Serum 25-Hydroxyvitamin D Levels Modulate the Acute-Phase Response Associated With the First Nitrogen-Containing Bisphosphonate Infusion

The acute-phase response (APR) is the most frequent side effect after the first dose of intravenous nitrogen-containing bisphosphonates (N-BPs). It has been demonstrated in vitro that N-BPs stimulate gamma delta T-cell proliferation and production of cytokines and that vitamin D is able to modulate them. Therefore, we have studied the relationship between bone metabolism parameters, particularly for 25-hydroxyvitamin D [25(OH)D], and APR in patients treated with 5 mg zoledronic acid intravenously. Ninety N-BP-naive osteoporotic women (63.7 +/- 10.6 years of age) were stratified for the occurrence of APR (APR(+)) or not (APR(-)) and quantified by body temperature and C-reactive protein (CRP). The APR(+) women had significantly lower 25(OH)D levels than the APR(-) women. Levels of 25(OH)D were normal (>30 ng/mL) in 31% of APR(+) women and in 76% of APR(-) women. The odds ratio (OR) to have APR in 25(OH)D-depleted women was 5.8 [95% confidence interval (Cl) 5.30-6.29; p <.0002] unadjusted and 2.38 (95% CI 1.85-2.81; p <.028) after multiple adjustments (for age, body mass index, CRP, calcium, parathyroid hormone, and C-telopeptide of type I collagen). Levels of 25(OH)D were negatively correlated with postdose body temperature (r =-0.64, p <.0001) and CRP (r = -0.79, p <.001). An exponential increase in fever and CRP has been found with 25(OH)D levels lower than 30 ng/mL and body temperature less than 37 degrees C, whereas normal CRP was associated with 25(OH)D levels above 40 ng/mL. The association between post-N-BPs APR and 25(OH)D suggests an interesting interplay among N-BPs, 25(OH)D, and the immune system, but a causal role of 25(OH)D in APR has to be proven by a randomized, controlled trial. However, if confirmed, it should have some practical implications in preventing APR. (C) 2010 American Society for Bone and Mineral Research.