What lies behind the vitamin D revolution?

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Rickets is caused by a deficiency of vitamin D, which is required for normal calcium absoprtion.
Rickets is caused by a deficiency of vitamin D, which is required for normal calcium absoprtion.

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At a glance

  • Vitamin D deficiency in childhood and adolescence impairs attainment of optimal bone mass.
  • A correlation between sunlight exposure and the incidence of viral upper respiratory infections has been observed.
  • Conditions that predispose a person to vitamin D deficiency include liver disease, chronic renal failure, and malabsorption syndromes.
  • Dietary sources of vitamin D are limited.

Generations of medical professionals have been taught to approach vitamin D supplementation with great caution and trepidation. As a fat-soluble vitamin known to enhance calcium absorption, vitamin D taken in excessive amounts was thought to raise the specter of hypercalcemia with its attendant risks of nephrolithiasis and even metastatic calcification. Our understanding of vitamin D's health benefits was limited to its familiar role in maintaining bone strength by means of regulating calcium uptake. But thanks to an explosion in vitamin D research, a broader perspective is rapidly evolving.

Powered by its pervasive influence on myriad physiological processes, vitamin D is staking its claim as "Nutrient of the Decade." We now recognize that vitamin D transcends the definition of a mere vitamin: It is actually a prohormone, and vitamin D receptors are expressed by cells in most organs, including the brain, heart, skin, gonads, prostate gland, and mammary glands. In the digestive tract and parathyroid glands, active vitamin D metabolites are responsible for calcium uptake. Vitamin D receptors are also involved in immune regulation and mediate response to infection and inflammatory processes. Additionally, the nutrient is associated with cell proliferation and differentiation.

Fracture prevention

Vitamin D's traditionally acknowledged role is in bone metabolism. The pathognomonic vitamin D deficiency disease is rickets, but less overt prolonged insufficiency results in osteomalacia. This condition is characterized by softening of the bones and musculoskeletal pain, the result of periosteal traction. Not surprisingly, an association between vitamin D repletion and relief of unexplained body aches has been observed in some studies.

Chronic vitamin D deficiency can result in secondary hyperparathyroidism with consequent osteoporosis. Vitamin D deficiency in childhood and adolescence impairs attainment of optimal bone mass. Frequently, clinicians neglect to assess vitamin D status and don't consider the treatment option of aggressive repletion when using drugs to manage osteopenia or osteoporosis. A new minimum threshold for vitamin D of 50-75 nmol/L (20-30 ng/mL) was recently proposed to prevent osteoporosis. However, vitamin D receptor polymorphisms modulate skeletal response to vitamin D supplementation even in healthy girls, and individual requirements for bone optimization may vary. A minimal threshold of 40 ng/mL for healthy bone metabolism has also been proposed.

The ultimate goal of osteoporosis treatment is fracture prevention. Considerable evidence suggests vitamin D can support muscle strength and thereby reduce the incidence of falls, particularly in elderly, at-risk patients. In addition, vitamin D arguably has an indirect role in staving off fractures: As a nondrug treatment for osteoporosis, the use of vitamin D reduces polypharmacy with various cardiovascular, anti-inflammatory, and psychiatric medications that can induce nutrient depletions and impair balance in frail seniors.

Cardiovascular disease

Vitamin D deficiency is associated with increased risk for cardiovascular events and mortality. In the Multi-Ethnic Study of Atherosclerosis, 25-hydroxyvitamin D (25[OH]D)levels were inversely associated with the risk of coronary artery calcification, a measure of coronary atherosclerosis.

Cardiovascular disease (CVD) represents the culmination of an array of predisposing influences, and vitamin D may intervene beneficially in several ways. Studies confirm an association between obesity and vitamin D deficiency, and low vitamin D status is predictive of insulin resistance. Overweight women replete with vitamin D shed pounds more successfully. Moreover, studies have found correlation between suboptimal vitamin D status and both hypertension and diabetes.

In renal disease, characterized by problematic vitamin D metabolism, CVD is rampant—but cardiovascular risk is known to be attenuated by vitamin D administration.

Evidence also indicates that vitamin D deficiency—common in elderly, debilitated patients—plays a role in congestive heart failure, which is mediated by the nutrient's effect on myocyte contractility.

Cancer

Sun exposure is clearly required for vitamin D sufficiency. However, latitude, season, time of day, weather conditions, shade, skin pigmentation, air pollution, clothing, use of sunscreen, and age impact cutaneous vitamin D activation. Below 32º latitude (corresponding to a line stretching from Los Angeles to Columbia, S.C.), sunlight exposure can activate vitamin D year-round. But above 44º north latitude (which extends from the northern tip of California to Boston), no cutaneous activation is possible from November through February.

It has long been noted that colon cancer rates increase with higher geographic latitude. This epidemiologic correlation was initially attributed to Western diet and lifestyle, but subsequent studies controlled for extraneous factors and confirmed the protective role of sunlight. Scientists were then able to establish the biological plausibility for the impact of vitamin D in cancer prevention, recognizing the vitamin's effects on cell proliferation, oncogenesis, and apoptosis. Since then, investigators have explored a putative involvement of vitamin D in both primary and secondary prevention of prostate cancer and breast cancer as well as non-Hodgkin's lymphoma, melanoma, and other malignancies.

Immunity

Cells involved in innate and adaptive immune responses —including macrophages, dendritic cells, T cells, and B cells—express the vitamin D receptor. In the 19th century, before the advent of antibiotics, caregivers recognized that individuals with TB could benefit from sunlight and fresh air during their stays in mountain sanitoria. Research has confirmed that host response to TB is partially mediated by vitamin D, and that vitamin D deficiency is associated with dysregulation of macrophage response.

The observed seasonal correlation between sunlight exposure and the incidence of viral upper respiratory infections has prompted speculation about the role played by vitamin D. Research confirms that vitamin D dramatically stimulates the expression of potent antimicrobial peptides. These compounds exist in neutrophils, monocytes, natural killer cells, and epithelial cells lining the respiratory tract, where they play a major role in protecting the lung from infection. The action of vitamin D serves as a key link between Toll-like receptor activation and antibacterial responses in innate immunity. An association between vitamin D insufficiency (25[OH]D <40 nmol/L) and acute respiratory tract infection was recently confirmed. As yet, prospective intervention studies are few and small in scale.

Autoimmunity

The incidence of certain autoimmune diseases correlates positively with latitude from the equator, as reflected by the epidemiology of rheumatoid arthritis, inflammatory bowel disease, type 1 diabetes, and multiple sclerosis (MS). Studies confirm that patients suffering from autoimmune disease have vitamin D levels below the international norm. There is substantial biological rationale for vitamin D as a cytokine modulator.

Animal models of autoimmune disease suggest a response effect with vitamin D administration; large human therapeutic trials using vitamin D are still lacking, but the first results of phase I/II studies are promising. Meanwhile, it is now acknowledged that administering vitamin D in patients with autoimmune diseases is justifiable.

Other conditions

Perhaps the most persuasive rationale for considering vitamin D optimization comes from a study of 3,400 French men, age 50 years and older, correlating vitamin D status with all-cause mortality. Men in the lowest quartile of 25(OH)D levels had a 44% higher death rate. The authors qualified their findings by stating that although the study controlled for lifestyle variables and comorbidities, a possibility exists that low levels of vitamin D are merely reflective, and not causative, of poor health status.

Because of the ubiquity of the nutrient's impact on physiologic processes, some researchers have proposed associations between vitamin D status and incidence of autism, allergic diseases, depression, schizophrenia, cognitive impairment, pre-eclampsia, fibromyalgia, Parkinson disease, polycystic ovary syndrome, and benign prostatic hyperplasia. Athletic trainers, cognizant of research suggesting that vitamin D may augment muscle strength, are increasingly embracing oral supplementation and UV-light exposure for purposes of performance enhancement.

Of course, a long-observed relationship between sunlight exposure and severity of psoriasis suggests mediation by vitamin D; topical calcipotriene (Dovonex), a synthetic vitamin D analogue, is a standard dermatologic treatment for the condition.

Vitamin D has received renewed interest for its role in pregnancy. Studies suggest that higher levels of vitamin D supplementation than are currently recommended for pregnant women may safeguard offspring from the risks of low birth weight, autism, juvenile diabetes, asthma and allergic rhinitis, and infectious diseases. The Canadian Pediatric Society recently recommended that pregnant women increase their intake of vitamin D to 2,000 IU/day.

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