RESUMO
Hypophosphatemic rickets/osteomalacia caused by FGF23 excess is conventionally treated with multiple doses of inorganic phosphate salts and active vitamin D analogs. However, conventional therapy targets the consequences of elevated FGF23 and not the elevated FGF23 itself and is associated with poor adherence and long-term complications such as nephrocalcinosis and secondary/tertiary hyperparathyroidism. Burosumab is a fully human IgG1 monoclonal antibody that binds to and neutralises FGF-23, thereby leading to improvement in phosphate homeostasis and healing of rickets and osteomalacia. Data from phase 2 and 3 trials report overall safety and efficacy and Burosumab is now FDA approved for treatment of XLH and TIO in children and adults. Cost and absence of long-term data are major issues with Burosumab which should be addressed in near future. At present, experts recommend Burosumab use in patients with severe disease or those with mild-moderate disease and a failed response to a trial of conventional therapy.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Osteomalacia , Adulto , Criança , Humanos , Osteomalacia/induzido quimicamente , Osteomalacia/tratamento farmacológico , Fatores de Crescimento de Fibroblastos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais/efeitos adversos , Raquitismo Hipofosfatêmico Familiar/tratamento farmacológicoRESUMO
OBJECTIVE: Osteomalacia is an uncommon, overlooked and debilitating metabolic bone disease with numerous aetiologies. Herein, we report an atypical cause of osteomalacia - intravenous iron therapy. METHODS: Description of a case report of hypophophatemic osteomalacia induced by ferric carboxymaltose infusions. RESULTS: A 70-year-old male with Rendu-Osler-Weber syndrome requiring repeated infusions of ferric carboxymaltose was admitted for disabling lower limb pain associated with persistent hypophosphatemia (1.6mg/dL) and increased urinary fractional excretion of phosphate (43%, UP04=118.3mg/dL), serum fibroblast growth factor 23 (324UA/mL), intact parathyroid hormone (110pg/mL) and bone alkaline phosphatase (40.1mcg/L). X-ray and CT of the feet showed severe diffuse bone demineralization. Feet MRI displayed a subchondral fracture of the cuneiform-navicular joints. Spine X-ray revealed dorsolumbar vertebral flattening. Somatostatin receptor PET scan excluded an occult tumor. Bone biopsy with histomorphometry confirmed the presence of osteomalacia. After excluding other causes, a diagnosis of hypophosphatemic osteomalacia induced by frequent ferric carboxymaltose infusions was made. The iron formulation was replaced by saccharated ferric oxide infusions and progressive titration of calcitriol up to 1.5mg/day and oral disodium phosphate up to 5740mg/day was started. After 6 months, there was a clear clinical and analytical improvement. CONCLUSION: Osteomalacia may be a consequence of prolonged hypophosphatemia induced by recurrent ferric infusions, which is an uncommon and neglected bone adverse event of this therapy. Phosphate levels and bone symptoms should be monitored during repetitive iron infusions, maintaining a high level of suspicion for osteomalacia as it is important to identify and treat it in a timely manner, minimizing its severe morbidity.
Assuntos
Hipofosfatemia , Osteomalacia , Masculino , Humanos , Idoso , Osteomalacia/induzido quimicamente , Osteomalacia/diagnóstico , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/diagnóstico , Fosfatos/uso terapêutico , Ferro/efeitos adversosRESUMO
We present a case of a 61-year-old healthy man who had bilateral femoral neck insufficiency fractures attributed to repeated iron transfusions, causing iron-induced hypophosphatemic rickets, requiring surgical intervention. Atraumatic insufficiency fractures present a diagnostic dilemma in orthopaedics. Chronic fractures with no acute precipitating trigger can often go unrecognized until complete fracturing or displacement occurs. Early identification of the risk factors in conjunction with a comprehensive history, clinical examination, and imaging can potentially avoid these serious complications. Atraumatic femoral neck insufficiency fractures have been sporadically reported in the literature, often unilateral and attributed to the use of long-term bisphosphonates. Through this case, we elaborate on the relatively unknown link between iron transfusions and insufficiency fractures. This case highlights the importance of early detection and imaging of such fractures from an orthopaedic perspective.
Assuntos
Fraturas do Fêmur , Fraturas do Colo Femoral , Fraturas de Estresse , Hipofosfatemia , Osteomalacia , Masculino , Humanos , Pessoa de Meia-Idade , Fraturas de Estresse/induzido quimicamente , Fraturas de Estresse/diagnóstico por imagem , Osteomalacia/induzido quimicamente , Osteomalacia/complicações , Osteomalacia/diagnóstico , Fraturas do Fêmur/induzido quimicamente , Fraturas do Fêmur/diagnóstico por imagem , Fraturas do Colo Femoral/induzido quimicamente , Fraturas do Colo Femoral/diagnóstico por imagem , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/complicaçõesAssuntos
Síndrome de Fanconi , Hipofosfatemia , Osteomalacia , Distúrbios do Metabolismo do Fósforo , Fraturas da Coluna Vertebral , Humanos , Síndrome de Fanconi/induzido quimicamente , Síndrome de Fanconi/complicações , Fraturas da Coluna Vertebral/induzido quimicamente , Fraturas da Coluna Vertebral/cirurgia , Fraturas da Coluna Vertebral/complicações , Osteomalacia/induzido quimicamente , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/complicaçõesRESUMO
Acquired fibroblast growth factor (FGF) 23-related hypophosphatemic osteomalacia is characterized clinically by muscle weakness, bone pain, and fractures. Its biochemical features include hypophosphatemia, caused by renal phosphate wasting, and inappropriately normal or low 1,25-dihydroxy-vitamin D levels. Recently, burosumab, a fully human monoclonal antibody targeting FGF23, was approved for the treatment of FGF23-related hypophosphatemic rickets and osteomalacia. We report the case of a 75-year-old Japanese woman with decompensated liver cirrhosis and hepatic encephalopathy, caused by primary biliary cholangitis, who complained of back pain and limited mobility resulting from multiple vertebral fractures. She was not receiving iron infusion therapy and denied alcohol consumption. The patient exhibited hypophosphatemia with a low tubular maximum reabsorption of phosphate per unit glomerular filtration rate (TmP/GFR) and a high circulating concentration of FGF23. Conventional therapy with alfacalcidol and oral phosphate slightly improved her serum phosphate concentration and back pain, but she experienced a hip fracture, causing her to become wheelchair-dependent. Burosumab was initiated 8 weeks after the hip fracture, which increased her serum phosphate concentration and TmP/GFR. Her mobility gradually improved, such that she could walk without a cane after 16 weeks of treatment. Her lumbar bone mineral density increased after 48 weeks. Hepatic encephalopathy developed once before the initiation of treatment and twice after the initiation of the therapy, but her liver function was preserved. This is the first study to report the efficacy and safety of burosumab treatment for FGF23-related hypophosphatemic osteomalacia with decompensated liver cirrhosis.
Assuntos
Raquitismo Hipofosfatêmico Familiar , Encefalopatia Hepática , Fraturas do Quadril , Hipofosfatemia , Osteomalacia , Humanos , Feminino , Idoso , Fator de Crescimento de Fibroblastos 23 , Osteomalacia/induzido quimicamente , Osteomalacia/tratamento farmacológico , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/metabolismo , Fatores de Crescimento de Fibroblastos , Fosfatos , Cirrose Hepática/complicações , Cirrose Hepática/tratamento farmacológicoRESUMO
A 52-year-old patient was initially diagnosed as hypophosphatemic osteomalacia in the Department of Endocrinology due to knee, foot and lumbosacral pain. The symptoms were not significantly relieved after phosphorus and vitamin D supplementation. Later, the imaging examination showed an orbital tumor in the right eye. The tumor was surgically removed, and the symptoms of systemic bone pain were relieved.
Assuntos
Hipofosfatemia , Neoplasias Orbitárias , Osteomalacia , Humanos , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/complicações , Pessoa de Meia-Idade , Neoplasias Orbitárias/complicações , Osteomalacia/induzido quimicamente , Osteomalacia/diagnóstico , Dor/complicações , Síndromes ParaneoplásicasRESUMO
Randomized control trials (RCTs) have shown that certain intravenous iron preparations can induce high levels of fibroblast growth factor 23 (FGF-23) and persistent hypophosphatemia. Repeated iron infusions may lead to prolonged hypophosphatemia and osteomalacia events not captured by RCTs. Several previous case reports have described skeletal adverse effects after repeated iron infusions. To characterize these effects, we conducted a systematic review of case reports. MEDLINE, Embase, Web of Science, and Cochrane databases were searched in March 2021. We selected case reports of patients ≥16 years old. Study quality was assessed using the tool from Murad and colleagues. We report the results in a narrative summary. We identified 28 case reports, reporting 30 cases. Ages ranged from 28 to 80 years (median 50 years). Most patients (n = 18) received ferric carboxymaltose (FCM), whereas 8 received saccharated ferric oxide (SFO) and 3 received iron polymaltose (IPM). All but 2 cases had more than five infusions (range 2 to 198, median 17). The lowest phosphate levels ranged from 0.16 to 0.77 mmol/L (median 0.36 mmol/L). Intact FGF-23 (iFGF-23) was high when measured. Serum 25OH vitamin D was low in 10 of 21 cases measured and 1,25(OH)2 vitamin D in 12 of 18. Alkaline phosphatase was high in 18 of 22 cases. Bone or muscle pain was reported in 28 of the 30 cases. Twenty patients had pseudofractures, 9 had fractures, and 6 patients had both. All 15 available bone scans showed focal isotope uptake. Case reports tend to report severe cases, so potential reporting bias should be considered. Osteomalacia is a potential complication of repeated iron infusion, especially in patients with gastrointestinal disorders receiving prolonged therapy. Pain and fractures or pseudofractures are common clinical findings, associated with low phosphate, high iFGF-23, high alkaline phosphatase, and abnormal isotope bone scan. Discontinuing or switching the iron formulation was an effective intervention in most cases. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Assuntos
Anemia Ferropriva , Raquitismo Hipofosfatêmico Familiar , Hipofosfatemia , Osteomalacia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Fosfatase Alcalina/uso terapêutico , Anemia Ferropriva/induzido quimicamente , Anemia Ferropriva/complicações , Anemia Ferropriva/tratamento farmacológico , Raquitismo Hipofosfatêmico Familiar/complicações , Compostos Férricos/efeitos adversos , Fatores de Crescimento de Fibroblastos/uso terapêutico , Humanos , Hipofosfatemia/induzido quimicamente , Ferro/efeitos adversos , Pessoa de Meia-Idade , Minerais , Osteomalacia/induzido quimicamente , Fosfatos , Vitamina D/uso terapêuticoRESUMO
Carboxymaltose iron (Ferinject®) is a formulation for intravenous (iv) administration, used for the treatment of iron deficiency anemia and/or iron deficiency when oral administration of iron is not effective or due to intolerance. Its safety profile is excellent with few, but not nonexistent, side effects. Hypophosphatemia has been described as one of them. It is usually mild, transient and asymptomatic. However, in some cases it may be accompanied by nausea, asthenia, in addition to muscular and neurological symptoms and hematological alterations. It is, therefore, a potentially serious adverse effect whose prevalence is unknown and which requires high clinical suspicion to be detected.
Assuntos
Hipofosfatemia , Osteomalacia , Compostos Férricos , Humanos , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/tratamento farmacológico , Hipofosfatemia/epidemiologia , Ferro/efeitos adversos , Maltose/efeitos adversos , Maltose/análogos & derivados , Osteomalacia/induzido quimicamente , Osteomalacia/tratamento farmacológicoRESUMO
BACKGROUND: No publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD). CASE PRESENTATION: We report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry. CONCLUSIONS: We believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.
Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Ácido Etidrônico/efeitos adversos , Osteomalacia/induzido quimicamente , Diálise Renal , Conservadores da Densidade Óssea/uso terapêutico , Osso e Ossos/diagnóstico por imagem , Calcitriol/uso terapêutico , Colecalciferol/uso terapêutico , Ácido Etidrônico/uso terapêutico , Humanos , Ílio/patologia , Masculino , Pessoa de Meia-Idade , Osteíte Fibrosa Cística/tratamento farmacológico , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológicoRESUMO
We investigated 2 outbreaks of osteomalacia as a result of phosphorus (P) deficiency in herds of lactating beef cows grazing subtropical native pastures in Uruguay. Cows exhibited pica, difficulty to stand and walk, rib fractures, and body weight loss even with adequate forage availability. Osteopenia and severe osteomalacia were observed on gross and histologic examination. The concentrations of bicarbonate-extractable P in soil (4.0, 4.1 mg P/kg), total P in pasture (0.9, 1.1 g P/kg), inorganic P in serum (1.0, 0.71 mmol P/L), and P in bone (73 mg P/mL) were all low. Although injectable and mineral salt supplements provided additional P in both outbreaks, these supplementary amounts were insufficient to prevent P deficiency. The P ingested by the cows from the pasture and supplements would have provided 20-55% of their daily P requirements of ~21 g P/d. Osteomalacia occurred in cattle at the 2 ranches as a result of severe P deficiency in the soil and forage, and inadequate P supplementation. Following diagnosis, control of P deficiency in beef cattle requires estimation of the amount of pasture P ingested and provision of sufficient additional supplementary P to meet the animals' requirements.
Assuntos
Doenças dos Bovinos , Osteomalacia , Fósforo , Ração Animal/análise , Animais , Bovinos , Doenças dos Bovinos/epidemiologia , Suplementos Nutricionais , Feminino , Lactação , Osteomalacia/induzido quimicamente , Osteomalacia/veterinária , Fósforo/análise , Fósforo/deficiência , Uruguai/epidemiologiaRESUMO
Tenofovir disoproxil fumarate (TDF) is an antiretroviral drug widely used as a first-line treatment of hepatitis B virus (HBV) and HIV. Increasing evidence has emerged associating its use with the development of Fanconi syndrome, renal insufficiency and bone disease. We report a case of a 61-year-old woman with a remote history of liver transplant for cirrhosis due to HBV. Over 1 year, the patient had recurrent falls, generalised myalgias and arthralgias, misdiagnosed as fibromyalgia. We discuss a complication of her transplant treatment regimen with the drug TDF leading to a rare but reversible disorder: tenofovir-induced Fanconi osteomalacia with renal phosphate wasting. Though recognised, this rare disorder was initially likely missed due to clinical unfamiliarity with the diagnosis, concomitant psychiatric symptoms and premature diagnostic closure.
Assuntos
Síndrome de Fanconi , Infecções por HIV , Hepatite B Crônica , Hipofosfatemia , Osteomalacia , Antivirais/uso terapêutico , Síndrome de Fanconi/induzido quimicamente , Síndrome de Fanconi/diagnóstico , Síndrome de Fanconi/tratamento farmacológico , Feminino , Infecções por HIV/complicações , Infecções por HIV/tratamento farmacológico , Vírus da Hepatite B , Hepatite B Crônica/tratamento farmacológico , Humanos , Hipofosfatemia/induzido quimicamente , Hipofosfatemia/diagnóstico , Hipofosfatemia/tratamento farmacológico , Pessoa de Meia-Idade , Osteomalacia/induzido quimicamente , Osteomalacia/diagnóstico , Osteomalacia/tratamento farmacológico , Tenofovir/efeitos adversosRESUMO
Not required for Clinical Vignette.
Assuntos
Vírus da Hepatite B , Hepatite B Crônica , Hipofosfatemia , Osteomalacia , Adenina/análogos & derivados , Antivirais/efeitos adversos , Hepatite B Crônica/tratamento farmacológico , Humanos , Hipofosfatemia/induzido quimicamente , Organofosfonatos , Osteomalacia/induzido quimicamente , Osteomalacia/tratamento farmacológicoRESUMO
Itai-itai (Japanese, "It hurts! It hurts!") disease (IID), a form of osteomalacia, can be induced in ovariectomized rats by long-term administration of cadmium (Cd). This IID rat model shows severe anemia, severe nephropathy, and osteomalacia accompanied by iron (Fe) deposition at the mineralization front. We characterized the pathogenesis of Cd-induced bone lesions by investigating the relationship between Fe deposition and osteoid tissue formation in ovariectomized rats. The rats were injected with CdCl2 (0.5 mg/kg) for 70 weeks, with or without co-injection of erythropoietin (EPO) for varying lengths of time to elucidate whether EPO prevents and/or cures anemia, and, with the restoration from anemia, lessens the osteoid tissue formation. Necropsies were performed at 25, 50, or 70 weeks. Fe deposition at the mineralization front of bone was found at 50 weeks and increased thereafter. Animals injected with EPO showed decreased Fe deposition, although there was no relation between EPO administration and osteoid formation in the femur. Because the increase in bone lesion severity was independent of the amount of Fe deposition, we suggest that Fe deposition is not involved in the etiology of Cd-induced femoral bone lesions.
Assuntos
Cádmio/toxicidade , Ferro/metabolismo , Osteomalacia/induzido quimicamente , Animais , Cádmio/administração & dosagem , Feminino , Fêmur/efeitos dos fármacos , Fêmur/patologia , Osteomalacia/patologia , Ovariectomia/efeitos adversos , Ratos , Ratos Sprague-DawleyAssuntos
Anemia Ferropriva/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Compostos Férricos/efeitos adversos , Fatores de Crescimento de Fibroblastos/sangue , Hipofosfatemia/tratamento farmacológico , Maltose/análogos & derivados , Osteomalacia/tratamento farmacológico , Adulto , Anemia Ferropriva/sangue , Compostos Férricos/uso terapêutico , Fator de Crescimento de Fibroblastos 23 , Humanos , Hipofosfatemia/sangue , Hipofosfatemia/induzido quimicamente , Masculino , Maltose/efeitos adversos , Maltose/uso terapêutico , Osteomalacia/sangue , Osteomalacia/induzido quimicamente , Resultado do TratamentoRESUMO
Chronic heavy metal exposure and the health hazards that ensue are important public-health problems. We highlight the occurrence of hypophosphataemic osteomalacia due to chronic cadmium exposure in the silver industry in India. Three silversmiths presented similarly with clinical, biochemical and radiological evidence of hypophosphataemic osteomalacia. Considering their occupation, their blood samples were screened for heavy metals and were found to have toxic levels of cadmium. They were initiated on neutral phosphate and calcitriol. On follow-up, they reported significant reduction in severity of symptoms. It is essential to maintain a high index of suspicion in diagnosing this condition. A thorough knowledge of the occupational background of patients, as well as ambient conditions at the workplace is of utmost importance in contemplating the possibility of such rare occurrences. Moreover, regulatory agencies and policy makers ought to survey the silver industry and ensure that the metals used are within permissible safe limits of exposure.
Assuntos
Intoxicação por Cádmio , Doenças Profissionais/induzido quimicamente , Osteomalacia/induzido quimicamente , Acidose Tubular Renal/induzido quimicamente , Adulto , Cádmio/sangue , Humanos , Hipofosfatemia/induzido quimicamente , Índia , Masculino , Osteomalacia/etiologia , PrataRESUMO
Aluminium utensils are ubiquitous in Indian households and other developing countries. Concerns have recently been raised on the pathological effects of aluminium on the human body, due to its leaching from utensils with long-term use, which has been associated with certain clinical conditions such as anaemia, dementia and osteo-malacia. While some studies suggest that cooking in utensils or aluminium foils is safe, others suggest that it may lead to toxic levels of aluminium in the body. However, studies have shown that leaching of aluminium from cooking utensils depends on many factors such as pH, temperature and cooking medium. In healthy controls, 0.01 %-1 % of orally ingested aluminium is absorbed from the gastrointestinal tract and is eliminated by the kidney. Although the metal has a tendency to accumulate in tissues and may result in their dysfunction, the literature suggests that the apprehension is more apt in patients with chronic renal insufficiency. This article offers solutions to mitigate the risk of aluminium toxicity.