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The Journal of Clinical Endocrinology... Feb 2016Vitamin D and calcium deficiencies are common worldwide, causing nutritional rickets and osteomalacia, which have a major impact on health, growth, and development of... (Review)
Review
BACKGROUND
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.
EVIDENCE
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.
PROCESS
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.
RESULTS
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.
CONCLUSION
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.
Topics: Calcium; Child; Child, Preschool; Consensus; Health Policy; Humans; Infant; Mothers; Osteomalacia; Recommended Dietary Allowances; Rickets; Risk Factors; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 26745253
DOI: 10.1210/jc.2015-2175 -
Endocrine Reviews Aug 2019The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand... (Review)
Review
The etiology of endemic rickets was discovered a century ago. Vitamin D is the precursor of 25-hydroxyvitamin D and other metabolites, including 1,25(OH)2D, the ligand for the vitamin D receptor (VDR). The effects of the vitamin D endocrine system on bone and its growth plate are primarily indirect and mediated by its effect on intestinal calcium transport and serum calcium and phosphate homeostasis. Rickets and osteomalacia can be prevented by daily supplements of 400 IU of vitamin D. Vitamin D deficiency (serum 25-hydroxyvitamin D <50 nmol/L) accelerates bone turnover, bone loss, and osteoporotic fractures. These risks can be reduced by 800 IU of vitamin D together with an appropriate calcium intake, given to institutionalized or vitamin D-deficient elderly subjects. VDR and vitamin D metabolic enzymes are widely expressed. Numerous genetic, molecular, cellular, and animal studies strongly suggest that vitamin D signaling has many extraskeletal effects. These include regulation of cell proliferation, immune and muscle function, skin differentiation, and reproduction, as well as vascular and metabolic properties. From observational studies in human subjects, poor vitamin D status is associated with nearly all diseases predicted by these extraskeletal actions. Results of randomized controlled trials and Mendelian randomization studies are supportive of vitamin D supplementation in reducing the incidence of some diseases, but, globally, conclusions are mixed. These findings point to a need for continued ongoing and future basic and clinical studies to better define whether vitamin D status can be optimized to improve many aspects of human health. Vitamin D deficiency enhances the risk of osteoporotic fractures and is associated with many diseases. We review what is established and what is plausible regarding the health effects of vitamin D.
Topics: Animals; Bone and Bones; Calcium; Female; Humans; Male; Osteomalacia; Rickets; Signal Transduction; Vitamin D; Vitamin D Deficiency
PubMed: 30321335
DOI: 10.1210/er.2018-00126 -
The Journal of Clinical Endocrinology... Dec 2022Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic...
Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical examination, laboratory investigations, genetic analysis (especially in the absence of a guiding family history), and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of vitamin D combined with phosphate salts, or anti-FGF23 antibody treatment (burosumab) for X-linked hypophosphatemia. The purpose of this article is to explore the approach to evaluating hypophosphatemic rickets and its treatment options.
Topics: Adult; Child; Child, Preschool; Humans; Familial Hypophosphatemic Rickets; Osteomalacia; Fibroblast Growth Factors; Rickets, Hypophosphatemic; Hypophosphatemia; Phosphates
PubMed: 35981346
DOI: 10.1210/clinem/dgac488 -
International Journal of Molecular... Nov 2022Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate... (Review)
Review
Among bone-material qualities, mineralization is pivotal in conferring stiffness and toughness to the bone. Osteomalacia, a disease ensuing from inadequate mineralization of the skeleton, is caused by different processes leading to decreased available mineral (calcium and/or phosphate) or enzymatic alterations. Vitamin D deficiency, which remains the major cause of altered mineralization leading to inadequate intestinal calcium and phosphate absorption, may be also associated with other conditions primarily responsible for abnormal mineralization. Given the reality of widespread vitamin D inadequacy, a full biochemical assessment of mineral metabolism is always necessary to rule out or confirm other conditions. Both too-high or too-low serum alkaline phosphatase (ALP) levels are important for diagnosis. Osteomalacic syndrome is reversible, at least in part, by specific treatment. Osteomalacia and bone mineralization themselves constitute largely unexplored fields of research. The true prevalence of the different forms of osteomalacia and the recovery after proper therapy have yet to be determined in the real world. Although non-invasive techniques to assess bone mineralization are not available in clinical practice, the systematic assessment of bone quality could help in refining the diagnosis and guiding the treatment. This review summarizes what is known of osteomalacia recent therapeutic developments and highlights the future issues of research in this field.
Topics: Humans; Calcium; Osteomalacia; Vitamin D Deficiency; Vitamin D; Phosphates
PubMed: 36499221
DOI: 10.3390/ijms232314896 -
The Indian Journal of Medical Research Oct 2020Defective mineralization of the growth plate and preformed osteoid result in rickets and osteomalacia, respectively. The leading cause of rickets worldwide is solar... (Review)
Review
Defective mineralization of the growth plate and preformed osteoid result in rickets and osteomalacia, respectively. The leading cause of rickets worldwide is solar vitamin D deficiency and/or dietary calcium deficiency collectively termed as nutritional rickets. Vitamin D deficiency predominates in high-latitude countries in at-risk groups (dark skin, reduced sun exposure, infants and pregnant and lactating women) but is emerging in some tropical countries due to sun avoidance behaviour. Calcium deficiency predominates in tropical countries, especially in the malnourished population. Nutritional rickets can have devastating health consequences beyond bony deformities (swollen wrist and ankle joints, rachitic rosary, soft skull, stunting and bowing) and include life-threatening hypocalcaemic complications of seizures and, in infancy, heart failure due to dilated cardiomyopathy. In children, diagnosis of rickets (always associated with osteomalacia) is confirmed on radiographs (cupping and flaring of metaphyses) and should be suspected in high risk individuals with the above clinical manifestations in the presence of abnormal blood biochemistry (high alkaline phosphatase and parathyroid hormone, low 25-hydroxyvitamin D and calcium and/or low phosphate). In adults or adolescents with closed growth plates, osteomalacia presents with non-specific symptoms (fatigue, malaise and muscle weakness) and abnormal blood biochemistry, but only in extreme cases, it is associated with radiographic findings of Looser's zone fractures. Bone biopsies could confirm osteomalacia at earlier disease stages, for definitive diagnosis. Treatment includes high-dose cholecalciferol or ergocalciferol daily for a minimum of 12 wk or stoss therapy in exceptional circumstances, each followed by lifelong maintenance supplementation. In addition, adequate calcium intake through diet or supplementation should be ensured. Preventative approaches should be tailored to the population needs and incorporate multiple strategies including targeted vitamin D supplementation of at-risk groups and food fortification with vitamin D and/or calcium. Economically, food fortification is certainly the most cost-effective way forward.
Topics: Adolescent; Calcium; Child; Female; Humans; Infant; Lactation; Osteomalacia; Pregnancy; Rickets; Vitamin D; Vitamin D Deficiency; Vitamins
PubMed: 33380700
DOI: 10.4103/ijmr.IJMR_1961_19 -
Frontiers in Endocrinology 2021X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the gene lead to elevated... (Review)
Review
X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient's needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.
Topics: Alkaline Phosphatase; Antibodies, Monoclonal, Humanized; Belgium; Consensus; Familial Hypophosphatemic Rickets; Fibroblast Growth Factor-23; Humans; Hypophosphatemia; Interdisciplinary Communication; Mutation; Osteomalacia; PHEX Phosphate Regulating Neutral Endopeptidase; Severity of Illness Index; Societies, Medical; Treatment Outcome; Vitamin D
PubMed: 33815294
DOI: 10.3389/fendo.2021.641543 -
International Journal of Molecular... Mar 2021During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of... (Review)
Review
During the last two decades, the potential impact of vitamin D on the risk of cardiovascular disease (CVD) has been rigorously studied. Data regarding the effect of vitamin D on CVD risk are puzzling: observational data indicate an inverse nonlinear association between vitamin D status and CVD events, with the highest CVD risk at severe vitamin D deficiency; however, preclinical data and randomized controlled trials (RCTs) show several beneficial effects of vitamin D on the surrogate parameters of vascular and cardiac function. By contrast, Mendelian randomization studies and large RCTs in the general population and in patients with chronic kidney disease, a high-risk group for CVD events, largely report no significant beneficial effect of vitamin D treatment on CVD events. In patients with rickets and osteomalacia, cardiovascular complications are infrequently reported, except for an increased risk of heart failure. In conclusion, there is no strong evidence for beneficial vitamin D effects on CVD risk, either in the general population or in high-risk groups. Whether some subgroups such as individuals with severe vitamin D deficiency or a combination of low vitamin D status with specific gene variants and/or certain nutrition/lifestyle factors would benefit from vitamin D (metabolite) administration, remains to be studied.
Topics: Cardiovascular Diseases; Dietary Supplements; Humans; Mendelian Randomization Analysis; Osteomalacia; Rickets; Risk Factors; Vitamin D; Vitamin D Deficiency
PubMed: 33809311
DOI: 10.3390/ijms22062896 -
Journal of Bone and Mineral Research :... Apr 2021Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate...
Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Osteomalacia; Paraneoplastic Syndromes; Quality of Life
PubMed: 33338281
DOI: 10.1002/jbmr.4233 -
Endocrine Practice : Official Journal... Jan 2023Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by... (Review)
Review
OBJECTIVE
Phosphate is crucial for cell signaling, energy metabolism, nucleotide synthesis, and bone mineralization. The gut-bone-parathyroid-kidney axis is influenced by parathyroid hormone, 1,25-dihydroxyvitamin D, and phosphatonins, especially fibroblast growth factor 23 (FGF23). These hormones facilitate maintenance of phosphate homeostasis. This review summarizes current knowledge regarding the phosphate homeostasis, phosphatonin pathophysiology, and clinical implications of FGF23-related hypophosphatemic disorders, with specific focus on burosumab treatment.
METHOD
A focused literature search of PubMed was conducted.
RESULTS
Phosphatonins including FGF23, secreted frizzled-related protein 4, matrix extracellular phosphoglycoprotein, and fibroblast growth factor 7 play a pathogenic role in several hypophosphatemic disorders. Excess FGF23 inhibits sodium-dependent phosphate cotransporters (NaPi-2a and NaPi-2c), resulting in hyperphosphaturia and hypophosphatemia. Additionally, FGF23 suppresses 1,25-dihydroxyvitamin D synthesis in the proximal renal tubule, and thus, it indirectly inhibits intestinal phosphate absorption. Disorders of FGF23-related hypophosphatemia include X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia/McCune-Albright syndrome, and tumor-induced osteomalacia (TIO). Complications of conventional therapy with oral phosphate and vitamin D analogs comprise gastrointestinal distress, hypercalcemia, nephrocalcinosis, and secondary/tertiary hyperparathyroidism. In both children and adults with XLH and TIO, the anti-FGF23 antibody burosumab exhibits a favorable safety profile and is associated with healing of rickets in affected children and improvement of osteomalacia in both children and adults.
CONCLUSION
The treatment paradigm for XLH and TIO is changing based on data from recent clinical trials. Research suggest that burosumab is effective and safe for pediatric and adult patients with XLH or TIO.
Topics: Adult; Humans; Child; Fibroblast Growth Factors; Familial Hypophosphatemic Rickets; Phosphates; Hypophosphatemia; Kidney; Bone and Bones; Osteomalacia
PubMed: 36210014
DOI: 10.1016/j.eprac.2022.09.007 -
AJNR. American Journal of Neuroradiology Jun 2022Phosphaturic mesenchymal tumors (PMTs) are neoplasms associated with tumor-induced osteomalacia. Patients typically present with pathologic fractures in the setting of...
Phosphaturic mesenchymal tumors (PMTs) are neoplasms associated with tumor-induced osteomalacia. Patients typically present with pathologic fractures in the setting of chronic hypophosphatemic hyperphosphaturic osteomalacia, as well as gradual muscle weakness, bone pain, and difficulty walking. Because of their rarity and nonspecific symptomatology, phosphaturic mesenchymal tumors often go undiagnosed for years. Even when discovered on imaging, the tumors can be diagnostically challenging for radiologists. Phosphaturic mesenchymal tumors often tend to be small and can be located nearly anywhere in the body, and, therefore, can mimic many other tumors. This case highlights the imaging and pathologic markers of a phosphaturic mesenchymal tumor, often found in a patient with tumor-induced osteomalacia.
Topics: Humans; Mesenchymoma; Neoplasms, Connective Tissue; Osteomalacia; Paraneoplastic Syndromes
PubMed: 35589138
DOI: 10.3174/ajnr.A7513