cholecystokinin and Osteoporosis

Proton-pump inhibitors, such as omeprazole, are widely used in the prevention and treatment of gastroesophageal diseases. However, an association between proton-pump inhibitors and the increased risk of bone fractures has been observed, especially in patients treated for extended periods. Conversely, 2-oxoglutarate, a precursor of hydroxyproline, the most abundant amino acid in bone collagen, counteracts the bone loss. The aim of the present study was to elucidate the influence of omeprazole on bone and investigate whether dietary 2-oxoglutarate supplementation could prevent the effects of omeprazole.. Eighteen male Sprague-Dawley rats were used. Rats received omeprazole in the diet and 2-oxoglutarate in the drinking water. Body and organ weights and serum concentrations of cholecystokinin and gastrin were measured. The femurs, tibias, and calvarias were collected. Histomorphometric analysis of bone and cartilage tissues was conducted. Bone densitometric and peripheral quantitative computed tomographic analyses of the femur and tibia were performed.. Omeprazole decreased the femur and tibia weights, the mechanical properties of the femur, the volumetric bone density and content, the trabecular and cortical bone mineral content, the total, trabecular, and cortical bone areas, the mean cortical thickness, and the periosteal circumference of the femur. Omeprazole had a minor effect on the examined bone morphology and exerted negligible effects on the cartilage. 2-Oxoglutarate lowered the gastrin concentration.. Omeprazole treatment exerts its effects mostly on bone mineralization and cancellous bone, adversely affecting bone properties. This adverse effect of omeprazole was not markedly abolished by 2-oxoglutaric acid, which acted as an anti-hypergastrinemic agent.

Topics: Animals; Anti-Ulcer Agents; Biomechanical Phenomena; Bone and Bones; Bone Density; Calcification, Physiologic; Cartilage; Cholecystokinin; Diet; Femur; Gastrins; Ketoglutaric Acids; Male; Omeprazole; Organ Size; Osteoporosis; Rats; Rats, Sprague-Dawley; Tibia

Critical to the discovery and development of drugs and vaccines is the rational selection of biochemical, immunologic or molecular targets. To understand the rationale for target selection, we review strengths and weaknesses of the four main approaches: whole animal disease models; molecular targeting; epidemiology/observation studies, and genomics. After classifying diseases into those with a relatively stable pathophysiology (e.g., hypertension and gout) versus those with an unstable pathophysiology (e.g., AIDS and influenza) to aid in understanding target selection, we provide examples of successful and unsuccessful selection of drug and vaccine targets, focusing on the molecular and epidemiological/observational approaches. We discuss the reasons that molecular targeting has led to successful control of many diseases, whereas the epidemiological/observational approach has had a checkered history. We also assess the potential power of the genomic approach, specifically the curative versus controlling/preventive strategies. With combined genetic and molecular approaches and judicious use of whole animal models and properly performed epidemiology/observation studies to select the appropriate targets, the future for controlling, preventing and even curing many diseases is very bright indeed.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Bone Density Conservation Agents; Cholecystokinin; Denosumab; Diphosphonates; Drug Design; Drug Evaluation, Preclinical; Epidemiologic Studies; Estrogen Replacement Therapy; Genomics; Humans; Osteoporosis; RANK Ligand