Abnormalities of mineral metabolism occur early in chronic kidney disease. Quantification of the prevalence of these abnormalities has not been described using current assays nor in large unselected populations. This outpatient cohort cross-sectional study was conducted in 153 centers, (71% primary care practices). Blood for parathyroid hormone (PTH), vitamin D metabolites, creatinine, calcium (Ca), and phosphorus (P) were drawn between June and October 2004. Low 1,25-dihydroxyvitamin D (1,25 OH2 D3) was defined as <22 pg/ml. The 1814 patients had a mean age of 71.1 years old; 48% had diabetes mellitus (DM). Low 1,25 OH2 D3 was evident at all estimated glomerular filtration rate (eGFR) levels: 13% in those with eGFR >80 ml/min, >60% in those with eGFR <30 ml/min. High PTH (>65pm/dl) occurred in 12% with eGFR >80 ml/min. Serum Ca and P were normal until eGFR was <40 ml/min. Significant differences in the mean and median values of 1,25 OH2 D3, PTH, but not 25(OH)D3 levels, were seen across deciles of eGFR (P<0.001). Multivariate analysis revealed that DM, increased urinary albumin/creatinine ratio and lower eGFR predicted lower values of 1,25 OH2 D3. A high prevalence of mineral metabolite abnormalities occurs in a large unreferred US cohort. Low 1,25 OH2 D3 and elevated PTH are common at higher eGFR than previously described. As bone, cardiovascular disease, and mineral metabolite are correlated; further studies are necessary to determine the importance of these findings relative to outcomes.

States of hypo- and hyperphosphatemia have deleterious consequences including rickets/osteomalacia and renal/cardiovascular disease, respectively. Therefore, the maintenance of appropriate plasma levels of phosphate is an essential requirement for health. This control is executed by the collaborative action of intestine and kidney whose capacities to (re)absorb phosphate are regulated by a number of hormonal and metabolic factors, among them parathyroid hormone, fibroblast growth factor 23, 1,25(OH) vitamin D, and dietary phosphate. The molecular mechanisms responsible for the transepithelial transport of phosphate across enterocytes are only partially understood. Indeed, whereas renal reabsorption entirely relies on well-characterized active transport mechanisms of phosphate across the renal proximal epithelia, intestinal absorption proceeds via active and passive mechanisms, with the molecular identity of the passive component still unknown. The active absorption of phosphate depends mostly on the activity and expression of the sodium-dependent phosphate cotransporter NaPi-IIb (SLC34A2), which is highly regulated by many of the factors, mentioned earlier. Physiologically, the contribution of NaPi-IIb to the maintenance of phosphate balance appears to be mostly relevant during periods of low phosphate availability. Therefore, its role in individuals living in industrialized societies with high phosphate intake is probably less relevant. Importantly, small increases in plasma phosphate, even within normal range, associate with higher risk of cardiovascular disease. Therefore, therapeutic approaches to treat hyperphosphatemia, including dietary phosphate restriction and phosphate binders, aim at reducing intestinal absorption. Here we review the current state of research in the field. © 2017 American Physiological Society. Compr Physiol 8:1065-1090, 2018.Copyright © 2018 American Physiological Society. All rights reserved.

Plasma phosphate concentration is maintained within a relatively narrow range by control of renal reabsorption of filtered inorganic phosphate (P(i)). P(i) reabsorption is a transcellular process that occurs along the proximal tubule. P(i) flux at the apical (luminal) brush border membrane represents the rate-limiting step and is mediated by three Na(+)-dependent P(i) cotransporters (members of the SLC34 and SLC20 families). The putative proteins responsible for basolateral P(i) flux have not been identified. The transport mechanism of the two kidney-specific SLC34 proteins (NaPi-IIa and NaPi-IIc) and of the ubiquitously expressed SLC20 protein (PiT-2) has been studied by heterologous expression to reveal important differences in kinetics, stoichiometry, and substrate specificity. Studies on the regulation of the abundance of the respective proteins highlight significant differences in the temporal responses to various hormonal and nonhormonal factors that can influence P(i) homeostasis. The phenotypes of mice deficient in NaPi-IIa and NaPi-IIc indicate that NaPi-IIa is responsible for most P(i) renal reabsorption. In contrast, in the human kidney, NaPi-IIc appears to have a relatively greater role. The physiological relevance of PiT-2 to P(i) reabsorption remains to be elucidated.

Our understanding of the regulation of phosphate balance has benefited tremendously from the molecular identification and characterization of genetic defects leading to a number of rare inherited or acquired disorders affecting phosphate homeostasis. The identification of the key phosphate-regulating hormone, fibroblast growth factor 23 (FGF23), as well as other molecules that control its production, such as the glycosyltransferase GALNT3, the endopeptidase PHEX, and the matrix protein DMP1, and molecules that function as downstream effectors of FGF23 such as the longevity factor Klotho and the phosphate transporters NPT2a and NPT2c, has permitted us to understand the complex interplay that exists between the kidneys, bone, parathyroid, and gut. Such insights from genetic disorders have allowed not only the design of potent targeted treatment of FGF23-dependent hypophosphatemic conditions, but also provide clinically relevant observations related to the dysregulation of mineral ion homeostasis in health and disease.Copyright © 2018. Published by Elsevier Ltd.

Renal phosphate handling critically determines plasma phosphate and whole body phosphate levels. Filtered phosphate is mostly reabsorbed by Na-dependent phosphate transporters located in the brush border membrane of the proximal tubule: NaPi-IIa (SLC34A1), NaPi-IIc (SLC34A3), and Pit-2 (SLC20A2). Here we review new evidence for the role and relevance of these transporters in inherited disorders of renal phosphate handling. The importance of NaPi-IIa and NaPi-IIc for renal phosphate reabsorption and mineral homeostasis has been highlighted by the identification of mutations in these transporters in a subset of patients with infantile idiopathic hypercalcemia and patients with hereditary hypophosphatemic rickets with hypercalciuria. Both diseases are characterized by disturbed calcium homeostasis secondary to elevated 1,25-(OH) vitamin D as a consequence of hypophosphatemia. In vitro analysis of mutated NaPi-IIa or NaPi-IIc transporters suggests defective trafficking underlying disease in most cases. Monoallelic pathogenic mutations in both SLC34A1 and SLC34A3 appear to be very frequent in the general population and have been associated with kidney stones. Consistent with these findings, results from genome-wide association studies indicate that variants in SLC34A1 are associated with a higher risk to develop kidney stones and chronic kidney disease, but underlying mechanisms have not been addressed to date.

Over the past 25 years, successive cloning of SLC34A1, SLC34A2 and SLC34A3, which encode the sodium-dependent inorganic phosphate (P) cotransport proteins 2a-2c, has facilitated the identification of molecular mechanisms that underlie the regulation of renal and intestinal P transport. P and various hormones, including parathyroid hormone and phosphatonins, such as fibroblast growth factor 23, regulate the activity of these P transporters through transcriptional, translational and post-translational mechanisms involving interactions with PDZ domain-containing proteins, lipid microdomains and acute trafficking of the transporters via endocytosis and exocytosis. In humans and rodents, mutations in any of the three transporters lead to dysregulation of epithelial P transport with effects on serum P levels and can cause cardiovascular and musculoskeletal damage, illustrating the importance of these transporters in the maintenance of local and systemic P homeostasis. Functional and structural studies have provided insights into the mechanism by which these proteins transport P, whereas in vivo and ex vivo cell culture studies have identified several small molecules that can modify their transport function. These small molecules represent potential new drugs to help maintain P homeostasis in patients with chronic kidney disease - a condition that is associated with hyperphosphataemia and severe cardiovascular and skeletal consequences.

PTH and Vitamin D are two major regulators of mineral metabolism. They play critical roles in the maintenance of calcium and phosphate homeostasis as well as the development and maintenance of bone health. PTH and Vitamin D form a tightly controlled feedback cycle, PTH being a major stimulator of vitamin D synthesis in the kidney while vitamin D exerts negative feedback on PTH secretion. The major function of PTH and major physiologic regulator is circulating ionized calcium. The effects of PTH on gut, kidney, and bone serve to maintain serum calcium within a tight range. PTH has a reciprocal effect on phosphate metabolism. In contrast, vitamin D has a stimulatory effect on both calcium and phosphate homeostasis, playing a key role in providing adequate mineral for normal bone formation. Both hormones act in concert with the more recently discovered FGF23 and klotho, hormones involved predominantly in phosphate metabolism, which also participate in this closely knit feedback circuit. Of great interest are recent studies demonstrating effects of both PTH and vitamin D on the cardiovascular system. Hyperparathyroidism and vitamin D deficiency have been implicated in a variety of cardiovascular disorders including hypertension, atherosclerosis, vascular calcification, and kidney failure. Both hormones have direct effects on the endothelium, heart, and other vascular structures. How these effects of PTH and vitamin D interface with the regulation of bone formation are the subject of intense investigation.Copyright © 2016 John Wiley & Sons, Inc.

Rickets is a metabolic bone disease that develops as a result of inadequate mineralization of growing bone due to disruption of calcium, phosphorus and/or vitamin D metabolism. Nutritional rickets remains a significant child health problem in developing countries. In addition, several rare genetic causes of rickets have also been described, which can be divided into two groups. The first group consists of genetic disorders of vitamin D biosynthesis and action, such as vitamin D-dependent rickets type 1A (VDDR1A), vitamin D-dependent rickets type 1B (VDDR1B), vitamin D-dependent rickets type 2A (VDDR2A), and vitamin D-dependent rickets type 2B (VDDR2B). The second group involves genetic disorders of excessive renal phosphate loss (hereditary hypophosphatemic rickets) due to impairment in renal tubular phosphate reabsorption as a result of FGF23-related or FGF23-independent causes. In this review, we focus on clinical, laboratory and genetic characteristics of various types of hereditary rickets as well as differential diagnosis and treatment approaches.

Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

X-linked hypophosphataemia (XLH) is the most common cause of inherited phosphate wasting and is associated with severe complications such as rickets, lower limb deformities, pain, poor mineralization of the teeth and disproportionate short stature in children as well as hyperparathyroidism, osteomalacia, enthesopathies, osteoarthritis and pseudofractures in adults. The characteristics and severity of XLH vary between patients. Because of its rarity, the diagnosis and specific treatment of XLH are frequently delayed, which has a detrimental effect on patient outcomes. In this Evidence-Based Guideline, we recommend that the diagnosis of XLH is based on signs of rickets and/or osteomalacia in association with hypophosphataemia and renal phosphate wasting in the absence of vitamin D or calcium deficiency. Whenever possible, the diagnosis should be confirmed by molecular genetic analysis or measurement of levels of fibroblast growth factor 23 (FGF23) before treatment. Owing to the multisystemic nature of the disease, patients should be seen regularly by multidisciplinary teams organized by a metabolic bone disease expert. In this article, we summarize the current evidence and provide recommendations on features of the disease, including new treatment modalities, to improve knowledge and provide guidance for diagnosis and multidisciplinary care.

X-linked Hypophosphatemia (XLH) is caused by loss of function mutations in the PHEX gene. Given the recent availability of a new therapy for XLH, a retrospective analysis of the most recent 261 Chinese patients with XLH evaluated at Peking Union Medical College Hospital was conducted. Clinical, biochemical, radiographic studies, as well as genetic analyses, including Sanger sequencing for point mutations and Multiplex Ligation-dependent Probe Amplification (MLPA) to detect large deletions/duplications were employed. Based on the structure of Neprilysin (NEP), a member of M13 family that includes PHEX, a three-dimensional (3D) model of PHEX was constructed, missense and nonsense mutations were positioned on the predicted structure to visualize relative positions of these two types of variants. Sex differences and genotype-phenotype correlations were also undertaken. Genetic analyses identified 166 PHEX mutations in 261 XLH patients. One hundred and eleven of the 166 mutations were unreported. Four mutational 'hot-spots' were identified in this cohort (P534L, G579R, R747X, c.1645+1 G>A). Missense mutations, but not nonsense mutations, clustered in the two putative lobes of the PHEX protein, suggesting these are functionally important regions of the molecule. Circulating levels of intact FGF23 were significantly elevated (median level 101.9 pg/mL; reference range 16.1-42.2 pg/mL). No significant sex differences, as well as no phenotypic differences were identified between patients with putative truncating and non-truncating PHEX mutations. However, patients with N-terminal PHEX mutations had an earlier age of onset of disease (P = 0.015) and higher iFGF23 levels (P = 0.045) as compared to those with C-terminal mutations. These data provide a comprehensive characterization of the largest cohort of patients with XLH reported to date from China, which will help in evaluating the applicability of emerging therapies for this disease in this ethnic group.Copyright © 2019 Elsevier Inc. All rights reserved.

Primary hyperparathyroidism (PHPT) is one of the most common of all endocrine disorders encountered by the practising histopathologist. The vast majority of lesions are sporadic in nature, approximately 85% of which are parathyroid adenomas, while hyperplasia and carcinoma account for 10-15% and fewer than 1%, of cases, respectively. Heritable forms of PHPT are much less common and present challenges both to clinicians and pathologists, particularly when they are the presenting feature of an endocrine syndrome. In such instances, pathologists play a key role in alerting physicians to the possibility of an underlying heritable endocrine syndrome and the potential for extra-endocrine manifestations. Therefore, a working knowledge of these disorders is essential for providing guidance to treating physicians. The aim of this update is to review the clinicopathological features, genetic bases and current management for patients with PHPT associated with multiple endocrine neoplasia (MEN) types 1, 2A and 4 and hyperparathyroidism-jaw tumour (HPT-JT) syndrome in the context of the 2017 World Health Organization (WHO) Classification of Tumours of the Endocrine Organs. Additionally, familial isolated hyperparathyroidism, familial hypocalciuric hypercalcaemia and neonatal severe hyperparathyroidism are discussed.© 2017 John Wiley & Sons Ltd.

Primary hyperparathyroidism is a common endocrine disorder of calcium metabolism characterised by hypercalcaemia and elevated or inappropriately normal concentrations of parathyroid hormone. Almost always, primary hyperparathyroidism is due to a benign overgrowth of parathyroid tissue either as a single gland (80% of cases) or as a multiple gland disorder (15-20% of cases). Primary hyperparathyroidism is generally discovered when asymptomatic but the disease always has the potential to become symptomatic, resulting in bone loss and kidney stones. In countries where biochemical screening tests are not common, symptomatic primary hyperparathyroidism tends to predominate. Another variant of primary hyperparathyroidism has been described in which the serum calcium concentration is within normal range but parathyroid hormone is elevated in the absence of any obvious cause. Primary hyperparathyroidism can be cured by removal of the parathyroid gland or glands but identification of patients who are best advised to have surgery requires consideration of the guidelines that are regularly updated. Recommendations for patients who do not undergo parathyroid surgery include monitoring of serum calcium concentrations and bone density.Copyright © 2018 Elsevier Ltd. All rights reserved.

In this paper, we explore nephrogenic hypophosphatemic osteomalacia associated with low-dose adefovir dipivoxil (ADV) therapy.Five patients who were treated with ADV for >2 years were included in this study. The metabolic index of phosphate and calcium, renal tubular function, renal function and pathological changes of the patients were investigated.Two male and three female patients were studied. All of the patients presented with a reduced serum phosphate level (0.38-0.60 mmol/L) accompanied with hyperphosphaturia at 10.9-23.8 mmol/24 h. The serum potassium level was also reduced or at lower range (2.56-3.54 mmol/L), but the 24-h urinary potassium was relatively increased. Urinalysis also demonstrated increased excretion of glucose in four patients. Urine protein electrophoresis showed low-to-moderate molecular weight protein. Three patients manifested urine acidification function impairment. Four patients had accompanying renal insufficiency. Three patients had difficulty walking and presented with a reduction in height (2.5-14 cm). Renal biopsy revealed that most of the glomeruli were normal accompanied by mild interstitial fibrosis with inflammatory cell infiltration. ADV treatment was subsequently ceased. Patients were treated with regular phosphate supplementation, citrate acid potassium and calcium bicarbonate. After 6-month treatment, the bone pain was significantly alleviated. Serum creatinine of one patient returned to normal levels and two patients who had difficulty walking were able to walk independently.The current study showed long-term and low-dose ADV treatment in a Chinese population may lead to proximal tubular impairment, metabolic acidosis, hypophosphatemia, hypokalemia, metabolic bone disease, renal osteopathia and renal functional damage.

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.

Rickets is a disease of the hypertrophic chondrocytes in the growth plate and is caused by hypophosphatemia-a derived defect in terminal chondrocyte apoptosis. This highlights the critical role of phosphorous in cartilage and bone metabolism. This review shows the role of phosphorous metabolism, transport and function in maintaining phosphorous supply to the growth plate, bone osteoblast and the kidney. Given that phosphorous is the common denominator of all rickets, this review proposes a new classification for the differential diagnosis of rickets, which is based on the mechanisms leading to hypophosphatemia-high PTH activity, high FGF23 activity or renal phosphaturia.

Nutritional rickets and osteomalacia are common in dark-skinned and migrant populations. Their global incidence is rising due to changing population demographics, failing prevention policies and missing implementation strategies. The calcium deprivation spectrum has hypocalcaemic (seizures, tetany and dilated cardiomyopathy) and late hypophosphataemic (rickets, osteomalacia and muscle weakness) complications. This article reviews sustainable prevention strategies and identifies areas for future research.The global rickets consensus recognises the equal contribution of vitamin D and dietary calcium in the causation of calcium deprivation and provides a three stage categorisation for sufficiency, insufficiency and deficiency. For rickets prevention, 400 IU daily is recommended for all infants from birth and 600 IU in pregnancy, alongside monitoring in antenatal and child health surveillance programmes. High-risk populations require lifelong supplementation and food fortification with vitamin D or calcium. Future research should identify the true prevalence of rickets and osteomalacia, their role in bone fragility and infant mortality, and best screening and public health prevention tools.

Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of infants, children, and adolescents; the consequences can be lethal or can last into adulthood. The goals of this evidence-based consensus document are to provide health care professionals with guidance for prevention, diagnosis, and management of nutritional rickets and to provide policy makers with a framework to work toward its eradication.A systematic literature search examining the definition, diagnosis, treatment, and prevention of nutritional rickets in children was conducted. Evidence-based recommendations were developed using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system that describe the strength of the recommendation and the quality of supporting evidence.Thirty-three nominated experts in pediatric endocrinology, pediatrics, nutrition, epidemiology, public health, and health economics evaluated the evidence on specific questions within five working groups. The consensus group, representing 11 international scientific organizations, participated in a multiday conference in May 2014 to reach a global evidence-based consensus.This consensus document defines nutritional rickets and its diagnostic criteria and describes the clinical management of rickets and osteomalacia. Risk factors, particularly in mothers and infants, are ranked, and specific prevention recommendations including food fortification and supplementation are offered for both the clinical and public health contexts.Rickets, osteomalacia, and vitamin D and calcium deficiencies are preventable global public health problems in infants, children, and adolescents. Implementation of international rickets prevention programs, including supplementation and food fortification, is urgently required.

We undertook this study to determine the prevalence and predictors of rhabdomyolysis in the hypophosphatemic state.To identify patients with hypophosphatemia, we reviewed medical admissions for the period of January through December 1989. The hypophosphatemic state was considered whenever the serum phosphate was less than or equal to 2.0 mg/dL. Rhabdomyolysis secondary to hypophosphatemia was defined when serum creatine kinase levels were greater than or equal to 224 IU/L; it occurred within 72 hours of the hypophosphatemic episode; and it subsequently normalized. Patients who had any other independent etiology for rhabdomyolysis were excluded. Clinical and biochemical characteristics of patients with rhabdomyolysis (Group I) and patients without rhabdomyolysis (Group II) were compared. Variables that predicted rhabdomyolysis in hypophosphatemia were identified by stepwise logistic regression using a backward elimination procedure.One hundred twenty-nine patients were found to have hypophosphatemia. Forty-six (Group I) of 129 patients (36%) showed biochemical evidence of rhabdomyolysis. There was no difference in serum phosphate and potassium concentrations between Group I and Group II patients. Patients in Group I showed higher values for serum osmolality (p less than 0.05), serum glutamic oxaloacetic transaminase (p less than 0.001), chloride (p less than 0.01), and blood urea nitrogen (less than 0.05) when compared with Group II patients. When biochemical profiles of patients with rhabdomyolysis were evaluated on the day of their peak creatine kinase level, only 16 patients were hypophosphatemic, and the majority of patients showed a transient increase in serum phosphate levels because of ongoing muscle cell injury. Of 17 potential predictors, six variables emerged including sodium, chloride, glucose, blood urea nitrogen, uric acid, and osmolality. These variables provided high sensitivity (0.88) as well as moderate specificity (0.79) for predicting the occurrence of rhabdomyolysis in hypophosphatemia.We conclude that rhabdomyolysis commonly occurs in the hypophosphatemic state and that at times severe hypophosphatemia as an etiology may be masked because of ongoing rhabdomyolysis. Serum sodium, chloride, glucose, blood urea nitrogen, uric acid, and osmolality have a predictive role for the occurrence of rhabdomyolysis in the hypophosphatemic state that shows a high specificity and a moderate sensitivity.

A 3-year-old child presented with severe hyperphosphatemia (phosphate 45 mg/dL) secondary to chronic enema use. Following aggressive correction of the hyperphosphatemia, hypophosphatemia ensued (phosphate 1.7 mg/dL). Concurrently, the patient developed severe intravascular hemolysis and RBC morphologic defects. The hemolysis and morphologic defects corrected with return to normal serum phosphate levels. Severe hypophosphatemia is a rare cause of intravascular hemolysis.

The Rickets Severity Score (RSS) was used to evaluate X-linked hypophosphatemic rickets (XLH), a genetic disorder mediated by increased circulating FGF23. The reliability of the RSS was assessed using data from a randomized, phase 2 clinical trial that evaluated the effects of burosumab, a fully human anti-FGF23 monoclonal antibody, in 52 children with XLH ages 5 to 12 years. Bilateral knee and wrist radiographs were obtained at baseline, week 40, and week 64. We evaluated the relationships of the RSS to the Radiographic Global Impression of Change (RGI-C), serum alkaline phosphatase (ALP), height Z-score, 6-minute walk test (6MWT) percent predicted, and the Pediatric Orthopedic Society of North America Pediatric Outcomes Data Collection Instrument (POSNA-PODCI). The RSS showed moderate-to-substantial inter-rater reliability (weighted kappa, 0.45-0.65; Pearson correlation coefficient (r), 0.83-0.89) and substantial intra-rater reliability (weighted Kappa, 0.66; r = 0.91). Baseline RSS correlated with serum ALP (r = 0.47). Baseline RSS identified two subgroups (higher [RSS ≥1.5] and lower RSS [RSS <1.5]) that discriminated between subjects with greater and lesser rachitic disease. Higher RSS was associated with more severe clinical features, including impaired growth (Z-score, -2.12 vs -1.44) and walking ability (6MWT percent predicted, 77% vs 86%), more severe self-reported pain (29.9 [more severe] vs 45.3 [less severe]) and less physical function (29.6 [more severe] vs 40.9 [less severe]). During burosumab treatment, greater reductions in RSS corresponded to higher RGI-C global scores (r = -0.65). Improvements in RSS correlated with decreased serum ALP (r = 0.47). These results show the reliability of the RSS in XLH, and demonstrate that higher RSS values are associated with greater biochemical, clinical, and functional impairments in children with XLH.Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations have revealed that the causes of rickets and osteomalacia are quite variable. Although these diseases can severely impair the quality of life of affected patients, rickets and osteomalacia can be completely cured or at least respond to treatment when properly diagnosed and treated according to the specific causes. On the other hand, there are no standard criteria to diagnose rickets or osteomalacia nationally and internationally. Therefore, we summarize the definition and pathogenesis of rickets and osteomalacia, and propose diagnostic criteria and a flowchart for the differential diagnosis of various causes of these diseases. We hope that these criteria and the flowchart are clinically useful for the proper diagnosis and management of these diseases.

X-linked hypophosphatemia (XLH) is the prototypic disorder of renal phosphate wasting, and the most common form of heritable rickets. Physicians, patients, and support groups have all expressed concerns about the dearth of information about this disease and the lack of treatment guidelines, which frequently lead to missed diagnoses or mismanagement. This perspective addresses the recommendation by conferees for the dissemination of concise and accessible treatment guidelines for clinicians arising from the Advances in Rare Bone Diseases Scientific Conference held at the NIH in October 2008. We briefly review the clinical and pathophysiologic features of the disorder and offer this guide in response to the conference recommendation, based on our collective accumulated experience in the management of this complex disorder.Copyright © 2011 American Society for Bone and Mineral Research.

The therapeutic response to chemically synthesized 1alpha-hydroxycholecalciferol (1alpha-OH-D3) was studied in three patients with autosomal recessive vitamin D dependency (ARVDD). The daily maintenance dose for vitamin D2, to prevent signs of vitamin D deficiency in these patients, was 40-54.4 mug/kg, or about 100 times normal (Table 1). Withdrawal of maintenance therapy with vitamin D2 resulted in the ultimate reappearance of the vitamin D depletion syndrome in patients 1 and 2 (Figs. 1 and 2). The third patient presented with the deficiency syndrome despite adequate vitamin D nutrition and was recognized to have ARVDD. Treatment with 1alpha-OH-D3 by mouth in all three patients at dose levels of 1-3 mug/24 hr (80-100 ng/kg) corrected hypocalcemia and suppressed parathyroid hormone-dependent renal loss of amino acids (Figs. 1, 2, and 4). Rickets healed in 7-9 weeks on 1alpha-OH-D3 alone (Fig. 3). The therapeutic response was rapid. It was usually seen first in the rise of serum calcium (Figs. 5 and 6). Withdrawal of 1alpha-OH-D3 was followed first by a fall of serum phosphorus, then by a fall in serum calcium; the latter occurred within about 2 weeks of withdrawal. Because the synthesis of 1alpha-OH-D3 is simpler than for 1alpha,25-dihydroxycholecalciferol and because the former is an effective therapeutic analog of vitamin D hormone, we believe these studies in ARVDD reveal 1alpha-OH-D3 to be the agent of choice for treatment of this and analogous diseases.

We report the beneficial effects of calcium infusions in a child with hereditary resistance to 1,25(OH)2D and alopecia. This patient after transient responsiveness to vitamin D derivatives became unresponsive to all therapy despite serum 1,25(OH)2D concentrations maintained at levels approximately 100-fold normal. A 7-mo trial with calcium infusions led to correction of biochemical abnormalities and healing of rickets. Bone biopsies (n = 3) showed a normal mineralization and the disappearance of the osteomalacia. Cultures of bone-derived cells demonstrated a lack of activation of 25-hydroxyvitamin D 24-hydroxylase and osteocalcin synthesis by 1,25(OH)2D3 (10(-9) and 10(-6) M). These results demonstrate that even in the absence of a normal 1,25(OH)2D3 receptor-effector system in bone cells, normal mineralization can be achieved in humans if adequate serum calcium and phosphorus concentrations are maintained; and calcium infusions may be an efficient alternative for the management of patients with this condition who are unresponsive to large doses of vitamin D derivatives.

To study the vitamin D receptor (VDR) gene in a young girl with severe rickets and clinical features of hereditary vitamin D resistant rickets, including hypocalcemia, hypophosphatemia, partial alopecia, and elevated serum levels of 1,25-dihydroxyvitamin D.We amplified and sequenced DNA samples from blood from the patient, her mother, and the patient's two siblings. We also amplified and sequenced the VDR cDNA from RNA isolated from the patient's blood.DNA sequence analyses of the VDR gene showed that the patient was homozygous for a novel guanine to thymine substitution in the 5'-splice site in the exon 8-intron J junction. Analysis of the VDR cDNA using reverse transcriptase-polymerase chain reaction showed that exons 7 and 9 were fused, and that exon 8 was skipped. The mother was heterozygous for the mutation and the two siblings were unaffected.A novel splice site mutation was identified in the VDR gene that caused exon 8 to be skipped. The mutation deleted amino acids 303-341 in the VDR ligand-binding domain, which is expected to render the VDR non-functional. Nevertheless, successful outpatient treatment was achieved with frequent high doses of oral calcium.

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.

X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.Ultragenyx Pharmaceutical and Kyowa Kirin International.Copyright © 2019 Elsevier Ltd. All rights reserved.

In X-linked hypophosphatemia (XLH), inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia. Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia, accelerated osteoarthritis, dental abscesses, and enthesopathy. Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia. This report summarizes results from a double-blind, placebo-controlled, phase 3 trial of burosumab in symptomatic adults with XLH. Participants with hypophosphatemia and pain were assigned 1:1 to burosumab 1 mg/kg (n = 68) or placebo (n = 66) subcutaneously every 4 weeks (Q4W) and were comparable at baseline. Across midpoints of dosing intervals, 94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo (p < 0.001). Burosumab significantly reduced the Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) stiffness subscale compared with placebo (least squares [LS] mean ± standard error [SE] difference, -8.1 ± 3.24; p = 0.012). Reductions in WOMAC physical function subscale (-4.9 ± 2.48; p = 0.048) and Brief Pain Inventory worst pain (-0.5 ± 0.28; p = 0.092) did not achieve statistical significance after Hochberg multiplicity adjustment. At week 24, 43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group (p < 0.001). Biochemical markers of bone formation and resorption increased significantly from baseline with burosumab treatment compared with placebo. The safety profile of burosumab was similar to placebo. There were no treatment-related serious adverse events or meaningful changes from baseline in serum or urine calcium, intact parathyroid hormone, or nephrocalcinosis. These data support the conclusion that burosumab is a novel therapeutic addressing an important medical need in adults with XLH.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc.