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.

Nutritional Rickets with Severe Complications in Syrian and Iraqi Refugee Children.

We investigated the presence of nutritional rickets in Syrian and Iraqi refugee infants who presented to hospital in Turkey in 2017. 25(OH)D levels were examined in 77 refugee children. Nutritional rickets was diagnosed in 22 (28.5%) children; 11 patients with rickets did not follow up.

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.

The relationship between maternal and child bone density in Nigerian children with and without nutritional rickets.

We found a positive relationship between bone density in Nigerian children with and without rickets and that of their mothers. After treatment, children with rickets had greater bone density than children without rickets, indicating that children genetically programmed to have greater bone density may have a higher risk of rickets. INTRODUCTION: To determine the relationship between bone density in children with and without rickets and that of their mothers METHODS: Using an unmatched case-control design, forearm areal bone mineral density (aBMD) was measured in 52 and 135 Nigerian children with and without rickets and their mothers, respectively. We performed multivariate linear regression analyses to assess the relationship between maternal and child aBMD Z-scores. RESULTS: Forearm aBMD Z-scores in children were associated with maternal aBMD Z-scores at metaphyseal (effect estimate 0.23; 95% CI 0.08 to 0.37) and diaphyseal (effect estimate 0.16; 0.01 to 0.30) sites, after adjustment for rickets in the child, child's age and sex, height-for-age Z-score, and weight-for-age Z-score. In the adjusted model, rickets was inversely associated with child's aBMD Z-score at the diaphyseal site only (- 0.45, - 0.65 to - 0.24). The positive relationship between maternal and child aBMD Z-scores was marginally greater in children with rickets (slope 0.56, r = 0.47) than without rickets (slope 0.19, r = 0.20) at the diaphyseal site only (P = 0.06 for interaction) but not at the metaphyseal site (slopes 0.35 and 0.30, respectively, P = 0.48). After treatment with calcium for 6 months, metaphyseal aBMD Z-scores were greater in children with treated rickets (effect estimate 0.26; 95% CI 0.02 to 0.49) than in those without rickets. CONCLUSION: In Nigerian children with and without rickets, forearm aBMD Z-scores were positively associated with maternal aBMD Z-scores. Active rickets in the child marginally modified the relationship at the diaphyseal site only. After treatment, children with rickets had greater metaphyseal aBMD Z-scores than children without rickets.

Cortical Matrix Mineral Density Measured Noninvasively in Pre- and Postmenopausal Women and a Woman With Vitamin D-Dependent Rickets.

Reduced bone mineral density (BMD) may be due to reduced mineralized bone matrix volume, incomplete secondary mineralization, or reduced primary mineralization. Because bone biopsy is invasive, we hypothesized that noninvasive image acquisition at high resolution can accurately quantify matrix mineral density (MMD). Quantification of MMD was confined to voxels attenuation photons above 80% of that produced by fully mineralized bone matrix because attenuation at this level is due to variation in mineralization, not porosity. To assess accuracy, 9 cadaveric distal radii were imaged at a voxel size of 82 microns using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT, Scanco Medical AG, Bruttisellen, Switzerland) and compared with VivaCT 40 (µCT) at 19-micron voxel size. Associations between MMD and porosity were studied in 94 healthy vitamin D-replete premenopausal women, 77 postmenopausal women, and in a 27-year-old woman with vitamin D-dependent rickets (VDDR). Microstructure and MMD were quantified using StrAx (StraxCorp, Melbourne, Australia). MMD measured by HR-pQCT and µCT correlated (R = 0.87; p < 0.0001). The precision error for MMD was 2.43%. Cortical porosity and MMD were associated with age (r2 = 0.5 and -0.4, respectively) and correlated inversely in pre- and postmenopausal women (both r2 = 0.9, all p < 0.001). Porosity was higher, and MMD was lower, in post- than in premenopausal women (porosity 40.3% ± 7.0 versus 34.7% ± 3.5, respectively; MMD 65.4% ± 1.8 versus 66.6% ± 1.4, respectively, both p < 0.001). In the woman with VDDR, MMD was 5.6 SD lower and porosity was 5.6 SD higher than the respective trait means in premenopausal women. BMD was reduced (Z-scores femoral neck -4.3 SD, lumbar spine -3.8 SD). Low-radiation HR-pQCT may facilitate noninvasive quantification of bone's MMD and microstructure in health, disease, and during treatment. © 2018 American Society for Bone and Mineral Research.

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.

The relationship of maternal bone density with nutritional rickets in Nigerian children.

Factors that affect maternal bone mineral density may be related to the risk of nutritional rickets in their offspring. Our aim was to determine the relationship between maternal areal bone mineral density (aBMD) and rickets in Nigerian children. Using a case-control design, we measured forearm aBMD in 56 and 135 mothers of children with and without nutritional rickets, respectively. Active rickets was confirmed or excluded in all children radiographically. Using logistic regression, we assessed the association of maternal aBMD, adjusted for parity, pregnancy and lactation status, duration of most recent completed lactation, age of menarche, height, body mass index, and maternal age with nutritional rickets. The median (range) age of all mothers was 30years (17-47years), and parity was 4 (1-12). A total of 36 (19%) were pregnant and 55 (29%) were currently breast feeding. Mean (±SD) metaphyseal forearm aBMDs were 0.321±0.057 and 0.316±0.053g/cm2 in mothers of children with and without rickets, respectively (P=0.60). Diaphyseal forearm aBMDs were 0.719±0.071 and 0.715±0.072g/cm2, respectively (P=0.69). In an adjusted analysis, maternal forearm aBMD, bone mineral content and bone area at metaphyseal and diaphyseal sites were not associated with rickets in the child. In the adjusted analysis, rickets was associated with shorter duration of most recently completed lactation (aOR 0.91 for each additional month; 95% CI 0.83-0.99), older maternal age (aOR 1.07 for each additional year; 1.00-1.14), and less frequent maternal use of lead-containing eye cosmetics (aOR 0.20; 95% CI 0.05-0.64), without any difference in maternal blood lead levels. Maternal age, parity, age of menarche, height, and body mass index were not associated with having had a child with rickets in multivariate analysis. Nutritional rickets in Nigerian children was not associated with maternal forearm aBMD. Other unidentified maternal characteristics and practices likely contribute to the risk of rickets in Nigerian children.

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.

More than metabolic: Considering the broader paleoepidemiological impact of vitamin D deficiency in bioarchaeology.

Vitamin D deficiency has traditionally been viewed as a metabolic bone disease by bioarchaeologists and considered primarily in terms of the development of specific musculoskeletal changes used for diagnosis in paleopathological research. These skeletal manifestations are usually interpreted as representing general ill-health. Clinical research shows that vitamin D is also integral to a number of extra-skeletal physiological processes including immunoregulation, blood pressure homeostasis, cell division, and programmed cell death. Vitamin D deficiency and sub-clinical insufficiency are thought to be risk factors for infectious and autoimmune diseases, as well as certain cancers and cardiovascular diseases. Epidemiological work indicates that the skeletal manifestations of vitamin D deficiency represent the extreme end of a spectrum of morbidity associated with negative health outcomes, including increased risk for secondary tuberculosis. This article provides a review of clinical research on the extra-skeletal roles of vitamin D and the pathological consequences of poor vitamin D status. Additionally, it presents an interpretive model for bioarchaeological analyses of rickets and osteomalacia for consideration of the whole-body impact of poor vitamin D nutriture and possible comorbidities that may have affected the wider population. Am J Phys Anthropol 160:183-196, 2016. © 2016 Wiley Periodicals, Inc.

A paradoxical presentation of rickets and secondary osteomyelitis of the jaw in Type II autosomal dominant osteopetrosis: Rare case reports.

Osteopetrosis is a rare genetic bone disorder arising due to a defect in the differentiation or function of osteoclast which results in a generalized increase in bone mass. Osteomyelitis is one of the most common complications because of decreased bone marrow function and compromised blood supply. Radiologist plays a vital role in diagnosing osteopetrosis. Here, we present two cases of autosomal dominant osteopetrosis Type II (ADO II) with secondary osteomyelitis changes which were reported to our department. One of these two cases presented with secondary osteomyelitis in both maxilla and mandible and features of rickets, which is very rarely seen in ADO II. To the best of our knowledge, the presentation of rickets with ADO is the first of its kind to be reported. In this paper, we describe the clinical and radiological features leading to the diagnosis of ADO in these two patients. Further, a review of the literature regarding ADO is discussed.

Defective skeletal mineralization in pediatric CKD.

Although traditional diagnosis and treatment of renal osteodystrophy focused on changes in bone turnover, current data demonstrate that abnormalities in skeletal mineralization are also prevalent in pediatric chronic kidney disease (CKD) and likely contribute to skeletal morbidities that continue to plague this population. It is now clear that alterations in osteocyte biology, manifested by changes in osteocytic protein expression, occur in early CKD before abnormalities in traditional measures of mineral metabolism are apparent and may contribute to defective skeletal mineralization. Current treatment paradigms advocate the use of 1,25(OH)2vitamin D for the control of secondary hyperparathyroidism; however, these agents fail to correct defective skeletal mineralization and may exacerbate already altered osteocyte biology. Further studies are critically needed to identify the initial trigger for abnormalities of skeletal mineralization as well as the potential effects that current therapeutic options may have on osteocyte biology and bone mineralization.

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.

The effect of nutritional rickets on bone mineral density.

CONTEXT: Nutritional rickets is caused by impaired mineralization of growing bone. The effect of nutritional rickets on areal bone mineral density (aBMD) has not been established. OBJECTIVE: Our objective was to determine if aBMD is lower in children with active rickets than in healthy control children. We expected that the reduction in aBMD would vary between the radial and ulnar metaphyses near the growth plates and the proximal diaphyses. DESIGN: Case-control study. SETTING: Primary care outpatient department of a teaching hospital in Jos, Nigeria. PARTICIPANTS: Nigerian children with radiographically-confirmed rickets were compared with a reference group of control children without rickets from the same community. MAIN OUTCOME MEASURES: Forearm bone density measurements were performed in all children with pDXA. Age, sex, and height-adjusted bone density parameters were compared between children with rickets and control subjects. RESULTS: A total of 264 children with active rickets (ages 13-120 months) and 660 control children (ages 11-123 months) were included. In multivariate analyses controlling for height, age, and gender, rickets was associated with a 4% greater bone area and 7% lower aBMD of the radial and ulnar metaphyses compared with controls (P < .001). The effects of rickets on the diaphyses of the radius and ulna were more pronounced with an 11% greater bone area, 21% lower aBMD, and 24% lower bone mineral apparent density than controls (P < .001). In children with rickets, aBMD values were unrelated to dairy product intake or serum calcium, phosphorus, alkaline phosphatase, or 25-hydroxyvitamin D. Metaphyseal aBMD was positively associated with radiographic severity score, attributed to bone edge detection artifact by densitometry in active rickets. CONCLUSION: Rickets results in increased bone area and reduced aBMD, which are more pronounced in the diaphyseal than in the metaphyseal regions of the radius and ulna, consistent with secondary hyperparathyroidism, generalized osteoid expansion and impaired mineralization.