A major health problem facing immigrant children: nutritional rickets.

OBJECTIVES: Nutritional rickets (NR) is still an important problem and one which increasing influxes of immigrants are further exacerbating. This study evaluated cases of mostly immigrant children followed up with diagnoses of NR in our pediatric endocrinology clinic. METHODS: Details of 20 cases diagnosed with NR between 2017 and 2020 were retrieved from file records. RESULTS: Twenty (11 male) cases were included in the study. Three (15%) were Turkish nationals and the others (85%) were immigrants. Hypocalcemia and hypophosphatemia were detected in 17 and 13, respectively. Alkaline phosphatase (ALP) values were normal in two cases, while ALP and parathyroid hormone (PTH) values were elevated in all other cases, and PTH levels were very high (473.64 ± 197.05 pg/mL). 25-hydroxyvitamin D levels were below 20 ng/mL in all cases. Patients with NR received high-dose long-term vitamin D or stoss therapy. Six patients failed to attend long-term follow-up, while PTH and ALP levels and clinical findings improved at long-term follow-up in the other 14 cases. CONCLUSIONS: The elevated PTH levels suggest only the most severe cases of NR presented to our clinic. Clinically evident NR is therefore only the tip of the iceberg, and the true burden of subclinical rickets and osteomalacia remains unidentified. Public health policies should therefore focus on universal vitamin D supplementation and adequate dietary calcium provision, their integration into child surveillance programs, adequate advice and support to ensure normal nutrition, exposure to sunlight, and informing families of the increased risk not only for resident populations but also for refugee and immigrant children.

Vitamin D supplementation for term breastfed infants to prevent vitamin D deficiency and improve bone health.

BACKGROUND: Vitamin D deficiency is common worldwide, contributing to nutritional rickets and osteomalacia which have a major impact on health, growth, and development of infants, children and adolescents. Vitamin D levels are low in breast milk and exclusively breastfed infants are at risk of vitamin D insufficiency or deficiency. OBJECTIVES: To determine the effect of vitamin D supplementation given to infants, or lactating mothers, on vitamin D deficiency, bone density and growth in healthy term breastfed infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to 29 May 2020 supplemented by searches of clinical trials databases, conference proceedings, and citations. SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs in breastfeeding mother-infant pairs comparing vitamin D supplementation given to infants or lactating mothers compared to placebo or no intervention, or sunlight, or that compare vitamin D supplementation of infants to supplementation of mothers. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility and risk of bias and independently extracted data. We used the GRADE approach to assess the certainty of evidence. MAIN RESULTS: We included 19 studies with 2837 mother-infant pairs assessing vitamin D given to infants (nine studies), to lactating mothers (eight studies), and to infants versus lactating mothers (six studies). No studies compared vitamin D given to infants versus periods of infant sun exposure. Vitamin D supplementation given to infants: vitamin D at 400 IU/day may increase 25-OH vitamin D levels (MD 22.63 nmol/L, 95% CI 17.05 to 28.21; participants = 334; studies = 6; low-certainty) and may reduce the incidence of vitamin D insufficiency (25-OH vitamin D < 50 nmol/L) (RR 0.57, 95% CI 0.41 to 0.80; participants = 274; studies = 4; low-certainty). However, there was insufficient evidence to determine if vitamin D given to the infant reduces the risk of vitamin D deficiency (25-OH vitamin D < 30 nmol/L) up till six months of age (RR 0.41, 95% CI 0.16 to 1.05; participants = 122; studies = 2), affects bone mineral content (BMC), or the incidence of biochemical or radiological rickets (all very-low certainty). We are uncertain about adverse effects including hypercalcaemia. There were no studies of higher doses of infant vitamin D (> 400 IU/day) compared to placebo. Vitamin D supplementation given to lactating mothers: vitamin D supplementation given to lactating mothers may increase infant 25-OH vitamin D levels (MD 24.60 nmol/L, 95% CI 21.59 to 27.60; participants = 597; studies = 7; low-certainty), may reduce the incidences of vitamin D insufficiency (RR 0.47, 95% CI 0.39 to 0.57; participants = 512; studies = 5; low-certainty), vitamin D deficiency (RR 0.15, 95% CI 0.09 to 0.24; participants = 512; studies = 5; low-certainty) and biochemical rickets (RR 0.06, 95% CI 0.01 to 0.44; participants = 229; studies = 2; low-certainty). The two studies that reported biochemical rickets used maternal dosages of oral D3 60,000 IU/day for 10 days and oral D3 60,000 IU postpartum and at 6, 10, and 14 weeks. However, infant BMC was not reported and there was insufficient evidence to determine if maternal supplementation has an effect on radiological rickets (RR 0.76, 95% CI 0.18 to 3.31; participants = 536; studies = 3; very low-certainty). All studies of maternal supplementation enrolled populations at high risk of vitamin D deficiency. We are uncertain of the effects of maternal supplementation on infant growth and adverse effects including hypercalcaemia. Vitamin D supplementation given to infants compared with supplementation given to lactating mothers: infant vitamin D supplementation compared to lactating mother supplementation may increase infant 25-OH vitamin D levels (MD 14.35 nmol/L, 95% CI 9.64 to 19.06; participants = 269; studies = 4; low-certainty). Infant vitamin D supplementation may reduce the incidence of vitamin D insufficiency (RR 0.61, 95% CI 0.40 to 0.94; participants = 334; studies = 4) and may reduce vitamin D deficiency (RR 0.35, 95% CI 0.17 to 0.72; participants = 334; studies = 4) but the evidence is very uncertain. Infant BMC and radiological rickets were not reported and there was insufficient evidence to determine if maternal supplementation has an effect on infant biochemical rickets. All studies enrolled patient populations at high risk of vitamin D deficiency. Studies compared an infant dose of vitamin D 400 IU/day with varying maternal vitamin D doses from 400 IU/day to > 4000 IU/day. We are uncertain about adverse effects including hypercalcaemia. AUTHORS' CONCLUSIONS: For breastfed infants, vitamin D supplementation 400 IU/day for up to six months increases 25-OH vitamin D levels and reduces vitamin D insufficiency, but there was insufficient evidence to assess its effect on vitamin D deficiency and bone health. For higher-risk infants who are breastfeeding, maternal vitamin D supplementation reduces vitamin D insufficiency and vitamin D deficiency, but there was insufficient evidence to determine an effect on bone health. In populations at higher risk of vitamin D deficiency, vitamin D supplementation of infants led to greater increases in infant 25-OH vitamin D levels, reductions in vitamin D insufficiency and vitamin D deficiency compared to supplementation of lactating mothers. However, the evidence is very uncertain for markers of bone health. Maternal higher dose supplementation (≥ 4000 IU/day) produced similar infant 25-OH vitamin D levels as infant supplementation of 400 IU/day. The certainty of evidence was graded as low to very low for all outcomes.

C-Terminal Fibroblast Growth Factor-23 Levels in Non-Nutritional Hypophosphatemic Rickets.

Fibroblast growth factor-23 (FGF23) is central to phosphate homeostasis. The author examined if blood levels of FGF23 allow discrimination of classic hypophosphatemic rickets from other causes of non-nutritional rickets with hypophosphatemia. Forty-two children (median age: 102 mo) with non-nutritional rickets and hypophosphatemia were clinically classified as having distal renal tubular acidosis (RTA, n = 12), Fanconi syndrome (n = 8), classic hypophosphatemic rickets (n = 11), vitamin D dependent rickets (n = 7) and Dent disease (n = 4). Median blood FGF23 (measured by C-terminal ELISA) concentrations were similar in all groups (P = 0.24). These levels did not correlate with phosphate, tubular maximum for phosphate, calcium, 25-hydroxyvitamin D, creatinine, and parathormone levels. Patients with distal RTA showed variable degree of proximal tubular dysfunction that resolved following alkali supplements. Blood FGF23 levels did not satisfactorily differentiate classic hypophosphatemic rickets from other causes of hypophosphatemic rickets.

Soluble Klotho causes hypomineralization in Klotho-deficient mice.

The type I transmembrane protein αKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient (kl/kl) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23-FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone.

Vitamin D Status in South Asian Populations - Risks and Opportunities.

Human body acquires a significant amount of vitamin D by cutaneous synthesis under the action of sunlight and less is supplied through nutritional sources. Diversified sociocultural and economic determinants have been identified that limit the dietary intake of vitamin D and enough distribution of sunlight to maintain optimal levels of 25-hydroxyvitamin D (25(OH)D). Consequently, the world has witnessed a high prevalence of hypovitaminosis D in resource-limited South Asian countries. The purpose of this review is to provide a South Asian perspective of vitamin D status, critically examining India, Pakistan, Bangladesh, and Sri Lanka, and to shed light on potential determinants (latitude and season, sunshine exposure habits, age, gender, and genetic factors) leading to hypovitaminosis D among a variety of population groups. Literature search was carried out using bibliographic databases "PubMed," "Google Scholar," and "ScienceDirect.com." Serum 25(OH)D level, 20-50 nmol/L, was mainly taken as vitamin D deficiency, and determinants of low serum 25(OH)D concentration of the population under study were also considered. The review concludes that vitamin D deficiency is highly prevalent among South Asian populations and global efforts are needed to overcome hypovitaminosis in the region. In addition, dietary diversification, supplementation and fortification of foods with vitamin D, adequate exposure to sunlight, and consumption of animal foods were suggested as viable approaches to maintain 25(OH)D levels for optimal health.

Congenital rickets due to vitamin D deficiency in the mothers.

BACKGROUND & AIMS: We wished to review all published reports of congenital rickets to identify the causes and characteristics. METHODS: 25 cases were identified in 19 published reports in which there was radiological and/or histological evidence of rickets in the first two weeks after birth. Cases of rickets associated with maternal renal failure were excluded as were infants born at less than 32 weeks gestation. RESULTS: There was evidence of maternal deficiency in 24 of these cases. In 16 cases the diagnosis of the rickets led to the identification of symptomatic osteomalacia in the mothers. Of the 12 mothers who had assays for serum 25-hydroxyvitamin D (25OHD) 11 had values less than 10 ng/mL. Presentations in the infants included craniotabes, wide skull sutures, rachitic rosaries, enlargement of the wrists, tetany and convulsions. In two cases rickets had been suspected from antenatal X-rays. In five cases fractures were found at the time of initial presentation. Of the 16 infants with serum calcium assays 15 had values lower than 8.8 mg/dL. Of 13 infants who had serum alkaline phosphatase assays 12 had abnormally high levels. Of the seven infants in whom serum 25OHD was measured before treatment, all had values less than 10 ng/mL. CONCLUSIONS: These reports provide strong support for the view that maternal deficiency leads to overt bone disease from before birth. Maternal deficiency probably also leads to impairment of bone quality in postnatal life. The importance of ensuring adequate vitamin D nutrition in pregnancy is emphasised.

Toxicity of aflatoxin B1 towards the vitamin D receptor (VDR).

This research describes an unexpected toxicity of the aflatoxin B1 towards the vitamin D receptors. Rickets is a childhood disease, and calcium deficiency is the aetiological cause in Africa, being primarily associated with nutritional problems; in this research the contribution of aflatoxin B1 exposure during the early months of life is an interesting factor to deepen in order to prevent liver damages or the development of rickets. The results show that the expression of vitamin D receptor in osteosarcoma cell line SAOS-2 is significantly down-modulated by exposure to aflatoxin B1. This seems to suggest that Aflatoxin B1, toxic towards the vitamin D receptor, interferes with the actions of the vitamin D on calcium binding gene expression in the kidney and intestine. Experimental data indicate a 58% and 86% decrease if the cells are exposed to 5 ng/mL and 50 ng/mL of aflatoxin B1, respectively. These results seem to indicate that natural occurrence of the aflatoxin B1 and allelic variant of vitamin D receptor on (F allele) increase the risk of developing rickets of African children.

Coupling fibroblast growth factor 23 production and cleavage: iron deficiency, rickets, and kidney disease.

PURPOSE OF REVIEW: High levels of fibroblast growth factor 23 (FGF23) cause the rare disorders of hypophosphatemic rickets and are a risk factor for cardiovascular disease and death in patients with chronic kidney disease (CKD). Despite major advances in understanding FGF23 biology, fundamental aspects of FGF23 regulation in health and in CKD remain mostly unknown. RECENT FINDINGS: Autosomal dominant hypophosphatemic rickets (ADHR) is caused by gain-of-function mutations in FGF23 that prevent its proteolytic cleavage, but affected individuals experience a waxing and waning course of phosphate wasting. This led to the discovery that iron deficiency is an environmental trigger that stimulates FGF23 expression and hypophosphatemia in ADHR. Unlike osteocytes in ADHR, normal osteocytes couple increased FGF23 production with commensurately increased FGF23 cleavage to ensure that normal phosphate homeostasis is maintained in the event of iron deficiency. Simultaneous measurement of FGF23 by intact and C-terminal assays supported these breakthroughs by providing minimally invasive insight into FGF23 production and cleavage in bone. These findings also suggest a novel mechanism of FGF23 elevation in patients with CKD, who are often iron deficient and demonstrate increased FGF23 production and decreased FGF23 cleavage, consistent with an acquired state that mimics the molecular pathophysiology of ADHR. SUMMARY: Iron deficiency stimulates FGF23 production, but normal osteocytes couple increased FGF23 production with increased cleavage to maintain normal circulating levels of biologically active hormone. These findings uncover a second level of FGF23 regulation within osteocytes, failure of which culminates in elevated levels of biologically active FGF23 in ADHR and perhaps CKD.

Does vitamin D sufficiency equate to a single serum 25-hydroxyvitamin D level or are different levels required for non-skeletal diseases?

OBJECTIVE: Clarify the concept of vitamin D sufficiency, the relationship between efficacy and vitamin D status and the role of Vitamin D supplementation in the management of non-skeletal diseases. We outline reasons for anticipating different serum vitamin D levels are required for different diseases. METHOD: Review the literature for evidence of efficacy of supplementation and minimum effective 25-hydroxyvitamin D (25-OHD) levels in non-skeletal disease. RESULTS: Evidence of efficacy of vitamin supplementation is graded according to levels of evidence. Minimum effective serum 25-OHD levels are lower for skeletal disease, e.g., rickets (25 nmol/L), osteoporosis and fractures (50 nmol/L), than for premature mortality (75 nmol/L) or non-skeletal diseases, e.g., depression (75 nmol/L), diabetes and cardiovascular disease (80 nmol/L), falls and respiratory infections (95 nmol/L) and cancer (100 nmol/L). CONCLUSIONS: Evidence for the efficacy of vitamin D supplementation at serum 25-OHD levels ranging from 25 to 100 nmol/L has been obtained from trials with vitamin D interventions that change vitamin D status by increasing serum 25-OHD to a level consistent with sufficiency for that disease. This evidence supports the hypothesis that just as vitamin D metabolism is tissue dependent, so the serum levels of 25-OHD signifying deficiency or sufficiency are disease dependent.

[Updates on rickets and osteomalacia: guidelines for diagnosis of rickets and osteomalacia].

Rickets and osteomalacia are disorders of calcification characterized by defects of bone and cartilage mineralization during growth, and bone mineralization in adults, respectively. The specific x-ray findings including a cupping, flaring, and fraying of metaphysis and the elevation of the level of serum alkaline phosphatase are essential for the diagnosis of rickets. In addition, hypophosphatemia, hypocalcemia, and some symptoms including born deformity, spinal curvature, craniotabes, enlargement of the anterior fontanel, rachitic rosary, and joint swelling are also important. Clinicians need to consider the different normal ranges of the levels of serum alkaline phosphatase and phosphate depending on their patient's age when they diagnose their childhood patients. In contrast, the radiographic diagnosis of osteomalacia is difficult. The hypophosphatemia or hypocalcemia and the elevation of serum bone alkaline phosphatase are essential for the diagnosis of osteomalacia. Moreover, some clinical features including muscle weakness and bone pain, the decrease of bone density, and the finding of multiple uptake in bone scintigraphy or of the pseudofracture in bone x-ray study are also important. It is very useful for the differential diagnosis to measure the serum levels of 25-hydroxy vitamin D and fibroblast growth factor 23.

Efficacy of a dose range of simulated sunlight exposures in raising vitamin D status in South Asian adults: implications for targeted guidance on sun exposure.

BACKGROUND: Vitamin D is essential for bone health, and cutaneous synthesis is an important source. South Asians cannot attain adequate amounts of vitamin D by following general recommendations on summer sunlight exposure at northerly latitudes, and increased exposure may be appropriate for improving their vitamin D status. OBJECTIVE: We examined the efficacy of a dose range of simulated summer sunlight exposures in raising vitamin D status in UK adults of South Asian ethnicity. DESIGN: In a dose-response study, healthy adults of South Asian ethnicity (n = 60; 20-60 y old) received 1 of 6 ultraviolet exposures ranging from 0.65 to 3.9 standard erythema doses (SEDs), which were equivalent to 15-90 min unshaded noontime summer sunlight at 53.5°N (Manchester, United Kingdom), 3 times/wk for 6 wk, while wearing casual clothes that revealed a 35% skin area. Serum 25-hydroxyvitamin D [25(OH)D] was measured weekly, and dietary vitamin D was estimated. RESULTS: At baseline, all completing participants (n = 51) were vitamin D insufficient [25(OH)D concentrations <20 ng/mL], and a high proportion of participants were deficient [35% of subjects had 25(OH)D concentrations <5 ng/mL, and 90% of subjects had 25(OH)D concentrations <10 ng/mL, which are concentrations at which osteomalacia and rickets occur). The 25(OH)D concentration rose significantly in all dose groups. Postcourse, all participants achieved 25(OH)D concentrations ≥5 ng/mL, whereas only 6 subjects attained 25(OH)D concentrations ≥20 ng/mL. Participants who received exposures ≥1.95 SEDs (equivalent to 45 min unshaded sunlight; n = 33) attained a mean (±SD) 25(OH)D concentration of 15.7 ± 5 ng/mL (mean rise: 8.7 ± 5.7 ng/mL; 95% CI: 6.8, 10.6 ng/mL; P < 0.001), and 94% of subjects achieved concentrations >10 ng/mL. CONCLUSIONS: Targeted guidance on sunlight exposure could usefully enhance vitamin D status to avoid deficiency [25(OH)D concentration >10 ng/mL] in South Asians living at latitudes distant from the equator. This trial was registered at the ISRCTN Register (www.isrctn.org) as 07565297.

Adamts1 is highly induced in rachitic bones of FGF23 transgenic mice and participates in degradation of non-mineralized bone matrix collagen.

Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.

Protective roles of DMP1 in high phosphate homeostasis.

PURPOSE: Dmp1 (dentin matrix protein1) null mice (Dmp1(-/-)) display hypophosphatemic rickets with a sharp increase in fibroblast growth factor 23 (FGF23). Disruption of Klotho (the obligatory co-receptor of FGF23) results in hyperphosphatemia with ectopic calcifications formed in blood vessels and kidneys. To determine the role of DMP1 in both a hyperphosphatemic environment and within the ectopic calcifications, we created Dmp1/Klotho compound deficient (Dmp1(-/-)kl/kl) mice. PROCEDURES: A combination of TUNEL, immunohistochemistry, TRAP, von Kossa, micro CT, bone histomorphometry, serum biochemistry and Scanning Electron Microscopy techniques were used to analyze the changes in blood vessels, kidney and bone for wild type control, Dmp1(-/-), Klotho deficient (kl/kl) and Dmp1(-/-)kl/kl animals. FINDINGS: Interestingly, Dmp1(-/-)kl/kl mice show a dramatic improvement of rickets and an identical serum biochemical phenotype to kl/kl mice (extremely high FGF23, hyperphosphatemia and reduced parathyroid hormone (PTH) levels). Unexpectedly, Dmp1(-/-)kl/kl mice presented elevated levels of apoptosis in osteocytes, endothelial and vascular smooth muscle cells in small and large blood vessels, and within the kidney as well as dramatic increase in ectopic calcification in all these tissues, as compared to kl/kl. CONCLUSION: These findings suggest that DMP1 has an anti-apoptotic role in hyperphosphatemia. Discovering this novel protective role of DMP1 may have clinical relevance in protecting the cells from apoptosis in high-phosphate environments as observed in chronic kidney disease (CKD).

When should we measure vitamin D concentration in clinical practice?

The many recently published data on vitamin D have raised much interest in the medical community. One of the consequences has been a great increase in the prescription of vitamin D concentration measurements in clinical practice. It must be reminded that only the measurement of 25-hydroxyvitamin D (25(OH)D) concentration is indicated to evaluate vitamin D status. Furthermore, since vitamin D insufficiency is so common, since treatment is inexpensive and has a large safety margin, and since we already have much data suggesting that besides its classic effects on bone and mineral metabolism, vitamin D may potentially be helpful for the prevention/management of several diseases, perhaps should it be prescribed to everyone without prior testing? In our opinion, there are however groups of patients in whom estimation of vitamin D status is legitimate and may be recommended. This includes patients in whom a "reasonably" evidence-based target concentration (i.e., based on randomized clinical trials when possible) should be achieved and/or maintained such as patients with rickets/osteomalacia, osteoporosis, chronic kidney disease and kidney transplant recipients, malabsorption, primary hyperparathyroidism, granulomatous disease, and those receiving treatments potentially inducing bone loss. Other patients in whom vitamin D concentration may be measured are those with symptoms compatible with a severe vitamin D deficiency or excess persisting without explanation such as those with diffuse pain, or elderly individuals who fall, or those receiving treatments which modify vitamin D metabolism such as some anti-convulsants. Measurement of Vitamin D concentrations should also be part of any exploration of calcium/phosphorus metabolism which includes measurement of serum calcium, phosphate and PTH.

Iron status and fibroblast growth factor-23 in Gambian children.

A relationship between iron and fibroblast growth factor-23 (FGF23) metabolic pathways has been proposed. Iron deficiency anaemia is prevalent in The Gambia and concentrations of fibroblast growth factor-23 FGF23 are elevated in a large percentage of Gambian children with rickets-like bone deformity. We speculate that low iron status may be involved in the aetiology of Gambian rickets. The aim of this study was to determine if there was a relationship between haemoglobin, as a marker of iron status, and FGF23 in samples from children with and without a history of rickets-like bone deformities in The Gambia. We conducted a retrospective analysis of studies carried out from 2006 to 2008 in children from a rural community in The Gambia where iron deficiency anaemia is endemic and where elevated circulating concentrations of FGF23 have been found. To investigate the relationship between circulating FGF23 and haemoglobin concentrations we used an age-adjusted linear regression model on data from children <18y of age with a family or personal history of rickets-like bone deformity (BD) (n=108) and from the local community (LC) (n=382). We found that circulating concentration of FGF23 was inversely correlated with haemoglobin concentration. This effect was more pronounced in BD children compared with LC children (interaction: P≤0.0001). Anaemia and elevated FGF23 were more prevalent in BD children compared to LC children (P=0.0003 and P=0.0001 respectively). In conclusion, there is a stronger relationship between FGF23 and haemoglobin in Gambian children with a history of rickets compared to local community children. This study provides support for the contention that iron may be involved in FGF23 metabolic pathways.

Should 25-hydroxyvitamin D and bone density using DXA be tested in adolescents with lumbar stress fractures of the pars interarticularis?

STUDY DESIGN: Retrospective study. OBJECTIVE: To determine if 25-hydroxyvitamin D (25[OH]D) level measurement and bone mineral density (BMD) using dual-energy x-ray absorptiometry (DXA) are indicated in children with a history of stress fracture of the pars interarticularis. SUMMARY OF BACKGROUND DATA: Healing rates of 4%-25% for bilateral and unilateral pars fractures, respectively, have previously been reported. Factors that may contribute to osteomalacia, rickets, and poor bone healing include low (25[OH]D) and low BMD. METHODS: Patients were seen at the Nebraska Spine Center between 2008 and 2010. Selection criteria included a diagnosis of pars fracture with DXA Z-score values (lumbar and hip) and pretreatment serum (25[OH]D) level measurement. Twenty-four patients were included. Vitamin D was defined as sufficient when ≥ 32 ng/mL, insufficient when 20 to < 32 ng/mL, and deficient when < 20 ng/mL. BMD was interpreted from DXA Z-scores using reference intervals defined in the literature. A Z-score <-2.0 was considered low for chronological age. RESULTS: The mean (± SD) vitamin D level was 29.9 ng/mL ± 10.8 (range, 9-56 ng/mL). Values were ≤ 10 ng/mL in 1 patient (4%), 11-20 ng/mL in 4 patients (17%), 21-30 ng/mL in 8 patients (33%), 31-50 ng/mL in 10 patients (42%), and > 50 ng/mL in 1 patient (4%). This correlated to 3 (13%) patients with deficient vitamin D (≤ 15 ng/mL), 12 (50%) patients with insufficient levels, and 9 (38%) with sufficient levels of vitamin D. The mean Z-scores were 0.43 ± 0.93 (lumbar, range, -1.3 to 2.8) and 1.0 ± 1.11 (hip, range, -0.5 to 3.0). All scores were consistent with normal bony mineralization for age. CONCLUSIONS: On the basis of these data, we recommend routine vitamin D testing and do not recommend routine DXA in adolescents with lumbar stress fractures of the pars interarticularis.

Vitamin D-dependent non-type 1, non-type 2 rickets in a 3-month-old Cornish Rex kitten.

UNLABELLED: CASE PRESENTATION AND ASSESSMENT: A 3-month-old female Cornish Rex kitten was found to have non-painful swelling of the carpal and tarsal regions when presented for routine neutering. The kitten was smaller in stature and less active than its siblings and, according to the owner, had a bunny-hopping gait, was reluctant to climb stairs and strained during defecation. Radiography of the affected limbs and a subsequent radiographic survey of the entire skeleton demonstrated features consistent with rickets. The three littermates were clinically and radiographically normal. As a nutritionally complete diet was being fed, it seemed most likely that the kitten had an inborn error related to vitamin D metabolism. Serum biochemistry demonstrated reduced total alkaline phosphatase activity and increased concentrations of parathyroid hormone. Concentrations of 1,25- and 25-hydroxycholecalciferol were markedly reduced, confirming the diagnosis of rickets. TREATMENT: The kitten was treated with calcitriol, administered orally once daily, and improved rapidly both clinically and radiologically. Serial laboratory studies suggested that the error in vitamin D metabolism was transient, and, at the time of writing, as an adult, the cat appears to require no ongoing replacement calcitriol therapy. CLINICAL RELEVANCE: This case emphasises the value of examining a full 'calcium profile' via a human or veterinary reference laboratory, and a favourable prognosis in some kittens with rickets makes such investigations worthwhile. Even when finances preclude detailed investigation, trial therapy using a nutritionally complete diet and physiological doses of calcitriol or cholecalciferol is inexpensive and can produce a good response.

Proceedings of the Rank Forum on Vitamin D.

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.