Osteomalacia. Diagnóstico y tratamiento / Osteomalacia. Diagnosis and treatment

Introducción: la osteomalacia se caracteriza por la falta de mineralización de la sustancia osteoide, que afecta al hueso cortical y al hueso esponjoso maduro. Es una enfermedad que se presenta en adultos y niños, aunque la causa es diferente en cada uno. Objetivo: exponer la generalidad de la osteomalacia por ser una enfermedad que produce serias afectaciones a la población que la padece, especialmente a los niños. Se enfatiza en el diagnóstico y su tratamiento. Desarrollo: a fin de resumir los elementos esenciales para establecer el diagnóstico de osteomalacia hay que plantear en primer lugar, la presencia de un trastorno de la mineralización ósea, de ahí que además de tener en cuenta las causas de la enfermedad, su curso clínico y la sintomatología. Conclusiones: una recomendación importante es no tener en cuenta la posibilidad de complicaciones en el curso de la enfermedad, como las fracturas, que, aunque sean parte del cuadro clínico, al producirse pueden ocasionar graves problemas, como el caso de las que aparecen en las costillas, que si se desplazan pueden interesar órganos vitales, de modo que en este tipo de pacientes no debe excluirse la posibilidad de emergencias o de urgencias reumatológicas tanto en los adultos como en los niños(AU)

Introduction: osteomalacia is characterized by the lack of mineralization of the osteoid substance, which affects cortical bone and mature cancellous bone. It is a disease that occurs in adults and children, although the cause is different in each. Objective: to expose the generality of osteomalacia for being a disease that causes serious affectations to the population that suffers it, especially to children. Emphasis is placed on the diagnosis and its treatment. Development: in order to summarize the essential elements to establish the diagnosis of osteomalacia, we must first consider the presence of a bone mineralization disorder, hence, in addition to taking into account the causes of the disease, its clinical course and the symptomatology. Conclusions: an important recommendation is not to take into account the possibility of complications in the course of the disease, such as fractures, which, although they are part of the clinical picture, can cause serious problems when they occur, as in the case of those that appear in the ribs, which if they move may involve vital organs, so that in this type of patients should not exclude the possibility of emergencies or rheumatological emergencies in both adults and children(AU)

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.

Hypophosphataemic rickets/osteomalacia: A descriptive analysis.

Background & objectives: Hypophosphataemic rickets/osteomalacia (HRO) is an uncommon metabolic bone disorder which affects all ages and either sex. It is characterized by low concentration of serum phosphate levels leading to impairment of mineralization of bone matrix with variable aetiology. We present clinical profile and treatment outcome of 17 patients of HRO. Methods: Seventeen consecutive patients (8 were < 18 yr of age, with median age of presentation being 27.5 yr) of HRO who came to the department of Endocrinology in a tertiary care hospital in north India from January 2000 to December 2006 were included in the present study. Their aetiology, clinical features, biochemical parameters, radiographic features, treatment and outcome were analyzed. Results: HRO was commoner in females (70.5%) with positive family history observed in 6 (35.3%) patients. Common presenting features were short stature (58.8%), backache (58.8%), bony deformities (58.8%), joint pain (52.9%), fractures (29.4%) and dental abnormalities (23.5%). Radiological abnormalities noted were generalized bony deformities (58.8%), fractures (29.4%), and pseudo fractures (17.6%). Mesenchymal tumours were localized in the pelvis in one patient and in the right jaw in another. The patients were treated with calcium (elemental calcium 1 g/d) and oral phosphate supplements (dose 30 – 50mg/kg/day in divided doses) along with active vitamin D supplements (dose 1- 3 μg/day) and followed up for a mean of 2 yr. Two patients also received growth hormone (GH) therapy in the dose of 2U/day for 6 and 18 months respectively. Symptomatic well being was reported by all the patients and improvement was noted in the levels of phosphate (P<0.005) and alkaline phosphatase (P<0.05) after treatment. Interpretation & Conclusions: A diagnosis of HRO should be considered in all patients presenting with short stature, deformities or musculoskeletal pains along with low serum phosphate with normal iPTH and 25 – hydroxy vitamin D.

A Case of Osteomalacia Related to Adefovir in a Patient with Chronic Hepatitis B / 대한소화기학회지

Adefovir dipivoxil, an acyclic nucleoside analogue, has been approved for the treatment of patients with chronic hepatitis B. This agent is efficacious particularly in those who have developed lamivudine resistance. The report according to hypophosphatemia induced by low dose adefovir therapy is very rare. We report one case in which osteomalacia with hypophosphatemia developed in a patient with chronic hepatitis B on adefovir dipivoxil at a low dose, 10 mg daily. A 66-year-old man, who had been taking adefovir for more than 4 years due to lamivudine resistance, presented with muscle weakness and bone pain in both thighs. After 3 years of adefovir therapy, hypophosphatemia and elevated serum alkaline phosphatase levels had been noted. A bone scan showed multiple hot uptakes. All the image findings and clinical symptoms, such as bone pain and muscle weakness were improved after correcting the hypophosphatemia with oral phosphorous supplementation.

Tumor-induced osteomalacia: a case report / Osteomalácia induzida por tumor: relato de caso

Tumor-induced osteomalacia (TIO) is a rare paraneoplasic syndrome with overproduction of fibroblast growth factor 23 as a phosphaturic agent, leading to chronic hyperphosphaturia and hypophosphatemia, associated with inappropriately normal or low levels of 1,25-dihydroxyvitamin D. Diagnosis of this disease is often challenging. The following case report described a middle-aged man with symptoms of bone pain and severe muscle weakness, who was found to have TIO. The tumor responsible for the symptoms was localized on his thigh and its resection resulted in normalization of blood chemistry and complaints. Subsequent microscopic examination revealed a phosphaturic mesenchymal tumor, mixed connective tissue type. The authors reinforce the importance of recognition of this disease, as severe disability and even death can be avoided with the surgical removal of the causative tumor.

Osteomalácia induzida por tumor (OIT) é uma síndrome paraneoplásica rara, causada por hiperprodução do agente fosfatúrico, levando a hipofosfatemia e hiperfosfatúria crônicas, associadas a níveis reduzidos ou inapropriadamente normais de 1,25-dihidroxivitamina D. O diagnóstico dessa doença é, geralmente, desafiador. O relato de caso aqui apresentado descreveu um homem de meia-idade, com quadro inicial de dor óssea, fraqueza muscular extrema e hipofosfatemia, com diagnóstico tardio de OIT. O tumor responsável pelos sintomas foi localizado em membro inferior, e sua exérese resultou em normalização das alterações bioquímicas e dos sintomas. O exame microscópico da lesão revelou tumor mesenquimal fosfatúrico, tecido conectivo misto. Os autores reforçam a importância do reconhecimento dessa entidade, uma vez que a remoção do tumor responsável pelos sintomas pode evitar sérias complicações ou mesmo a morte.

Osteomalacia tumoral / Tumoral osteomalacia

La osteomalacia tumoral (OT) u osteomalacia oncogénica es un síndrome paraneoplásico producido por una pérdida renal de fosfato. Es una enfermedad rara, con aproximadamente 130 casos publicados. Recientemente, se han descrito varios factores de origen óseo que participarían en el mantenimiento de la homeostasis del fósforo; en conjunto se los denomina ?fosfatoninas?, y el más conocido es el Factor de Crecimiento Fibroblástico 23 (FGF-23). Ésta es una hormona proteica detectable en el suero de sujetos sanos y ha sido relacionado con la fisiopatología de tres tipos de raquitismo/osteomalacia con hipofosfatemia: dos enfermedades hereditarias (raquitismo u osteomalacia hipofosfatémicos asociado/a al cromosoma X [XLH], y raquitismo u osteomalacia autosómicos dominantes [ADHR]), y la OT. Los tumores asociados a la OT son de origen mesenquimático, de crecimiento lento, complejos y polimórficos. En general estos tumores son benignos, de tamaño pequeño, asintomáticos y de localización incierta; también se ha descrito el cuadro en asociación con neoplasias malignas. El diagnóstico presuntivo requiere la documentación de hipofosfatemia y de una disminución marcada en la reabsorción tubular de fósforo. Deben registrarse los antecedentes familiares, y proceder a estudios de localización del tumor: la TC y la RNM son de poca utilidad, y recientemente se ha visto la sensibilidad de centellogramas con análogos de somatostatina y del PET scan con fluorodesoxiglucosa. El diagnóstico de certeza se obtiene si se logra la reversión de la hipofosfatemia con la extracción del tumor. El tratamiento médico requiere dosis altas de fosfatos y calcitriol por vía oral, no siempre bien tolerados. Se han usado también el octreotide y el calcimimético cinacalcet. El tratamiento curativo es la remoción quirúrgica del tumor causante.

Prevalência de deficiência e insuficiência de vitamina D e sua correlação com PTH, marcadores de remodelação óssea e densidade mineral óssea, em pacientes ambulatoriais / Prevalence of vitamin D deficiency and its correlation with PTH, biochemical bone turnover markers and bone mineral density, among patients from ambulatories

A deficiência de vitamina D (VD) leva ao raquitismo e à osteomalacia e sua insuficiência, caracterizada pelo hiperparatireoidismo secundário, pode resultar osteoporose. Apesar de amplamente prevalente, a insuficiência de VD ainda é pouco reconhecida e subtratada. Os autores estudaram 180 pacientes atendidos em ambulatório de endocrinologia em Belo Horizonte, que tiveram os níveis de 25(OH)VD mensurados, correlacionando-os com paratormônio (PTH), marcadores de remodelação óssea e densidade mineral óssea. Para caracterização de níveis insuficientes de VD, foram correlacionados os níveis de 25(OH)VD com os de PTH, definindo-se, nesta série, ponto de corte de 25(OH)VD de 32 ng/ml. Foi encontrada correlação inversa e significativa entre 25(OH)VD e PTH e entre 25(OH)VD e C-telopeptídeo. A prevalência de insuficiência de VD na população estudada foi de 42,4 por cento. Conclui-se que a insuficiência de VD tem alta prevalência entre pacientes que freqüentam nossos consultórios, alertando para a importância da sua investigação na prática clínica e na instituição de políticas para sua prevenção.

Consequences of VD deficiency include rickets and osteomalacia. However, marginal concentrations of 25-hydroxyvitamin D (25(OH)VD) are associated with secondary hyperparathyroidism and osteoporosis. In this context, levels of 25(OH)VD capable to elevate parathyroid hormone (PTH) could be considered as insufficient. The VD insufficiency, although widely prevalent, is still under-recognized and under-treated. The authors have studied 180 patients followed in a endocrinology clinic in Belo Horizonte, who had 25(OH)VD measured, correlating it with PTH, biochemical bone turnover markers and bone mineral density. To determine the sufficiency of VD, 25(OH)VD was correlated with PTH and the cutoff found was of 32ng/ml. CTX-1 and PTH were significantly negative correlated to 25(OH)VD and the prevalence of VD insufficiency was 42 percent. One concludes that the VD insufficiency is widely prevalent among patients who frequently come to our offices, alerting us for the importance to assess VD status more often and to practice politics for prevention of VD insufficiency.

Vitamin D deficiency osteomalacia: the continuing challenge

Vitamin D deficiency has long been recognized to be commonest in Pakistani immigrants then in the general population in UK. We report 2 cases [patients] from our metabolic bone disease clinic in Karachi, Pakistan. The patients presented with bone deformities secondary to vitamin D deficiency. Diet, lack of sunlight exposure and wearing the veil were identified as risk factors in one case, but the other case did not have obvious risk factors. Similar cases have been identified in our clinic, confirming that despite abundant UV light, vitamin D insufficiency is a problem in people living in Pakistan. Osteomalacia presents in a clinically florid form in our population. Metabolic studies to determine the pathophysiology of vitamin D deficiency in Asian population within homeland are long overdue. It may be cost effective to pool resources inorder to setup national or regional resources to study this problem

Hiperparatireoidismo associado à osteomalacia hipofosfatêmica do adulto: relato de caso e revisão da literatura / Hyperparathyroidism associated with hypophosphatemic osteomalacia: case report and review of the literature

A osteomalacia hipofosfatêmica é uma doença rara caracterizada por hipofosfatemia, níveis elevados de fosfatase alcalina e diminuição da densidade óssea. O tratamento é realizado com suplementação oral com fosfato e vitamina D e, nos casos de osteomalacia oncogênica, com a ressecção do tumor. Relatamos o caso de uma paciente que apresentou quadro de osteomalácia hipofosfatêmica de causa indeterminada. Apesar de extensivamente procurado, nenhum tumor produtor de substância hipofosfatêmica foi localizado. A paciente foi tratada como suplementação de fosfato e vitamina D por longo período, evoluindo com quadro de hiperparatireoidismo terciário. A retirada de três paratireóides não normalizou os níveis de PTH e a paciente recusou-se a continuar a investigação e o tratamento. Após dez anos de tratamento irregular, foi internada por insuficiência respiratória causada por colabamento do arcabouço costal e múltiplas fraturas, evoluindo para o óbito. Os autores discutem a relação entre osteomalácia e hiperparatireoidismo e o curso agressivo da doença.

Historia de los mecanismos fisiológicos y bioquímicos de la vitamina D / History of physiological and biochemical mechanisms of vitamin D

La historia moderna en relación con los mecanismos fisiológicos y bioquímicos de la hormona D se inicia con los trabajos del bioquímico de origen noruego, R. Nicolaysen, quien, influido por los trabajos de las dietas en los diferentes animales, concluye que la captación del calcio es guiada por un factor desconocido que alerta al intestino a las necesidades del calcio y termina con los estudios del investigador sueco Arvid Carlsson, premio nobel de medicina por sus hallazgos en las señales de transducción a nivel del sistema nervioso central; además realiza varios trabajos con la Vitamina D que demuestran las mismas ideas de Nicolaysen. En estos 60 años se narra la historia de la hormona D, se describen los estudios de Wasserman y los grandes trabajos de Héctor De Luca, descubridor de la 25 hidroxivitamina D, y Fraser y Kodiecek, el calcitriol. Se describe a la vez el conocimiento de la adaptación intestinal, la fotobiología de la vitamina D, los otros metabolitos de la vitamina D, los análogos de los hormona D, el sistema enzimático CYP, el receptor de la vitamina D, la transcaltaquia y los nuevos mecanismos de la hormona D. Faltando por descubrir muchos efectos de esta hormona y que le brindaron un futuro más halagüeño

Distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómico dominante por mutación del factor de crecimiento fibroblástico 23 en una familia / Different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets caused by a FGF23 mutation in one family

In this report we describe different forms of clinical presentation of an autosomal dominant hypophosphatemic rickets (ADHR) in 4 members of the same family as well as the treatment used in these patients and their response to it. Patient No 1: a 60 year old female who consulted for bone pain: Bone densitometry showed osteoporosis. Laboratory assays showed hypophosphatemia with low renal phosphate threshold, high total alkaline phosphatase, normal intact PTH and normal serum calcium. With neutral phosphate and calcitriol, the biochemical parameters normalized and bone densitometry improved significantly in less than a year. Patient No 2 her grand daughter consulted at 1 year and 8 months of age for growth retardation (height at percentile 3) and genu varum. Laboratory assays showed low serum phosphate and high total alkaline phosphatase; thickening and irregular epiphyseal borders of the wrists were observed radiologically. She began treatment with calcitriol and phosphorus with normalization of laboratory parameters and increase in growth (height increasing to percentile 50 after 20 months of therapy). Patient No 3: mother of patient No 2, she had no clinical manifestations and normal densitometry but presented low serum phosphate (1.9 mg/dl) that normalized with neutral phosphate therapy. Patient No 4: he was the youngest son of Patient No 1, who had had hypophosphatemic rickets, by age 5; his serum phosphate normalized without treatment At age 29, he presented normal serum phosphate and bone densitometry. Genomic DNA analysis performed in patient No 3, showed missense mutation with substitution of arginine at position 179 for glutamine. The family was catalogued as having autosomal dominant hypophosphatemic rickets/osteomalacia.

Describimos distintas formas de presentación clínica de un raquitismo hipofosfatémico autosómicodominante en 4 miembros de una misma familia y su respuesta al tratamiento. Paciente N° 1: de sexofemenino de 60 años que consultó por dolores costales y pélvicos, con osteoporosis densitométrica, hipofosfatemia con bajo umbral renal de fósforo, PTH intacta normal y calcemia normal. Tratada con fósforo neutro y calcitriol logró la normalización bioquímica y una notable mejoría de la densitometría en menos de un año. Paciente N° 2: su nieta, consultó al año y ocho meses de edad por presentar talla en percentil 3 y genu varum. En el laboratorio mostró hipofosfatemia y fosfatasa alcalina total muy elevada y en la Rx de mano, ensanchamiento y deflecamiento epifisario compatible con raquitismo. Tratada con fósforo neutro y calcitriol, normalizó los parámetros bioquímicos y logró un ascenso en el percentil de talla de 3 a 50 a los 20 meses de tratamiento. Paciente N° 3: la madre de la paciente N° 2, quien sin ninguna manifestación clínica y con densitometría ósea normal presentó hipofosfatemia que se normalizócon tratamiento con fosfato neutro. Paciente N° 4: el tío de la paciente N° 2, tuvo raquitismo hipofosfatémico de niño,y luego de los 5 años normalizó el fósforo sin tratamiento. Estudiado a los 29 años presentó fósforo normal y densitometría ósea normal. El análisis del ADN genómico de la paciente N° 3 mostró una mutación con sentido erróneo en el gen del factor de crecimiento fifroblástico 23 (sustitución de arginina por una glutamina en posición 179). Por lo tanto se llegó al diagnóstico de raquitismo/osteomalacia hipofosfatémico autosómico dominante.

Osteomalacia in females

This is a descriptive study conducted in Orthopaedic unit 1, Civil Hospital Karachi from January 2000 to December 2003. Two hundred female patients were included in this series of which 128 were unmarried, 52 were multipara having more than 5 children. 128 were students. Main presenting symptoms were waddling gait and generalized body pain. Serum calcium was low in 60 patients, serum alkaline phosphatase level was elevated in all cases, serum phosphorus was below normal in 108 patients, serum P.T.H. was elevated in 108 patients. Serum vitamin D2 level was decreased in 140 patients. Loosers zone was main radiological finding noted in 130 cases

Papel da histomorfometria óssea no diagnóstico diferencial da osteomalacia / Role of bone histomorphometry in the differential diagnosis of osteomalacia

A osteomalacia é uma doença ósteo-metabólica em que há deficiente mineralização do osso, e é definida pela histomorfometria óssea por apre-sentar espessura do rebordo osteóide (O.Th) maior do que 15µm, e inter-valo de tempo para mineralização (MLT) maior do que 100 dias. As princi-pais etiologias de osteomalacia são a deficiência de ação da vitamina D e a hipofosfatemia. Neste trabalho, 14 pacientes com osteomalacia diag-nosticados clínica e laboratorialmente foram divididos em dois grupos: 6 pacientes com deficiente ação de vitamina D e 8 hipofosfatêmicos. Todos os pacientes apresentaram ao exame histomorfométrico aumento do O.Th e do MLT compatível com o diagnóstico de osteomalacia. A superfície de reabsorção óssea estava aumentada no grupo com defi-ciência de ação da vitamina D. Em seis pacientes hipofosfatêmicos, a superfície de reabsorção óssea estava ausente, em um paciente dentro da normalidade mas em um paciente encontrava se aumentada. Con-clusão: a histomorfometria dinâmica óssea através da análise dos parâmetros de formação confirmam o diagnóstico de osteomalacia, enquanto que os parâmetros de reabsorção permitem uma orientação etiológica.

Proximal muscle weakness-beware of ricket/osteomalacia

Progressive weakness of the muscles of the limbs is one of usual reasons for attendence at neurology clinics throughout the world. This prospective study carried at Neurology Department KEMC, Lahore analyses the features of rickets / osteomalacia, presenting to us as proximal muscle weakness. The effect of treatment is also discussed