Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition.

In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.

Monthly intravenous alendronate treatment can maintain bone strength in osteogenesis imperfecta patients following cyclical pamidronate treatment.

Objectives Osteogenesis imperfecta (OI) is a skeletal dysplasia characterized by recurrent fractures due to congenital bone fragility. The only bisphosphonate approved for OI in Japan is pamidronate (PAM). To investigate whether monthly intravenous alendronate (ALN) infusions can maintain bone strength in OI children following cyclical PAM treatment. Methods A prospective and non-inferiority study was conducted. Eight school-age OI patients aged 8.5±2.0 years who were treated with cyclical PAM for 6.0±2.3 years were enrolled and switched to monthly intravenous ALN (0.030 mg/kg/month). Changes in L1-4 bone mineral density (BMD) Z-scores, fracture rates, and bone turnover markers for 12 months were analyzed. Results Average BMD Z-scores were -3.0±1.9, -2.9±2.0, and -2.2±2.0 in 12 months before enrollment, at enrollment, and after 12 months of ALN treatment, respectively. BMD Z-scores increased significantly during treatment with both PAM and ALN (p=0.012), and the effect of ALN was not inferior to that of PAM (p=0.67). There was no change in fracture rates (p=0.86) and bone turnover markers during the 12 months before and after enrollment. Additionally, ALN showed no remarkable side effects. Conclusions Our results suggest that monthly intravenous ALN can maintain bone strength after primary usage of cyclical PAM. We concluded that monthly intravenous ALN as a maintenance treatment following cyclical PAM administration can be an option for OI children.

Radiation therapy combined with bone-modifying agents ameliorates local control of osteolytic bone metastases in breast cancer.

Bone-modifying agents (BMAs) are frequently used for the treatment of bone metastases. Both BMA and radiation therapy (RT) are effective; however, there are few studies that have evaluated the efficacy of the combination treatment. We evaluated the effectiveness of RT + BMA in breast cancer-induced osteolytic bone metastasis as compared to BMA alone. A total of 43 lesions in 25 patients were evaluated. The median follow-up period was 18 (range, 2-90) months. None of the lesions was treated with chemotherapy or molecular targeted drugs during the follow-up period for evaluating the local response. Patients with complete or partial response were considered as responders, while those with stable or progressive disease were considered as non-responders. The rate of response with RT + BMA was significantly higher than that with BMA alone (P = 0.001). The cumulative incidence rate of response at 6 months was 54.4% in the RT + BMA group and 27.5% in the BMA alone group. The median time to response was 4 (range, 2-11) months in the RT + BMA group and 6 (range, 4-16) months in the BMA alone group. The overall survival rate in the responder group (83.1% at 1 year) was significantly higher than that in the non-responder group (37.5% at 1 year) (P = 0.029). In conclusion, RT combined with BMA was found to be more effective than BMA alone for the treatment of osteolytic bone metastasis, which thereby improves the prognosis.

Multifaceted approach to a rare clinical case of calciphylaxis in a renal transplant recipient.

Calcific uremic arteriolopathy (CUA) is a highly morbid condition usually found in ESRD patients that has rarely been reported after renal transplantation and renal function restoration. Furthermore, little is known about the optimal management of CUA in this setting. Herein, we report on the clinical case of AB, a 70-year-old woman who developed CUA after renal transplantation and renal function restoration. However, other risk factors for CUA such as diabetes and warfarin treatment, due to mechanical aortic valve implantation, were present. Thirty-eight months after renal transplantation she developed erythema and livedo reticularis in both legs and a gradually enlarging skin ulcer in the right leg. A skin biopsy of the ulcer showed features compatible with the CUA, such as sub-intimal calcification and luminal obstruction of the small dermal arterioles, tissue ischemia and signs of adipocytes degeneration. A multidisciplinary approach was adopted, including medical and non-medical treatments such as surgical debridement and vacuum-assisted closure therapy. Medical treatments included a five weeks course of once a week intravenous infusion of pamidronate and intravenous sodium thiosulfate (STS) at increasing doses. Four months after beginning the therapy with STS, a complete healing of the ulcer on the right leg and the disappearance of the livedo reticularis on the left leg was noted. In conclusion, although rare CUA may develop also in renal transplanted patients, a timely and combined therapeutic approach is essential for its resolutive treatment. Sodium thiosulfate therapy has proven to be effective and tolerated.

WNT1-associated osteogenesis imperfecta with atrophic frontal lobes and arachnoid cysts.

A rare form of osteogenesis imperfecta (OI) caused by Wingless-type MMTV integration site family 1 (WNT1) mutations combines central nervous system (CNS) anomalies with the characteristic increased susceptibility to fractures. We report an additional case where arachnoid cysts extend the phenotype, and that also confirms the association of intellectual disabilities with asymmetric cerebellar hypoplasia here. Interestingly, if the cerebellum is normal in this disorder, intelligence is as well, analogous to an association with similar delays in a subset of patients with sporadic unilateral cerebellar hypoplasia. Those cases typically appear to represent vascular disruptions, and we suggest that most brain anomalies in WNT1-associated OI have vascular origins related to a role for WNT1 in CNS angiogenesis. This unusual combination of benign cerebellar findings with effects on higher functions in these two situations raises the possibility that WNT1 is involved in the pathogenesis of the associated sporadic cases as well. Finally, our patient reacted poorly to pamidronate, which appears ineffective with this form of OI, so that a lack of improvement is an indication for molecular testing that includes WNT1.

Primary isolated hepatosplenic sarcoidosis mimicking malignancy and causing symptomatic hypercalcaemia.

This is a case of a 67-year-old woman, known to have multiple medical problems, mainly papillary thyroid cancer status post-total thyroidectomy and cervical neck dissection in addition to radioactive iodine currently in remission for 1 year, who presented to the hospital with severe weakness and fatigue. The initial workup showed significant hypercalcaemia and suppressed Parathyroid hormone (PTH). The patient was treated with hydration and pamidronate and her hypercalcaemia and symptoms improved. The differential was wide, however, a CT scan of the chest, abdomen and pelvis did show multiple liver and splenic nodular lesions; therefore, malignancy was the highest possible diagnosis. Biopsy of the splenic lesion confirmed the diagnosis of sarcoidosis. Therefore, the patient was diagnosed with primary isolated nodular hepatosplenic sarcoidosis mimicking malignancy and causing significant symptomatic hypercalcaemia.

A case of severe, irreversible hypocalcemia after one dose of pamidronate administered for hypercalcemia of malignancy.

This is a case report of a patient who developed severe, irreversible hypocalcemia after receiving one dose of pamidronate 90 mg for hypercalcemia of malignancy. Hypocalcemia is a known risk of bisphosphonate treatments, but the incidence of severe hypocalcemia is rare, and the risk factors are well established. However, in the treatment of hypercalcemia of malignancy, the treatment objective is to reduce the elevated serum calcium level, and the bisphosphonate is usually given as one time dose only. The potential for developing severe hypocalcemia may not be considered a significant concern in this setting compared to the setting of the treatment of bone metastasis, where the baseline serum calcium level is not elevated and the bisphosphonate is administered at a regular interval of every three to four weeks. Furthermore, there is unawareness of prevalence of vitamin D deficiency in cancer patients, especially in those with advanced cancer, which may lead to inadvertent, severe hypocalcemia from bisphosphonate treatment. The objective of this case report is to bring awareness to the risk of severe hypocalcemia in patients with hypercalcemia of malignancy and the high prevalence of unrecognized vitamin D deficiency in cancer patients.

Sodium thiosulfate and pamidronate for treatment of calciphylaxis: case report / Tiosulfato de sodio y pamidronato para el tratamiento de calcifilaxis: reporte de caso

Abstract Introduction: Calciphylaxis is an infrequent disease that almost exclusively affects patients with chronic kidney disease, although cases have been observed in patients without renal function impairment. The diagnosis is mainly made by clinical manifestations and subsequently confirmed by radiological and histological study. The optimal treatment is not known, although there is a consensus that a multifactorial approach is required. Clinical Case: A 68-year-old woman on hemodialysis for 2 years, who presented a painful nodular lesion in the left thigh, a skin biopsy was performed resulting in a diagnosis of calciphylaxis. Treatment and Outcome: Treatment was started with intravenous sodium thiosulfate. Pamidronate is added intravenously, three months later, due to an unfavorable evolution. After 6 months of treatment, improvement in nodular lesions and healing of the ulcerated lesion was observed to be generally well tolerated treatment. Conclusion: The combined treatment of sodium thiosulfate, pamidronate and calcitomimetics has been effectiveand safe for the treatment of calciphylaxis, inducing complete remission.

Resumen: Introducción: La calcifilaxis es una enfermedad infrecuente que afecta casi exclusivamente a pacientes con insuficiencia renal, aunque se han observado casos en pacientes sin deterioro de la función renal. El diagnóstico es clínico confirmándose con estudio radiológico e histológico. No se conoce con exactitud el tratamiento óptimo, aunque hay consenso en que se requiere un abordaje multifactorial. Caso Clínico: Mujer de 68 años en hemodiálisis desde hace 2 años, que presenta una lesión nodular dolorosa en muslo izquierdo, resultando un diagnostico compatible con calcifilaxis, tras biopsia cutánea. Tratamiento y resultado: Inicia tratamiento con tiosulfato de sodio vía venosa. Tres meses más tarde y ante la evolución desfavorable, se añade al tratamiento pamidronato vía intravenosa. Tras 6 meses de tratamiento se observa mejoría de las lesiones nodulares y cicatrización de la lesión ulcerada, habiéndose experimentado buena tolerancia. Conclusión: El tratamiento combinado de tiosulfato de sodio, pamidronato y calcimiméticos ha resultado efectivo y seguro para el tratamiento de la calcifilaxis, induciendo su remisión completa.

Distrofia ósea esclerosante mixta / Mixed-sclerosing-bone-dystrophy

El término "distrofia ósea esclerosante mixta" describe la combinación de las características radiológicas correspondientes a melorreostosis, osteopoiquilosis y osteopatía estriada, como entidades individuales, que ocurren en un mismo paciente. El objetivo de esta comunicación es presentar el caso clínico de una paciente con diagnóstico de distrofia ósea esclerosante mixta y, a partir de este caso, realizar una revisión sobre el tema. (AU)

The term "mixed-sclerosing-bone-dystrophy" describes the combination of the radiological characteristics corresponding to melorheostosis, osteopoikilosis and osteopathia striata, as individual conditions, ocurring in the same patient. The aim of this communication is to present the clinical case of a patient diagnosed with mixed-sclerosing-bone-dystrophy and, based on this case, to undertake a review of this condition. (AU)

Sodium thiosulfate and pamidronate for treatment of calciphylaxis: case report.

INTRODUCTION: Calciphylaxis is an infrequent disease that almost exclusively affects patients with chronic kidney disease, although cases have been observed in patients without renal function impairment. The diagnosis is mainly made by clinical manifestations and subsequently confirmed by radiological and histological study. The optimal treatment is not known, although there is a consensus that a multifactorial approach is required. CLINICAL CASE: A 68-year-old woman on hemodialysis for 2 years, who presented a painful nodular lesion in the left thigh, a skin biopsy was performed resulting in a diagnosis of calciphylaxis. TREATMENT AND OUTCOME: Treatment was started with intravenous sodium thiosulfate. Pamidronate is added intravenously, three months later, due to an unfavorable evolution. After 6 months of treatment, improvement in nodular lesions and healing of the ulcerated lesion was observed to be generally well tolerated treatment. CONCLUSION: The combined treatment of sodium thiosulfate, pamidronate and calcitomimetics has been effectiveand safe for the treatment of calciphylaxis, inducing complete remission.

INTRODUCCIÓN: La calcifilaxis es una enfermedad infrecuente que afecta casi exclusivamente a pacientes con insuficiencia renal, aunque se han observado casos en pacientes sin deterioro de la función renal. El diagnóstico es clínico confirmándose con estudio radiológico e histológico. No se conoce con exactitud el tratamiento óptimo, aunque hay consenso en que se requiere un abordaje multifactorial. CASO CLÍNICO: Mujer de 68 años en hemodiálisis desde hace 2 años, que presenta una lesión nodular dolorosa en muslo izquierdo, resultando un diagnostico compatible con calcifilaxis, tras biopsia cutánea. TRATAMIENTO Y RESULTADO: Inicia tratamiento con tiosulfato de sodio vía venosa. Tres meses más tarde y ante la evolución desfavorable, se añade al tratamiento pamidronato vía intravenosa. Tras 6 meses de tratamiento se observa mejoría de las lesiones nodulares y cicatrización de la lesión ulcerada, habiéndose experimentado buena tolerancia. CONCLUSIÓN: El tratamiento combinado de tiosulfato de sodio, pamidronato y calcimiméticos ha resultado efectivo y seguro para el tratamiento de la calcifilaxis, induciendo su remisión completa.

Análisis Histomorfométrico de la Asociación de Aceite de Oliva y Bisfosfonatos en la Remodelación Ósea Periimplantaria / Histomorphometric Analysis of the Association of Olive Oil and Bisphosphonates on Peri-Implant Bone Remodeling

RESUMEN: Los bisfosfonatos son potentes inhibidores de la resorción ósea. El aceite de oliva (O) presenta propiedades anti-inflamatorias y anti-oxidantes. Estudiar el efecto del tratamiento combinado de alendronato (AL) y pamidronato (PA) por vía subcutánea y de O vía oral sobre la regeneración tisular de cavidades óseas neoformadas.: 54 ratas macho de la línea Wistar, se dividieron en 6 grupos. Grupo control (C), recibieron solución salina vía subcutánea. Grupo (AL) recibió 0,5 mg de AL/Kg de peso corporal de por vía subcutánea. Grupo (PA) recibió de igual manera que el grupo anterior. Grupo (O) fue tratado con aceite de oliva con la dieta, 50 g/ Kg de comida. Grupo (ALO) recibió tratamiento combinado con AL y O. Grupo (PAO) recibió de igual tratamiento. Los sacrificios para la toma de muestras fueron a los 15, 30, 60 y 90 días. Para los estudios histopatológicos los cortes fueron teñidos con HE y observados con microscopía óptica. Los estudios estadísticos se realizaron a través del análisis de la variancia. A los quince días las áreas de los osteocitos del grupo PA se diferencian significativamente sólo respecto al grupo AL. En cuanto a la Densidad trabecular se observa un incremento de tejido óseo en todos los grupos. O mejora cualitativamente la estructura del hueso trabecular y cortical, preservando la mineralización, el tamaño y la estructura de los cristales minerales Esto sugiere que O representa una opción terapéutica prometedora para la prevención y tratamiento de las patologías óseas.

ABSTRACT: Bisphosphonates are potent inhibitors of bone resorption. Olive oil (O) has anti-inflammatory and anti-oxidant properties. To study the effect of combined treatment with alendronate (AL) and pamidronate (PA) subcutaneously or orally, and on tissue regeneration of newly formed bone cavities, we divided 54 male Wistar rats into 6 groups. Control group (C) received saline subcutaneously. Group (AL) received 0.5 mg of AL / kg body weight subcutaneously. Group (PA) received the same as the previous group. (O) was treated with olive oil diet, 50 g / kg of food. Group (ALO) received combined treatment with AL and O. Group (PAO) received the same treatment. The animals were euthanized for sampling at 15, 30, 60 and 90 days. For histopathology sections were stained with HE and observed these with light microscopy. Statistical studies were performed by analysis of variance. Fifteen days osteocytes areas of the PA group were significantly different only for the AL group. As the density increased trabecular bone tissue was observed in all groups. O qualitatively improved the structure of trabecular and cortical bone mineralization while preserving the size and structure of the mineral crystals. This suggests that O represents a promising therapeutic option for prevention and treatment of bone diseases.

Use of pamidronate for osteoporosis treatment in public health care in Brazil / Uso de pamidronato para o tratamento da osteoporose no sistema público de saúde no Brasil

Abstract Purpose: The use of bisphosphonates for osteoporosis is effective in reducing the risk of fractures. However, oral formulations are sometimes not well tolerated or are contraindicated. Due to its availability in Brazilian public health system, pamidronate is frequently prescribed for osteoporosis, despite the lack of studies demonstrating its anti-fracture efficacy and the absence of FDA or EMEA approval for this purpose. The aim of this study was to evaluate the bone mineral density (BMD) response to pamidronate in a group of women with osteoporosis in a tertiary care hospital. Patients and methods: The medical records of women with osteoporosis who received pamidronate for up to two years of treatment were reviewed. Patients were stratified at high or intermediate risk of fracture. Results: A total of 70 women were in treatment with pamidronate. Among them, 74% were at high risk of fracture. A significant gain in spine BMD after 24 months of treatment was observed (p = 0.012). There was no difference between the groups of high and not high risk of fracture. At the femur, no significant increase in BMD was present, though, a strong negative correlation with high PTH levels (r = −0.61; p = 0.003) was seen. In the multivariate analysis BMI at 12 months had impact in the response to the treatment. Conclusion The intravenous pamidronate in a group of postmenopausal women with predominant high risk of fracture promoted an isolated gain in the spine BMD, even though, clinical randomized trials are needed to confirm its anti-fracture efficacy.

Resumo Justificativa: O uso de bisfosfonatos para a osteoporose é eficaz na redução do risco de fraturas. No entanto, as formulações orais às vezes não são bem toleradas ou são contraindicadas. Em razão da sua disponibilidade no sistema público de saúde brasileiro, o pamidronato é frequentemente prescrito para a osteoporose, apesar da falta de estudos que demonstrem a sua eficácia antifratura e da ausência de aprovação da Food and Drug Administration (FDA) ou da European Medicine Agency (Emea) para essa finalidade. O objetivo deste estudo foi avaliar a resposta da densidade mineral óssea (DMO) ao pamidronato em um grupo de mulheres com osteoporose em um hospital terciário. Pacientes e métodos: Revisaram-se os prontuários médicos de mulheres com osteoporose que receberam pamidronato por até dois anos de tratamento. As pacientes foram estratificadas em risco alto ou intermediário de fratura. Resultados: Estavam em tratamento com pamidronato 70 mulheres. Entre elas, 74% tinham alto risco de fratura. Observou-se um ganho significativo na DMO da coluna vertebral após 24 meses de tratamento (p = 0,012). Não houve diferença entre os grupos de risco de fratura alto e não alto. No fêmur, não foi encontrado aumento significativo na massa óssea; contudo, observou-se uma forte correlação negativa com altos níveis de PTH (r = −0,61; p = 0,003). Na análise multivariada, o IMC aos 12 meses tinha impacto na resposta ao tratamento. Conclusão O pamidronato intravenoso em um grupo de mulheres na pós-menopausa predominantemente com alto risco de fratura promoveu um ganho isolado na DMO da coluna vertebral, embora sejam necessários ensaios clínicos randomizados para confirmar sua eficácia antifratura.

Crisis hipercalcémica causada por adenoma paratiroideo: reporte de un caso clínico / Hypercalcemic crisis due to parathyroid adenoma: report of a clinical case

La hipercalcemia es un trastorno común que representa aproximadamente el 0,6% de todas las admisiones médicas agudas. El hiperparatiroidismo primario (HPTP) y las neoplasias malignas son las dos causas más comunes de elevación de los niveles séricos de calcio; constituyen, en conjunto, alrededor del 90% de todos los casos. La presentación sintomática clásica de la hipercalcemia se observa con relativa poca frecuencia en el mundo desarrollado; la presentación más común es la detección asintomática en las pruebas bioquímicas. Sin embargo, en casos raros, el HPTP puede desarrollar hipercalcemia aguda, grave y sintomática, llamada crisis hipercalcémica (CH). Esta condición se asocia a alteraciones profundas en el estado mental y las funciones cardíaca, renal y gastrointestinal en presencia de concentraciones marcadamente elevadas de calcio sérico y paratohormona (PTH). Mientras que algunas elevaciones en el calcio sérico pueden ser bien toleradas, los síntomas de la CH son severos. Si el tratamiento se retrasa, la CH puede provocar la muerte. Describimos el caso de un paciente masculino que ingresa en la unidad de cuidados críticos por una CH secundaria a un HPTP por adenoma paratiroideo. (AU)

Hypercalcaemia is a most common disorder, accounting for approximately 0,6% of all acute medical admissions. Primary hyperparathyroidism (PHPT) and malignancy are the two most common causes of increased serum calcium levels, together accounting for about 90% of all cases. The classical symptomatic presentation of hypercalcaemia is seen relatively rarely in the developed world, the most common presentation being asymptomatic and detected following on biochemical testing. However, in rare cases HPTP can result in acute, severe and symptomatic hypercalcemia, called hypercalcemic crisis (HC). This condition is associated with profound disturbances in mental status, and cardiac, renal, and gastrointestinal function in the presence of markedly increased serum calcium and parathyroid hormone (PTH) concentrations. While some elevations in serum calcium can be well tolerated, symptoms of HC are severe. If treatment is delayed, HC can result in death. We describe herein a case of a male patient who was admitted to the intensive care unit as a consequence of HC resulting from elevated PTH, secondary to a parathyroid adenoma. We describe the case of a male patient who was admitted to the critical care unit for a HC mediated by PTH secondary to a parathyroid adenoma. (AU)