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 γδ 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 (CI) 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 °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. © 2010 American Society for Bone and Mineral Research.