Drug-induced prevention of gastrectomy- and ovariectomy-induced osteopaenia in the young female rat.

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.

Gastrectomized rats respond with exaggerated hypercalcemia to oral and intravenous calcium loads because of impaired ability of bone to take up Ca2+.

BACKGROUND: Gastrectomy (Gx) causes osteopenia. The hypothesis tested in the present study is that Gx affects Ca homeostasis and that an impaired ability to handle Ca contributes to the Gx-evoked osteopenia. METHODS: SHAM-operated and Gx rats were compared with respect to changes in blood Ca2+ after oral or intravenous loads of CaCl2 1-2 weeks or 2-4 months after the operations. RESULTS: Different doses of oral CaCl2 raised blood Ca2+ more in Gx than in SHAM rats, more so after 2-4 months than after 1-2 weeks. The rise was greater in fasted (48 h) rats than in fed rats regardless of whether they were SHAM or Gx. While SHAM rats tolerated high doses of CaCl2 well, Gx rats died when exposed to quite modest doses, particularly 2-4 months after Gx. Intravenous infusion of CaCl2 (2,500 micromol/kg/h) induced a greater and steeper rise in blood Ca2+ in Gx rats than in SHAM rats. Kinetic analysis of the blood Ca2+ data showed Gx rats to display: 1) a decreased Ca2+ elimination clearance from the central distribution compartment (blood), 2) a reduced size of the peripheral distribution compartment (the so-called bone fluid compartment). and 3) a spectacular decrease in the intercompartmental clearance (transfer of Ca2+ from blood to bone). These effects were notably apparent after 2-4 months. At sacrifice, the Gx-evoked osteopenia was confirmed by planimetric analysis of the calvariae. revealing 40% reduction of bone tissue after 2-4 months. CONCLUSIONS: Based on the present data we argue that Gx rats respond with exaggerated hypercalcemia to oral and intravenous CaCl2 loads because of a greatly impaired transfer of Ca+ from blood to bone. We suggest that with time this impairment results in osteopenia.

Post-gastrectomy osteopenia in the rat: bone structure is preserved by retaining 10%-30% of the oxyntic gland area.

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.

Effects of calcium deficiency and calcium supplementation on gastrectomy-induced osteopenia in the young male rat.

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.

Comparison of osteopenia after gastrectomy, ovariectomy and prednisolone treatment in the young female rat.

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.

Does combined gastrectomy and ovariectomy induce greater osteopenia in young female rats than gastrectomy alone?

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.

Evidence that peroral calcium does not activate the gastrin-ECL-cell axis in the rat.

The ECL cells are histamine- and pancreastatin-secreting endocrine cells in the oxyntic mucosa, thought to release a blood Ca2+-lowering peptide hormone upon stimulation by gastrin. Previously, we have shown that the ECL cells do not respond to perturbations in blood Ca2+. In the present study, we examine if Ca2+ in the gastric lumen will affect the activity of the gastrin-ECL-cell axis. Freely fed or food deprived (48 h) rats were given an oral load of CaCl2 (or NaCl), and the blood Ca2+ concentration was monitored. The serum gastrin concentration at sacrifice, 3 h after ingestion of CaCl2, was measured together with two parameters of ECL cell activity: the oxyntic mucosal histidine decarboxylase (HDC) activity and the serum pancreastatin concentration. The circulating concentrations of calcitonin and parathyroid hormone (PTH) were also measured. Oral CaCl2 raised the blood Ca2+ in a dose-dependent manner. The two highest doses (which caused damage to the oxyntic mucosa) raised the serum gastrin concentration and the HDC activity in both fed and fasted rats; the serum pancreastatin concentration remained unaffected. Oral CaCl2 raised the serum calcitonin concentration and lowered the serum PTH concentration. The effects of high doses of oral CaCl2 on the serum gastrin concentration and on the oxyntic mucosal HDC activity could be reproduced by a high dose of NaCl. Thus the effects are probably not due to Ca2+ per se. We conclude that the gastrin-ECL-cell axis in the rat does not respond to peroral Ca2+. Since the ECL cells do not respond to either circulating or peroral Ca2+ they are unlikely to secrete a calciotropic hormone.

Perturbations in blood Ca(2)+ do not affect the activity of rat stomach enterochromaffin-like cells.

BACKGROUND: Gastrin stimulates uptake of Ca(2)+ into bone and causes transient hypocalcemia, possibly by releasing a peptide hormone from enterochromaffin-like (ECL) cells, which are histamine- and peptidehormone-producing cells in the acid-producing part of the stomach. However, if ECL cells secrete a calciotropic hormone, it is to be expected that their activity is affected by the serum Ca(2)+ concentration. METHODS: Food-deprived male rats were infused with human (Leu)15-gastrin-17 and/or ethylenediamine-tetraacetic acid and CaCl(2). The blood Ca(2)+ level was monitored throughout the experiments (3 h), and the serum concentrations of gastrin, parathyroid hormone, and calcitonin were measured at death. The activity of the ECL cells was assessed by measuring the histidine decarboxylase (HDC) activity. RESULTS: Gastrin produced the expected increase in HDC activity, but neither hyper- nor hypo-calcemia affected the RDC activity of either hypo- or hyper-gastrinemic rats. CONCLUSION: Perturbations in blood Ca(2)+ do not seem to affect ECL cells, which is at odds with the view that ECL cells harbor a calciotropic hormone.