Background:  Enhanced bone demineralization occurs in HIV disease and may be accelerated by certain ART. We reported that T-cell production of RANKL, the obligate cytokine for osteoclastogenesis, is induced by HIV-1 gp120, with a positive feedback loop between RANKL secretion and HIV replication, and that low pharmacologic levels of 2 anti-HIV protease inhibitors, ritonavir (RTV) and saquinavir, but no other ART drugs, blocked the physiologic suppression of RANKL via degradation of the nuclear adapter protein TRAF6 by interferon-γ in the proteasome. We sought clinical confirmation of these events.

Methods:  Serum RANKL, peripheral osteoclast differentiation, markers of bone turnover, and bone mineral density were assessed in HIV^– and HIV⁺ postmenopausal women, the latter ART naive or on various ART regimens.

Results:  Prevalence of osteoporosis at the lumbar spine was greater in HIV⁺ than HIV^– women (41% vs 22%; p < 0.05). Annual change in total hip bone mineral density correlated with all biochemical markers (osteocalcin, p = 0.004; BSAP, p = 0.037; NTx, p = 0.008). Serum RANKL was elevated in all HIV⁺ women, regardless of ART use, compared to HIV^– controls (p = 0.046), but did not differ among the HIV⁺ ART-naive or ART-treated. In contrast, those on RTV had greater levels of osteoclast differentiation than the ART-naive (p = 0.01), or those on other ART regimens (p = 0.008). This difference was paralleled by increased levels of bone turnover markers (osteocalcin, p = 0.004; BSAP, p = 0.02; NTx, p = 0.04) and BMD at the lumbar spine (p = 0.02) in RTV-treated patients.

Conclusions:  We have in vivo support for our in vitro model of HIV-mediated bone resorption and its facilitation by 2 anti-HIV drugs. Our work also suggests a therapeutic approach through modulation of TRAF6 signaling.

Keywords: RANKL ; HIV; Osteopenia