gastrins and Bone-Diseases--Metabolic

Recent researches have failed to uncover a clear explanation for proton pump inhibitors' bone-loss effects. In light of pantoprazole's effects on gastrin secretion, the goal of this study was to see if it caused bone loss through gastrin secretion.. Forty male rats were divided into control, octreotide (Oct), pantoprazole (Pan), and pantoprazole plus octreotide (Pan+Oct) groups. Serum calcium, phosphorous, alkaline phosphatase, parathyroid hormone, and gastrin were measured before and three months after the treatment, and bone densitometry was examined. The rats' femoral bones were examined stereologically at the end of the investigation.. The Pan group had considerably greater levels of serum alkaline phosphatase, parathyroid hormone (PTH), and gastrin, but this was prevented in the presence of Oct, a gastrin secretion inhibitor. All parameters of femoral bone densitometry in the Pan group were significantly lower than the control after treatment which was considerably inhibited in the presence of Oct. Furthermore, when compared to the control and Oct groups, the rats in the Pan group had a lower trabecular volume, femur bone weight, and volume, as well lower number of osteocytes. The amount of osteoclasts, on the other hand, was much higher in the Pan group than in the other groups.. Overall findings revealed that pantoprazole caused bone loss, which could be prevented by adding octreotide. Because these detrimental effects were not detected in rats given both Oct and Pan, it was suggested that the effect of Pan on bone was produced by a hypergastrinemic condition.

Topics: Alkaline Phosphatase; Animals; Bone Diseases, Metabolic; Gastrins; Male; Octreotide; Pantoprazole; Parathyroid Hormone; Rats

Multiple studies have reported an association between proton pump inhibitor (PPI) use and fracture. However, the causality of this association is questionable, as there is not a well defined mechanism of action, nor is there evidence of an effect on PPIs on areal bone mineral density (aBMD) using dual photon X-ray absorptiometry (DXA). It is possible that PPIs may induce changes in bone structure which would predispose to fracture in the absence of changes in aBMD. We used three-dimensional quantitative computed tomography (3D-QCT) imaging to determine if long-term PPI use was associated with structural changes in bone independent of aBMD.. We enrolled a sample of long-term (≥5 years) PPI users matched to a similar cohort of persons with no PPI use in the previous 5 years. All subjects underwent assessment of aBMD using DXA, volumetric BMD using 3D-QCT, as well as markers of bone metabolism. Measures of bone strength, including buckling ratio and section modulus, were also compared between the two samples.. 104 subjects were enrolled (52 PPI users and 52 PPI non-users). There were no differences detected in standard BMD, volumetric BMD, markers of bone metabolism or measures of bone strength between the two groups.. Long-term PPI use is not associated with any changes in bone mineral density or bone strength that would predispose to an increased risk of fracture. These findings provide further evidence that the association between PPI use and fracture is not causal.

Topics: Absorptiometry, Photon; Aged; Alkaline Phosphatase; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Calcium; Cohort Studies; Collagen Type I; Female; Femur Neck; Gastrins; Humans; Imaging, Three-Dimensional; Linear Models; Magnesium; Male; Manitoba; Middle Aged; Multivariate Analysis; Osteocalcin; Osteoporosis; Parathyroid Hormone; Peptides; Phosphates; Proton Pump Inhibitors; Time Factors; Tomography, X-Ray Computed; Vitamin D

Both ovariectomy (Ovx) and gastrectomy (Gx) induce osteopaenia in rats and humans. While the effect of Ovx has been ascribed to oestrogen deficiency, the underlying mechanism behind Gx is poorly understood. Alendronate, oestrogen and parathyroid hormone (PTH) are known to prevent the osteopaenia induced by Ovx in rats. The purpose of the present study was to determine whether alendronate, oestrogen or PTH could also prevent Gx-evoked osteopaenia. Rats were Ovx-, Gx-, or were sham-operated (Sham) and were then treated with alendronate (50 micro g/kg/day), oestrogen (10 micro g/kg/day) or PTH(1-84) (75 micro g/kg/day) for eight weeks. At sacrifice, serum PTH was unaffected by surgery (Ovx, 64+/-8 pg/ml; Gx, 75+/-13 pg/ml; Sham, 58+/-11 pg/ml). The bone mineral density (BMD) of the fifth lumbar vertebra (L5) was analysed. Ovx and Gx reduced the BMD (ash weight/Volume) of the L5 by 15+/-4% and 22+/-3% respectively. Trabecular BMD and the cortical bone mineral content (BMC) of the femur were assessed using peripheral computed tomography. Both Ovx and Gx markedly reduced trabecular BMD in the metaphyseal area of the distal femur (Ovx, -37+/-7%; Gx, -49+/-7%). The cortical BMC of the femur was only slightly reduced. Alendronate prevented trabecular bone loss after both Ovx and Gx, while oestrogen and PTH prevented trabecular bone loss after Ovx but not after Gx. In conclusion, the bisphosphonate alendronate prevented both Ovx- and Gx-induced trabecular bone loss. In contrast, PTH and oestrogen prevented Ovx-induced but not Gx-induced trabecular bone loss, suggesting that the mechanism behind the trabecular bone loss in Ovx rats differs from that in Gx rats. The results support the notion that the mechanism of action for the bone-sparing effect of these drugs differs. The ability of alendronate, and probably also other bisphosphonates, to prevent Gx-evoked osteopaenia in the rat might be of potential clinical interest when dealing with post-Gx osteopaenia in humans.

Topics: Alendronate; Analysis of Variance; Animals; Biomarkers; Bone Density; Bone Diseases, Metabolic; Estradiol; Female; Gastrectomy; Gastrins; Humans; Models, Animal; Osteocalcin; Osteoporosis, Postmenopausal; Ovariectomy; Parathyroid Hormone; Random Allocation; Rats; Rats, Sprague-Dawley; Recombinant Proteins; Tomography, X-Ray Computed

The acid-producing part of the rat stomach (fundus) is rich in endocrine cells, i.e. ECL cells and A-like cells. The ECL cells operate under gastrin control and manufacture histamine, the chromogranin-derived peptide pancreastatin and an unidentified peptide hormone. The A-like cells produce ghrelin, a newly discovered growth hormone-releasing hormone. Surgical removal of the entire glandular stomach (gastrectomy, Gx) or the acid-producing part (fundectomy, Fx) causes osteopenia, which is striking in the calvaria. We speculate that the osteopenia develops after surgical removal of the fundus, because the fundus hosts agents that preserve bone. This study examines how much of the fundus is needed to preserve normal skull bone.. Increasing portions of the fundus were resected surgically. The serum gastrin, ghrelin and pancreastatin concentrations were measured. The rats were killed after 10 weeks and the calvariae were subjected to transillumination analysis and quantitative histomorphometry.. Fx elevated serum gastrin in proportion to the amount of fundus resected, i.e., the more fundus that was resected, the higher the serum gastrin concentration. Serum ghrelin and pancreastatin concentrations were reduced proportionally to the amount of fundus resected. In rats subjected to 90% or 100% Fx, the calvariae displayed the anticipated pattern of bone loss. No bone loss was seen when 70% or less of the fundus was resected.. The results of the present study indicate that 10%-30% of the fundic mucosa is needed to preserve bone. The Gx/Fx-evoked osteopenia may be explained by hormonal deficiency caused by surgically eliminating or diminishing one of the endocrine cell populations in the fundic mucosa.

Topics: Animals; Bone Diseases, Metabolic; Chromogranin A; Gastrectomy; Gastric Fundus; Gastric Mucosa; Gastrins; Ghrelin; Growth Hormone; Male; Pancreatic Hormones; Parietal Cells, Gastric; Peptide Hormones; Peptides; Rats; Rats, Sprague-Dawley; Skull

The stomach is rich in endocrine cells, including those producing ghrelin, which is thought to play a role in the control of body growth. Omeprazole treatment is associated with hypergastrinaemia, resulting in growth of the oxyntic mucosa in general and the enterochromaffin-like (ECL) cells in particular. In the present study, we examined the effects of long-term omeprazole treatment on young male rats with respect to body growth and stomach.. Male rats (24 days old) were treated with omeprazole (400 micromol/kg/day) or vehicle for 77 days. The body weight was recorded twice per week. At sacrifice, dual-energy X-ray absorptiometry (DXA) was used to assess total bone area, bone mineral content (BMC), bone mineral density (BMD) and body composition (fat and lean body mass). The lengths of the spine and the femur were recorded. The plasma concentrations of gastrin and histamine were determined by radioimmunoassays. The endocrine cells of the stomach were examined by immunocytochemistry.. The body weight gain was suppressed by omeprazole treatment. The bone area, BMC and BMD were reduced, while the lengths of the spine and the femur and the body composition were unchanged. Omeprazole-induced hypergastrinaemia was associated with enlargement of the oxyntic area and with hyperplasia of ECL cells but not of A-like cells and D cells. In contrast, the enterchromaffin (EC) cell density in the antrum was reduced.. Omeprazole treatment of young male rats reduces body weight and bone mass gain. The densities of ECL cells in the oxyntic mucosa was increased and of the EC cells in the antral mucosa reduced.

Topics: Age Factors; Animals; Anti-Ulcer Agents; Bone Diseases, Metabolic; Calcification, Physiologic; Enterochromaffin-like Cells; Enzyme Inhibitors; Gastrins; Ghrelin; Male; Omeprazole; Peptide Hormones; Peptides; Rats; Rats, Sprague-Dawley; Stomach; Weight Gain

In man and experimental animals, partial and total gastrectomy and gastric vagotomies disturb extracellular mineral homeostasis, osteopenia being among the late outcomes. The sequence of events is complex and insufficiently understood. We report on the long-term effects of gastric fundectomy (FX; FX-1, n=11; sham-operated controls, n=14) sparing gastric vagal fibers at the lesser curvature in the rat, a procedure eliminating gastric acid production but preserving gastric reservoir function. After FX-1 there was a marked increase of gastrinemia [FX-1: 590 (SE 95); controls: 82 (5) pg-equiv/ml; P<0.001], serum 1,25-dihydroxyvitamin D [FX-1: 188 (17); controls: 86 (6) pg/ml; P<0.001], phosphaturia [FX-1: 32 (2); controls 23 (2) micromol/h; P<0.001] due to increased fractional phosphate clearance, elevated urinary net acid [FX-1: 21 (2); controls: 16 (1) micromol/h; P=0.03], and low urinary pH. The urinary excretion of hydroxyproline was increased [FX-1: 137 (15); controls: 99 (8) micromol/h; P=0.01], and crosslinks were also high. These changes were associated with a significant decrease of bone ash calcium, magnesium, and phosphorus. Bone histomorphometry revealed signs of high bone turnover. No signs of hyperparathyroidism were detectable. Acute stimulation of serum gastrin by gastric acid abolishing omeprazole failed to provoke extra-osseous changes, as seen in the long-term after fundectomy. It was concluded that the described type of fundectomy disturbs gastrinemia, acid-base and phosphorus metabolism, thereby initiating osteopenia. This animal model may be suitable for research into post-gastrectomy bone disease.

Topics: Acid-Base Equilibrium; Animals; Autonomic Nervous System; Bone Density; Bone Diseases, Metabolic; Gastrectomy; Gastric Acid; Gastric Fundus; Gastrins; Humans; Male; Neurotransmitter Agents; Omeprazole; Phosphates; Rats; Rats, Sprague-Dawley; Vagus Nerve; Vitamin D

Gastrectomy leads to osteopenia in the rat. The present study describes the effects of gastrectomy on bone morphology. Rats were subjected to gastrectomy or sham operation. Four weeks after the operation the rats were killed and both tibiae were removed. Bone morphology of the left tibia was analyzed with quantitative computer tomography, the right tibia with histomorphometry. Bone length, bone mineral content, as well as indices of bone resorption and formation were measured in the metaphysis and the diaphysis. Gastrectomy had no effect on longitudinal bone growth but it led to a low bone mineral content at both sites. Bone resorption was increased by gastrectomy, as shown by an increase in the medullary cavity area in the diaphysis. Gastrectomy also reduced bone formation, as shown by a decreased periosteal circumference and a decrease in the mean periosteal bone apposition in the diaphysis. In conclusion, gastrectomy-evoked osteopenia reflects impaired formation and increased resorption of bone.

Topics: Animals; Body Weight; Bone and Bones; Bone Density; Bone Diseases, Metabolic; Bone Regeneration; Bone Resorption; Calcification, Physiologic; Calcitonin; Calcium; Diaphyses; Gastrectomy; Gastrins; Male; Osteogenesis; Parathyroid Hormone; Periosteum; Rats; Rats, Sprague-Dawley; Tibia; Weight Gain

Highly selective vagotomy (HSV) or sham operation was performed in male rats. Fifteen weeks later bone mineralization, fractional intestinal absorption and balance, urinary excretion, and serum levels of calcium, magnesium and phosphorus, together with serum gastrin, parathyroid hormone, calcitonin, vitamin D metabolites, osteocalcin, isoenzymes of alkaline phosphatase, and the urinary excretion of cyclic AMP and hydroxyproline were assessed. HSV induced chronic hypergastrinemia and enhanced the weight of the fundus, antrum, and pancreas. Body weight, food intake, intestinal absorption, mineral balance, and bone mineralization were unaffected by HSV, whereas serum parathyroid hormone levels and urinary hydroxyproline excretion were increased. It is concluded that in the rat 1) HSV has a trophic effect on gastric and extragastric tissues; 2) gastric acid production is not a major determinant of intestinal calcium absorption; and 3) normal bone mass in the presence of signs of hyperparathyroidism indicates an intrinsic capacity of HSV to interfere with calcium metabolism, probably via hypergastrinemia, gastrin being an element of the gastro-parathyroid axis. Our present findings underscore the fact that osteopenia after HSV in man may be a rare finding, but it cannot be ruled out that bone disease found after partial or total gastrectomy may be due in part to concomitant vagotomy.

Topics: Animals; Body Weight; Bone and Bones; Bone Diseases, Metabolic; Eating; Gastrins; Humans; Male; Minerals; Rats; Rats, Sprague-Dawley; Vagotomy, Proximal Gastric

Bone mineral metabolism was studied in 20 male patients, between 8 and 18 years, after surgical treatment for peptic ulcer (ten Billroth 1 and ten Billroth 2 gastrectomies) and in 16 sex- and aged-matched healthy controls. The bone mineral content was statistically reduced only in the Billroth 2 group. Serum 25(OH)D was lower in all patients, but fractional calcium absorption was similar to the control value. This may be due to increases in 1,25(OH)2D and parathyroid activity (particularly in Billroth 2). Serum osteocalcin levels and hydroxyproline excretion were higher than in the controls. A positive linear correlation emerged not only between serum 1,25(OH)2D and PTH levels but also between each of these and serum osteocalcin and urine hydroxyproline. Both PTH and calcitriol were inversely correlated with the bone mineral mass in Billroth 2, confirming a trend observed in Billroth 1. Although calcitonin values were normal, basal gastrin levels were severely impaired in all patients. In response to a mixed meal, increases in gastrin and calcitonin were significantly lower than in the controls. The calcitonin response to intravenous calcium and pentagastrin infusion was not significantly different to the controls. The percentage increase in gastrin and calcitonin responses to oral calcium correlated positively with the reduction in bone mineral content only in the Billroth 2 group, suggesting a reduction in calcitonin release may contribute to gastric surgery osteopenia in these patients.

Topics: Adolescent; Bone Density; Bone Diseases, Metabolic; Calcitonin; Calcitriol; Child; Gastrectomy; Gastrins; Humans; Male; Parathyroid Hormone; Peptic Ulcer