Long-term effectiveness of zoledronic acid in patients with Paget's disease of bone - a retrospective cohort study.

PURPOSE: The aims of the current study were to describe clinical and biochemical features of patients with Paget disease of bone (PDB) followed at our medical center, and to examine the long-term effectiveness of zoledronate. METHODS: Retrospective cohort study included consecutive patients≥18 years with a diagnosis of PDB, followed in the Rabin Medical Center (RMC) Institute of Endocrinology from 1973 to 2023. The cohort comprised two groups: patients treated/not treated with zoledronic acid (ZOL/NZOL). The primary outcome was the percentage of patients who achieved a biochemical therapeutic response. RESULTS: Overall, 101 patients with PDB were included, 68 in the ZOL group and 33 in the NZOL group. The mean age was 65.2 ± 10.0 years, and 47% were female. Notably, 77% exhibited monostotic involvement, and only 3% had experienced fractures attributed to PDB. Mean ALP level at diagnosis was 160 ± 70.6 U/L. The median follow-up duration was 17 years since PDB diagnosis, comparable between the groups. Primary outcome was more prevalent in the ZOL compared to the NZOL group [42 patients (88%) VS 11 patients (52%) respectively, P = 0.004]. At the end of follow-up, mean ALP levels in the NZOL group were significantly higher than the levels in the ZOL group irrespective of the number of infusions received. CONCLUSION: The majority of patients with PDB experience a mild disease course, marked by monostotic involvement and a low prevalence of fractures. Zoledronic acid effectively manages PDB, providing sustained biochemical response. The necessity for multiple zoledronic acid injections remains questionable, often implemented due to osteoporosis.

Paget disease of bone in a southeastern Veteran population.

BACKGROUND: Paget disease of bone (PDB) is a disorder of accelerated bone remodeling resulting in bone overgrowth and impaired integrity that traditionally is described to be more frequent in individuals of European descent. Based on clinical observation, we hypothesized that among the US Southeastern Veteran population, the disease is more common among African American patients. MATERIALS AND METHODS: We conducted a cross-sectional study using the Veterans Affairs' Clinical Data Warehouse (CDW) and review of electronic medical records (EMR). Using the CDW, we identified patients from the Birmingham VA Medical Center (BVAMC) with an International Classification of Diseases code for PDB between January 2000 and December 2020. We extracted their self-reported race from the CDW and determined the proportion of African American patients, which we compared to the proportion of White patients. As a secondary goal, we extracted relevant clinical characteristics from the EMR. The statistical analysis was done using Stata/SE 14.2 for Mac. RESULTS: We identified 285 individuals from the BVAMC with PDB between January 2000 and December 2020. The proportion of African American patients was significantly higher than White patients (0.51 vs. 0.4, p = 0.0036). African American patients presented at a younger age than their peers (mean[standard deviation] age at diagnosis: 64.6[11.6] vs. 70.1[10.7] years, p = 0.0009) but did not have higher alkaline phosphatase levels, higher proportion of polyostotic disease, or of symptoms and complications. CONCLUSIONS: In the BVAMC population, PDB is more common among African American patients than White patients. Our findings and other publications hint at the existence of a cluster of PDB among the African American population in the US Southeast.

Optineurin regulates osteoblast function in an age-dependent fashion in a mouse model of Paget's disease of bone.

Paget's disease of bone (PDB) is a degenerative disorder affecting the skull and bones. Hyperactive osteoclasts (OCs) initiate bone degradation in the early stage, followed by increased bone formation by osteoblasts (OBs) in trabecular bones during the advanced stage. This OB-OC uncoupling results in bone deformations and irregular trabecular bone patterns. Current mouse models poorly replicate the advanced-stage characteristics of PDB. Optineurin (Gene: OPTN in humans, Optn in mice, protein: OPTN) has been implicated in PDB by genetic analyses. We identified PDB-like cortical lesions associated with OC hyperactivation in an Optn knockout (Optn-/-) mouse model. However, the effects of OPTN dysfunction on OBs and trabecular bone in advanced PDB remain unclear. In this study, we used the Optn-/- mouse model to investigate trabecular bone abnormalities and OB activity in PDB. Micro-computed tomography analysis revealed severe pagetic alterations in craniofacial bones and femurs of aged Optn-/- mice, resembling clinical manifestations of PDB. Altered OB activity was observed in aged Optn-/- mice, implicating compensatory OB response in trabecular bone anomalies. To elucidate the role of OC-OB interactions in PDB, we conducted in vitro experiments using OC conditioned media (CM) to examine the effects on OB osteogenic potential. We found OC CM restored compromised osteogenic induction of Optn-/- bone marrow stromal cells (BMSCs) from young mice, suggesting OCs maintain OB activity through secreted factors. Strikingly, OC CM from aged Optn-/- mice significantly enhanced osteogenic capability of Optn-/- BMSCs, providing evidence for increased OB activity in advanced stages of PDB. We further identified TGF-ß/BMP signaling pathway in mediating the effects of OC CM on OBs. Our findings provide insights into Optn's role in trabecular bone abnormalities and OB activity in PDB. This enhances understanding of PDB pathogenesis and may contribute to potential therapeutic strategies for PDB and related skeletal disorders.

A rare case of asymptomatic Paget's disease of the skull in a 60-year-old Asian female.

Background and Aim: Paget's disease of the bone refers to a chronic cumulative disorder characterized by enhanced osteoclastic function followed by a secondary surge in osteoblastic activity. The condition can manifest as a polyostotic or monostotic bone disease with most patients having an asymptomatic presentation, although some may complain of pain localized to the affected bone while others express symptoms of nerve compression. A pagetic bone is predisposed to develop pathological fractures, bony deformities, and a rare yet detrimental transformation into osteosarcoma. Detection is often accidental when performing radiographic tests for other indications or when elevated blood levels of alkaline phosphatase (ALP) are detected. Treatment with third-generation bisphosphonates is helpful in preventing further bone resorption and, additionally, reduces bony pains that are believed to be caused by excessive metabolic activity. Here, we present a case of a middle-aged asymptomatic female with elevated serum ALP levels up to 1537 IU/L (reference range 40-150 U/L) during her pre-operative evaluation for elective cholecystectomy.99m Tc-methylene diphosphonate bone scintigraphy revealed diffuse uptake in the skull and, hence, was diagnosed as a case of isolated Paget's disease of the skull. Relevance for Patients: The rarity of this disease in Southeast-Asians, its uncontrived detection, and the isolated skull involvement, imparts high clinical relevance on this case. Early detection and management of this disease can help prevent the development of life-threatening complications in affected patients, hence decreasing the morbidity.

Spinal Paget's disease with bilevel cord compression and ischemic non-compressive myelopathy treated with zoledronic acid.

Cord compression and ischemic non-compressive myelopathy are a complication of spinal Paget's disease (SPD). SPD usually touches a single spine level. We report an unusual case with bilevel spinal cord compression and dysfunction which was medically treated due to resolution of the vascular steal syndrome.

The potential for over diagnosis of Paget's disease of bone using macroscopic analysis.

OBJECTIVE: This study explores the validity of Paget's disease of bone (PDB) reported in unpublished skeletal reports, based on macroscopic analysis alone. MATERIALS: The high prevalence of 'suspected' Paget's disease (10.7%) in an early modern sample from St John's the Evangelist Church in Redhill, Surrey is reassessed. METHODS: Signs of PDB were examined in 53 well-preserved adults aged 35 + years using macroscopic, radiographic and histological techniques. RESULTS: Macroscopic features of PDB were identified in 8 individuals (15%), with 5 individuals later rejected using radiography. Two individuals showed classic radiographic features of PDB, with a third presenting possible features in radiography (5.7%). These three cases were confirmed by histological analysis. CONCLUSIONS: PDB should not be suggested as a single diagnosis in cases of bone hypertrophy without confirmation using radiography. SIGNIFICANCE: The growing popularity of 'big data' projects and limited collections access means that unpublished cases of PDB are often included in large scale analyses, impacting our understanding of the evolution of this disease. Using macroscopic analysis alone leads to overdiagnosis. Histological analysis is unnecessary when radiographic features are present, but provides a useful diagnostic step in long bones in advanced cases of PBD. LIMITATIONS: The radiographic sample in this study was limited to three individuals. SUGGESTIONS FOR FURTHER RESEARCH: The conclusion that radiography alone can be used to identify PDB in archaeological cases merits further research on a larger number of cases.

Stress Fracture of the Femoral Shaft in Paget's Disease of Bone: A Case Report.

Paget's disease of bone (PDB) is a progressive bone disorder characterized by increased osteoclast-mediated bone resorption and abnormal bone formation. Incomplete atypical femoral fracture, appearing radiographically as a stress fracture at the lateral aspect of the femur, is an uncommon low-trauma fracture frequently seen in association with long-term bisphosphonate therapy. We describe the case of a 61-year-old female patient with PDB who developed a stress fracture at the lateral femoral cortex after 5 doses of intravenous bisphosphonate. The conservative treatment plan included discontinuation of bisphosphonate, a continuation of calcium and vitamin D supplementation, and limited weight-bearing for 3 months. The patient's pain level gradually improved after switching to the new treatment plan. At the latest follow-up, approximately 5 years after the initiation of conservative treatment, the patient remained pain-free, and her PDB was well-controlled. However, the fracture line was still visible on the most recent radiograph. Although it remains unclear whether a stress fracture at the lateral femoral cortex occurred due to bisphosphonate therapy or PDB, this case highlights the importance of careful evaluation of any lesion that appears in PDB patients receiving bisphosphonate therapy.

Enfermedad de Paget de hueso esporádica. Serie de casos y revisión de la literatura / Sporadic Paget's disease of the bone. Case series and literature review

RESUMEN La enfermedad de Paget ósea es una enfermedad metabólica del hueso de etiología no esclarecida, que se caracteriza por una fase de resorción aumentada seguida por una fase de osteoformación aberrante. Es frecuente en Europa, Norteamérica, Nueva Zelanda y Australia, pero infrecuente en Asia, Medio Oriente y África. En población colombiana hay reportes de casos. Generalmente cursa asintomática y se diagnostica incidentalmente por hallazgos radiográficos o fosfatasa alcalina elevada. El uso de bifosfonatos favorece el control del recambio óseo y permite prevenir complicaciones como las fracturas. Se presenta una serie de casos en Colombia y una revisión de la literatura.

A B S T R A C T Paget's disease of the bone is a metabolic bone disease of unknown origin, and is characterised by an increased phase of resorption, followed by an aberrant osteoformation phase. It is common in Europe, North America, New Zealand, and Australia, but infrequent in Asia, the Middle East, Africa, and in the Colombian population there are case reports. It is usually asymptomatic and is diagnosed incidentally by radiographic findings or an elevated alkaline phosphatase. The use of bisphosphonates favours the control of bone turnover and prevents complications such as fractures. A series of cases in Colombia is presented, along with a review of the literature.

Paget's Disease of Bone Affecting Peripheral Limb: Difficulties in Diagnosis: A Case Report.

In terms of management of Paget's disease of bone (PDB), early diagnosis and proper management achieving remission is essential with lifelong specialist follow-up. We present the case of a 40-year-old woman with PDB affecting mainly the distal extremities (ankle and wrist). The patient visited our hospital in 2012 with heel pain. Plain radiography revealed osteoporosis, and a bone scan revealed hot uptake. Initial laboratory investigations showed normal serum calcium, 25-hydroxy-vitamin D, and parathyroid hormone levels; however, osteocalcin, C-terminal telopeptide of type I collagen, and bone alkaline phosphatase levels were elevated. A bone mineral density scan showed T- and Z-scores of -2.5 and -2.7, respectively, and bisphosphonate treatment was initiated. Biopsy performed on the calcaneal lateral wall revealed inconclusive findings. Follow-up biopsy on the left distal radius was performed 7 years later to investigate wrist pain, and this examination led to a final diagnosis as PDB. We suggest inconclusive biopsy result during the early phase of PDB and highly recommend follow-up evaluation in osteoporosis with atypical behavior.

Complex Femoral Reconstruction Following Pathologic Subtrochanteric Femur Fracture Secondary to Paget's Disease of the Bone: A Case Report with Long-Term Follow-up.

INTRODUCTION: Paget's disease (PD) is the most common metabolic bone disorder after osteoporosis. Clinically, it can result in pain, bony deformity, pathologic fractures, and, in the late stage, progression to malignancy. At a pathophysiological level, PD manifests as an imbalance between the homeostasis of bone destruction and formation. Bones most often involved with this disease process include the pelvis, femur, tibia, vertebra, and skull. The goals of orthopedic intervention in PD are two-fold: Prevention of pathologic fracture with internal stabilization and reconstruction following fracture, which is often complicated by poor bone quality and advanced deformity. In this case report, authors detail a patient with PD who presented with a pathologic left subtrochanteric femur fracture requiring a novel complex femoral reconstruction with a 29-year follow-up period. To the best of our knowledge, no such report exists, particularly with this degree of long-term follow-up. CASE REPORT: A 70-year-old Caucasian man with PD presented with an atypical subtrochanteric femur fracture after a ground level fall. Due to his significant femoral deformity and osteopenia, proximal femoral resection followed by composite femoral allograft reconstruction with total hip arthroplasty was performed. Long-term durability of this novel reconstruction method as well as longitudinal clinical and radiographic outcomes is described. CONCLUSION: Complex pathologic fractures in patients with PD can be effectively treated with composite femoral allograft reconstruction and total hip arthroplasty with good long-term radiographic and clinical outcomes. Broadly, it is important to note the unique healing pattern seen in PD bone and to consider the implications it may have when planning surgical intervention.

Paget's Disease of Bone Affecting Peripheral Limb: Difficulties in Diagnosis: A Case Report

In terms of management of Paget's disease of bone (PDB), early diagnosis and proper management achieving remission is essential with lifelong specialist follow-up. We present the case of a 40-year-old woman with PDB affecting mainly the distal extremities (ankle and wrist). The patient visited our hospital in 2012 with heel pain. Plain radiography revealed osteoporosis, and a bone scan revealed hot uptake. Initial laboratory investigations showed normal serum calcium, 25-hydroxy-vitamin D, and parathyroid hormone levels; however, osteocalcin, C-terminal telopeptide of type I collagen, and bone alkaline phosphatase levels were elevated. A bone mineral density scan showed T- and Z-scores of −2.5 and −2.7, respectively, and bisphosphonate treatment was initiated. Biopsy performed on the calcaneal lateral wall revealed inconclusive findings. Follow-up biopsy on the left distal radius was performed 7 years later to investigate wrist pain, and this examination led to a final diagnosis as PDB. We suggest inconclusive biopsy result during the early phase of PDB and highly recommend follow-up evaluation in osteoporosis with atypical behavior.

DIAGNOSIS AND MANAGEMENT OF PAGET'S DISEASE OF BONE - SERIES OF 8 CASES.

Paget's disease of bone is a chronic condition characterized by focal abnormalities of absorption and formation of bone, and it may lead to anatomical deformities, pain, fractures, and malignant transformation. It is common in the UK, Australia, New Zealand, and North America and has a strong hereditary component, affecting first- to third-degree relatives. The etiology remains unclear and treatment is based on control of the disease with bisphosphonates, with the aim of relieving symptoms and correcting laboratory abnormalities. Surgical treatment may also be necessary to correct deformities or treat pathological fractures. This study evaluated the management and course of 8 patients with Paget's disease of bone, followed in the Orthopedic Clinic of this hospital. Among these patients, 1 had concomitant advanced prostate carcinoma, highlighting the association between Paget's disease and secondary bone diseases that can affect the differential diagnosis. Level of evidence IV, Study type: Case Series.

A doença de Paget Óssea é uma afecção crônica, caracterizada por distúrbio focal da absorção e formação ósseas, podendo levar a deformidades anatômicas, dor, fraturas e malignização das lesões. É frequente no Reino Unido, Austrália, Nova Zelândia e América do Norte. Mantém forte relação de incidência com parentes de primeiro a terceiro graus. Sua etiologia ainda permanece incerta e o tratamento se baseia no controle da doença, com uso de bisfosfonados, visando melhora dos sintomas e das alterações laboratoriais. O tratamento cirúrgico também pode ser necessário, para correção de deformidades ou para tratamento de fraturas. Este estudo compilou oito pacientes em acompanhamento pela doença de Paget Óssea, no Ambulatório de Ortopedia deste hospital, acerca do tratamento realizado e como evoluíram. Dentre os pacientes acompanhados, houve um caso de carcinoma de próstata concomitante ao Paget, chamando atenção para outras patologias ósseas que são diagnósticos diferenciais ou coexistem com a doença. Nível de evidência IV, Tipo de Estudo: Série de Casos.

Diagnosis and management of paget's disease of bone - series of 8 cases / Diagnóstico e manejo da doença de paget óssea - série de 8 casos

ABSTRACT Paget's disease of bone is a chronic condition characterized by focal abnormalities of absorption and formation of bone, and it may lead to anatomical deformities, pain, fractures, and malignant transformation. It is common in the UK, Australia, New Zealand, and North America and has a strong hereditary component, affecting first- to third-degree relatives. The etiology remains unclear and treatment is based on control of the disease with bisphosphonates, with the aim of relieving symptoms and correcting laboratory abnormalities. Surgical treatment may also be necessary to correct deformities or treat pathological fractures. This study evaluated the management and course of 8 patients with Paget's disease of bone, followed in the Orthopedic Clinic of this hospital. Among these patients, 1 had concomitant advanced prostate carcinoma, highlighting the association between Paget's disease and secondary bone diseases that can affect the differential diagnosis. Level of evidence IV, Study type: Case Series.

RESUMO A doença de Paget Óssea é uma afecção crônica, caracterizada por distúrbio focal da absorção e formação ósseas, podendo levar a deformidades anatômicas, dor, fraturas e malignização das lesões. É frequente no Reino Unido, Austrália, Nova Zelândia e América do Norte. Mantém forte relação de incidência com parentes de primeiro a terceiro graus. Sua etiologia ainda permanece incerta e o tratamento se baseia no controle da doença, com uso de bisfosfonados, visando melhora dos sintomas e das alterações laboratoriais. O tratamento cirúrgico também pode ser necessário, para correção de deformidades ou para tratamento de fraturas. Este estudo compilou oito pacientes em acompanhamento pela doença de Paget Óssea, no Ambulatório de Ortopedia deste hospital, acerca do tratamento realizado e como evoluíram. Dentre os pacientes acompanhados, houve um caso de carcinoma de próstata concomitante ao Paget, chamando atenção para outras patologias ósseas que são diagnósticos diferenciais ou coexistem com a doença. Nível de evidência IV, Tipo de Estudo: Série de Casos.

A microscopic evaluation of Paget's disease of bone from a Byzantine monastic crypt in Jordan.

Paget's disease of bone (PDB) is a metabolic bone disease that has been present in human populations for over 2000 years, with the earliest cases reported in Western Europe. Now present globally, PDB is one of the most common metabolic bone diseases in modern populations. This study details possible PDB of an adult male (MNR-EN Skull 3) with abnormally thickened cranial bones (17 mm). The skull was recovered from commingled skeletal remains excavated from the Robebus crypt at the Byzantine monastery of Mount Nebo, Jordan (c. late 4-7th C). Micro-CT imaging and histological sections of the bone samples revealed an abnormal pattern of bone remodeling, with atypical osteon formation, convoluted and enlarged trabeculae, and an overall pattern of highly vascularized bone. Polarized microscopy produced a mix of woven bone and lamellar bone, the mosaic pattern of atypical bone remodeling indicative of PDB. Coupled with the dense, thickened nature of the vault bones, these data suggest that the individual had PDB. To our knowledge, this represents the earliest evidence of PDB in the Middle East supported by micro-analysis, and adds to the emerging paleopathological literature involving commingled skeletal remains and the potential for identifying unique disease processes.

Paget's Disease of Bone: Diagnosis and Treatment.

Paget's disease of bone is a common bone disorder characterized by disorganized bone remodeling. The most likely etiology is a slow paramyxoviral infection in genetically susceptible individuals; however, the exact cause is unknown. Enhanced bone resorption due to an increased activity of osteoclasts recruits numerous osteoblasts to resorption sites, with large quantities of new bone matrix produced as a result. The accelerated bone resorption and formation are not as closely coupled as in a healthy bone; a disorganized bone tissue is formed. Many patients are asymptomatic; rising serum alkaline phosphatase or incidental finding of characteristic radiographic lesions are often the only diagnostic clues. Common clinical manifestations include bone pain, bowing of long bones, enlarged skull, and hearing loss. An elevated serum alkaline phosphatase level correlates with the disease activity. The diagnosis is confirmed by characteristic radiographic findings and by nuclear scintigraphy of the bone (the most sensitive test). Bisphosphonates, such as zoledronic acid, pamidronate, alendronate, and risedronate, are the mainstay of treatment. Patients who do not tolerate bisphosphonates can be treated with calcitonin.

Paget's Disease: Skeletal Manifestations and Effect of Bisphosphonates.

BACKGROUND: Paget's disease of bone leads to change in the shape and size of the bone and results in reduced bone strength, leading to the complications of deformity, arthritis, and fracture. Due to unknown reasons, Paget's disease is rare in Asian descendants. We report the cases of Paget's disease who visited our institute for 15 years and reviewed the literatures. METHODS: We retrospectively reviewed the medical records and radiograms of 8 patients (6 female and 2 male) who were diagnosed as Paget's disease of bone. Diagnosis was confirmed by typical radiological feature in the involved skeletons and/or pathologic findings. RESULTS: Pelvis, skull and spine were three most frequently involved bones. All involved bones in our cases showed changes in shape and trabecular pattern which resulted in bowing of lower extremity, secondary osteoarthritis, compression fracture of spine and enlargement of skull. Mean follow time was 4.71 years and all patient were treated bisphosphonate (BP). Use of BP controlled the level of serum alkaline phosphatase level effectively. CONCLUSIONS: We have reviewed eight patients who were previously diagnosed as Paget's disease of bone in our institute. We could identify typical radiologic and clinical findings such as bowing deformity of long bone, secondary osteoarthritis, compression fracture and osteomyelitis of mandible that deteriorated the quality of their living.

Beethoven's autopsy revisited: A pathologist sounds a final note.

This review of the original autopsy report of Beethoven's remains indicates Paget's disease within the skull, which was dense and twice normal thickness, with dilated vessels at the petrous bone. The facial nerves were enlarged and the eighth nerves atrophied despite their sharing a common meatus at the internal auditory canal. Nephrolithiasis and pyelonephritis with cortical and perinephric abscesses were also reported. The hypercalcaemia was probably caused by hyperparathyroidism, which may be associated with Paget's disease, and both may have played a role in his psychiatric symptoms as well as in his abdominal pain and gastrointestinal complaints. Since Paget's disease may also be associated with gout, some of the joint pains could be attributable to this as well. Hypovitaminosis A from chronic pancreatitis is suggested as a cause of painful eyes and either quinine abuse or severe hypercalcaemia as a cause of arrhythmias. Beethoven died of terminal cirrhosis with chronic pancreatitis, most likely related to chronic excessive intake of alcohol. Thus, Paget's disease, complicated by hyperparathyroidism, gout, and attempts to find relief of symptoms through the use of alcohol, quinine, and possibly salicylates can explain virtually all of Beethoven's medical problems, some of which appear to have influenced his musical compositions.

Vertigo as the first manifestation of paget's disease: a case report.

Paget's disease of bone is characterized by the dysfunction of the bone architecture due to the extreme increase of the osteoclast and osteoblast activity which results in the production of pathological bone. The particular disease afflicts any skeleton bone. Its sources have not been specified yet. There is evidence for the existence of strong genetic background as well as the effect of environmental factors. The neurological complications are relatively rare and are related to the central and peripheral nervous system (headache, ataxia, vertigo, loss of hearing, smell etc.). In our case, we present a patient with vertigo as the first manifestation of Paget's disease.