Background:  Tenofovir (TDF) use has been associated with proximal renal tubulopathy (PRT), reduced calculated glomerular filtration rates (cGFR), and losses in bone mineral density. Bone resorption results in a compensatory increase in osteoblast activity indicated by an increase in serum alkaline phosphatase (sAP). A few small studies have reported a positive correlation between renal phosphate losses, increased bone turnover and sAP. We analyzed sAP dynamics relative to TDF use in a large observational cohort.

Methods:  sAP was measured at baseline and 1, 3, 6, and 12 months after initiating (698 patients), reinitiating (380 patients), and discontinuing (127 patients) combined ART (cART) with and without TDF. We assessed correlations between changes in sAP and TDF use, cGFR, age, gender, weight, ethnicity, smoking status, diabetes mellitus, blood pressure, HIV-1 plasma RNA, CD4 cell count, AIDS status, previous ART, and the use of protease inhibitors (PI), cotrimoxazole, and didanosine/TDF.

Results:  While TDF-use was associated with a significant increase in sAP from a median of 74 (IQR 60 to 98) U/L to a plateau of 99 (82 to 123) U/L (p <0.0001) after 6 months, no change was seen with TDF-sparing regimes (71; 57 to 94 U/L at baseline, 78; 62 to 97 U/L after 6 months; p = 0.4). TDF-related increases in sAP were similar in cART-naïve and -experienced patients. TDF discontinuation resulted in a return of sAP to baseline within 3 months. Multivariate linear regression analysis revealed a strong positive correlation between sAP and TDF use after 6 (p = 0.006) and 12 months (p <0.0001), as well as between sAP and age (p = 0.001) at 6 months. sAP negatively correlated with PI use (p = 0.02) at 12 months, with significant differences in the extent of sAP increases between individual PI (p = 0.0003), being lowest with nelfinavir and highest with saquinavir. There was no correlation between sAP and baseline cGFR or the extent of TDF-related cGFR reductions.

Conclusions:  Our study confirms the highly significant association between TDF use and increased sAP in a large observational cohort. TDF-associated PRT causes excessive renal phosphate and calcium losses and 1-hydroxylation defects of vitamin D. This is thought to induce compensatory osteolysis, but also to stimulate regenerative osteoblast activity leading to the observed increase in sAP. As suggested by earlier studies, the extent of the increases in sAP may depend on PI-specific effects on osteoblasts.