Vitamin D and Musculoskeletal Health in the Elderly: Have We Seen the Light?

By Susan T. Marcolina, MD, FACP, and Sabine von Preyss-Friedman, MD, CMD. Dr. Marcolina is a board-certified internist and geriatrician in Issaquah, WA; Dr. von Preyss-Friedman is a certified medical director by the American Medical Director's Association and an Associate Clinical Professor of Medicine, University of Washington, Department of Medicine, Division of Gerontology, Section for Long-term Care; they report no financial relationship to this field of study.

In 1969, a band called the fifth dimension popularized the refrain "Let the sun shine in," in a hit song from the Broadway musical Hair, though it is doubtful they were advocating for the increased cutaneous manufacture and dietary intake of vitamin D. Over the past four decades, however, numerous clinical studies have uncovered the importance of this "sunshine vitamin" to skeletal, neuromuscular, and overall general medical health. Despite this knowledge, there continues to be a high incidence of vitamin D insufficiency in the United States and worldwide, which affects more than 1 billion persons.1 Though virtually all population subsets have vitamin D deficiency, certain groups, particularly elderly home-bound or long-term care residents, are disproportionately affected.2,3

The lack of vitamin D has significant ramifications for both diminished bone health and overall general medical health due to increased vulnerability to osteoporosis, osteomalacia, falls, fracture, and tooth loss. Given that hypovitaminosis D is a treatable condition, heightened awareness is necessary among primary care physicians to ensure adequate vitamin D nutrition to vulnerable populations. Part 1 of this series will focus on the relationship between vitamin D and musculoskeletal health; part 2 will focus on its relationship to periodontal disease and loss of dentition, areas of importance to quality of life and health in geriatric patients.

Sources of Vitamin D

Two forms of vitamin D are vitamin D2 (ergocalciferol), derived from irradiation of the yeast and plant sterol ergosterol, and vitamin D3 (cholecalciferol) found in fatty fish and manufactured in the skin. The vitamin D from food and supplements is primarily in the form of D3 (D). Few foods aside from oily fish and egg yolks naturally contain vitamin D. For this reason, in the United States, dairy products such as milk, certain cereals, and juices are fortified with vitamin D.

Exposure of skin to sunlight can also generate vitamin D; however, several factors influence vitamin D skin synthesis (see Table 1).4-8 In general, exposure of the arms and legs to sunlight for an average of 5-30 minutes from 10 am to 3 pm twice a week is adequate.4,6,9 Although darker skinned individuals genetically have lower bone turnover and 9-11% greater bone mineral density than whites, they are at increased risk for osteoporosis and fractures because melanin serves as an effective sunscreen, thus putting them at risk for vitamin D, as well as calcium, insufficiency.10

Photobiology and Metabolism of Vitamin D

The initial step in the photochemical production of vitamin D occurs when solar ultraviolet B radiation (UVB; 290-315 nm wavelength) penetrates the skin to convert the precursor 7-dehydrocholesterol in the epidermis to previtamin D3, which is then thermodynamically converted to vitamin D3. This UVB-mediated cutaneous synthesis does not cause vitamin D intoxication because any excess vitamin D or previtamin D is converted to biologically inert photoproducts. Additionally, epidermal cells can produce the active 1,25(OH)2D locally, which can regulate cellular differentiation and melanin production, and provides negative feedback to modulate further vitamin D cutaneous production.

Dietary and cutaneously derived vitamin D, complexed to chylomicrons, is absorbed and transported via lymphatics to the venous system or to adipose depots. In the circulation, vitamin D3 undergoes enzymatic modification (by hepatic D-25 hydroxylase) to 25(OH)D, the major circulating form of vitamin D. This inactive form is then converted in the kidneys (via the 25-hydroxyvitamin D-1 alpha hydroxylase enzyme) to the biologically active form, 1,25 dihydroxycholecalciferol [1,25(OH)2D]. This rate-limiting step is tightly controlled by a variety of factors including serum parathyroid hormone (PTH) and phosphorus.6

The ratio of the total serum concentrations of the two major vitamin D metabolites, 25(OH)D and 1,25(OH)2D, is about 1,000:1. The 25(OH) vitamin D is used clinically to determine vitamin D status. Its long half-life of two weeks makes it suitable as a biomarker of vitamin D reserves.9 Serum 1,25(OH)2D values do not correlate with clinical disease status; therefore, information on serum 1,25(OH)2D concentration is not useful for clinical diagnosis and treatment.6

Vitamin D and Calcium Homeostasis

The active vitamin D metabolite, 1,25(OH)2D, is one of the primary biologic regulators of calcium homeostasis and is more technically a steroid hormone. It is believed to function in a similar fashion as other steroid hormones by binding with the vitamin D receptor (VDR), resulting in its biological effects on the kidney (down-regulates its own production), small intestine (increases the efficiency of calcium absorption), parathyroid glands (modulates PTH release), and on the bony skeleton (increases the mineral content) to regulate calcium and phosphorus blood levels.

Classification and Causes of Vitamin D Deficits in Geriatric Patients

The prevalence of vitamin D deficiency, 25(OH)D levels < 20 ng/mL or 50 nmol/L, is 41% in outpatients aged 49-83 years and up to 57% in hospitalized patients.11,12 Certain medical conditions can cause or exacerbate vitamin D deficiency in the elderly (see Table 2).13-17

Patients with osteoporosis are vulnerable to vitamin D inadequacy. As a matter of fact, 52% of postmenopausal women receiving osteoporosis medications have vitamin D insufficiency (levels < 30 ng/mL or 75 nmol/L) and, therefore, do not obtain the maximal benefit from their medications.18 Patients with severe vitamin D deficiency, 25(OH)D levels < 10 ng/mL (25 nmol/L), have concomitant osteomalacia (defective mineralization of the skeletal osteoid matrix) and this condition causes generalized musculoskeletal pain, which may be misdiagnosed as fibromyalgia. Evaluation of the 25-hydroxyvitamin D status of such patients can provide a basis for treatment.

Degrees of immobility are important factors that affect skeletal, as well as general, health in geriatric (and other) populations. Sorva et al demonstrated that supplementation for very low levels of vitamin D (< 12 ng/mL or 15 nmol/L) slightly improved PTH levels but neither the increased vitamin D levels or the decreased PTH levels affected serum calcium levels or carboxyterminal crosslinked telopeptide of type I collagen levels (marker of bone resorption) in immobilized geriatric patients. Such observations suggest that interventions aimed at increasing physical mobility may augment the effects of vitamin D supplementation on skeletal health in addition to the other medical benefits of increased mobility for this population.19

Assessment of Vitamin D Status

When vitamin D levels are inadequate, calcium and phosphorus homeostasis is impaired. A panel of experts has determined that the optimal range of circulating 25(OH)D concentrations for optimal skeletal health: 1) reduces serum PTH levels to a minimum maintained level (approximately 20 pg/mL), and 2) increases intestinal calcium absorption to its maximal level (approximately 30-40% of dietary intake). This range of 25(OH)D blood levels is 30-40 ng/mL (75-100 nmol/L).20

Additionally, Lappe et al, in a 4-year prospective, population-based, double-blind, placebo-controlled trial of 1,180 white postmenopausal women (age > 55 years), found a decreased (nonskin) all-cancer (breast, colon, lung, uterus, hematopoetic) risk with improvement in vitamin D status to > 80 nmol/L.21

Candidates for Vitamin D 25(OH) Screening

Screening measurements of vitamin D 25(OH) levels are advised for all patients who are homebound or institutionalized, as well as patients who have known or are evaluated for osteoporosis. Patients with known impaired absorption and those with a medical risk factor listed in Table 2 are candidates for screening as well. Thus, it could be argued that all elderly patients, particularly elderly female patients, should be screened.

Consequences of Vitamin D Deficiency

Vitamin D deficits in adults diminish the efficiency of intestinal calcium absorption, which causes ionized calcium to drop, triggering PTH release. The secondary hyperparathyroidism stimulates osteoblast-mediated osteoclast activity, resulting in increased bony resorption with concomitant diminished bone mineral density (osteoporosis) and stability of the osteoid matrix (osteomalacia) with increased risk for fragility fractures and diffuse musculoskeletal pain and dysfunction.6

Dietary Epidemiologic Data for U.S. Geriatric Population

According to NHANES III data, less than 10% of older adults (51-70 years of age) and 2% of the elderly (older than age 70) population met vitamin D requirements from dietary (food plus supplement) sources alone. Unfortunately, a follow-up study of the serum 25(OH)D status of the U.S. population from 2000 to 2004 demonstrated decreased levels of 5-9 nmol/L in comparison to NHANES III, particularly in a subgroup of white non-Hispanic males, despite adjustment for changes in assay measurements. This suggests that older men and women remain at risk for osteoporosis, osteomalacia, and significant disability from fragility fractures (osteoporotic or low-trauma fractures typically involving the distal radius, hip, and vertebral bodies).22

Fragility Fractures and Vitamin D

Approximately 30 million adults in the United States have osteoporosis of the hip. Hip fractures are the most serious and expensive of the fragility fractures and the risk increases exponentially with age. A Cochrane Review reported that 50% of osteoporotic fractures are nonvertebral and falls are the primary reason for these fractures.23 Thirty percent of persons older than age 65 and 50% of persons older than age 80 fall each year. Such falls cause injuries that result in disability, loss of independence, and subsequent admission to a nursing home.24-26

Randomized trials27 and population studies of elderly persons all found a significantly decreased incidence of hip fracture over several years of follow-up, provided serum hydroxyvitamin D levels were approximately 70 nmol/L (30 ng/mL) or greater.28-30 Interestingly, Gerdhem et al also found a correlation of levels of 25-hydroxyvitamin D ≤ 50 nmol/L (20 ng/mL) with significantly decreased gait speed, Romberg balance test, and thigh muscle strength, all of which may have contributed to the two-fold increase in risk of fracture compared to women with 25(OH) vitamin D levels of 75 nmol/L (30 ng/mL) or greater. The RECORD trial showed no antifracture efficacy for patients receiving 800 IU of vitamin D daily; however, the mean 25(OH) vitamin D levels increased from 15.2 to 24.8 ng/mL, which is below the threshold levels that provide antifracture efficacy.31

Neuromuscular Benefits from Vitamin D Supplementation

There is support from clinical studies that vitamin D insufficiency contributes to age-related muscle weakness with decreased physical performance32 and falls.33 Vitamin D appears to stimulate muscle cell growth through the binding of the active 1,25 dihydroxyvitamin D metabolite to a specific vitamin D nuclear receptor in muscle tissue. Sorensen et al noted an increased number and size of type II (fast twitch) muscle fibers of elderly women after only three months of therapy.34,35

Another study provided additional support for the beneficial effect of vitamin D supplementation on muscle function. Pfeifer et al conducted a 20-month double-blind controlled trial of 242 ambulatory, healthy men and women older than age 70 treated with calcium (1,000 mg) alone or in combination with vitamin D (800 IU) and found a significant decrease in falls for the calcium plus vitamin D group [mean 25(OH)D levels after treatment, 84 nmol/L or 33.5 ng/mL]. Additionally, functional kinesthetic improvements, such as an 8% increase in quadriceps strength and an 11% decrease in the time to perform the up and go test (TUG), were seen only in the calcium plus vitamin D group.36

Considerations for Over-the-Counter Vitamin D Supplements

The selection of supplements with the USP (United States Pharmacopoeia) Dietary Supplement Verification Program certification logo insures that the product contains the amount of vitamin D specified on the label and is free of contaminating substances such as lead.37 Since neither the FDA nor other federal or state authorities routinely test over-the-counter vitamin D or calcium supplements for quality issues, it is important to identify and use products that have been independently tested by laboratories such as ConsumerLab.com.38 ConsumerLab tests products for: content (verification of the amount of calcium and vitamin D indicated on the label); purity (the product is not contaminated with lead or other substances that may pose health problems); and absorbability (the product is formulated for efficient absorption from the gut).

Dosages for Geriatric Patients: Vitamin D

It is most cost-effective to use vitamin D3 (cholecalciferol) or vitamin D2 (ergocalciferol) supplements for patients adherent to vegetarian or vegan diets. Some studies have indicated diminished potency (less than one-third that of D3) and duration of action for D2 supplements,39,40 whereas other studies have shown relative equipotency.41

Vitamin D3 is available in 400, 1,000, 5,000, and 50,000 IU capsules and D2 is available as 400 IU and 50,000 IU capsules. Clinical studies showed a threshold effect for vitamin D: A minimal dose of vitamin D of 700-800 IU/d alone42,43 or in combination with at least 500 mg/d of calcium was effective in significantly reducing fracture risk,44 whereas a dose of 400 IU/d was not effective at preventing falls in the elderly,45 or reducing the risk of fragility fractures.46,47

Initial treatment of vitamin D deficiency, 25(OH)D < 20 ng/mL (50 nmol/L), requires 50,000 IU of vitamin D2 or D3 orally once per week for 6-8 weeks, followed by 800-1,000 IU vitamin D3 daily. Serum 25(OH)D levels should be checked after the initial 8 weeks.

The recommended dosage for nutritional vitamin D insufficiency, 25(OH)D levels of 20-30 ng/dL or 50-75 nmol/L, is 800-1,000 IU vitamin D3 daily, which will normalize levels in the average adult over a period of three months, though individual patients may need higher doses.48

In malabsorptive states, higher dosages (10-50,000 IU D2 or D3) or treatment with hydroxylated vitamin D metabolites such as calcitriol may be necessary.15

Vitamin D Metabolites

Calcidiol (25 hydroxyvitamin D) and calcitriol (1,25-dihydroxyvitamin D) are available in capsules. Calcitriol is readily available in the United States in capsules of 0.25 and 0.5 mg and is most useful in patients with decreased synthesis of 1,25(OH) vitamin D, such as those with chronic renal failure.49

Monitoring

It is important to monitor progress and compliance with vitamin D supplementation with serum 25 hydroxyvitamin D levels because the reduction in fracture incidence occurs when mean serum concentrations exceed 75 nmol/L (about 30 ng/mL) and this change may result from both improved bone health and greater muscle strength.20

25(OH) vitamin D serum concentrations should be measured approximately three months after initiation of therapy and the dosage should be adjusted accordingly.48

Patients on calcitriol with diminished renal function must be monitored for serum calcium and phosphorus levels.49

Concomitant Calcium Intake

Vitamin D exerts its effect on bone predominantly by increasing the intestinal absorption of calcium. Bone effects will only become significant if there is an adequate amount of calcium intake; therefore, vitamin D should always be combined with adequate amounts of calcium. It is recommended that patients older than age 50 should maintain a calcium intake of at least 1,200 mg/d. Patients with malabsorption may require higher calcium intake.15,50

Toxicity

Since vitamin D is a fat-soluble vitamin and is stored in adipose tissue, the possibility of intoxication with cumulative intake is of concern, though practically and pharmacologically, it would be rare. Heaney et al, in a pharmacokinetic study of vitamin D supplementation, demonstrated that equilibrium levels of serum 25(OH)D increased with oral dosing of D3 by 0.7 nmol/L for every microgram (1 mg = 40 IU) of vitamin D3 per day. Even though patients with severely decreased 25(OH)D levels can achieve a much greater increase with values up to 2-2.5 nmol/L per microgram of vitamin D per day, patients can be safely supplemented with 800 IU of vitamin D daily as recommended in clinical studies.51

Of note is the fact that, for patients with sarcoidosis and other granulomatous diseases, optimal levels of 25(OH)D should be in the range of 20-30 ng/mL (50-75 nmol/L) due to autonomous elaboration of the active 1,25 dihydroxyvitamin D by macrophages.52 Additionally, thiazide diuretics in an antihypertensive regimen may result in symptomatic hypercalcemia in combination with calcium and vitamin D supplementation.53

Conclusions

Vitamin D plays an important role in overall general health due to its broad endocrine and paracrine functions, particularly with regard to musculoskeletal health. Serum levels of 25(OH)D convey important information regarding body stores and clinical studies in geriatric patients have established guidelines for these levels based upon improvements in muscle strength, balance, and decreased incidence of falls and fragility fractures.

Recommendations

All geriatric patients should have an assessment of serum 25 hydroxyvitamin D levels as part of their general periodic evaluations. Vitamin D deficient and insufficient states need to be treated with high-dose vitamin D3 to optimize physical function, prevent fractures, and prevent decline in quality of life. Serum levels in the 30-40 ng/mL (75-100 nmol/L) range should be maintained with at least 700-800 IU/d of dietary vitamin D in conjunction with sensible exposure to sunlight to prevent photoaging and skin cancer. Regular physical activity and oral vitamin D intake are important adjunctive measures to optimize physical performance and quality of life for geriatric patients. Vitamin D requirements may need to be customized for individual patients depending upon their medications and medical conditions.

References

1. Lips P, et al. A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: Baseline data from the Multiple outcomes of Raloxifene Evaluation Clinical Trial. J Clin Endocrinol Metab 2001;86:1212-1221.

2. Simonelli C, et al. Prevalence of vitamin D inadequacy in a minimal trauma fracture population. Curr Med Res Opin 2005;21:1069-1074.

3. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463-1470.

4. Holick MF, et al. Age, Vitamin D and solar ultraviolet. Lancet 1989;1:1104-1105.

5. Holick MF, Garabedian M. Vitamin D: Photobiology, metabolism, mechanism of action and clinical applications. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006:129-137.

6. Holick MF. High prevalence of vitamin D inadequacy and implications for health. Mayo Clin Proc 2006;81:353-373.

7. Chen TC. Photobiology of vitamin D. In: Holick MF, ed. Vitamin D: Molecular Biology, Physiology and Clinical Applications. Totowa, NJ: Humana Press; 1999:17-37.

8. Clemens TL, Henderson SL. Increased skin pigment reduces the capacity of the skin to synthesize vitamin D3. Lancet 1982;1:74-76.

9. Sato Y, et al. Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure in hospitalized, elderly women with Alzheimer's disease: A randomized controlled trial. J Bone Miner Res 2005;20:1327-1333.

10. Kyriakidou-Himonas M, et al. Vitamin D supplementation in postmenopausal black women. J Clin Endocrinol Metab 1999;84:3988-3990.

11. Thomas MK, et al. Hypovitaminosis D in medical inpatients. N Engl J Med 1998;338:777-783.

12. Malabanan A, et al. Redefining vitamin D insufficiency. Lancet 1998;351:805-806.

13. Snijder MB, et al. Adiposity in relation to vitamin D states and parathyroid levels: A population-based study in older men and women. J Clin Endocrinol Metab 2005;90:4119-4123.

14. Leif M, et al. Effect of thyroid on bone and mineral metabolism. Endocrinol Metab Clin N Am 1990;19:35-63.

15. Bernstein CN, et al. American Gastroenterological Association technical review on osteoporosis in gastrointestinal diseases. Gastroenterology 2003;124:795-841.

16. Scharia SH, et al. Alfacalcidiol vs plain vitamin D in inflammation induced bone loss. J Rheumatol Suppl 2005;76:26-32.

17. Pack A. Bone health in people with epilepsy: Is it impaired and what are the risk factors? Seizure 2008;17:181-186.

18. Holick MF, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90: 3215-3224.

19. Sorva A, et al. Serum ionized calcium, intact PTH and novel markers of bone turnover in bedridden elderly patients. Eur J Clin Investig 1994;24:806-812.

20. Bischoff-Ferrari HS, et al. Estimation of optimal serum concentrations of 25 hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006;84:18-28.

21. Lappe JM, et al. Vitamin D and calcium supplementation reduces cancer risk: Results of a randomized trial. Am J Clin Nutr 2007;85:1586-1591.

22. Looker AC, et al. Serum 25-hydroxyvitamin D status of the US population: 1988-1994 compared with 2000-2004. Am J Clin Nutr 2008;88:1519-1527.

23. Gillespie LD, et al. Interventions for preventing falls in elderly people. Cochrane Database Syst Rev 2003;(4): CD000340.

24. Tinetti ME, Williams CS. Falls, injuries due to falls, and the risk of admission to a nursing home. N Engl J Med 1997;337:1279-1284.

25. O'Loughlin JL, et al. Incidence of and risk factors for falls and injurious falls among the community-dwelling elderly. Am J Epidemiol 1993;137:342-354.

26. Ray NF, et al. Medical expenditures for the treatment of osteoporotic fractures in the United States in 1995: Report form the National Osteoporosis Foundation. J Bone Miner Res 1997;12:24-35.

27. Bischoff-Ferrari HA, et al. Fracture prevention with vitamin D supplementation: A meta-analysis of randomized controlled trials. JAMA 2005;93:2257-2264.

28. Looker AC, Mussolino ME. Serum 25 hydroxyvitamin D and hip fracture risk in older US white adults. J Bone Miner Res 2008;23:143-150.

29. Cauley JA, et al. Serum 25 hydroxyvitamin D concentrations and risk for hip fractures. Ann Intern Med 2008; 149:242-250.

30. Gerdhem P, et al. Association between 25 hydroxyvitamin D levels, physical activity, muscle strength and fractures in the prospective population based OPRA study of elderly women. Osteoporos Int 2005;16:1425-1431.

31. Grant AM, et al. Oral vitamin D and calcium for secondary prevention of low trauma fractures in elderly people (Randomized Evaluation of Calcium or Vitamin D, RECORD): A randomized, placebo-controlled trial. Lancet 2005;365:1621-1628.

32. Zamboni M, et al. Relation between vitamin D, physical performance and disability in elderly persons. J Gerontol Med Sci 2002;57A:M7-M11.

33. Bischoff HA, et al. Effects of vitamin D and calcium supplementation on falls: A randomized controlled trial. J Bone Miner Res 2003;18:343-351

34. Sorensen OH, et al. Myopathy in bone loss of aging: Improvement by treatment with 1 alphahydroxycholecalciferol and calcium. Clin Sci (Lond) 1979;56:157-161.

35. Bischoff HA, et al. In situ detection of 1,25 dihydroxy D3 receptor in human skeletal muscle tissue. Histochem J 2001;33:19-24.

36. Pfeifer M, et al. Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals. Osteoporos Int 2009;20:315-322.

37. About USP-An Overview. Available at: www.usp.org/aboutUSP. Accessed Feb. 21, 2009.

38. Consumer Lab.com Product Review: Bone Supplements (Calcium and Vitamin D). Available at: www.consumerlab.com/results/review.asp?reviewid=calcium. Accessed Feb. 25, 2009.

39. Armas LA, et al. Vitamin D2 is much less effective than vitamin D3 in humans. J Clin Endocrinol Metab 2004;89: 5387-5391.

40. Romagnia E, et al. Short and long-term variations in serum calciotrophic hormones after a single very large dose of ergocalciferol (vitamin D2) or cholecalciferol (vitamin D3) in the elderly. J Clin Endocrinol Metab 2008; 93:3015-3020.

41. Holick MF, Biancuzzo RM. Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25(OH)D. J Clin Endocrinol Metab 2008;93:677-681.

42. Broe KE, et al. A higher dose of vitamin D reduces the risk of falls in nursing home residents: A randomized, multiple-dose study. J Am Geriatr Soc 2007;55:234-239.

43. Trivedi DP, et al. Effect of 4 monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: A randomized, double blind, controlled trial. BMJ 2003; 326:469.

44. Chapuy MC, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992;326: 1637-1642.

45. Graafmans WC, et al. Falls in the elderly: A prospective study of risk factors and risk profiles. Am J Epidemiol 1996;143:1129-1136.

46. Meyer HE, et al. Can vitamin D supplementation reduce the risk of fracture in the elderly? A randomized controlled trial. J Bone Miner Res 2002;17:709-715.

47. Lips P, et al. Vitamin D supplementation an fracture risk in elderly persons a randomized double blind controlled clinical trial. Ann Intern Med 1996:124:400-406.

48. Dawson-Hughes B, et al. Estimates of optimal vitamin D status. Osteoporos Int 2005;16:713-716.

49. Reichel H, Koeffler HP. Role of vitamin D endocrine system in health and disease. N Engl J Med 1989;320: 980-991.

50. Standing Committee on the Scientific Evaluation of Dietary Reference Intakes, Food and Nutrition Board of the Institute of Medicine. Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D and Fluoride. Washington DC: National Academy Press; 1997.

51. Heaney RP, et al. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204-210.

52. Adams JS, et al. Hypercalcemia caused by granuloma-forming disorders. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. Washington, DC: American Society for Bone and Mineral Research; 2006:200-202.

53. Crowe M, et al. Hypercalcemia following vitamin D and thiazide therapy in the elderly. Practitioner 1984;228: 312-313.