Incidence of Hypercalciuria and Hypercalcemia During Vitamin D and Calcium Supplementation in Older Women

John Christopher Gallagher, MD Lynette M. Smith, MSc; Vinod Yalamanchili, MD


Menopause. 2014;21(11):1173-1180. 

In This Article


Study Design

The clinical trial was a 1-year randomized, double-blind, placebo-controlled study (Vitamin D Supplementation in Older Women [VIDOS]) that aimed to determine the effects of increasing vitamin D3 doses. One hundred sixty-three white women were studied at Creighton University Medical Center (Omaha, NE). The women, aged 57 to 90 years, were at least 7 years postmenopause. The main inclusion criterion was vitamin D insufficiency, defined as a serum 25(OH)D level of 20 ng/mL (50 nmol/L) or less. Women were enrolled from winter/spring 2007 to 2008 and followed for 1 year. Complete details of the trial are given in the primary article.[9]

Exclusion criteria were as follows: significant health problems, active nephrolithiasis or history of more than two kidney stones in their lifetime, chronic renal failure (serum creatinine >1.4 mg/dL), chronic liver disease, medical conditions severe enough to prevent reasonable physical activity, serum 25(OH)D levels lower than 5 ng/mL (12.5 nmol/L), serum calcium levels of 10.3 mg/dL (2.575 mmol/L) or more or serum calcium levels more than 0.3 mg/dL higher than the upper normal limit on two baseline tests, and 24-hour urine calcium levels higher than 300 mg/dL (7.5 mmol) on two baseline tests. Those currently taking bisphosphonates or who had taken them for more than 3 months in the past were excluded. Use of fluoride, parathyroid hormone (PTH) or its derivatives, calcitonin, estrogen (in the last 6 mo), corticosteroids (>10 mg/d), phenytoin or phenobarbital, or high-dose thiazide (>37.5 mg/d) was not allowed. Multivitamins containing vitamin D were not allowed in the study.

Randomization and Treatment

Women were randomly assigned to one of eight groups: vitamin D3 400, 800, 1,600, 2,400, 3,200, 4,000, or 4,800 IU/day, or placebo. Women, providers, researchers, and persons who assessed outcomes were blinded to treatment assignment. The statistician had access to treatment assignments. Randomized blocks with block sizes of 8 and 16, stratified by screening serum 25(OH)D levels lower than 15 versus 15 ng/mL or more (<37.4 vs ≥37.4 nmol/L), were used. The study statistician generated the randomization list using SAS software (SAS Institute Inc, Cary, NC).

After analyzing dietary calcium levels from 7-day food diaries, we gave calcium citrate supplements (Citracal; Bayer HealthCare, Morristown, NJ) to women to maintain total calcium intake between 1,200 and 1,400 mg/day; they were advised to take calcium tablets twice daily and vitamin D after food intake. The Institutional Review Board at Creighton University approved the study protocol, and participants were enrolled after they have signed an informed consent form. A Data Safety and Monitoring Board was established at the beginning of the study. Adherence was measured at 3, 6, 9, and 12 months by counting the pills remaining in the bottles; new bottles of vitamin D and calcium were supplied at each of these visits.

Outcomes and Follow-up

The primary outcomes of this study were dose responses to serum 25(OH)D and serum PTH after treatment with vitamin D3. Secondary outcomes were serum and 24-hour urine calcium.

Fasting venous blood specimens were collected at baseline and at 3, 6, 9, and 12 months. All serum and urine chemistry values were measured at the Creighton University Clinical Chemistry Laboratory using standard autoanalyzer equipment. 25(OH)D level was measured by radioimmunoassay at the Bone Metabolism Laboratory (Diasorin Inc, Stillwater, MN). The reference range for serum calcium at the Creighton University Medical Center is 8.5 to 10.2 mg/dL. Data from a previous study were used to define a reference range for 24-hour urine calcium (30-300 mg [0.75-7.5 mmol]).[10] Dietary intake of calcium and vitamin D was calculated by a dietician from the 7-day food diaries at baseline and 12 months (Food Processor II Plus nutrition and diet analysis system; ESHA Research, Salem, OR).

Management of Hypercalcemia and Hypercalciuria

Hypercalcemia. During the study, hypercalcemia was defined as a fasting serum calcium level that was 0.3 mg/dL or 1 SD higher than the upper reference range of 10.2 mg/dL (ie, >10.5 mg/dL). For poststudy analysis, hypercalcemia was defined as a serum calcium level exceeding the upper normal limit of 10.2 mg/dL (2.55 mmol/L).

Hypercalciuria. During the study, hypercalciuria was defined as a 24-hour urine calcium level exceeding 400 mg (10 mmol). For poststudy analysis, hypercalciuria was defined as a 24-hour urine calcium level higher than 300 mg, which is the upper normal limit. Hypercalciuria may occur spuriously when an individual collects urine specimens for longer than 24 hours. To account for this potential error of overcollection, we averaged 24-hour urine creatinine levels for all urine collections at the end of the study; if a 24-hour creatinine level was 20% higher than the mean for all tests, that episode of hypercalciuria was excluded from the analysis.

When severe hypercalciuria (>400 mg/d [10 mmol]) or hypercalcemia (≥10.5 mg/dL) developed, tests were repeated within 2 weeks. When calcium levels were elevated, calcium supplements were withdrawn, dietary calcium levels were rechecked, and laboratory tests were repeated within 2 weeks. When the elevation persisted, calcium was withdrawn. When the condition still persisted, vitamin D was withdrawn.

Statistical Methods

The endpoints for this secondary analysis were urine and serum calcium. Analysis was performed using all women who were randomized. For those who dropped out or were removed from the study, the data (if available) were included in the analysis. For the purpose of this analysis, hypercalcemia was defined in the usual clinical terms—a serum calcium level of 10.3 mg/dL (2.75 mmol/L) or more. Similarly, hypercalciuria was defined as a 24-hour urine calcium level higher than 300 mg (7.5 mmol/L), and severe hypercalciuria was defined as a 24-hour urine calcium level higher than 400 mg (10 mmol/L).

Descriptive statistics are presented as means (SDs), unless otherwise specified. Mixed-effects models were used to estimate the effects of time and dose on urine and serum calcium. Dose and time were included as fixed effects in the model, and participant was included as a random effect. Log transformation was applied to urine calcium to meet modeling assumptions. Interactions between dose and time were also explored. Model fit was examined by observing various residual plots.

As post hoc comparison, we compared women with hypercalciuria by dividing them into three groups based on 24-hour urine calcium levels during the course of the study (defined as 24-hour urine)—women with a urine calcium level higher than 400 mg (10 mmol), women with a urine calcium level between 300 and 400 mg (7.5-10 mmol), and women with a urine calcium level lower than 300 mg (7.5 mmol)—in a complete case analysis (they had to have a urine calcium measurement at each time point to be included in this analysis). Analysis of variance models and [chi] 2 tests were used to compare participant characteristics between these three categories. Variables that were significant in univariate models were used as predictors in multivariate generalized logistic regression. Estimated glomerular filtration rate was included in the model based on clinical experience.

We looked at calcium levels of 300 mg or higher at any time during the study versus calcium levels lower than 300 mg during the study, using a logistic regression model. Receiver operating characteristic (ROC) analysis was used to find a cutpoint for the variable with the greatest predictive value to give a predictive category for detecting hypercalciuria. It was also tested in a multivariate logistic model.

SAS software version 9.2 (SAS Institute Inc) was used for analysis. P values less than 0.05 were considered statistically significant.