Bone and mineral metabolism in BB rats with long-term diabetes. Decreased bone turnover and osteoporosis

The effect of long-term diabetes mellitus on bone and mineral metabolism was studied in BB rats. Diabetic rats were treated with 1 U of long-acting insulin every other day for 12 wk and compared with nondiabetic littermates. Urinary calcium excretion was increased greater than 10-fold, but serum total and diffusible calcium remained normal. Serum concentrations of both 1 alpha, 25-dihydroxyvitamin D3 and vitamin D-binding protein were significantly decreased in diabetic rats. The intestinal calbindin-D 9K concentration was decreased by nearly 50%, and active duodenal calcium absorption was totally abolished. Trabecular bone volume measured in the tibial metaphysis was decreased by 44%, and the osteoblast and osteoid surfaces were less than 10% of values observed in control rats, whereas the osteoclast surface was unchanged by diabetes. The daily bone formation (bone mineral apposition rate) measured by labeling twice with calcein was decreased by 86% in diabetic rats. The serum concentration of osteocalcin, a biochemical marker of osteoblast function, was similarly decreased (mean +/- SE 23 +/- 3 and 62 +/- 4 micrograms/L in diabetic [n = 15] and nondiabetic [n = 15] rats, respectively). Serum osteocalcin was significantly correlated with the serum concentration of insulinlike growth factor I (r = 0.89, P less than 0.001). Bone strength measured as the energy needed to fracture the femur was markedly decreased (5.3 +/- 1.4 and 8.4 +/- 1.3 N.m.degree in diabetic and nondiabetic rats, respectively; P less than 0.01). These histological, chemical, and biomechanical data clearly indicate that long-standing diabetes in BB rats results in severe low-turnover osteoporosis probably related to decreased osteoblast recruitment and/or function.     

糖尿病雄性大鼠骨代谢特点的观察

目的观察Ⅰ型糖尿病雄性大鼠骨代谢的特点以及骨密度和骨组织形态计量学指标的变化。方法采用高糖高脂饮食加腹腔注射小剂量链脲佐菌素诱导建立Ⅱ型糖尿病大鼠模型。20周后处死大鼠,测定股骨和腰椎骨密度、骨形态计量学以及骨代谢相关指标（血清骨钙素、抗酒石酸酸性磷酸酶、24h尿Ca、24h尿羟脯氨酸）,此外还观察了GHbAlc、胆固醇、低密度脂蛋白-胆固醇、胰岛素样生长因子-1等变化。结果Ⅱ型糖尿病大鼠血清骨钙素、股骨和腰椎骨密度以及骨形态计量学指标反映骨形成参数均明显低于正常对照组,而血抗酒石酸酸性磷酸酶活性和尿钙、尿羟脯氨酸排出量以及形态计量学反映骨吸收参数均明显高于正常大鼠。结论Ⅱ型糖尿病大鼠的骨吸收加快丽骨形成不足。导致其骨量下降和骨形态计量学特性改变。     

Amylin and bone metabolism in streptozotocin-induced diabetic rats.

Amylin (AMY) is a 37 amino acid peptide cosecreted with insulin (INS) by pancreatic beta-cells and absent in type 1 diabetes, a condition frequently associated with osteopenia. AMY binds to calcitonin receptors, lowers plasma calcium concentration, inhibits osteoclast activity, and stimulates osteoblasts. In the present study, we examined the effects of AMY replacement on bone loss in a streptozotocin (STZ)-induced rodent model type 1 diabetes. Of 50 male Wistar rats studied, 40 were made diabetic with intraperitoneal STZ (50 mg/kg; plasma glucose concentrations > 11 mM within 5 days). Ten nondiabetic control (CONT) rats received citrate buffer without STZ. Diabetic rats were divided into four groups (n = 10/group) and injected subcutaneously with rat AMY (45 mg/kg), INS (12 U/kg), both (same doses), or saline (STZ; diabetic controls) once per day. After 40 days of treatment and five 24-h periods of urine collection for deoxypyridinoline (DPD), the animals were killed, blood was sampled, and femurs were removed. The left femur was tested for mechanical resistance (three-point bending). The right femur was tested for total, diaphyseal (cortical bone), and metaphyseal (trabecular bone) bone densities using dual-energy X-ray absorptiometry (DXA). Bone was ashed to determine total bone mineral (calcium) content. None of the treatments had any significant effect on femoral length and diameter. Untreated diabetic rats (STZ; 145+/-7N) had lower bone strength than did nondiabetic CONT (164+/-38; p < 0.05). Total bone mineral density (BMD; g/cm2) was significantly lower in STZ (0. 2523+/-0.0076) than in CONT (0.2826+/-0.0055), as were metaphyseal and diaphyseal densities. Diabetic rats treated with AMY, INS, or both had bone strengths and bone densities that were indistinguishable from those in nondiabetic CONT. Changes in bone mineral content paralleled those for total BMD (T-BMD). Plasma osteocalcin (OC) concentration, a marker for osteoblastic activity, was markedly lower in untreated diabetic rats (7. 6+/-0.9 ng/ml); p < 0.05) than in nondiabetic CONT (29.8+/-1.7; p < 0.05) or than in AMY (20.1+/-0.7; p < 0.05). Urinary DPD excretion, a marker for bone resorption, was similar in untreated and AMY-treated diabetic rats (35.0+/-3.1 vs. 35.1+/-4.4 nmol/mmol creatinine), intermediate in rats treated with INS (49.9+/-2.7), and normalized in diabetic rats treated with both agents (58.8+/-8.9 vs. 63.2+/-4.5 in CONT). Thus, in our STZ rat model of diabetic osteopenia, addition of AMY improved bone indices apparently by both inhibiting resorption and stimulating bone formation.     

Effect of acute increases in bone matrix degradation on circulating levels of bone-Gla protein

Serum bone Gla-protein (BGP), also called osteocalcin, is a specific and sensitive measure of bone turnover in a variety of metabolic bone disorders. Although some BGP diffuses into the circulation after synthesis by osteoblasts, most is incorporated into bone matrix where it remains until bone is resorbed. Thus, serum BGP could reflect bone formation, bone resorption, or a combination of both. The relationship of serum BGP to the components of bone turnover was evaluated in 18 normal women (mean age 48 yr; range 30-70) who received a continuous 24-h intravenous infusion of the 1-34 synthetic fragment of bovine parathyroid hormone. Mean +/- SE for urinary hydroxyproline excretion, an index of bone resorption, increased (from 22.7 +/- 2.2 to 38.5 +/- 3.7 micrograms/100 ml glomerular filtrate [GF], p less than .001), whereas levels of serum alkaline phosphatase, an index of bone formation, were unchanged (from 20 +/- 1 to 20 +/- 1 U/liter, NS). Despite the increase in bone resorption, levels of serum BGP decreased (from 8.8 +/- 0.8 to 6.8 ng/dl, p less than .001). The data suggest that circulating levels of BGP are a measure of bone formation but, at least in subjects with normal renal function, not a measure of bone resorption. Presumably BGP in bone matrix is degraded during osteoclastic resorption into fragments that either are not recognized by an antiserum raised against the native molecule or are rapidly cleared from the circulation.     

The effects of metabolic acidosis on bone formation and bone resorption in the rat

Metabolic acidosis (MA) has been implicated in the pathogenesis of both osteomalacia and osteopenia. Alterations in the secretion of parathyroid hormone and in the metabolism of vitamin D may contribute to such skeletal changes. To minimize the influence of these factors, quantitative bone histology and measurements of bone formation using double tetracycline labeling were done in thyroparathyroidectomized (TPTX) rats with MA induced by ammonium chloride (TPTX-A), and in both non-acidotic TPTX (TPTX-C) and intact (C) controls. To evaluate the response of both cortical and trabecular bone to MA, histologic studies were done at three separate sites in the tibia, cortical bone from the mid-shaft, and trabecular bone from the epiphysis and from the metaphysis. Plasma pH was lower in TPTX-A, 7.24 +/- 0.10, than in either TPTX-C, 7.39 +/- 0.03, or C, 7.43 +/- 0.04, P less than 0.01, and urinary hydroxyproline excretion increased from 89.8 +/- 8.7 in TPTX-C to 150.2 +/- 25.9 micrograms/mg/creatinine in TPTX-A, P less than 0.01. Resorption surface at the epiphysis increased from 1.8 +/- 0.6% in TPTX-C to 4.0 +/- 1.6% in TPTX-A, P less than 0.05, values not different from those in C, 3.1 +/- 1.1%. Resorption surface was unchanged at other skeletal sites, but total bone volume at the metaphysis fell from 15.5 +/- 5.6% in TPTX-C to 9.0 +/- 4.3% in TPTX-A, P less than 0.05. Bone formation was reduced at each skeletal site in TPTX-A vs. TPTX-C, P less than 0.05 for all values, but histologic evidence of osteomalacia was not observed.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased circulating levels of γ-carboxyglutamic acid-containing protein and decreased bone mass in children on anticonvulsant therapy

Summary In order to investigate the pathophysiology of anticonvulsant-induced osteopenia, circulating levels of bone γ-carboxyglutamic acid-containing protein (Bone Gla Protein: BGP) and urinary excretion of BGP were measured in 16 chidren on chronic anticonvulsant therapy and in 12 control children. Using microdensitometry analysis, osteopenia was found in 25% of the anticonvulsant therapy group, but it was not observed in the control group. Serum BGP and A1-P levels were significantly increased in the anticonvulsant group compared with the control group (P<0.05 andP<0.01, respectively), and a positive correlation was found between serum BGP and A1-P levels (P<0.05). Urinary excretion of BGP and hydroxyproline showed an increase in the anticonvulsant group, but it was not statistically significant. On the other hand, there was no significant difference between the two groups in serum levels of vitamin D metabolites, PTH, calcitonin, Ca, or P or in urinary excretion of Ca or P. It is suggested, therefore, that the increased BGP level in children receiving anticonvulsant therapy is a reflection of high bone turnover due to anticonvulsant drug complications.     

A study on urinary free gamma-carboxyglutamic acid in patients with idiopathic urinary calcium stone]

Currently, urinary excretion of free gamma-carboxyglutamic acid (gamma-gla.), a terminal amino acid degraded from gamma-gla. containing protein including bone Gla. Estimated to be a more specific marker for bone metabolism and useful clinically rather than urinary excretion of hydroxyproline. In addition, serum levels of BGP have proved to be a significantly valuable indicator for bone metabolism, especially for process of bone formation, in recent studies. Therefore, we measured these parameters in 40 patients with idiopathic urinary calcium (Ca) stone and investigated bone metabolism in those patients. However, in majority of cases studied, urinary levels of gamma-gla. as well as that of hydroxyproline proved to be definite difference from that in healthy subjects (n = 12) and failed to suggest the presence of abnormality in bone turnover in the background of stone formation. Urinary excretion of hydroxyproline were 6.68 +/- 3.89 micrograms/mg.Cr in the patients and 6.95 +/- 3.08 micrograms/mg.Cr in healthy subjects. Urinary excretion of gamma-gla were 55.0 +/- 15.8 nmol/mg.Cr in the patients and 47.2 +/- 7.3 nmol/mg.Cr in healthy subjects.     

高转换型骨质疏松模型的生化特点

应用摘除卵巢的方法。建立大鼠高转换型骨质疏松模型。本模型有以下生化特征；血清骨钙素水平明显升高；血浆酸性磷酸酶活性增强：全尿钙、全尿羟脯氨酸和肌酐含量增高。提示血浆酸性磷酸酶活力可以作为此模型动物骨吸收的特异指标，血清骨钙素水平可用于评价骨转换率。用总尿钙和总尿羟脯氨酸指标评价骨量丢失，其敏感性高于尿钙/肌酐、羟脯氨酸/肌酐。     

Mineral metabolism and bone mass at peripheral and axial skeleton in diabetes mellitus

Bone mineral content (BMC), mineral homeostasis, and diabetes control were evaluated in 31 Caucasian insulin-dependent diabetic patients (disease duration 18.3 +/- 7.7 yr, mean +/- SD) with normal kidney function. To evaluate bone mass, we performed radiogrammetry and single- and dual-photon absorptiometry. In women, a significantly lower mean BMC was found in the distal radius, at a mixed trabecular-cortical (P less than .01) and a cortical (P less than .05) site, as well as in the lumbar spine (P less than .02). In diabetic men, mean BMC was significantly reduced at the trabecularcortical (P less than .01) and cortical (P less than .05) sites of the radius but not in the lumbar spine. When expressed as densities (i.e., BMC/width or lumbar BMC/area), only the BMC/width at the radius cortical area was significantly reduced in women (P less than .05). The results of the radiogrammetry showed a larger endosteal diameter in the diabetic women, resulting in a significantly lower cortical thickness (P less than .05). Diabetic men did not show abnormalities on radiogrammetry. Diabetic patients had diminished serum calcium and phosphorus concentrations (P less than .001), whereas serum parathyroid, 25-hydroxyvitamin D3, and concentrations of both total and free 1,25-dihydroxyvitamin D3 were normal. No correlation between parameters of diabetes control (HbA1, insulin dose, and triglycerides) or calcium-regulating hormones and BMC were found. These data confirm that, despite large overlap of individual values, mean bone mass at the peripheral skeleton is significantly decreased in diabetic patients. Moreover, we report that the BMC of the lumbar spine is significantly reduced in female diabetic patients.     

The effect of oral phosphate administration on major indices of skeletal metabolism in normal subjects

The effect of brief periods of phosphate administration on indices of human skeletal metabolism was investigated. Thirteen subjects (8 women, 5 men; 19-36 years old) received 2 g of oral phosphate daily for 5 days. Serum phosphorus rose 26% (3.8 +/- 0.1 mg/dl to 4.8 +/- 0.1 mg/dl; p less than .01) while total calcium fell (9.3 +/- 0.1 mg/dl to 8.9 +/- 0.1 mg/dl; p less than .01). Parathyroid hormone levels increased by 50% (14.1 +/- 2.0 pg/ml to 21.5 +/- 1.7 pg/ml; p less than .05) although values remained within the normal range. A persistent phosphaturia (0.64 +/- 0.10 g/g Cr to 1.8 +/- 0.4 g/g Cr; p less than .05) and a 69% fall in urinary calcium (80.8 +/- 10.0 mg/g Cr to 24.6 +/- 6.0 mg/g Cr; p less than .001) were observed. 1,25-dihydroxyvitamin D3 and urinary hydroxyproline concentrations did not change significantly but the bone gamma-carboxyglutamic acid protein (BGP) concentration rose 41% by day 2 (9.6 +/- 1.3 mg/ml to 13.5 +/- 2.2 mg/ml; p less than .005) and remained elevated throughout the study period. These results support the possibility that brief periods of phosphate administration may be useful in the therapy of disorders associated with low bone turnover, such as osteoporosis.     

Human lactation: forearm trabecular bone loss, increased bone turnover, and renal conservation of calcium and inorganic phosphate with recovery of bone mass following weaning

The calcium (Ca) metabolism of established human lactation was studied in 40 adult women (mean age 32.4 years) who had been breast-feeding for 6 months (Lac) and in 40 age-matched controls (Con) using fasting urine and blood biochemistry and forearm single-photon bone mineral densitometry (BMD). Serial studies were performed up to 6 months after weaning in Lac women and repeated once in Con women. During lactation the significant findings were (1) a selective reduction (7.1%, P less than 0.03) in BMD at the ultradistal site containing 60% trabecular bone, but not at two more proximal, chiefly cortical bone sites; (2) increased bone turnover affecting bone resorption [fasting hydroxyproline excretion, Lac 2.22 +/- 0.12 mumol/liter GF (mean +/- SEM), Con 1.19 +/- 0.04, P less than 0.001] and affecting bone formation (plasma alkaline phosphatase, Lac 81.9 +/- 2.5 IU/liter, Con 53.5 +/- 2.7, P less than 0.001, and serum osteocalcin, Lac 14.0 +/- 0.7 microgram/liter, Con 7.3 +/- 0.4, P less than 0.001); and (3) renal conservation in the fasting state of both Ca and inorganic phosphate (Pi) with a resultant moderate increase in plasma Pi but not in plasma Ca (total or ionized). There were no differences between the groups in serum parathyroid hormone (PTH, intact and midmolecule assays), 25-hydroxy- and 1,25-dihydroxyvitamin D, nephrogenous cyclic AMP production, or plasma creatinine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of age and risk factors on bone density and bone turnover in healthy premenopausal women

The influence of age and risk factors on bone density and bone turnover was evaluated in 249 healthy premenopausal women. Risk factors were assessed by standardized questionnaires and included reproductive history and lifestyle factors (intake of calcium and vitamin D supplements, consumption of caffeine, smoking habits and physical activity). Bone mineral density (BMD) measurements were obtained in the distal forearm, the lumbar spine and the proximal femur. Bone turnover were assessed by plasma bone Gla proteins (pBGP) and fasting urinary hydroxyproline corrected for creatinine (fUHPr/Cr). Peak bone density seems to be achieved before the age of 30 years, whereafter we found no appreciable bone loss at any skeletal site. Accordingly, the levels of pBGP and fUHPr/Cr were increased before the age of 30, whereafter the values stabilized at a lower level. A dairy calcium intake above 660 mg/day significantly increased BMD in the spine and proximal femur by 3%–5%. Physical activity alone had no influence on BMD, but in combination with calcium intake an additive effect was observed. Women who had an active lifestyle (corresponding to at least 1 h of daily walking) and a dairy calcium intake above 660 mg/day had a 3%–7% increase in BMD compared with more sedentary women with a calcium intake below this limit. Vitamin D supplements, caffeine, smoking and reproductive history did not consistently influence BMD or bone turnover. Only pBGP was selectively reduced by smoking and current use of oral contraceptives, respectively. We conclude that there is no appreciable change in BMD before the menopause once skeletal maturity has been reached. Dietary calcium intake increases peak bone density and this positive effect can be potentiated by an active lifestyle. Other putative risk factors had no influence on premenopausal BMD.     

Increased bone volume and reduced bone turnover in vitamin D-replete rabbits by the administration of 24R,25-dihydroxyvitamin D3.

To study the effect of a large dose of 24R,25(OH)2D3 on bone metabolism, we treated vitamin D-replete rabbits with the agent for eight weeks. Fifteen rabbits 20 weeks of age were divided into three groups of five animals each. Group I received only the vehicle; groups II and III were given the agent at doses of 10 micrograms/kg/d, and 100 micrograms/kg/d, respectively. Through the dosing period, serum calcium, phosphorus, alkaline phosphatase, and creatinine levels were not altered. By the end of the experiment, serum 1,25(OH)2D or serum 25(OH)D levels did not change, nor did the PTH level. Serum 24,25(OH)2D levels for groups I, II, and III were 5.25 +/- 3.40, 76.16 +/- 19.90 (p less than .01), and 199.0 +/- 30.90 (p less than .01) ng/ml, respectively. The bone mineral content (BMC) significantly increased in group III. The percentages of BMC increase in group III over group I were 14.5% on the femur, 34.1% (p less than .01) on the sixth lumbar vertebra, and 23.3% (p less than .05) on the seventh lumbar vertebra. A marked increase of bone mineral densities in the cancellous bone-rich regions was seen in group III. Bone histomorphometry on the seventh lumbar vertebra demonstrated that both the eroded surface and the osteoclast number were reduced and the surfaces indicating bone formation such as the osteoid surface and the tetracycline double labeled surface were also reduced. However, both the osteoid thickness and the mineral apposition rate increased and the mineral formation rate at the tissue level remained approximately equal to that in the control.(ABSTRACT TRUNCATED AT 250 WORDS)     

118例甲亢患者骨密度及骨代谢指标的研究

目的：为探讨甲亢患者骨密度与骨代谢指标的改变。方法：本文测定了１１８例甲亢患者腰椎（Ｌ２～４）及股骨上端（Ｎｅｃｋ、Ｗａｒｄ三角、Ｔｒｏｃｈ）骨密度、血清骨钙素（ＢＧＰ）、甲状旁腺素中间片段（ＰＴＨ－ｍ）及尿脱氧吡啶啉（Ｄｐｄ）。结果：甲亢患者骨密度低于正常对照组，ｔ检验具显著差异（ｐ＜０．０１）、血清ＢＧＰ及Ｄｐｄ高于正常对照组，ｔ检验具显著差异（ｐ＜０．０１），与骨密度呈负相关ｒ＝－０．２１３５、－０．２０５０（ｐ＜０．０５）；而ＰＴＨ－ｍ低于正常对照组，与骨密度无相关性ｒ＝０．０８３０（ｐ＞０．０５）。结论：甲亢为高转换型骨质疏松，ＢＧＰ、Ｄｐｄ可作为骨形成及骨吸收的敏感指标     

妊娠妇女性激素、骨密度、骨代谢生化指标的变化及相关性研究

目的：探讨妊振妇女骨密度和骨代谢的变化及其与性激素的关系。方法：随机选取63例健康脑力劳动孕妇和21例健康脑力劳动妇女分别测定骨密度,血清Ca、P、ALP、BGP和E2、P、FSH、LH、PRL以及尿HP/Cr、Ca/Cr比值。结果：孕期骨密度虽有下降但无显变化（P＞0.05),ALP和BGP在晚孕期有显变化（P＜0.05)且此变化与E2成正相关（r=0.61、0.36)。结论：妊娠期骨密度虽无明显变化,但晚孕期骨转换率明显增加且与E2呈正相关。提示可通过测定E2了解孕期骨代谢情况,并及时予以补钙等措施可能有益。     

Longitudinal study of bone metabolism after ethanol withdrawal in alcoholic patients.

The pathogenesis of osteopenia in chronic alcoholism remains unclear, and many ethanol-related abnormalities have been advocated to explain bone loss. A direct inhibitory effect of ethanol on osteoblast function was suggested by in vivo and in vitro studies. We measured biochemical markers of bone turnover in 12 alcoholic men before and during a 2 week period of alcohol withdrawal, and we compared the results with those obtained in 15 nonalcoholic men. Our alcoholic patients presented with (1) decreased serum concentrations of bone gla protein (BGP), suggesting decreased bone formation; (2) increased urinary excretion of hydroxyproline, suggesting increased bone resorption; (3) increased renal threshold of phosphate excretion without modification of serum PTH concentration, suggesting a direct effect of ethanol on the renal handling of phosphate. The rapid increase in serum BGP concentrations following ethanol withdrawal suggests that low serum BGP concentrations in alcoholics may result from a direct toxic effect of ethanol on osteoblast function and/or numbers.     

Increased cathepsin K and tartrate-resistant acid phosphatase expression in bone of streptozotocin-induced diabetic rats

The effect of insulin-dependent diabetes mellitus (IDDM) on bone metabolism was evaluated using the streptozotocin (STZ)-induced diabetic rat 1 week after the induction of diabetes. The urinary excretion of cross-linked N-telopeptides of type I collagen (NTx) and deoxypyridinoline (Dpd) in diabetic rats increased to 3.6-fold and 1.2-fold the control level, respectively. The amount of hydroxyproline and calcium in the distal femur of diabetic rats significantly decreased to 76% and 90% of the control, respectively. The levels of serum osteocalcin and alkaline phosphatase (ALP) activity in the distal femur of the diabetic rats were significantly reduced to about 40% and 70% of the control levels, respectively. The decrease in the expression osteocalcin was observed in distal femur of the diabetic rats, although the level of ALP mRNA was unchanged. The activity and the mRNA level of tartrate-resistant acid phosphatase (TRAP) increased to 1.5- and 2.3-fold the control level, respectively, in distal femur of the diabetic rats. The activity, protein, and mRNA levels of cathepsin K of diabetic rats also elevated to about 2-, 2.3-, and 2-fold the control levels, respectively. These results suggest that IDDM contributes to bone loss through changes in gene expression of TRAP and cathepsin K in osteoclasts as well as osteocalcin in osteoblasts resulting in increased bone resorptive activity and decreased bone formation.     

Effect of etidronate disodium on bone turnover following surgical menopause

Summary A longitudinal study was performed to document the effect of surgical menopause and postmenopausal etidronate disodium therapy on several nonhistomorphometric indices of bone turnover. Twenty healthy, premenopausal women undergoing oophorectomy for nonmalignant conditions were studied preoperatively and at 3 monthly intervals postoperatively. Sequential measurements of serum calcium (Ca), alkaline phosphatase (AP), bone Gla protein (BGP), and urinary calcium and hydroxyproline excretion, expressed as a ratio of urinary creatinine (UCa/Cr and UOHp/Cr, respectively) were obtained. Twenty-four-hour whole body retention of diphosphonate (WBR) and radial bone density were also measured. When a postoperative increase in bone turnover was observed, patients were randomized to receive either 400 mg etidronate disodium daily or placebo for 3 months. Oophorectomy was associated with a significant increase in WBR, Ca, AP, and BGP and an insignificant rise in UCa/Cr. A variable pattern of UOHp/Cr was seen. Patients on placebo maintained these elevated levels of Ca, BGP, and UCa/Cr. WBR and AP continued to rise. Etidronate disodium therapy resulted in a fall towards premenopausal levels in WBR, Ca, and UCa/Cr. AP and BGP were unchanged. Three months after stopping etidronate, BGP fell significantly and the decrease in Ca was maintained; however, WBR and UCa/Cr had returned towards pretreatment values. Bone density measurements did not change significantly. An increase in several of the indices of bone turnover was seen following oophorectomy. Etidronate disodium suppressed this increase, affecting indices of both resorption and formation. This effect on formation may be an unavoidable consequence of normal resorption-formation coupling. The ability of etidronate alone to maintain postmenopausal bone mass has yet to be established. However, the suppressive effect of this diphosphonate on the accelerated bone turnover found after oophorectomy suggests that etidronate may have a potentially useful role as an inhibitor of resorption in a pulsed regimen.     

Determinants of bone gamma-carboxyglutamic acid-containing protein in plasma of healthy aging subjects

The gamma-carboxy glutamic acid (Gla)-containing protein of mammalian bone (BGP, also called osteocalcin) is a 49 amino acid polypeptide containing two to three residues of gamma-carboxyglutamic acid. BGP is synthesized by osteoblastlike cells, and plasma BGP in laboratory animals is derived principally from recently synthesized BGP. These data, taken together with observations that plasma BGP levels are elevated in patients with disorders of high bone turnover, suggest that plasma BGP is a marker of osteoblast activity. Since low bone formation rates may play an important role in the loss of bone mass with age, we have examined the determinants of plasma BGP levels in aging subjects, using a region-specific radioimmunoassay for human BGP based on the synthetic C-terminal peptide hBGP37-49. In 147 carefully screened healthy subjects, aged 23-91, BGP did not change with age, whereas alkaline phosphatase (AP) showed a significant positive correlation (r = 0.30, P less than 0.001). Creatinine clearance (GFR) declined by 0.9 ml/min/yr and correlated with both BGP (r = -0.21, P less than 0.001) and AP (r = -0.21, P less than 0.001). However, correlation of AP with age persisted after controlling for GFR. BGP was not correlated with serum PTH, urine Ca/GFR, or urine cAMP/GFR. In 48 patients with known parenchymal renal disease studied for comparison, plasma BGP was increased at a serum creatinine of greater than or equal to 1.8 mg/dl. Our results indicate that plasma BGP, a specific marker of bone metabolism, is not predictably related to age per se. This result is in contrast to the age-related rise in total AP. Subtle changes in renal function can affect plasma BGP levels.     

Cyclosporin A in the oophorectomized rat: unexpected severe bone resorption

Local factors, such as interleukin-1, may mediate the accelerated bone remodeling in the acute estrogen-deficient rat. Cyclosporin A (CsA), which in vitro inhibits some of these local factors, was administered to oophorectomized (OX) rats in an attempt to modify this high turnover state. Three groups of 15 rats were studied. Group A was sham operated, group B was OX, and group C was OX and received CsA (15 mg/kg per day) by gavage commencing 4 days postoophorectomy for 28 days. Estradiol levels were determined to confirm oophorectomy. Blood was sampled on days -7, 0, 7, 14, 21, and 28 for ionized calcium (Ca2+), 1,25-(OH)2-vitamin D, PTH, and bone gla protein (BGP). Rats received tetracycline hydrochloride for bone histomorphometric labeling. All results were compared to group A. Body weight was increased in group B (p less than 0.003) but not in group C. There was no difference in Ca2+ or PTH between the groups. BGP levels were higher in group B by day 28 (p less than 0.005); BGP levels were increased in group C from days 7-28 (p less than 0.002). 1,25-(OH)2-vitamin D was significantly increased in group C (p less than 0.0001) but not in group B. Tibial bone histomorphometry revealed increased measurements of bone formation and osteoclast number without a loss of bone volume (BV/TV) in group B. Group C showed a dramatic increase in bone turnover with significant loss of BV/TV (p less than 0.001). In conclusion, CsA in the OX rat resulted in unexpected enhanced bone remodeling with high BGP levels and severe bone resorption.(ABSTRACT TRUNCATED AT 250 WORDS)