Exercise can cause a decrease in serum total and ionized calcium (iCa) during prolonged moderate-to-vigorous endurance exercise, which is a trigger for parathyroid hormone (PTH) secretion (1,2,5,6,10). PTH defends serum calcium (Ca) by increasing intestinal Ca absorption, inhibiting renal Ca excretion, and stimulating the mobilization of skeletal Ca. If exercise induces an increase in bone resorption that is not accompanied by stimulation of bone formation, the repeated disruption of Ca homeostasis during exercise training may contribute to bone loss, such as that observed in cyclists (3,7,11).
Consuming a Ca-enriched beverage before and during endurance exercise has been found to be effective in reducing the disruption in Ca homeostasis during exercise. The decrease in iCa and the increase in PTH were attenuated when a Ca-enriched beverage or meal was consumed before and/or during exercise (1,5,6,10). This Ca supplementation was effective in attenuating the increase in bone resorption in some experiments (5,6,10), but not others (1,10). The discordance may relate to the timing of Ca dosing.
Beverages that are likely to be consumed during exercise usually contain little or no Ca. This is due, in part, to the difficulty of getting calcium into solution. Other Ca supplements are typically in pill or chewable form, but whether this mode of delivery mitigates the disruption of Ca homeostasis during exercise has not been studied. Timing is also important for exercise planning. Most experiments have investigated preexercise supplementation beginning 60 min or more before the onset of exercise (6,10). Although this may be appropriate for a planned research exercise visit, this degree of advanced planning may be difficult for regular exercise. Investigating the timing of ingestion that may be more suitable (i.e., as close to the onset of exercise as possible) is important in designing future studies to determine whether Ca supplementation before exercise has a favorable effect on bone health.
Accordingly, the aim of this study was to determine whether consuming a chewable Ca supplement (1000 mg) 30 min before exercise attenuates the decrease in serum iCa and increases in serum PTH and bone resorption (as measured by C-terminal telopeptide of type I collagen [CTX]) when compared with a placebo supplement.
This was a randomized, double-blinded, placebo-controlled study of the effects of preexercise Ca supplementation on the iCa, PTH, and CTX responses to vigorous exercise. Eligible participants were randomized to take a chewable supplement containing either Ca citrate (1000 mg elemental Ca) or placebo (PL) 30 min before exercise. Active and placebo products were provided by Marigot Ltd. (Cork, Ireland). The study was approved by the Colorado Multiple Institutional Review Board, and all volunteers provided written informed consent to participate.
Participants were 51 competitive male road cyclists, 18 to 45 yr old. To be considered a competitive cyclist, prospective participants must have competed in road cycling races for at least 1 yr with plans to participate in at least 10 more races in the next calendar year. Exclusion criteria included thyroid stimulating hormone level <0.5 or >5.0 mU·L−1, creatinine clearance <50 mL·min−1, PTH >69 pg·mL−1, 25(OH) vitamin D <20 ng·mL−1, hypercalcuria determined by spot urine calcium-to-creatinine ratio ≥0.31, bone mineral density (BMD) t-score < −2.5, and use of drugs known to influence bone metabolism (teriparatide, calcitonin, oral steroids, sex hormones, and bisphosphonates) within the past 6 months. If participants reported taking a calcium supplement or a vitamin supplement containing calcium, they were asked to discontinue use 24 h before the research visit. Participants were instructed to fast overnight (minimum of 8 h) before their exercise visit. No dietary instructions were given regarding the meals they consumed the day before the visit.
Dual-energy x-ray absorptiometry
Total body, lumbar spine (L1–L4), and proximal femur (total hip, trochanter, femoral neck, and subtrochanter) BMD and t-scores were measured on a Discovery-W dual-energy x-ray absorptiometry instrument (Hologic Inc, Waltham, MA). Fat-free mass and fat mass were obtained from the total body scan. All scans were performed by trained technicians. Intrainstrument coefficient of variation (CV) values for scans completed on men <50 yr are as follows: −0.8% total mass, 2.6% fat mass, 1.1% fat-free mass, 0.8% lumbar spine BMD, 0.9% total hip BMD, 1.9% femoral neck BMD, 1.1% trochanter BMD, and 0.99% subtrochanteric BMD.
Simulated 35-km time trial
Participants performed a laboratory-based cycling bout (simulated 35-km time trial) in the fasted state and took the CA or PL supplement 30 min before exercise. Dermal Ca loss was estimated during exercise as previously described (2). Nude, dry body weight was measured before and after exercise. Participants were allowed to drink deionized water ad libitum during the exercise bouts, and total fluid intake was recorded. Sweat volume was estimated from change in weight adjusted for fluid intake and urine production.
Blood sampling and analysis
An indwelling intravenous catheter was placed before exercise for all blood sampling. Blood samples were collected before, immediately after, and 30 min after exercise. Serum iCa, pH, and hematocrit (Hct) were measured immediately after sample collection using a cartridge-based whole blood analyzer (iSTAT, Abbott, East Windsor, NJ); the reported CV for iCa is 1.1%. Intact PTH before and immediately after exercise was measured in duplicate using a two-site chemiluminescent enzyme-labeled immunometric assay on an Immulite 1000 analyzer (Siemens, Tarrytown, NY). Intra- and interassay CV values for PTH are 2.9%–3.5% and 4.8%–6.8%. CTX before and 30 min after exercise was measured in duplicate to assess change in bone resorption (CTX; Nordic Bioscience Diagnostics, Herlev, Denmark). The intra- and interassay CV values for CTX are 2.7%–10.3% and 2.5%–9.2%.
Serum values of iCa, PTH, and CTX were adjusted for plasma volume (PV) shifts based on change in Hct (15). Because the iSTAT measures Hct based on conductivity, Hct values were not adjusted for trapped plasma, and no conversion from venous to whole body Hct was performed. Adjusted and unadjusted values are identified using the subscripts “adj” and “unadj” (e.g., iCaadj vs iCaunadj).
The sample size for the study was based on the observation in a previous study that Ca supplementation 60 min before exercise attenuated the increase in PTH by 17.8 ± 20.0 pg·mL−1 (10). A sample size of 21 participants per group provided 80% power to detect this magnitude of difference between groups. Statistical analyses were performed using SAS version 9.3 (SAS Institute Inc., Cary, NC). Data are reported as mean ± SD unless otherwise specified. Changes in outcomes of interest were compared between groups using a linear contrast in a regression model, controlling for the baseline value of the outcome measure to improve the precision of the estimates. The same analysis was repeated for PV-adjusted outcome measures and relative changes in PV-adjusted measures. Within-group changes in outcomes were evaluated as a secondary analysis using paired t-tests. Pearson's product–moment correlation coefficients were used to estimate the linear associations among changes in iCa, PTH, and CTX. Statistical significance was accepted as P < 0.05.
Self-reported weekly training data were collected during a 4- to 10-month period (Table 1). Training frequency (CA = 3.9 ± 0.8 d·wk−1, PL = 3.9 ± 1.1 d·wk−1, P > 0.95) and duration (CA = 523.8 ± 137.9 min·wk−1, PL = 501.4 ± 172.0 min·wk−1, P > 0.63) were similar between the groups. The prevalence of low bone mass, defined as a t-score ≤−1.0, was 31% (6 CA and 10 PL) at the lumbar spine, 8% (2 CA and 2 PL) at the total hip, and 29% at the femoral neck (7 CA and 8 PL).
Responses to exercise
The simulated time trial was completed in 58.7 ± 3.2 min by the CA group and 60.4 ± 4.4 min by the PL group (P = 0.13). Estimated sweat loss (CA = 1.41 ± 0.22 L, PL = 1.43 ± 0.25 L, P = 0.78) and dermal calcium loss (CA = 89.6 ± 34.3 mg; PL = 94.6 ± 49.0 mg; P = 0.69) were similar in both groups. PV shifts were also similar between the groups. The decrease in serum iCaunadj from before to immediately after exercise was greater (P = 0.03) in the PL group compared with the CA group (mean, CA = −0.14 mg·dL−1, 95% confidence interval [CI] = −0.22 to −0.07, vs PL = −0.25 mg·dL−1, 95% CI = −0.32 to −0.19) (Table 2). Attenuation of the increase in PTHunadj from before to immediately after exercise by Ca supplementation approached significance (mean, CA = 49.4 pg·mL−1, 95% CI = 31.6–67.2, vs PL = 72.3 pg·mL−1, 95% CI = 55.7–88.9; P = 0.07), but there was no indication of an effect of Ca to attenuate the increase in CTXunadj (P = 0.68) from before to 30 min after exercise (CA = 0.16 ng·mL−1, 95% CI = 0.10–0.22; PL = 0.17 ng·mL−1, 95% CI = 0.12–0.23). Adjusting for PV shifts did not change these conclusions (Table 2). Comparisons based on relative changes in CTXadj, PTHadj, and iCaadj were consistent to the absolute changes (Fig. 1).
When pooled across groups, the change in serum iCaunadj in response to exercise was inversely associated with the change in PTHunadj (r = −0.49, P < 0.001), and the change in PTHunadj was directly related to change in CTXunadj (r = 0.36, P = 0.01) (Fig. 2).
The aim of this study was to determine whether taking a chewable Ca supplement before vigorous exercise mitigates the exercise-induced decrease in serum iCa and increases in PTH and bone resorption. Our major finding was that Ca supplementation 30 min before exercise attenuated the decrease in serum iCaadj and iCaunadj and the attenuation in PTHadj and PTHunadj approached significance. However, the use of a chewable calcium supplement did not alter the CTXadj or CTXunadj response. The decrease in iCaadj and iCaunadj and the increase in PTHadj and PTHunadj from before to after exercise, despite preexercise Ca supplementation, indicates that the rate of Ca loss from the vascular compartment exceeded the rates of Ca absorption from the gut and mobilization from bone.
Ingestion of a 1000-mg Ca supplement 30 min before exercise in the current study attenuated the PTHadj and PTHunadj responses by a similar magnitude as in our previous study of competitive cyclists, in which participants consumed a Ca-enriched beverage 20 min before exercise or in 250-mg aliquots during exercise (total of 1000 mg in both cases) (1). In that study, PTH was similarly attenuated by both dosing protocols. Neither protocol was successful in significantly attenuating the CTX response; there was a nonsignificant decline only when Ca was consumed before exercise. By contrast, the timing of Ca supplementation influenced the PTH response to 60 min of vigorous walking in a study of older women (10). Women consumed a Ca-enriched beverage every 15 min, starting either 15 min or 60 min before exercise, and continuing during exercise. Starting Ca supplementation 15 min before exercise attenuated the decrease in iCa, but not the increases in PTH or CTX. By contrast, starting Ca supplementation 60 min before exercise prevented the decrease in iCa, attenuated the increase in PTH by almost 70%, and also tended (P = 0.08) to suppress the CTX response (10). In young female cyclists, a high Ca meal (1352 mg) 120 min before exercise attenuated the changes in iCa, PTH, and CTX in response to 90 min of moderate intensity exercise when compared with a low Ca meal (46 mg) (6). Collectively, these studies indicate that intestinal Ca absorption can play an important role in defending serum Ca during exercise.
The availability of Ca in the small intestine for absorption may reduce the extent to which skeletal Ca is mobilized during exercise to defend serum Ca. There is some evidence that the timing of Ca supplementation relative to the performance of exercise has the potential to enhance skeletal adaptations to exercise training. Collegiate basketball players were found to have a marked decrease in total and leg bone mineral content during 1 yr of practice and competition, but the following year, when supplemental Ca was provided during practices and games, bone mineral content increased in these athletes (7). By contrast, taking supplemental Ca with meals (i.e., not timed with exercise) did not influence the trajectory of BMD change for 1 yr in competitive road cyclists (1). Further research will be necessary to determine whether minimizing the disruption of Ca homeostasis during acute exercise sessions can enhance the skeletal adaptations to exercise training.
The optimal dose and timing of Ca supplementation to minimize the disruption of Ca homeostasis during exercise are not known. The minimal dose that has been demonstrated to be effective in attenuating PTH was 1000 mg, but lower doses have not been evaluated (1). The failure to attenuate the CTX response to vigorous exercise with a chewable Ca supplement 30 min before exercise in the current study may reflect the need to ingest Ca sooner. If Ca is not positioned in the gut to be absorbed early in an exercise session, it is possible that resorption is stimulated and remains activated for some period, even after PTH returns to baseline (8). Consumption of a Ca-enriched beverage starting 60 min before and continuing during exercise was effective in attenuating the increase in CTX (5,10). However, consumption of a Ca-enriched beverage closer to the onset of exercise failed to diminish the CTX response (1,10), suggesting that it was the timing of Ca supplementation in the current study, and not the use of a chewable supplement, that was the reason for the lack of efficacy.
Although CTX provides a relative index of bone resorption activity, it does not provide a quantitative estimate of the amount of Ca that is mobilized from bone (14). In the current study, the provision of supplemental Ca did not attenuate the exercise-induced increase in CTXadj and CTXunadj, but samples were obtained only 30 min after exercise. It is possible that CTX returned to the basal level faster in the CA than the PL condition, reflecting less reliance on skeletal Ca to restore serum Ca homeostasis, but a longer sampling protocol would be necessary to evaluate this. Quantifying the mobilization of Ca from the skeleton and absorption of intestinal Ca during exercise would provide insight into the development of strategies (e.g., Ca supplementation) to optimize the skeletal adaptations to exercise training. It may be possible to do this using stable isotope kinetics, but to the best of our knowledge, this approach has never been used during exercise.
Although the exercise-induced increase in PTH leads to an activation of bone resorption, resulting in what seems to be a catabolic response, it remains possible that PTH could have an anabolic effect on bone. Paradoxically, PTH has both anabolic and catabolic actions on bone, whereby transient increases in PTH are anabolic and chronic elevation is catabolic (12). Teriparatide, a PTH analog that is used to treat osteoporosis, increases bone resorption in a manner similar to vigorous exercise and yet has anabolic effects on bone because it also stimulates bone formation (16). This has been shown to occur in a dynamic fashion, whereby bone resorption was increased within hours after a single dose of teriparatide, but the increase in bone formation was not apparent until 24 h later (13). After 28 d of daily teriparatide dosing, bone formation (i.e., P1NP) was increased by ~100%, whereas CTX was increased by <10% (4). It is possible that the exercise-induced increase in PTH also has a delayed effect on bone formation, but evidence does not support this (8,9). Future research is needed to fully investigate the bone formation potential of exercise in light of the bone resorption response we observed.
It is also possible that people with low bone mass may respond to this type of intervention differently than people with normal bone mass. Our study population included individuals with t-scores between −1.0 and −2.5, which would meet criteria for low bone mass. However, because of the low number of participants in this category, we did not analyze whether they responded differently than their peers with t-scores greater than −1.0. However, we think it is unlikely that the difference in BMD scores would influence the outcomes because of the consistent findings across multiple laboratories that endurance exercise stimulates PTH secretion (2,6,9). Our working hypothesis is that the repeated activation of PTH and CTX by exercise is the cause of the bone loss observed in this population, and we hope to address the effect of bone health status on these markers in a future clinical trial.
In conclusion, taking a chewable Ca supplement 30 min before exercise attenuated the decrease in iCa and increase in PTH during exercise but did not prevent an increase in CTX. Ca supplementation may need to occur earlier before exercise to reduce the mobilization of skeletal Ca during exercise. Further studies are needed to determine whether adequate Ca supplementation before and/or during exercise can fully mitigate the exercise-induced increases in PTH and bone resorption. Given the paradoxical actions of PTH on bone, it must also be determined whether preventing the increase in PTH is likely to be beneficial or harmful to bone.
This study was supported in part by the National Institutes of Health award nos. R01 AG018857, UL1 TR001082, P30 DK048520, T32 DK007658, and T32 AG000279. Marigot Ltd. provided Ca and PL supplements.
The authors have no conflicts of interest to declare. The results of the study are presented clearly, honestly, and without fabrication, falsification, or inappropriate data manipulation. Results of the present study do not constitute endorsement by the American College of Sports Medicine.
Dr. Vanessa D. Sherk and Dr. Sarah J. Wherry are co-first authors.
D. B., P. W., and W. K. contributed to the study design. D. B. and K. S. contributed to study conduct and data collection. V. S., S. W., P. W., and W. K. contributed to data analysis and interpretation. V. S., S. W., P. W., and W. K. drafted the manuscript. V. S., S. W., D. B., K. S., P. W., and W. K. revised the manuscript content. V. S., S. W., D. B., K. S., P. W., W. K., and W.K. approved the final version of manuscript and take responsibility for the integrity of the data.
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