Hypophosphatemic Osteomalacia Research Articles

Adefovir induced hypophosphatemic osteomalacia

To the Editor,It is known that there is a high rate of nephrotoxicity with a dosage of 60–120 mg/day of adefovir-dipivoxil (Hepsera®). However, a dosage of 10 mg/day has been found to be safe [1,2]...

Hypophosphataemic Osteomalacia in Patients on Adefovir Dipivoxil

Fanconi syndrome results from generalised renal tubular toxicity and, owing to phosphate wasting can cause hypophosphataemic osteomalacia. Large clinical trials advocated the safety of adefovir dipivoxil at a daily dose of 10 mg, the standard dose given to patients with hepatitis B. We diagnosed Fanconi syndrome in conjunction with severe osteomalacia in 2 hepatitis B-positive patients on standard-dose adefovir therapy. The first patient was a 40-year-old male with a 5 month history of bone pain involving his knees, ankles, and ribs. He had been receiving adefovir dipivoxil for 27 months before the development of hypophosphataemia, urinary phosphate wasting, and aminoaciduria. These abnormalities resolved within weeks of discontinuation of adefovir dipivoxil and supplementation with elemental phosphate, calcium carbonate, and cholecalciferol. The second patient was a 53-year-old female with a 6 month history of lethargy, cachexia, and generalized bone pain. She had been receiving adefovir for 64 months before the development of these symptoms. She had hypophosphataemia, hypocalcaemia, metabolic acidosis, and severe vitamin D deficiency, but initially no urinary phosphate wasting. Four months of high-dose cholecalciferol supplementation unmasked her Fanconi syndrome including significant urinary phosphate wasting. The patient improved within weeks of discontinuation of adefovir and supplementation with elemental phosphate, calcium carbonate, and calcitriol. Despite large clinical trials advocating the safety of adefovir dipivoxil at 10-mg daily, long-term use of this agent may be nephrotoxic and in rare cases, cause Fanconi syndrome and severe hypophosphataemic osteomalacia. Clinicians prescribing this drug should be aware of this potential complication.

Hypophosphatemic Osteomalacia as a Long-Term Complication After Liver Transplantation

Hypophosphatemic Osteomalacia as a Long-Term Complication After Liver Transplantation

A Case of FGF23-related Hypophosphatemic Osteomalacia Caused by Long-term Administration of Saccharated Ferric Oxide.

A Case of FGF23-related Hypophosphatemic Osteomalacia Caused by Long-term Administration of Saccharated Ferric Oxide.

Normal plasma FGF23 levels kinetic in tenofovir-related hypophosphatemic osteomalacia in an HIV-infected patient with von Recklinghausen disease

The antiretroviral agent tenofovir can cause hypophosphatemic osteomalacia due to renal phosphate wasting. The potential role for Fibroblast Growth Factor 23 (FGF23), a phosphaturic hormone is unknown. We evaluated FGF23 plasma concentrations in an HIV-positive patient with neurofibromatosis in whom hypophosphatemia developed during tenofovir therapy. This patient presented with diffuse pain, hypophosphatemia and tubular dysfunction with inadequate phosphate reabsorption. The full recovery after tenofovir discontinuation indicates that the hypophosphatemia was related to tenofovir and not to von Recklinghausen disease. Our data argue against a role for FGF23 in tenofovir-induced hypophosphatemia nor in the regulation of hypophosphatemia in this situation.

The Search for Primary Tumor in a Patient With Oncogenic Osteomalacia

Abstract: We report a case of oncogenic osteomalacia in which F-18 FDG PET imaging played a crucial role in detecting the occult neoplasm. A 39-year-old female patient presented with low backache and bilateral lower limb pain of 3-year duration. On evaluation, she was found to have hypophosphatemic osteomalacia and was referred for F-18 FDG PET scan because her initial clinical and radiologic evaluation failed to detect a tumor. F-18 FDG PET scan revealed a hypermetabolic focus in right popliteal fossa, which was correlated as a tumor in soft tissues of right popliteal fossa on magnetic resonance imaging. Following surgical excision of tumor, final histopathology revealed a benign phosphaturic mesenchymal tumor of mixed connective tissue origin. Postoperatively, her symptoms alleviated and serum phosphates normalized within 2 weeks. We suggest that F-18 FDG PET should be performed in such cases to localize occult neoplasm that may be otherwise missed on conventional radiologic imaging.

Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice

Fibroblast growth factor 23 (FGF-23) plays causative roles in the development of several hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets/osteomalacia (XLH) and tumor-induced rickets/osteomalacia. Patients with hypophosphatemic rickets/osteomalacia often complain of muscle weakness and bone pain that severely affect daily activities of these patients. The purpose of this study was to examine whether anti-FGF-23 antibodies, which have been shown to improve hypophosphatemia and rachitic changes of juvenile Hyp mice in a murine model of XLH, also ameliorate hypophosphatemic osteomalacia and affect muscle force and spontaneous motor activity in adult Hyp mice. Repeated injections of anti-FGF-23 antibodies increased serum phosphate and 1,25-dihydroxyvitmain D levels and enhanced mineralization of osteoid in adult Hyp mice, whereas bone length did not change. We found that grip strength was weaker and that spontaneous movement was less in adult Hyp mice than in wild-type mice. In addition, FGF-23 antibodies increased grip strength and spontaneous movement. These results suggest that the inhibition of excess FGF-23 action not only ameliorates hypophosphatemia and impaired mineralization of bone but also improves muscle weakness and daily activities of patients with FGF-23-related hypophosphatemic rickets/osteomalacia.

A Case of Adult-onset Hypophosphatemic Osteomalacia Who was Misdiagnosed as Fibromyalgia Syndrome

A Case of Adult-onset Hypophosphatemic Osteomalacia Who was Misdiagnosed as Fibromyalgia Syndrome

Hypophosphatemic Osteomalacia in Neurofibromatosis Type 1: Insufficiency Fractures

Hypophosphatemic Osteomalacia in Neurofibromatosis Type 1: Insufficiency Fractures

Bilateral insufficiency fracture of the femoral head and neck in a case of oncogenic osteomalacia

We describe a case of oncogenic osteomalacia in an adult male who presented with low back pain and bilateral hip pain. Extensive investigations had failed to find a cause. A plain pelvic radiograph showed Looser's zones in both femoral necks. MRI confirmed the presence of insufficiency fractures bilaterally in the femoral head and neck. Biochemical investigations confirmed osteomalacia which was unresponsive to treatment with vitamin D and calcium. A persistently low serum phosphate level suggested a diagnosis of hypophosphataemic osteomalacia. The level of fibroblast growth factor-23 was highly raised, indicating the cause as oncogenic osteomalacia. This was confirmed on positron-emission tomography, MRI and excision of a benign fibrous histiocytoma following a rapid recovery. The diagnosis of oncogenic osteomalacia may be delayed due to the non-specific presenting symptoms. Subchondral insufficiency fractures of the femoral head may be missed unless specifically looked for.

Hypophosphatemic Osteomalacia after Low-Dose Adefovir Dipivoxil Therapy for Hepatitis B

A 40-yr-old male presented with a 5-month history of bone pain involving both knees, ankles, and several ribs with no antecedent trauma. He had an antalgic gait, tenderness involving the bony margins of both knees, but no synovitis. He had a history of chronic hepatitis B infection, receiving lamivudine at a daily dose of 100 mg for 43 months and adefovir dipivoxil (adefovir) at a daily dose of 10 mg for the past 29 months. He had been receiving tramadol hydrochloride intermittently for pain relief. Investigations revealed a reduced serum phosphate level of 2.0 mg/dl (0.64 mmol/liter), normal serum corrected calcium of 8.8 mg/dl (2.20 mmol/liter), PTH of 39 pg/ml (4.1 pmol/liter), 25-hydroxyvitamin D3 level of 24.4 ng/ml (61 nmol/liter), and 1,25-hydroxyvitamin D level of 57 pmol/liter. Bone-specific alkaline phosphatase was elevated at 85.4 g/liter (normal, 3.7–20 g/liter). The urine deoxypyridinoline/creatinine ratio was elevated at 11 nmol/mmol (normal, 2.3–5.4 nmol/ mmol) with an estimated glomerular filtration rate of 60.1 ml/min. A 24-h urinalysis demonstrated hyperphosphaturia at 1.054 g/d (34 mmol/d) [normal, 0.465– 0.93 g/d (15–30 mmol/d)], hypercalciuria at 580 mg/d (14.5 mmol/d) [normal, 100 –300 mg/d (2.5–7.5 mmol/d)], glycosuria, and massive aminoaciduria. The 24-h creatinine excretion was normal at 1.41 g/d (12.5 mmol/d) [normal, 1.02–2.03 g/d (9 –18 mmol/d)]. Calculated maximal tubular phosphate reabsorption was reduced at 0.3% (normal, 0.8 –1.3%). Magnetic resonance imaging of both knees revealed microfractures across the femoral and tibial metaphyses (Fig. 1). A whole body bone scan showed intense uptake at the subchondral bone of both knees and several bilateral ribs (Fig. 2A). The diagnosis of hypophosphatemic osteomalacia in the context of Fanconi’s syndrome secondary to adefovir therapy was made. Fanconi’s syndrome is a recognized complication of high-dose adefovir therapy when used in the treatment of HIV (1). However, at the time of writing, there were only two other published reports of hypophosphatemic osteomalacia after low-dose adefovir therapy (2, 3). Fifteen weeks after cessation of adefovir and after regular phosphate supplementation, the patient reported significant improvement in his knee and other bony pain. ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2010 by The Endocrine Society doi: 10.1210/jc.2009-2051 Received September 23, 2009. Accepted October 27, 2009. * T.W. and C.M.G. are joint first authors. FIG. 1. Left knee coronal proton-density weighted magnetic resonance image. There are incomplete undisplaced fractures across the femoral and tibial metaphyses, consistent with recent insufficiency fractures. S P E C I A L F E A T U R E

Progressive course of hypophosphatemic osteomalacia during 25-year follow up

Hypophosphatemic osteomalacia is defined as mineralization of the newly formed bone matrix (osteoids) in adults as a consequence of the phosphate deficiency. A female from Belgrade, aged 62 years fell ill in 1982. when she was 36. She first felt pains in bones associated with chronic fatigue. In 1986. during her hospitalization the presence of neoplastic hematologic, endocrinologic, urogenital and gastroenterologic system deseases was excluded. Hypophosphatemic osteomalacia was diagnosed on the basis of the history, clinical presentation, physical examination, radiologic finding and laboratory analyses (lower serum phosphorus level). The initial therapy included a mixture of phosphates, vitamin D and calcium. The doses were several times corrected over the following four years. In 1990 she had a mild clinical deterioration requiring recorrection of the mentioned therapy. In 1993 bilateral femoral neck fractures occurred and subsequent osetosynthe as was performed. The disease had a progressive character in spite of the administered drug therapy so that multiple fractures occurred in 2000. During the last hospitalization in 2008. neither new pseudo fractures nor fractures were found although biochemical profile of the hypophosphatemic osteomalacia was still present. The aim of this study was to emphasize the complexity in both diagnostic and therapeutic approach in the case of hypophosphatemic osteomalacia. In the presented case the patient showed a complicated and progressive course. In our opinion such course was a consequence of impossible etiologic treatment and discontinued therapy

Late onset of X-linked hypophosphatemic osteomalacia

Late onset of X-linked hypophosphatemic osteomalacia

Resolution of Severe Oncogenic Hypophosphatemic Osteomalacia after Resection of a Deeply Located Soft-Tissue Tumour

Oncogenic osteomalacia is a rare metabolic bone disease characterized by phosphate leakage from the kidney and subsequent hypophosphatemia. It is caused by a phosphaturic factor produced by certain tumours. Removal of such tumours can completely cure the condition. Here, we report the case of a patient who was crippled with oncogenic osteomalacia. Extensive study revealed a tumour deeply located in the pelvis; removal of the tumour resulted in complete recovery. The tumour was identified as a mesenchymal tumour (mixed connective-tissue variant). The diagnostic evaluation, differential diagnosis, and treatment are discussed.

Determination of fibroblast growth factor 23

Fibroblast growth factor 23 (FGF-23) is a recently discovered hormone, which plays a key role in phosphate regulation. To investigate whether FGF-23 can be determined reliably, we validated the three available FGF-23 assays. Currently, two intact FGF-23 assays (Kainos; Immutopics) and one C-terminal FGF-23 assay (Immutopics) are available. We determined intra- and inter-assay variation, linearity and matrix interference in these assays. Moreover, we compared assay results from healthy subjects with those of patient groups with expected high FGF-23 concentrations. Intra-assay variation was reasonably good in all three assays. Inter-assay variation and linearity were poor for the intact Immutopics assay but reasonable for both other assays. Immutopics assays gave best results in ethylenediaminetetraacetic acid (EDTA) plasma, while the Kainos assay showed comparable reproducibility in EDTA plasma and serum. Although the manual of the Kainos assay states that an automatic washing machine can be used, acceptable results were only found by manual washing. Patients with kidney disease and patients with hypophosphatemic osteomalacia had increased C-terminal FGF-23 concentrations compared with healthy controls. Two assays of reasonable quality are available for FGF-23, the intact FGF-23 assay (Kainos) provided proper attention is paid to the washing procedure, and the C-terminal assay (Immutopics).

Hypophosphatemic rickets and osteomalacia due to a parathyroid adenoma: A case-report

Hypophosphatemic rickets and osteomalacia due to a parathyroid adenoma: A case-report

Hypophosphatemia induced by intravenous administration of saccharated ferric oxide: Another form of FGF23-related hypophosphatemia

Fibroblast growth factor 23 (FGF23) is a humoral factor that is produced by osteocytes and regulates phosphate and vitamin D metabolism. Several hypophosphatemic diseases including X-linked, autosomal dominant and autosomal recessive hypophosphatemic rickets/osteomalacia and tumor-induced rickets/osteomalacia are caused by excess actions of FGF23. These diseases are characterized by hypophosphatemia associated with impaired proximal tubular phosphate reabsorption and inappropriately low serum 1,25-dihydroxyvitamin D [1,25(OH) 2D] levels for hypophosphatemia. Saccharated ferric oxide is widely used in Japan for iron-deficiency anemia. While it has been shown that saccharated ferric oxide induces hypophosphatemic osteomalacia, the mechanism of this hypophosphatemia remains to be clarified. We here describe three hypophosphatemic patients caused by intravenous administration of saccharated ferric oxide. Hypophosphatemia in these patients were associated with impaired renal tubular phosphate reabsorption, rather low serum 1,25(OH) 2D and high FGF23 levels. All these biochemical features improved by the cessation of saccharated ferric oxide. These results indicate that hypophosphatemia caused by saccharated ferric oxide is another form of FGF23-related hypophosphatemia.

Clinical aspect of recent progress in phosphate metabolism. Hyperphosphatemia and hypophosphatemia

Serum inorganic phosphate (Pi) concentrations are generally maintained at 2.5-4.5 mg/dL in adults. In children, serum Pi levels are higher than those in adults. Hyperphosphatemia may be the consequence of (1) a decreased excretion of Pi, or (2) an external or internal cause of acute Pi loading to extracellular fluid, and the chronic kidney disease (CKD) is the most frequent cause of hyperphosphatemia. Hyperphosphatemia due to the increased Pi reabsorption is associated with hyperparathyroidism, tumoral calcinosis, and so on. Hypophosphatemia may be caused by (1) a decreased Pi intake, (2) an increased excretion of Pi, or (3) the transcellular shift of Pi from the extracellular to the intracellular space. Hypophosphatemia due to the increased excretion of Pi can be observed in various diseases, including Fanconi syndrome, hereditary hypophosphatemic rickets/osteomalacia, and tumor-induced hypophosphatemic osteomalacia.

FGF23 Elevation and Hypophosphatemia after Intravenous Iron Polymaltose: A Prospective Study

Parenteral iron administration has been associated with hypophosphatemia. Fibroblast growth factor 23 (FGF23) has a physiological role in phosphate homeostasis via suppression of 25-hydroxyvitamin D [25(OH)D] activation and promotion of phosphaturia. We recently reported a case of iron-induced hypophosphatemic osteomalacia associated with marked FGF23 elevation. Our objective was to prospectively investigate the effect of parenteral iron polymaltose on phosphate homeostasis and to determine whether any observed change was related to alterations in circulating FGF23. Eight medical outpatients prescribed iv iron polymaltose were recruited. Plasma phosphate, 25(OH)D, 1,25-dihydroxyvitamin D [1,25(OH)(2)D], PTH, FGF23, and urinary tubular reabsorption of phosphate were measured prior to iron administration and then weekly for a minimum of 3 wk. Plasma phosphate fell from 3.4 +/- 0.6 mg/dl at baseline to 1.8 +/- 0.6 mg/dl at wk 1 (P < 0.0001) associated with a fall in percentage tubular reabsorption of phosphate (90 +/- 4.8 to 68 +/- 13; P < 0.001) and 1,25(OH)(2)D (54 +/- 25 to 9 +/- 8 pg/ml; P < 0.001). These indices remained significantly suppressed at wk 2 and 3. 25(OH)D levels were unchanged. FGF23 increased significantly from 43.5 pg/ml at baseline to 177 pg/ml at wk 1 (P < 0.001) with levels correlating with both serum phosphate (R = -0.74; P <0.05) and 1,25(OH)(2)D (R = -0.71; P < 0.05). Parenteral iron suppresses renal tubular phosphate reabsorption and 1alpha-hydroxylation of vitamin D resulting in hypophosphatemia. Our data suggest that this is mediated by an increase in FGF23.

Recombinant MEPE can increase hydroxyapatite in vitro

The matrix extracellular phosphoglycoprotein (MEPE) gene is highly expressed in tumors that cause oncogenic hypophosphatemic osteomalacia (OHO). MEPE is also known as one of the bone-tooth matrix proteins and is associated with bone and teeth mineralization. We developed a rabbit polyclonal antibody directed against recombinant human MEPE after cloning its cDNA from the cDNA library of a human brain cDNA library. Using this antibody, we analyzed the distribution of MEPE in dog dental germ tissue by immunohistochemistry. In these specimens, MEPE was predominantly expressed by odontoblast cells and predentin, but not by dental pulp cells. Furthermore we used a steady-state agarose gel system, and the results suggested that MEPE could induce hydroxyapatite (HA). We propose that this protein has a potential effect on dental rehabilitation. Key words: MEPE, hydroxyapatite, steady-state agarose gel system.