This is the first prospective controlled study to report in detail the effects of vitamin D and calcium on serum and 24-hour urine calcium levels in older women. During a year of three monthly tests, 8.8% of women developed hypercalcemia, and 32% women developed hypercalciuria.
No relationship was found between episodes of hypercalcemia or hypercalciuria and vitamin D3 dose or serum 25(OH)D level, but 24-hour urine calcium was weakly related to the 12-month serum 25(OH)D level. Women who developed hypercalciuria seemed to be different from those who developed hypercalcemia, as shown in Figure 4, but we found no difference in any variable to explain this finding. It is notable that hypercalcemia and hypercalciuria occurred in the placebo group that received only calcium and placebo vitamin D; thus, even a modest calcium supplementation of 600 mg/ day may be too high for some women. Sixteen percent of women increased urine calcium levels by more than 400 mg, and another 14% of women increased urine calcium levels by more than 300 mg. These results would be clinically relevant if other risk factors for stone formation are present because stone formers compose 6% of the population.
Although all of the women were vitamin D Ydeficient upon entry into the study, there is no evidence that treatment with vitamin D and calcium can cause hypercalcemia and hypercalciuria in this group, as shown in a previous study.
Few studies have reported the occurrence of hypercalciuria or hypercalcemia. In a placebo-controlled study of 583 older women in France, participants were randomized to either calcium 1,200 mg given as calcium phosphate and vitamin D 800 IU/day or double placebo; the baseline dietary calcium level was 558 mg/day. With calcium plus vitamin D, there was a significant increase in serum calcium, but there was no information on hypercalcemia. The 24-hour urine calcium level increased from 119 to 167 mg (from 3.0 to 4.1 mmol) compared with placebo, and 3.4% of women had levels higher than 350 mg (8.7 mmol). In a placebo-controlled study, 192 older women were treated twice daily with a combination tablet of vitamin D 400 IU/day and calcium 500 mg/day given as calcium carbonate; the baseline calcium intake was 736 mg. Twenty percent of women in the treatment group had 24-hour urine calcium excretion above the normal threshold compared with placebo (159 mg [4.0 mmol] vs 94 mg [2.3 mmol]; P < 0.001). There was no significant difference in the incidence of hypercalcemia between the two groups (7.4% vs 11.5%).
In a 4-year controlled study of calcium supplements given as calcium citrate only versus placebo, 236 healthy postmenopausal women with a baseline calcium intake of 711 mg/day took calcium 1,234 mg/day; thus, women had a total calcium intake of approximately 2,000 mg/day. In this study, 50% of women in the calcium-treated group and 8% in the placebo group had 24-hour urine calcium levels exceeding 350 mg/day (8.7 mmol), and 44% of women had to reduce their calcium supplement. Only one woman on calcium supplementation developed mild hypercalcemia.
In the WHI trial, the group given vitamin D 400 IU/day together with a calcium supplement of 1,000 mg had a 17% increase in kidney stones compared with placebo (hazards ratio, 1.17; 95% CI, 1.02-1.34). Because the baseline dietary calcium level was 1,100 mg and the final calcium intake was 2,200 mg/ day, it was more probable that the high calcium intake was the major contributing factor given the findings in this study. It is commonly thought that vitamin D increases calcium absorption; however, we showed that vitamin D 400 IU/day had no effect on calcium absorption in this older age group of women and that vitamin D up to a dose of 2,400 IU/day had no effect on calcium absorption in younger women. It seems improbable therefore that vitamin D 400 IU/day could cause hypercalciuria and renal stones in the WHI trial.
One explanation for the absence of kidney stones in calcium intervention studies of osteoporosis is that the studies were small and lasted only 2 to 3 years compared with the WHI trial that followed women for 7 years. In the observational study from the WHI trial, there was a 2.5% incidence of kidney stones during 7 years of follow-up. Stone risk decreased by 28% with the highest quartile of dietary calcium intake and decreased by 20% with higher water intake. However, the trial included women with a history of renal stones.
In the Nurses Heath Study II of women aged 27 to 44 years, higher dietary calcium was associated with a 45% lower stone risk, but calcium supplements had no effect on stone risk. Similar results were found in the Health Professional Study in men, but a later analysis of the same study reported that the effects of dietary calcium on stone risk reduction only applied to men younger than 60 years and not to men older than 60 years. In a 16-year follow-up of women in the Nurses Health Study I, higher dietary calcium was shown to reduce stone risk by 35%, whereas use of calcium supplements increased stone episodes by 20%; this was the first study to link calcium supplementation to stone risk.
The strengths of our study include the systematic measurement of serum and 24-hour urine calcium levels, use of 7-day food diaries to record nutritional intake, adjustment for known covariates, excellent compliance, and measurement of serum and 24-hour urine calcium every 3 months. We excluded women who had a baseline 24-hour urine calcium level higher than 300 mg (7.5 mmol), thereby limiting those at risk for hypercalciuria; thus, we may have underestimated the effects of the supplements.
Our study has some limitations. We did not use fixed-dose calcium; thus, women with low calcium intake received higher supplemental calcium. However, 70% of the women received an average of 600 to 800 mg/day. Because we did not have a placebo group without calcium supplementation, we could not ensure that hypercalciuria in these women was caused only by the calcium supplements.
These results may not apply to other age groups or ethnic groups because of differences in calcium and vitamin D metabolism.
Healthcare practitioners who advise women on osteoporosis prevention seldom consider the issues of hypercalcemia and hypercalciuria, which can be determined by testing serum and urine calcium levels on a continuous basis. It is known that 5% to 8% of men and women have idiopathic hypercalciuria, which is a risk factor for kidney stones; one would expect that the millions of men and women taking calcium supplements belong to this risk group. The epidemiologic studies discussed above suggest that high dietary calcium intake is associated with a lower risk for kidney stones and that calcium supplements increase the risk.
Menopause. 2014;21(11):1173-1180. © 2014 The North American Menopause Society