The High Prevalence of Inadequate Serum Vitamin D Levels and Implications for Bone Health

Jean-Yves Reginster

Curr Med Res Opin. 2005;21(4):579-585. 

Abstract and Introduction

Background: Inadequate serum vitamin D is associated with secondary hyperparathyroidism, associated with secondary hyperparathyroidism, increased bone turnover, and bone loss, which increased bone turnover, and bone loss, which increase fracture risk. Osteomalacia has also been increase fracture risk. Osteomalacia has also been observed in severe cases. Indeed, vitamin D and observed in severe cases. Indeed, vitamin D and calcium are essential components of management calcium are essential components of management strategies for the prevention and treatment of strategies for the prevention and treatment of osteoporosis. Despite this, many people currently do osteoporosis. Despite this, many people currently do not have adequate vitamin D levels. This problem has been documented in many studies around the world, regardless of age, health status, or latitude, and is especially common among older adults, who are also likely to have osteoporosis. Factors that contribute to low vitamin D include low exposure to sunlight, decreased synthesis in skin and reduced intestinal absorption related to aging, and limited dietary sources. Supplementation is the most effective means of correcting poor vitamin D nutrition. However, few patients with osteoporosis currently take sufficient vitamin D supplements.
Scope: This review article discusses the role of vitamin D in osteoporosis and skeletal health, and summarizes what is known about the high prevalence of inadequate serum vitamin D and recommendations for supplementation.
Conclusion: Greater awareness of the importance of vitamin D for skeletal health and more aggressive supplementation efforts are urgently needed to address this important public health problem.

Introduction

Osteoporosis is a chronic, progressive disease characterized by reduced bone mass and microarchitectural deterioration of bone. It is highly prevalent, affecting approximately one-third of women aged 60-70 years, and two-thirds of those aged 80 years and older - roughly 200 million women worldwide.[1] It is the major cause of fractures - the most serious clinical consequence of osteoporosis - in middle-aged and elderly adults. An estimated 40% of women and 13% of men aged 50 years and older will sustain an osteoporotic fracture in their remaining lifetime[2]; however, these figures likely underestimate future risk because they are based on the assumption that life expectancy will remain stable. When accounting for future mortality trends, these fracture estimates rise to 47% for women and 22% for men.[3]

Fractures have a profound impact on quality of life. Approximately 20%-25% of women over age 50 years have had one or more vertebral fracture, the most common osteoporotic fracture.[1] They are associated with back pain, height loss, deformity and immobility. Hip fracture is often devastating, leading to chronic pain, reduced mobility, disability and loss of independence. In Europe and the US combined, more than 650 000 patients have hip fractures each year.[4] Both vertebral and hip fractures are associated with excess mortality. For instance, approximately 20% of hip fracture patients aged 50 years and older die within 1 year.[5]

Vitamin D and calcium are essential components of osteoporosis management strategies. Inadequate serum vitamin D is associated with secondary hyperparathyroidism, increased bone turnover, and bone loss; in severe cases, osteomalacia also occurs ( ). Despite these consequences, many people currently do not have adequate vitamin D levels. A high prevalence of inadequate vitamin D has been documented in many studies worldwide, regardless of age, health status, or latitude, but is especially common in older adults, who are also likely to have osteoporosis. This review article discusses the role of vitamin D in osteoporosis and skeletal health, and summarizes what is known about the high prevalence of inadequate serum levels of vitamin D and recommendations for supplementation.

  Consequences of Inadequate Serum Vitamin D Levels

Vitamin D and its Activation

Vitamin D was mistakenly classified as a vitamin based on early findings that cod liver oil prevented rickets in children; however, because of its nuclear receptor and ability to upregulate gene expression, vitamin D is actually a steroid hormone. Vitamin D consists of two similar molecules, vitamin D2(ergocalciferol) and vitamin D3(cholecalciferol), which differ insofar as vitamin D2has a double bond between C22 and C23 and a methyl group on C24 Dietary vitamin D is absorbed in the small intestine via the intestinal lymphatic system in the presence of bile acids. It is synthesized in skin via the conversion of provitamin D3(7-dehydrocholesterol) to vitamin D3by ultraviolet B (UVB) and heat.

Once absorbed in the gut or formed in the skin, vitamin D is hydroxylated in the liver to 25-hydroxyvitamin D [25(OH)D], which can accumulate in certain tissues - serum 25(OH)D reflects these stores, making it the most reliable indicator of vitamin D status. Some of the circulating 25(OH)D is subsequently converted to the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D], in the kidney. Thus, patients with impaired renal function may not effectively metabolize 25(OH)D and may benefit from treatment with low dose active vitamin D [1,25(OH)2D, calcitriol] or vitamin D analogues, recognizing that there is a narrow window of therapeutic efficacy versus toxicity.

Role of Vitamin D in Musculoskeletal Health

The active form has various important physiologic activities, such as upregulating intestinal calcium and phosphate absorption (Figure 1). When vitamin D levels are inadequate, calcium absorption is impaired and there is a compensatory increase in parathyroid hormone (PTH) levels. This results in increased bone resorption and accelerated bone loss[6,7] (Figure 1).

Pathophysiology of inadequate vitamin D and calcium intake. ECF = extracellular fluid

In addition to its role in calcium homeostasis, data from epidemiologic, clinical and laboratory studies suggest a direct effect of vitamin D on muscle strength. Receptors for 1,25(OH)2D have been identified in skeletal muscle tissue,[8-10] and low vitamin D levels have been associated with reversible myopathy in patients with osteomalacia.[11] Several studies have also demonstrated a correlation between low serum vitamin D and age-related muscle weakness,[12] musculoskeletal pain,[13] increased body sway,[14] increased risk of falls[14-18] and falls-related fractures.[14]

At present, there is no consensus on the optimal level of vitamin D; however, it has been suggested that serum 25(OH)D levels > 30 ng/mL are required for maximal calcium absorption and optimal health.[19,20] At progressively lower levels, consequences become more serious; osteomalacia has been observed at 25(OH)D levels < 8 ng/mL, and values < 20 ng/mL have been associated with decreases in bone density, decreases in intestinal calcium absorption, and decrements in lower extremity function.[21] Thus, inadequate levels of vitamin D and calcium are important risk factors for osteoporosis and fractures. Indeed, low serum 25(OH)D has been associated with low bone mineral density (BMD)[22] and hip fracture[23] in epidemiologic studies.

Factors Associated With Inadequate Serum Levels of Vitamin D

Sources of vitamin D are limited and include diet or synthesis in skin from exposure to ultraviolet light. Dietary sources of vitamin D are rare, and include oily fish and fish liver oil (e.g., salmon, mackerel, and cod) and fortified milk in the United States, although milk is not universally fortified with vitamin D in other countries.[24]

Synthesis of vitamin D in the skin can be hindered by factors which reduce ultraviolet light penetration and intensity, including sunscreen use, clothing, darkly pigmented skin, season and latitude. At high latitudes in the northern hemisphere, sunlight does not induce cutaneous production of vitamin D in the winter months[25]>; despite this, the prevalence of low serum 25(OH)D was lower in northern Europe than in southern Europe.[26] Similarly, a global study that investigated vitamin D status by geographic region in postmenopausal women with osteoporosis reported no apparent relationship between the prevalence of low serum 25(OH)D and latitude; in fact, the prevalence appeared to be increased at low latitudes, suggesting that other factors (e.g., supplement use, skin pigmentation, clothing, metabolism rate, dietary habits, etc.) may overwhelm the latitudinal association.[27]

Among the population at greatest risk for osteoporosis, multiple factors often contribute to inadequate serum levels of vitamin D ( ). These include dietary deficiencies, reduced intestinal absorption, and low endogenous vitamin D synthesis due to minimal exposure to sunlight, and decreased efficiency of the conversion of 7-dehydrocholesterol - the vitamin D3precursor - to pre-vitamin D in aging skin.[28-30] In addition, decreased renal conversion of 25(OH)D to 1,25(OH)2D has been reported in elderly patients with osteoporosis.[31]

  Factors That Contribute to Inadequate Serum Vitamin D Levels Among Older Adults

Given the factors described above, supplementation is often the simplest and most effective means of obtaining adequate vitamin D. Despite this, few patients with osteoporosis currently take vitamin D supplements. For instance, one study showed that most patients with hip fractures did not adhere to recommendations for vitamin D and calcium supplementation despite having received detailed information about their importance.[32] This may be because the tendency for adherence declines as the number of medications increases and older adults often consume a high number of doses of different medications each day. Additionally, although milk may be vitamin D fortified in some countries, milk drinking is not reliable among older adults, especially those with a high prevalence of lactose intolerance.

Benefits of Vitamin D Supplementation

Supplementation is an effective means of improving vitamin D status. In a recent 1-year, randomized, doubleblind, placebo-controlled trial, supplementation with vitamin D and calcium significantly increased BMD, increased serum 25(OH)D and significantly decreased serum intact PTH and biochemical bone remodelling markers in postmenopausal women ( n = 192) with low baseline serum vitamin D (< 12 ng/mL).[33] Another prospective study determined that supplementation with oral cholecalciferol (vitamin D,3 500 IU/day [12.5 µg]) and calcium (500 mg/day) prevented wintertime acceleration in bone turnover and bone loss in healthy adults.[34] These positive effects of vitamin D and calcium supplementation on BMD and bone turnover are similar to those previously reported in an institutionalized population with low serum vitamin D[35] and later in an ambulatory population of men and women.[36] Similarly, 400 IU vitamin D3(10 µg) daily improved vitamin D status in older adults, increased serum concentrations of 1,25-dihydroxyvitamin D - the physiologically active form of vitamin D - in subjects with low serum vitamin D, and reduced serum PTH levels.[37]

Although reductions in fracture risk during treatment with vitamin D in some studies (see below) were previously believed to be due primarily to skeletal effects including increases in BMD, several studies suggest that vitamin D might also increase muscle strength, reducing the risk of falls. The authors of a meta-analysis of randomized controlled trials - the highest level of evidence - concluded that supplementation with vitamin D reduced the risk of falls by more than 20% among elderly populations.[16] In a randomized, double-blind trial, treatment with daily vitamin D plus calcium for 3 months reduced the risk of falls by 49% versus calcium alone among institutionalized women.[17] A significant reduction in the risk of falls was also reported using a vitamin D analogue for 36 weeks in a study of community-dwelling older adults in Switzerland, in a subgroup with calcium intakes above 512 mg daily.[18] Similarly, a reduction in body sway and falls was observed with short-term (8 weeks) calcium and vitamin D supplementation versus calcium alone in postmenopausal women with osteoporosis.[14]

Several trials provide evidence that vitamin D supplementation helps reduce fracture risk, although some of these trials used supplements containing both vitamin D and calcium. One randomized trial reported that 800 IU vitamin D (20 µg) plus 1.2 g elemental calcium daily reduced the risk of hip fracture by 43% in institutionalized women with a high prevalence of low serum vitamin D and low calcium intake.[38] In a population-based, 3-year intervention study among 9605 older adults, the patients who received supplementation with 400 IU vitamin D (10 µg) plus calcium ( n = 4957) had a 16% reduction in fracture risk compared with those enrolled in a program to identify and correct potential dietary or environmental problems ( n = 5063).[39] A 22% reduction in hip, spine or wrist fractures was observed in a randomized, double-blind, placebo-controlled trial in community-dwelling adults in the UK who received 100 000 IU vitamin D3(2.5 mg) every 4 months for 5 years.[40] One large randomized controlled trial failed to find an effect on fracture risk for vitamin D alone; however, the lack of effect may have been because the population involved did not have a high prevalence of vitamin D deficiency.[41] Supporting evidence also comes from a large observational study of postmenopausal women, which found that the use of supplements containing vitamin D was associated with a lower risk of hip fracture, whereas milk and calcium intake were not.[23]

Prevalence of Inadequate Serum Vitamin D

Epidemiologic investigations document the continued and widespread high prevalence of inadequate serum levels of vitamin D among osteoporosis patients and the elderly. Very low serum 25(OH)D levels (< 10 ng/mL) are common among institutionalized patients[42]; however, several studies have found a high prevalence among community-dwelling or healthy, ambulatory older adults (Figure 2).[43] A recent cross-sectional study demonstrated that the prevalence of low 25(OH)D (< 20 ng/mL) in healthy postmenopausal women ( n = 319; mean age, 64.9 years) was 71% in spring.[44] Another study reported that 25(OH)D was undetectable (< 2 ng/mL) in 98% of elderly adults in Italy.[45] Most studies reported that the prevalence of low vitamin D was higher in women than in men. In most studies of older adults, the prevalence of low serum vitamin D (< 20 ng/mL) was higher than 30%, regardless of season,[46] gender,[26] latitude,[26] or race[47] (Figure 3).

Prevalence of 25(OH)D < 12 ng/mL in women over 70 years old, stratified by age group and residential status. From reference 43, with permission

Prevalence of 25(OH)D < 12 ng/mL among 824 elderly subjects aged 70-75 years in Europe, by latitude. Adapted from reference 26

Several studies have found that more than 50% of patients with osteoporosis have inadequate levels of vitamin D. A recent cross-sectional observational study demonstrated that up to 52% of North American women currently undergoing treatment for postmenopausal osteoporosis had suboptimal vitamin D levels, defined as serum 25(OH)D below 30 ng/mL.[48] Other studies have reported very low serum vitamin D - in the range associated with osteomalacia - among postmenopausal women with osteoporosis. The results of one study demonstrated that 32.8% of women with osteoporosis without fractures had vitamin D levels less than 20 ng/ mL and 5.5% had values less than 12 ng/mL.[49] Isaia and colleagues reported a 76% prevalence of low vitamin D (< 12 ng/mL) among women with osteoporosis in Italy.[50] In a global study of vitamin D status, low serum vitamin D (< 20 ng/mL) was reported in 28.4% of postmenopausal women with osteoporosis (Figure 4).[27]

Prevalence of 25(OH)D < 20 ng/mL among 7564 postmenopausal women with osteoporosis aged 31-80 years, by region. Adapted from reference 27

In patients with a history of fractures or falls, 97% had serum 25(OH)D levels below 30 ng/mL in one study[51] and 72.5% had vitamin D levels below 20 ng/mL in another.[52] In a US population, very low vitamin D levels (below 12 ng/mL) were observed in 50% of postmenopausal, free-living women hospitalized for acute hip fracture with no secondary causes of bone loss.[53] Similarly, studies from the United Kingdom and South Africa have found that 13%-33% of patients with hip fractures had histological evidence of osteomalacia that was potentially associated with chronic low vitamin D.[54-57]

Inadequate serum vitamin D is a global problem, irrespective of latitude. For example, a high prevalence of low vitamin D levels has been reported among older adults in North America (Canada and the United States), Scandinavia (Denmark, Finland, Norway, and Sweden) and Europe (Belgium, France, Germany, Ireland, The Netherlands, Switzerland, and the United Kingdom).[27] Among community-dwelling postmenopausal women with osteoporosis living in southern California, an example of a highly sunny climate, 53% had serum vitamin D levels < 30 ng/mL.[58] Inadequate serum vitamin D was also common among postmenopausal women living in Australia, with 42% having serum 25(OH)D less than 50 nM (20 ng/mL) and 10% having levels less than 28 nM (~10 ng/mL) during summer months; in the winter, the proportions increased to 51% and 14%, respectively.[59] A secondary analysis based on this study population demonstrated that the observed seasonal periodicity of serum vitamin D was associated with an increased proportion of falls resulting in fracture.[60]

Recommended Dose

The Institute of Medicine Adequate Intake (AI) for the United States and Canada is 400 IU (10 µg) daily for people age 70 years and under, and 600 IU (15 µg) daily for those over age 70 years.[61] The Scientific Committee for Food, established by the Commission of the European Communities, recommends 400 IU (10 µg) vitamin D3daily for elderly people, and suggested that this dose would meet the requirements of all adults, even those with suboptimal sunlight exposure.[62] Similarly, the United States Food and Drug Administration 'Daily Value' recommendation for vitamin D3is 400 IU (10 µg), irrespective of age.[63]

Vitamin D toxicity has not been reported from excessive sunlight exposure, and has only been associated with dietary intake when daily doses exceed 10 000 IU (250 µg).[64] Doses of 4000 IU (100 µg) daily and 50 000 IU (1.25 mg) weekly have been given without toxicity.[65,66] Other studies using higher doses of vitamin D at longer intervals have also been conducted. For instance, the results of a recent randomized, doubleblind, placebo-controlled trial ( n = 2686) demonstrated that 100 000 IU (2.5 mg) vitamin D3every 4 months was safe and effective in decreasing the incidence of osteoporotic fractures.[40]

Conclusion

Vitamin D is of paramount importance for mineral homeostasis and skeletal health, and maintaining adequate vitamin D nutrition is an essential component of management strategies for the prevention and treatment of osteoporosis. Nevertheless, inadequate serum vitamin D is currently a highly prevalent, global health issue, especially among elderly adults and osteoporosis patients. Consequently, greater awareness and more aggressive action are needed, as most physicians and their patients do not realize how widespread the problem is.

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