Cause Of Rickets Research Articles

Mutation of theCYP2R1Vitamin D 25-Hydroxylase in a Saudi Arabian Family with Severe Vitamin D Deficiency

Inherited forms of vitamin D deficiency are rare causes of rickets and to date have been traced to mutations in three genes, VDR, encoding the 1α,25-dihydroxyvitamin D receptor, CYP27B1, encoding the vitamin D 1α-hydroxylase, and CYP2R1, encoding a microsomal vitamin D 25-hydroxylase. Multiple mutations have been identified in VDR and CYP27B1 in patients with rickets, and thus, the roles of these two genes in vitamin D metabolism are unassailable. The case is less clear for CYP2R1, in which only a single mutation, L99P in exon 2 of the gene, has been identified in Nigerian families, and because multiple enzymes with vitamin D 25-hydroxylase activity have been identified. Here we report molecular genetic studies on two siblings from a Saudi family who presented with classic symptoms of vitamin D deficiency. The affected offspring inherited two different CYP2R1 mutations (367+1, G→A; 768, iT), which are predicted to specify null alleles. We conclude that CYP2R1 is a major vitamin D 25-hydroxylase that plays a fundamental role in activation of this essential vitamin.

Early Animal Models of Rickets and Proof of a Nutritional Deficiency Hypothesis

In the period between 1880 and 1930, the role of nutrition and nutritional deficiency as a cause of rickets was established based upon the results from 6 animal models of rickets. This greatly prevalent condition (60%-90% in some locales) in children of the industrialized world was an important clinical research topic. What had to be reconciled was that rickets was associated with infections, crowding, and living in northern latitudes, and cod liver oil was observed to prevent or cure the disease. Several brilliant insights opened up a new pathway to discovery using animal models of rickets. Studies in lion cubs, dogs, and rats showed the importance of cod liver oil and an antirachitic substance later termed vitamin D. They showed that fats in the diet were required, that vitamin D had a secosteroid structure and was different from vitamin A, and that ultraviolet irradiation could prevent or cure rickets. Several of these experiments had elements of serendipity in that certain dietary components and the presence or absence of sunshine or ultraviolet irradiation could critically change the course of rickets. Nonetheless, at the end of these studies, a nutritional deficiency of vitamin D resulting from a poor diet or lack of adequate sunshine was firmly established as a cause of rickets.

The enthesopathy of vitamin D-resistant osteomalacia in adults

A case of an adult patient with vitamin D-resistant osteomalacia or X-linked hypophosphatemic osteomalacia (XLH) with diffuse calcification of entheses is reported. XLH is the most frequent cause of rickets in developed countries. It is characterized by an impaired renal transport of the phosphate and mutation of PFEX (phosphate regulating gene, with homologies to endopeptidase on the X-chromosome). In childhood, the classic clinical presentation includes short stature and bow leg. While at this age the main radiographic features are characterised by rickets, in adult life they are dominated by a generalised calcific enthesopathy. Concerning the pathogenesis of the enthesopathic lesions of XLH, no convincing hypothesis has yet been made. As in our patient, the extension and the severity of enthesopathy seems not related to the severity of the biochemical changes nor to the treatment with calcitriol. The calcified enthesopathy is an integral part of XLH and it is possible that it is found in adult because many years are necessary to produce it.

Not all rickets is vitamin D deficiency

Although vitamin D deficiency is a common cause of rickets, other types of rickets, including hereditary forms, must be considered in the differential diagnosis. The patient described here presented for evaluation of bowing of his lower extremities, and was ultimately diagnosed with X-linked hypophosphatemic rickets, a disorder caused by renal wasting of phosphate that occurs as a result of a mutation in the PHEX gene.

Relationship of calcium absorption with 25(OH)D and calcium intake in children with rickets

Nutritional rickets has long been considered a disease caused by vitamin D deficiency, but recent data indicate that inadequate dietary calcium intake is an important cause of rickets, particularly in tropical countries. Children with rickets due to calcium deficiency do not have very low 25(OH)D concentrations, and serum 1,25(OH)(2) D values are markedly elevated. Studies of Nigerian children with rickets demonstrated they have high fractional calcium absorption. A high-phytate diet was demonstrated to increase calcium absorption compared with the fasting state, and enzymatic dephytinization did not significantly improve calcium absorption. When given vitamin D, children with rickets have a marked increase in 1,25(OH)(2) D concentrations without any change in fractional calcium absorption. No positive relationship was found between fractional calcium absorption and serum 25(OH)D concentrations in children on low-calcium diets. More research is needed to understand the interaction between calcium and vitamin D and the role of vitamin D in calcium absorption.

Acute Renal Failure and Anuria Associated with Vitamin D Intoxication in Two Alpaca (Vicugna pacos) Cria

V itamin D deficiency is the leading cause of rickets in growing llamas and alpacas in North America, New Zealand, and Australia. Prophylactic treatment with vitamin D supplements is a common husbandry practice in North America. This case report describes the clinical course, diagnostics, and pathological findings in 2 alpaca cria (Vicugna pacos), presenting at 18 days and 8 days of age, with presumptive vitamin D intoxication. Both cria developed tissue mineralization and acute renal failure after administration of excessive doses of vitamin D. Presentation of camelids with a history of vitamin D administration associated with hypercalcemia, hyperphosphatemia, and renal dysfunction strongly suggests vitamin D intoxication. Early recognition of these signs can improve clinical outcomes.

Metabolic bone disease in lion cubs at the London Zoo in 1889: the original animal model of rickets

In 1889 Dr. John Bland-Sutton, a prominent London surgeon, was consulted about fatal rickets in over 20 successive litters of lion cubs born at the London Zoo. He evaluated the diet and found the cause of rickets to be nutritional in origin. He recommended that goat meat with crushed bones and cod-liver oil be added to the lean horsemeat diet of the cubs and their mothers. Rickets were reversed, the cubs survived, and subsequent litters thrived. Thirty years later, in classic controlled studies conducted in puppies and young rats, the definitive role of calcium, phosphate and vitamin D in prevention and therapy of rickets was elucidated. Further studies led to identifying the structural features of vitamin D.Although the Bland-Sutton diet provided calcium and phosphate from bones and vitamins A and D from cod-liver oil, some other benefits of this diet were not recognized. Taurine-conjugated bile salts, necessary for intestinal absorption of fat-soluble vitamins, were provided in the oil cold-pressed from cod liver. Unlike canine and rodent species, felines are unable to synthesize taurine, yet conjugate bile acids exclusively with taurine; hence, it must be provided in the diet. The now famous Bland-Sutton “experiment of nature,” fatal rickets in lion cubs, was cured by addition of minerals and vitamin D. Taurine-conjugated bile salts undoubtedly permitted absorption of vitamins A and D, thus preventing the occurrence of metabolic bone disease and rickets.

Tumour-induced osteomalacia: a curable condition

Osteomalacia is a condition characterised by failure of bone mineralisation. While abnormalities of vitamin D supply, metabolism or action are the most common and well-known causes, chronic phosphate deficiency, due to either insufficient input (intake or absorption) or renal losses are also important causes of rickets or osteomalacia.1 Hypophosphataemia also commonly co-exists with vitamin D deficiency, pursuant to secondary hyperparathyroidism. Other causes include chronic calcium deficiency, hypophosphatasia, fluoride and aluminium excess. In respect of chronic hypophosphataemia-associated rickets/ osteomalacia, the commonest aetiology is X-linked dominant hypophosphataemia, XLH, (1:20000 births).1 Others include Fanconi syndrome, autosomal dominant hypophosphataemic rickets (ADHR) and tumour-induced osteomalacia (TIO).2

Ganglioneuroblastoma-associated Vitamin D Deficiency Rickets

Vitamin D deficiency is the most common cause of rickets mainly in breast-fed dark-skinned, African or Asian children receiving inadequate sunlight exposure. We report a case of a 1.5 year-old Afro-Italian male infant living in South Italy who came to our observation with the typical clinical picture of vitamin D deficiency rickets. The child was exclusively breast-fed for 8 months without vitamin D supplements. Owing to the rarity of vitamin D deficiency rickets in the South of Italy he underwent several investigations, which demonstrated the association with an abdominal ganglioneuroblastoma. To our knowledge, ganglioneuroblastoma has never been reported in association with vitamin D deficiency rickets. Although the association between these 2 rare conditions may be coincidental, the protective action of vitamin D against cancer suggests that vitamin D deficiency might have contributed to the development of ganglioneuroblastoma in our patient.

Incidence and prevalence of nutritional and hereditary rickets in southern Denmark

To estimate the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets. Population-based retrospective cohort study based on a review of medical records. Patients aged 0-14.9 years referred to or discharged from hospitals in southern Denmark from 1985 to 2005 with a diagnosis of rickets were identified by register search, and their medical records were retrieved. Patients fulfilling the diagnostic criteria of primary rickets were included. We identified 112 patients with nutritional rickets of whom 74% were immigrants. From 1995 to 2005, the average incidence of nutritional rickets in children aged 0-14.9 and 0-2.9 years was 2.9 and 5.8 per 100,000 per year respectively. Among immigrant children born in Denmark, the average incidence was 60 (0-14.9 years) per 100,000 per year. Ethnic Danish children were only diagnosed in early childhood and the average incidence in the age group 0-2.9 years declined from 5.0 to 2.0 per 100,000 per year during 1985-1994 to 1995-2005. Sixteen cases of hereditary rickets were diagnosed during the study period giving an average incidence of 4.3 per 100,000 (0-0.9 years) per year. The prevalence of hypophosphatemic rickets and vitamin D-dependent rickets type 1 was 4.8 and 0.4 per 100,000 (0-14.9 years) respectively. Nutritional rickets is rare in southern Denmark and largely restricted to immigrants, but the incidence among ethnic Danish children was unexpectedly high. Hereditary rickets is the most common cause of rickets in ethnic Danish children, but nutritional rickets is most frequent among all young children.

Rickets and osteomalacia in northeast Iran: report of 797 cases

ABSTRACTAim: To study the clinical, biochemical and radiographic features of rickets and osteomalacia in north‐east of Iran.Methods: We retrospectively reviewed the medical records of all patients with diagnosis of rickets and osteomalacia during the past 20 years (1986–2006) in the rheumatology outpatient clinic of Imam Reza Hospital, Mashhad, Iran.Results: There were 797 patients (795 female, 2 male). Their ages were between 8–74 years. Most cases were in their second decade of life. The most common clinical findings were: bone pain 96.4%, muscle weakness 81%, abnormal gait 43%, and bone deformity 19.6%. The most common laboratory finding was high serum alkaline phosphatase (92%) followed by hypophosphatemia 54.6%, and hypocalcemia (21%). Radiographic findings were: epiphyseal growth plate alterations 74.4%, osteopenia 63%, ground glass appearance 28.6%, and Looser's zones 26.5%. All except four patients were cured with vitamin D and calcium.Conclusion: Rickets and osteomalacia are common disorders in our region. Females especially in the growing years are often involved. The most common cause of rickets and osteomalacia in our region is vitamin D deficiency probably due to inadequate sun exposure.

Rickets

Worldwide, rickets is the most common form of metabolic bone disease in children. Despite the concept that it is a rare disease, it is on the increase in many regions, including Western Europe and the USA, and in many ethnic subgroups that have immigrated to temperate regions. Vitamin D deficiency is the main cause of rickets, though nutritional deficiency of calcium and phosphorous generates the same clinical picture. Rickets also occurs when the metabolites of vitamin D are deficient. This may be due to an inherited cause or secondary to disorders of the gut, pancreas, liver or kidney from disruption of vitamin D metabolism.

An outbreak of rickets in Corriedale sheep: Evidence for a genetic aetiology

CASE HISTORY: A skeletal disease characterised by lameness, limb deformities and reduced growth rate occurred over two successive years in lambs born on a commercial sheep farm in Marlborough. A genetic aetiology was considered likely following exclusion of other known causes of rickets and because of the progressive nature of the disease, even after affected animals were transferred to another property. CLINICAL FINDINGS: Affected lambs appeared normal at birth but developed clinical signs during the first 2 months of life. The most severely affected animals either died or were euthanised within the first year of life, but some survived to breeding age. Serum biochemistry revealed hypocalcaemia, hypophosphataemia and increased concentrations of 1,25 dihydroxyvitamin D. The mean serum 25 hydroxyvitamin D concentration was similar to that of control lambs. PATHOLOGICAL FINDINGS: Gross lesions included enlarged costochondral junctions, bilateral irregularity of articular surfaces on humeral heads due to collapse of subchondral bone, thickened cortices in long bones and irregular thickening of physeal cartilages. Microscopically, tongues of hypertrophic chondrocytes extended from physes into metaphyseal regions; metaphyseal trabeculae were thick, disorganised and often lined by wide osteoid seams. Osteoclastic activity was excessive both in cortical and trabecular bone. DIAGNOSIS: Inherited rickets in Corriedale sheep. CLINICAL RELEVANCE AND CONCLUSIONS: This disease is likely to be present in several Corriedale sheep flocks in New Zealand and may have been misdiagnosed as arthritis or other diseases causing lameness and/or poor growth. A defect in end-organ responsiveness to 1,25 dihydroxyvitamin D is the likely mechanism. This disease of sheep may be a useful model for studying vitamin D metabolism and the treatment of inherited forms of rickets in human beings.

Osteonecrosis of the jaw and bisphosphonates in children and adolescents

Nutritional rickets most commonly results from vitamin D deficiency and is typically associated with inadequate sunlight. Thus, the existence of rickets in many tropical countries, where sunlight is abundant, is unexpected, and has suggested that genetic, hormonal, and other nutritional factors may cause rickets in susceptible children. We recently identified a missense mutation (Leu99Pro) in exon 2 of CYP2R1, the gene encoding the key hepatic vitamin D 25hydroxylase, in members of 2 of 10 Nigerian families in which more than 1 subject had rickets. One proband (T133), his affected brother (T133-1) and their father (T133-5) were homozygous (CYP−/−) for the L99P allele; his mother and two sisters were heterozygous (CYP−/+) for the L99P allele, and one of the sisters had a history of genu varum that resolved spontaneously as a toddler. The second proband (K170) and her affected sister were both heterozygous for the L99P mutation. Their mother was homozygous for the wild type allele while their clinically unaffected father was heterozygous. Biochemical analyses showed that homozygous brothers T133 and T133-1 were hypocalcemic with elevated alkaline phosphatase; their homozygous father T133-5 and all heterozygous subjects had normal serum calcium and alkaline phosphatase concentrations. Because in vitro analyses of CYP2R1 function had shown that the L99P enzyme retained modest residual activity, we administered 50,000 IU of ergocalciferol (D2) or cholecalciferol (D3) on separate occasions to subjects and determined serum levels of 25 (OH)D2 and 25(OH)D3 by isotope-dilution liquid chromatography-tandem mass spectrometry on days 0, 1, 3, and 7. Peak values were achieved on day 3 (see Table). We conclude that homozygous or heterozygous mutation of the CYP2R1 gene is a cause of rickets, and represents a new form of vitamin D dependent rickets. Remarkably, the phenotype appears to improve with age and treatment with calcium, suggesting the involvement of other genetic, hormonal or environmental factors that can compensate for loss of CYP2R1 vitamin D 25 hydroxylase activity. The role of variant alleles of CYP2R1 in the pathogenesis of vitamin D deficiency and/or metabolic bone disease worldwide remains to be determined.

Rickets: Vitamin D and Calcium Deficiency

To the Editor In his historical perspective, Jeffrey O'Riordan accounts for the appearance of rickets in London in the early 17th century from reduced UV exposure and vitamin D deficiency, resulting from coal burning and air pollution.1 However, we propose another hypothesis to account for the appearance of rickets, which also accounts for O'Riordan's observation that rickets was reported initially in the country, where presumably there was less smoke. Rickets was evidently a popularly known disease in the early 17th century and was described in the Netherlands as early as 1614.2 The appearance of rickets was coincident with another cultural practice increasingly adopted in 17th century London: wet-nursing. Infants from wealthier parishes were sent out of London to wet-nurses in country parishes.3 Rickets was more common among affluent than working-class children. Francis Glisson observed, “this disease doth more frequently invade the cradles of the rich than afflict poor men's children.”4 Swinburne pointed out that “there was a suspicion among families and doctors that a bad wet-nurse or poor feeding provoked the condition.”2 Infants who were wet-nursed in the country were likely to have as much sun exposure as other children in the wet-nurse's family. Wet-nurses often nursed several children simultaneously. The concentration of calcium in breast milk declines as the duration of breast feeding increases.5 Consequently, the continuous lactation of the wet-nurse would have resulted in a relatively low calcium concentration of her breast milk. Cereal porridges used in weaning,2 possibly with high phytate content, would have further aggravated a marginal calcium intake. We propose that the calcium intake of many infants who were wet-nursed and weaned to cereal porridges was insufficient to permit adequate bone mineralization. The resultant hypocalcemia and secondary hyperparathyroidism are likely to have increased vitamin D catabolism and converted relative vitamin D insufficiency to vitamin D deficiency.6 The latter hypothesis emphasizes the role of low dietary calcium intakes in the pathogenesis of rickets and is analogous to the situation in developing countries today, where calcium deficiency is an important cause of nutritional rickets. Whereas vitamin D–deficient rickets typically manifests in the first year of life, Glisson described manifestations primarily in the second year,4 similar to children with inadequate calcium intake. Calcium deficiency likely contributed to the appearance of rickets in England, which was probably supplanted 200 years later by vitamin D deficiency as the principal cause of rickets during the industrial revolution.

Rickets: Vitamin D and Calcium Deficiency

I am grateful to Thacher et al. for their comments and for drawing attention to the recent paper by Swinburne,1 which appeared while my Perspective was in press. Two of Swinburne's observations especially interested me. The first was finding records of early recipes for treating rickets in the handwritten papers of the Fairfax family, dated February 25, 1632. These can be seen in a facsimile reproduction2 published in 1890 and were written before the word “rickets” appeared in print in the Bills of Mortality for 1634. “The children get little knobs on their ribs, like pinheads or rosary beads, or of similar size.” The size of the pinheads or rosary beads at that time is not known, but Monna3 suggested, reasonably, that this might be rickets. The text that is quoted is part of a report to the Bishop of 's-Hertogenbosch, which was commissioned because of concerns about the conduct of pilgrimages in that part of Holland. The text was based on the statement of a Hermitess, supported by her predecessor in the hermitage. They also gave the features of the Ailment of St Machutus, which were that the lower limbs appeared as though they were sitting cross-legged together with swelling of the abdomen. The Ailment of St Machutus apparently was often accompanied by the Ailment of St Willibrord. Despite concerns on religious grounds, the pilgrimages continued for many years, and presumably her successors in the Hermitage took over the diagnosis and the treatment, which involved using water from a well in Diessen, 30 km away, and a religious routine. It should be said that whether they were actually dealing with rickets, at that time, must be debatable. “The disease is most frequent in the ranks of the highest citizens, next amongst the dregs of the populace, least amongst those of moderate means. The cause in the first group I take to be the intemperance of the parents and the fact that the infants are entrusted to the care of hired wet nurses.” “As to the Rickets, it was a distemper in England, almost worn out, but now it becomes in play again. But in the time of King Charles 1,” (who lived 1600–49) “it was almost epidemical, few families escaping it; especially those who were rich and opulent, and put their children out to nurse…. These nurses spoil and destroy…. two thirds of the poor children entrusted to their care.” He also referred to “drunken nurses” being particularly bad. If his word “destroy” means that the children died, the situation was dreadful. In this context, the paper to which Thakker et al. refer, by Fildes,6 gives information about burials of “nurse-children” in a part of England. The proportion that died cannot be deduced from the paper to compare with Baynard's apparently very high estimate, nor are the causes of death determinable. Likewise, it is not possible to compare the mortality associated with wet nursing and the prevailing infant mortality rate then. After nearly four centuries, we cannot establish the cause of rickets at that time, so it is feasible only to suggest possibilities, and the significance of vitamin D deficiency and calcium deficiency will remain speculative. I am grateful to Drs Layinka Swinburne, Adriaan Monna, and Olav Bijvoet for help, especially in locating and translating manuscripts.

Calcium and Vitamin D: What Is Known About the Effects on Growing Bone

The objective of these investigations was to determine if the receptor-dependent effects of 1,25-dihydroxyvitamin D were essential for normal skeletal growth. Mice with targeted ablation of the vitamin D receptor were engineered, and the skeletal consequences of vitamin D receptor ablation were studied in the presence of normal and abnormal mineral ion homeostasis. Prevention of abnormal mineral ion homeostasis resulted in the development of a normal skeleton in the absence of a functional vitamin D receptor. The metabolic cause of rickets was found to be hypophosphatemia. The major receptor-dependent actions of 1,25-dihydroxyvitamin D on skeletal development are indirect and are a reflection of the role of this hormone on intestinal calcium absorption.

Don’t be “D”-ceived by vitamin D levels

One would think that something as seemingly straightforward as the normal range for the serum concentration of vitamin D (25(OH)D) would be fairly well established, especially with the growing current interest in calcium and vitamin D nutrition. Unfortunately, this is not the case.In states of dietary vitamin D deficiency assessed by measuring the serum level of 25(OH)D, there is enhanced hydroxylation of the substrate, resulting in increasing concentrations of 1,25(OH)2D. Thus, when individuals who are vitamin D deficient are given oral vitamin D, their 1,25(OH)2D levels increase. In contrast, providing additional oral vitamin D to individuals who are D sufficient has no effect on their 1,25(OH)2D levels.Complicating this already complex situation is the situation of dietary calcium deficiency. Although not commonly seen in US children, this is a common cause of rickets in Nigeria. In the current issue of The Journal, Thacher et al studied 16 Nigerian children with established calcium deficient rickets. They provided a single oral does of vitamin D to these children, and then examined their vitamin D metabolites. The children experienced an increase in 1,25(OH)2D similar to that seen in vitamin D deficient individuals, suggesting that calcium deficiency increases the demand for vitamin D to maintain 1,25(OD)2D levels. This observation has interesting implications. It suggests that “normal” values for 25(OH)D may be somewhat affected by dietary calcium intake. It also reminds us that there may be an increased need for vitamin D in states of calcium deficiency rickets. One would think that something as seemingly straightforward as the normal range for the serum concentration of vitamin D (25(OH)D) would be fairly well established, especially with the growing current interest in calcium and vitamin D nutrition. Unfortunately, this is not the case. In states of dietary vitamin D deficiency assessed by measuring the serum level of 25(OH)D, there is enhanced hydroxylation of the substrate, resulting in increasing concentrations of 1,25(OH)2D. Thus, when individuals who are vitamin D deficient are given oral vitamin D, their 1,25(OH)2D levels increase. In contrast, providing additional oral vitamin D to individuals who are D sufficient has no effect on their 1,25(OH)2D levels. Complicating this already complex situation is the situation of dietary calcium deficiency. Although not commonly seen in US children, this is a common cause of rickets in Nigeria. In the current issue of The Journal, Thacher et al studied 16 Nigerian children with established calcium deficient rickets. They provided a single oral does of vitamin D to these children, and then examined their vitamin D metabolites. The children experienced an increase in 1,25(OH)2D similar to that seen in vitamin D deficient individuals, suggesting that calcium deficiency increases the demand for vitamin D to maintain 1,25(OD)2D levels. This observation has interesting implications. It suggests that “normal” values for 25(OH)D may be somewhat affected by dietary calcium intake. It also reminds us that there may be an increased need for vitamin D in states of calcium deficiency rickets. Early response to vitamin D2 in children with calcium deficiency ricketsThe Journal of PediatricsVol. 149Issue 6PreviewTo assess the effect of vitamin D2 administration on serum vitamin D metabolite concentrations in calcium deficiency rickets. Full-Text PDF

Wet-nursing and rickets

Layinka Swinburne (JRSM August 20061) provides fascinating documentation that rickets was well-established in London by the early 17th century. However, the widespread prevalence of rickets is commonly ascribed to the industrial revolution of the 19th century, with increased pollution and closely crowded urban dwellings reducing the exposure of children to sunshine.2 The origin of rickets before the industrial revolution may relate to the widespread practice of wet-nursing alluded to in the article. Infants from wealthier parishes were sent out of London to wet-nurses in country parishes.3 Nursed children of wealthy parents apparently had the greatest risk of rickets. The wetnurse engaged in continuous breast feeding, even nursing several children simultaneously. Nursed children were included in the country family of the wet-nurse and not necessarily deprived of sunshine. As the duration of lactation increases, the concentration of calcium in breast milk declines.4 Consequently, the calcium intake of very young infants who were wet-nursed was probably considerably less than required for adequate bone mineralization. Although calcium in breast milk is more bioavailable than that of cow's milk, the concentration of calcium in breast milk is only about one quarter the concentration of calcium in cow's milk. As Swinburne points out, non-dairy weaning paps would further aggravate marginal calcium intake. The appearance of nutritional rickets in the 17th century probably resulted primarily from restricted calcium intake rather than from vitamin D deficiency, coinciding with the increased adoption of wetnursing. Nutritional rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency.5 Nutritional rickets may most often result from relative calcium and vitamin D deficiencies interacting with genetic and environmental factors. Although calcium deficiency as a cause of rickets has been relatively recently described, it may have been the primary cause of nutritional rickets prior to the industrial revolution.

Nutritional rickets around the world: causes and future directions

Nutritional rickets has been described from at least 59 countries in the last 20 years. Its spectrum of causes differs in different regions of the world. We conducted a systematic review of articles on nutritional rickets from various geographical regions published in the last 20 years. We extracted information about the prevalence and causes of rickets. Calcium deficiency is the major cause of rickets in Africa and some parts of tropical Asia, but is being recognised increasingly in other parts of the world. A resurgence of vitamin D deficiency has been observed in North America and Europe. Vitamin D-deficiency rickets usually presents in the 1st 18 months of life, whereas calcium deficiency typically presents after weaning and often after the 2nd year. Few studies of rickets in developing countries report values of 25(OH)D to permit distinguishing vitamin D from calcium deficiency. Rickets exists along a spectrum ranging from isolated vitamin D deficiency to isolated calcium deficiency. Along the spectrum, it is likely that relative deficiencies of calcium and vitamin D interact with genetic and/or environmental factors to stimulate the development of rickets. Vitamin D supplementation alone might not prevent or treat rickets in populations with limited calcium intake.