RESUMO
PURPOSE: Osteonecrosis of the jaw (ONJ) has been reported in patients with a history of aminobisphosphonate use. This study was conducted in order to define ONJ clinically and radiographically and gain insights into its pathophysiology. EXPERIMENTAL DESIGN: Eleven multiple myeloma (MM) patients with ONJ were included in the study. Patients underwent clinical, biochemical, radiographic, and molecular profiling. Ten MM patients on aminobisphosphonates without ONJ and five healthy volunteers were used as controls for biochemical and molecular studies. RESULTS: MM patients with ONJ were treated with either pamidronate (n = 3), zoledronate (n = 4), or both agents sequentially (n = 4) for a mean of 38.7 months. Radiographic studies showed bone sclerosis and fragmentation on plain films and computerized tomography. Quantitative regional analysis of NaF-PET and FDG-PET scans confirmed an increased standardized uptake value (SUVmax) in areas of ONJ. The target to background ratio of SUVmax was significantly greater for NaF-PET compared with FDG-PET scan. Biochemical bone marker data and transcriptional profiling studies showed that genes and proteins involved in osteoblast and osteoclast signaling cascades were significantly down-regulated in patients with ONJ. CONCLUSIONS: ONJ was associated with a mean duration of 38.7 months of aminobisphosphonate exposure. Radiographic and functional imaging confirmed sites of clinically established ONJ. Gene and protein studies are consistent with altered bone remodeling, evidenced by suppression of both bone resorption and formation.
Assuntos
Conservadores da Densidade Óssea/efeitos adversos , Difosfonatos/efeitos adversos , Doenças Maxilomandibulares/induzido quimicamente , Mieloma Múltiplo/complicações , Osteonecrose/induzido quimicamente , Idoso , Idoso de 80 Anos ou mais , Remodelação Óssea , Feminino , Fluordesoxiglucose F18 , Perfilação da Expressão Gênica , Humanos , Doenças Maxilomandibulares/diagnóstico por imagem , Doenças Maxilomandibulares/metabolismo , Masculino , Pessoa de Meia-Idade , Osteogênese , Osteonecrose/diagnóstico por imagem , Osteonecrose/metabolismo , Tomografia por Emissão de PósitronsRESUMO
PURPOSE: The increasing incidence of osteonecrosis of the jaw and its possible association with high cumulative doses of bisphosphonate led us to study the effects of high doses of zoledronic acid (ZA) on bone remodeling. EXPERIMENTAL DESIGN: Five-week-old C57BL6 mice were treated with saline or ZA weekly for 3 weeks at increasing doses (0.05-1 mg/Kg). Effects of ZA on bone remodeling were studied using standard assays. RESULTS: We observed an increase in bone mineral density and content in treated animals at doses of 0.05 mg/Kg, which was not further enhanced at higher doses of ZA. Trabecular bone volume at the proximal tibia and the distal femur assessed by histomorphometry and microCT, respectively, increased significantly in ZA-treated groups. There was however no difference between 0.5 and 1 mg/kg, suggesting a ceiling effect for ZA. ZA led to decreased numbers of osteoclasts and osteoblasts per bone perimeter that paralleled a significant reduction of serum levels of TRAC5b and osteocalcin in vivo. Effects on osteoblasts were confirmed in in vitro assays. Mechanical testing of the femur showed increased brittleness in ZA-treated mice. CONCLUSIONS: High doses of ZA inhibit both osteoclast and osteoblasts function and bone remodeling in vivo interfering with bone mechanical properties. No dose response was noted beyond 0.5 mg/kg suggesting that lower doses of ZA may be adequate in inhibiting bone resorption. Our data may help inform future studies of ZA use with respect to alternate and lower doses in the treatment of patients with cancer bone disease.
Assuntos
Remodelação Óssea/efeitos dos fármacos , Osso e Ossos/efeitos dos fármacos , Osso e Ossos/fisiologia , Linhagem da Célula/efeitos dos fármacos , Difosfonatos/administração & dosagem , Difosfonatos/farmacologia , Imidazóis/administração & dosagem , Imidazóis/farmacologia , Osteoblastos/efeitos dos fármacos , Adulto , Animais , Densidade Óssea/efeitos dos fármacos , Conservadores da Densidade Óssea/administração & dosagem , Conservadores da Densidade Óssea/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Osteoblastos/citologia , Osteoblastos/fisiologia , Células Tumorais Cultivadas , Ácido ZoledrônicoRESUMO
Osteolytic bone disease in multiple myeloma (MM) is associated with upregulation of osteoclast (OCL) activity and constitutive inhibition of osteoblast function. The extracellular signal-regulated kinase 1/2 (ERK1/2) pathway mediates OCL differentiation and maturation. We hypothesized that inhibition of ERK1/2 could prevent OCL differentiation and downregulate OCL function. It was found that AZD6244, a mitogen-activated or extracellular signal-regulated protein kinase (MEK) inhibitor, blocked OCL differentiation and formation in a dose-dependent manner, evidenced by decreased alphaVbeta3-integrin expression and tartrate-resistant acid phosphatase positive (TRAP+) cells. Functional dentine disc cultures showed inhibition of OCL-induced bone resorption by AZD6244. Major MM growth and survival factors produced by OCLs including B-cell activation factor (BAFF) and a proliferation-inducing ligand (APRIL), as well as macrophage inflammatory protein (MIP-1alpha), which mediates OCL differentiation and MM, were also significantly inhibited by AZD6244. In addition to ERK inhibition, NFATc1 (nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1) and c-fos were both downregulated, suggesting that AZD6244 targets a later stage of OCL differentiation. These results indicate that AZD6244 inhibits OCL differentiation, formation and bone resorption, thereby abrogating paracrine MM cell survival in the bone marrow microenvironment. The present study therefore provides a preclinical rationale for the evaluation of AZD6244 as a potential new therapy for patients with MM.