Vitamin D and Calcium: Implications for Healthy Aging

This is the first article in a continuing series of articles on nutrition in older adults. Upcoming articles in this Clinical Geriatrics series will discuss vitamin B₁₂, popular diets, and nutritional assessment of the geriatric patient.
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Successful aging involves maintaining cognitive and physical stamina, high quality of life, and independence. Receiving adequate nutrition is an essential component of healthy aging, and this includes taking measures to ensure adequate levels of vitamin D, a prohormone that promotes the absorption of calcium. Vitamin D and calcium have long been recognized for their essential role in preserving bone health. More recently, vitamin D receptors have been identified in cells throughout the body, including in the liver, breasts, colon, kidneys, skin, and prostate. They have also been found in macrophages and in skeletal and cardiac muscles. These discoveries have afforded new insights on a diverse array of physiological processes that involve vitamin D and underscore the need for ensuring adequate intake. We review the importance of vitamin D and calcium in preserving musculoskeletal, cardiometabolic, and cognitive health among older adults, and discuss their potential impact on cancer. We also propose clinical guidelines for evaluating and maintaining vitamin D status in this population.

Musculoskeletal Health

Calcium and vitamin D are essential for preserving bone health and skeletal muscle health, which, in turn, helps preserve physical function. Peak bone mass is typically achieved in early adulthood before beginning a gradual decline over the ensuing decades. For women, this decline is compounded by accelerated bone remodeling during the perimenopausal and menopausal phases. Lifestyle factors such as lack of exercise, smoking, and excessive alcohol consumption have also been found to compromise bone health.¹

The National Osteoporosis Foundation defines low bone density (osteopenia) as a T score between -1.0 and -2.5. It defines osteoporosis, characterized by more severe bone density loss and deterioration of bone tissue, as a T score of ≤-2.5.² Osteoporosis is estimated to affect 55% of Americans 50 years of age and older.² Rates are higher for women than for men (80% vs 20%, respectively), with postmenopausal women at an increasingly greater risk of osteoporosis with advancing age.

The inverse relationship between bone density and fracture risk is well established. One study estimated that in 2005, osteoporosis caused at least 2 million incident fragility fractures in the United States, at a cost of nearly $17 billion.³ The greatest burden from osteoporosis was on adults 65 years of age and older, who accounted for 70% of incident fragility fractures and 87% of costs. The authors estimated that these rates would increase by at least 50% by 2025, due to a burgeoning elderly population.³

Several studies have shown that osteoporosis-related fractures increase the risk of morbidity and mortality and decrease quality of life in older adults.^4,5 Patients who experience a fragility fracture have a significantly greater risk of a subsequent fracture, with the degree of risk varying according to the site of the index fracture.⁴

Calcium supplementation^6-8 and adequate vitamin D intake^9,10—important for regulation of calcium homeostasis—have been shown to reduce bone loss and fracture risk among older individuals. Administered concomitantly, they improve skeletal muscle function and reduce the risk of falls. Pfeiffer and associates¹¹ randomized women 70 years and older with a serum 25-hydroxyvitamin D (25(OH)D) level <20 ng/mL to 1200 mg of calcium with or without 800 IU of vitamin D for 8 weeks. At 8 weeks, patients who received the calcium–vitamin D combination demonstrated a 9% decrease in body sway compared with baseline. After 12 months of follow-up, 16% of patients given vitamin D plus calcium experienced one or more falls versus 28% of patients who received calcium monotherapy.¹¹

Vitamin D status has been linked to additional musculoskeletal health issues. Studies have demonstrated an inverse correlation between 25(OH)D levels and the incidence and radiographic progression of osteoarthritis of the knee¹² and hip.¹³ A 12-month longitudinal study by Houston and colleagues¹⁴ assessed the relationship between 25(OH)D levels and physical performance in community-dwelling adults aged 70 to 89 years. Participants considered vitamin D deficient at baseline (ie, those whose 25(OH)D level improved to ≥20 ng/mL at 12-month follow-up) demonstrated significantly greater improvement in Short Physical Performance Battery scores than those whose vitamin D level remained unchanged (P=.01). Other studies have shown that older men¹⁵ and women¹⁶ with a 25(OH)D level <20 ng/mL are more likely to be diagnosed with frailty, a biologic syndrome characterized by multisystem decline and vulnerability to adverse outcomes that can lead to functional impairment, disability, and death. Taken together, these and other studies indicate that vitamin D levels should be maintained at ≥20 ng/mL to preserve musculoskeletal health and function in elderly adults.

Vitamin D and Cardiometabolic Health

Research has established relationships between diabetes mellitus, the metabolic syndrome, and cardiovascular disease (CVD); diabetes, for example, is widely recognized as a leading cause of CVD.¹⁷ Cardiometabolic conditions are highly prevalent among US elders. It is estimated that at least 20% of adults aged 65 to 75 years and 40% of those older than 80 years have type 2 diabetes mellitus,¹⁸  42% aged 70 years and older have the metabolic syndrome,¹⁹ and 19.8% aged 65 years and older have coronary artery disease.²⁰ Multiple studies have demonstrated a correlation between serum 25(OH)D levels and cardiometabolic disorders.²¹ A 2010 meta-analysis of 28 observational studies, which cumulatively included 99,745 participants, found that individuals with the highest serum 25(OH)D levels had a 43% reduced risk of cardiometabolic disorders compared with those who had the lowest levels. Studies have also linked low serum 25(OH)D levels to specific cardiometabolic conditions, including diabetes and CVD.²¹

Diabetes and the Metabolic Syndrome

Penckover and associates¹⁷ reviewed the literature and concluded that evidence supports a strong correlation between the risk of diabetes and vitamin D deficiency (serum 25(OH)D level, <20 ng/mL). Comparisons of vitamin D levels between people with and without diabetes also tend to show lower levels in people with diabetes.¹⁷ A meta-analysis by Mitri and colleagues²² concluded that individuals with a 25(OH)D  level >25 ng/mL had a 43% lower risk of developing type 2 diabetes than those whose 25(OH)D levels were <14 ng/mL. Parker and associates²¹ concluded that individuals with higher vitamin D levels were 55% less likely to develop type 2 diabetes mellitus and 51% less likely to have the metabolic syndrome. An inverse correlation between 25(OH)D level and glycated hemoglobin level has also been reported.²³

Experts continue to make progress in ascertaining the physiological explanations for these findings. Low vitamin D levels appear to have an adverse effect on pancreatic tissue, contributing to beta cell dysfunction and impaired insulin secretion.^24,25 In response to an oral glucose tolerance test among healthy, glucose-tolerant individuals, those with 25(OH)D concentrations <20 ng/mL demonstrated greater decompensated beta cell function, insulin resistance, and a higher plasma glucose level than participants without vitamin D deficiency (hypovitaminosis D).²⁶

A subanalysis of data from the Nurses Health Study found that women whose self-reported combined intakes of calcium >1200 mg daily and vitamin D >800 IU daily had reduced risk of incident diabetes (relative risk [RR], 0.67) compared with those reporting a combined intake of calcium <600 mg daily and vitamin D <400 IU daily.²⁷ Other studies have reported that correcting vitamin D deficiency in adults improved glucose tolerance and decreased fasting plasma glucose levels.^17,28  The cumulative evidence from these studies suggests a need to evaluate 25(OH)D status in patients with diabetes or glucose homeostasis and indicates that serum levels should be maintained between 30 ng/mL and 40 ng/mL.

Cardiovascular Health

Multiple studies have reported associations between vitamin D deficiency and CVD.^29,30 A meta-analysis of data from 13 studies concluded that individuals with 25(OH)D levels <25 ng/mL had an increased risk of CVD and CVD-related mortality,³¹ and a cross-sectional analysis of data from NHANES III (Third National Health and Nutrition Examination Survey) found that 29.3% of individuals with vitamin D deficiency had CVD compared with 21.4% of participants who were not deficient (P<.0001).²⁹ Another cross-sectional study, which involved a large cohort of patients referred for angioplasty, reported an increased risk of death from heart failure or sudden cardiac death in patients with 25(OH)D levels <10 ng/mL.³² The study also demonstrated an inverse association between vitamin D levels and left ventricular function. In contrast, a recent Cochrane review found that women taking calcium supplements with or without vitamin D had a modest increased risk of myocardial infarction;³³ however, a prospective study of self-reported supplement use among a large cohort of older women (age at baseline, 55-69 years) showed a decrease in overall mortality among those reporting calcium supplementation at doses ranging between 400 mg and 1300 mg daily.³⁴ This association was lost among users reporting calcium supplementation >1300 mg daily.³⁴

Data from NHANES III was also used to analyze the relationship between hypertension and vitamin D level. Stratifying participants according to vitamin D level found that systolic blood pressure (SBP) was 3.0 mm Hg lower and diastolic blood pressure was 1.6 mm Hg lower for people in the highest quintile (25(OH)D, ≥34 ng/mL) compared with those in the lowest quintile (25(OH)D, ≤16 ng/mL).³⁵ This inverse association was stronger for those 50 years and older. Some evidence indicates that vitamin D plus calcium supplementation may lower blood pressure.^36,37 A group of women (median age, 74 years) who received 8 weeks of supplementation with 800 IU of vitamin D₃ plus 1200 mg calcium experienced a 9.3% decrease in SBP compared with a group given only calcium.³⁶ A meta-analysis of 40 randomized controlled trials conducted to determine the effect of calcium supplementation on blood pressure concluded that calcium supplementation resulted in an overall decrease of 1.9 mm Hg in systolic blood pressure and 1.0 mm Hg in diastolic blood pressure.³⁷ These studies provide additional evidence that maintaining 25(OH)D levels >30 ng/mL, along with maintaining adequate calcium intake, may help preserve normal blood pressure. Because blood pressure tends to increase with age, this finding is highly relevant for older adults.

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Vitamin D and Calcium for Cancer

Several studies have shown an inverse association between vitamin D levels and the incidence of various cancers, including cancers of the breast, colon, ovary, endometrium, and kidneys.²⁶ Higher vitamin D levels have also been linked to lower case-fatality rates among individuals with breast, prostate, colon, and lung cancers.³⁸

Ma and colleagues pooled data from 18 studies and found that individuals with the lowest intake of vitamin D as well as those with the lowest serum 25(OH)D levels had an increased relative risk of colorectal cancer compared with those having the highest intake and the highest serum levels of vitamin D.³⁹ However, a meta-analysis by Buttigliero and colleagues⁴⁰ that included 25 studies revealed that while low vitamin D levels correlated with worse prognosis with some cancer types, evidence was insufficient to recommend vitamin D supplementation for patients with cancer.

The National Cancer Institute (NCI) and the Institute of Medicine (IOM)⁴¹ have each concluded that the relationship between cancer risk and vitamin D is unclear, with studies providing inconsistent evidence. The NCI does acknowledge that findings from laboratory studies indicate that vitamin D may be cancer-protective. Neither organization, however, recommends for or against vitamin D supplementation to reduce cancer risk.⁴² Likewise, although some studies suggest a role for calcium in reducing the risk for developing colon cancer, a 2008 Cochrane review concluded that evidence was insufficient to recommend the general use of calcium supplementation for the prevention of colon cancer.⁴³ In 2009, a US Food and Drug Administration review of data linking calcium supplementation with reduced risk of breast, colon, and prostate cancer found no evidence to support such claims and concluded that there may be limited evidence to support a modest reduction in risk of colon cancer associated with calcium intake.⁴⁴

Vitamin D and Cognition

Studies have implicated vitamin D in nervous system function.⁴⁵ In a study involving men and women 60 years and older, a 25(OH)D level <20 ng/mL was associated with low mood and some cognitive impairment.⁴⁶ The authors called for further investigation, however, before recommending vitamin D supplementation to prevent cognitive decline and mood disorders in this demographic.

A recent analysis of NHANES III data for 3325 adults 65 years and older concluded that individuals with insufficient, deficient, or severely deficient serum 25(OH)D levels performed worse on cognitive tests than their counterparts with levels ≥30 ng/mL.⁴⁷ The authors recommend additional investigation into whether vitamin D deficiency impairs cognitive ability.

Vitamin D and Calcium Recommendations

The IOM recommends that adults maintain 25(OH)D levels ≥20 ng/mL.⁴¹ This guideline is based primarily on data from large randomized trials involving bone outcomes.⁴⁸ Although evidence is lacking from large randomized prospective trials to provide conclusive evidence of a causal relationship between 25(OH)D status and cardiac, metabolic, and cancer outcomes, observational evidence suggests that maintaining 25(OH)D levels between 30 ng/mL and 40 ng/mL may be essential for optimal health.^49,50 Another reason to keep plasma 25(OH)D within this range is evidence that levels <31 ng/mL, combined with poor dietary calcium intake, lead to secondary hyperparathyroidism.⁴⁹

The IOM recently updated dietary reference intakes for calcium and vitamin D.⁴¹ The new recommended daily allowance (RDA) for vitamin D for persons aged 19 to 70 years is 600 IU, and the RDA for calcium is 1000 mg. For individuals older than 70 years, the IOM recommends an RDA of vitamin D of at least 800 IU and an RDA of calcium of 1200 mg.⁴¹

These and other dietary guidelines are made at the population level. Determining patients’ appropriate vitamin D needs requires clinicians to assess each patient individually. Factors to consider include age, skin pigmentation, sunlight exposure, sunscreen use, intake of vitamin D rich foods and supplements, comorbidities, and use of medications that increase vitamin D clearance. Based on the evidence indicating that a plasma 25(OH)D level of 30 ng/mL to 40 ng/mL helps preserve cardiovascular, metabolic, and cognitive health among older adults, we recommend ensuring that vitamin D intake is sufficient to achieve and maintain this level.

Excessive vitamin D intake is harmful, and hypercalcemia is a hallmark of vitamin D intoxication. Toxicity rarely results from eating fortified foods and is typically due to excessive supplementation or overdose. Daily doses of vitamin D <10,000 IU rarely cause toxicity.⁴¹ Excess calcium intake from food alone is also almost impossible, but calcium intake that exceeds the recommended level can lead to hypercalciuria, hypercalcemia, increased risk of kidney stones, vascular and soft tissue calcification, and constipation. A recent meta-analysis associated calcium supplementation with a 30% increase in the risk of myocardial infarction.⁵¹ However, another meta-analysis found no increased risk of cardiovascular events associated with the use of calcium supplements.⁵² Although calcium is important for maintaining skeletal health and reducing the risk of fracture, these studies linking calcium supplementation to cardiovascular risks suggest it is prudent to recommend calcium-rich foods as the primary source of this mineral. Supplements should be reserved for individuals unable to tolerate dairy products or unable to obtain the RDA of calcium from diet alone.

Vitamin D Deficiency

The primary source of data on vitamin D status in the United States is from the NHANES studies, which reveal a marked drop in mean serum vitamin D levels over the past several decades, from 30 ng/mL in 1988 through 1994 to 24 ng/mL in 2001 through 2004.⁵³ Nearly 75% of the general population and 90% of the pigmented population (blacks, Hispanics, and Asians) in the United States have vitamin D (plasma 25(OH)D, <30 ng/mL). A plasma 25(OH)D concentration of <20 ng/mL represents vitamin D deficiency. Concentrations between 20 ng/mL and 30 ng/mL represent insufficiency, whereas those of at least 30 ng/mL to 40 ng/mL are currently considered to indicate vitamin D sufficiency. The prevalence of vitamin D deficiency in the United States has nearly doubled over the past decade.^53,54

Causes of Deficiency

One reason vitamin D deficiency is so common is the relatively small number of foods that naturally contain vitamin D, such as oily fish (eg, tuna, herring, salmon). Although some foods sold in the United States have been fortified with vitamin D, including dairy products, orange juice, and ready-to-eat cereal, consumption of these foods is often not sufficient to maintain plasma 25(OH)D at a level >20 ng/mL.

Sunlight facilitates vitamin D production, but many older adults do not receive sufficient exposure to keep their plasma 25(OH)D level >20 ng/mL.⁵⁵ As people have become more aware of the relationship between excessive sunlight exposure and skin cancer, the use of sunscreen has increased, which has likely contributed to the growing prevalence of vitamin D deficiency.

Obesity, which is prevalent in the United States among adults of all ages, is also a factor in vitamin D production. People who are obese tend to have lower basal vitamin D levels. After whole-body irradiation (a surrogate for sun exposure), obese individuals demonstrated an incremental increase in serum 25(OH)D level that is 57% less than the increase observed in people who are not obese.⁵⁶

Certain medications, such as rifampin, isoniazid, and glucocorticoids, along with certain anticonvulsants, including carbamazepine, primidone, valproic acid, phenobarbital, and phenytoin, accelerate vitamin D clearance. This can reduce vitamin D levels and increase the risk of vitamin D deficiency.

Age-related changes also contribute to a greater risk of vitamin D deficiency, a condition that often goes undetected in older adults despite being common. People 70 years and older are said to produce 30% less vitamin D than younger individuals in response to equivalent amounts of sunlight exposure⁵⁷ and to absorb vitamin D less efficiently from dietary sources. Aging is also associated with a reduction in hydroxylation of 25(OH)D to 1,25(OH)₂D₃ (also called calcitriol), the nutrient’s active form.

Treatment

Vitamin D supplementation constitutes an acceptable alternative for increasing plasma 25(OH)D levels. Two forms of vitamin D are available for supplementation: vitamin D₃ (cholecalciferol) and vitamin D₂ (ergocalciferol). One recent study indicated that vitamin D₃ is slightly more effective than D₂ at increasing serum 25(OH)D levels.⁵⁸ Although sun exposure offers a natural way to obtain vitamin D, the risk of skin cancer prevents physicians from recommending this as a treatment for vitamin D deficiency.

A two-phase protocol is typically used when initiating vitamin D supplementation (Table). High-dose vitamin D₂ (≥50,000 IU), available by prescription, is usually administered for repletion, and vitamin D₃ is generally used to maintain 25(OH)D levels. For patients whose 25(OH)D levels have dropped to <15 ng/mL, we recommend repletion with oral ergocalciferol, administered at a dose of 50,000 IU twice weekly for 4 to 6 weeks. Patients’ whose plasma 25(OH)D levels are between 15 ng/mL and 30 ng/mL can be given the same 50,000 IU dose of ergocalciferol,  administered once a week for 4 to 6 weeks. The serum level of 25(OH)D should be rechecked 8 to 12 weeks after initial repletion, with the initial phase repeated if the level remains ≤30 ng/mL. Once the patient’s 25(OH)D level exceeds 30 ng/mL, a daily maintenance dose of cholecalciferol 2000 IU is recommended.

Conclusion

Multiple studies have established that the role of vitamin D extends beyond bone health, and—although not conclusive—data have linked insufficient levels of vitamin D to cardiometabolic disorders, cancer, and cognitive impairment. Many people have insufficient or deficient serum levels of vitamin D, especially older adults. This is because it is difficult to obtain the RDA of vitamin D through diet and sun exposure. Prospective trials to evaluate plasma 25(OH)D levels at baseline and after supplementation with respect to various clinical end points are needed, to provide high-quality evidence establishing the appropriate role of vitamin D in maintaining health. To mirror clinical practice, these trials should involve large cohorts, including older volunteers and those with a variety of comorbidities. One such trial is currently being planned, but until evidence becomes available from this and other studies, clinical practice must be based on the data available. Currently, the data regarding calcium supplements is conflicting. There is strong evidence to support the use of calcium supplements to maintain bone health, but some evidence suggests there is an increased risk of myocardial infarction among women. Despite this potentially increased risk, use of calcium supplementation in older women has been associated with overall reduced mortality in this population.

We recommend that providers assess vitamin D levels in their elderly patients and use supplements when necessary to correct insufficient or deficient levels. After reviewing the available data, it appears maintaining plasma 25(OH)D levels between 30 ng/mL and 40 ng/mL in elderly patients helps preserve musculoskeletal, cardiovascular, metabolic, cognitive, and functional health.

Dr. Steinle has received salary support from the Mid Atlantic Nutrition and Obesity Research Center (NORC), University of Maryland School of Medicine. The other authors report no relevant financial relationships.

Drs. Sareh, Sourwine, and Steinle are from the Department of Medicine, University of Maryland School of Medicine; and Dr. Rochester is from the Department of Pharmacy Practice and Science, University of Maryland School of Pharmacy. Dr. Steinle is also from the Baltimore Veterans Administration Medical Center, Baltimore, MD.

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