Rickets, Vitamin D, and Ca/P Metabolism.

Rickets was a major public health problem dating from Roman times, and medical descriptions of rickets date from the 17th century. Sniadecki first advocated treatment by exposure to sunshine in 1822; contemporaneously, several British physicians advocated use of cod liver oil. Both approaches were successful. Work in 1924 showed that exposure to UV light endowed fats and other foods with antirachitic properties. Vitamins D2 and D3, the antirachitic agent in cod liver oil, were, respectively, produced by UV radiation of ergosterol and 7-dehydrocholesterol. Calcitriol (1,25[OH]2D3) was identified as the biologically active form of vitamin D in the early 1970s. The vitamin D 25-hydroxylase, 24-hydroxylase, and 1α-hydroxylase were cloned in the 1990s and their genetic defects were soon delineated. The vitamin D receptor was also cloned and its mutations identified in vitamin D-resistant rickets. Work with parathyroid hormone (PTH) began much later, as the parathyroids were not identified until the late 19th century. In 1925, James B. Collip (of insulin fame) identified PTH by its ability to correct tetany in parathyroidectomized dogs, but only in the 1970s was it clear that only a small fragment of PTH conveyed its activity. Congenital hypoparathyroidism with immune defects was described in 1968, eventually linked to microdeletions in chromosome 22q11.2. X-linked hypophosphatemic rickets was reported in 1957, and genetic linkage analysis identified the causative PHEX gene in 1997. Autosomal dominant hypophosphatemic rickets similarly led to the discovery of FGF23, a phosphate-wasting humoral factor made in bone, in 2000, revolutionizing our understanding of phosphorus metabolism.

A brief history of rickets.

The review provides a historical perspective on the convergence of our understanding of the physiology and pathophysiology of bone, calcium, phosphorus, vitamin D, parathyroid hormone, and FGF-23 their impact on rickets.

Tocopherols, tocotrienols and tocomonoenols: Many similar molecules but only one vitamin E.

The aim of this article is to correct a very general error in scientific articles, in textbooks and in the Internet that has become an accepted fact. In this literature, the term "vitamin E″ is used for several similar molecules (both tocopherols and tocotrienols) that have never been shown to have vitamin property, i.e. a protective effect against the human deficiency disease. In fact, the name "vitamin E″ should only be used to define molecules that prevent the human deficiency disease "Ataxia with Vitamin E Deficiency" (AVED). Only one such molecule is known, α-tocopherol. This error may confuse consumers as well as medical doctors, who prescribe vitamin E without realizing that the current use of the name includes molecules of unknown, if not unwanted functions.

The Role of Vitamin D in Pediatric Orthopedics.

Understanding the role of vitamin D is an important component of the proper care of the pediatric orthopedic patient. Vitamin D is an essential component of bone metabolism in the growth and development of the pediatric skeleton, which can be acutely affected by changes to the body's vitamin D, calcium, and phosphate levels, resulting in pathologic conditions such as rickets or fractures. This article reviews the main areas in which vitamin D relates to pediatric orthopedics and highlights some of the areas where future research is being directed.

Rickets.

Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.

Optimal Dose of Calcium for Treatment of Nutritional Rickets: A Randomized Controlled Trial.

Calcium supplementation is indicated for the treatment of nutritional rickets. Our aim was to determine the optimal dose of calcium for treatment of children with rickets. Sixty-five Nigerian children with radiographically confirmed rickets were randomized to daily supplemental calcium intake of 500 mg (n = 21), 1000 mg (n = 23), or 2000 mg (n = 21). Venous blood, radiographs, and forearm areal bone density (aBMD) were obtained at baseline and at 8, 16, and 24 weeks after enrollment. The primary outcome was radiographic healing, using a 10-point radiographic severity score. The radiographic severity scores improved in all three groups, but the rate of radiographic healing (points per month) was significantly more rapid in the 1000-mg (-0.29; 95% confidence interval [CI] -0.13 to -0.45) and 2000-mg (-0.36; 95% CI -0.19 to -0.53) supplementation groups relative to the 500-mg group. The 2000-mg group did not heal more rapidly than the 1000-mg group. Of those who completed treatment for 24 weeks, 12 (67%), 20 (87%), and 14 (67%) in the 2000-mg, 1000-mg, and 500-mg groups, respectively, had achieved a radiographic score of 1.5 or less (p = 0.21). Serum alkaline phosphatase decreased and calcium increased similarly in all groups. Forearm diaphyseal aBMD improved significantly more rapidly in the 2000-mg group than in the 500-mg and 1000-mg groups (p < 0.001). Daily calcium intakes of 1000 mg or 2000 mg produced more rapid radiographic healing of rickets than 500 mg, but 2000 mg did not have greater benefit than 1000 mg. Some children require longer than 24 weeks for complete healing of nutritional rickets. © 2016 American Society for Bone and Mineral Research.

Two cases of rickets presenting with poor growth, hypotonia, and respiratory problems.

Rickets is a rare disease in developed countries. In children, it is a disease which affects growing bone. Depending on the severity, it can present with a wide variety of symptoms. Because it is such a rare disease in developed countries, symptoms suggesting rickets are often not easily recognized. This can cause a delay in diagnosing and treating rickets. Often unnecessary and sometimes invasive investigations are performed. First leading clues to rickets on physical examination are poor growth, especially length, thickening of wrists, bow legs, and craniotabes. At further examination, special attention should be paid to osteopenia and cupping and fraying at the metaphyses on X-rays. Laboratory results suggestive for rickets are elevated alkaline phosphatase and disturbances in calcium and phosphate homeostasis. In this report, we present two cases presenting with poor growth, severe pain, and respiratory problems secondary to calcipenic rickets.

Vitamin D and skeletal health in infancy and childhood.

During growth, severe vitamin D deficiency in childhood can result in symptomatic hypocalcaemia and rickets. Despite the suggestion from some studies of a secular increase in the incidence of rickets, this observation may be driven more by changes in population demographics than a true alteration to age, sex and ethnicity-specific incidence rates; indeed, rickets remains uncommon overall and is rarely seen in fair-skinned children. Additionally, the impact of less severe vitamin D deficiency and insufficiency has received much interest in recent years, and in this review, we consider the evidence relating vitamin D status to fracture risk and bone mineral density (BMD) in childhood and adolescence. We conclude that there is insufficient evidence to support the suggestion that low serum 25-hydroxyvitamin D [25(OH)D] increases childhood fracture risk. Overall, the relationship between 25(OH)D and BMD is inconsistent across studies and across skeletal sites within the same study; however, there is evidence to suggest that vitamin D supplementation in children with the lowest levels of 25(OH)D might improve BMD. High-quality randomised trials are now required to confirm this benefit.

Radiographic changes in nutritional ricket hips in children in response to treatment.

PURPOSE: To review radiographic changes in the proximal femurs of children of different ages during the course of treatment for nutritional rickets. METHODS: Pelvic radiographs of 161 children aged ≤ 13 years with nutritional rickets were retrospectively reviewed. Patients were treated with dietary counselling and vitamin D and calcium supplementation. Patients were followed up at week 3 and thereafter at a 2-month interval until ulnar convexity was achieved. Sequential radiographs of the hips in children of different ages were reviewed for each growth plate in terms of (1) the direction of growth, (2) active areas, (3) contribution of growth, and (4) the structure of the epiphysis. Radiographs were superimposed for comparison by matching the triradiate cartilage and the ischial portion of the obturator foramen. RESULTS: The direction of growth of the growth plates was from the physeal plate that is the longitudinal growth plate of the neck (LGP), the femoral neck isthmus (FNI), and the trochanteric growth plate (TGP) to the diaphyseal region, and from the perichondrium to the ossification centre in the proximal femoral epiphysis. Before the age of one year, the growth zone of the proximal femur was homogenous, with no differentiation between the LGP, FNI, and TGP. By the age of 2 years, the differentiation was more clearly established; the FNI was usually smaller than the TGP and LGP. By the age of 3 years, the FNI became prominent and the TGP remained small. By the age of 4 years, the ossification centre of the greater trochanter appeared, and the LGP extended medially as a medial overhang (MOH). During the children's growth, the LGP, FNI, or TGP remained active to a variable extent and were distinct until the age of 6 years. Gradually, the periphery of the LGP became less active than the centre of the LGP and gave rise to the 'eye sign'. The MOH generally ceased to be active beyond the age 9 years. By the age of 12 years, the TGP and FNI were minimally active and only the centre of the LGP remained active. CONCLUSION: The mineralisation process of healing rickets provides a useful biological marker for patterns of growth. Knowledge of the quantitative contribution of various growth plates of the proximal femur in childhood may increase the understanding of the pathomechanism of hip deformations.

Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia.

Although recent studies have established that osteocytes function as secretory cells that regulate phosphate metabolism, the biomolecular mechanism(s) underlying these effects remain incompletely defined. However, investigations focusing on the pathogenesis of X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), and autosomal recessive hypophosphatemic rickets (ARHR), heritable disorders characterized by abnormal renal phosphate wasting and bone mineralization, have clearly implicated FGF23 as a central factor in osteocytes underlying renal phosphate wasting, documented new molecular pathways regulating FGF23 production, and revealed complementary abnormalities in osteocytes that regulate bone mineralization. The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and ß-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and ß-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events. These discoveries indicate that ADHR, XLH, and ARHR represent three related heritable hypophosphatemic diseases that arise from mutations in, or dysregulation of, a single common gene product, FGF23 and, in ARHR and XLH, complimentary DMP1 and PHEX directed events that contribute to abnormal bone mineralization.

RICKETS IN RURAL KENYAN PRESCHOOL CHILDREN: CASE REPORT.

Clinical rickets has not been reported previously in Embu district, Kenya. Baseline clinical assessments performed for a nutrition intervention study in preschool children (n=324) identified 28 cases of rickets (8.6% of study sample). Clinical characteristics included: delays of sitting, walking, and teething; bone and chest deformities; widened wrists and ankles; and bowed lower extremities. Risk factors identified were short duration of breastfeeding with feeding of cereal-based supplements with little or no milk, low calcium intake, limited sunlight exposure. Vitamin D and calcium deficiencies likely contributed to these cases. Treatment with Vitamin D3 and milk resulted in clinical improvement.

Rickets in Denmark.

Rickets is a heterogeneous group of diseases of the growing child caused by defect mineralization of bone. Nutritional rickets is caused by deficiency of vitamin D, calcium or both. Several hereditary forms of rickets exist where the disease proceeds into adulthood. Nutritional rickets was common in the past, but by introduction of preventative administration of cod liver oil and vitamin D supplementation, nutritional rickets became a rarity. During the last decades, case reports of nutritional rickets reappear in the industrialized countries. It is the general conception that in the industrialized countries, hereditary rickets is the most prevalent cause of rickets today. However, the incidence of nutritional rickets and the incidence and prevalence of hereditary rickets in Scandinavia are unknown. The most common form of hereditary rickets is hypophosphatemic rickets (HR). The geno- and phenotype among Scandinavian patients have not been characterized. Especially, the disease in adult patients is not well described. Moreover, there are conflicting reports of the benefits of medical treatment throughout childhood, and in addition on gender differences in disease severity.

The effect of vitamin D on bone and osteoporosis.

The main effect of the active vitamin D metabolite 1,25(OH)2D is to stimulate the absorption of calcium from the gut. The consequences of vitamin D deficiency are secondary hyperparathyroidism and bone loss, leading to osteoporosis and fractures, mineralization defects, which may lead to osteomalacia in the long term, and muscle weakness, causing falls and fractures. Vitamin D status is related to bone mineral density and bone turnover. Vitamin D supplementation may decrease bone turnover and increase bone mineral density. Several randomized placebo-controlled trials with vitamin D and calcium showed a significant decrease in fracture incidence. However, very high doses of vitamin D once per year may have adverse effects. When patients with osteoporosis are treated with a bisphosphonate, they should receive a vitamin D and calcium supplement unless the patient is vitamin D replete. These subjects are discussed in detail in this review. Finally, the knowledge gaps and research agenda are discussed.

Vitamin D supplementation of Canadian infants: practices of Montreal mothers.

Health policy in North America advocates that all breastfed infants receive a vitamin D supplement of 400 IU per day for the primary prevention of rickets. Despite this recommendation, rickets still occurs in Canada. It is not known whether vitamin D deficiency in the Canadian population is solely attributable to inadequacies in vitamin supplementation. Thus, the evaluation of current practices, including awareness and compliance with recommendations, is clearly needed. The objective of this study was to describe the vitamin D supplementation practices of mothers of newborns living in the Montreal area. This was a cross-sectional telephone survey of 343 mothers delivering a healthy term infant from December 2007 to May 2008 at the Royal Victoria Hospital (Montreal, Que.). Ninety percent of all mothers breastfed their infants during the first 6 months; 53% did so exclusively. Of mothers exclusively breastfeeding, 74% reported meeting the Health Canada recommendation. The main reason for not adhering to the recommendation was the assumption by mothers who began to feed fortified formula (400 IU.L-1) that supplementation was no longer necessary. Fifty percent of infants receiving mixed feedings without supplementation prior to 6 months did not achieve the recommended intake. Receiving advice about supplementation and the higher education of mothers were significant positive determinants of supplementation practices. This work identified infants consuming mixed feedings and those consuming only formula in the first 6 months as groups at high risk for not meeting the recommended 400 IU.day-1 of vitamin D. Therefore there may still be gaps in knowledge regarding vitamin D supplementation.

Maternal vitamin D status: implications for the development of infantile nutritional rickets.

The mother is the major source of circulating 25-hydroxyvitamin D concentration in the young infant. Maternal vitamin D status is an important factor in determining the vitamin D status of the infant and their risk of developing vitamin D deficiency and infantile nutritional rickets. There is evidence that the current supplementation recommendations, particularly for pregnant and lactating women, are inadequate to ensure vitamin D sufficiency in these groups. A widespread and concerted effort is needed to ensure daily supplementation of breastfed and other infants at high risk with vitamin D 400 IU from birth and of pregnant women in high-risk communities with 2000 IU. Future studies are required to determine the optimal doses of vitamin D supplementation in pregnancy and during lactation, and for normalizing vitamin D stores in infancy to reduce the prevalence of infantile nutritional rickets. Operational research studies are needed to understand the best methods of implementing supplementation programs and the factors that are likely to impede their success.

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.

Guided growth for pathological physes: radiographic improvement during realignment.

BACKGROUND: Children with rickets are prone to having deformities of the lower extremities that are bilateral and often symmetrical. Although initially attributed to pathological or "sick" physes, the deformities are eventually seen in the metaphyses and diaphyses of the long bones; if left untreated, they may result in bone pain and stress fractures. The orthopaedists' role in managing these children is to correct and maintain alignment. Alternatively, we have exploited the use of hemiepiphysiodesis or guided growth, using staples or, more recently, the 8-plate (Orthofix, Verona, Italy). While gradually normalizing the mechanical axis, we have noted improvement in the appearance and width of all of the ipsilateral physes, not only at the knee but at the hip and ankle as well. This report summarizes our observations of the effects on the pathological physes in a group of patients with rickets who were preferentially treated with guided growth, often starting at a young age. METHOD: This retrospective review approved by an institutional review board included 14 children with rickets, including 10 treated with staples and 4 with 8-plates, who collectively underwent a total of 68 hemiepiphysiodeses (guided growth) and 35 osteotomies. Each was under appropriate medical management during the entire course of treatment, before and after surgery. We measured the mechanical axis deviation and anatomic angles of the femur and proximal tibia, noting the width and appearance of their physes at the hips, knees, and ankles preoperatively and upon correction of the axis. RESULTS: Of the 10 stapled patients, we noted 24 (45%) of 53 migrations and 41% rebound deformity. Four patients with 15 deformities that corrected with 8-plates experienced no hardware migration; for them, it is too early to comment on rebound deformity. While gradually correcting the mechanical axis, we have noted improvement in the appearance and width, not only of the pan-genu physes but also of remote physes at the hip and ankle. We suspect that the improved quality of the physes reflects not only the normalization of the mechanical axis but also the corresponding resolution of the waddling (varus) or circumduction (valgus) gait pattern. CONCLUSION: We recommend early intervention, via guided growth, to restore and preserve a neutral axis so that the child can enjoy a normal lifestyle while maximizing the growth potential of his or her physes, not only of the knees but the hips and ankles as well. We believe that by correcting and maintaining alignment, secondary bony deformities may be ameliorated and osteotomies for angular correction deferred if not avoided altogether. LEVEL OF EVIDENCE: IV (retrospective clinical series).

Congenital rickets presenting with hypocalcaemic seizures

At Ataturk University Hospital, eight infants who presented with hypocalcaemic seizures were subsequently found to have rickets. Their mothers had osteomalacia. Neither mothers nor infants received vitamin D supplementation. Maternal vitamin D deficiency and non-supplementation in the infants were causes of rickets in these patients. It is recommended that neonatal hypocalcaemia may be due to maternal vitamin D deficiency and all unsupplemented vitamin D infants presenting with seizures should be investigated for rickets.

Congenital rickets presenting with hypocalcaemic seizures.

At Ataturk University Hospital, eight infants who presented with hypocalcaemic seizures were subsequently found to have rickets. Their mothers had osteomalacia. Neither mothers nor infants received vitamin D supplementation. Maternal vitamin D deficiency and non-supplementation in the infants were causes of rickets in these patients. It is recommended that neonatal hypocalcaemia may be due to maternal vitamin D deficiency and all unsupplemented vitamin D infants presenting with seizures should be investigated for rickets.

Rickets: not a disease of the past.

Rickets develops when growing bones fail to mineralize. In most cases, the diagnosis is established with a thorough history and physical examination and confirmed by laboratory evaluation. Nutritional rickets can be caused by inadequate intake of nutrients (vitamin D in particular); however, it is not uncommon in dark-skinned children who have limited sun exposure and in infants who are breastfed exclusively. Vitamin D-dependent rickets, type I results from abnormalities in the gene coding for 25(OH)D3-1-alpha-hydroxylase, and type II results from defective vitamin D receptors. The vitamin D-resistant types are familial hypophosphatemic rickets and hereditary hypophosphatemic rickets with hypercalciuria. Other causes of rickets include renal disease, medications, and malabsorption syndromes. Nutritional rickets is treated by replacing the deficient nutrient. Mothers who breastfeed exclusively need to be informed of the recommendation to give their infants vitamin D supplements beginning in the first two months of life to prevent nutritional rickets. Vitamin D-dependent rickets, type I is treated with vitamin D; management of type II is more challenging. Familial hypophosphatemic rickets is treated with phosphorus and vitamin D, whereas hereditary hypophosphatemic rickets with hypercalciuria is treated with phosphorus alone. Families with inherited rickets may seek genetic counseling. The aim of early diagnosis and treatment is to resolve biochemical derangements and prevent complications such as severe deformities that may require surgical intervention.