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• W2035934476 abstract "Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials. Vitamin D deficiency, which classically manifests as bone disease (either rickets or osteomalacia), is characterized by impaired bone mineralization. More recently, the term vitamin D insufficiency has been used to describe low levels of serum 25-hydroxyvitamin D that may be associated with other disease outcomes. Reliance on a single cutoff value to define vitamin D deficiency or insufficiency is problematic because of the wide individual variability of the functional effects of vitamin D and interaction with calcium intakes. In adults, vitamin D supplementation reduces the risk of fractures and falls. The evidence for other purported beneficial effects of vitamin D is primarily based on observational studies. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. Conclusive demonstration of these benefits awaits the outcome of controlled clinical trials. The past decade has seen renewed interest in the sunshine vitamin, vitamin D, because new data suggest that its benefits extend beyond healthy bones. Accompanying this renewed interest has been a proliferation of published studies related to the effects of vitamin D in many varying clinical conditions. This article discusses the definition of vitamin D insufficiency, identifies the sources of variation in vitamin D status, reviews the evidence for the clinical benefits of vitamin D, and recognizes indications for vitamin D testing. Representative studies were selected to highlight some of the limitations of current knowledge related to vitamin D insufficiency and the clinical benefits of vitamin D. We selected studies with the strongest level of evidence for clinical decision making related to vitamin D and health outcomes from our personal libraries of the vitamin D literature and from a search of the PubMed database using the term vitamin D in combination with the following terms related to the potential nonskeletal benefits of vitamin D: mortality, cardiovascular, diabetes mellitus, cancer, multiple sclerosis, allergy, asthma, infection, depression, psychiatric, and pain. The level of evidence was assessed with the following hierarchy: meta-analyses of randomized controlled trials (RCTs), RCTs, nonrandomized intervention studies, meta-analyses of observational studies (cohort and case-control studies), and observational studies.1Harbour R Miller J A new system for grading recommendations in evidence based guidelines.BMJ. 2001; 323: 334-336Crossref PubMed Scopus (1254) Google Scholar The road to the discovery of vitamin D began with recognition of the childhood bone disease of rickets. The first formal medical treatise on rickets was published by Francis Glisson in 1650, when it was identified as a new disease that was more frequent in the rich than in the poor. During the industrial revolution of the 1800s, the prevalence of rickets increased dramatically, ranging from 40% to 60% among children in crowded and polluted urban areas. In 1822, Sniadecki was the first to recognize and report the association of rickets with a lack of sunlight exposure. By the mid-1800s, cod liver oil had been established as an effective treatment for rickets. The work of Mellanby and McCollum led to the discovery of vitamin D as the agent in cod liver oil that had antirachitic properties. This discovery eventually led to the fortification of milk and other foods with vitamin D in the 1930s, and as a result rickets all but disappeared in North America and Europe. The terminology related to the biochemistry of vitamin D can be confusing. Vitamin D has 2 forms and several metabolites. The 2 forms are vitamin D2 and vitamin D3, also called ergocalciferol and cholecalciferol, respectively. Vitamin D3 is produced in the skin in response to ultraviolet B radiation from sunlight or can be obtained from the diet (ie, animal sources such as deep sea fatty fish, egg yolks, or liver) or from supplements. Few foods naturally have substantial vitamin D content, and dietary vitamin D is obtained primarily through fortified foods or supplements. Vitamin D2, which is found in some plants in the diet and is produced commercially by irradiation of yeast, is used for fortification and supplementation. Both vitamin D2 and vitamin D3 can be used for supplementation. Both forms of vitamin D undergo identical metabolism (Figure). Some evidence indicates that vitamin D2 may be metabolized more rapidly than vitamin D3,2Armas LA Hollis BW Heaney RP Vitamin D2 is much less effective than vitamin D3 in humans.J Clin Endocrinol Metab. 2004; 89: 5387-5391Crossref PubMed Scopus (906) Google Scholar, 3Trang HM Cole DE Rubin LA Pierratos A Siu S Vieth R Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2.Am J Clin Nutr. 1998; 68: 854-858PubMed Google Scholar but with regular daily intake they can be considered bioequivalent.4Holick MF Biancuzzo RM Chen TC et al.Vitamin D2 is as effective as vitamin D3 in maintaining circulating concentrations of 25-hydroxyvitamin D.J Clin Endocrinol Metab. 2008; 93: 677-681Crossref PubMed Scopus (624) Google Scholar, 5Thacher TD Obadofin MO O'Brien KO Abrams SA The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets.J Clin Endocrinol Metab. 2009; 94: 3314-3321Crossref PubMed Scopus (60) Google Scholar Both forms of vitamin D are converted to 25-hydroxyvitamin [25(OH)D] in the liver, and the serum level of 25(OH) D is measured to determine the adequacy of vitamin D status. In the kidney, 25(OH)D is hydroxylated to 1,25-dihydroxyvitamin D [1,25(OH)2D], which is the only biologically active form of vitamin D. Acting principally on the duodenum, 1,25(OH)2D increases calcium absorption. It also acts on bone cells, both osteoblasts and osteoclasts, to mobilize calcium. The characteristics of 1,25(OH)2D are those of a hormone, and consequently vitamin D is a prohormone rather than a true vitamin. The structure of 1,25(OH)2D is similar to that of other steroid hormones. As long as sunlight exposure is adequate, 1,25(OH)2D can be produced by the body without the requirement for ingestion in the diet. Like other hormones, 1,25(OH)2D circulates at picogram concentrations that are 1000 times less than those of the precursor 25(OH)D. Based on the need for increased calcium absorption, the synthesis of 1,25(OH)2D is tightly regulated and stimulated primarily by serum parathyroid hormone (PTH), as well as low serum calcium or phosphorus levels, and inhibited by circulating FGF23 produced by osteocytes.6Plum LA DeLuca HF The functional metabolism and molecular biology of vitamin D action.in: Holick MF Vitamin D: Physiology, Molecular Biology, and Clinical Applications. 2nd ed. Humana Press, New York, NY2010: 61-97Google Scholar Although produced in the kidney, 1,25(OH)2D acts at a distance in the intestinal cell to increase calcium absorption or in the bone to stimulate differentiation and activation of osteoblasts and osteoclasts.7Holick MF Vitamin D deficiency.N Engl J Med. 2007; 357: 266-281Crossref PubMed Scopus (10637) Google Scholar Determination of vitamin D status is not based on measurement of serum 1,25(OH)2D concentrations. Vitamin D status is assessed by measuring the prohormone 25(OH) D, which is an indicator of supply rather than function. The most stable and plentiful metabolite of vitamin D in human serum, 25(OH)D has a half-life of about 3 weeks, making it the most suitable indicator of vitamin D status. In the past, vitamin D deficiency was identified by the presence of bone disease, either rickets or osteomalacia. Bone disease caused by vitamin D deficiency is associated with serum 25(OH)D values below 10 ng/mL (to convert to nmol/L, multiply by 2.496). More recently, the term vitamin D insufficiency has been used to describe suboptimal levels of serum 25(OH)D that may be associated with other disease outcomes. Precisely defining vitamin D deficiency or insufficiency on the basis of 25(OH)D values is still a matter of much debate. A useful but rather simplistic classification of vitamin D status is shown in the Table. A cutoff value of 30 ng/mL is sometimes used for optimal vitamin status. On the basis of measured concentrations of 25(OH)D, many patients are given a diagnosis of vitaminD deficiency or insufficiency when most have no evidence of disease.TABLEClassification of Vitamin D Status by 25(OH)D Concentrationa25(OH)D = 25-hydroxyvitamin D.,bTo convert from ng/mL to nmol/L, multiply by 2.496.25(OH)D concentrationClassification≤10 ng/mL11–20 ng/mLInsufficient>20 ng/mLOptimala 25(OH)D = 25-hydroxyvitamin D.b To convert from ng/mL to nmol/L, multiply by 2.496. Open table in a new tab As discussed in detail in recent reviews,8Kennel KA Drake MT Hurley DL Vitamin D deficiency in adults: when to test and how to treat.Mayo Clin Proc. 2010; 85: 752-757Abstract Full Text Full Text PDF PubMed Scopus (379) Google Scholar, 9Prentice A Goldberg GR Schoenmakers I Vitamin D across the lifecycle: physiology and biomarkers.Am J Clin Nutr. 2008; 88: 500S-506SPubMed Google Scholar investigators have considered various functional measures to assess the adequacy of vitamin D status. One functional definition of optimal vitamin D status is the 25(OH)D level that maximally suppresses PTH secretion, because the major stimulus for PTH secretion is a low level of serum ionized calcium. In adults, multiple cross-sectional examinations of the relationship between serum PTH and 25(OH)D levels demonstrate a plateau in suppression of PTH when the 25(OH)D level reaches approximately 30 ng/mL.10Chapuy MC Preziosi P Maamer M et al.Prevalence of vitamin D insufficiency in an adult normal population.Osteoporos Int. 1997; 7: 439-443Crossref PubMed Scopus (1249) Google Scholar This is the rationale for selecting 30 ng/mL as the cutoff value for defining optimal vitamin D status. However, this definition represents an average value at a population level but does not account for the wide variation in the 25(OH) D level that represents adequacy at an individual level. Many patients have very low 25(OH)D values without evidence of increased production of PTH, and conversely, 25(OH)D levels greater than 30 ng/mL do not guarantee PTH suppression.10Chapuy MC Preziosi P Maamer M et al.Prevalence of vitamin D insufficiency in an adult normal population.Osteoporos Int. 1997; 7: 439-443Crossref PubMed Scopus (1249) Google Scholar Another limitation of this definition is that, in children, an elevated PTH level does not indicate inadequate vitamin D status and has been associated with increased calcium absorption.11Abrams SA Griffin IJ Hawthorne KM Gunn SK Gundberg CM Carpenter TO Relationships among vitamin D levels, parathyroid hormone, and calcium absorption in young adolescents.J Clin Endocrinol Metab. 2005; 90: 5576-5581Crossref PubMed Scopus (146) Google Scholar In puberty, the PTH concentration increases, which may stimulate increased periosteal bone formation and increased bone accrual. In fact, preliminary evidence suggests that, with adequate calcium intake, a high-normal PTH level and low-normal 25(OH)D level may result in greater bone size and mass during puberty.12Tylavsky FA Ryder KM Li R et al.Preliminary findings: 25(OH)D levels and PTH are indicators of rapid bone accrual in pubertal children.J Am Coll Nutr. 2007; 26: 462-470Crossref PubMed Scopus (33) Google Scholar Another method used in some research studies for defining optimal vitamin D status is the 25(OH)D level at which there is no incremental increase in 1,25(OH)2D levels after administration of vitamin D, because the level of 1,25(OH)2D is adequate to meet demand.13Peacock M Selby PL Francis RM Brown WB Hordon L Vitamin D deficiency, insufficiency, sufficiency and intoxication: What do they mean?.in: Norman AW Schaefer K Grigoleit H-G Herrath DV Vitamin D: Chemical, Biochemical and Clinical Update. Walter de Gruyter, Berlin, Germany1985: 569-570Google Scholar, 14Thacher TD Fischer PR Isichei CO Pettifor JM Early response to vitamin D2 in children with calcium deficiency rickets.J Pediatr. 2006; 149: 840-844Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 15Docio S Riancho JA Perez A Olmos JM Amado JA Gonzalez-Macias J Seasonal deficiency of vitamin D in children: a potential target for osteoporosis-preventing strategies?.J Bone Miner Res. 1998; 13: 544-548Crossref PubMed Scopus (179) Google Scholar Similar to the findings related to PTH in adults, an incremental increase in the level of 1,25(OH)2D was observed after administration of vitamin D in children when values of 25(OH)D were less than 25 to 30 ng/mL.5Thacher TD Obadofin MO O'Brien KO Abrams SA The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets.J Clin Endocrinol Metab. 2009; 94: 3314-3321Crossref PubMed Scopus (60) Google Scholar In situations of very low calcium intakes, some evidence suggests that the demand for 1,25(OH)2D may be greater.14Thacher TD Fischer PR Isichei CO Pettifor JM Early response to vitamin D2 in children with calcium deficiency rickets.J Pediatr. 2006; 149: 840-844Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar, 16Steingrimsdottir L Gunnarsson O Indridason OS Franzson L Sigurdsson G Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake.JAMA. 2005; 294: 2336-2341Crossref PubMed Scopus (383) Google Scholar, 17Thacher TD Fischer PR Obadofin MO Levine MA Singh RJ Pettifor JM Comparison of metabolism of vitamins D(2) and D(3) in children with nutritional rickets.J Bone Miner Res. 2010; 25: 1988-1995Crossref PubMed Scopus (39) Google Scholar Thus, vitamin D requirements may vary based on customary calcium intake. Another functional measure of vitamin D status is the 25(OH)D level that results in maximal intestinal calcium absorption. By combining the results of 3 studies in adults, Heaney18Heaney RP Functional indices of vitamin D status and ramifications of vitamin D deficiency.Am J Clin Nutr. 2004; 80: 1706S-1709SPubMed Google Scholar concluded that optimal calcium absorption occurred at 25(OH)D levels of 32 ng/mL or greater. In contrast, another study found no association between 25(OH)D levels and calcium absorption in healthy women.19Aloia JF Chen DG Yeh JK Chen H Serum vitamin D metabolites and intestinal calcium absorption efficiency in women.Am J Clin Nutr. 2010; 92: 835-840Crossref PubMed Scopus (68) Google Scholar Fractional calcium absorption was high (>50%) in Nigerian children with presumed dietary calcium deficiency rickets and low dietary calcium intakes despite low normal serum 25(OH)D concentrations.5Thacher TD Obadofin MO O'Brien KO Abrams SA The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets.J Clin Endocrinol Metab. 2009; 94: 3314-3321Crossref PubMed Scopus (60) Google Scholar, 20Graff M Thacher TD Fischer PR et al.Calcium absorption in Nigerian children with rickets.Am J Clin Nutr. 2004; 80: 1415-1421PubMed Scopus (43) Google Scholar After vitamin D administration and a marked increase in 25(OH) D and 1,25(OH)2D concentrations, fractional calcium absorption did not increase any further.5Thacher TD Obadofin MO O'Brien KO Abrams SA The effect of vitamin D2 and vitamin D3 on intestinal calcium absorption in Nigerian children with rickets.J Clin Endocrinol Metab. 2009; 94: 3314-3321Crossref PubMed Scopus (60) Google Scholar In these studies in children, fractional calcium absorption was not related to serum 1,25(OH)2D levels either before or after vitamin D administration. In a study of adults attending an osteoporosis clinic, concentrations of 1,25(OH)2D and intestinal calcium absorption did not appear to decline until 25(OH) D concentrations fell to 4 ng/mL or less, a level that is generally considered to be indicative of severe vitamin D deficiency.21Need AG O'Loughlin PD Morris HA Coates PS Horowitz M Nordin BE Vitamin D metabolites and calcium absorption in severe vitamin D deficiency.J Bone Miner Res. 2008; 23: 1859-1863Crossref PubMed Scopus (210) Google Scholar More recently, the criterion for optimal vitamin D status has moved away from being defined as the 25(OH) D concentration needed to achieve skeletal health to that which demonstrates optimal benefits on nonskeletal health outcomes. The evidence related to these outcomes will be considered later in this review. Factors known to influence 25(OH)D levels include race, vitamin D intake, sun exposure, adiposity, age, and physical activity. Even when all the factors known to influence 25(OH)D concentrations are taken into account, most of the individual variation of 25(OH)D values is difficult to explain. Consequently, it is difficult to assess the risk of clinical or biochemical consequences of vitamin D insufficiency in a patient on the basis of concentrations of 25(OH) D alone. The duration of vitamin D insufficiency, the responsiveness of the vitamin D receptor, dietary calcium intake, and individual calcium requirements likely modify the clinical consequences of vitamin D deficiency or insufficiency based on levels of 25(OH)D. A single exposure to summer sun in a bathing suit for 20 minutes produces the equivalent of 15,000 to 20,000 IU of vitamin D3. In a study of Hawaiian surfers with sun exposure of at least 15 hours per week for the preceding 3 months, 25(OH)D levels ranged from 11 up to 71 ng/mL, demonstrating wide individual variation.22Hollis BW Wagner CL Drezner MK Binkley NC Circulating vitamin D3 and 25-hydroxyvitamin D in humans: an important tool to define adequate nutritional vitamin D status.J Steroid Biochem Mol Biol. 2007; 103: 631-634Crossref PubMed Scopus (147) Google Scholar Outdoor sun exposure and time spent outdoors are better predictors of serum 25(OH)D values than dietary vitamin D intake.23Heaney RP Davies KM Chen TC Holick MF Barger-Lux MJ Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.Am J Clin Nutr. 2003; 77: 204-210PubMed Google Scholar The 25(OH)D level achieved with the same oral dose of vitamin D varies widely by individual.23Heaney RP Davies KM Chen TC Holick MF Barger-Lux MJ Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol.Am J Clin Nutr. 2003; 77: 204-210PubMed Google Scholar, 24Aloia JF Patel M Dimaano R et al.Vitamin D intake to attain a desired serum 25-hydroxyvitamin D concentration.Am J Clin Nutr. 2008; 87: 1952-1958PubMed Google Scholar The level of 25(OH)D that results in clinical consequences probably varies with calcium intake, race, age, body fat, and individual genetic factors, all of which may influence calcium homeostasis. Genetic variation represented by polymorphisms of certain genes in the vitamin D metabolic pathway explains some of the interindividual variability of 25(OH)D concentrations, particularly polymorphisms of the enzyme 7-dehydrocholesterol reductase in the skin, cytochrome P450 25-hydroxylase in the liver, and vitamin D–binding protein in the circulation.25Ahn J Yu K Stolzenberg-Solomon R et al.Genome-wide association study of circulating vitamin D levels.Hum Mol Genet. 2010; 19: 2739-2745Crossref PubMed Scopus (641) Google Scholar The functional effect of a particular level of 25(OH)D depends on the uptake of 25(OH)D by target cells and the efficiency of 1α-hydroxylation to produce 1,25(OH)2D. Some controversy exists regarding the best method for measuring 25(OH)D levels. Radioimmunoassay has been the most common method reported in the literature and was the method used in some of the large-scale population studies of vitamin D, such as the National Health and Nutrition Examination Survey (NHANES) and the Women's Health Initiative (WHI). The accuracy of measurement varies widely between individual laboratories and between different assay methods. In one study, identical serum samples were provided to 6 different laboratories, and the chemiluminescent assay tended to return higher values for 25(OH)D.26Binkley N Krueger D Cowgill CS et al.Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.J Clin Endocrinol Metab. 2004; 89: 3152-3157Crossref PubMed Scopus (493) Google Scholar Competitive protein-binding assays are also known to generally yield higher 25(OH)D values. When serum samples were spiked with an additional 20 ng/mL of 25(OH)D, the increment in 25(OH)D level was less than 20 ng/mL in all the laboratories, except the one using high-performance liquid chromatography. Antibodies used in some radioimmunoassays do not detect both 25(OH)D2 and 25(OH)D3. The use of a standard cutoff value for adequate vitamin D status is problematic if applied to all laboratories and all methods. A single serum sample could be assessed as showing adequate vitamin D status in one laboratory and an insufficient level in another, with differences of up to 17 ng/mL.26Binkley N Krueger D Cowgill CS et al.Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization.J Clin Endocrinol Metab. 2004; 89: 3152-3157Crossref PubMed Scopus (493) Google Scholar, 27Granado-Lorencio F Mosteiro JS Herrero-Barbudo C Navarro ED Blanco-Navarro I Perez-Sacristan B 25-OH-vitamin D assay variation and subject management in clinical practice.Clin Biochem. 2010; 43: 531-533Crossref PubMed Scopus (6) Google Scholar More recently, large medical laboratories have begun using liquid chromatography–tandem mass spectrometry, which identifies the 25-hydroxylated forms of both vitamin D2 and D3.28Singh RJ Quantitation of 25-OH-vitamin D (25OHD) using liquid tandem mass spectrometry (LC-MS-MS).Methods Mol Biol. 2010; 603: 509-517Crossref PubMed Scopus (37) Google Scholar The total 25(OH)D, which is the sum of 25(OH)D2 and 25(OH)D3, is used to evaluate vitamin D status. Since 2003, there has been more than a 15-fold increase in the volume of 25(OH)D measurements at Mayo Clinic in Rochester, MN (Singh R., personal communication), reflecting the increasing attention clinicians are giving to vitamin D status. The classical manifestation of vitamin D deficiency is nutritional rickets, which results from inadequate mineralization of growing bone. Consequently, rickets is a disease of children. Far from being eradicated, nutritional rickets continues to occur throughout the world, with reports from at least 60 countries in the past 20 years.29Thacher TD Fischer PR Strand MA Pettifor JM Nutritional rickets around the world: causes and future directions.Ann Trop Paediatr. 2006; 26: 1-16Crossref PubMed Scopus (218) Google Scholar In a review of published cases of rickets in the United States, most occurred in children younger than 30 months.30Weisberg P Scanlon KS Li R Cogswell ME Nutritional rickets among children in the United States: review of cases reported between 1986 and 2003.Am J Clin Nutr. 2004; 80: 1697S-1705SCrossref PubMed Google Scholar The vast majority of cases in the United States occurred in African American infants who were fed with breast milk rather than formula. Florid rickets manifests with leg deformities; enlargement of the growth plates of the wrists, ankles, and costochondral junctions; and rib cage deformities. Subtle symptoms that should raise the clinical suspicion of rickets in children include bone pain in the legs, delayed age of standing or walking, frequent falling, and delayed growth. Hypocalcemic seizures in the first year of life may be the initial manifestation of rickets. Radiography of the long bones at the knees and the wrists is necessary to confirm the diagnosis of rickets. Radiography demonstrates impaired mineralization of the growth plates, evident by widening of the growth plate and fraying of the margin of the metaphyses.31Thacher TD Fischer PR Pettifor JM Lawson JO Manaster BJ Reading JC Radiographic scoring method for the assessment of the severity of nutritional rickets.J Trop Pediatr. 2000; 46: 132-139Crossref PubMed Scopus (161) Google Scholar Biochemical features most consistently include hypophosphatemia and an elevated alkaline phosphatase level. As a result of vitamin D deficiency, serum concentrations of 25(OH)D are very low in patients with rickets, usually less than 5 ng/mL. However, concentrations of 25(OH)D may not be markedly reduced if rickets results from calcium deficiency or if the child has recently received vitamin D or sun exposure. In some tropical countries, where sun exposure is plentiful, calcium deficiency is more important than vitamin D deficiency as a cause of rickets.32Fischer PR Rahman A Cimma JP et al.Nutritional rickets without vitamin D deficiency in Bangladesh.J Trop Pediatr. 1999; 45: 291-293Crossref PubMed Scopus (93) Google Scholar, 33Thacher TD Fischer PR Pettifor JM et al.A comparison of calcium, vitamin D, or both for nutritional rickets in Nigerian children.N Engl J Med. 1999; 341: 563-568Crossref PubMed Scopus (246) Google Scholar However, even in the United States, only 22% of children with nutritional rickets had deficient levels of 25(OH)D, indicating that calcium deficiency as a cause of rickets needs to be considered domestically as well.34DeLucia MC Mitnick ME Carpenter TO Nutritional rickets with normal circulating 25-hydroxyvitamin D: a call for reexamining the role of dietary calcium intake in North American infants.J Clin Endocrinol Metab. 2003; 88: 3539-3545Crossref PubMed Scopus (125) Google Scholar Osteomalacia refers to the failure of organic osteoid formed by osteoblasts to become mineralized with calcium and phosphorus. Although histological osteomalacia is characteristic of rickets, the term osteomalacia is generally used to describe the bone disease caused by vitamin D deficiency in adults, who no longer have growing bones. The clinical manifestations of these 2 conditions are different. Bone pain is a characteristic feature of osteomalacia, and it can be confused with arthritis or fibromyalgia. Bone pain due to osteomalacia primarily affects the bones between the joints, whereas arthritis usually causes predominantly joint pain, and fibromyalgia causes more diffuse muscle and soft tissue pain; however, it can be difficult to distinguish between these disorders. Proximal muscle weakness and gait instability are often present. Because the growth plates have closed in adults, the radiographic features differ from those typical of rickets. Radiography may reveal pseudofractures of the pelvis, femurs, metatarsals, or lateral margins of the scapulae. The biochemical features of osteomalacia are similar to those of rickets, with increased serum alkaline phosphatase and PTH values, and low calcium, phosphorus, and 25(OH)D values in most cases. A review of all the archived cases of bone biopsy–proven osteomalacia seen by the Bone Histomorphometry Laboratory at Mayo Clinic concluded that radiographic examination as well as serum calcium, phosphorus, and alkaline phosphatase assays are adequate screening tests in patients who have a clinical presentation suggestive of osteomalacia, but that 25(OH)D values may be normal.35Bingham CT Fitzpatrick LA Noninvasive testing in the diagnosis of osteomalacia.Am J Med. 1993; 95: 519-523Abstract Full Text PDF PubMed Scopus (68) Google Scholar In a cross-sectional study of iliac bone biopsy specimens obtained at autopsy, an excess accumulation of osteoid, which corresponds with histological osteomalacia, was found only in patients with 25(OH)D values less than 25 ng/mL.36Priemel M von Domarus C Klatte TO et al.Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients.J Bone Miner Res. 2010; 25: 305-312Crossref PubMed Scopus (454) Google Scholar However, even patients with very low values of 25(OH)D did not consistently have evidence of osteomalacia. Apart from the deficiency diseases of rickets and osteomalacia, recent evidence suggests other skeletal and nonskeletal benefits of vitamin D. In evaluating the evidence, it is important to recognize the limitations inherent in the study design and methodology. Important issues that apply to vitamin" @default.
• W2035934476 created "2016-06-24" @default.
• W2035934476 creator A5033016079 @default.
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• W2035934476 date "2011-01-01" @default.
• W2035934476 modified "2023-10-16" @default.
• W2035934476 title "Vitamin D Insufficiency" @default.
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• W2035934476 doi "https://doi.org/10.4065/mcp.2010.0567" @default.
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