Long-term effects of withdrawal of bisphosphonate incadronate disodium (YM175) on bone mineral density, mass, structure, and turnover in the lumbar vertebrae of ovariectomized rats.

This study was designed to evaluate the long-term effects of incadronate disodium (YM175) after its withdrawal on cancellous bone mass in ovariectomized (OVX) rats. Thirteen-week-old female SD rats were randomized into four groups: sham-operated, OVX, low-YM, and high-YM (0.01 mg/kg or 0.1 mg/kg subcutaneously [sc], three times a week after OVX) groups. After 4 weeks of treatment with vehicle or YM175, rats from each group were killed at time points of 0 (baseline), 3, 6, 9, and 12 months after withdrawal of the agent. Bone mineral density (BMD) of the lumbar vertebrae was measured by dual-energy X-ray absorptiometry (DXA). Bone volume (BV/TV), trabecular number and trabecular separation (Tb.N and Tb.Sp), eroded surface (ES/BS), osteoclast number and osteoclast surface (N.Oc/BS and Oc.S/BS), osteoid surface (OS/BS), and bone formation rate (BFR/BS) were measured as histomorphometric parameters of the fifth lumbar vertebra. BMD, BV/TV, Tb.N, and Tb.Sp in YM175-treated groups were maintained at the same level as in the sham group until 12 months after withdrawal in the high-YM group and until 3 months after withdrawal in the low-YM group. YM175 decreased both bone formative and resorptive parameters in histomorphometry. Serum bone-specific alkaline phosphatase (ALP) and urinary deoxypyridinoline at both doses of YM175 also showed a suppressive effect of this agent on bone turnover. These results indicate that YM175, after withdrawal, still maintains bone volume dose dependently by depressing bone resorption and formation in OVX rats. Intermittent YM175 treatment with a long interval may be sufficient to maintain the bone volume and structure in OVX rats.     

The effects of clodronate on increased bone turnover and bone loss due to ovariectomy in rats

The present study was carried out to investigate the ability of clodronate to inhibit ovariectomy-induced bone loss and increased bone turnover in rats. Estradiol was administered as a reference compound. Seventy Sprague-Dawley rats were ovariectomized (OVX) or sham-operated (Sham) at the age of 90 days and divided into seven groups. Two Sham and two OVX groups received subcutaneously either the vehicle of clodronate or the vehicle of estradiol. Other OVX groups were given s.c. either disodium clodronate at two dose levels (5 mg/kg or 12.5 mg/kg twice a week) or 17β-estradiol (10 μg/kg five times a week) for 8 weeks. Femur length, volume, dry weight, and ash weight were determined, and proximal ends of tibiae were used for bone histomorphometry. Markers of bone metabolism were measured from urine and serum. A significant loss of 54% of trabecular bone area of proximal tibial metaphysis was found at 8 weeks after ovariectomy. Clodronate and estradiol inhibited (p < 0.001) this osteopenia. Both drugs prevented the decrease in ash weight/volume of the femur. The inhibitory effect of clodronate and estradiol on bone resorption in OVX rats could be detected also in decreased urinary excretion of hydroxyproline and lysylpyridinoline (p < 0.001). Clodronate and estradiol decreased (p < 0.001) the ovariectomy-induced enhanced tibial endocortical mineral apposition rate (Ec.MAR) on the lateral cortex to the level of the Sham group. In contrast, periosteal MAR analyzed on the medial side of tibial cortical bone did not change significantly in the OVX/Veh group. Estradiol decreased periosteal MAR to below the level in the Sham group (p < 0.01). These results suggest that ovariectomy of growing rats resulted in tibial and femoral osteopenia two months later. Clodronate as well as estradiol can suppress bone resorption and turnover in ovariectomized rats, inhibiting the development of osteopenia. Both clodronate doses (5 and 12.5 mg/kg) had beneficial effects in ovariectomized animals.     

Skeletal effects of calcitonin treatment and withdrawal in ovariectomized rats

The study was designed to determine, by histomorphometric techniques, bone changes as a function of time during long-term treatment with salmon calcitonin (CT) and after withdrawal of the hormone in ovariectomized (OVX) rats. Groups of OVX rats were treated with vehicle alone or CT on alternate days for 30, 60, or 90 days. Additional groups of sham-operated control rats were treated with vehicle alone. Rats from each of the three groups were sacrificed at each time point. All treatments in the remaining rats were then terminated at 90 days, followed by sacrifice of rats from each group at 30 and 60 days after withdrawal of vehicle or CT treatment. The proximal tibia from each animal was processed undecalcified for quantitative bone histomorphometry. Compared with control rats, the proximal tibiae of vehicle-treated OVX rats were characterized by cancellous osteopenia and significant increases in osteoclast surface, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate. CT treatment of OVX rats partially prevented cancellous bone loss by approximately 50% and significantly decreased most of the above indices of bone turnover relative to vehicle-treated OVX rats. However, soon after withdrawal of CT, OVX rats previously treated with the hormone exhibited rapid loss of cancellous bone associated with increased bone turnover. These results in an animal model of estrogen depletion suggest that early postmenopausal women who are withdrawn from prophylactic CT treatment may be at high risk for subsequent bone loss.     

Skeletal effects of withdrawal of estrogen and diphosphonate treatment in ovariectomized rats

Summary The study was designed to determine the skeletal effects of withdrawal of estrogen and diphosphonate treatment in the estrogen-deplete state. Groups of ovariectomized (OVX) rats were treated with vehicle alone, estrogen, or the diphosphonates etidronate or risedronate for a 180-day period. A group of sham-operated control rats was treated for 180 days with vehicle alone. All treatments were then terminated, followed by sequential sacrifice of rats at 0, 35, 90, 180, and 360 days after withdrawal of treatment. The proximal tibia from each animal was processed undecalcified for quantitative bone histomorphometry. At the end of the treatment period, vehicle-treated OVX rats were characterized by cancellous osteopenia and increased bone turnover relative to vehicle-treated control rats. Treatment of OVX rats with estrogen or diphosphonates depressed bone turnover and protected against cancellous osteopenia. During the withdrawal period, OVX rats previously treated with estrogen exhibited rapid bone loss associated with increased bone turnover. The bone protective effect of the hormone in OVX rats was nearly completely lost by 90 days of withdrawal. In contrast, OVX rats maintained low levels of bone turnover and normal cancellous bone mass at 180 days of withdrawal from diphosphonate treatment. The results suggest that estrogen-deplete women who are withdrawn from estrogen replacement are at high risk for subsequent bone loss. They further suggest that widely spaced periods of intermittent diphosphonate treatment may be sufficient to prevent the development of osteopenia in postmenopausal and oophorectomized women.     

双侧卵巢切除山羊不同时间段骨形态计量学与骨密度的变化

采用骨病理形态学、骨计量学与骨密度测定法,动态观察了山羊假手术组（Ｓｈａｍ）和双侧卵巢切除组（ＯＶＸ）术前、术后３月、６月、１２月和１８月各不同时间段髂骨骨病理形态学、骨小梁体积百分比（Ｖｖ％）,骨小梁宽度和腰椎（Ｌ２－Ｌ４）骨密度的变化。结果显示：Ｓｈａｍ组术后各时间段髂骨骨病理形态学、骨小梁体积百分比和骨小当宽度无明显变化（Ｐ〉０．０５）。Ｌ２￣Ｌ４骨密度呈缓慢上升趋势,至术后１８月比术前增高     

Parathyroid hormone monotherapy and cotherapy with antiresorptive agents restore vertebral bone mass and strength in aged ovariectomized rats

Previous studies have shown that parathyroid hormone (PTH) monotherapy and cotherapy with estrogen or risedronate augment vertebral bone mass and bone strength in young, ovariectomized (OVX) rats. The current study was designed to determine whether PTH has similar bone anabolic effects in aged OVX rats at a much later stage of estrogen depletion. Female Sprague Dawley rats were subjected to sham surgery or bilateral ovariectomy at three months of age and maintained untreated for one year after surgery to allow for the development of vertebral osteopenia in OVX rats. Groups of baseline control and OVX rats were sacrificed at the end of this pretreatment period. The remaining OVX rats were then treated for ten weeks with vehicle, antiresorptive agents alone (estrogen, risedronate, or calcitonin), or PTH alone. Other groups of OVX rats were treated concurrently with PTH and each of the antiresorptive agents. The first and fourth lumbar vertebral bodies were processed undecalcified for quantitative bone histomorphometry and biomechanical testing, respectively. As expected, bone mass and compressive strength were decreased in the lumbar vertebral body of baseline OVX rats compared to baseline control rats. This bone loss was associated with decreases in trabecular number and width and an increase in trabecular separation. Treatment with estrogen, risedronate, or calcitonin alone failed to reverse the changes in bone mass, structure, and strength induced by ovariectomy. In contrast, treatment of OVX rats with PTH alone restored vertebral cancellous bone volume and ash density to the level of vehicle-treated control rats and increased vertebral maximum load, stress, and normalized load to well above this level. The hormone significantly increased trabecular width, but not number, in the lumbar vertebral body of OVX rats. Concurrent treatments with PTH and the antiresorptive agents did not augment cancellous bone and biomechanical competence to a greater, or lesser, extent than treatment with PTH alone. Compressive strength correlated significantly with bone mass and trabecular width in the lumbar vertebral body. These results indicate that PTH completely restores lost bone mass and improves bone strength in the vertebral body of aged OVX rats with established osteopenia. With our previous study in younger OVX rats, the current study demonstrates that the anabolic effect of PTH is independent of age and the stage of estrogen depletion in the rat skeleton.     

降钙素对卵巢切除大鼠骨转换的影响

尽管降钙素已在临床用于防治骨质疏松症，但其对骨转换的影响并未阐明，为此本实验以骨组织形态计量学为手段，观察了降钙素对卵巢切除大鼠小梁骨体积和骨转换的影响。实验分三组：卵巢切除后用降钙素组、卵巢切除后用生理盐水组和假手术组。取胫骨干骺端作不脱钙骨切片，行骨组织计量学测定。结果表明，与假手术组相比，卵巢切除后用生理盐水组其小梁骨体积明显下降，破骨细胞表面积、成骨细胞表面积、类骨质表面积、矿化表面积、矿化沉积率和骨形成率均明显升高。相反，卵巢切除后用降钙素组其小梁骨体积恢复正常，骨转换指标也接近假手术组。说明降钙素不仅抑制卵巢切除大鼠骨吸收，而且抑制其骨形成，使骨转换降低，从而预防卵巢切除大鼠骨丢失。     

去卵巢后大鼠不同部位的骨组织计量学与骨密度研究

目的 观察大鼠去除卵巢后不同部位骨的骨组织计量学参数与骨密度以及两之间的相关性。方法 分别进行卵巢去除和伪手术，56d时处死大鼠，取离体胫骨，股骨测量骨密度与组织学参数%Tb.Ar,Tb.Th,Tb.N。结果 OVX后5d时，股骨远端和胫胫骨近端大部分骨组织计量学参数下降；全股骨和股骨远端1/3处骨密度降低；股骨部分骨组织计量学参数与骨密度测量值之间存在正相关性且差异有显性。结论 切除大鼠卵巢56d时，大鼠骨组织计量学参数下降显，骨密度测量以股骨较为敏感，骨组织计量学与骨密度测量值之间的相关性以股骨明显。     

Maintenance of bone mineral density of femoral cortex in ovariectomized rats after withdrawal of concurrent administration of human parathyroid hormone (1–34) and incardronate disodium (YM175)

The aim of this study was to evaluate the potential use of a combination of human parathyroid hormone (1–34) [hPTH(1–34)] and bisphosphonate (incadronate disodium cycloheptylaminomethylenedisphosphonate monohydrate, YM175) as a therapy for osteoporosis. We examined the effects of concurrent administration of PTH and YM175 or single administration and the persistence of their therapeutic effect after withdrawal on bone mineral density (BMD) of the femur in ovariectomized rats with established osteopenia. One hundred and two 11-week-old Sprague-Dawley rats were divided into sham operation and ovariectomy (OVX) groups. OVX rats were untreated for the first 4 weeks post ovariectomy to allow for the development of moderate ovariectomy to allow for the development of moderate osteopenia. These animals were then subjected to various treatment regimens with either PTH, YM175, or both for 4 weeks. The animals were then killed at 4 or 12 weeks, after withdrawal of the treatment and the bone mineral density (BMD) of distal, middle, proximal part, and total area of the femur were determined by dual-energy X-ray absorptiometry (DXA). In the distal femur (cancellous bone-rich region), treatment with YM failed to restore BMD in OVX rats, while treatment with PTH alone (P<.01) or PTH + YM175 (P<.01) reversed BMD in OVX rats after 4 weeks of treatments. The restored distal BMD by PTH or PTH + YM175 treatments could be maintained thereafter until 12 weeks withdrawal. In midshaft of the femur (cortical bone-rich region), treatment with PTH (P<.05), YM175 (P<.05), and PTH + YM175 (P<.01) all could increase BMD after 4 weeks of treatments in the OVX rats, but only concurrent treatment with PTH + YM175 maintained the BMD of femoral midshaft for 12 weeks after withdrawal of the treatment. These results suggest that (1) concurrent treatment with PTH and YM175 could result in a bone gain not only in cancellous bone but also in cortical bone of the femur, and (2) the restored BMD could be maintained for 12 weeks after cessation of the treatment in cortical bone only by concurrent use of PTH + YM175 in immature ovariectomized rats     

强骨饮对去势大鼠股骨颈骨形态计量学的影响

目的探讨中药强骨饮对去势大鼠骨形态计量学的影响。方法选择雌性SD大鼠60只,随机分为强骨饮组（治疗组）、仙灵骨葆组（对照组）和空白对照组,切除大鼠卵巢2月后,给予中药强骨饮灌胃治疗,并与仙灵骨葆组和空白对照组对照治疗,后分别于3月、4.5月、6月取股骨颈包埋切片,全自动图像分析及骨形态计量学软件处理,观察中药对骨形态计量学参数的影响。结果卵巢切除后大鼠骨小梁面积百分数（%Tb.Ar）下降,骨小梁数量（Tb.N）下降,骨小梁宽度（Tb.Th）下降,经强骨饮治疗3月、4.5月、6月后,与空白对照组比较,Tb.Th差异具有显著性（P〈0.01）、与仙灵骨葆组比较,Tb.N差异具有显著性（P〈0.05）。结论中药强骨饮具有增加骨量,提高骨质量的作用,说明中药强骨饮对骨质疏松有明显的治疗作用。     

Treatment of ovariectomized rats with the complex of rhIGF-I/IGFBP-3 Increases cortical and cancellous bone mass and improves structure in the femoral neck

Sixteen-week-old Sprague-Dawley rats were ovariectomized (Ovx) or sham-operated and housed for 8 weeks to develop osteopenia prior to systemic administration of rhIGF-I (0.9 and 2.6 mg/kg) alone or the rhIGF-I/IGFBP-3 (0.9, 2.6 and 7.5 mg/kg) complex. After 8 weeks of treatment, proximal femurs were fixed, embedded, and cut through the midneck region. Structural and dynamic histomorphometric analyses were performed using standard techniques. Ovx increased endocortical resorption and modeling-dependent periosteal formation which resulted in decreased cortical bone area. Despite increased bone formation, trabecular number, thickness, and area were all reduced due to increased resorption. Structural changes following Ovx included fewer struts and nodes, a higher percentage of the simpler strut forms, and reduced endocorticotrabecular cnnnectivity. Eight weeks of treatment with rhIGF-I or rhIGF-I/IGFBP-3 promoted periosteal and endocortical bone formation and reduced the endocortical resorption induced by Ovx. Both rhIGF-I formulations stimulated bone formation on existing trabecular surfaces which increased trabecular thickness and area but not trabecular number. These treatments prevented further deterioration of the trabecular network caused by Ovx and preserved endocortico-trabecular connectivity. In summary, changes in the femoral neck following Ovx appear to be similar in rats and humans. The highest dose of rhIGF-I/IGFBP-3 used in this study showed the best results in promoting cortical and cancellous bone formation, and appears to be promising therapy for human osteopenias.     

中药骨康对去卵巢大鼠腰椎骨形态计量学的影响

目的 探讨中药骨康对卵巢切除大鼠骨质疏松症的治疗作用。方法 选择6m龄SD大鼠48只。随机分为假手术模型组（Sham）、手术模型组（OVX）、尼尔雌醇组（E2）、中药骨康组。切除大鼠卵巢3m后。大鼠骨质疏松症模型制备成功，分别给予尼尔雌醇、中药骨康灌胃治疗，并与Sham组和OVX组对照。治疗3m后，体内双荧光标记，取第2腰椎包埋切片。全自动图像分析及松质骨骨形态计量学软件处理。观察中药对骨形态计量学参数的影响。结果 卵巢切除后大鼠骨小梁面积百分数（％Tb．Ar）下降35．84％，骨小梁数量（Tb．N）下降16．60％，骨小梁宽度（Tb．Th）下降25．79％，表明绝经后骨质疏松症动物模型成立。骨康治疗3个月后，与OVX组相比，Oc．N／mm^2下降42．80％，有显著性差异（P〈0．01）；％Tb．Ar、Tb．Th、Tb．N和MAR有上升趋势（P〉0．05）；15．Sp，％L．Pm、BFR／BS、BFR／TV和Oc．N／mm，BFR／BV有下降趋势（P〉0．05）。结论 中药骨康具有降低骨转换以及促进骨形成和抑制骨吸收的双重作用，说明中药骨康对骨质疏松有明显的治疗作用。     

Cancellous bone resorption in the proximal ilium of the ovariectomized rat

Summary Bone histomorphometry was performed on the proximal ilium of mature Sprague-Dawley rats following ovariectomy, and these rats were compared with sham-operated controls. Bone volume per unit tissue volume (BV/TV), osteoid surface, and the depth and extent of eroded cavities were measured in animals killed at intervals after operation. The rate of bone loss and the mean osteoid surface in the proximal ilium of the ovariectomized rats was significantly greater than that of the control rats over a 210-day postoperative period. The eroded surface and mean trabecular thickness in the proximal ilium of the ovariectomized rats were not significantly different from that of the control rats, and therefore failed to explain the difference in the rate of bone loss. The distribution of the depths of trabecular eroded cavities in the ilium of ovariectomized rats was different from that in the control rats. The loss of trabecular bone mass in the proximal ilium of ovariectomized, mature rats appeared due to increased activity of individual osteoclasts, rather than to increased osteoclast numbers and thinning of trabeculae.     

孕激素对去势雌性大鼠骨密度及骨形态计量作用的初步研究

目的　了解孕激素对去势雌性大鼠骨密度及骨形态计量作用。方法　 5 0只 6月龄Wistar雌性大鼠随机分为 5组 :假手术组和卵巢切除组、卵巢切除后分别加安宫黄体酮 2mg组、安宫黄体酮 2 0mg组和倍美力组。手术后 7d喂药 ,用药后 3个月处死。测定各组大鼠子宫湿重、全身及股骨骨密度并取大鼠椎骨、胫骨组织切片进行形态计量分析。结果　两组孕激素组子宫湿重与卵巢切除组相同 ,均显著低于假手术组与倍美力组 (P <0 0 0 1)。假手术、雌、孕激素组全身骨密度测定均大于卵巢切除组 (P <0 0 5 )。各组股骨骨密度无显著差异。组织切片观察显示 ,假手术与倍美力组骨小梁粗壮、饱满、结构完整 ;卵巢切除组则纤细、断裂、完整性差。孕激素组骨小梁结构优于卵巢切除组但不及假手术及倍美力组。计量分析显示孕激素组椎骨骨小梁面积明显大于卵巢切除组(P <0 0 5 ) ,但低于倍美力组 (P <0 0 5 )。胫骨骨小梁面积与卵巢切除组相仿 ,均明显低于假手术和倍美力组 (P <0 0 5 )。孕激素 2mg与 2 0mg组间无明显差异。结论　两种剂量的安宫黄体酮对卵巢切除大鼠骨质疏松均有一定防治作用 ,但从骨组织形态计量分析 ,其作用较弱 ,与结合雌激素相比 ,尚不足以维持骨量     

龟地散与钙剂对去放巢大鼠骨重,骨密度,骨强度的影响

使用补肾健骨中药龟地散对切除卵巢的雌性大鼠进行不同剂量的药物治疗,并与模型对照组和钙剂组进行比较。实验结果表明：龟地散显提高模型对照组大鼬有密度值（Ｐ〈０．０５）和骨矿含量（Ｐ〈０．０５）,从而抑制骨矿溶解和丢失。与模型对照组相比,龟地散明显增加骨质疏松大鼠的骨重（Ｐ〈０．０１）,并且对大鼠的骨长、骨直径、骨面积和体重也有一定的影响。龟地散还具有显提高大鼠骨强度（Ｐ〈０．０１）等方面的作用。单     

Effects of two non-endurance exercise protocols on established bone loss in ovariectomized adult rats

Summary The effects of non-endurance exercise on bone properties were evaluated in 9-month-old sham-operated (SH) and ovariectomized (OVX) rats. The studies were started 3 months postsurgery, after bone mass was decreased in OVX rats. The sham and OVX rats were either kept sedentary (SED) or were trained to run with one of two protocols: 12 m/minute, 50 minutes/day, 4 days/week (low intensity, frequent, EX-1); or 21 m/minute, 40 minutes/day, 1 day/week (moderate intensity, infrequent, EX-2). A group of seven rats evaluated at the beginning of the study served as baseline control. The bone mineral was assessed by the ash weight of the left femur, tibia, and 4th lumbar vertebra. Biomechanical (strength, deformation, stress, strain, and stiffness) and morphometric (length, cortical and medullary area, moment of inertia) properties were evaluated for the right femur. There was a significantly lower bone mineral and mechanical properties in OVX-SED (n=7) than in SH-SED (n=10) rats. The OVX-EX-1 (n=6) rats had higher ash content of femur and tibia than OVX-SED rats, but the change was significant only for tibia. The EX-2 had no effect on the ash content, but femur stress was higher in OVX-EX-2 (n=8) than in OVX-SED rats. The femur yield force and deformation were improved in OVX rats with both exercise protocols, whereas the vertebra ash weight, femur strain, modulus of elasticity, length, cortical area, and moment of inertia were not changed. Non-endurance exercise did not affect bone properties in either SH-EX-1 (n=7) or SH-EX-2 (n=8) groups. We conclude that non-endurance exercise has beneficial effects on established osteopenia in ovariectomized rats.     

Long-term effect of incadronate disodium (YM-175) on fracture healing of femoral shaft in growing rats.

The aim of this study was to investigate the long-term effect of incadronate on fracture healing of the femoral shaft in rats. Female Sprague-Dawley 8-week-old rats were injected subcutaneously (sc) with either vehicle (V group) or two doses of incadronate (10 microg/kg and 100 microg/kg) three times a week for 2 weeks. Right femoral diaphysis was then fractured and fixed with intramedullary stainless wire. Just after fracture, incadronate treatment was stopped in pretreatment groups (P groups: P-10 and P-100) or continued in continuous treatment groups (C groups: C-10 and C-100). All rats were killed at 25 weeks or 49 weeks after surgery. Fractured femur was evaluated radiologically and mechanically and then stained in Villanueva bone stain and embedded in methyl methacrylate. Undecalcified cross-sections from the fracture area were evaluated microradiologically and histomorphometrically. Radiographic observation showed that the fracture line disappeared in all groups. Cross-sectional area in the C-100 group was the biggest among all groups and in the C-10 group was larger than that in the V group at 25 weeks. Histological and histomorphometric observations showed that the process of fracture healing was delayed under continuous treatment with incadronate as evidenced by the delay of both lamellar cortical shell formation and resolution of original cortex in C groups. Percent linear labeling perimeter, mineral apposition rate (MAR), and bone formation rate (BFR) in C groups significantly decreased compared with the other groups, indicating that the callus remodeling was suppressed under continuous treatment, especially with a high dose. Mechanical study showed that the stiffness and ultimate load of the fractured femur in the C 100 group were the highest among all groups at both 25 weeks and 49 weeks. In conclusion, this study showed that long-term continuous treatment with incadronate delayed the process of fracture healing of femur in rats, especially under high dose but it did not impair the recovery of mechanical integrity of the fracture.     

Loss of vertebral bone and mechanical strength in estrogen-deficient rats is prevented by long-term administration of zoledronic acid

This study investigated the protective effect of long-term treatment with the bisphosphonate zoledronic acid on bone mass, structure, and strength in adult, estrogen-deficient rats. Rats were ovariectomized (OVX) at the age of 4 months and divided into four groups of 20 rats: one group of saline-treated OVX controls, and three groups of OVX rats treated with 0.3, 1.5, or 7.5 g/kg/week s.c. zoledronic acid (ZOL). An additional group of sham-operated, saline-treated rats served as normal controls. Biochemical assays were performed after 16 and 51 weeks, respectively, and bone mineral density (BMD) determinations after 17 and 52 weeks, respectively. Before the end of the experiment animals were injected with tetracyclines for the determination of dynamic bone indexes. Finally, animals were sacrificed after 52 weeks, and vertebral bones (LV5) were subjected to mechanical compression testing. LV4 were used for histology and LV2 for microcomputed tomography. ZOL treatment abolished the rise of osteocalcin and reduced urinary deoxypyridinoline excretion. BMD was reduced in the OVX group in comparison to sham controls, and the decline was dose-dependently prevented by ZOL treatment. Tetracycline labeling showed a significant increase in bone formation rate (BFR) in OVX rats which was abolished by ZOL treatment. The same was observed for osteoid perimeter (Os.Pm) suggesting that ZOL diminished the high bone turnover associated with estrogen deficiency. Architectural parameters (BV/TV, Tb.Th*, Tb.N*, Tb.Sp*, SMI, CD) underwent the expected changes toward structural deterioration which was completely prevented by ZOL administration at doses of 1.5 and 7.5 g/kg/week s.c. Similar results were obtained in compression testing: maximum stress fell significantly after OVX, and this effect was effectively prevented by ZOL treatment. Regression analysis suggests that in this rat model, SMI and Tb.Th* significantly contribute to compressive strength, albeit to a smaller degree than total cross-sectional area. The data further suggest that in the aged OVX rat, SMI and TB.Th* change in an interdependent way. ZOL prevents this process by inhibiting plate thinning and the transition into rod-shaped trabeculae.     

周期性与连续性给予羟乙膦酸钠对去势大鼠骨质疏松症治疗作用的比较

用不脱钙骨切片的骨组织形态计量学方法比较周期性口服、周期性腹腔注射和连续性口服羟乙膦酸钠（ＨＥＢＰ）对去势雌性大鼠骨质疏松的治疗作用。剂量均为每日３６ｍｇ／ｋｇ。周期为连续５日，停药２５日后再重复循环，共９０日。结果表明周期性口服ＨＥＢＰ的大鼠较单纯去势大鼠的骨转换率降低，胫骨骨小梁骨量显著增加，从而可减缓骨质疏松程度；连续性口服ＨＥＢＰ的大鼠虽然骨小梁骨量也显著增加，但骨转换率不仅较单纯去势大鼠，也较正常大鼠显著降低，骨小梁质量欠佳，骨重建受损；周期性腹腔注射ＨＥＢＰ的大鼠骺板显著增厚，骨小梁类骨质显著增加，软骨基质和骨矿化均受损。此为临床应用ＨＥＢＰ防治骨质疏松提供可借鉴的资料。     

Cortical bone mass,composition, and mechanical properties in female rats in relation to age,long-term ovariectomy,and estrogen substitution

Summary The study comprised 12 groups of female rats: 6 groups of intact rats killed at 2, 6, 9, 12, 15, and 24 months of age, 4 groups of rats ovariectomized at 6 months and killed together with the intact rats at 9, 12, 15, and 24 months of age, and 2 groups of rats (one intact and one ovariectomized) treated with estrogen (2 g estradiol valerate/rat/week s.c.) for 8 months before they were killed at 24 months of age. The composition, dimensions, and mechanical strength of intact bone and bone collagen from femoral diaphyses were investigated in relation to age, ovariectomy, and estrogen administration. Up to 6–9 months of age, the axial length, percentage ash, density, and compressive mechanical stress increased, whereas percentage collagen decreased. An age-related increase in bone mass, crosssectional area, and wall thickness and a decrease in mechanical quality of bone collagen were apparent from 2 to 24 months of age. An age-related periosteal bone formation and the absence of endosteal bone resorption were demonstrated in intact rats. Compared with intact rats, ovariectomy was followed by an increase in body weight, a tendency to reduced percentage ash and a depressed bone mass, crosssectional area, and wall thickness of femoral diaphyses. The compressive mechanical stress of intact bone and the mechanical quality of bone collagen were unaffected by ovariectomy. Ovariectomy did not influence the periosteal bone formation but induced an endosteal bone resorption not present in the intact rats. The estrogen treatment of the ovariectomized rats normalized the body weight of the rats and brought to an end the endosteal bone resorption induced by ovariectomy. Estrogen treatment of both ovariectomized and intact rats tended to reduced the rate of periosteal bone formation.