ABSTRACT
Osteoporosis is a common health problem. The endocannabinoid pathway has been implicated as an important regulator of bone turnover. Rimonabant is a potent cannabinoid receptor1 (CB1) receptor antagonist with wide therapeutic use as an antiobesity drug that has been withdrawn due to side effects in the form of depression and suicidal attacks. This study investigated whether glucocorticoid induced bone loss is linked to CB1 signaling and whether modulation of CB1 function affects the deleterious effects of glucocorticoid treatment on bone remodeling in rats. Sixty four rats were divided into two main groups: group 1 (G1) consisted of 12-14 month old rats and group 2 (G2) consisted of 3-4 month old rats. Each main group subdivided into four subgroups as follows: (NC1) and (NC2), the negative control groups, (MP1) and (MP2), received methylprednisolone (glucocorticoid), (RIM1) and (RIM2), received rimonabant, (MP + RIM1) and (MP + RIM2) received methylprednisolone with rimonabant. There was a significant decrease in bone mineral density (BMD) and bone mineral content (BMC) of the tibia bones together with a decrease in osteoprotegrin (OPG) expression but with a significant increase in receptor activator of nuclear factor kappa B ligand (RANKL) expression in osteoporotic rats. These parameters were reversed with co-administration of rimonabant with methylprednisolone in young rats, though it increased the severity of osteoporosis in older rats. Image analysis technique revealed that there was a significant improvement in cortical bone thickness (CBT) and mean trabecular bone density (TBD) in young group only after rimonabant either alone or with glucocorticoid. CB1 receptors play age related different roles in bone turnover. So, CB1 antagonist can be used to prevent corticosteroid induced osteoporosis in young age but should be avoided in old age.
Subject(s)
Cannabinoid Receptor Antagonists/pharmacology , Glucocorticoids/adverse effects , Methylprednisolone/adverse effects , Osteoporosis , Piperidines/pharmacology , Pyrazoles/pharmacology , Receptor, Cannabinoid, CB1/antagonists & inhibitors , Age Factors , Aging/metabolism , Alkaline Phosphatase/blood , Animals , Bone Density/drug effects , Bone Remodeling/drug effects , Bone Remodeling/physiology , Calcium/blood , Gene Expression Regulation/drug effects , Male , Osteocalcin/blood , Osteoporosis/blood , Osteoporosis/chemically induced , Osteoporosis/metabolism , Osteoporosis/pathology , Osteoprotegerin/blood , Osteoprotegerin/genetics , RANK Ligand/blood , RANK Ligand/genetics , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptor, Cannabinoid, CB1/metabolism , Rimonabant , Tibia/drug effects , Tibia/metabolism , Tibia/pathologyABSTRACT
BACKGROUND: Medullary carcinomas of the breast account for fewer than 7% of all invasive breast cancers. Some investigators include medullary carcinomas in the favourable histologic subtype, despite its aggressive histologic appearance. However, others fail to confirm its favourable prognosis. METHODS: This was a retrospective analysis of sixty-one (61) cases of breast cancer cases diagnosed with Medullary Carcinoma, presenting to the Kuwait Cancer Control Center between 1995 and 2005. RESULTS: Median survival time was 122 months and the seven-year disease free survival was 82%. Overall survival rate was not assessed as no cases died during the study period. No cases were metastatic from the start and only eight cases developed metastases, local recurrence or contralateral breast primary. 68.8% of the cases were Stage I or IIA (i.e. no lymph node affection). CONCLUSION: There is no overt favourable prognosis of medullary carcinoma when compared to invasive ductal carcinoma. Prognosis is more related to stage than histologic subtyping. The majority of cases were negative estrogen and progesterone receptor status and node negative.