Vitamin D natural selection hypotheses:

Rickets is often a result of vitamin D3 deficiency. The vitamin D natural selection hypothesis suggests that vitamin D production from sunlight is a selective force for human skin color variation. The correlation between human skin color and latitude is thought to be the result of positive selection to varying levels of solar ultraviolet radiation. Northern latitudes have selection for lighter skin that allows UV rays to produce vitamin D from 7-dehydrocholesterol. Conversely, latitudes near the equator have selection for darker skin that can block the majority of UV radiation to protect from toxic levels of vitamin D, as well as skin cancer.

An anecdote often cited to support this hypothesis is that Arctic populations whose skin is relatively darker for their latitude, such as the Inuit, have a diet that is historically rich in vitamin D. Since these people acquire vitamin D through their diet, there is not a positive selective force to synthesize vitamin D from sunlight.

Environment mismatch:

Ultimately, vitamin D deficiency arises from a mismatch between a populations previous evolutionary environment and the individual’s current environment. This risk of mismatch increases with advances in transportation methods and increases in urban population size at high latitudes.

Similar to the environmental mismatch when dark-skinned people live at high latitudes, Rickets can also occur in religious communities that require long garments with hoods and veils. These hoods and veils act as sunlight barriers that prevent individuals from synthesizing vitamin D naturally from the sun.

In a study by Mithal et al., Vitamin D insufficiency of various countries was measured by lower 25-hydroxyvitamin D. 25(OH)D is an indicator of vitamin D insufficiency that can be easily measured. These percentages should be regarded as relative vitamin D levels, and not as predicting evidence for development of rickets.

Asian immigrants living in Europe have an increased risk for vitamin D deficiency. Vitamin D insufficiency was found in 40% of non-Western immigrants in the Netherlands, and in more than 80% of Turkish and Moroccan immigrants.

The Middle East, despite high rates of sun-exposure, has the highest rates of rickets worldwide. This can be explained by limited sun exposure due to cultural practices and lack of vitamin D supplementation for breast-feeding women. Up to 70% and 80% of adolescent girls in Iran and Saudi Arabia, respectively, have vitamin D insufficiency. Socioeconomic factors that limit a vitamin D rich diet also plays a role.

In the United States, vitamin D insufficiency varies dramatically by ethnicity. Among males aged 70 years and older, the prevalence of low serum 25(OH) D levels was 23% for non-Hispanic whites, 45% for Mexican Americans, and 58% for non-Hispanic blacks. Among women, the prevalence was 28.5%, 55%, and 68%, respectively.

A systematic review published in the Cochrane Library looked at children up to three years old in Turkey and China and found there was a negative association between vitamin D and rickets. In Turkey children getting vitamin D had only a 4% chance of developing rickets compared to children who received no medical intervention. In China, a combination of vitamin D, calcium and nutritional counseling was linked to a decreased risk of rickets.

With this evolutionary perspective in mind, parents can supplement their nutritional intake with vitamin D enhanced beverages if they feel their child is at risk for vitamin D deficiency,

Maternal deficiencies may be the cause of overt bone disease from before birth and impairment of bone quality after birth. The primary cause of congenital rickets is vitamin D deficiency in the mother's blood, which the baby shares. Vitamin D ensures that serum phosphate and calcium levels are sufficient to facilitate the mineralization of bone. Congenital rickets may also be caused by other maternal diseases, including severe osteomalacia, untreated celiac disease, malabsorption, pre-eclampsia, and premature birth. Rickets in children is similar to osteoporosis in the elderly, with brittle bones. Pre-natal care includes checking vitamin levels and ensuring that any deficiencies are supplemented.

Also exclusively breast-fed infants may require rickets prevention by vitamin D supplementation or an increased exposure to sunlight.

In sunny countries such as Nigeria, South Africa, and Bangladesh, there is sufficient endogenous vitamin D due to exposure to the sun. However, the disease occurs among older toddlers and children in these countries, which in these circumstances is attributed to low dietary calcium intakes due to a mainly cereal-based diet.

Those at higher risk for developing rickets include:

- Breast-fed infants whose mothers are not exposed to sunlight

- Breast-fed infants who are not exposed to sunlight

- Breast-fed babies who are exposed to little sunlight

- Adolescents, in particular when undergoing the pubertal growth spurt

- Any child whose diet does not contain enough vitamin D or calcium

Osteomalacia is the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bone metabolism causes inadequate bone mineralization. Osteomalacia in children is known as rickets, and because of this, use of the term "osteomalacia" is often restricted to the milder, adult form of the disease. Signs and symptoms can include diffuse body pains, muscle weakness, and fragility of the bones. In addition to low systemic levels of circulating mineral ions necessary for bone and tooth mineralization, accumulation of mineralization-inhibiting proteins and peptides (such as osteopontin and ASARM peptides) occurs in the extracellular matrix of bones and teeth, likely contributing locally to cause matrix hypomineralization (osteomalacia).

The most common cause of osteomalacia is a deficiency of vitamin D, which is normally derived from sunlight exposure and, to a lesser extent, from the diet. The most specific screening test for vitamin D deficiency in otherwise healthy individuals is a serum 25(OH)D level. Less common causes of osteomalacia can include hereditary deficiencies of vitamin D or phosphate (which would typically be identified in childhood) or malignancy.

Vitamin D and calcium supplements are measures that can be used to prevent and treat osteomalacia. Vitamin D should always be administered in conjunction with calcium supplementation (as the pair work together in the body) since most of the consequences of vitamin D deficiency are a result of impaired mineral ion homeostasis.

Nursing home residents and the homebound elderly population are at particular risk for vitamin D deficiency, as these populations typically receive little sun exposure. In addition, both the efficiency of vitamin D synthesis in the skin and the absorption of vitamin D from the intestine decline with age, thus further increasing the risk in these populations. Other groups at risk include individuals with malabsorption secondary to gastrointestinal bypass surgery or celiac disease, and individuals who immigrate from warm climates to cold climates, especially women who wear traditional veils or dresses that prevent sun exposure.

Prevention of osteomalacia rests on having an adequate intake of vitamin D and calcium. Vitamin D3 Supplementation is often needed due to the scarcity of Vitamin D sources in the modern diet.

Elderly people have a higher risk of having a vitamin D deficiency due to a combination of several risk factors, including: decreased sunlight exposure, decreased intake of vitamin D in the diet, and decreased skin thickness which leads to further decreased absorption of vitamin D from sunlight.

Those most likely to be affected by vitamin D deficiency are people with little exposure to sunlight. Climate, dress habits, avoiding sun exposure and too much sunscreen protection limit the production of vitamin D.

This fundamental fat-soluble vitamin has been long known for its important role in calcium absorption in the body, especially in musculoskeletal health. The health impacts commonly caused by deficiency of Vitamin D are rickets in children and osteoporosis in the elderly populations. Low levels of Vitamin D have also been associated with other conditions such as heart disease, cancer and kidney disease but further research is required. Recent evidence suggests Vitamin D is also linked to many other health diseases such as cardiovascular disease, chronic kidney disease, diabetes mellitus, multiple sclerosis and some form of cancer.

Pregnancy also poses as another high risk factor for vitamin D deficiency. The status levels of vitamin D during the last stages of pregnancy directly impact the new borns first initial months of life. Babies who are exclusively breastfed with minimal exposure to sunlight or supplementation can be at greater risk of vitamin D deficiency,as human milk has minimal vitamin D present. Recommendations for infants of the age 0–12 months are set at 5 ug/day, to assist in preventing rickets in young babies. 80% of dark skinned and or veiled women in Melbourne were found to have serum levels lower than 22.5 nmol/L considering them to be within moderate ranges of vitamin D deficiency.

Autosomal dominant hypophosphatemic rickets (ADHR) is a rare hereditary disease in which excessive loss of phosphate in the urine leads to poorly formed bones (rickets), bone pain, and tooth abscesses. ADHR is caused by a mutation in the fibroblast growth factor 23 (FGF23). ADHR affects men and women equally; symptoms may become apparent at any point from childhood through early adulthood. Blood tests reveal low levels of phosphate (hypophosphatemia) and inappropriately normal levels of vitamin D. Occasionally, hypophosphatemia may improve over time as urine losses of phosphate partially correct.

ADHR may be lumped in with X-linked hypophosphatemia under general terms such as "hypophosphatemic rickets". Hypophospatemic rickets are associated with at least nine other genetic mutations. Clinical management of hypophospatemic rickets may differ depending on the specific mutations associated with an individual case, but treatments are aimed at raising phosphate levels to promote normal bone formation.

Perinatal and infantile hypophosphatasia are inherited as autosomal recessive traits with homozygosity or compound heterozygosity for two defective TNSALP alleles. The mode of inheritance for childhood, adult, and odonto forms of hypophosphatasia can be either autosomal dominant or recessive. Autosomal transmission accounts for the fact that the disease affects males and females with equal frequency. Genetic counseling is complicated by the disease’s variable inheritance pattern, and by incomplete penetration of the trait.

Hypophosphatasia is a rare disease that has been reported worldwide and appears to affect individuals of all ethnicities. The prevalence of severe hypophosphatasia is estimated to be 1:100,000 in a population of largely Anglo-Saxon origin. The frequency of mild hypophosphatasia is more challenging to assess because the symptoms may escape notice or be misdiagnosed. The highest incidence of hypophosphatasia has been reported in the Mennonite population in Manitoba, Canada where one in every 25 individuals are considered carriers and one in every 2,500 newborns exhibits severe disease. Hypophosphatasia is considered particularly rare in people of African ancestry in the U.S.

Bone disease is common among the elderly individual, but adolescents can be diagnosed with this disorder as well. There are many bone disorders such as osteoporosis, Paget's disease, hypothyroidism. Although there are many forms of bone disorders, they all have one thing in common; abnormalities of specific organs involved, deficiency in vitamin D or low Calcium in diet, which results in poor bone mineralization.

In circumstances where other pathologies are excluded (for example, cancer), a pathologic fracture is diagnostic of osteoporosis irrespective of bone mineral density.

Pathologic fractures in children and adolescents can result from a diverse array of disorders namely; metabolic, endocrine, neoplastic, infectious, immunologic, and genetic skeletal dysplasias.

- Osteogenesis imperfecta

- Primary hyperparathyroidism

- Simple bone cyst

- Aneurismal bone cyst

- Disuse osteoporosis

- Chronic osteomyelitis

- Osteogenesis imperfecta

- Rickets

- Renal osteodystrophy

- Malignant infantile osteopetrosis

- juvenile osteoporosis

- juvenile rheumatoid arthritis

X-linked hypophosphatemia (XLH), also called X-linked dominant hypophosphatemic rickets, X-linked vitamin d-resistant rickets, is an X-linked dominant form of rickets (or osteomalacia) that differs from most cases of rickets in that ingestion of vitamin D is relatively ineffective. It can cause bone deformity including short stature and genu varum (bow leggedness). It is associated with a mutation in the PHEX gene sequence (Xp.22) and subsequent inactivity of the PHEX protein. The prevalence of the disease is 1:20000. The leg deformity can be treated with Ilizarov frames and CAOS surgery.

Oral phosphate, 9, calcitriol, 9; in the event of severe bowing, an osteotomy may be performed to correct the leg shape.

Endocrine disorder is more common in women than men, as it is associated with menstrual disorders.

Hypophosphatasia is often discovered because of an early loss of deciduous (baby or primary) teeth with the root intact. Researchers have recently documented a positive correlation between dental abnormalities and clinical phenotype. Poor dentition is also noted in adults.

Resection of the tumor is the ideal treatment and results in correction of hypophosphatemia (and low calcitriol levels) within hours of resection. Resolution of skeletal abnormalities may take many months.

If the tumor cannot be located, treatment with calcitriol (1-3 µg/day) and phosphorus (1-4 g/day in divided doses) is instituted. Tumors which secrete somatostatin receptors may respond to treatment with octreotide. If hypophosphatemia persists despite calcitriol and phosphate supplementation, administration of cinacalcet has been shown to be useful

Tumor-induced osteomalacia is usually referred to as a paraneoplastic phenomenon, however, the tumors are usually benign and the symptomatology is due to osteomalacia or rickets. A benign mesenchymal or mixed connective tissue tumor (usually phosphaturic mesenchymal tumor and hemangiopericytoma) are the most common associated tumors. Association with mesenchymal malignant tumors, such as osteosarcoma and fibrosarcoma, has also been reported.

Locating the tumor can prove to be difficult and may require whole body MRI. Some of the tumors express somatostatin receptors and may be located by octreotide scanning.

A phosphaturic mesenchymal tumor is an extremely rare benign neoplasm of soft tissue and bone that inappropriately produces fibroblast growth factor 23. This tumor may cause tumor-induced osteomalacia, a paraneoplastic syndrome, by the secretion of FGF23, which has phosphaturic activity (by inhibition of renal tubular reabsorption of phosphate and renal conversion of 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D). The paraneoplastic effects can be debilitating and are only reversed on discovery and surgical resectionof the tumor.

Primary hypophosphatemia is the most common cause of nonnutritional rickets. Laboratory findings include low-normal serum calcium, moderately low serum phosphate, elevated serum alkaline phosphatase, and low serum 1,25 dihydroxy-vitamin D levels, hyperphosphaturia, and no evidence of hyperparathyroidism.

Other rarer causes include:

- Certain blood cancers such as lymphoma or leukemia

- Hereditary causes

- Liver failure

- Tumor-induced osteomalacia

Treatment for secondary juvenile osteoporosis focuses on treating any underlying disorder.

Hypophosphatemia is caused by the following three mechanisms:

- Inadequate intake (often unmasked in refeeding after long-term low phosphate intake)

- Increased excretion (e.g. in hyperparathyroidism, hypophosphatemic rickets)

- Shift from extracellular to intracellular space. This can be seen in treatment of diabetic ketoacidosis, refeeding, short-term increases in cellular demand (e.g. hungry bone syndrome) and acute respiratory alkalosis.

Juvenile osteoporosis is osteoporosis in children and adolescents.Osteoporosis is rare in children and adolescents. When it occurs, it is usually secondary to some other condition, "e.g." osteogenesis imperfecta, rickets, eating disorders or arthritis. In some cases, there is no known cause and it is called idiopathic juvenile osteoporosis. Idiopathic juvenile osteoporosis usually goes away spontaneously.

Also, child abuse should be suspected in recurring cases of bone fracture.

A vitamin deficiency can cause a disease or syndrome known as an avitaminosis or hypovitaminosis. This usually refers to a long-term deficiency of a vitamin. When caused by inadequate nutrition it can be classed as a "primary deficiency", and when due to an underlying disorder such as malabsorption it can be classed as a "secondary deficiency". An underlying disorder may be metabolic as in a defect converting tryptophan to niacin. It can also be the result of lifestyle choices including smoking and alcohol consumption.

Examples are vitamin A deficiency, folate deficiency, scurvy, vitamin D deficiency, vitamin E deficiency, and vitamin K deficiency. In the medical literature, any of these may also be called by names on the pattern of "hypovitaminosis" or "avitaminosis" + "[letter of vitamin]", for example, hypovitaminosis A, hypovitaminosis C, hypovitaminosis D.

Conversely hypervitaminosis is the syndrome of symptoms caused by over-retention of fat-soluble vitamins in the body.

- Vitamin A deficiency can cause keratomalacia.

- Thiamine (vitamin B1) deficiency causes beriberi and Wernicke–Korsakoff syndrome.

- Riboflavin (vitamin B2) deficiency causes ariboflavinosis.

- Niacin (vitamin B3) deficiency causes pellagra.

- Pantothenic acid (vitamin B5) deficiency causes chronic paresthesia.

- Vitamin B6

- Biotin (vitamin B7) deficiency negatively affects fertility and hair/skin growth. Deficiency can be caused by poor diet or genetic factors (such as mutations in the BTD gene, see multiple carboxylase deficiency).

- Folate (vitamin B9) deficiency is associated with numerous health problems. Fortification of certain foods with folate has drastically reduced the incidence of neural tube defects in countries where such fortification takes place. Deficiency can result from poor diet or genetic factors (such as mutations in the MTHFR gene that lead to compromised folate metabolism).

- Vitamin B12 (cobalamin) deficiency can lead to pernicious anemia, megaloblastic anemia, subacute combined degeneration of spinal cord, and methylmalonic acidemia among other conditions.

- Vitamin C (ascorbic acid) short-term deficiency can lead to weakness, weight loss and general aches and pains. Longer-term depletion may affect the connective tissue. Persistent vitamin C deficiency leads to scurvy.

- Vitamin D (cholecalciferol) deficiency is a known cause of rickets, and has been linked to numerous health problems.

- Vitamin E deficiency causes nerve problems due to poor conduction of electrical impulses along nerves due to changes in nerve membrane structure and function.

- Vitamin K (phylloquinone or menaquinone) deficiency causes impaired coagulation and has also been implicated in osteoporosis

Radiation exposure increases the risk of primary hyperparathyroidism. A number of genetic conditions including multiple endocrine neoplasia syndromes also increase the risk.