Alkaline Phosphatase ; metabolism ; Asian Continental Ancestry Group ; Bone Density Conservation Agents ; therapeutic use ; China ; Denosumab ; therapeutic use ; Diabetes Mellitus, Type 2 ; complications ; Female ; Humans ; Hyperlipidemias ; complications ; Hypertension ; complications ; Middle Aged ; Osteitis Deformans ; complications ; diagnostic imaging ; drug therapy ; metabolism ; Pelvic Bones ; diagnostic imaging ; Renal Insufficiency, Chronic ; complications ; Singapore ; Tibia ; diagnostic imaging ; Treatment Outcome

Paget's disease of bone (PDB) is a common metabolic bone disease that is characterized by aberrant focal bone remodeling, which is caused by excessive osteoclastic bone resorption followed by disorganized osteoblastic bone formation. Genetic factors are a critical determinant of PDB pathogenesis, and several susceptibility genes and loci have been reported, including SQSTM1, TNFSF11A, TNFRSF11B, VCP, OPTN, CSF1 and DCSTAMP. Herein, we report a case of Chinese familial PDB without mutations in known genes and identify a novel c.163G>C (p.Val55Leu) mutation in FKBP5 (encodes FK506-binding protein 51, FKBP51) associated with PDB using whole-exome sequencing. Mutant FKBP51 enhanced the Akt phosphorylation and kinase activity in cells. A study of osteoclast function using FKBP51V55L KI transgenic mice proved that osteoclast precursors from FKBP51V55L mice were hyperresponsive to RANKL, and osteoclasts derived from FKBP51V55L mice displayed more intensive bone resorbing activity than did FKBP51WT controls. The osteoclast-specific molecules tartrate-resistant acid phosphatase, osteoclast-associated receptor and transcription factor NFATC1 were increased in bone marrow-derived monocyte/macrophage cells (BMMs) from FKBP51V55L mice during osteoclast differentiation. However, c-fos expression showed no significant difference in the wild-type and mutant groups. Akt phosphorylation in FKBP51V55L BMMs was elevated in response to RANKL. In contrast, IκB degradation, ERK phosphorylation and LC3II expression showed no difference in wild-type and mutant BMMs. Micro-CT analysis revealed an intensive trabecular bone resorption pattern in FKBP51V55L mice, and suspicious osteolytic bone lesions were noted in three-dimensional reconstruction of distal femurs from mutant mice. These results demonstrate that the mutant FKBP51V55L promotes osteoclastogenesis and function, which could subsequently participate in PDB development.
Acid Phosphatase ; Animals ; Asian Continental Ancestry Group ; Bone Diseases, Metabolic ; Bone Remodeling ; Bone Resorption ; Femur ; Humans ; Mice ; Mice, Transgenic ; Osteitis Deformans* ; Osteoblasts ; Osteoclasts ; Osteogenesis ; Phosphorylation ; Phosphotransferases ; Tacrolimus Binding Proteins ; Transcription Factors

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.
Alkaline Phosphatase ; Arthritis ; Asian Continental Ancestry Group ; Congenital Abnormalities ; Diagnosis ; Diphosphonates* ; Female ; Fractures, Compression ; Humans ; Lower Extremity ; Mandible ; Medical Records ; Osteitis Deformans ; Osteoarthritis ; Osteomyelitis ; Pelvis ; Retrospective Studies ; Skeleton ; Skull ; Spine

Humans ; Male ; Middle Aged ; Osteitis Deformans

Paget's disease of bone is characterized by highly localized areas of increased bone resorption accompanied by exuberant, but aberrant new bone formation with the primary cellular abnormality in osteoclasts. Paget's disease provides an important paradigm for understanding the molecular mechanisms regulating both osteoclast formation and osteoclast-induced osteoblast activity. Both genetic and environmental etiologies have been implicated in Paget's disease, but their relative contributions are just beginning to be defined. To date, the only gene with mutations in the coding region linked to Paget's disease is sequestosome-1 (SQSTM1), which encodes the p62 protein, and these mutations lead to elevated cytokine activation of NF-B in osteoclasts but do not induce a "pagetic osteoclast" phenotype. Further, genetic mutations linked to Paget's appear insufficient to cause Paget's disease and additional susceptibility loci or environmental factors may be required. Among the environmental factors suggested to induce Paget's disease, chronic measles (MV) infection has been the most studied. Expression of the measles virus nucleocapsid gene (MVNP) in osteoclasts induces pagetic-like osteoclasts and bone lesions in mice. Further, mice expressing both MVNP in osteoclasts and germline mutant p62 develop dramatic pagetic bone lesions that were strikingly similar to those seen in patients with Paget's disease. Thus, interactions between environmental and genetic factors appear important to the development of Paget's disease. In this article we review the mechanisms responsible for the effects of mutant p62 gene expression and MVNP on osteoclast and osteoblast activity, and how they may contribute to the development of Paget's disease of bone.
Animals ; Bone Resorption ; Chronic Disease ; Clinical Coding ; Gene Expression ; Humans ; Measles ; Measles virus ; Mice ; Nucleocapsid ; Osteitis Deformans* ; Osteoblasts ; Osteoclasts ; Osteogenesis ; Phenotype

Paget's disease (PD) of bone is characterized by increase of bone resorption by atypical osteoclasts, followed by rapid new bone formation resulting in a disorganized mosaic bone. Although the pathophysiology is not fully understood, bisphosphonate, which is a potent anti-resorptive agent for treatment of osteoporosis, have been the most effective agents available for the treatment of PD. We report a case of PD of bone in a 49-year-old woman patient, who was treated with intravenous zoledronate.
Bone Density Conservation Agents ; Bone Resorption ; Diphosphonates ; Female ; Humans ; Middle Aged ; Osteitis Deformans ; Osteoclasts ; Osteogenesis ; Osteoporosis

Paget's disease of bone (PDB) is a disorder featuring high-level bone turnover associated with the presence of disorganized and immature bone tissue with excessive levels of fibrosis. The risk of deformity is very high. The etiology of PDB is not well understood, but includes both genetic and environmental factors among which is bone trauma. Hypercalcemia can occur as a complication of PDB in patients who are immobilized and dehydrated. However, to date, no case of severe hypercalcemia with metastatic calcifications in multiple organs has been reported in any PDB patient. The drugs of choice for treatment of PDB are bisphosphonates. These drugs effectively suppress bone turnover. Patients with extensive PDB may require higher doses of bisphosphonates, and acquired resistance to a particular bisphosphonate may be overcome by use an alternative drug. Here, we report a case of suspicion of PDB. The patient presented with hypercalcemia and metastatic calcifications and his condition improved dramatically after treatment with zoledronic acid.
Bone and Bones ; Congenital Abnormalities ; Diphosphonates ; Fibrosis ; Humans ; Hypercalcemia* ; Imidazoles ; Osteitis Deformans ; Wounds and Injuries

Paget's disease of bone (PDB) is a disorder featuring high-level bone turnover associated with the presence of disorganized and immature bone tissue with excessive levels of fibrosis. The risk of deformity is very high. The etiology of PDB is not well understood, but includes both genetic and environmental factors among which is bone trauma. Hypercalcemia can occur as a complication of PDB in patients who are immobilized and dehydrated. However, to date, no case of severe hypercalcemia with metastatic calcifications in multiple organs has been reported in any PDB patient. The drugs of choice for treatment of PDB are bisphosphonates. These drugs effectively suppress bone turnover. Patients with extensive PDB may require higher doses of bisphosphonates, and acquired resistance to a particular bisphosphonate may be overcome by use an alternative drug. Here, we report a case of suspicion of PDB. The patient presented with hypercalcemia and metastatic calcifications and his condition improved dramatically after treatment with zoledronic acid.
Bone and Bones ; Congenital Abnormalities ; Diphosphonates ; Fibrosis ; Humans ; Hypercalcemia* ; Imidazoles ; Osteitis Deformans ; Wounds and Injuries

Bisphosphonates are the most widely used medications for treating high bone turnover osteoporosis, Paget's disease of bone, multiple myeloma and metastatic carcinomas, etc. However, a destructive complication of bisphosphonate-related osteonecrosis of the jaw (BRONJ) can occur. The treatments of BRONJ are challenging and the currently recommended managements for BRONJ are still controversial. Our case demonstrated that teriparatide can be a treatment of choice for intractable BRONJ, which had not been cured for 2 years even with the proper surgical treatment and withdrawal of bisphosphonates.
Bisphosphonate-Associated Osteonecrosis of the Jaw ; Diphosphonates ; Multiple Myeloma ; Osteitis Deformans ; Osteoporosis ; Teriparatide

OBJECTIVETo study the clinical manifestations, radiologic findings, pathologic diagnosis and differential diagnosis of primary osteosarcoma in elderly patients.

METHODSTwelve cases of primary osteosarcoma occurring in patients older than 60 years were encountered during the period from 1985 to 2010. The clinical manifestations, radiologic features and pathologic findings were studied and the follow-up data were analyzed.

RESULTSThe sites of involvement included long bones (number = 7), ilium (number = 1), craniofacial bones (number = 2) and soft tissue (number = 2). Radiologic examination showed a mixture of osteosclerotic and osteolytic lesions in 10 patients, soft tissue lesions with high-density areas in 2 patients and soft tissue lesions with periosteal reaction in 8 patients. Histologically, most cases showed features of conventional osteosarcoma. There were 2 cases of malignant fibrous histiocytoma-like osteosarcoma, 2 cases of chondroblastic osteosarcoma and 1 case of well-differentiated intraosseous osteosarcoma. Immunohistochemical study played little role in pathologic diagnosis. Ten patients had undergone amputation, including one patient who had received adjuvant chemotherapy beforehand. Nine patients had follow-up information available. Three of them died of lung metastasis and 1 died of cardiovascular disease.

CONCLUSIONSPrimary osteosarcoma rarely occurs in elderly patients and can easily be missed. Correlation with clinical, radiologic and histologic features is important for arriving at a correct diagnosis.

12E7 Antigen ; Aged ; Antigens, CD ; metabolism ; Bone Neoplasms ; diagnostic imaging ; metabolism ; pathology ; surgery ; Cell Adhesion Molecules ; metabolism ; Chondrosarcoma ; pathology ; Diagnosis, Differential ; Female ; Femoral Neoplasms ; diagnostic imaging ; metabolism ; pathology ; surgery ; Follow-Up Studies ; Humans ; Ilium ; Lung Neoplasms ; secondary ; Lymphoma ; pathology ; Male ; Middle Aged ; Osteitis Deformans ; pathology ; Osteosarcoma ; diagnostic imaging ; metabolism ; pathology ; surgery ; Radiography ; Soft Tissue Neoplasms ; diagnostic imaging ; metabolism ; pathology ; surgery ; Vimentin ; metabolism