Diagnosis and management of tumor-induced osteomalacia: a single center experience.

PURPOSE: The aim of this study is to review the clinical and laboratory characteristics, diagnostic and treatment modalities of tumor-induced osteomalacia (TIO) cases managed in a single center. MATERIAL METHODS: Demographic and clinical features, biochemical findings, diagnostic procedures, treatment modalities, and outcomes of nine patients who had the diagnosis of TIO were reviewed retrospectively. RESULTS: Mean age of the study group (F/M: 4/5) was 45.8 ± 10.8 years, and mean time from the onset of symptoms to diagnosis was 4.7 ± 2.8 years. The clinical manifestations were muscle weakness and difficulty in walking (8/9), hip pain (3/9), multiple fractures (2/9), stress fracture (2/9). Mean plasma phosphorus concentration was 1.28 ± 0.4 mg/dl at presentation. We performed radionuclide imaging modalities (18F-FDG PET/CT, Ga68-DOTATATE PET/CT, octreotide scintigraphy) in seven of nine patients, and tumor was detected in all. Lower extremity (n = 6; %67), head region (n = 2; %22) and thorax (n = 1; %11) were the tumor locations of our cases. Eight patients underwent surgery and remission was achieved postoperatively in all of the operated patients and plasma phosphorus level normalized in 4 ± 2 days. Pathological examination revealed mesenchymal tumors with different subtypes. Recurrence occurred in three patients at 13 ± 10.5 months after the first surgery. Two patients were reoperated and radiotherapy was also performed in one of them. CONCLUSION: Hypophosphatemia necessitates careful evaluation for the etiology. TIO is one of the important causes of adult-onset hypophosphatemic osteomalacia. Diagnosis of TIO is essential because the laboratory and clinical findings resolve after appropriate treatment.

Hypophosphatemia: A Practical Guide to Evaluation and Management.

Phosphate plays a critical and diverse role in human physiology. In addition to its importance in skeletal mineralization, it is essential for energy homeostasis, enzyme function, and cell membrane integrity. These diverse functions of phosphate provide an explanation for the range of symptoms and clinical manifestations observed in patients with both acute and chronic causes of hypophosphatemia. Normal phosphate homeostasis involves several major systems, including the gastrointestinal tract, bones, and kidneys. Phosphate balance is maintained directly and indirectly by 1α,25-dihydroxyvitamin D3, parathyroid hormone, and the osteocyte-derived phosphatonin fibroblast growth factor 23. This review discusses normal phosphate homeostasis, the clinical manifestations and causes of hypophosphatemia, and an approach to establish a diagnosis and appropriate management.

[Tumor localization and treatment of tumor-induced osteomalacia]. / Tumorlokalisation und Therapie der onkogenen Osteomalazie.

Tumor-induced osteomalacia (TIO) or oncogenic osteomalacia (OOM) is a rare paraneoplastic renal phosphate wasting syndrome. The disease is mostly triggered by small, benign mesenchymal tumors that express somatostatin receptors (SSTR) and produce excessive levels of fibroblast growth factor 23 (FGF 23) or other phosphatonins. These reduce the phosphate back resorption in the proximal tubules of the kidneys, thereby causing hypophosphatemia and lead to an absolute or relatively low calcitriol serum concentration. The main symptoms include muscle weakness, bone pain and recurrent insufficiency fractures secondary to sometimes pronounced osteomalacia. The suspected diagnosis can only be confirmed by determination of the phosphate level. It can often take years before the tumor is successfully localized. The necessary tumor localization is often the most difficult step in the treatment before the OOM can be curatively treated by open surgical resection of the tumor. In recent years new approaches for faster tumor localization and treatment of the tumor have been developed. Positron emission tomography (PET) in co-registration with computed tomography (68Ga-DOTA-TATE PET/CT) is currently the most sensitive imaging methodology for tumor detection. The application of the monoclonal FGF 23 antibody burosumab represents a promising new option in the treatment of inoperable adult OOM.

Challenges in the management of tumor-induced osteomalacia (TIO).

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.

FGF23-related hypophosphatemic rickets/osteomalacia: diagnosis and new treatment.

FGF23 is a phosphaturic hormone produced by bone. FGF23 reduces serum phosphate by suppressing proximal tubular phosphate reabsorption and intestinal phosphate absorption. After the identification of FGF23, several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) have been shown to be caused by excessive actions of FGF23. Circulatory FGF23 is high in patients with these hypophosphatemic diseases while FGF23 is rather low in those with chronic hypophosphatemia from other causes such as vitamin D deficiency. These results indicate that FGF23 measurement is useful for the differential diagnosis of hypophosphatemia. Chemiluminescent enzyme immunoassay for FGF23 has been approved for clinical use in Japan. The first choice treatment for patients with TIO is complete removal of responsible tumors. However, it is not always possible to find and completely remove responsible tumors. Phosphate and active vitamin D have been used for patients with hypophosphatemic diseases caused by excessive actions of FGF23 including TIO patients with unresectable tumors. However, these medications have limited effects and several adverse events. The inhibition of excessive FGF23 actions has been considered to be a novel therapy for these hypophosphatemic diseases. Human MAB for FGF23, burosumab, has been shown to improve biochemical abnormalities, roentgenological signs of rickets, growth, fracture healing and impaired mineralization in patients with XLH. Burosumab has been approved in several countries including Europe, North America and Japan. Long-term effects of burosumab need to be addressed in future studies.

FGF23 and Associated Disorders of Phosphate Wasting.

Fibroblast growth factor 23 (FGF23), one of the endocrine fibroblast growth factors, is a principal regulator in the maintenance of serum phosphorus concentration. Binding to its cofactor αKlotho and a fibroblast growth factor receptor is essential for its activity. Its regulation and interaction with other factors in the bone-parathyroid-kidney axis is complex. FGF23 reduces serum phosphorus concentration through decreased reabsorption of phosphorus in the kidney and by decreasing 1,25 dihydroxyvitamin D (1,25(OH)2D) concentrations. Various FGF23-mediated disorders of renal phosphate wasting share similar clinical and biochemical features. The most common of these is X-linked hypophosphatemia (XLH). Additional disorders of FGF23 excess include autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets, fibrous dysplasia, and tumor-induced osteomalacia. Treatment is challenging, requiring careful monitoring and titration of dosages to optimize effectiveness and to balance side effects. Conventional therapy for XLH and other disorders of FGF23-mediated hypophosphatemia involves multiple daily doses of oral phosphate salts and active vitamin D analogs, such as calcitriol or alfacalcidol. Additional treatments may be used to help address side effects of conventional therapy such as thiazides to address hypercalciuria or nephrocalcinosis, and calcimimetics to manage hyperparathyroidism. The recent development and approval of an anti-FGF23 antibody, burosumab, for use in XLH provides a novel treatment option.

Osteomalacia hipofosfatémica tumoral: descripción de 2 casos / Tumor-induced hypophosphatemic osteomalacia: description of 2 cases

No disponible

[Rickets/Osteomalacia. Anti-FGF23 antibody therapy in patients with FGF23-related hypophosphatemic rickets and osteomalacia.]

Fibroblast growth factor 23(FGF23)is a phosphaturic hormone, and its excess causes several kinds of congenital and acquired hypophosphatemic diseases. A combination of oral active vitamin D3 and phosphate salt is the current standard therapy for patients with FGF23-related hypophosphatemic rickets and osteomalacia. However, these medications may cause long-term complications, such as secondary hyperparathyroidism and chronic kidney disease. Therefore, an anti-FGF23 neutralizing antibody that blocks FGF23 activity has been produced. X-linked hypophosphatemic rickets(XLHR)is the most prevalent form of hereditary FGF23-related hypophosphatemia. The safety and efficacy of a human anti-FGF23 antibody, KRN23 or burosumab, has been confirmed in adults and children with XLHR. Moreover, Burosumab is being tested as a potential treatment for patients with tumor-induced osteomalacia(TIO), which is the most prevalent form of acquired FGF23-related hypophosphatemia.

Osteomalacia induced by long-term low-dose adefovir dipivoxil: Clinical characteristics and genetic predictors.

CONTEXT: Adefovir dipivoxil (ADV) was an important cause of adult-onset hypophosphatemic osteomalacia. However, its clinical characteristics and mechanisms have not been well defined. OBJECTIVE: The objective of the study was to summarize the clinical characteristics of ADV-induced osteomalacia and to explore the association between ADV-associated tubulopathy and polymorphisms in genes encoding drug transporters. DESIGN, SETTING, PATIENTS, AND MAIN OUTCOME MEASURE: Seventy-six affected patients were clinically studied. The SLC22A6 and ABCC2 genes were screened and compared with healthy people from the HapMap. RESULTS: Hypophosphatemia, high serum alkaline phosphatase (ALP) levels, hypouricemia, nondiabetic glycosuria, proteinuria, metabolic acidosis and high bone turnover markers were the main metabolic characteristics. Fractures and pseudofractures occurred in 39 patients. Stopping ADV administration, supplementing calcitriol and calcium was effective during the follow-up period. Single SNP analysis revealed a higher percentage of the G/A genotype at c.2934 in exon 22 of the ABCC2 gene (rs3740070) in patients than in healthy people (12% [7 of 58 patients] vs. 0% [0 of 45 patients]; P=0.017), while there was no subject with homozygosity for the A allele at c.2934. CONCLUSIONS: ADV can be nephrotoxic at a conventional dosage. The G/A genotype at c.2934 of the ABCC2 gene may be a predictor of patients at greater risk for developing ADV-associated tubulopathy. Larger case-control studies are needed to further verify this finding.

Urinary ß-2 Microglobulin Levels Sensitively Altered in an Osteomalacia Patient Receiving Add-on Adefovir Dipivoxil Therapy for Hepatitis B Virus Infection.

Adefovir dipivoxil (ADV) is effective for hepatitis B virus (HBV) infection; however, ADV may provoke renal injury resulting in osteomalacia, and this side effect is seldom recognized until bone fractures emerge. We herein present a 66-year-old woman with HBV infection who received ADV for 6 years. Although she exhibited no sign of bone fractures, her urinary ß-2 microglobulin (ß2MG) level increased to 83,837 µg/L and scintigraphy revealed minimal fractures of the third rib. ADV was subsequently reduced and her urinary ß2MG rapidly fell to 3,637 µg/L. Conversely, her urinary N-acetyl-ß-D-glucosaminidase, and serum phosphate, alkaline phosphatase levels did not respond.

Pathologic Femoral Neck Fracture Due to Fanconi Syndrome Induced by Adefovir Dipivoxil Therapy for Hepatitis B.

In Fanconi syndrome, hypophosphatemic osteomalacia is caused by proximal renal tubule dysfunction which leads to impaired reabsorption of amino acids, glucose, urate, and phosphate. We present a rare case of a 43-year-old Korean male who was found to have insufficiency stress fracture of the femoral neck secondary to osteomalacia due to Fanconi syndrome. He had been receiving low-dose adefovir dipivoxil (ADV, 10 mg/day) for the treatment of chronic hepatitis B virus infection for 7 years and he subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. The incomplete femoral neck fracture was fixed with multiple cannulated screws to prevent further displacement of the initial fracture. After cessation of ADV and correction of hypophosphatemia with oral phosphorus supplementation, the patient's clinical symptoms, such as bone pain, muscle weakness, and laboratory findings improved.

Global Consensus Recommendations on Prevention and Management of Nutritional Rickets.

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.

A case of severe osteomalacia caused by Tubulointerstitial nephritis with Fanconi syndrome in asymptomotic primary biliary cirrhosis.

BACKGROUND: Primary biliary cirrhosis (PBC) is an immune-mediated chronic cholestatic liver disease, characterized by increased concentrations of serum IgM and the presence of circulating anti-mitochondrial antibodies. Although bone diseases such as osteoporosis or osteodystrophy are commonly associated with PBC, osteomalacia which is caused by abnormal vitamin D metabolism, mineralization defects, and phosphate deficiency has not been recognized as a complication of PBC. CASE PRESENTATION: We report the case of a 49-year-old Japanese woman who complained of multiple fractures. Hypophosphatemic osteomalacia was diagnosed from a low serum phosphorus level, 1,25-dihydroxyvitamin D3 level, high levels of bone specific alkaline phosphatase and the findings of bone scintigraphy, although a bone biopsy was not performed. Twenty four hour urine demonstrated a low renal fractional tubular reabsorption of phosphate, increased fractional excretion of uric acid and generalized aminoaciduria. An intravenous bicarbonate loading test suggested the presence of proximal renal tubular acidosis (RTA). These biochemical data indicated Fanconi syndrome with proximal RTA. A kidney biopsy demonstrated the features of tubulointerstitial nephritis (TIN). The patient was also suspected as having primary biliary cirrhosis (PBC) because of high levels of alkaline phosphatase, IgM and the presence of anti-mitochondrial M2 antibody, though biochemical liver function was normal. Sequential liver biopsy was compatible with PBC and the diagnosis of PBC was definite. After administration of 1,25 dihydroxyvitamin D3, neutral potassium phosphate, sodium bicarbonate for osteomalacia and subsequent predonizolone for TIN, symptoms of fractures were relieved and renal function including Fanconi syndrome was ameliorated. CONCLUSION: In this case, asymptomatic PBC was shown to induce TIN with Fanconi syndrome with dysregulation of electrolytes and vitamin D metabolism, which in turn led to osteomalacia with multiple fractures. Osteomalacia has not been recognized as a result of the renal involvement of PBC. PBC and its rare complication of TIN with Fanconi syndrome should be considered in adult patients with unexplained osteomalacia even in the absence of liver dysfunction.

A Practical Approach to Vitamin D Deficiency and Rickets.

Rickets is a condition in which there is failure of the normal mineralisation (osteomalacia) of growing bone. Whilst osteomalacia may be present in adults, rickets cannot occur. It is generally caused by a lack of mineral supply, which can either occur as a result of the deficiency of calcium (calciopaenic rickets, now known as parathyroid hormone-dependent rickets) or of phosphate (phosphopaenic rickets, now called FGF23-dependent rickets). Renal disorders may also interfere with the process of mineralisation and cause rickets. Only parathyroid hormone-dependent rickets and distal renal tubular disorders will be discussed in this chapter. The most common cause of rickets is still vitamin D deficiency, which is also responsible for other problems. Disorders of vitamin D metabolism or responsiveness may also cause similar issues. Distal renal tubular acidosis may also be caused by a variety of metabolic errors similar to those of osteoclasts. One form of distal renal tubular acidosis also causes a type of osteopetrosis. This chapter describes these conditions in detail and sets out a logical approach for treatment.

Pathogenesis and diagnostic criteria for rickets and osteomalacia - proposal by an expert panel supported by Ministry of Health, Labour and Welfare, Japan, The Japanese Society for Bone and Mineral Research and The Japan Endocrine Society.

Rickets and osteomalacia are diseases characterized by impaired mineralization of bone matrix. Recent investigations revealed that the causes for rickets and osteomalacia are quite variable. While these diseases can severely impair the quality of life of the 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 the diagnostic criteria and a flowchart for the differential diagnosis of various causes for these diseases. We hope that these criteria and flowchart are clinically useful for the proper diagnosis and management of patients with these diseases.

[My Back is Still Hurting!]. / Der Rücken tut aber noch immer weh!

We present the case of a 39-year-old man who reported to the primary care physician for low back pain. Pain persisted despite extensive assessment and therapy. During the course, bilateral femoral neck fractures occurred and due to multiple enrichments in scintigraphy chronic multifocal (sterile) osteomyelitis was suspected. In the further follow-up the appropriate diagnosis of osteomalacia was established in bone biopsy and adequate treatment with Vitamin D was initiated. During therapy, the patient was free of pain or discomfort.

[Metabolic bone and joint diseases].

Metabolic bone and joint diseases in adults include osteomalacia, rheumatoid arthritis, gouty arthritis. Recently, the newest molecular biology procedures and the clinical observation studies can produce good results for understanding of these diseases. From this perspective, the author introduced updated information of the pathophysiology, the latest diagnostic criteria and the therapy of these diseases.

Paraneoplastic syndromes in rheumatology.

For patients that present with musculoskeletal symptoms, diagnostic procedures carried out by physicians and rheumatologists are primarily aimed at confirming or excluding the occurrence of primary rheumatic diseases. Another important trigger for musculoskeletal disease, however, is the presence of a tumour. Careful clinical investigation and knowledge of the gestalt of musculoskeletal syndromes related to respective tumour entities is of utmost importance for the diagnosis of paraneoplastic rheumatic diseases such as hypertrophic osteoarthropathy, paraneoplastic polyarthritis, RS3PE syndrome, palmar fasciitis and polyarthritis, cancer-associated myositis and tumour-induced osteomalacia. This places great responsibility on rheumatologists in diagnosing malignancies and referring the patient for effective treatment. The selective influence of tumours on musculoskeletal tissue is surprising and indicates that tumours alter tissues such as the periosteum, synovial membrane, subcutaneous connective tissue, fascia, muscles and bones by specific molecular processes. Some of the underlying mechanisms have been unravelled, providing valuable information on the physiologic and pathophysiologic roles of mediators such as vascular endothelial growth factor and fibroblast growth factor 23.