Nutritional handling of calcium, phosphorous and vitamin D
Rickets occurs when the body fails to deposit calcium into growing bone, which may be due to any of three conditions:
- A deficiency of vitamin D from lack of sun exposure and/or inadequate diet
- A deficiency of dietary calcium
- A deficiency of phosphorus from excessive losses or, rarely, an inadequate dietary intake.
This commentary describes briefly the nutritional handling of these three related nutrients.
Sources of Nutrients
- Dietary vitamin D
There is little vitamin D in the ‘natural’ diet of most people. It is present in liver, fatty fish, fortified foods and supplements. A minimal amount is present in breast milk.
- Calcium
The main dietary source in many countries is dairy products, but it is present in lesser quantities in cereals and vegetables. Low-extraction cereals (white flour, for example) contain less calcium and phosphorus but also contain less phytate, so the percent of minerals absorbed is higher. Bread may be fortified with calcium. Dietary deficiency may contribute to rickets in Nigeria, South Africa and Turkey.
- Phosphorus
It is abundant in the diet but may be insufficient in rapidly growing, low birth weight babies when a ‘phosphate depletion syndrome’ may occur. In other words, these babies experience very low concentrations of plasma and urinary phosphorus. Since calcium cannot be deposited in bone without phosphorus, this condition can lead to osteopenia/rickets with the unused calcium creating hypercalciuria. Phosphorus may be precipitated in the stomach by antacids.
- Skin production of Vitamin D
The amount depends on latitude, season, personal habits and customs. Ultraviolet B radiation of wavelength 290 - 310 nm leads to the conversion (photolysis) of 7-dihydrocholesterol, which is present in the stratum Malpighi of the skin, to precholecalciferol, which then undergoes thermally induced rearrangement of its double bonds to form cholecalciferol (vitamin D3). Cholecalciferol is carried through the body by vitamin D binding protein.
- From mother
An inadequate vitamin D status (from lack of sun exposure and/or poor diet) in pregnant women contributes to hypocalcaemia and rickets in her baby
Gut handling
- Bile salts
Adequate concentration of bile salts in the duodenum is essential for micellar solubilisation, which is essential for absorption of cholesterol and fat-soluble vitamins including D.
- Lipases in breast milk, stomach, and pancreatic juice contribute to hydrolysis of fat. If hydrolysis is inadequate, calcium soaps are lost through steatorrhoea. Steatorrhoea also occurs if the structure of dietary triglyceride in the newborn is very different from that in breast milk. Phytate in cereals inhibits absorption of calcium and phosphorus.
- Enterocyte disease
Coeliac disease, for example, may inhibit vitamin D and calcium absorption. The amount of transport out of the cell is reduced if carrier proteins are inadequate, as in a beta or hypobetalipoproteinaemia.
- Enterocyte normal function
An active form of Vitamin D, 1:25 OHD (calcitriol), which is made in the kidney, stimulates calcium transport in the intestine. This is the first mechanism that links vitamin D with calcium. A rare hereditary peripheral resistance to calcitriol may occur in all tissues, limit calcium absorption and cause alopecia.
- Ileum
Lactose that reaches the lower ileum aids calcium absorption. Minimal amounts of active vitamin D appear in bile so enterohepatic circulation adds little to vitamin D status. In disease or absence of the ileum, interruption of the enterohepatic circulation may reduce bile salt secretion, which affects the absorption of calciferol - see 6 above. Liver
- Cholecalciferol is hydroxylated to become 25 hydroxy cholecalciferol, (25-OHD, calcidiol). In rickets caused by simple vitamin D deficiency, the concentration of 25-OHD is always reduced. There is some hepatic degradation of 25-OHD with excretion into the bile of inactive metabolites. This degradation is increased by certain anticonvulsants and in hyperparathyroidism via the action of calcitriol. The hyperparathyroidism may be either primary or secondary to limited amounts of absorbed calcium. Hepatic/bile duct disease limits bile acid secretion.
Kidney
- Renal tubules normal function
25-OHD is further hyroxylated in cells of the proximal renal tubules to become the active metabolite 1:25 OHD (calcitriol). This conversion is enhanced by parathormone, calcium depletion and hypophosphataemia. A rare hereditary failure of conversion may occur.
- Glomerular function
Any cause of glomerular failure leads to retention of phosphorus with a reciprocal hypocalcaemia and secondary hyperparathyroidism.
- Tubular disorders may lead to excessive phosphaturia. One type of disorder is due to a gene-controlled, phosphate-only leak (hereditary hypophosphataemic rickets from a sex-linked dominant or, rarely, an autosommal recessive gene, McCune-Albright polyostotic fibrous dysplasia, or hypercalciuric rickets). Alternatively, the leak may be secondary to tubular damage and involve leaks of other substances as well as phosphorus. These causes of tubular mixed leaks may be secondary to hereditary disorders (galactosaemia, tyrosinosis, cystinosis, or Wilsons disease, for example). Substances produced by some tumours and also in the epidermal nevus syndrome induce phosphaturia sometimes leading to rickets before the tumour is clinically obvious. If the calcium supply is adequate but it cannot be deposited in bones because of insufficient phosphate, (for example, in a parenteral nutrition regimen, or breast milk in extremely low birth weight babies) hypercalcaemia with risk of nephrocalcinosis and stones may occur.
Parathyroid glands
- If there is any tendency for plasma calcium to fall, the amount of parathormone rises and usually ‘protects’ the plasma calcium. This mechanism leads to loss of calcium from bones and an increased renal tubular leak of phosphorus. This ‘secondary hyperparathyroidism’ may occasionally progress to a tertiary stage, which proceeds independently of the rickets itself.
Bone and other tissues
- When there is inadequate dietary calcium, vitamin D induces maturation of osteoclasts, which liberate stored calcium from the bone. Apart from bone, most other tissues have vitamin D receptors including bone marrow (stem cells), prostate and skin 43.
Commonest cause of rickets
From the above description, it is clear that there are many possible causes of rickets. In the majority of cases, however, the cause is a deficiency of vitamin D, from lack of sun exposure and/or poor diet. The list below provides some indications when simple vitamin D deficiency is UNLIKELY TO BE the cause of the RICKETS
Age
- Below 6 months.
Radiological bone changes are unusual at this age except in very low birth weight babies, in which case, calcium and phosphorus deficiency should also be considered. Vitamin D deficiency at this age usually presents as hypocalcaemia and its complications, is usually accompanied by evidence of osteomalacia in the mother, and only occasionally has the classical radiographic signs of rickets.
- Between 3 and 10 years.
Toddler rickets is no longer a threat at this age, and the increased demands of the prepubertal growth spurt and adolescence are not yet apparent.
Radiographs:
These show a periosteal reaction and or a moth-eaten metaphysis rather than only the classical cupping, splaying, and fraying
Plasma biochemistry
Blood urea is greater than 7 mmol/l (5 mmol/l in newborn) and creatinine is greater than 100 umol/l. Alkaline phosphatase is not raised. Phosphorus is greater than 2 mmol/l (2.5 mol/l in newborn) or less than 1.2 mmol/l (1.5 mmol/l in newborn). Plasma 25-OHD is not low, so long as early treatment can be excluded. Plasma calcitriol is very high or very low. Vitamin D metabolite levels are often not determined in a routine case.
Geography
The child is more likely to be found in tropical or subtropical Africa or Turkey when calcium deficiency may play a role.
Response to treatment
Oral calciferol 150 mcg (6000 IU) daily (halve the dose for those less than 6 months of age) is NOT followed by radiographic evidence of some healing after two to four months of compliant treatment. The early biochemical signs of successful treatment are an initial rise to well above normal levels in alkaline phosphatase and 1,25-OHD with their later gradual fall accompanied by a rise to normal levels of 25-OHD. This monitoring is not usually necessary, however.
See Also: Rickets, Part 2.
This commentary is partly based on the following review: Wharton BA, Bishop NJ. Seminar: Rickets. Lancet. 2003; 362:1389-1400.
The topic was prepared by B A Wharton on behalf of the Advisory Committee on Child Health and Nutrition, April 2004.
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