Abstract Contrary to frequent claims, vitamin D insufficiency does not generally cause malabsorption of calcium because serum 1,25(OH)2D, which is the major determinant of calcium absorption, is maintained by secondary hyperparathyroidism. Nevertheless, because malabsorption of calcium has been described in osteomalacia, there must be a 25(OH)D level below which the serum 1,25(OH)2D can no longer be sustained, although it has never been defined. This paper seeks to define it. We examined the records of 3661 patients and found 319 with a serum 25(OH)D ≤40 nM, in whom calcium absorption, serum calcium, PTH, bone markers, and vitamin D metabolites had been measured. They were grouped according to their serum 25(OH)D into four categories, 0–10, 11–20, 21–30, and 31–40 nM, and differences between the groups were tested by ANOVA. Correlations between the variables were also examined. Serum calcium, 1,25(OH)2D, and calcium absorption were significantly decreased and serum PTH and alkaline phosphatase (ALP) and urine hydroxyproline were increased in those with 25(OH)D ≤10 nM. Serum ALP and urine hydroxyproline were more strongly related, inversely, to calcium absorption than to the vitamin D metabolites. We conclude that vitamin D deficiency does not reduce serum 1,25(OH)2D, and therefore calcium absorption, until the serum 25(OH)D falls to ∼10 nM. At this level, the substrate concentration seems to be insufficient to maintain the level of the dihydroxy metabolite despite secondary hyperparathyroidism. Further studies are needed to see how these changes correlate with the histological changes of osteomalacia.

Nutritional rickets remains a public health problem in many countries, despite dramatic declines in the prevalence of the condition in many developed countries since the discoveries of vitamin D and the role of ultraviolet light in prevention. The disease continues to be problematic among infants in many communities, especially among infants who are exclusively breast-fed, infants and children of dark-skinned immigrants living in temperate climates, infants and their mothers in the Middle East, and infants and children in many developing countries in the tropics and subtropics, such as Nigeria, Ethiopia, Yemen, and Bangladesh. Vitamin D deficiency remains the major cause of rickets among young infants in most countries, because breast milk is low in vitamin D and its metabolites and social and religious customs and/or climatic conditions often prevent adequate ultraviolet light exposure. In sunny countries such as Nigeria, South Africa, and Bangladesh, such factors do not apply. Studies indicated that the disease occurs among older toddlers and children and probably is attributable to low dietary calcium intakes, which are characteristic of cereal-based diets with limited variety and little access to dairy products. In such situations, calcium supplements alone result in healing of the bone disease. Studies among Asian children and African American toddlers suggested that low dietary calcium intakes result in increased catabolism of vitamin D and the development of vitamin D deficiency and rickets. Dietary calcium deficiency and vitamin D deficiency represent 2 ends of the spectrum for the pathogenesis of nutritional rickets, with a combination of the 2 in the middle.

Before the twentieth century, it was not possible to describe the essentials of a diet that could support life, growth and reproduction of higher animals. The discovery of vitamin A by McCollum and Davis in 1913 ushered in the era of accessory food substances culminating in the achievement of that goal. It included the discovery of vitamin D and its production in skin caused by ultraviolet light. This was followed by a description of its actions at the physiological level that resulted in a healthy skeleton and beyond. To carry out these functions, vitamin D is converted to a hormone that acts through a nuclear receptor. The findings leading to this concept and their importance to biology and medicine are presented.

Vitamin D has many physiological functions including upregulation of intestinal calcium and phosphate absorption, mobilization of bone resorption, renal reabsorption of calcium as well as actions on a variety of pleiotropic functions. It is believed that many of the hormonal effects of vitamin D involve a 1,25-dihydroxyvitamin D 3 -vitamin D receptor-mediated transcriptional mechanism involving binding to the cellular chromatin and regulating hundreds of genes in many tissues. This comprehensive historical review provides a unique perspective of the many steps of the discovery of vitamin D and its deficiency disease, rickets, stretching from 1650 until the present. The overview is divided into four distinct historical phases which cover the major developments in the field and in the process highlighting the: (a) first recognition of rickets or vitamin D deficiency; (b) discovery of the nutritional factor, vitamin D and its chemical structure; (c) elucidation of vitamin D metabolites including the hormonal form, 1,25-dihydroxyvitamin D 3 ; (d) delineation of the vitamin D cellular machinery, functions and vitamin D-related diseases which focused on understanding the mechanism of action of vitamin D in its many target cells.

Although vitamin D deficiency was first recognized as rickets/osteomalacia in the early 1600s, it was only a century ago that vitamin D, the nutritional factor responsible, was discovered. This discovery was made difficult by the fact that the substance could be synthesized in human skin by exposure to UV light and could also be present in the diet in animal-derived (D₃) and plant-derived forms (D₂). Prior to 1920, the frequency of vitamin D deficiency in the general population of industrialized cities was high. The discovery of vitamin D led to the widespread fortification of foods e.g. milk and the virtual eradication of rickets in developed nations. Vitamin D₃ was first chemically synthesized in the 1930s and its metabolism to the active form 1,25-dihydroxyvitamin D₃ and its mode of action in calcium and phosphate homeostasis were elucidated in the latter half of the 20th century. Synthetic vitamin D analogs that mimic the physiological effects of vitamin D are now used therapeutically in diseases such as bone disease, chronic kidney disease and psoriasis. Thus, a wide range of disciplines played critical roles in the rich history of vitamin D and these are described in this short historical overview.

Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium and phosphate, along with Vitamin D is a group of structurally related, fat-soluble compounds responsible for increasing intestinal absorption of calcium and phosphate, along with numerous other biological functions. In humans, the most important compounds within this group are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). The name Vitamin D is a misnomer; technically vitamin D is not a vitamin, but rather Rickets, a childhood disease, is characterized by impeded growth and soft, weak, deformed long bones that bend and bow under their weight as children start to walk. Maternal vitamin D deficiency can cause fetal bone defects from before birth and impairment of bone quality after birth. Rickets typically presents between 3 and 18 months of age. This condition can be caused by vitamin D, calcium or phosphorus deficiency. Vitamin D deficiency remains the main cause of rickets among young infants in most countries because breast milk is low in vitamin D, and darker skin, social customs, and climatic conditions can contribute to inadequate sun exposure. A post-weaning Western omnivore diet characterized by high intakes of meat, fish, eggs and vitamin-D–fortified milk is protective, whereas low intakes of those foods and high (unfortified) cereal/grain intake contribute to risk. For young children with rickets, supplementation with vitamin D plus calcium was superior to the vitamin alone for bone healing. Characteristics of osteomalacia are softening of the bones, leading to bending of the spine, bone fragility, and increased risk for fractures. Osteomalacia is usually present when 25-hydroxyvitamin D levels are less than about 10 ng/mL. Osteomalacia can progress to osteoporosis, a condition of reduced bone mineral density with increased bone fragility and risk of bone fractures. Osteoporosis can be a long-term effect of calcium and/or vitamin D insufficiency, the latter contributing by reducing calcium absorption. In the absence of confirmed vitamin D deficiency there is no evidence that vitamin D supplementation without concomitant calcium slows or stops the progression of osteomalacia to osteoporosis. For older people with osteoporosis, taking vitamin D with calcium may help prevent hip fractures, but it also slightly increases the risk of stomach and kidney problems. The reduced risk for fractures is not seen in healthier, community-dwelling elderly. Low serum vitamin D levels have been associated with falls, but taking extra vitamin D does not appear to reduce that risk. Athletes who are vitamin D deficient are at an increased risk of stress fractures and/or… "Vita…

g to bone loss and increased fragility. A well-balanced diet that includes sufficient intake of these nutrients is essential for maintaining bone health and preventing skeletal deterioration [ 14 ]. When dietary calcium intake is insufficient, the body compensates by increasing bone resorption through elevated parathyroid hormone (PTH) levels, which accelerates osteoclast activity and reduces bone mineral density (BMD). In adults aged 50 and older, calcium and vitamin D deficiency is linked to higher PTH levels, contributing to increased bone loss [ 15 ]. Similarly, another study shows that calcium supplementation in postmenopausal women suppresses PTH, helping to preserve BMD [ 16 , 17 ]. Vitamin D plays a crucial role in maintaining calcium balance by enhancing calcium and phosphorus absorption from the gastrointestinal tract. When vitamin D levels are insufficient, calcium absorption decreases, leading to lower serum calcium levels, which triggers PTH release and increases bone resorption. Additionally, vitamin D deficiency impairs the function of osteoblasts, the cells responsible for bone formation, leading to reduced bone formation and increased bone loss [ 18 , 19 ]. In particular, the combined effect of calcium and vitamin D deficiencies exacerbates the deterioration of bone health. While calcium deficiency alone increases bone resorption, inadequate vitamin D further compounds the issue by limiting calcium absorption and impairing bone formation. This imbalance of increased resorption and decreased formation significantly weakens the skeletal structure, leading to conditions such as osteoporosis [ 20 , 21 ]. Postmenopausal women and older adults are particularly vulnerable, as age-related declines in hormone levels, particularly estrogen, contribute to skeletal aging by accelerating bone resorption and decreasing bone formation [ 22 ]. Additionally, reduced skin synthesis of vitamin D with age further exacerbates bone loss, leading to faster rates of skelet

min D insufficiency. Approximately 35% of adults in the United States have vitamin D deficiency. Symptoms and Causes Image content: This image is available to view online. View image online ( https://my.clevelandclinic.org/-/scassets/images/org/health/articles/15050-vitamin-d-deficiency ) Anyone can have vitamin D deficiency, including infants, children and adults. What are the signs and symptoms of vitamin D deficiency? Severe lack of vitamin D in children causes rickets. Symptoms of rickets include: Incorrect growth patterns due to bowed or bent bones. Muscle weakness. Bone pain. Deformities in joints. This is very rare. Children with a mild vitamin deficiency may just have weak, sore and/or painful muscles . Lack of vitamin D isn’t quite as obvious in adults. Signs and symptoms might include: Fatigue. Bone pain. Muscle weakness, muscle aches or muscle cramps . Mood changes, like depression. However, you may have no signs or symptoms of vitamin D deficiency. What causes vitamin D deficiency? In general, the two main causes of vitamin D deficiency are: Not getting enough vitamin D in your diet and/or through sunlight. Your body isn’t properly absorbing or using vitamin D. There are several specific causes of vitamin D deficiency, including: Certain medical conditions. Weight loss-surgeries. Certain medications. Several different biological and environmental factors can also put you at a greater risk of developing vitamin D deficiency, such as older age and the amount of melanin (pigment) in your skin. Medical conditions that can cause vitamin D deficiency Medical conditions that can cause vitamin D deficiency include: Cystic fibrosis , Crohn's disease and celiac disease : These conditions can prevent your intestines from adequately absorbing enough vitamin D through supplements, especially if the condition is untreated. Obesity : A body mass index greater than 30 is associated with lower vitamin D levels. Fat cells keep vitamin D isolated so that it’s not rele