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Changes in Bone Biomarkers in ARV-naïve HIV+ Men Randomized to NVP/LPV/r or AZT/3TC/LPV/r Help Explain Limited Loss of Bone Mineral Density over the First 12 Months after ART Initiation
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Reported by Jules Levin
CROI 2011 March 2 Boston
M van Vonderen1, Patrick Mallon*2, B Murray3, P Doran2, M van Agtmael4, S Danner4, P Lips4, P Reiss5, for MEDICLAS Study Group
1Med Ctr Leeuwarden, The Netherlands; 2Mater Misericordiae Univ Hosp, Univ Coll Dublin, Ireland; 3St Vincent`s Univ Hosp, Dublin, Ireland; 4VU Univ Med Ctr, Amsterdam, The Netherlands; and 5Academic Med Ctr, Univ of Amsterdam, The Netherlands
Background: ART initiation in HIV+, ARV-naïve men is associated with loss of bone mineral density (BMD), with greater BMD loss in those randomized to zidovudine/lamivudine/lopinavir/ritonavir (AZT/3TC/LPV/r) vs nevirapine/lopinavir/ritonavir (NVP/LPV/r), most evident in the first 12 months of ART (Metabolic Effects of Different Classes of AntiretroviralS [MEDICLAS] study). This is accompanied by increases in bone biomarkers, which may offer insights into mechanisms underlying bone loss.
Methods: In the MEDICLAS study, we examined changes in markers of bone resorption (tartrate-resistant acid phosphatase 5b [TRAP5b] and C-terminal telopeptide of type 1 collagen [ß-CTx]) and bone formation (bone-specific alkaline phosphatase [BAP] and procollagen type 1 N propeptide [P1NP]) on stored serum collected at baseline, months 3, 12, and 24. Standardized biomarker values were used to derive bone remodeling balance index (BRBI [formation to resorption marker]) and bone turnover index (BTI, [(formation+resorption)/2]). Between to group differences were evaluated by mixed model repeated measures analysis with correction for differences in baseline values.
Results: Of 48 male patients (age 42±10 years, 81% Caucasian) 26 were randomized to NVP/LPVr and 22 to AZT/3TC/LPV/r. Markers of bone resorption significantly increased early after ART initiation in both groups, with greater increases in the AZT/3TC/LPV/r group (ß-CTx p = 0.01, TRACP5b p = 0.05) and the greatest increases observed by month 3; TRAP5b media, IRQ, +37%, 22.5 to 66, with AZT/3TC/LPV/r vs +29%, 5 to 41, with NVP/LPV/r, both p <0.0001 and ß-CTx +99%, 62 to 155, with AZT/3TC/LPV/r vs 77%, 6 to 281, for NVP/LPV/r both p ²0.001. In contrast, markers of bone formation rose later, with the greatest rises observed at month 12; BAP +60%, 33 to 89, for AZT/3TC/LPV/r vs +49%, 29 to 92, for NVP/LPV/r, both p <0.0001 and P1NP +76%, 38 to 150, for AZT/3TC/LPV/r vs +43%, 10 to 122, for NVP/LPV/r, both p <0.01, with no significant between to group differences. Those with greater increases in BRBI to month 12 experienced greater loss of spine BMD to month 12 (Rho -0.34 to -0.38, all p <0.05). BRBI did not correlate with change in hip BMD and there were no correlations between changes in BTI and BMD at either spine or hip.
Conclusions: Early increases in bone resorption markers, with delayed increases in bone formation markers, represent a catabolic window during which net loss of BMD may occur. These data help explain limited loss of BMD with ART initiation and support short to term bisphosphonate use as anti to resorptive therapy to prevent this early bone loss.
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