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Editorials
Calcium deficiency rickets: extending the spectrum of ‘nutritional’ rickets Jeremy Allgrove,1,2 M Zulf Mughal3 Rickets is a condition of growing children in which there is failure of normal mineralisation of the epiphyseal growth plate. Normal growth plate development is dependent upon a cascade of events that consists of resting chondrocytes becoming preproliferative, proliferative, hypertrophic and finally apoptotic, which is a signal for the invasion of the growth plate by bone-forming cell precursors that replace the apoptosed cartilage cells with bone cells that mineralise the epiphyseal growth plate into true bone. Eventually, the growth plate is obliterated as the metaphyseal and epiphyseal ends of the bones fuse. It is therefore evident that rickets can only occur in growing children in whom the growth plate is still not fused. The final step of apoptosis is promoted by phosphate which has to be present in sufficient concentration to facilitate apoptosis1. In the absence of enough phosphate, apoptosis does not proceed correctly, the growth plate widens and there is failure of normal invasion of bone-forming cell precursors. This results
1
Consultant Paediatric Endocrinologist, Barts Health NHS Trust, Royal London Hospital, London, UK; 2 Honorary Consultant Paediatric Endocrinologist, Great Ormond Street Hospital for Children NHS Trust, London, UK; 3Consultant in Paediatric Bone Disorders & Honorary Professor of Child Health, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Correspondence to Dr Jeremy Allgrove, Consultant Paediatric Endocrinologist, Barts Health NHS Trust, Royal London Hospital, Whitechapel, London E1 1BB, UK; [email protected]
794
in the typical radiological appearances of rickets. Thus, it can be seen that any cause of hypophosphataemia may be associated with the development of rickets. Primary hypophosphataemic disorders are usually associated with raised Fibroblast Growth Factor 23 (FGF23) and normal parathyroid hormone (PTH) concentrations. By contrast, secondary hypophosphataemia is caused by relative calcium deficiency resulting from inadequate absorption either because of vitamin D deficiency, or because of an absolute deficiency of calcium in the diet, both of which result in raised PTH and excess phosphate excretion. The only biochemical feature that is common to all forms of rickets is hypophosphataemia. Vitamin D deficiency is an important cause of nutritional rickets in many parts of the world2 and is the commonest cause of ‘nutritional’ rickets. Following industrialisation of cities in Europe, the incidence of rickets rose considerably and, during the early part of the twentieth century, it was recognised that it could be prevented by the addition of products such as fish oil to the diet, and the incidence of rickets fell considerably. There now appears to be resurgence of nutritional rickets among children of ethnic minorities living in Europe and North America3 and, in spite of abundant sunshine, vitamin D-deficiency rickets in not uncommon in Middle Eastern countries. Main factors that give rise to vitamindeficiency rickets include residence at latitudes where solar ultraviolet B radiation needed for cutaneous vitamin D synthesis
does not reach ground levels during winter months, maternal vitamin D status during pregnancy, prolonged breastfeeding without provision of vitamin D supplements (human milk contains only about a 40 IU (1 mg) per litre), darkly pigmented skin (melanin absorbs ultraviolet B radiation, thus diminishing cutaneous vitamin D synthesis) and wearing of clothing which covers most of the skin surface area, and because of voluntary sunshine avoidance for religious and cultural reasons. Sunblock also reduces ultraviolet absorption. Vitamin D itself is of little direct importance in promoting bone mineralisation except as a mediator of calcium absorption. However, it has been recognised for some time that the tendency to develop rickets is not only dependent on vitamin D concentrations but also how much calcium is available for absorption, and that an increased intake of calcium goes some way to protecting the individual from the effects of vitamin D deficiency. Thus, adolescents in India who have vitamin D deficiency are more likely to develop rickets than their counterparts in Manchester who have an equivalent degree of vitamin D deficiency but who have a considerably higher intake of milk.4 It is also not possible to be dogmatic about what concentration of 25OHD is necessarily associated with rickets since calcium intake has a significant effect on this. In many ‘sun-rich’ tropical and subtropical parts of Africa (South Africa, Nigeria and the Gambia) and Bangladesh, cases of rickets have been reported in children who have adequate, or near-adequate body stores of vitamin D, as reflected by serum 25-hydroxyvitamin D (25OHD) levels. Diets of these rachitic children are low in calcium rich dairy products, and the bulk of their dietary calcium comes from cereals and legumes, which are rich in phytic acid that is known to inhibit Arch Dis Child September 2014 Vol 99 No 9
Downloaded from http://adc.bmj.com/ on November 19, 2014 - Published by group.bmj.com
Editorials intestinal calcium absorption. Since treatment with calcium alone improves biochemical, radiological and histological features of rickets, it is thought that dietary calcium deficiency is the main cause of rickets in these children. The results of many studies suggest that dietary calcium deficiency by itself, or in combination with vitamin D deficiency, may be an important factor in the pathogenesis of rickets. Thacher and colleagues present results of an elegant randomised controlled trial of vitamin D treatment in Nigerian children with calcium-deficiency rickets.5 They found that healing of rickets was more rapid in children who received vitamin D in addition to calcium carbonate, even though baseline serum 25OHD levels, which reflect the vitamin D status, were not different. Thus, it can be seen that the causes of rickets related to vitamin D and calcium are at two ends of a spectrum from severe vitamin D deficiency with adequate calcium intake at one end and normal vitamin D and very low calcium intake at the other. Clearly, there are some situations in which a combination of the two, with various degrees of influence, will result in rickets. The definition of ‘nutritional’ rickets, therefore, should be widened to include both vitamin D and calcium deficiency-related causes. The treatment of nutritional rickets depends on the principal cause. Where 25OHD concentrations are markedly depressed (usually
Editorials
Calcium deficiency rickets: extending the spectrum of ‘nutritional’ rickets Jeremy Allgrove,1,2 M Zulf Mughal3 Rickets is a condition of growing children in which there is failure of normal mineralisation of the epiphyseal growth plate. Normal growth plate development is dependent upon a cascade of events that consists of resting chondrocytes becoming preproliferative, proliferative, hypertrophic and finally apoptotic, which is a signal for the invasion of the growth plate by bone-forming cell precursors that replace the apoptosed cartilage cells with bone cells that mineralise the epiphyseal growth plate into true bone. Eventually, the growth plate is obliterated as the metaphyseal and epiphyseal ends of the bones fuse. It is therefore evident that rickets can only occur in growing children in whom the growth plate is still not fused. The final step of apoptosis is promoted by phosphate which has to be present in sufficient concentration to facilitate apoptosis1. In the absence of enough phosphate, apoptosis does not proceed correctly, the growth plate widens and there is failure of normal invasion of bone-forming cell precursors. This results
1
Consultant Paediatric Endocrinologist, Barts Health NHS Trust, Royal London Hospital, London, UK; 2 Honorary Consultant Paediatric Endocrinologist, Great Ormond Street Hospital for Children NHS Trust, London, UK; 3Consultant in Paediatric Bone Disorders & Honorary Professor of Child Health, Royal Manchester Children’s Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK Correspondence to Dr Jeremy Allgrove, Consultant Paediatric Endocrinologist, Barts Health NHS Trust, Royal London Hospital, Whitechapel, London E1 1BB, UK; [email protected]
794
in the typical radiological appearances of rickets. Thus, it can be seen that any cause of hypophosphataemia may be associated with the development of rickets. Primary hypophosphataemic disorders are usually associated with raised Fibroblast Growth Factor 23 (FGF23) and normal parathyroid hormone (PTH) concentrations. By contrast, secondary hypophosphataemia is caused by relative calcium deficiency resulting from inadequate absorption either because of vitamin D deficiency, or because of an absolute deficiency of calcium in the diet, both of which result in raised PTH and excess phosphate excretion. The only biochemical feature that is common to all forms of rickets is hypophosphataemia. Vitamin D deficiency is an important cause of nutritional rickets in many parts of the world2 and is the commonest cause of ‘nutritional’ rickets. Following industrialisation of cities in Europe, the incidence of rickets rose considerably and, during the early part of the twentieth century, it was recognised that it could be prevented by the addition of products such as fish oil to the diet, and the incidence of rickets fell considerably. There now appears to be resurgence of nutritional rickets among children of ethnic minorities living in Europe and North America3 and, in spite of abundant sunshine, vitamin D-deficiency rickets in not uncommon in Middle Eastern countries. Main factors that give rise to vitamindeficiency rickets include residence at latitudes where solar ultraviolet B radiation needed for cutaneous vitamin D synthesis
does not reach ground levels during winter months, maternal vitamin D status during pregnancy, prolonged breastfeeding without provision of vitamin D supplements (human milk contains only about a 40 IU (1 mg) per litre), darkly pigmented skin (melanin absorbs ultraviolet B radiation, thus diminishing cutaneous vitamin D synthesis) and wearing of clothing which covers most of the skin surface area, and because of voluntary sunshine avoidance for religious and cultural reasons. Sunblock also reduces ultraviolet absorption. Vitamin D itself is of little direct importance in promoting bone mineralisation except as a mediator of calcium absorption. However, it has been recognised for some time that the tendency to develop rickets is not only dependent on vitamin D concentrations but also how much calcium is available for absorption, and that an increased intake of calcium goes some way to protecting the individual from the effects of vitamin D deficiency. Thus, adolescents in India who have vitamin D deficiency are more likely to develop rickets than their counterparts in Manchester who have an equivalent degree of vitamin D deficiency but who have a considerably higher intake of milk.4 It is also not possible to be dogmatic about what concentration of 25OHD is necessarily associated with rickets since calcium intake has a significant effect on this. In many ‘sun-rich’ tropical and subtropical parts of Africa (South Africa, Nigeria and the Gambia) and Bangladesh, cases of rickets have been reported in children who have adequate, or near-adequate body stores of vitamin D, as reflected by serum 25-hydroxyvitamin D (25OHD) levels. Diets of these rachitic children are low in calcium rich dairy products, and the bulk of their dietary calcium comes from cereals and legumes, which are rich in phytic acid that is known to inhibit Arch Dis Child September 2014 Vol 99 No 9
Downloaded from http://adc.bmj.com/ on November 19, 2014 - Published by group.bmj.com
Editorials intestinal calcium absorption. Since treatment with calcium alone improves biochemical, radiological and histological features of rickets, it is thought that dietary calcium deficiency is the main cause of rickets in these children. The results of many studies suggest that dietary calcium deficiency by itself, or in combination with vitamin D deficiency, may be an important factor in the pathogenesis of rickets. Thacher and colleagues present results of an elegant randomised controlled trial of vitamin D treatment in Nigerian children with calcium-deficiency rickets.5 They found that healing of rickets was more rapid in children who received vitamin D in addition to calcium carbonate, even though baseline serum 25OHD levels, which reflect the vitamin D status, were not different. Thus, it can be seen that the causes of rickets related to vitamin D and calcium are at two ends of a spectrum from severe vitamin D deficiency with adequate calcium intake at one end and normal vitamin D and very low calcium intake at the other. Clearly, there are some situations in which a combination of the two, with various degrees of influence, will result in rickets. The definition of ‘nutritional’ rickets, therefore, should be widened to include both vitamin D and calcium deficiency-related causes. The treatment of nutritional rickets depends on the principal cause. Where 25OHD concentrations are markedly depressed (usually
