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Background: Both gastrectomy (GX) and ovariectomy (OVX) induce osteopenia in man and experimental animals. The present study addresses the question--can alendronate, estrogen or parathyroid hormone (PTH) be used to treat established GX- or OVX -evoked osteopenia?, Methods: Rats were GX-, OVX- or SHAM-operated 8 weeks before starting the treatment with drugs. Each group was then treated for 8 weeks with 50 microg/kg/day alendronate, 10 microg/kg/day estrogen or 75 microg/kg/day PTH(1-84); n = 8 rats/group. Peripheral Quantitative Computed Tomography (pQCT) was used to measure trabecular bone mineral density (BMD) and various cortical bone parameters., Results: At killing, 16 weeks after surgery, GX and OVX rats had a greatly reduced trabecular BMD in the metaphysis of the distal femur (GX -44% and OVX -55%). Alendronate increased the trabecular BMD by 44% in GX rats and by 64% in OVX rats, while PTH increased it by 51% and 115%, respectively. However, estrogen increased the trabecular BMD in GX rats (35%), but not in OVX rats (15%, not significant). Cortical bone parameters were adversely (but moderately) affected by GX, but not by OVX or by treatment with the three drugs., Interpretation: Alendronate, estrogen and PTH restored the trabecular bone loss in rats with an established GX-evoked osteopenia. In contrast, alendronate and PTH, but not estrogen, restored the trabecular bone loss after OVX. Hence, the mechanism underlying GX-evoked bone loss differs from that underlying OVX-evoked bone loss. The ability of alendronate, estrogen and PTH to reverse the GX-evoked osteopenia in the rat may be of clinical interest when dealing with bone loss in humans after GX.

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.

Background: 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., Methods: 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., Results: 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., Conclusions: 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.

Background: Surgical removal of the stomach (gastrectomy, Gx) induces osteopenia. In this study we compared the osteopenic effect of Gx with that induced by calcium (Ca) deficiency., Methods: Young male rats were subjected to Gx and/or low Ca diet (-Ca). A group of Gx rats received standard diet + oral Ca supplementation (+Ca). The rats were killed at various times after the operation/start of treatment (longest time 12 weeks). After 8 weeks on low Ca diet, the blood Ca2+ concentration was lowered slightly in both Sham-operated and Gx rats. The calvariae were subjected to transillumination analysis and quantitative histomorphometry. Also the tibiae were subjected to histomorphometry., Results: Transillumination of the calvariae revealed extensive bone loss in the rats that had been subjected to Gx and/or low Ca diet. Gx + Ca induced the same bone loss as Gx alone. These observations were later confirmed in quantitative terms by histomorphometry (Sham-Ca 56%, Gx 35%, Gx + Ca 32%, Gx - Ca 58% less bone area than in Sham). The osteopenia induced by Gx + low Ca diet seetned more rapid in onset than that induced by Gx or low Ca diet alone. Tibiae from Gx rats and rats given a low Ca diet displayed a reduced trabecular bone volume (Sham-Ca 27% remaining, Gx 36%, Gx + Ca 44%, Gx - Ca 17%) and reduced trabecular number (Sham-Ca 44% remaining, Gx 41%, Gx + Ca 56%, Gx - Ca 33%). The trabecular thickness was reduced in the Gx rats and Gx - Ca rats (Gx 78% remaining, Gx - Ca 63%) but not in Sham-operated rats receiving a low Ca-diet (95% remaining)., Conclusion: Although the pattern of osteopenia was qualitatively quite similar in Gx rats and Ca-deficient rats, in quantitative terms the low Ca diet was more detrimental to bone than Gx. Ca deficiency induced a similar degree of osteopenia in both Sham and Gx rats. Ca supplementation failed to prevent the Gx-induced osteopenia.

Osteopenia develops in experimental animals following surgical removal of the ovaries (ovariectomy. Ovx) or the stomach (gastrectomy, Gx). Though the effect of Ovx has been ascribed to estrogen deficiency, the mechanism behind the Gx-evoked osteopenia remains unknown. In order to compare Gx- and Ovx-evoked osteopenia, young female rats were subjected to Ovx, gx, the combination of ovx and Gx, or sham operation (SHAM). Serum osteoclast-derived tartrate-resistant acid phosphatase 5b was measured as an index of bone resorption, and serum osteocalcin as an index of bone formation/turnover. Bone resorption predominated over bone formation during the first 4 days after Ovx but not later. Bone resorption predominated over bone formation throughout the first 4-week period after Gx. the changes were not additive in the ovx+Gx group. Transillumination and histomorphometry of the calvariae revealed extensive osteopenia in the Gx and the Ovx+Gx groups but not in the Ovx group. Peripheral quantitative computerized tomography of the femur metaphysis showed a decrease in the trabecular bone mineral density (BMD) in all three groups although Ovx+Gx seemed to induce greater trabecular bone loss than Gx alone. However, dual energy X-ray absorptiometry (DXA) of the intact femurs revealed reduced bone mineral content (BMC) in the Gx and Ovx+Gx groups but not in the Ovx group. Indeed, cortical bone was impaired by Gx and Ovx+Gx but not by Ovx. Hence, it seems clear that the Gx-evoked osteopenia differs from that induced by Ovx but that the osteopenia induced by Ovx+Gx is only marginally greater than that induced by Gx alone.

Rat models of osteopenia include ovariectomy and long-term glucocorticoid treatment. Although ovariectomy produces significant trabecular bone loss after 2 weeks, long-term glucocorticoid treatment has been reported to cause osteopenia in some studies but not in others. In the present 8-week-study, we compared the osteopenia associated with gastrectomy (GX) to that induced by ovariectomy (OVX) or prednisolone (PRE) treatment. Female Sprague-Dawley rats (10 weeks old) were subjected to GX, OVX, PRE treatment or SHAM operation. At the end of the study, calvariae, femurs and fifth lumbar vertebrae (L5) were collected and subjected to bone density measurement (femur and L5), transillumination (calvaria) and histomorphometry (calvaria and femur). Bone density was reduced in L5 and the distal femur in the OVX and GX groups, but not in the PRE group. Transillumination of the calvaria showed marked bone loss in the GX rats, but not in the other groups. Morphometric analysis of the femur revealed reduced trabecular bone volume, trabecular thickness, trabecular number and osteoclast number, but increased osteoclast surface (expressed as per cent of the trabecular bone surface covered by osteoclasts) in the GX and OVX rats. The PRE rats seemed unaffected. Cortical thickness was reduced in the GX rats, but not in the other groups. The findings indicate that GX induces osteopenia in, e.g., femur and vertebra of a magnitude similar to or greater than that induced by OVX, while at the same time inducing osteopenia in the calvaria. Although osteoclast activation seems to contribute, the precise mechanism underlying the GX-evoked osteopenia remains obscure.

In this study the relationships of bone mineral density (BMD) and bone structure parameters calculated from 2D microtomography images to bone strength were investigated. Femurs from 21 male Sprague Dawley rats were subjected to dual-energy X-ray absorptiometry, computerized microtomography (CmicroT) and either three-point cantilever bending (femoral shaft) or two-point bending compression (femoral neck). Gastrectomy was performed on 12 animals and 9 were sham operated. From the tomograms bone structure analysis was performed using a software routine based on grey level run-length method. Correlations of BMD and bone structure parameters to mechanical parameters were investigated as were differences between the gastrectomized and the control samples. The reductions of BMD between the groups were 21 and 27% in the femoral neck and shaft, respectively. For the shaft, the correlations of BMD to all mechanical parameters were significant and BMD was a consistent predictor of bone strength for cortical bone. However, in the femoral neck where cancellous bone predominates, BMD was weakly correlated only to deflection. A significant correlation between trabecular thickness and neck bone strength was found. Hence, compared to trabecular thickness, BMD was of limited value in predicting bone strength in the femoral neck.

Background: Gastrectomy induces osteopenia. In this study, we tested if resection of defined parts of the stomach could reproduce the gastrectomy-evoked osteopenia., Methods: Rats were subjected to gastrectomy (surgical removal of the glandular part of the stomach), fundectomy (extirpation of the acid-producing part, fundus) or antrectomy (extirpation of the gastrin-producing part, antrum). Calvariae, tibiae and femurs were examined at various times after the operations. The calvariae were subjected to transillumination. Calvariae and tibiae were sectioned and analysed by histomorphometry, tibia sections by the aid of a Merz grid and calvaria sections using computer-assisted image analysis. The intact femurs were subjected to computerized microtomography., Results: Gastrectomy (hypogastrinemia) and fundectomy (hypergastrinemia) resulted in osteopenia, while antrectomy (hypogastrinemia) had less effect on bone. Gastrectomy/fundectomy were associated with loss of trabecules in the tibia and with reduced bone volume in both tibia and calvaria. In contrast, there was only little reduction of cortical bone in the femur., Conclusion: Gastrectomy-evoked osteopenia can be reproduced by selective resection of the acid-producing part of the rat stomach (i.e. fundectomy). Antrectomy was less effective. In the long bones, the osteopenia was manifested primarily in trabecular bone and less in cortical bone. The calvaria displayed marked osteopenia. Although the findings indicate that the stomach, notably the acid-producing (oxyntic) mucosa, is important for bone metabolism, the precise mechanisms behind the gastrectomy/fundectomy-evoked osteopenia remain unidentified. Clearly, lack of gastrin is not responsible. The oxyntic mucosa is rich in peptide hormone-producing cells (the so-called ECL cells), with unidentified physiological significance. The ECL cells, which operate under the control of gastrin, have been put forward as a possible source of an osteotropic hormone.

The enterochromaffin-like (ECL) cells of the oxyntic mucosa (fundus) of the stomach produce, store and secrete histamine, chromogranin A-derived peptides such as pancreastatin, and an unanticipated but as yet unidentified peptide hormone. The cells are stimulated by gastrin and pituitary adenylate cyclase activating peptide and suppressed by somatostatin and galanin. Choline esters and histamine seem to be without effect on ECL cell secretion. The existence of a gastrin-ECL cell axis not only explains how gastrin stimulates acid secretion but also may help to explore the functional significance of the ECL cells with respect to the nature and bioactivity of its peptide hormone. From the results of studies of gastrectomized/fundectomized and gastrin-treated rats, it has been speculated that the anticipated ECL-cell peptide hormone acts on bone metabolism.

Rationale and Objectives: We investigate the methodological aspects of computerised microtomography (Cm 1) for monitoring the development of osteoporosis in male Sprague-Dawley rats., Methods: 120 Rats were gastrectomized or sham operated. Femurs were prepared and tomograms with spatial resolutions of 5-500 mm were made. Bone diameters, bone areas and moments of inertia were determined from the tomograms. Optimal slice position and the need for spatial resolution for future in vivo applications were investigated. In order to minimise the absorbed dose to the specimen, a theoretical model for determination of optimal irradiation conditions is developed., Results: Gastrectomy caused dramatic changes in the bone architecture. The main features were vaccuolisation of the bone and reduced amounts of compact bone. While the outer diameters of tubular bones were largely unaffected, their inner diameters were greatly increased following gastrectomy. Relative bone area and moment of inertia were greatly reduced. Optimal photon energy was 12 keV., Conclusions: It is possible to monitor gastrectomy-evoked changes in bone morphology at various sites in rats with computerised microtomography. The changes are suggestive of osteoporosis.

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.

Background: Gastrectomy induces bone loss, suggesting that the stomach is important for calcium homeostasis. In this study we examined the effects of gastrectomy, with or without CaCl2 supplementation, on the structure of the calvaria of the rat., Methods: The calvaria were dissected out and transilluminated, and the calvaria thickness was measured before (micrometer) and after fixation and sectioning (microscopy). Sections of the skull were analysed planimetrically for bone tissue area, using computer-assisted image analysis., Results: The time course of the gastrectomy-produced bone loss was studied. After 4 weeks the remaining bone represented about 70% of that in control rats, and after 8 weeks the value was 50%. The thickness of the calvaria was lower in gastrectomized rats than in sham-operated controls. Bone marrow and samples from liver and spleen were examined; no differences were found between experimental and control groups. Daily ingestion of 100 mg CaCl2.2H2O did not prevent the bone loss., Conclusions: It is unlikely that the gastrectomy-produced bone loss reflects calcium deficiency. The results rather support the view that the stomach is important for calcium homeostasis through another mechanism, perhaps involving a hypothetical gastric hormone.