Serum 25-Hydroxyvitamin D Level and Acute-Phase Reaction Following Initial Intravenous Bisphosphonate Tarak Srivastava, Hongying Dai, Connie J Haney, and Uri S Alon Bone and Mineral Disorder Clinic, Section of Nephrology, Children’s Mercy Hospital and University of Missouri at Kansas City, Kansas City, KS, USA To the Editor: Children often will complain of severe musculoskeletal pain and will develop fever with a first course of intravenous bisphos- phonates. Acute-phase reaction (APR) can be severe enough for the child to refuse further therapy. (1,2) The mechanism underlying the APR from intravenous bisphosphonates is not known. (3,4) However in a double-blind, randomized, crossover, placebo-controlled study in 12 children, treatment with Ator- vastatin did not alleviate the APR. (1) Recently, Bertoldo and colleagues (5) reported an association between serum 25- hydroxyvitamin D [25(OH)D] level and APR after bisphosphonate infusion. In essence, lower levels of vitamin D were associated more frequently with APR, and vice versa. (5) We report the results of reanalysis of our data in order to evaluate a possible asso- ciation between serum 25(OH)D level and APR following initial intravenous bisphosphonate treatment in children. In our bone and mineral disorder clinic, intravenous infusion of bisphosphonates is given on two consecutive days, referred to as a cycle. In our published study, children received two cycles given 3 to 4 months apart. (1) Children completed the visual analogue pain scale (0 to 100 mm) at baseline before the infusion (pain scale 1). Pain scale 2 was completed on day 1 late in the evening, pain scale 3 on day 2 in the morning prior to the second infusion, pain scale 4 was completed on day 2 late in the evening after the infusion, and pain scale 5 in the morning of day 3. The children’s families also recorded whether they needed medica- tions to alleviate their pain or fever as either ‘‘Yes’’ or ‘‘No.’’ For musculoskeletal pain, children were given oxycodone, consid- ered not to interfere with the inflammatory markers that were being evaluated. For fever (398C), if tepid sponging did not bring the temperature down, patients were instructed to take acetaminophen. APR was categorized as presence of fever needing acetaminophen and/or musculoskeletal pain requiring oxycodone. Nonparametric Spearman correlation between serum 25(OH)D level and pain scales and multivariate regression modeling with backward elimination were performed using SPSS 18.0. A p value less than .05 was considered significant. The mean age of 12 children (10 girls and 2 boys) was 12.1  4.2 years. In the first cycle, 7 children (58.3%) developed APR. There was no significant correlation between serum 25(OH)D level (Mayo Medical Laboratories, Rochester, MN, USA) and pain scale prior to bisphosphonate infusion. In contrast, following bisphosphonate infusion, an inverse correlation was found be- tween pain scale and serum 25(OH)D (Table 1 and Fig. 1). These findings remained true for the second cycle (2 children develop- ed APR) and for the two cycles combined together (data not shown). The two cycles then were combined for multivariate analysis. The correlation between serum 25(OH)D level and sum of pain scales after infusion remained significant even after adjusting for confounding variables such as treatment arms (placebo versus Atorvastatin), body mass index (BMI), parathyr- LETTER TO THE EDITOR J JBMR Table 1. The Statistical Correlation of 25-Hydroxyvitamin D and Visual Analogue Pain Scale Obtained at Different Time Points With the Initial Intravenous Bisphosphonate Therapy Correlation coefficient p Value Pain prior to bisphosphonate infusion (pain scale 1) 0.323 0.306 Postinfusion pain (pain scale 2) 0.752 0.005 Postinfusion pain (pain scale 3) 0.545 0.067 Postinfusion pain (pain scale 4) 0.555 0.061 Postinfusion pain (pain scale 5) 0.591 0.043 Sum of postinfusion pain scales (pain scales 2 to 5) 0.696 0.012 Note: There is a robust inverse correlation between 25-hydroxyvitamin D and pain following bisphosphonate infusion. Address correspondence to: Tarak Srivastava, MD, Bone and Mineral Disorder Clinic, Section of Nephrology, Children’s Mercy Hospital and University of Missouri at Kansas City, 2401 Gillham Road, Kansas City, MO 64108, USA. E-mail: tsrivastava@cmh.edu Journal of Bone and Mineral Research, Vol. 26, No. 2, February 2011, pp 437–438 DOI: 10.1002/jbmr.290 ß 2011 American Society for Bone and Mineral Research 437