Vitamin D deficiency
Vitamin D deficiency is a prevalent nutritional disorder characterized by inadequate levels of vitamin D, a fat-soluble vitamin essential for maintaining calcium and phosphate homeostasis to support bone mineralization and overall health.[1] It manifests clinically as rickets in children, causing softened and deformed bones, and osteomalacia in adults, leading to bone pain and muscle weakness.[2] This condition affects bone integrity by impairing the absorption of calcium, magnesium, and phosphate in the intestines.[1] The primary cause of vitamin D deficiency is insufficient exposure to ultraviolet B (UVB) sunlight, which triggers cutaneous synthesis of vitamin D3 (cholecalciferol), accounting for 80–90% of bodily stores in sun-exposed individuals.[3] Dietary sources, including fortified foods, fatty fish, and supplements, provide only limited amounts, and factors like malabsorption disorders, obesity, and darker skin pigmentation further exacerbate risk by reducing bioavailability or synthesis efficiency.[1] Common symptoms include proximal muscle weakness, throbbing bone pain, low back pain, and fatigue, often progressing subtly until severe complications arise.[4] Globally, vitamin D deficiency impacts over 1 billion people, with prevalence rates as high as 40% in Europe (including 13% severe cases) and approximately 42% in the United States as of recent national surveys (e.g., NHANES 2015–2016 and later analyses).[5][3][1] At-risk groups include older adults, individuals with limited sun exposure (e.g., those in northern latitudes or indoor lifestyles), pregnant and lactating women, and people with chronic conditions like kidney disease or inflammatory bowel disease.[2] Beyond skeletal effects, low vitamin D levels are associated with heightened risks of cardiovascular disease through pro-inflammatory pathways, type 2 diabetes, metabolic syndrome, obesity, autoimmune disorders, and certain cancers.[6][7][8] Guidelines vary on diagnostic thresholds; the Institute of Medicine considers serum 25-hydroxyvitamin D levels below 20 ng/mL (50 nmol/L) as inadequate for bone health, while the Endocrine Society's 2024 guidelines do not endorse specific cutoffs for the general population and recommend against routine testing in healthy adults under 75 years.[9][10] Early detection via blood tests and treatment with supplementation can prevent long-term complications, underscoring its public health significance.[1]Definitions and Classifications
Diagnostic Thresholds
Serum 25-hydroxyvitamin D [25(OH)D] serves as the primary biomarker for assessing vitamin D status, as it captures contributions from both endogenous production in the skin and dietary or supplemental intake, providing a reliable indicator of overall body stores.[2] Unlike the active form, 1,25-dihydroxyvitamin D [1,25(OH)2D], which is tightly regulated by parathyroid hormone and has a short half-life of 4 to 6 hours, 25(OH)D has a longer half-life of 2 to 3 weeks, making it a more stable and representative measure of vitamin D availability over time.[11] Measurements are typically reported in nanograms per milliliter (ng/mL) or nanomoles per liter (nmol/L), with a conversion factor of 1 ng/mL ≈ 2.5 nmol/L.[12] Diagnostic thresholds for vitamin D deficiency are defined based on serum 25(OH)D concentrations, though guidelines vary due to differences in evidence interpretation and target health outcomes. The Institute of Medicine (IOM, now National Academy of Medicine) in its 2011 report established <12 ng/mL (<30 nmol/L) as indicative of deficiency, 12–20 ng/mL (30–50 nmol/L) as inadequate for bone and overall health, and ≥20 ng/mL (≥50 nmol/L) as generally adequate for most individuals.[2] In contrast, the Endocrine Society's 2011 clinical practice guideline defined deficiency as <20 ng/mL (<50 nmol/L), insufficiency as 20–29 ng/mL (50–75 nmol/L), and sufficiency as ≥30 ng/mL (≥75 nmol/L), emphasizing higher levels for optimal bone mineralization and prevention of secondary hyperparathyroidism.[13] However, the Endocrine Society's 2024 update no longer endorses universal thresholds for defining sufficiency, insufficiency, or deficiency in the general population, recommending instead that 25(OH)D levels be interpreted in the context of specific clinical indications rather than routine screening.[10] Thresholds can vary by age, ethnicity, and health context to account for physiological differences and disease-specific needs. For instance, older adults may require higher levels (e.g., ≥30 ng/mL) due to reduced renal efficiency in converting 25(OH)D to its active form and increased risk of falls and fractures.[2] Ethnic variations influence interpretation, as individuals with darker skin pigmentation (e.g., those of African or South Asian descent) often have lower 25(OH)D levels due to reduced cutaneous synthesis but may exhibit adequate bone health at concentrations below 20 ng/mL that would be considered insufficient in lighter-skinned populations.[14] In contexts like optimal bone health or chronic disease management, some experts advocate for ≥30 ng/mL to maximize benefits such as calcium absorption, though evidence for extraskeletal outcomes remains context-dependent.[13]Types of Deficiency
Vitamin D deficiency is broadly classified by its underlying etiology into nutritional, malabsorption-related, genetic, and acquired forms, each contributing to impaired vitamin D status through distinct mechanisms.[15] This classification helps in identifying targeted interventions, as the causes range from environmental and dietary factors to inherent metabolic defects. Importantly, vitamin D deficiency is distinguished from insufficiency; while insufficiency refers to suboptimal serum 25-hydroxyvitamin D [25(OH)D] levels (typically 20–30 ng/mL or 50–75 nmol/L) that may pose long-term health risks without immediate symptoms, deficiency denotes more severe reductions (often <20 ng/mL or <50 nmol/L, with severe cases <10–12 ng/mL) that can lead to overt clinical manifestations such as rickets in children or osteomalacia in adults.[1][15][16] Nutritional deficiency arises primarily from inadequate dietary intake of vitamin D or insufficient cutaneous synthesis due to limited sunlight exposure. Populations at risk include those with vegan diets lacking fortified foods or animal-derived sources like fatty fish and egg yolks, as well as individuals in regions with minimal ultraviolet B radiation, such as northern latitudes or those practicing cultural sun avoidance.[1] This form is the most common globally and often overlaps with lifestyle factors, though it can be mitigated through supplementation or dietary adjustments.[17] Malabsorption-related deficiency occurs when gastrointestinal disorders hinder the uptake of dietary vitamin D and its fat-soluble nature exacerbates the issue in the presence of bile salt deficiencies or mucosal damage. Conditions such as celiac disease, inflammatory bowel disease (e.g., Crohn's disease), and short bowel syndrome impair absorption in the small intestine, leading to persistently low 25(OH)D levels despite adequate intake or exposure.[18] For instance, in celiac disease, villous atrophy directly reduces nutrient absorption, contributing to secondary vitamin D deficiency that may persist even after gluten-free diet initiation.[19] These cases often require higher-dose supplementation to overcome the absorption barrier.[20] Genetic forms of vitamin D deficiency are rare and result from inherited mutations disrupting vitamin D metabolism or action, typically presenting as hereditary rickets in infancy or early childhood. Type I vitamin D-dependent rickets (VDDR1) stems from biallelic mutations in the CYP27B1 gene, which encodes the 1α-hydroxylase enzyme responsible for converting 25(OH)D to its active form, 1,25-dihydroxyvitamin D, leading to low active vitamin D despite normal precursor levels.[21] In contrast, type II VDDR (also known as hereditary vitamin D-resistant rickets or HVDRR) arises from mutations in the VDR gene encoding the vitamin D receptor, rendering target tissues unresponsive to the hormone even at high doses; these mutations are heterogeneous and autosomal recessive.[22] Additional rare variants, such as those in CYP2R1 (25-hydroxylase) for VDDR1B, further illustrate the genetic spectrum, often requiring lifelong high-dose calcitriol therapy.[23] Acquired forms encompass iatrogenic and organ-specific impairments that develop postnatally and accelerate vitamin D catabolism or block activation. Medications like anticonvulsants (e.g., phenytoin, phenobarbital, and carbamazepine) induce hepatic cytochrome P450 enzymes, enhancing the breakdown of 25(OH)D and leading to deficiency in up to 40% of long-term users, particularly children with epilepsy.[24] Renal impairment in chronic kidney disease similarly disrupts 1α-hydroxylation in the kidneys, resulting in low 1,25-dihydroxyvitamin D and secondary hyperparathyroidism, affecting over 80% of advanced-stage patients.[25] Hepatic diseases, including cirrhosis, compromise 25-hydroxylation in the liver, correlating with disease severity and poor outcomes, as seen in various etiologies like alcoholic liver disease.[26] These acquired types underscore the need for routine monitoring in at-risk patients to prevent progression to skeletal disorders.[27]Clinical Manifestations
Signs and Symptoms
Vitamin D deficiency often presents asymptomatically in mild cases, particularly when serum 25-hydroxyvitamin D levels are only moderately reduced, allowing individuals to remain unaware of the condition until routine testing.[28] As deficiency progresses to severe levels, subjective and observable symptoms emerge, primarily affecting the musculoskeletal system and overall well-being.[1] Common early indicators include fatigue, which can manifest as persistent tiredness unresponsive to rest, alongside nonspecific mood changes such as depression or irritability linked to vitamin D's role in immune modulation.[17] Individuals may also experience frequent infections due to impaired immune function, though these are often subtle and overlooked.[29] Musculoskeletal symptoms dominate the clinical picture, with bone pain typically described as a dull ache in the lower back, pelvis, or extremities, and muscle weakness leading to aches, cramps, or difficulty with daily activities.[30] In children, these manifestations can include delayed growth and skeletal deformities such as bowing of the legs, representing early or pre-rickets changes where bones soften under weight-bearing stress.[31] Affected children may exhibit slowed linear growth and generalized weakness, contributing to motor delays.[32] In adults, proximal myopathy is characteristic, involving weakness in the muscles closest to the trunk, which can result in a waddling gait and challenges rising from a seated position.[33] Physical examination in symptomatic cases may reveal tenderness upon palpation over affected bones, such as the ribs or long bones, reflecting underlying mineralization defects.[30] In extreme severe deficiency accompanied by hypocalcemia, signs of neuromuscular irritability like tetany—manifesting as muscle spasms or carpopedal spasms—can occur, though these are rare and indicate advanced decompensation.[34]Complications
Vitamin D deficiency leads to impaired bone mineralization, resulting in osteomalacia in adults, characterized by softening of the bones due to defective mineralization of the osteoid matrix.[35] This condition manifests as bone pain, muscle weakness, and increased susceptibility to fractures, often progressing from prolonged hypovitaminosis D.[36] Additionally, chronic deficiency contributes to osteoporosis by inducing secondary hyperparathyroidism, which accelerates bone resorption and loss of bone density.[37] In the elderly, this heightened bone fragility elevates the risk of fractures, particularly hip fractures, with studies showing a significant association between low vitamin D levels and increased fracture incidence.[38] In children, severe vitamin D deficiency causes rickets, a disorder marked by softening and weakening of bones in growing areas, leading to skeletal deformities such as bowed legs, widened wrists, and frontal bossing.[39] Rickets also impairs linear growth, resulting in short stature and delayed overall development if untreated.[40] These deformities arise from the failure of mineralization at the growth plates, directly linked to inadequate vitamin D-mediated calcium and phosphate absorption.[41] Beyond skeletal effects, extraskeletal complications include hypocalcemia, which can precipitate neuromuscular irritability and, in severe cases, seizures due to low ionized calcium levels.[40] Proximal myopathy associated with vitamin D deficiency weakens muscles, increasing the propensity for falls, especially among older adults.[42] Chronic untreated deficiency promotes secondary hyperparathyroidism through persistent hypocalcemia, stimulating parathyroid hormone overproduction and leading to high-turnover bone disease.[43] Severe vitamin D deficiency is linked to higher all-cause mortality risk, particularly in vulnerable populations, with increased risks from fall-related injuries and susceptibility to infections due to impaired immune function.[44][45] For instance, deficient elderly individuals face elevated all-cause mortality, partly attributable to these complications.[46] Recent evidence from 2024 and 2025 studies highlights emerging associations between vitamin D deficiency and cognitive decline in older adults, with low levels correlating to accelerated brain aging and higher dementia risk.[47] These findings also reinforce the role of deficiency in exacerbating falls among the elderly, potentially through combined effects on muscle function and cognition.[48]Risk Factors
Demographic and Physiological Factors
Certain demographic and physiological factors significantly influence the risk of vitamin D deficiency by affecting its synthesis, metabolism, or bioavailability. Infants and the elderly are particularly vulnerable populations. In infants, limited endogenous synthesis due to minimal sun exposure and reliance on breast milk, which contains low levels of vitamin D, heightens the risk, especially in those exclusively breastfed without supplementation.[49][50] Among the elderly, age-related declines in skin's capacity to produce vitamin D upon UVB exposure, combined with reduced dietary intake, contribute to higher deficiency rates.[42][51] Skin pigmentation plays a key role in vitamin D production, as higher melanin content in darker-skinned individuals absorbs UVB radiation, thereby reducing cutaneous synthesis of vitamin D. This physiological barrier is more pronounced in regions with limited sunlight, increasing deficiency prevalence among people with darker skin tones.[52][53] Genetic variations further modulate susceptibility; polymorphisms in the vitamin D receptor (VDR) gene and vitamin D-binding protein (DBP) gene can alter vitamin D metabolism and transport, leading to lower circulating levels in affected individuals.[54][55] Sex-specific physiological changes also contribute, with postmenopausal women facing elevated risk due to estrogen decline, which influences vitamin D metabolism and bone health.[56][57] Similarly, obesity, defined as BMI greater than 30 kg/m², promotes vitamin D sequestration in adipose tissue, reducing its bioavailability in the bloodstream.[58][59] These factors interact with environmental influences like sun exposure but stem primarily from inherent physiological traits.Lifestyle and Environmental Factors
Limited sun exposure is a primary lifestyle factor contributing to vitamin D deficiency, as ultraviolet B (UVB) radiation from sunlight is essential for cutaneous synthesis of vitamin D. Indoor lifestyles, which reduce opportunities for UVB exposure, significantly increase deficiency risk, particularly in regions where individuals spend most of their time indoors due to work or leisure activities. Latitude plays a critical role, with higher latitudes (above 37°N) receiving insufficient UVB during winter months, often requiring more than 15 minutes of midday sun exposure on face and arms several times a week to maintain adequate levels, though practical exposure is frequently lower. Clothing that covers much of the skin, such as traditional garments or protective attire, further limits UVB penetration, exacerbating deficiency in populations with cultural or religious practices that emphasize modesty.[60] Occupational factors amplify these risks, especially for shift workers and those in indoor professions who have minimal daytime sunlight exposure. A 2024 study of U.S. Armed Forces personnel found higher rates of vitamin D deficiency among indoor occupations, including shift workers, healthcare providers, and submariners, attributing this to disrupted circadian rhythms and limited outdoor access that hinder natural vitamin D production. These patterns highlight how work environments can systematically reduce UVB exposure, leading to suboptimal serum 25-hydroxyvitamin D levels.[61] Dietary habits also influence vitamin D status, with low intake of natural and fortified sources being a key contributor to deficiency. Foods such as fatty fish (e.g., salmon, mackerel), egg yolks, and fortified products like milk, cereals, and orange juice provide significant vitamin D, yet populations with restricted consumption—due to preferences, availability, or economic factors—face elevated risks. Vegan and vegetarian diets, which exclude or limit animal-derived sources, heighten vulnerability, as plant-based foods naturally contain little vitamin D unless fortified; studies show vegans exhibit the lowest serum levels among dietary groups.[2][62] Seasonal variations further compound these lifestyle influences, with deficiencies peaking in winter in temperate climates due to reduced UVB intensity and shorter daylight hours. In such regions, serum vitamin D levels can drop substantially from summer to winter, often falling below sufficiency thresholds despite stable dietary intake. Urbanization trends exacerbate this globally, as city dwellers experience decreased outdoor time from sedentary routines, high-rise living, and pollution, contributing to rising deficiency rates; recent analyses indicate that urban lifestyles correlate with lower vitamin D status amid ongoing societal shifts toward indoor activities.[63][64]Medical and Pathological Factors
Malabsorption syndromes significantly impair the intestinal uptake of vitamin D, leading to deficiency in affected individuals. In celiac disease, untreated patients exhibit reduced absorption of 25-hydroxyvitamin D due to villous atrophy and inflammation in the small intestine, resulting in lower serum levels compared to healthy controls.[65] Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is associated with a 64% higher odds of vitamin D deficiency, primarily from malabsorption in the inflamed gut mucosa and reduced dietary intake.[66] Bariatric surgery, such as Roux-en-Y gastric bypass, further exacerbates this risk by altering the anatomy of the digestive tract, bypassing sites of fat-soluble vitamin absorption and leading to postoperative declines in 25(OH)D levels in up to 42% of patients, even with supplementation.[67] Renal and hepatic impairments disrupt key steps in vitamin D metabolism, contributing to deficiency through impaired activation. Chronic kidney disease (CKD) limits the renal 1-alpha hydroxylation of 25(OH)D to its active form, 1,25-dihydroxyvitamin D, with hypovitaminosis D prevalent in more than 80% of pre-dialysis CKD patients and linked to disease progression and mortality.[68] Hepatic impairment in chronic liver disease similarly hinders the initial 25-hydroxylation in the liver, resulting in widespread vitamin D deficiency that correlates with fibrosis severity and decompensation.[26] Certain medications induce vitamin D deficiency by accelerating its catabolism or interfering with absorption and metabolism. Anticonvulsants like phenytoin activate cytochrome P450 enzymes, enhancing the breakdown of vitamin D metabolites and causing biochemical evidence of deficiency in 10-30% of long-term users.[69] Glucocorticoids promote vitamin D catabolism via induction of degrading enzymes and suppress intestinal calcium absorption, contributing to secondary deficiency in patients on prolonged therapy.[70] Critical illness in intensive care unit (ICU) settings often involves systemic inflammation that accelerates vitamin D loss and impairs its synthesis. Up to 70% of critically ill patients present with deficiency, associated with increased mortality, prolonged mechanical ventilation, and longer ICU stays due to inflammatory downregulation of vitamin D-binding proteins.[71] Malignancies such as lymphoma and granulomatous diseases can lead to vitamin D deficiency through hypercatabolism and dysregulated metabolism. In lymphoma, tumor-related inflammation and cytokine release increase hepatic catabolism of 25(OH)D, resulting in low serum levels that worsen prognosis. Granulomatous conditions like sarcoidosis, while sometimes causing hypercalcemia from ectopic 1-alpha hydroxylation, frequently coexist with baseline deficiency from chronic inflammation and reduced sun exposure, exacerbating overall depletion.[72] Pregnancy and lactation impose heightened physiological demands on vitamin D, often leading to maternal depletion. Deficiency affects 5-50% of pregnant women due to increased transfer to the fetus and expanded maternal blood volume, with levels dropping further during lactation to support infant needs, potentially reaching insufficiency in over 50% without supplementation.[73]Pathophysiology
Metabolic Pathways
Vitamin D can be obtained through cutaneous synthesis or dietary intake. In the skin, ultraviolet B (UVB) radiation from sunlight converts 7-dehydrocholesterol, a cholesterol derivative present in the epidermis, into previtamin D3 through photolysis of its B-ring. Previtamin D3 then undergoes thermal isomerization over several days to form vitamin D3 (cholecalciferol).[60][74] Dietary sources provide two main forms: vitamin D2 (ergocalciferol), derived from plants and fungi via UVB irradiation of ergosterol, and vitamin D3 (cholecalciferol), found in animal products such as fatty fish, egg yolks, and liver.[75][76][77] The activation of vitamin D occurs in two sequential hydroxylation steps. In the liver, vitamin D (D2 or D3) is hydroxylated at the 25-position by cytochrome P450 enzymes, primarily CYP2R1, to produce 25-hydroxyvitamin D (25(OH)D), the major circulating form. This reaction requires NADPH and molecular oxygen as cofactors: \text{Cholecalciferol} + \text{NADPH} + \text{O}_2 \xrightarrow{\text{CYP2R1}} 25(\text{OH})\text{D} + \text{NADP}^+ + \text{H}_2\text{O} Subsequently, in the kidney, 25(OH)D undergoes 1α-hydroxylation by the enzyme CYP27B1 to yield the active hormone 1,25-dihydroxyvitamin D (1,25(OH)₂D), also known as calcitriol.[78][79][80][81] The metabolic pathways of vitamin D are tightly regulated by hormonal feedback loops involving parathyroid hormone (PTH), calcium levels, and fibroblast growth factor 23 (FGF23). Low serum calcium stimulates PTH secretion from the parathyroid glands, which in turn upregulates CYP27B1 expression in the kidney to increase 1,25(OH)₂D production, thereby enhancing intestinal calcium absorption. Elevated 1,25(OH)₂D and phosphate levels promote FGF23 secretion from osteocytes, which suppresses CYP27B1 to reduce 1,25(OH)₂D synthesis and inhibits renal phosphate reabsorption, forming a negative feedback loop with PTH to maintain mineral homeostasis.[82][83][84][85] Degradation of active vitamin D prevents excessive accumulation and is primarily mediated by 24-hydroxylation. The enzyme CYP24A1, induced by 1,25(OH)₂D itself, catalyzes the initial 24-hydroxylation of 1,25(OH)₂D and 25(OH)D, leading to the formation of inactive metabolites such as 24,25-dihydroxyvitamin D and calcitroic acid, which are excreted in bile and urine. This catabolic pathway ensures fine-tuned regulation of vitamin D activity.[80][86][87]Physiological Consequences
Vitamin D deficiency disrupts calcium and phosphate homeostasis primarily through diminished production of the active hormone calcitriol (1,25-dihydroxyvitamin D), leading to impaired intestinal absorption of these minerals.[1] Low serum levels of 25-hydroxyvitamin D [25(OH)D], the main circulating form, reduce the substrate available for conversion to calcitriol by the enzyme 1α-hydroxylase in the kidneys.[1] This results in decreased active transport of calcium and phosphate across the intestinal epithelium, as calcitriol normally upregulates transporters such as TRPV6 and calbindin.[88] Consequently, hypocalcemia and hypophosphatemia develop, triggering compensatory mechanisms to maintain serum calcium.[1] The hallmark physiological response is secondary hyperparathyroidism, where reduced calcitriol and hypocalcemia stimulate parathyroid hormone (PTH) secretion from the parathyroid glands.[88] PTH elevation occurs via two main pathways: direct sensing of low extracellular calcium by parathyroid calcium-sensing receptors and reduced calcitriol-mediated suppression of PTH gene expression.[88] This can be summarized as: \text{Low } 25(\mathrm{OH})D \rightarrow \text{ decreased } 1,25(\mathrm{OH})_2D \rightarrow \text{ hypocalcemia } \rightarrow \uparrow \mathrm{PTH} Elevated PTH promotes bone resorption by osteoclasts to mobilize calcium from skeletal stores, while also enhancing renal calcium reabsorption and phosphate excretion.[1] Prolonged exposure leads to mineralization defects, where insufficient calcium and phosphate availability impairs the calcification of osteoid matrix in bone, resulting in softened bone tissue.[89] Beyond skeletal effects, vitamin D deficiency exerts extraskeletal consequences through the vitamin D receptor (VDR), a nuclear receptor that mediates genomic actions. In immune modulation, low calcitriol reduces expression of antimicrobial peptides such as cathelicidin (LL-37), which are crucial for innate defense against pathogens at epithelial barriers.[90] For muscle function, VDR signaling supports myogenesis and contractility; deficiency downregulates VDR in skeletal muscle, impairing mitochondrial oxidative capacity and protein synthesis, thereby compromising muscle strength and regeneration.[91] VDR activation by calcitriol influences the transcription of over 200 genes across various tissues, affecting processes like cell differentiation and proliferation.[92] In deficiency states, reduced ligand availability diminishes VDR binding to vitamin D response elements in gene promoters, altering expression of targets involved in calcium transport, immune regulation, and extracellular matrix remodeling.[93]Diagnosis and Screening
Diagnostic Methods
The primary diagnostic method for vitamin D deficiency involves measuring serum levels of 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D, which reflects overall vitamin D status from both dietary intake and endogenous synthesis.[15] The gold standard assay is liquid chromatography-tandem mass spectrometry (LC-MS/MS), which provides high specificity and accuracy by distinguishing between 25(OH)D2 and 25(OH)D3 metabolites, though it requires specialized equipment and is more labor-intensive.[94] Automated immunoassays, such as chemiluminescent or enzyme-linked methods, are more widely used in clinical settings due to their simplicity and speed but can exhibit variability in results compared to LC-MS/MS, particularly at low concentrations.[95] To assess secondary effects of deficiency, additional laboratory markers are evaluated alongside 25(OH)D. Serum calcium levels may be low or normal in early deficiency but often normalize due to compensatory mechanisms; parathyroid hormone (PTH) is typically elevated as it mobilizes calcium from bone; and alkaline phosphatase (ALP) may increase in cases of osteomalacia, indicating heightened bone turnover.[96] These markers help confirm the clinical impact but are not specific to vitamin D deficiency alone.[97] For patients with suspected bone-related complications, dual-energy X-ray absorptiometry (DXA) scans measure bone mineral density to detect osteopenia or osteoporosis associated with prolonged deficiency, providing a T-score for risk stratification.[98] Diagnostic limitations include inter-assay variability, where immunoassays can overestimate or underestimate 25(OH)D by up to 20% compared to LC-MS/MS, and seasonal fluctuations in levels, with lower concentrations in winter due to reduced sunlight exposure.[99] [100] According to the 2024 Endocrine Society consensus, routine 25(OH)D testing is not cost-effective for the general population and should be reserved for high-risk individuals, such as those with malabsorption syndromes or chronic kidney disease, to optimize resource allocation.[10] Emerging point-of-care testing (POCT) devices, utilizing immunoassay technology, enable rapid 25(OH)D assessment in minutes without laboratory processing, showing promise for community-based or resource-limited settings despite ongoing validation for accuracy.[101]Screening Recommendations
Screening for vitamin D deficiency is not recommended for the general population, as evidence does not support universal testing due to lack of proven benefits in reducing disease risk among healthy individuals. Instead, selective screening is advised for high-risk groups to identify and address potential deficiencies early. The Endocrine Society's 2024 clinical practice guideline recommends against routine measurement of serum 25-hydroxyvitamin D [25(OH)D] levels in most healthy individuals, including many at-risk groups such as the elderly (aged 75 years and older), those with obesity, individuals with darker skin pigmentation, and pregnant persons; however, testing remains appropriate for conditions that predispose to deficiency, such as malabsorption disorders (e.g., celiac disease or inflammatory bowel disease) or chronic kidney disease. The guideline also favors empiric supplementation without prior testing for certain groups like the elderly ≥75 years and pregnant individuals.[10][11] Targeted screening is particularly emphasized for pregnant individuals and those in institutionalized settings, where deficiency rates are elevated due to limited sun exposure and dietary constraints. A 2025 systematic review of evidence-based guidelines confirms that while no major authority endorses population-wide screening, approximately two-thirds recommend testing at-risk populations (e.g., those with osteoporosis risk) to mitigate potential complications; separate guidelines support testing for pregnant women. Frequency of screening varies by group: annual testing is suggested for ongoing high-risk individuals like those with malabsorption, while in obstetrics, evaluation is often recommended at prenatal booking or once per pregnancy for those with risk factors.[102][10] Barriers to effective screening include limited access in low-resource settings, where testing infrastructure may be inadequate, and risks of over-testing in well-resourced areas, which can lead to unnecessary costs and false positives without clinical benefit. To enhance public health impact, integration of vitamin D screening into routine check-ups for osteoporosis prevention is advocated, particularly for older adults, aligning with broader bone health strategies.[103]Treatment and Management
Non-Pharmacological Approaches
Non-pharmacological approaches to addressing vitamin D deficiency primarily involve increasing endogenous production through ultraviolet B (UVB) radiation exposure and optimizing dietary intake of natural and fortified sources, though these methods often require consistent application for meaningful improvements in serum levels. UVB exposure from sunlight remains the most accessible method, as it triggers cutaneous synthesis of vitamin D3 (cholecalciferol), the primary form utilized by the body. Guidelines recommend 10-30 minutes of midday sun exposure on the arms, legs, or face several times per week, adjusted for skin type, latitude, and season, to achieve adequate synthesis without excessive risk. For individuals with darker skin tones or those living in higher latitudes, longer exposure times may be necessary due to reduced UVB penetration. For severe deficiencies or cases where natural exposure is insufficient, narrowband UVB phototherapy offers a targeted intervention, often administered in clinical settings. This therapy uses specific wavelengths (around 311 nm) to stimulate vitamin D production with lower doses than broadband UVB, reducing side effects like erythema. Dosing protocols generally involve 2-3 sessions per week for 8-12 weeks, starting at minimal erythema doses and titrating based on response, which can elevate serum levels by up to 20 ng/mL in responsive patients. Dietary modifications play a supportive role by emphasizing foods naturally rich in vitamin D, such as fatty fish (e.g., salmon, mackerel), egg yolks, and fortified products like milk, orange juice, and cereals, though these alone rarely correct deficiency due to the limited bioavailability and quantity in typical diets. Increasing intake to 600-800 IU daily from fortified sources can contribute modestly to overall status, but efficacy is constrained by absorption variability and the body's reliance on UVB synthesis for the majority of needs. Combining dietary changes with exposure strategies enhances outcomes, particularly in populations with low baseline intake. To ensure safety and effectiveness, individuals should implement gradual increases in UVB exposure to build tolerance and avoid burns, while making seasonal adjustments—such as prioritizing midday sessions in winter or shaded exposure in summer. Regular monitoring via blood tests every 3-6 months allows for personalization, especially in high-risk groups like the elderly or those with limited mobility. Overall, consistent non-pharmacological interventions can raise serum 25-hydroxyvitamin D levels by 10-20 ng/mL over 3-6 months, though results vary by baseline status, compliance, and environmental factors.Supplementation Strategies
Vitamin D supplementation for deficiency typically involves cholecalciferol (vitamin D3) or ergocalciferol (vitamin D2), with vitamin D3 preferred due to its superior efficacy in raising serum 25-hydroxyvitamin D [25(OH)D] levels and its longer half-life compared to vitamin D2.[104] Vitamin D2, derived from plant sources, has a shorter duration of action because its metabolite, 25(OH)D2, binds less avidly to vitamin D-binding protein, leading to faster clearance.[105] In contrast, vitamin D3, obtained from animal sources or synthesized in the skin, more effectively sustains elevated 25(OH)D concentrations over time.[106] For severe vitamin D deficiency, defined by serum 25(OH)D levels below 20 ng/mL, an initial loading dose regimen is recommended to rapidly replete stores. The Endocrine Society guidelines suggest 50,000 IU of vitamin D2 or D3 administered orally once weekly for 8 weeks, or an equivalent daily dose of 6,000 IU, to achieve levels above 30 ng/mL.[13] This approach corrects deficiency in most adults without underlying absorption issues, though individual responses vary based on baseline levels and body weight. Following the loading phase, maintenance therapy aims to prevent recurrence by sustaining adequate 25(OH)D levels. A daily dose of 1,500–2,000 IU of vitamin D3 is typically advised for adults, with adjustments made based on follow-up serum measurements to target 30–50 ng/mL.[13] Lower doses around 800 IU daily may suffice for mild insufficiency, but higher amounts are often needed in obese individuals due to sequestration in adipose tissue. Magnesium serves as an essential cofactor in the enzymatic activation of vitamin D to its active form, 1,25-dihydroxyvitamin D, facilitating hydroxylation steps in the liver and kidneys.[107] Supplementation with magnesium (e.g., 300–400 mg daily) may enhance vitamin D efficacy in those with concurrent deficiency, but routine co-administration of vitamin K is not recommended unless high-dose vitamin D is used to mitigate potential vascular calcification risks.[108] Monitoring involves retesting serum 25(OH)D levels 3–6 months after initiating supplementation to assess response and adjust dosing as needed.[109] Concurrent calcium levels should be checked periodically to detect early hypercalcemia, particularly in long-term therapy. Long-term intake exceeding 10,000 IU daily poses risks of vitamin D toxicity, manifesting as hypercalcemia, which can lead to nausea, polyuria, and renal impairment.[110] Toxicity thresholds vary, but serum 25(OH)D above 150 ng/mL often correlates with these adverse effects. Approximate dosing can be guided by the formula for loading dose:\text{Dose (IU)} = 40 \times (75 - \text{serum 25(OH)D (nmol/L)}) \times \text{body weight (kg)}
This equation provides an estimate tailored to the deficit and body size, though clinical judgment is required for precise application.