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Rickets is a failure of the normal development and mineralization of the growth plate (physis) resulting in characteristic radiographic features. Normal mineralization depends on a series of metabolic steps requiring adequate calcium and Vitamin D, an essential fat soluble vitamin. Two sources of Vitamin D are naturally available in skin and diet.

Rickets usually develops around 3-6 months of age; it can also be seen in the newborn (especially premature) infant. The many different causes of rickets can now all be predicted by following the physiological pathways described above. After learning and understanding the physiology of Vitamin D (a prohormone), and the action of the hormone 1,25 dihydroxy Vitamin D the many causes of rickets can be logically described.

Ergocalciferol is the precursor of Vitamin D normally present in the deeper layers of the epidermis of the skin and chemically altered by ultraviolet light to an active form of Vitamin D called Vitamin D3. This is the major natural source of Vitamin D. There is a seasonal variation in temperate climates in the Vitamin D levels being highest in the autumn and lowest in the spring reflecting the length of daylight and the amount of ultraviolet light in the sunshine.

The first place to start logically is from a lack of ultraviolet light penetrating the skin to activate ergocalciferol to produce Vitamin D3. The cloudy winter months and northern latitude climates predispose children to rickets. Industrial air pollution also prevents ultra violet light from reaching the skin. In the early 20th century before Vitamin D was discovered and added to milk, rickets was a very common pediatric disease. However, rickets is not just a historical curiosity and still occurs in both the developed world and the developing world.

Even in sunnier climates rickets can still occur and must not be forgotten. Covering the entire body with clothes excludes ultraviolet light from reaching the skin. The dark skin of certain racial groups also decreases the amount of ultraviolet light from penetrating to the deeper layer of the skin and metabolizing ergocalciferol. A recent paper describes a high prevalence of Vitamin D deficiency in Orthodox Jewish mothers in Israel. In Israel the modest clothing of Orthodox Jewish women exposes very little of their skin to sunlight.

The second source of Vitamin D is in the diet. Surprisingly this is the minor source of Vitamin D that occurs naturally. A small amount of naturally occurring Vitamin D2 is found in dairy products such as milk, eggs and also in liver. Vitamin D is now added to many foods such as milk. This fortification of milk is mandated by law to prevent rickets which was common in children in the early 20th century.

Lack of Vitamin D in the diet or malabsorption of Vitamin D from the small bowel are the next steps in the pathway that can lead to rickets. Small bowel malabsorption can occur from gluten sensitive enteropathy (coeliac disease and sprue). However, children with cystic fibrosis seldom, if ever, develop rickets.

Children adopted from Russia have been described with radiographic features of rickets but lacking the biochemical changes due to early initiation of Vitamin D therapy. Both limited sunshine exposure and no vitamin supplementation in these institutionalized children was the cause.

Absorption of Vitamin D2 occurs in the proximal three quarters of the small bowel. This absorption of the fat soluble Vitamin D2 requires bile salts. The bile salts emulsify Vitamin D2 and allow absorption of this fat soluble vitamin to occur. Enterohepatic recirculation of bile salts conserves these solvents. Ingested Vitamin D2 enters the chylomicrons and is absorbed through the lymphatics. After absorption of Vitamin D2 from the small bowel it is then transported to the liver.

Vitamin D2 (dietary origin) and Vitamin D3(skin origin) are similar in their biochemical structure and are metabolized in our bodies in an identical way. These two forms of Vitamin D however are not biologically active and must be altered by two steps of hydroxylation to become active. In the liver the first hydroxylation of Vitamin D occurs. This hydroxylation occurs in the mitochondria of hepatocytes to produce 25-hydroxy Vitamin D.

Liver disease can cause rickets for several reasons. The essential first hydroxylation of Vitamin D occurs in the liver. More importantly by the failure of production of bile salts or blockage of their pathway in the biliary system leads to lack of solvents essential for Vitamin D absorption. Lack of these bile salts in the small bowel in infants with biliary atresia for example may cause rickets. Seizure medication (barbiturates and phenytoin) increases the mitochondrial enzymes within the liver for metabolism of Vitamin D to biologically inactive metabolites and can be another rare hepatic cause of rickets.

The second hydroxylation of Vitamin D occurs in the kidney. This metabolic step is performed within the mitochondria of the proximal renal tubule. The second hydroxylation produces the biologically active form of Vitamin D as 1,25 dihydroxy Vitamin D.

Hereditary forms of loss of phosphate from the proximal renal tubule can also occur with the best-known being Fanconi syndrome. With these renal tubular abnormalities producing loss of urinary phosphate there may also be loss of amino acids, glucose, protein and bicarbonate in the urine.
Vitamin D resistant rickets represents an abnormality of the renal tubule with excess loss of phosphate in the urine. In fact it is not really the same disease as rickets and may be thought of as "phosphate diabetes". There is loss of phosphate in the urine with Vitamin D resistant rickets in comparison to the glucose urine loss seen with diabetes mellitus. This is usually inherited as an X-linked disorder. Because this disease does not respond to normal doses of Vitamin D it is called Vitamin D resistant. Another name that is used to describe Vitamin D resistant rickets is hypophosphatemic rickets emphasizing that loss of phosphate is the primary cause of the rickets
Functioning as a chemical messenger produced at a single site (the kidney) and carried by the blood to its target organs 1,25 Vitamin D fulfills the definition of a hormone. 1,25 dihydroxy Vitamin D acts on its target tissues in a similar manner to other steroid hormones. This hormone acts on the proximal small bowel increasing absorption of calcium and at the growth plate of bones for the process of enchondral ossification. Enchondral ossification is the process by which cartilage is changed to bone producing longitudinal growth of bones at the physis or growth plate.

Vitamin D can therefore more accurately be called a prohormone. The actual hormone is 1,25 dihydroxy Vitamin D and is manufactured at only one specific site - the proximal renal tubule of the kidney. Secreted from the kidney into the blood this hormone has homeostatic actions that help maintain the serum calcium and phosphate levels. Mineralization and production of new bone is the other target site.
Radiographs of the knee and wrist in the AP projection should be obtained for the diagnosis of rickets. Regardless of the many cause of rickets the end result on the radiograph is identical. This also means that the cause of rickets cannot be diagnosed from the radiograph. These long bones are chosen because they represent the areas of most rapid turnover of bone at the physis or growth plate. The entire skeleton is involved with rickets and changes can be present in any of the growth plates. For example expansion of the metaphysis at the junction of bone and cartilage at the anterior ribs is the cause of the clinically palpated rickety rosary. Changes of rickets on the radiograph are:

Widening of the growth plate: with fraying (histologically this corresponds to increased cartilage which is radiolucent)
Expansion of the metaphysis occurs often described as cupping. This may produce soft tissue swelling as a clinical presentation.
Decreased density of the zone of provisional calcification (the zone of provisional calcification is a white line of dense bone normally present at the metaphyseal end of the growth plate)
Abnormal trabecular pattern
Periosteal new bone along the adjacent metaphysis and shaft
Bowing of the legs is a common clinical and radiographic sign in children who are already walking

A very rare form of rickets is also described with soft tissue tumors. These benign mesenchymal tumors produce metabolites called phosphatonins that increase renal phosphate loss. This mechanism of phosphate loss in the urine is therefore identical to Vitamin D Resistant rickets. This type of rickets is called oncogenic rickets.

The commonest soft tissue tumor to produce oncogenic rickets is the hemangiopericytoma. Oncogenic rickets can be cured by resection of the tumor.

An identical mechanism of renal tubular loss of phosphate can be a side effect of the drug ifosfamide. This iatrogenic cause of rickets may be seen in children treated for Wilms tumor.

Most probably the rarest of all causes of rickets occur secondary to a lack of Vitamin D end-organ receptors.

Elevation of the serum alkaline phosphate is the most sensitive biochemical test for rickets. The fall in serum calcium with rickets stimulates all the four parathyroid glands. Secondary hyperparathyroidism therefore occurs in response to rickets and this prevents a pathological fall in the serum calcium, which is often within the low range of normal.

Osteomalacia can be defined as delayed or inadequate mineralization of mature cortical and cancellous bone. Bone is constantly being both resorbed and produced even in the adult skeleton. There is a failure of mineralization of bone matrix with osteomalacia. Osteomalacia occurs in both children and adults.

Osteomalacia has an identical cause and pathology but it usually separated from rickets to simplify descriptions of disease. Increased osteoid, which is non-mineralized and therefore radiolucent is present in Looser's zones or pseudofractures. Bone pain, which is non-specific, is the commonest symptom of osteomalacia.

Hypophosphatasia (not to be confused with hypophosphatemic or Vitamin D resistant rickets)
Metaphyseal dysplasias. The bone collar around the edge of the growth plate is preserved in metaphyseal dysplasias and this can be helpful in the differential diagnosis. Schmid metaphyseal dysplasia for example can have a radiographic appearance similar to rickets. These two diseases can be differentiated biochemically by the serum alkaline phosphatase, which is always elevated in rickets. In hypophosphatasia the alkaline phosphatase is decreased but remains normal in cases of metaphyseal dysplasia.
Repetitive Stress ("gymnast wrist"). In the wrist the repetitive stress may give a radiographic appearance of widening of the growth plate of the distal radius and ulna that could be mistaken for rickets.