Summary Points
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Hypercalcemia and hypercalciuria were observed in all groups including the placebo arm of this study.
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The occurrence of hypercalcemia and hypercalciuria had no relationship with vitamin D dosage.
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Hypercalcemia (>10.2 mg/dL) occurred in 8.8% of women and hypercalciuria (>300 mg/d) occurred in 30.6% of women participating in this study. The majority of women who developed hypercalcemia or hypercalciuria did not have any relevant symptoms.
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Because all groups received calcium supplementation to achieve total daily intake of approximately 1200 mg, the possible effects of calcium intake on hypercalcemia and hypercalciuria cannot be assessed.
AUTHOR: Carrie Decker, ND, Founder and Medical Director, Blessed Thistle, Madison, WI
PEER REVIEWER: J. Adam Rindfleisch, Assoicate Professor, Associate Residency Program Director, Integrative Medicine Fellowship Program Director, Department of Family Medicine, University of Wisconsin, Madison
Synopsis: In a randomized, placebo-controlled trial, variable vitamin D dosage from 400 IU to 4800 IU and daily calcium supplementation (to achieve total intake of 1200 mg) was provided to postmenopausal Caucasian women with vitamin D insufficiency for a period of 1 year. All individuals were supplemented with calcium, with the placebo group not receiving vitamin D. Vitamin D dosage was not found to be related to incidence of hypercalcemia or hypercalciuria.
Source: Gallagher JC, et al. Incidence of hypercalciuria and hypercalcemia during vitamin D and calcium supplementation in older women. Menopause 2014;21:1173-1180.
With a significant number of postmenopausal women supplementing calcium and vitamin D for bone health and other perceived benefits, the possibility of over-supplementation and possible negative effects are of concern. Calcium supplementation has been shown to be related to increased cardiovascular events,1 and combination calcium with vitamin D supplementation has been connected with renal complications such as nephrolithiasis.2 The purpose of this study is to assess serum and urinary parameters related to the cardiovascular and renal risks associated with variable vitamin D dosage in combination with calcium supplementation.
One hundred sixty-three Caucasian women between the ages of 57 and 90 years old with vitamin D insufficiency (< 20 ng/mL) were enrolled in this study. Women were excluded if they had a history of multiple kidney stone events, chronic liver or kidney disease, and other significant health problems. Criteria for exclusion also included having a serum 25-hydroxyvitamin D (25[OH]D) level of < 5 ng/mL, serum calcium levels > 10.3 mg/dL, and 24-hour urine calcium levels higher than 300 mg/dL. Individuals were also not included in the study if they were recently or currently taking medications with known effects on calcium or vitamin D levels, including bisphosphonates, fluoride, parathyroid hormone, calcitonin, estrogen, corticosteroids (>10 mg/d), phenytoin or phenobarbital, or high-dose thiazide.
Individuals were randomly assigned to eight groups to receive vitamin D3 at a dosage of 400, 800, 1600, 2400, 3200, 4000, or 4800 IU/day or placebo. Baseline dietary intake of vitamin D and calcium were assessed from 7-day food diaries, and all individuals were supplemented with 200 mg tablets of calcium citrate to achieve a daily total intake of 1200 mg, to be taken in divided doses. Measurements of serum calcium and 24-hour urine calcium levels were assessed at baseline, and at 3, 6, 9, and 12 months. Dietary intake of vitamin D and calcium were also assessed at 12 months. Primary outcomes of serum 25(OH)D and serum parathyroid hormone (PTH) levels were also assessed, but are reported separately.3
During the study, hypercalcemia was defined as a fasting serum calcium level > 10.5 mg/dL (upon which treatment adjustments were considered), and for post-study analysis, it was defined as 10.2 mg/dL. Similarly, hypercalciuria during the study was addressed when calcium levels from 24-hour urine collection exceeded 400 mg, and for post-study analysis, it was defined as levels higher than 300 mg.
One hundred and forty-seven women completed the study, and data were analyzed according to intention-to-treat (including the 11 who discontinued treatment but not the five lost to follow-up). The mean 24-hour urine calcium levels (across all groups) significantly increased from 141 mg at baseline to 185 mg at 12 months (P < 0.0001). The mean serum calcium level increased from 9.47 mg/dL at baseline to 9.52 mg/dL at 12 months, but was not significant. Twenty episodes of hypercalcemia (in 14 women) and 88 episodes of hypercalciuria (in 48 women) were observed. Episodes of hypercalcemia and hypercalciuria were not significantly associated with vitamin D dosage or serum 25(OH)D level.
Hypercalcemia was transient and did not require an adjustment to treatment. Hypercalciuria occurred once in one-half of the women and more than once in the other half, and required an adjustment to treatment in five of these individuals when the condition was not transient (as determined by repeated measurement within 2 weeks). A baseline level of 24-hour urine calcium > 132 mg was shown to be a risk factor for the development of hypercalciuria (OR, 15.3; 95% CI, 5.44-43.01; P < 0.0001), while a 1-year increase in age was associated with a decreased risk of developing hypercalciuria (OR, 0.90; 95% CI, 0.84-0.97; P = 0.0044). Two individuals who had five occurrences of hypercalcemia were not included in the analysis, as they were suspected to have mild primary hyperparathyroidism.
Eleven serious adverse events were observed in 11 women, including diverticulitis, congestive heart failure, fracture, angina, syncope, stroke, chronic obstructive pulmonary disease exacerbation, and partial thyroidectomy for a nodule. None of these events were attributed to vitamin D use nor elevated serum calcium/PTH . There was a small but significant increase in serum creatinine of 0.068 (95% CI, 0.041-0.096; P < 0.0001) in the 12-month period of this study. No symptomatic kidney stone episodes occurred.
COMMENTARY
Supplementation of vitamin D up to 4800 IU/day in combination with calcium to achieve total daily intake of 1200 mg has been shown to be safe and not connected to the development of nephrolithiasis or other significant adverse effects. This was demonstrated in a population of postmenopausal women who did not have hypercalcemia, hypercalciuria, other known health risks, or take many medications known to possibly increase these risks. In other studies in which adverse effects of kidney stones were seen, higher doses of calcium of 1000 mg were utilized in combination with 400 IU of vitamin D3.2
Although this study was a thorough investigation of a wide spectrum of vitamin D dosages, the final findings lack completeness, as there was not a control group with either vitamin D or calcium supplementation as a part of the study. Because of this, it cannot be determined if the fairly frequent incidence of hypercalciuria and less frequent hypercalcemia was associated with calcium supplementation or if they would normally occur in this population. As 24-hour urinary calcium levels are rarely assessed when there are not renal stones, the occurrence of asymptomatic hypercalciuria in an aging female population is largely unknown. Transient hypercalcemia is also a common finding, and, as it resolved without adjustments to treatment, it may not be attributed to this level of calcium supplementation. The significant finding of a mild increase in creatinine may be normal variation with increasing age, as this is known to occur.4
The exclusion of individuals with hypercalcemia and hypercalciuria, while important for the safety of this study, excludes a portion of the general population who often may be recommended to supplement their diet with calcium and/or vitamin D. In postmenopausal women, hypercalcemia and hypercalciuria is most commonly associated with hyperparathyroidism and is estimated to affect 21/1000 women between 55-75 years old.5 A general screening of these parameters, particularly urinary levels, is not a part of every well woman exam, yet many postmenopausal women receive these general bone health guidelines. The risk of hypercalcemia and hypercalciuria and associated symptoms are likely minimized by the findings of this study by the exclusion of this portion of the population. To reduce likelihood of hypercalcemia and hypercalciuria, the authors of this study suggest that assessment of these parameters initially and after 3 months of treatment should be considered.
Although the exclusion criteria for this study encompassed a wide variety of substances that may have an effect on the parameters being assessed in this study, multiple medications that are commonly prescribed were not. Atorvastatin is one of these, as it is known to increase serum 25(OH)D levels. Other medications also may have an effect on vitamin D levels (and vice versa); however, quality studies have not been performed.6,7 Proton pump inhibitors also may have an effect on calcium metabolism,8 and individuals using these medications were not excluded from this study.
Genetic polymorphisms of the vitamin D receptor gene are associated with hypercalciuria and the formation of urolithiasis.9,10 As the assessment of single-nucleotide polymorphisms and the use of this information for an individualized approach to medicine are becoming increasingly common, the possibility of utilizing this information for improved patient safety and outcomes also may be considered.
Vitamin D supplementation up to 4800 IU daily has been shown to be safe for daily use in individuals without other known risks, and was not shown to be connected with the development of either hypercalciuria or hypercalcemia. Although it was not reported in this paper, the additional publication related to this research did report serum 25(OH)D in excess of normal limits to occur with higher doses of daily vitamin D3 supplementation.3 A daily intake of 800 IU of vitamin D3 was found to be adequate to achieve serum 25(OH)D levels of > 50 nmol/L. If hypercalcemia or hypercalciuria is suspected or has been shown previously, these parameters should be assessed prior to and after 3 months of treatment to ensure patient safety.
References
- Bolland MJ, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: Meta-analysis. BMJ 2010;341:c3691.
- Jackson RD, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med 2006;354:669-683.
- Gallagher JC, et al. Dose response to vitamin D supplementation in postmenopausal women: A randomized trial. Ann Intern Med 2012;156:425-437.
- Tiao JY, et al. The effect of age on serum creatinine levels in an aging population: Relevance to vascular surgery. Cardiovasc Surg 2002;10:445-451.
- Adami S, et al. Epidemiology of primary hyperparathyroidism in Europe. J Bone Miner Res 2002;17(Suppl 2):N18-23.
- Robien K, et al. Drug-vitamin D interactions: A systematic review of the literature. Nutr Clin Pract 2013;28:194-208.
- Wang Z, et al. Interplay between vitamin D and the drug metabolizing enzyme CYP3A4. J Steroid Biochem Mol Biol 2013;136:54-58.
- Ito T, Jensen RT. Association of long-term proton pump inhibitor therapy with bone fractures and effects on absorption of calcium, vitamin B12, iron, and magnesium. Curr Gastroenterol Rep 2010;12:448-457.
- Rendina D, et al. Association between vitamin D receptor gene polymorphisms and fasting idiopathic hypercalciuria in recurrent stone-forming patients. Urology 2004;64:833-838.
- Liu W, et al. Vitamin D receptor gene (VDR) polymorphisms and the urolithiasis risk: An updated meta-analysis based on 20 case-control studies. Urolithiasis 2014;42:45-52.
As a significant number of postmenopausal women supplement calcium and vitamin D for bone health, the possibility of over-supplementation is a concern.
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