Vitamin D and Fracture Reduction: An Evaluation of the Existing Research

Vitamin D and Fracture Reduction:
An Evaluation of the Existing Research

This section is compiled by Frank M. Painter, D.C.
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FROM:   Alternative Medicine Review 2008 (Mar);   13 (1):   21–33 ~ FULL TEXT

Susan E. Brown, PhD, CNS

Osteoporosis Education Project and
Nutrition Education and Consulting Service,
Syracuse, NY, USA.

This article re-evaluates the literature on vitamin D and fracture reduction, highlighting the relevance of new understandings for fracture prevention. A new set of science-based research guidelines for clinical trials on vitamin D and fracture is proposed. The existing clinical trials on vitamin D and fracture are analyzed, focusing on studies that most closely meet the proposed guidelines. An estimation of the true fracture-reduction potential of therapeutic-level vitamin D supplementation is offered. The analysis outlined in this article leads to a series of striking conclusions. First, most of the available clinical trials and meta-analyses of vitamin D and fracture underestimate the true fracture reduction potential of vitamin D. Second, achievement of vitamin D serum sufficiency levels (now set in the United States, Europe, and many other places at a minimum of 32 ng per mL) could provide for a 50- to 60-percent fracture reduction. And third, providing for vitamin D sufficiency is the simplest, most life-supporting, and most cost effective means of significantly reducing the incidence of osteoporotic fractures worldwide. Given the urgent need, the Osteoporosis Education Project (OEP) has initiated a call for universal vitamin D repletion as the primary basis for osteoporotic fracture prevention worldwide.

Current Scientific Knowledge about Vitamin D and its Relevance to the Study of Vitamin D and Fracture Prevention

The Vitamin D Paradigm Shift

Extensive research over the past 20 years documents a remarkable “paradigm shift” in understanding of vitamin D. This new knowledge about vitamin D has significant implications for the study of vitamin D and fracture prevention. It is now generally recognized that the body utilizes much more vitamin D than previously thought. In 2003, Dr. Robert Heaney, noted bone health researcher, established that healthy individuals utilize approximately 3,000-4,000 IU of vitamin D daily. [6]

Despite sun-phobia engendered by fear of skin cancer, the vast majority of vitamin D is obtained from sunlight exposure. For most individuals, 80-90 percent of vitamin D requirement is cutaneously produced from sunlight. [6] Furthermore, sun exposure results in production of much more vitamin D than previously thought. Studies show that bathing suit exposure during summer, until skin just begins to turn pink, results in skin production of 10,000-50,000 IU of cholecalciferol. [7]

Unlike other vitamins, vitamin D is a hormone precursor. It is known that vitamin D is produced in the skin and hydroxylated in the liver to produce 25-hydroxyvitamin D (25(OH)D), and further hydroxylated in the kidney to form the active hormone, 1,25-dihydroxyvitamin D3 (1,25(OH2)D). In addition, it is now known vitamin D can be converted into the active hormone by many tissues in addition to the kidney, and this active vitamin D hormone (1,25(OH2)D) plays many more roles within the human body than previously known. Vitamin D has long been known to control calcium and phosphorus absorption. It is also now known to be important in the control of cell proliferation, the promotion of cell differentiation, and the down-regulation of hyperproliferative cell growth, all of which protect from cancers. Vitamin D also enhances immunity, protects against inflammation, is cardio-protective, and is preventive of autoimmune conditions. [8-11]

New Insights into Vitamin D and Bone Health

In regard to bone health, there are many manifestations of vitamin D deficiency/insuffi ciency beyond rickets, the classic disease of vitamin D deficiency. Suboptimal calcium absorption, secondary hyperparathyroidism, increased bone resorption, decreased muscle strength, and increased risk of falling can be vitamin D deficiency/insuffi ciency disorders that increase fracture risk.

Research has quantified the blood level of vitamin D required for normalization of parathyroid hormone and optimum calcium absorption. Low vitamin D leads to decreased calcium absorption and lower blood calcium levels, which in turn causes an increase in parathyroid hormone. Rising parathyroid hormone stimulates bone breakdown to liberate calcium for transfer into the blood. This response to low vitamin D stabilizes blood calcium at the expense of bone. Studies in both the United States and Europe have found serum 25(OH)D levels of 32 ng/mL are needed to normalize parathyroid hormone and optimize calcium absorption. [12-16]

The amount of vitamin D necessary for normalization of parathyroid hormone and optimization of intestinal calcium absorption has also been quantified. Heaney demonstrated calcium absorption performance was 65-percent higher at serum vitamin D levels averaging 34 ng/mL than with lower vitamin D levels.

In a vitamin D-deficient state the small intestine absorbs no more than 10-15 percent of dietary calcium; whereas, in a vitamin D-suffi cient state, 30-40 percent of ingested calcium is absorbed.6 It should also be noted that researchers have documented cases where 48 ng/ mL vitamin D was unable to normalize bone-damaging high parathyroid hormone levels. [17]

Research has quantified the blood level of vitamin D required for normalization of muscle strength and coordination. Vitamin D inadequacy leads to impaired musculoskeletal functioning, poor coordination, and increased risk of falling. Lower extremity neuromuscular function improves as serum 25(OH)D increases, up to at least the therapeutic range achieved in the more successful trials. [12,18,19] Clinical trials reaching suffi ciency levels show a rapid reduction in fracture incidence, likely attributable in part to a rapid reduction in falls.

A rapid reduction in falls has been observed among elderly in long-term care with the administration of 800 IU vitamin D. Broe et al reported a 72- percent reduction in falls in an elderly population after five months of treatment with 800 IU vitamin D.20 In a previous study, Bischoff-Ferrari et al found a 49-percent reduction in falls among geriatric-care elderly women using a combination of 800 IU vitamin D3 and 1,200 mg calcium carbonate compared to those given 1,200 mg calcium carbonate without vitamin D. [18]

In osteoporotic fracture, vitamin D deficiency is the rule, not the exception. For example, a Minnesota hospital study of 82 minimal-trauma fracture patients ages 52-97 found 97 percent of the fractures were hip fractures and all but two patients had deficient vitamin D status (less than 30 ng/mL).21 In a large British study, vitamin D deficiency was found in 95 percent of hip-fracture patients [22] and 78 percent of hip-fracture patients in a Boston study were vitamin D deficient. [23] Findings such as these have led some researchers to suggest vitamin D level is the best predictor of fracture risk. [24]

Vitamin D Requirements Revisited

The amount of vitamin D supplementation or sunlight exposure needed to achieve minimum vitamin D suffi ciency (commonly defined as a 32 ng/mL 25(OH)D blood level) depends on many factors and can vary significantly from individual to individual. Thus, the requirement for vitamin D supplementation needs to be individualized. Variables influencing vitamin D requirement are summarized in Table 1.

Table 1. Variables Influencing Vitamin D Requirements
Sunlight exposure
Skin pigmentation
Baseline vitamin D level
Intestinal absorption rates
Type of vitamin D supplement (D3 is 3x more potent than D2) Age (with age there is a reduced photoconversion of 7-dehydrocholesterol to vitamin D)
Genetic variation in vitamin D receptor activity

On average, the amount of vitamin D supplementation required to reach a therapeutic vitamin D blood level is higher than previously thought. If 32 ng/ mL 25(OH)D blood level is accepted in the United States as the necessary minimum for preventing bone loss, a minimum daily intake of 2,600 IU of vitamin D3 would meet the needs of 97 percent of U.S. residents. [12] The current governmental Adequate Intake (AI) level for vitamin D is far below this at 400 IU for adults ages 51-70 and 600 IU for adults over 70. A 2,600 IU intake also exceeds the official “lowest observed adverse effect level” (LOAEL) of 2,000 IU established by the U.S. Food and Nutrition Board.

Supplementation with 400 IU vitamin D has repeatedly been found to have no impact on fracture incidence. Supplementation with 800 IU vitamin D has been proven moderately effective for fracture reduction. The recent Bischoff-Ferrari et al meta-analysis of fracture prevention with vitamin D demonstrated this point. The pooling of 12 major studies showed supplementation with 400 IU vitamin D daily failed to influence fracture incidence, while 700-800 IU daily reduced hip fracture by 26 percent and all fractures by 23 percent. 25 Similar meta-analysis results were reported by Tang et al. [26] The fracture reduction potential of higherdose sufficiency level vitamin D has not been tested.

Vitamin D at an 800 IU daily dose results in minimum suffi ciency levels of serum vitamin D (32 ng/ mL) in some, but not all, subjects. Thus, studies using 800 IU dosages will not bring all participants to a suf- ficiency level of vitamin D. For example, the multi-year British RECORD trial intervention using 800 IU vitamin D for older adults raised vitamin D blood levels to an average of 24.8 ng/mL.27 In a Swiss study, average vitamin D levels increased from 12.3 ng/mL to 26.2 ng/mL in ambulatory elderly given 800 IU D3 daily for three months. [18] In both cases, vitamin D levels achieved were well below the effective therapeutic threshold of 32 ng/mL. Osteoporosis researcher Bischoff-Ferrari estimates 700-1,000 IU vitamin D supplementation for eight weeks will result in less than half of average healthy adults achieving serum vitamin D levels of 30 ng/mL. [14]

Extra-Skeletal Benefits of Vitamin D

A plethora of new research suggests the same blood level of vitamin D suffi ciency found to prevent fracture (=32 ng/mL) also reduces the risk of other health afflictions. For several years researchers have noted strong evidence for a protective effect of vitamin D on a variety of disorders, including muscle weakness, numerous cancers, multiple sclerosis, and diabetes. [9] Garland et al estimated from known data points that 50 percent of colon cancer incidence in North America could be prevented by maintenance of a serum 25(OH) D level =34 ng/mL. Furthermore, they project a 30- percent reduction in breast cancer incidence in North America with lifelong maintenance of serum 25(OH)D levels equal to or above 42 ng/mL. [31]

In addition to colon and breast cancer, an inverse association between serum vitamin D concentration and the risk of various other cancers, including ovarian cancer and prostate cancer, has been documented. 32 Recently, William Grant, PhD, director of the Sunlight Nutrition and Health Research Center, compiled 651 papers on vitamin D and cancer and tabulated data on 28 cancers reported to be UVB/vitamin D sensitive in observational studies (W. B. Grant, SUNARC, San Francisco, private communication). In 2007, Lappe et al reported the findings of the first intervention trial examining vitamin D and cancer. In this four-year, population-based, double-blind, randomized, placebo controlled trial, postmenopausal women given 1,100 IU vitamin D experienced a 60- to 77-percent reduction in the risk of developing any type of cancer. [33]

New evidence has accumulated that vitamin D sufficiency plays an important role in immune competence, specifically in the innate immune system. [34] Verifying this, a recent three-year study of postmenopausal African-American women found vitamin D supplementation (800 IU/day for two years and then 2,000 IU/ day for the third year) reduced the incidence of colds and influenza by more than two-thirds. [35]

Extent of Vitamin D Deficiency

  • Vitamin D deficiency is widespread. It was recently established that at least one billion people worldwide are vitamin D deficient. [36]

  • Two-thirds of postmenopausal women studied in rural Nebraska had vitamin D levels below 32 ng/ mL. [37]

  • In a Boston area study of women and men ages 65 and over, more than 90 percent had vitamin D levels below that required for optimum parathyroid hormone control. [17]

  • Vast numbers of children are vitamin D deficient. For example, in Maine, 48 percent of Caucasian girls ages 9-13 were vitamin D deficient at the end of winter and 17 percent were still deficient at the end of summer. [38]

  • More than one-half of African-Americans in the United States are either chronically or seasonally at risk of vitamin D deficiency. Melanin skin pigmentation absorbs vitamin-D-producing UVB radiation; thus, a dark-skinned person needs six times more sun exposure to produce the same amount of vitamin D as a lighter-skinned individual. [8]

  • In Boston, 52 percent of African-American and Hispanic adolescent boys and girls are vitamin D deficient throughout the year. [39]

  • The vitamin D status of 57 percent of Massachusetts General Hospital patients studied in 1998 was below the adequate, healthful level. [40]

  • At Boston Medical Center, 32 percent of students and doctors ages 18-29 were vitamin D deficient at the end of winter. [41]

  • Up to 90 percent of UK elderly and 86 percent of elderly Swiss are known to be vitamin deficient. [36]

  • In Saudi Arabia, serum vitamin D concentrations in young people are very low, ranging from 2.4 ng/mL to 19.3 ng/mL. [42]

  • In New Delhi, a study of 760 children from lower and upper economic sectors found the mean vitamin D level to be 11.8 ng/mL, indicating a high degree of vitamin D insufficiency among Indian school children. [43]

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