Risedronate prevents exercise-induced hypercalcemia but not nausea or vomit in humans: a double blind randomized controlled trial

Abstract

Reportedly, nausea or vomiting after heavy exercise was associated with post-exercise increased blood calcium (Ca) levels, which was correlated with enhanced bone resorption. We conducted a randomized, double-blind, placebo-controlled trial, enrolling 104 healthy trained male members of the Japan Ground Self-Defense Forces. Risedronate (17.5 mg) or placebo was prescribed 3 and 10 days before heavy exercise lasting approximately 5 h. The primary outcome was the severity of nausea or vomiting assessed by a visual analog scale during or post-exercise. The secondary outcomes included clinical symptoms associated with heat illness, post-exercise serum total Ca (tCa), whole blood ionized Ca (iCa), and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) levels. The mean age was 26 years. The exercise resulted in a 4.5% weight loss. The two groups were comparable in terms of the symptoms, including primary outcome. However, post-exercise tCa and TRACP-5b were significantly lower with risedronate. A similar result was observed for iCa. The post-exercise urinary Ca/Magnesium ratio and the incidence of hypercalcemia (defined as tCa or iCa levels ≥ each median value of all subjects) were significantly lower with risedronate (78.0% vs. 58.5%). A stronger treatment effect of risedronate on blood Ca levels was observed in participants who lost substantial body weight. Post-exercise hypercalcemia is attributed to enhanced bone resorption but not the cause of nausea.

Fig. 1

(a) The study protocol for exercise intensity, scheduled medication, and sample collection. Exercise intensity shows the proportion to the maximum intensity. (b) Measurement method for the visual analog scale (VAS) score of nausea or vomiting, and its example.

Fig. 2

(a) CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the study. (b) The number of participants randomized to each group by the waves. The numbers in parentheses denote the number of participants who completed this study.

Fig. 3

(a, b) Comparison of (a) the incidence and (b) visual analog scale (VAS) scores of nausea or vomiting during or after the heavy exercise between the two groups in the intention-to-treat (ITT) analyses. (c,d) Comparison of serum total calcium (tCa) levels after the heavy exercise between the two groups in the (c) ITT and (d) per-protocol (PP) analyses.

Fig. 4

(a,b) Comparison of urinary calcium/magnesium (Ca/Mg) ratio just after the heavy exercise between the two groups in the (a) ITT and (b) per-protocol (PP) analyses. (c,d) The treatment effects of risedronate on post-exercise blood Ca levels (c: serum total Ca [tCa], d: whole blood ionized Ca [iCa]) against percent change of body weight (%ΔBW). Data were adjusted for wave type and each value before the heavy exercise (8 days after 1st medication). P-values are shown for interaction between %ΔBW and treatment effect. The black lines represent the estimated point at a given level of %ΔBW and the gray areas represent the 95% confidence interval (CI). The cut-offs of (A) and (B) (corresponding to the upper boundary of 95% CI) show the %ΔBW below which risedronate significantly reduced blood Ca levels as compared to placebo.