Bone Mineral Density Decline According to Renal Tubular Dysfunction and Phosphaturia in Tenofovir-exposed HIV-infected Patients

José L. Casado; Carmen Santiuste; Monica Vazquez; Sara Bañón; Marta Rosillo; Ana Gomez; María J. Perez-Elías; Carmen Caballero; José M. Rey; Santiago Moreno

Disclosures

AIDS. 2016;30(9):1423-1431. 

In This Article

Abstract and Introduction

Abstract

Introduction: The mechanisms underlying the effect of tenofovir disoproxil fumarate (TDF) on the decline of bone mineral density (BMD) have not been established, especially the effect of renal tubular dysfunction.

Methods: Longitudinal study of 90 patients with two successive dual X-ray absorptiometry scans after evaluation of serum and urinary parameters (proteinuria, albuminuria, phosphaturia, uricosuria, glycosuria, β-2-microglobulin, and retinol-binding protein).

Results: After a median of 38 months on TDF, osteopenia at spine and hip was observed in 49 and 48%, and osteoporosis in 9 and 2%, respectively. There was a lineal correlation between BMD at femoral neck and time on TDF (Spearman's rho = -0.27; P = 0.01). One or more tubular abnormalities were observed in 80% of cases (hyperphosphaturia, 50%). A lower BMD correlated with phosphaturia (r = -0.25; P = 0.03), even with phosphataemia within normal limits. In fact, patients with previous improvement in phosphaturia had better BMD at inclusion (Spearman's rho = -0.33; P < 0.01). A second dual X-ray absorptiometry, after a median of 40.8 months (33.8–45.1; 627.7 patients-year on TDF), showed additional BMD reduction at hip in 50% of cases (36% with bone loss >3%), a decline associated with phosphaturia (β, -0.31; P = 0.01) or number of tubular abnormalities (β, -0.41; P = 0.01), but also with use of boosted protease inhibitors (β, -0.47; P = 0.03) and BMD at inclusion (β, -0.33; P = 0.03).

Conclusion: Chronic abnormal phosphaturia explains, at least in part, progressive bone loss during TDF therapy. These data suggest that tubular dysfunction leads to an altered equilibrium between phosphataemia, phosphaturia, and bone as mechanism of progressive BMD decline.

Introduction

Despite the improvement observed with the use of effective combination antiretroviral therapy (cART), progressive aging, and prolonged treatment could favour an increased incidence of long-term comorbidities.[1] Among them, a reduction in bone mineral density (BMD) has been observed after cART initiation, suggesting an indirect role through immune mechanisms or a direct effect for antiretroviral drugs.[2,3]

Specifically, the use of tenofovir disoproxil fumarate (TDF) has been associated with a more marked BMD decline,[4] and even TDF use was associated with nonpathologic fractures after adjusting by classical factors of BMD deterioration.[5] Also, significant BMD improvement has been described in small cohorts of patients who discontinue TDF.[6,7]

TDF has been shown to affect osteoblast genes, suggesting a direct mechanism for bone alteration.[8] Moreover, the use of TDF has been associated with parathyroid hormone (PTH) increase,[9] and with changes in bone turnovers biomarkers.[10] However, several studies showed an increased rate of proximal tubular dysfunction in TDF-treated patients. In vitro and animal studies support the notion that mitochondria are the major targets of TDF toxicity in the kidney,[11] and drug accumulation in the tubule cells is the pathogenic mechanism for tubular dysfunction.

Thus, phosphaturia as part of renal tubular dysfunction could be the putative mechanism associated with BMD decrease, in a similar manner, but in a lesser extent, to that observed in tumour-induced osteomalacia[12] or in Fanconi syndrome.[13] Nevertheless, to date, there are no longitudinal studies showing the evolution of BMD during TDF therapy according to the degree of tubular alteration or phosphaturia. To evaluate this important issue, we developed a prospective study to investigate the impact of tubular parameters on bone controlling by other classical factors of bone and kidney deterioration.

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