RESUMEN
Intravenous bisphosphonate (BP) therapy has become the standard of care for the treatment of cancers that metastasize to bone. BPs are associated with osteonecrosis of alveolar bones, a condition known as osteonecrosis of the jaw (ONJ). The incidence or pathogenesis of ONJ is largely unknown. The lesions are characterized by areas of exposed necrotic bone that do not heal after 8 weeks in the absence of radiation to the head and neck. ONJ lesions have been recalcitrant to conventional therapies. Lesions in cancer patients treated with BPs develop in association with periodontal disease, tooth extraction and/or in association with increased mechanical force due to partial/complete dentures. We hypothesized that intravenous BPs in cancer patients impair normal bone remodeling, thereby increasing the incidence of osteonecrotic lesions and that these lesions can be detected using cone beam computerized tomography (CBCT). From CBCTs taken at the University of Missouri at Kansas City School of Dentistry, 26 subjects had a cancer diagnosis and were on BP therapy. From these 26 subjects, 18 presented visible, exposed necrotic bone. We observed both sclerotic and radiolucent lesions. Lesions could be detected and measured in reconstructed images where most were found to expand to large areas of the bone. We were able to identify necrotic bodies or 'involucrums' within the ONJ lesions, suggesting that this could be the mechanism for the formation of a clinically visible sequestrum. We propose that CBCT can potentially identify and follow the progression of both pre- and postclinical lesions in ONJ patients, allowing better diagnosis and assessment of disease status.
Asunto(s)
Tomografía Computarizada de Haz Cónico , Difosfonatos/efectos adversos , Enfermedades Maxilomandibulares/inducido químicamente , Enfermedades Maxilomandibulares/diagnóstico , Modelos Biológicos , Osteonecrosis/inducido químicamente , Osteonecrosis/diagnóstico , Humanos , Enfermedades Maxilomandibulares/diagnóstico por imagen , Osteonecrosis/diagnóstico por imagen , Implantación de PrótesisRESUMEN
The mechanisms whereby bone mineralizes are unclear. To study this process, we used a cell line, MLO-A5, which has highly elevated expression of markers of the late osteoblast such as alkaline phosphatase, bone sialoprotein, parathyroid hormone type 1 receptor, and osteocalcin and will mineralize in sheets, not nodules. In culture, markers of osteocytes and dendricity increase with time, features of differentiation from a late osteoblast to an early osteocyte. Mineral formation was examined using transmission electron microscopy, scanning electron microscopy with energy-dispersive X-ray analysis, and atomic force microscopy. At 3-4 days of culture, spheres of approximately 20-50 nm containing calcium and phosphorus were observed budding from and associated with developing cellular projections. By 5-6 days, these calcified spheres were associated with collagen fibrils, where over time they continued to enlarge and to engulf the collagen network. Coalescence of these mineralized spheres and collagen-mediated mineralization were responsible for the mineralization of the matrix. Similar calcified spheres were observed in cultured fetal rat calvarial cells and in murine lamellar bone. We propose that osteoid-osteocytes generate spherical structures that calcify during the budding process and are fully mineralized on their developing cellular processes. As the cellular process narrows in diameter, these mineralized structures become associated with and initiate collagen-mediated mineralization.