Determinants of bone diseases in tenofovir-treated HIV patients (2016)

Bedimo et al. [1] have recently reported the results of a prospective, cross-sectional study aimed at investigating the mechanisms of increased bone loss in male study participants with HIV and hepatitis C virus (HCV) monoinfections or HIV/HCV coinfections. They found that HIV and HCV were significantly and independently associated with lower bone mineral density (BMD). The statistical models adjusted for tenofovir (TDF) use greatly attenuated the association of HIV with decreased BMD, suggesting that the effect of HIV on BMD was mainly driven by TDF. Furthermore, Bedimo et al. [1] documented that, at variance with HCV, HIV infection was associated also with altered bone turnover, as documented by increased C-telopeptide X (CTX) and osteocalcin serum concentrations. Here, we intend to extend these findings by assessing the potential contribution of TDF overexposure on bone diseases, in consideration of the recently reported associations between high TDF plasma concentrations and the development of kidney impairment [2,3]. In this retrospective analysis, we included all HIV-infected patients from our local database treated with TDF for at least 6 months and with at least one assessment of TDF plasma trough concentrations. Bone diseases were assessed through evaluation of BMD by dual-energy x-ray absorptiometry (DXA) (osteopenia and osteoporosis were diagnosed as a spine or hip T-score between −1 and −2.5 or ≤2.5, respectively) and/or by markers of bone formation and resorption such as osteocalcin (reference values: 11–46 ng/ml) and CTX (reference values: <580, <704 and <1000 pg/ml for all patients <50 years, men >50 years and women >50 years, respectively). A total of 198 out of the 478 patients from our database fulfilling the inclusion criteria performed at least one DXA evaluation. They were at a mean of 2080 ± 1209 days of therapy with TDF and were mainly given a protease inhibitor (54%) or a non-nucleoside reverse transcriptase inhibitor (34%) as the third drug of the antiretroviral therapy. Overall, 150 out of the 198 patients (76%) had DXA alterations (92 and 90 patients with osteopenia and osteoporosis, respectively). As shown in Table 1, these patients had lower BMI, were older and were treated longer with TDF as compared with patients with normal DXA, whereas no differences on TDF trough concentrations were found (157 ± 139 vs. 142 ± 136 ng/ml, P = 0.51). The same trends were confirmed also when repeating the analysis by considering only patients with osteoporosis. Data on markers of bone turnover were available for 133 out of the 478 patients. Significantly higher TDF concentrations were found in patients with altered vs. normal osteocalcin levels (TDF concentrations: 288 ± 173 vs. 153 ± 115 ng/ml, P < 0.01). Conversely, no association between TDF concentrations and CTX level were documented (TDF concentrations: 147 ± 103 vs. 165 ± 128 ng/ml, P = 0.74 in patients with altered vs. normal CTX values).Table 1: Patients characteristics clustered according to the development or not of bone diseases.In agreement with previous findings, we firstly documented that a large proportion of HIV-infected patients on long-term antiretroviral therapy developed bone metabolism alterations; these events were significantly associated with patients’ age and lower BMI [4,5]. We also extended the findings by Bedimo et al.[1] by recognizing that bone disease was significantly associated with the duration of TDF therapy but not with TDF plasma trough concentrations. The latter finding seems to argue against a potential contribution of TDF overexposure on the development of bone diseases, at variance with findings in HIV-infected patients experiencing TDF-related kidney complications [2,3]. This may be eventually related to the fact that, at variance with kidney diseases – in which a direct mechanism linked to the selective accumulation of TDF within renal tubular cells has been identified [6–8] – TDF is only one of the risk factors for bone loss, and its effect may be eventually diluted by the presence of other clinical covariates (such as patients’ sex, age, diet, BMI, etc.) known to play a key pathogenetic role in bone diseases [4,5]. This hypothesis has been indirectly confirmed by the findings that patients with altered osteocalcin levels have significantly higher TDF plasma trough concentrations compared with patients with physiologic osteocalcin levels, whereas no association was found with CTX levels. Taken together, these results suggest an essential involvement of TDF only in the process of bone formation. Indeed, assuming that osteocalcin is a marker which is secreted solely by osteoblasts; is pro-osteoblastic; and whose alterations induce pathologic alterations in BMD [9], it can be reasonably speculated that the detrimental effects of TDF on bone metabolism might be driven mainly by osteocalcin-mediated loss of osteoblast function. Accordingly, our results provide, for the first time, in-vivo indirect evidence showing that the effect of TDF on osteoblast activity is concentration dependent, as previously documented in vitro in osteoblast cultures [10]. In conclusion, in this hypothesis-generating study, we have provided preliminary evidence showing that exposure of patients to high plasma TDF concentrations might induce early pathologic alterations in bone turnover, eventually favoring the development of osteopenia/osteoporosis through impaired bone formation in high-risk HIV-infected patients. Acknowledgements All authors have read and approved the text. Conflicts of interest C.G. has received educational grants from Merck Sharp & Dome, Janssen-Cilag, Bristol Myers Squibb, Gilead, Boehringer Ingelheim and Abbvie. G.R. has received educational grants from Merck Sharp & Dome, Janssen-Cilag, Bristol Myers Squibb, Gilead, Boehringer Ingelheim, ViiV Healthcare and Abbvie. D.C. has received educational/travel grants from Merck Sharp & Dome, Janssen-Cilag, Bristol Myers Squibb and ViiV Healthcare.