Hypophosphatemic Osteomalacia Research Articles

Pathological Femoral Fracture due to Osteoporosis and Hypophosphatemic Osteomalacia Following Adefovir Therapy in a Patient with Chronic Hepatitis B

Pathological Femoral Fracture due to Osteoporosis and Hypophosphatemic Osteomalacia Following Adefovir Therapy in a Patient with Chronic Hepatitis B

Adefovir dipivoxil induced hypophosphatemic osteomalacia in chronic hepatitis B: a comparative study of Chinese and foreign case series

BackgroundAdefovir dipivoxil (ADV)-induced renal tubular dysfunction and hypophosphatemic osteomalacia (HO) have been given great consideration in the past few years. However, no standard guidance is available due to a lack of powerful evidence from appropriate long-term prospective case-control studies and variations in the definition of renal adverse events. The aim of this study is to clarify clinical features of ADV-related HO in Chinese chronic hepatitis B patients with long-term ADV treatment in Chinese and non-Chinese comparative case series.MethodsRetrieval of case reports was based on Pubmed, CNKI, Wan Fang and VIP databases using the key words adefovir dipivoxil, hypophosphatemia, osteomalacia and Fanconi syndrome. We divided patients into Chinese (C group) and Foreign (F group) groups according to their nationality. Comparisons involving demographics, clinical manifestations, tests, treatment and prognosis were conducted between the two groups.ResultsOf the patients screened, 120 Chinese patients were identified in the C group, and 32 non-Chinese patients were identified in the F group. The average age of the C group was younger than that of the F group (51.89 years ±10.96 years versus 56.47 years ±11.36 years, t = − 2.084, P = 0.039). No significant difference was found in gender (male to female, 3.29:1 versus 3:1, χ2 = 0.039, P = 0.844). Although there was no significant difference in the duration of ADV therapy before ostalgia onset, the C group tended to develop adverse events earlier, by 2–3 years, while the F group developed adverse events at 4–5 years (Z = − 1.517, P = 0.129). Prognosis was good after adjustment of the ADV dose and supplemental administration of phosphate and calcitriol. Time to resolution of tubular dysfunction was commenced at the first month, and Chinese patients were more prone to recover in the first 3 months than non-Chinese patients (91.3% of patients in the C group versus 56.3% in the F group, Z = − 3.013, P = 0.003).ConclusionsSufficient attention is required for middle-aged males before and during exposure to long-term ADV therapy, regardless of nationality. The clinical picture, laboratory and radiograph alterations are important clues for those patients and are usually characterized by polyarthralgia, renal tubular dysfunction and mineralization defects. Implementation of an early renal tubular injury index is recommended for patients with higher risk, which would prevent further renal injury.

Acquired Fanconi syndrome and hypophosphatemic osteomalacia in two patients treated with adefovir and tenofovir

Acquired Fanconi syndrome and hypophosphatemic osteomalacia in two patients treated with adefovir and tenofovir

Acquired hypophosphatemic osteomalacia is easily misdiagnosed or neglected by rheumatologists: A report of 9 cases.

The aim of the present study was to assist rheumatologists in differentiating hypophosphatemic osteomalacia (HO) from mimic rheumatology diseases. Clinical data was obtained from 9 patients with acquired HO, initially misdiagnosed as mimic rheumatologic diseases. The data were retrospectively analyzed and a literature review was performed. The etiology of the cases was as follows: Adefovir dipivoxil-induced Fanconi syndrome was present in 6 of the cases, 2 were tumors and 1 case was chronic nephropathy. The chief complaint was thoracic or back pain and arthralgia, followed by progressive muscle weakness and dramatic movement limitation. All patients were transferred to 3-6 hospitals for extended periods due to misdiagnosis with conditions such as ankylosing spondylitis, chronic arthritis, lumbar disc disease, osteoporosis and somatoform disorder. Hypophosphatemia was observed in the patients and bone scans revealed diffusely decreased tracer uptake, with multiple hot spots of fractured sites and involved joints. Furthermore, patients' bone density was markedly low compared with the normal range for their age and sex. In the present study, 6 of the patients recovered when adefovir dipivoxil was stopped. In 1 case, hypophosphatemia was ameliorated following tumor resection. The remaining patients, 1 with sub-skull tumor and 1 with chronic kidney disease, had poor prognoses due to incurable diseases. In conclusion, diagnosing HO is challenging for rheumatologists and physicians. Basic examinations of electrolyte balance and bone mineral density should be performed, as should tumor screening and a careful collection of patient medical history and drugs in young patients with unexplained thoracic or back pain and muscle weakness. Removing any secondary etiology, such as drugs may dramatically improve the patients clinical manifestations and result in an improved prognosis.

Hypophosphatemic osteomalacia caused by adefovir dipivoxil: case report and literature review

A 61-years male patients with chronic hepatitis B developed hypophosphatemic following long-term use of in our hospital. With adefovir dipivoxil and osteomalacia as the search terms, we searched Wanfang database and Chinese Biomedical bibliographic database since 2005, and retrieved 79 cases of dipivoxil-induced hypophosphatemic osteomalacia. Of the 80 cases, there were 63 males and 17 females with a mean age of (52±11) years. The average duration of disease to first diagnosis made was 17 months, the average duration of administration to the onset of the disease was 62 months, and the average duration of hepatitis B was 11 years. The most common clinical manifestation was progressive bone pain in all parts of the body (80/80 cases); the most common laboratory finding was decreased serum phosphorus (80/80 cases), followed by abnormal urine tests (55/56 cases) including increased urinary phosphorus, urinary protein and positive urinary occult blood. The X-ray, CT and MRI showed different degrees of decreased bone density, osteoporosis, and bone fracture in severe patients (76/77 cases). It is suggested that clinicians should pay attention to the renal damage during the treatment of dipivoxil, and the renal function, electrolyte and bone density should be monitored regularly. Key words: Anti-retrovviral agents; Adefovir dipivoxil; Osteomalacia; Fanconi syndrome; Hypophosphatemia

FGF23 Neutralizing Antibody Partially Improves Bone Mineralization Defect of HMWFGF2 Isoforms in Transgenic Female Mice.

Mice overexpressing high molecular weight FGF2 isoforms (HMWTg) in osteoblast lineage phenocopy human X-linked hypophosphatemic rickets (XLH) and a Hyp murine model of XLH demonstrating increased FGF23/FGF receptor signaling and hypophosphatemic rickets/osteomalacia. Because HMWFGF2 was upregulated in bones of Hyp mice and abnormal FGF23 signaling is important in XLH, HMWTg mice were used to examine the effect of the FGF23 neutralizing antibody (FGF23Ab). Eight-week-old female Vector control mice and HMWTg mice were treated with FGF23Ab or control IgG. A single injection of FGF23Ab rescued abnormal hypophosphatemia in HMWTg. The decreased type II sodium-dependent phosphate co-transporter (Npt2a) was rescued by FGF23Ab treatment. Inappropriately low serum 1,25(OH)2 D in HMWTg mice was normalized by FGF23Ab treatment, which is accompanied by increased anabolic vitamin D hydroxylase Cyp27b1 and decreased catabolic vitamin D hydroxylase Cyp24 mRNA in kidney. Long-term treatment with FGF23Ab normalized femur length and significantly increased vertebrae BMD and BMC, and femur BMC in HMWTg mice compared to IgG-treated HMWTg mice. Micro-computed tomography (μCT) revealed increased cortical porosity and decreased cortical apparent density in the HMWTg-IgG group compared with the Vector-IgG group; however, FGF23Ab treatment rescued defective cortical mineralization, decreased porosity, and increased apparent density in HMWTg mice. Bone histomorphometry analysis showed FGF23Ab treatment decreased osteoid volume, increased intra-label thickness, mineralization apposition rate, and bone formation rate in HMWTg mice. FGF23Ab improved disorganized double labeling in femurs from HMWTg mice. Quantitative real-time PCR analysis of tibia shafts showed FGF23Ab treatment normalized the osteocalcin (Ocn) mRNA expression in HMWTg mice, but further increased expression of SIBLING protein-related and pyrophosphate-related genes that are important in matrix mineralization, suggesting that HMWFGF2 modulates these genes independent of FGF23. We conclude that FGF23Ab partially rescued hypophosphatemic osteomalacia in HMWTg. However, long-term treatment with FGF23Ab further increased SIBLING protein-related genes and pyrophosphate-related genes in bone that could contribute to incomplete rescue of the mineralization defect. © 2018 American Society for Bone and Mineral Research.

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.

Correction to: Tubulointerstitial nephritis-induced hypophosphatemic osteomalacia in Sjögren's syndrome: a case report and review of the literature.

The Funding statement was omitted from the original publication; the authors have requested that this be noted and now presented in this article.

Strict Phosphorus-Restricted Diet Causes Hypophosphatemic Osteomalacia in a Patient With Chronic Kidney Disease

Strict Phosphorus-Restricted Diet Causes Hypophosphatemic Osteomalacia in a Patient With Chronic Kidney Disease

Clinical features of hypophosphatemic osteomalacia induced by long-term low-dose adefovir dipivoxil.

ObjectiveTo investigate the predictors of hypophosphatemic osteomalacia induced by adefovir dipivoxil (ADV) and to monitor for early detection.Patients and methodsHospitalized patients who were diagnosed with ADV-related hypo-phosphatemic osteomalacia were recruited and retrospectively analyzed in our hospital from January 2012 to December 2016. A telephone interview was conducted at 1, 3, 6, 9, 12, and 24 months after cessation of ADV.ResultsIn the 8 patients enrolled in the study, the hypophosphatemic osteomalacia symptoms developed at an average of 5.14 (4–7) years since ADV treatment (10 mg/d). The average alkaline phosphatase (ALP) level was 279.50 (137–548) U/L, which was significantly higher than the normal level (45–125 U/L). The serum phosphorus level was an average of 0.59 (0.43–0.69) mmol/L, which was lower than the normal range (2.06–2.60 mmol/L). Serum calcium levels of the enrolled patients remained within normal limits. Reduced estimated glomerular filtration rate (eGFR <29 mL/min/1.73 m2) was seen in 4 cases. The clinical manifestations were mainly progressive systemic bone and joint pain, frequent fractures, trouble in walking, height reduction (4–6 cm), and so on. After cessation of ADV, symptoms like bone pain resolved gradually. Serum phosphorus level restored to normal in 4.5 months after the withdrawal of ADV. However, in 4 patients, renal function failed to return to normal in 24 months.ConclusionMore attention should be paid to the duration of ADV treatment. The level of serum phosphorus and ALP, as well as renal function, should be monitored for early detection of potential adverse drug reactions.

Identification of a novel loss-of-function PHEX mutation, Ala720Ser, in a sporadic case of adult-onset hypophosphatemic osteomalacia

Adults presenting with sporadic hypophosphatemia and elevations in circulating fibroblast growth factor-23 (FGF23) concentrations are usually investigated for an acquired disorder of FGF23 excess such as tumor induced osteomalacia (TIO). However, in some cases the underlying tumor is not detected, and such patients may harbor other causes of FGF23 excess. Indeed, coding-region and 3’UTR mutations of phosphate-regulating neutral endopeptidase (PHEX), which encodes a cell-surface protein that regulates circulating FGF23 concentrations, can lead to alterations in phosphate homeostasis, which are not detected until adulthood. Here, we report an adult female who presented with hypophosphatemic osteomalacia and raised serum FGF23 concentrations. The patient and her parents, who were her only first-degree relatives, had no history of rickets. The patient was thus suspected of having TIO. However, no tumor had been identified following extensive localization studies. Mutational analysis of the PHEX coding-region and 3’UTR was undertaken, and this revealed the patient to be heterozygous for a novel germline PHEX mutation (c.2158G>T; p.Ala720Ser). In vitro studies involving the expression of WT and mutant PHEX proteins in HEK293 cells demonstrated the Ala720Ser mutation to impair trafficking of PHEX, with ~20% of the mutant protein being expressed at the cell surface, compared to ~80% cell surface expression for WT PHEX (p<0.05). Thus, our studies have identified a pathogenic PHEX mutation in a sporadic case of adult-onset hypophosphatemic osteomalacia, and these findings highlight a role for PHEX gene analysis in some cases of suspected TIO, particularly when no tumor has been identified.

Multilevel “fish vertebrae” in a patient with tumor-induced osteomalacia

Abstract Background and importance: “Fish vertebra” is an uncommon anomaly of vertebral body shape, consisting of central depression of the superior and inferior vertebral surfaces. It has been associated with various conditions: osteoporosis, osteomalacia, hyperparathyroidism, Paget disease, sickle cell disease, multiple myeloma and systemic lupus erythematosus. Clinical presentation: A 29-year-old male patient, previously treated for ankylosing spondylitis (with NSAIDs and TNFα inhibitor), without any clinical improvement, was admitted to our Neurosurgical Department. He complained of difficult gait, possible only with the aid of a cane, low back pain and bilateral hip pain, but without leg pain. He denied any history of recent trauma. Neurological examination was normal. Plain thoracic and lumbar spine X-rays revealed multilevel “fish vertebrae”. Lumbar spine MRI and contrast thoraco-abdominal CT scan showed fractures of multiple structures: left L4 pedicle, right L4 lamina and pars interarticularis, right II-VII costal arches, left I-V costal arches and bilateral sacral alae. We performed extensive laboratory tests that detected low seric phosphorous and PTH levels, with increased alkaline phosphatase, indicating a possible endocrinological cause for this condition. Subsequently, we decided to transfer the patient to an Endocrinological Department. A diagnosis of hypophosphatemic osteomalacia was established and increased FGF23 levels, later determined, suggested it was tumor-induced osteomalacia. Whole-body MRI was unable to locate the tumor, but Gallium-68 DOTATATE PET/CT revealed a small (15 mm in diameter), hyperfixating mass in the head of the right femur. The patient was treated with oral calcitriol and phosphate, with alleviation of symptoms. Surgical excision of the tumor was recommended, but the patient decided to postopone the operation. Conclusion: Modern medical imaging and biochemical testing have made the leap from merely observing vertebral biconcavities to diagnosing their cause and, consequently, the possibility to adequately treat uncommon causes of “fish vertebra”, such as neuroendocrine tumor-induced osteomalacia.

Erratum to: Nutritional Rickets and Osteomalacia in the Twenty-first Century: Revised Concepts, Public Health, and Prevention Strategies.

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.

Middle Aged Man with Bilateral Lower Limb Weakness and Non-Traumatic Fractures: Case of Hypophosphatemic Osteomalacia

Middle Aged Man with Bilateral Lower Limb Weakness and Non-Traumatic Fractures: Case of Hypophosphatemic Osteomalacia

Musculoskeletal oncogenic osteomalacia–An experience from a single centre in South India

BackgroundOncogenic osteomalacia is an acquired form of hypophosphatemic osteomalacia where the tumour resection may lead to cure of the disease. Tumours originating from the musculoskeletal region form an important subgroup of oncogenic osteomalacia. MethodsThis was a retrospective study conducted at a tertiary care centre in south India where we analyzed the hospital records of all the patients with musculoskeletal oncogenic osteomalacia from January 2010–April 2016. ResultsA total number of 73 patients were diagnosed to have adult onset hypophosphatemic osteomalacia out of which 13 patients (M: F=6:7; mean age: 45.38±18.23 years) with musculoskeletal oncogenic osteomalacia were included in the study. Common presenting symptoms were bony pains, proximal myopathy and fractures. Mean duration of symptoms from the initial hospital visit was 58.46±64.48 months. The initial mean fibroblast growth factor (FGF) 23 levels being 828.86±113.22RU/ml (Normal range: 22–91). Imaging modalities used for localization of the tumour: DOTATATE PET/CT (8 patients), FDG PET/CT (3 patients), 1 patient (Both DOTATATE PET/CT and FDG PET/CT) and whole body Tc 99m Red blood cell (RBC) blood pool scintigraphy (2 patients). 9 patients underwent surgery and all achieved remission. 4 patients denied surgical consent. ConclusionMusculoskeletal oncogenic osteomalacia is a major subgroup of oncogenic osteomalacia which need more extensive whole body imaging for the localization of the tumour. Surgical excision often leads to remission of the disease.

Phosphaturic mesenchymal tumor (PMT): Exceptionally rare disease, yet crucial not to miss

Phosphaturic mesenchymal tumors (PMTs) are very rare tumors which are frequently associated with Tumor Induced Osteomalacia (TIO), a paraneoplastic syndrome that manifests as renal phosphate wasting. The tumor cells produce a peptide hormone-like substance known as fibroblast growth factor 23 (FGF23), a physiologic regulator of phosphate levels. FGF23 decreases proximal tubule reabsorption of phosphates and inhibits 1-α-hydroxylase, which reduces levels of 1-α, 25-dihydroxyvitamine D3. Thus, overexpression of FGF23 by the tumor cells leads to increased excretion of phosphate in the urine, mobilization of calcium and phosphate from bones, and the reduction of osteoblastic activity, ultimately resulting in widespread osteomalacia. Patients typically present with gradual muscular weakness and diffuse bone pain from pathologic fractures. The diagnosis is often delayed due to the non-specific nature of the symptoms and lack of clinical suspicion. While serum phosphorus and FGF23 testing can assist in making a clinical diagnosis of PMT, the responsible tumor is often difficult to locate. The pathologic diagnosis is often missed due to the rarity of PMTs and histologic overlap with other mesenchymal neoplasms. While patients can experience severe disabilities without treatment, excision is typically curative and results in a dramatic reversal of symptoms. Histologically, PMT has a variable appearance and can resemble other low grade mesenchymal tumors. Even though very few cases of PMT have been reported in the world literature, it is very important to consider this diagnosis in all patients with hypophosphatemic osteomalacia. Here we present a patient who suffered for almost 5 years without a diagnosis. Ultimately, the PMT was located on a 68Ga-DOTA TATE PET/CT scan and subsequently confirmed by histologic and immunohistologic study. Interestingly, strong positivity for FGFR1 by IHC might be related to the recently described FN1-FGFR1 fusion. Upon surgical removal, the patient’s phosphate and FGF23 levels returned to normal and the patient’s symptoms resolved.

Iron Replacement as A Therapeutic Approach For Renal Phosphate Wasting With Associated Iron Deficiency

ABSTRACT Objective: Fibroblast growth factor 23 (FGF23) dysregulation is implicated in the pathogenesis of hypophosphatemic disorders, including X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets, and tumor-induced osteomalacia (TIO). Studies have suggested a role of iron deficiency in triggering FGF23 dysregulation in ADHR. Methods: We report a case of adult-onset FGF23-mediated hypophosphatemic osteomalacia with associated iron deficiency that had significant clinical improvement and reduction in FGF23 with iron replacement. Results: A 41-year-old female presented with progressively worsening muscle weakness and diffuse pain for 4 years, resulting in wheelchair dependence. She had hypophosphatemia, renal phosphate wasting, and an elevated FGF23. Extensive imaging for TIO was nonlocalizing. Family history was negative for bone disease. Despite phosphorus and calcitriol therapy, her phosphorus remained low and she had progres...

Idiopathic hypophosphatemic osteomalacia: recurrent pseudofracture of the proximal femur in a 65-year-old man

Idiopathic hypophosphatemic osteomalacia: recurrent pseudofracture of the proximal femur in a 65-year-old man

Long-term iron polymaltose infusions associated with hypophosphataemic osteomalacia: a report of two cases and review of the literature.

Iron-induced hypophosphataemic osteomalacia remains under-recognized as a potential complication of parenteral iron therapy. We here report two cases of symptomatic hypophosphataemic osteomalacia with multiple insufficiency fractures in the context of chronic gastrointestinal blood loss, necessitating monthly iron polymaltose infusions over prolonged periods of time. Respective blood tests revealed severe hypophosphataemia [0.29 and 0.43; normal range (NR) 0.8-1.5 mmol/l] in the presence of normal serum calcium and 25-hydroxy vitamin D levels. Urinary fractional phosphate excretion was elevated (16% and 24%; NR < 5%) and the tubular maximum phosphate reabsorption was reduced, consistent with renal phosphate wasting. Serum fibroblast growth factor 23 (FGF23) obtained in one patient was significantly elevated at 285 pg/ml (NR < 54 pg/ml). Bone mineral density was significantly reduced and whole-body bone scans revealed metabolic bone disease and multiple insufficiency fractures consistent with osteomalacia. Cessation of iron infusions resulted in clinical and biochemical improvement within 2 months in one patient whereas the second patient required phosphate and calcitriol supplementation to improve symptomatically. Iron-induced hypophosphataemic osteomalacia is thought to be due to reduced degradation of FGF23, resulting in phosphaturia and reduced synthesis of 1,25-dihydroxy vitamin D. Monitoring of patients on long-term parenteral iron is recommended to avoid clinically serious adverse effects.

Dramatic mitigation of bone pain after phosphorus replacement therapy in a subject with FGF23-related hypophosphatemic osteomalacia.

IntroductionFibroblast growth factor 23 (FGF23) is secreted from bone and suppresses the absorption of phosphorus in renal proximal tubule and in intestinal tract. Therefore, the increase of serum FGF23 levels leads to hypophosphatemic situations. Tumor-induced osteomalacia is often induced by various tumors, but it is often difficult to identify the localization of tumor, because most of the FGF23-producing tumors are small and could be observed in any part of the body.Case descriptionHere we report a case of elderly female subject with FGF23-related hypophosphatemic osteomalacia who repeatedly experienced severe bone pain and fragility fracture in various parts of the body. Although we failed to identify the localization of tumor in this subject even with various examination, after starting phosphorus replacement therapy with relatively small amounts of calcium phosphate (1.5 g/day) (phosphorus content: 270 mg), hypophosphatemia was ameliorated and repeated bone pain was dramatically mitigated without any surgical operation.Discussion and EvaluationEven when we fail to identify the localization of tumor in subjects with FGF23-related hypophosphatemic osteomalacia, phosphorus replacement therapy for hypophosphatemia could reduce the bone pain.ConclusionsWe should be aware of the possibility that phosphorus replacement therapy exert marked beneficial effects for the reduction of bone pain in subjects with FGF23-related hypophosphatemic osteomalacia even when we fail to identify tumor localization.