active anti-retroviral therapy (HAART). As many as 15% of patients taking tenofovir develop osteopenia resulting in pathological fractures. Recent studies in our lab indicate that tenofovir-induced osteopenia is due to reduction of extracellular adenosine resulting from tenofovir-mediated blockade of Pannexin-1, a transporter for ATP which is hydrolysed in the extracellular space to adenosine, and the effect of tenofovir on bone can be reversed by dipyridamole, an agent that blocks adenosine re-uptake. To further confirm this effect we studied the effect tenofovir on bone in Pannexin-1 knockout mice (PANX1KO) mice.

Methods: PANX1KO animals were treated daily with 75mg/Kg of tenofovir, 25 mg/kg tenofovir or both during 4 weeks, after that bone mineral density (BMD) was measured. Additionally, primary osteoclasts were differentiated in the presence of different concentrations of Tenofovir and dipyridamole. The differentiation stage and extracellular ATP levels were studied.

Results: Consistent with previous experiments, tenofovir treatment of extracellular ATP in cultures of wild type (WT) bone marrow-derived primary osteoclasts as well as an increase in osteoclast differentiation. However, the addition of dipyridamole inhibited osteoclast differentiation (p=0.0068). The dipyridamole-induced inhibition was reversed with Tenofovir in a dose dependent manner (0.0055). In contrast, osteoclasts from PANX1KO mice did not decrease ATP release when treated with Tenofovir (p= 0.3292). Additionally, PANX1KO mice osteoclast differentiation was also inhibited by dipyridamole (p=0.0005), which was not reversed by dipyridamole treatment (p= 0.9756). In WT mice, Tenofovir treatment reduced bone mineral density by 10% (p< 0.05, n=10) and this effect was reversed in the animals who received Dipyridamole in addition to Tenofovir. In contrast, tenofovir did not affect bone mineral density in PANX1KO mice (p >0.99, n=4).

Conclusion: Tenofovir, a commonly used drug, induces osteopenia in many patients. The results presented here support the hypothesis that tenofovir reduces bone density by inhibiting ATP release with subsequent adenosine-mediated inhibition of osteoclast differentiation. These effects can be reversed by treatment with dipyridamole.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/pannexin-1-ko-mice-are-unresponsive-to-tenofovir-induced-bone-loss/