calcitriol and Osteomalacia

FGF23 is an endocrine FGF produced by osteocytes, which increases excretion of phosphate and suppresses the production of 1,25 (OH) 2D. Excessive action of FGF23 causes various forms of hypophosphatemic rickets/osteomalacia, while the loss of function of FGF23 results in the condition called familial hyperphosphatemic tumoral calcinosis. 1,25 (OH) 2D stimulates the production of FGF23, and the interaction between FGF23 and 1,25 (OH) 2D plays a central role in mineral homeostasis. In addition to the its roles in mineral homeostasis, recent studies have suggested the direct action of FGF23 on osteoblasts and chondrocytes.

Topics: Animals; Bone and Bones; Calcification, Physiologic; Calcinosis; Cartilage; Chondrocytes; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Homeostasis; Humans; Hyperostosis, Cortical, Congenital; Hyperphosphatemia; Osteoblasts; Osteocytes; Osteomalacia; Phosphates; Rickets, Hypophosphatemic; Vitamin D

Vitamin D activity requires an adequate vitamin D status as indicated by the serum level of 25-hydroxyvitamin D and appropriate expression of genes coding for vitamin D receptor and 25-hydroxyvitamin D 1α-hydroxylase, the enzyme which converts 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D. Vitamin D deficiency contributes to the aetiology of osteomalacia and osteoporosis. The key element of osteomalacia, or rickets in children, is a delay in mineralization. It can be resolved by normalisation of plasma calcium and phosphate homeostasis independently of vitamin D activity. The well characterised endocrine pathway of vitamin D metabolism generates plasma 1,25-dihydroxyvitamin D and these endocrine activities are solely responsible for vitamin D regulating plasma calcium and phosphate homeostasis and protection against osteomalacia. In contrast, a large body of clinical data indicate that an adequate serum 25-hydroxyvitamin D level improves bone mineral density protecting against osteoporosis and reducing fracture risk. Recent research demonstrates that the three major bone cell types have the capability to metabolise 25-hydroxyvitamin D to 1,25-dihydroxyvitamin D to activate the vitamin D receptor and modulate gene expression. Dietary calcium intake interacts with vitamin D metabolism at both the renal and bone tissue levels to direct either a catabolic action on bone through the endocrine system when calcium intake is inadequate or an anabolic action through a bone autocrine or paracrine system when calcium intake is sufficient.

Topics: 25-Hydroxyvitamin D3 1-alpha-Hydroxylase; Bone and Bones; Bone Density; Calcification, Physiologic; Calcium; Child; Gene Expression Regulation; Humans; Osteomalacia; Osteoporosis; Phosphates; Receptors, Calcitriol; Vitamin D; Vitamin D Deficiency

Topics: Adult; Aged; Calcium; Child; Female; Humans; Jaw Neoplasms; Male; Middle Aged; Mouth Neoplasms; Osteomalacia; Paraneoplastic Syndromes; Parathyroid Hormone; Vitamin D

Serum phosphate is maintained within a certain range by intestinal phosphate absorption, renal phosphate handling, and dynamic equilibrium with the intracellular phosphate or phosphate in bone. Of these, renal phosphate handling is believed to be the main determinant of the serum phosphate level at least in a chronic state. Most of the phosphate filtered from the glomeruli is reabsorbed in proximal tubules through type 2a and 2c sodium-phosphate co-transporters. Therefore, chronic hypophosphatemia and hyperphosphatemia are usually caused by changes in renal phosphate handling. Several humoral factors, including parathyroid hormone and insulin-like growth factor-I, have been known to affect proximal tubular phosphate reabsorption. In addition, fibroblast growth factor 23 (FGF23) was shown to inhibit phosphate reabsorption by suppressing the expression of type 2a and 2c sodium-phosphate co-transporters. FGF23 also reduces the circulatory 1,25-dihydroxyvitamin D [1,25 (OH)2D] level. FGF23 is produced by bone, especially by osteocytes, and works in the kidney by binding to the Klotho-FGF receptor complex. It has been shown that excess actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia with impaired proximal tubular phosphate reabsorption and a rather low 1,25 (OH)2D level. In contrast, deficient actions of FGF23 result in familial hyperphosphatemic tumoral calcinosis with enhanced proximal tubular phosphate reabsorption and high 1,25 (OH)2D. These results indicate that FGF23 is a hormone regulating phosphate and vitamin D metabolism. In addition, several hypophosphatemic and hyperphosphatemic diseases can be classified as endocrine diseases caused by the aberrant actions of FGF23. It is possible that some drugs that modulate the action of FGF23 can be novel therapeutic measures for abnormal phosphate metabolism in the future.

Topics: Animals; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperphosphatemia; Hypophosphatemia; Kidney; Osteomalacia; Phosphates; Phosphorus Metabolism Disorders; Rickets; Vitamin D

It is true to say that it is just over the past decade and even more so in this new decade that it has become appreciated how vitally important vitamin D is for optimum health. This 'sunshine' vitamin could justifiably be called 'the nutrient of this decade'. Until recently, vitamin D was known primarily for its role in bone health. However, as a result of advances in research this perspective has changed. While it is true to say that the classic function of vitamin D is to control calcium and vitamin D metabolism, we now know that the importance of vitamin D spreads far wider than just bone health. There is much ongoing research with regard to its emerging role in immunopathology, as a potent inhibitor of cellular growth, stimulator of insulin secretion, modulator of immune function and inhibitor of renin production. This review discusses the current evidence with regard to the clinical consequences of vitamin D deficiency and underscores the fact that physicians should be vigilant in searching for and treating this preventable and treatable condition. Furthermore, this review highlights the fact that the time is opportune for rheumatologists to agree upon clinical guidelines to advise practitioners as to when and in which patients to check for, what target vitamin D level to aim for and how best to treat vitamin D deficiency.

Topics: Biomarkers; Dietary Supplements; Humans; Osteomalacia; Parathyroid Hormone; Prevalence; Vitamin D; Vitamin D Deficiency

Recent studies have added new dimensions to the fund of knowledge on vitamin D. In addition to the classic role of vitamin D in preventing rickets and osteomalacia, a preventive effect against osteoporotic fractures has been convincingly established, and abundant evidence suggests a role in preventing malignancies and autoimmune diseases. Serum 25-OH-vitamin D assay is a simple test for evaluating vitamin D status. However, recent review articles indicate that current reference ranges for serum 25-OH-vitamin D are too low. An appropriate lower normal limit may be between 50-100 nmol/l (20-40 ng/ml). Standard supplement dosages may fail to provide concentrations above this range.

Topics: Fractures, Bone; Humans; Osteomalacia; Osteoporosis; Rickets; Risk Factors; Vitamin D; Vitamin D Deficiency

Topics: Calcitriol; Diagnosis, Differential; Humans; Male; Middle Aged; Neoplasms; Osteomalacia; Phosphorus; Vitamin D

Both FGF-23 and PTH inhibit renal phosphate reabsorption. We treated two patients with TIO and FGF-23-mediated hypophosphatemia with cinacalcet to test the hypothesis that medicinally induced hypoparathyroidism would decrease renal phosphate wasting. Cinacalcet treatment resulted in increased renal phosphate reabsorption, allowed for a decrease in phosphate supplementation, and showed evidence of bone healing in one of the two patients.. Tumor-induced osteomalacia (TIO) is a rare, acquired disease of renal phosphate wasting, which results in hypophosphatemia and osteomalacia. It is caused by mesenchymal tumors that produce the phosphate and vitamin D-regulating hormone, fibroblast growth factor (FGF)-23. Removal of the tumor is curative, but the tumors are often difficult to locate. Medical treatment involves high doses of oral phosphate and calcitriol, but the phosphate is often poorly tolerated and leads to diarrhea. Because PTH also promotes phosphaturia, and patients with hypoparathyroidism are hyperphosphatemic in the setting of elevated serum FGF-23, we postulated that the calcium-sensing receptor agonist, cinacalcet, which can induce hypoparathyroidism, would be an effective adjuvant in the treatment of TIO.. Two subjects with presumed TIO in whom the tumor was not located after extensive testing and who did not tolerate medical therapy with phosphorus and calcitriol were treated with cinacalcet.. Neither treatment with phosphorus nor combined treatment with phosphorus and calcitriol had an effect on serum FGF-23 levels. Treatment with cinacalcet resulted in increased renal phosphate reabsorption and serum phosphorus and allowed for a decrease in phosphate supplementation to a dose that was tolerated. On this regimen, one patient showed significant bone healing as shown by resolution of activity on bone scan and lack of osteomalacia as assessed by histomorphometry.. These data show that medically induced hypoparathyroidism with cinacalcet is a therapeutic option for disorders of FGF-23-mediated hypophosphatemia and that, in the absence of PTH, the phosphaturic effect of FGF-23 is decreased.

Topics: Bone and Bones; Calcitriol; Calcium; Cinacalcet; Drug Therapy, Combination; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hydrochlorothiazide; Hypoparathyroidism; Hypophosphatemia; Kidney; Male; Middle Aged; Naphthalenes; Neoplasms; Osteomalacia; Parathyroid Hormone; Phosphates; Phosphorus; Treatment Outcome; Vitamin D

Topics: Adult; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Foot Diseases; Humans; Hypophosphatemia; Male; Neoplasm Proteins; Neoplasms, Connective Tissue; Osteomalacia; Paraneoplastic Syndromes; Skin Neoplasms; Toes; Vitamin D

Oncogenic osteomalacia, or tumour-induced osteomalacia (TIO), is a rare paraneoplastic syndrome characterised by hypophosphataemia, phosphaturia, inappropriately low serum levels of 1,25-dihydroxyvitamin D for hypophosphataemia. TIO is caused by mesenchymal tumours that secrete phosphaturic substances, leading to increased renal wasting of phosphates. These tumours are very small in size and grow slowly. Localisation of these tumours has always been difficult with the available biochemical and imaging techniques. At times, despite all efforts, the tumour could not be localised. We report our experience with a 42-year-old woman with TIO where whole-body magnetic resonance imaging could not localise the tumour, a scapular haemangiopericytoma. PET/CT was helpful in the localisation of the tumour which, when surgically removed, resulted in the normalisation of biochemical parameters with clinical improvement.

Topics: Adult; Bone Diseases; Contrast Media; Female; Fluorodeoxyglucose F18; Hemangiopericytoma; Humans; Magnetic Resonance Imaging; Osteomalacia; Paraneoplastic Syndromes; Positron-Emission Tomography; Radiopharmaceuticals; Scapula; Tomography, X-Ray Computed; Vitamin D

Oncogenic osteomalacia (OOM) is characterised by tumour production of fibroblast growth factor 23 (FGF23) that results in hypophosphataemia and renal phosphate wasting, reduced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis and osteomalacia. Here, we demonstrate the roles of serum FGF23 and 1,25(OH)2D3, together with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), as biomarkers for OOM. A previously well 52-year-old man presented with a 2-year history of generalised musculoskeletal pain and proximal myopathy. He had hypophosphataemia, elevated serum alkaline phosphatase activity, low serum 1,25(OH)2D3 and a reduced tubular maximum of phosphate/glomerular filtration rate. These findings indicated a diagnosis of OOM, but magnetic resonance imaging (MRI) and octreotide scintigraphy did not identify any tumours. Treatment with oral phosphate and calcitriol resolved the symptoms and biochemical abnormalities within 6 months. Four years later, he relapsed whilst on treatment with oral phosphate and calcitriol. Serum FGF23 concentration was elevated and MRI identified a 2 cm tumour within Hoffa's fat pad of the left knee. Removal of the tumour resulted in a complete resolution of symptoms and normalisation of the serum biochemical abnormalities including serum FGF23. Histology demonstrated a phosphaturic mesenchymal tumour, mixed connective tissue variant (PMTMCT), which revealed immunostaining with anti-LYVE-1 antibody and hence the presence of lymphatic vessels. Serum FGF23 and 1,25(OH)2D3 were found to be reliable biomarkers for OOM. In addition, the demonstration of lymphatics in the PMTMCT helps to distinguish this tumour from most typical benign haemangiomas.

Topics: Administration, Oral; Alkaline Phosphatase; Biomarkers; Biomarkers, Tumor; Bone Neoplasms; Calcitriol; Chondrosarcoma, Mesenchymal; Endothelium, Vascular; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyaluronan Receptors; Hypophosphatemia; Knee; Lymphatic Vessels; Male; Middle Aged; Osteomalacia; Paraneoplastic Syndromes; Phosphates; Predictive Value of Tests; Vitamin D

Tumor-induced osteomalacia is a rare acquired metabolic disorder characterized by hypophosphatemia and inappropriately low serum levels of 1,25-dihydroxyvitamin D. Symptoms include chronic muscle and bone pain, weakness, and fatigue in association with a high risk of fragility fractures due to osteomalacia. The diagnosis is commonly delayed for years due to the nonspecific nature of the presenting symptoms, failure to include determination of serum phosphorus levels in blood chemistry testing, and difficulty in identifying the responsible tumor. The pathogenesis of tumor-induced osteomalacia involves tumor expression of fibroblast growth factor 23, a hormone that inhibits proximal renal tubular reabsorption of phosphate and down-regulates renal conversion of 25-hydroxyvitamin D to its active form, 1,25-dihydroxyvitamin D. The metabolic abnormalities may be partially or completely corrected with phosphate supplementation and calcitriol. A definitive diagnosis and treatment require excision of the responsible tumor.

Topics: Bone Density Conservation Agents; Calcitriol; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Male; Mandibular Neoplasms; Middle Aged; Osteomalacia; Phosphorus; Vitamin D

Oncogenic osteomalacia is a rare condition characterized by a low serum phosphate, reduced tubular reabsorption of phosphate and a low or inappropriately normal 1,25 dihydroxyvitamin D and is usually secondary to a phosphaturic mesenchymal tumor. Complete tumor resection results in resolution of all features. We report a patient with oncogenic osteomalacia and concurrent secondary hyperparathyroidism. Serum phosphate failed to normalize preoperatively with octreotide therapy, although this treatment did suppress serum FGF23. The postoperative course was distinguished by marked hyperphosphatemia that was associated with elevated serum 1,25 dihydroxyvitamin D concentrations.

Topics: Aged; Antineoplastic Agents, Hormonal; Biomarkers; Bone and Bones; Combined Modality Therapy; Female; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hyperparathyroidism; Octreotide; Osteomalacia; Phosphates; Tomography, X-Ray Computed; Treatment Outcome; Vitamin D

Topics: Adenocarcinoma; Aged, 80 and over; Fibroblast Growth Factor-23; Fibroblast Growth Factors; Humans; Hypophosphatemia; Male; Osteomalacia; Parathyroid Hormone; Prostatic Neoplasms; Syndrome; Vitamin D

A 45-year-old man was admitted to our hospital because of bone pain and hypophosphatemia. He had undergone surgery 2 years previously for a "benign unclassified mesenchymal tumor" in the skull, but there were no clinical symptoms related to osteomalacia. His laboratory examination revealed low serum phosphate, high alkaline phosphatase, and normal calcium levels. The diagnosis of tumor-induced osteomalacia due to phosphaturic mesenchymal tumor mixed connective tissue variant (PMTMCT) was made by re-examining the pathologic specimens. Oral supplementation with phosphate and 1-25-dihydroxyvitamin D relieved his clinical symptoms and laboratory values returned to normal. However, subcutaneous administration of octreotide had no clinical effect. Clinicians and pathologists should be aware of the existence of PMTMCT especially nonphosphaturic or asymptomatic variants of this disorder.

Topics: Cranial Fossa, Posterior; Fractures, Spontaneous; Humans; Hypophosphatemia, Familial; Magnetic Resonance Imaging; Male; Mesenchymoma; Middle Aged; Neoplasm Recurrence, Local; Octreotide; Osteomalacia; Phosphates; Radiosurgery; Skull Base Neoplasms; Vitamin D

In 2 women with distal renal tubular acidosis and osteomalacia, alkali treatment cured the bone disease and was accompanied by marked increases in the serum 1,25 dihydroxyvitamin D concentration, without a significant change in the 25-hydroxyvitamin D concentration.

Topics: Acidosis, Renal Tubular; Adult; Alkalies; Biopsy; Bone and Bones; Fatal Outcome; Female; Humans; Kidney Tubules, Distal; Middle Aged; Myocardial Infarction; Osteomalacia; Vitamin D

The homeostasis of inorganic phosphate (P(i)) is regulated by parathyroid hormone (PTH), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), and P(i)itself in the intestine, kidney, and bone in all the mammalian species studied. Determinations of the serum concentrations of PTH, 1,25(OH)(2)D and osteocalcin were done in 82 southern Romanian Landrace pigs originating from three herds with dietary P(i)deficiency. Serum P(i)concentrations were negatively correlated with those of 1,25(OH)(2)D. In lactating animals and sucklings, the linear relationships between P(i)and 1,25(OH)(2)D were not present. Serum P(i)concentrations were positively correlated with those of PTH. In lactating animals and young pigs, the linear relationships between P(i)and PTH were not evident. PTH and 1,25(OH)(2)D concentrations were negatively correlated. The serum concentrations of 1,25(OH)(2)D and osteocalcin were positively correlated. Milk P(i)concentrations ranging from 3.10 to 7.49 mmol/L were correlated positively with urinary P(i)concentrations ranging from 0.26 to 11.37 mmol/L. In conclusion, similarly to other species, P(i)homeostasis is achieved in pigs by feedback mechanisms between P(i), PTH and 1,25(OH)(2)D and osteocalcin production is induced by 1,25(OH)(2)D. The effect of lactation on P(i)homeostasis remains to be explored.

Topics: Animal Nutritional Physiological Phenomena; Animals; Calcium; Homeostasis; Magnesium; Osteocalcin; Osteomalacia; Parathyroid Hormone; Phosphates; Phosphorus, Dietary; Rickets; Romania; Swine; Swine Diseases; Vitamin D

Topics: Adult; Alkaline Phosphatase; Anticonvulsants; Female; Humans; Hyperparathyroidism, Secondary; Intellectual Disability; Osteomalacia; Renal Insufficiency; Vitamin D

A case of tumor-induced phosphaturic osteomalacia in a 54 year old man is reported. The patient was admitted because of progressive muscle spasms with pain and weakness in the bilateral thighs. Laboratory data showed hypophosphatemia, decreased tubular resorption of phosphate (TRP), a low 1,25-dihydroxyvitamin D level, and a high serum alkaline phosphatase level. Radiologic examinations revealed multiple lesions of osteomalacia in the ribs, and a small mass in the lower posterior mediastinum. After removal of the tumor, clinical symptoms disappeared and hypophosphatemia, decreased TRP, and the 1,25-dihydroxyvitamin D level were corrected. Microscopical examination revealed that the tumor was composed of mature adipose tissues, osseous tissues, and primitive stromal zones including osteoclast-like giant cells, non-mineralized woven bone, and various sized blood vessels. Patho-physiologic observations suggested that the tumor secreted some humoral substances inhibiting 25-hydroxyvitamin D-1 alpha-hydroxylase activity, renal phosphate resorption, and parathyroid hormone production.

Topics: Alkaline Phosphatase; Humans; Hypophosphatemia; Male; Mediastinal Neoplasms; Mesenchymoma; Middle Aged; Osteomalacia; Phosphates; Radionuclide Imaging; Ribs; Tomography, X-Ray Computed; Vitamin D