Dosing

There has been great debate about the proper level of intake of calcium and vitamin D, based on the significant amount of conflicting data that exists in the literature. Much of this is the result of data that suggest that vitamin D intake may have significant health benefits including reduction in cancer, prevention of autoimmunity including diabetes, prevention of preeclampsia in pregnancy, and decreases in heart attack and strokes. When evaluating the issue of appropriate levels of calcium and vitamin D intake, one must review the existing data for skeletal manifestations and complications of low vitamin D or calcium intake (or high intake) versus the extraskeletal potential benefits or risks that have been raised. Therefore, this article separates these 2 issues of skeletal health versus extraskeletal health as they relate to appropriate levels of calcium and vitamin D intake, and examines the potential complications and benefits that could be realized.

Both calcium and vitamin D are necessary for normal bone formation. Calcium is a major constituent of bone matrix, and vitamin D is necessary for intestinal absorption of calcium and uptake into bone. Vitamin D can be produced in the skin; however, even in warm-weather climates, people often produce inadequate vitamin D and require exogenous sources as supplementation. Vitamin D, along with parathyroid hormone and calcitonin, play an integral role in calcium and phosphorus metabolism in target tissues, specifically bone, intestine, and kidney. Vitamin D must be metabolically activated before having a physiologic effect ( Fig. 1 ). 7-Dehydrocholesterol is photometabolized in the skin to vitamin D ₃ , and then undergoes 25-hydroxylation in the liver. The 25-hydroxyvitamin D ₃ is further hydroxylated to 1,25-dihydroxyvitamin D ₃ , which is the most biologically active form, or to 24,25-dihydroxyvitamin D ₃ . The kidney regulates how much of the active form (ie, 1,25-dihydroxyvitamin D ₃ ) is available, based on serum calcium levels.

Metabolic activation of vitamin D.

( Adapted from Bordelon P, Ghetu M, Langan R. Recognition and management of vitamin D deficiency. Am Fam Physician 2009;80:841–6; with permission.)

In addition, when vitamin D levels are low, patients can develop secondary hyperparathyroidism. When vitamin D levels are low, parathyroid hormone is secreted to raise serum calcium levels, causing increasing bone resorption and normalization of calcium activity, and therefore vitamin D deficiency secondary to hyperparathyroidism may result in significant bone loss and increased fracture risk. Adequate supplementation with vitamin D can reduce or eliminate the secondary hyperparathyroidism, and reduce the fracture risk. Usually a 25-OH vitamin level of 30 μg/dL is necessary to eliminate secondary hyperparathyroidism. When vitamin D levels are adequate, calcium absorption from the intestinal tract averages about 30% to 40%. In vitamin D–deficient states, calcium absorption decreases to about 10% to 15%. To maintain serum calcium levels, parathyroid hormone is released, secondary hyperparathyroidism occurs, and calcium is released from bone.

Supplementation with vitamin D ₃ (cholecalciferol) is more effective than vitamin D ₂ , and therefore is the preferred mode of supplementation. As stated earlier, calcium homeostasis is regulated through numerous hormones, most specifically 1,25-dihydroxyvitamin D ₃ , and it is required for normal bone homeostasis. Maintenance of serum calcium levels is the primary function of these regulatory hormones, so if serum calcium, in response to either hypercalciuria, inadequate intake, or other mechanisms, is noted, the body will attempt to regulate these hormones. Inadequate intake of calcium has been associated with lower bone mineral densities.

Supplementation of calcium and vitamin D ₃ at the previous Recommended Daily Allowance, although showing increase in bone density, has not consistently been associated with decreased fracture rates in population analyses. Supplementation with calcium 1000 mg per day and vitamin D ₃ 400 international units (IU) per day, although associated with increased hip bone mineral density, has not been not associated with a statistically significant reduction in fractures.

However, some studies have shown that patients taking calcium and vitamin D do have a reduction in overall fracture risk, although the mechanism may be independent of its skeletal effects. Numerous studies have shown that adequate vitamin D is important in fall prevention. Vitamin D receptors are prevalent in muscle cells, and several vitamin D receptors on muscle cells decrease with age. By binding to the receptors on muscle cells, several pathways are activated, which allows calcium uptake in the muscle cells. In addition, phosphate metabolism increases and muscle cell proliferation or differentiation occurs. 1,25-Dihydroxyvitamin D may also modulate muscle contractility. Patients with significant vitamin D deficiency have type 2 fiber atrophy of the muscles. Numerous studies have shown that patients who received vitamin D supplementation, be it vitamin D ₃ , vitamin D ₂ , or even activated vitamin D supplements, were shown to have decreased risk of falling when given in concentrations of greater than 700 IU per day. However, megadosing of vitamin D ₃ administered yearly at 500,000 IU resulted in increased fall rates within the first 3 months of supplementation and increased fracture, suggesting that daily therapy may be preferred to large doses given less frequently.

Reduced risk of falling likely translates into reduced risk of fractures, specifically hip fracture, especially when serum concentrations of vitamin D are increased. These effects likely become more important as patients get older, because low vitamin D levels are more prevalent and there are decreased numbers of vitamin D receptors on muscle cells. Therefore, if vitamin D and calcium reduce fractures, it is possible that the mechanism may be independent of changes in bone density, but may also be related to increased muscle strength and reduction in fall risk.

Although few would dispute the need for supplementation of calcium and vitamin D ₃ , there is a paucity of randomized, controlled data examining this question. Studies typically involve retrospective analyses, and cannot control for dietary intake, sun exposure, or even use of supplements. In 2010, the Institute of Medicine attempted to review the dietary reference intakes based on the best data available. Although most studies are of levels of supplementation of calcium in the range from 500 to 1000 mg per day, and of vitamin D ₃ in the range from 400 to 1000 units per day, many investigators have suggested that higher-dose supplementation of vitamin D may provide additional benefits. However, there are few, if any, consistent data for very high-dose vitamin D intake (>10,000 IU/d), and oversupplementation may have potential side effects. Ingestion of too much calcium or vitamin D may have its own set of issues as well. Many patients may be intolerant of certain calcium preparations. Increased consumption of calcium has been associated with hypercalciuria and nephrolithiasis, and concerns have been raised regarding cardiovascular complications, specifically vascular calcification (discussed later), constipation, and interaction with the absorption of other minerals. High levels of vitamin D have been associated with increased risk of fracture, when getting more than 75 μg per deciliter. Other concerns regarding vitamin D include increased risk of mortality (eg, from pancreatic cancer), potential cardiovascular risk related to increased hypercalcemia and hypercalciuria, as well as growth retardation in children and infants. Therefore, recommendations about use of high-dose vitamin D at this time, without adequate substantiation in the literature, cannot be recommended.

However, the old recommendation of 400 units of vitamin D seems not to have been adequate. The Institute of Medicine based recommendations on the Recommended Daily Allowance, which is derived from the Estimated Average Requirement (EAR) and needs to exceed the requirement for 97.5% of the population. The EAR represents the estimated median requirement, necessary for adequate need for 50% of the population.

When taking into account these recommendations, the dietary intake of calcium and degree of sun exposure are difficult to quantify and may affect a patient’s individual need. In addition, upper limits of tolerability may be present, more than which there is increased risk to certain individuals, and therefore the Institute of Medicine developed tolerable upper intake level (UL), which is the average high daily intake that is likely to pose no risk of adverse events to any individual in the population. For most patients, dietary calcium recommended intake ranges from 1000 to 1300 mg per day, although, after menopause, calcium requirements slightly increase ( Table 1 ). This intake is contradictory to some earlier recommendations of 1500 mg per day that were advanced by certain organizations. In addition, it is important to emphasize that not all calcium supplementation should be taken at once, because it may overwhelm the intestine’s ability to absorb, so it must be done in split dosing, not to exceed 500 to 600 mg per dose.

The dietary intake for vitamin D is more controversial, because recommendations have varied from as low as 400 IU per day of vitamin D ₃ to as high as 2000 to 4000 IU per day, depending on the perspective of the author and interpretation of the literature. However, there is little debate in the literature that increasing to at least 600 to 800 IU per day is safe and may provide additional benefits, although there are patients who may benefit from greater amounts, based on certain individual disease conditions. Many would argue that at least 1000 IU of vitamin D ₃ per day, or 2000 IU per day if there is evidence of vitamin D deficiency, would be appropriate, with the goal of achieving a 25-OH vitamin D level of 30 ng/dL. The advocates of high-dose vitamin D ₃ also must remember the potential complications that have been found in numerous studies. Therefore, the upper limit of tolerability was established for men and women, increasing it to 4000 IU, although the report suggests that up to 10,000 IU per day are probably safe in most circumstances. Although there are those who advocate use of higher doses, there is little if any support in the literature for this, and there is potential for significant toxicity if advocated on a consistent basis.

There are individual circumstances that require higher doses of calcium and vitamin D. In addition, the role of serum measurement of 25-hydroxyvitamin D has been studied. There are many who advocate routine screening as part of health physicals in an attempt to monitor intake as well as effectiveness and adequate absorption. The prevalence of vitamin D insufficiency is high, and serum measurement can help to solve this. However, this may present an undue economic burden and, in lower-risk populations, this may not be considered cost-effective.

A level of greater than 20 ng/dL is considered necessary for maintenance of bone health, although many believe that a level of 30 ng/dL or more might be a better target for the other extraskeletal manifestations. Some studies, including randomized controlled data, suggested that raising 25-hydroxyvitamin D levels from 21 to 29 ng/mL reduces fracture risk by up to 33%. The Institute of Medicine report targets a level of 20 ng/dL, citing a lack of consistency in the literature for benefits at more than that level. Many have been critical of this approach, citing that dosing of 600 IU/d of vitamin D ₃ is often inadequate even to assume a level of 20 ng/dL, the lack of side effects when pushing the level to 30 ng/mL, and the literature that does support benefits both for bone and elsewhere. Therefore, supplementation of at least 1000 IU/d seems safe and appropriate in almost any circumstance. Use of a high dose of vitamin D weekly or monthly without adequate screening or in low-risk populations is not indicated based on the best available data and lack of any clear documented benefit compared with daily dosing. No population has been identified in which there is a definite advantage.

Most studies and review articles suggest that the combination of calcium and vitamin D ₃ reduces the incidence of fractures in patients with osteoporosis. Studies published by Dawson and colleagues, showed that calcium and vitamin D ₃ supplementation did reduce fracture incidence in elderly populations, although it is unclear whether or not this is the sole effect of calcium or of vitamin D. The use of calcium and vitamin D ₃ for bone health seems not to be in question at this time.