Trabecular and endocortical bone remodeling in postmenopausal osteoporosis: Comparison with normal postmenopausal women

To assess the bone turnover abnormalities which characterize postmenopausal osteoporosis with vertebral fractures (PMOp), a transiliac bone biopsy was performed after double labeling of the mineralizing front with tetracycline in 50 untreated PMOp patients who were compared with 13 healthy age-matched volunteer females. The analysis of bone remodeling and structure parameters demonstrated that PMOp is a disease affecting both the cancellous and the endocortical envelopes and characterized by increased resorption and by a marked decrease in the osteoblastic apposition rate due to a reduced duration of bone formation. This induces a decrease in the width of both individual osteons and trabeculae. In PMOp, the wide spectrum of bone turnover as compared with the controls, associated with the typical bimodal distribution of cancellous osteoid perimeter, allowed us to identify two subsets, one with normal turnover (NT) and one with high turnover (HT) representing 30% of the cases. When compared to NT, HT was characterized by increased osteoclast number, lower bone volume, thinner osteons, increased formation at the tissue-level and markedly decreased duration of formation. In HT the marked decrease in the duration of activity of osteoblasts and the markedly increased number of osteoclasts induced a greater decrease in bone volume, despite the increase of bone formation at the tissue level. These subsets could not be distinguished by any clinical or biochemical parameter except for serum bone gla protein (osteocalcin) which was significantly higher (as a group) in HT than in NT. The underlying cause for these two subsets is unknown. We conclude that PMOp affects the cancellous and the endocortical bone. Bone loss results from a wide spectrum of bone turnover abnormalities, with two distinct subsets, one with normal turnover and one with high turnover.     

Can serum osteocalcin levels predict bone turnover in patients with osteoporosis?

The assessment of bone metabolism by biochemical markers remains difficult problem. Serum osteocalcin, synthesized in bone cells, is now becoming a sensitive indicator of bone turnover in patients with metabolic bone diseases. We measured serum osteocalcin levels by radioimmunoassay in 18 patients with osteoporosis and examined whether they reflect bone formation, resorption or both. We found that serum osteocalcin levels in biopsy-identified osteoporotics were widely ranged (1.8 – 18.8 ng/ml). Tetracycline double labeling method exibited two types of labeling pattern in the iliac bone, that is double labeled or no double labeled (impaired labeled) pattern. Serum concentrations of osteocalcin in patients with double labeling were significantly higher than those with impaired labeling (11.2±4.0 vs 4.1 ±2.1 ng/ml, P<0.01). Furthermore, serum osteocalcin levels showed a significantly positive linear correlation with the parameters reflecting bone formation, but not with bone resorption. These data indicate that serum osteocalcin levels reflect bone formation in osteoporotics and thereby could be a useful indicator of osteoblastic function in osteoporosis.     

Glucocorticoid-induced inhibition of osteoblastic bone formation in ewes: A biochemical and histomorphometric study

The mechanisms underlying glucocorticoid-induced osteoporosis in humans are a defect in bone formation associated with increased bone resorption. The latter may be due to elevated parathyroid hormone (PTH) levels induced by the impairment of intestinal calcium absorption caused by corticosteroids. In this study we analysed the effects of corticosteroids in old ewes, a potential model for the study of human bone turnover. Two groups of seven 9-year-old female sheep were selected. The first group was injected intramuscularly with a daily dose of 30 mg methylprednisone (MP) during the first 2 months and 15 mg during the last month. After 2 and 3 months of treatment, blood samples were taken. At the end of the experiment the animals were slaughtered and the iliac crest kept for bone histomorphometry. Serum osteocalcin (sOC) rapidly and markedly decreased in the MP-treated group compared with controls (–77%;p<0.01). In contrast, at the end of the experiment serum calcium and PTH levels were similar in both groups. Histomorphometric analysis showed a significant reduction in the wall width of trabecular packets. Dynamic parameters reflecting bone formation at the tissue and cell levels were significantly lower in the MP-treated group than in controls, with a highly significant decrease in the mineralization rate (MAR: –63%,p<0.05) and double-labeled perimeter (dLPm/B.Pm: –92%p<0.05). The bone formation rate (BFR/B.Pm) also decreased by 84% and the adjusted apposition rate (Aj.AR) by 80%. The increase in the total formation period was mainly due to an increase in the inactive period. Significant correlations were found between sOC and MAR, dLPm/B.Pm and BFR/B.Pm (withr respectively 0.67, 0.76 and 0.51). In conclusion, the effects of corticosteroid on ewe bone remodeling are essentially characterized by a major bone formation defect without evidence of secondary hyperparathyroidism, although this cannot be totally excluded by our results. Ewes treated with glucocorticoids could represent a good model for evaluating the effects of drugs candidates for all bone conditions characterized by reduced bone formation resulting from osteoblastic depression.     

Carbamazepine does not alter biochemical parameters of bone turnover in healthy male adults

It is still not completely clear whether or not carbamazepine (CBZ) causes alterations in vitamin D status and in bone metabolism. The objective of this study was therefore to investigate prospectively in healthy adults the effects of CBZ on serum levels of 25-hydroxyvitamin D (25OHD) and on biomarkers of bone formation and resorption. Twenty-one free-living male adults were taking 800 mg/day CBZ for 10 weeks. The study was performed from December 1997 until September 1998 at a geographic latitude of 51°N. Blood samples were collected before treatment (t₁), 33 days (SE 2.5) after starting treatment (t₂), and 70 days (SE 3.6) after starting treatment (t₃). In 13 out of the 21 subjects blood samples were also drawn 64 days (SE 9.0) after treatment had been terminated (t₄). Serum 25OHD levels remained constant during study periods t₁–t₃. 25OHD levels were, however, significantly higher at t₄ compared to t₁–t₃. Serum concentrations of intact osteocalcin, a bone formation marker, and C-telopeptide, a bone resorption marker, were similar during all examinations. Moreover, serum levels of parathyroid hormone, calcium, and inorganic phosphate did not change. Data indicate that CBZ per se does not alter bone metabolism and does not lead to decreased circulating 25OHD levels in young males without epilepsy. Variations in 25OHD levels are in line with the seasonal fluctuations in vitamin D status.     

Stage-dependent changes in trabecular bone turnover and osteogenic capacity of marrow cells during development of type II collagen-induced arthritis in mice

Rheumatoid arthritis (RA) is a disease characterized by inflammatory polyarthritis leading to destruction of the joints and reduction in bone mass. However, the relationship between bone mass and turnover is not yet clear in RA patients. To clarify the effect of bone turnover and marrow osteogenic capacity on mass and structure during the development of arthritis, we examined DBA1/J mice for 8 weeks after the first immunization with bovine type II collagen at the age of 9 weeks. Localized arthritis developed at 4 weeks and advanced arthritis at 6 weeks postimmunization. Urinary deoxypyridinoline levels in arthritic mice were significantly higher at 4 weeks, and levels were maintained thereafter. Their serum osteocalcin levels were significantly reduced compared with controls at 2 and 6 weeks, but did not differ significantly from those in the control group at 4 and 8 weeks. Three-dimensional (3D) trabecular bone volume of the proximal tibia measured by 3D microcomputed tomography (micro-CT) in the arthritic mice became significantly lower at 4 weeks and decreased further at 6 weeks compared with controls. Parameters of 3D trabecular bone structure, such as structure model index and trabecular bone pattern factor, were increased at 4 and 6 weeks, respectively. Trabecular osteoclast number increased and bone formation rates decreased at 8 weeks. The number of total bone marrow cells (BMCs), adherent stromal cells, and area of mineralized nodule formation in the tibia of arthritic mice were significantly reduced compared with controls at 6 weeks. Numbers of total fibroblastic colony-forming units (CFU-f) and alkaline phosphatase (ALP)-positive CFU-f colonies also decreased. However, the values of these osteogenic parameters corrected for the total BMCs and/or adherent stromal cells did not differ significantly between the arthritic and control groups. These data indicate that an increase in bone resorption led to the reduction in trabecular bone mass and deterioration of 3D structure during the localized arthritic stage. The reduction in bone marrow osteogenic potential in the advanced arthritic stage was due to the reduction in the number of total bone marrow cells, and differentiation of osteogenic cells was apparently unaffected. The reduction in bone formation may not be substantial in this arthritic model.     

Serum bone gla protein (BGP) and other markers of bone mineral metabolism in postmenopausal osteoporosis

Summary Bone gla protein, the vitamin K-dependent protein synthesized by osteoblasts and measured in blood by radioimmunoassay, has been used as an index of the rate of bone turnover. The relationship of bone gla protein with other markers of bone mineral metabolism was determined in 31 untreated postmenopausal women with the osteoporotic syndrome. In addition to serum osteocalcin (BGP) we measured parathyroid hormone (PTH) (carboxyl and mid-molecule fragments), 25(OH)D, alkaline phosphatase, estradiol (E₂), estrone (E₁), dietary calcium intake, 24 hour urinary calcium excretion, and bone mineral density by CT scan of the lumbar vertebrae. Significant osteopenia was present on CT in untreated postmenopausal osteoporotic women (bone density in 18 out of 31 was below the critical value of 60 mg/cm³). Serum BGP correlated positively with CT scan (r+0.647,P<0.001). CT and age were negatively correlated (r−0.661,P<0.001) while CT and E₂ showed a positive correlation (r+0.554,P<0.01). Unexpectedly, BGP and age revealed a significant negative correlation (r−0.421,P<0.05). These findings suggest a state of low bone turnover in this group with untreated postmenopausal osteoporosis.     

Osteocalcin levels in diabetic subjects

Summary Because a series of reports suggests the existence of altered bone and mineral metabolism in diabetes mellitus, we studied 106 diabetic subjects (42 insulin-dependent (IDD) and 64 noninsulin dependent (NIDD)) to determine whether a difference in bone turnover (evaluated by serum osteocalcin (OC)) could be found in comparison with normal controls. OC levels in diabetic subjects were lower than the age- and sex-specific predicted values. The reduction was especially evident in male and female NIDD (Z-score: −1.12±0.92, t=8.4,P<0.001 and −0.84±0.86, t=4.0,P<0.01, respectively) and male IDD (Z-score: −0.90±0.86, t=4.5,P<0.01). The mean Z-score for female IDD, albeit negative (−0.31±0.79; t=1.6; 0.2>P>0.1), was not significantly different from normal. Total serum calcium (Ca) and calcitonin (CT) showed an apposite pattern, being higher in all the diabetic subgroups (with the exception of Ca in female IDD), whereas parathyroid hormone (PTH) was lower than expected in each diabetic subset. By multiple regression analysis, the reduction of OC was related to PTH and CT levels and to the type of treatment. Subjects controlled with diet showed differences of greater magnitude from the expected normal values than those treated with oral hypoglycemic agents or insulin (Z-score: −1.28±1.05 vs. −0.85±0.90 and −0.63±0.97, respectively;P=0.05). However, the variance explained by these three factors was small, suggesting that other variables (possibly α,25(OH)₂D) exerted important influences on OC levels.     

引导性骨再生中成骨细胞来源的实验观察

目的 研究 长管骨引导性骨再生成骨细胞来源,进一步完善引导性骨再生理论。方法 将４２只成年雄性新西兰兔在双侧桡骨中段制作标准骨缺损不愈合模型,用硅胶膜呈管状包囊一侧骨缺损,另一侧作为对照侧。１只兔术后１￣１２周分别于每周进行Ｘ线检查;３０只兔,随机分为６组,分别于术后３天、１、２、３、４、５周外死取材,分别进行常规ＨＥ染色,ＳＰ方法ＢＭＰ、ＢＧ抗体的免疫组化染以。结果 隔膜在骨缺损局部生成隔离密闭     

Static and dynamic bone histomorphometry in children with osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a genetic disorder characterized by increased bone fragility and low bone mass. Four clinical types are commonly distinguished. Schematically, type I is the mildest phenotype, type II is usually lethal, type III is the most severe form compatible with postnatal survival, and type IV is moderately severe. Although mutations affecting collagen type I are responsible for the disease in most patients, the mechanisms by which the genetic defects cause abnormal bone development have not been well characterized. Therefore, we evaluated quantitative static and dynamic histomorphometric parameters in tetracycline-labeled iliac bone biopsies from 70 children, aged 1.5 to 13.5 years, with OI types I (n = 32), III (n = 11), and IV (n = 27). Results were compared with those of 27 age-matched controls without metabolic bone disease. Biopsy core width, cortical width, and cancellous bone volume were clearly decreased in all OI types. Decreased cancellous bone volume was due to a 41%–57% reduction in trabecular number and a 15%–27% lower trabecular thickness. Regression analyses revealed that trabecular number did not vary with age in either controls or OI patients, indicating that no trabecular loss occurred. The annual increase in trabecular thickness was 5.8 μm in controls and 3.6 μm in type I OI, whereas no trabecular thickening was evident in type III and IV OI. Wall thickness, which reflects the amount of bone formed during a remodeling cycle, was decreased by 14% in a subgroup of 17 type I OI patients, but was not determined in the other OI types. The remodeling balance was less positive in type I OI than in controls, and probably close to zero in types III and IV. Surface-based parameters of bone remodeling were increased in all OI types, indicating increased recruitment of remodeling units. No defect in matrix mineralization was found. In conclusion, there was evidence of defects in all three mechanisms, which normally lead to an increase in bone mass during childhood; that is, modeling of external bone size and shape, production of secondary trabeculae by endochondral ossification, and thickening of secondary trabeculae by remodeling. Thus, OI might be regarded as a disease in which a single genetic defect in the osteoblast interferes with multiple mechanisms that normally ensure adaptation of the skeleton to the increasing mechanical needs during growth.     

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     

Subchondral bone in osteoarthritis

Summary To determine whether subchondral bone in osteoarthritis differs from that seen in normal human aging, osteoarthritic femoral heads removed for total hip arthroplasty were compared with normal age-matched and young autopsy controls. Standardized, 1-cm deep, weight-bearing and nonweight-bearing subchondral bone blocks, as well as cancellous core bone, 2–4 cm deep to the articular surface, were examined in each femoral head. Mineralization was assessed using density fractionation and chemical analysis, and compared to histomorphometry. In osteoarthritis, both weight-bearing and nonweight-bearing surface subchondral bone showed a lower degree of mineralization than age-matched and young controls. Histomorphometric analysis showed that subchondral bone thickness, as well as all osteoid parameters and eroded surfaces, were increased in osteoarthritic samples versus controls. Mineralization in the deep cancellous core bone increased with normal aging but underwent less change with osteoarthritis. Histomorphometry of the cancellous core showed that osteoid parameters, but not bone volume, were increased in osteoarthritis versus controls. In conclusion, osteoarthritis is associated with a thickening of the subchondral bone with an abnormally low mineralization pattern.     

Ovariectomy and trabecular bone remodeling in the dog

Summary The early effects of ovariectomy (OX) on serum biochemistry and trabecular bone remodeling in the dog were investigated. Adult beagle dams were ovariectomized (n=8) or sham-ovariectomized (n=6) and followed for 6 months. All dogs received an iliac crest biopsy at the time of surgery to establish baseline remodeling data. A second contralateral biopsy was obtained at sacrifice. Serum osteocalcin became significantly elevated approximately 8 weeks following OX and remained elevated for the duration of the study. Histomorphometric analysis of serial transilial specimens showed that, at 6 months, OX had significantly increased the rate of bone remodeling in the ilium. Six months following OX in the dog, changes in serum biochemistry and trabecular bone remodeling in the ilium are consistent with those seen in postmenopausal women suffering from “high remodeling osteoporosis”.     

The influence of ibuprofen on fracture repair: biomechanical, biochemical, histologic, and histomorphometric parameters in rats

Ibuprofen is a widely used cyclo-oxygenase inhibitor in clinical practice. It has been demonstrated by others to have an inhibitory effect on fracture repair in animals. In the present study, we were unable to demonstrate any significant alterations in fracture biomechanics as measured by torsion testing and fracture stage in mature Sprague-Dawley rats treated with 30 mg/kg/day oral dose of ibuprofen, starting 3 days following fracture, over a 12-week time interval. Fracture histology and serum osteocalcin levels were no different in treated animals than control animals. Furthermore, histomorphometric parameters of bone remodeling, including bone volume and bone formation rate in the intact tail vertebrae of these animals with unilateral femur fractures, were no different between treated and control animals.     

Acute effects of deflazacort and prednisone on rates of mineralization and bone formation

The aims of this study were to determine (1) whether acute suppression of bone formation could be evaluated after the administration of corticosteroids in man by quantitative bone histomorphometry; and (2) whether there were significant differences between the effects of prednisone and its analog deflazacort. Thirteen patients who needed high-dose corticosteroid therapy were randomly allocated to two groups of treatment (prednisone or deflazacort). Quantitative bone histomorphometry, using the technique of triple labeling, and biochemical measurements of bone turnover were studied. There were no differences in biochemical indices of bone turnover between prednisone and deflazacort at the beginning and end of the 15 days of treatment course. During corticosteroid treatment, there were no significant changes in biochemical indices of bone turnover but a significant decline in total alkaline phosphatase (P<0.01). Histomorphometric indices, as revealed by measurements of tetracycline interval and extent of labeling, showed no significant differences in either mineral apposition rate or bone formation rate in the two groups. We conclude that the acute glucocorticoid suppression of bone turnover by glucocorticoids is not detectable within the first 2 weeks of treatment by histomorphometric techniques. No differences in bone effects of prednisone and deflazacort were detected in this short-term study.     

Minocycline prevents the decrease in bone mineral density and trabecular bone in ovariectomized aged rats

In the current study, we examined the effects of minocycline, on the osteopenia of ovariectomized aged rats. Old female rats were randomly divided into five groups: sham, ovariectomized control and ovariectomized treated with minocycline, 17β-estradiol, or both agents. Bone samples were collected 8 wk after the treatment. Ovariectomy reduced bone mineral density of the whole femur and at the condylar, distal metaphyseal and head-neck-trochanter regions 10%–19% and the loss of bone density was prevented by treatment with minocycline or 17β-estradiol. Histomorphometric analysis of distal femur showed ovariectomy reduced the trabecular bone area, the trabecular bone number, trabecular bone thickness and increased the trabecular bone separation. The microanatomic structure of trabecular bone also showed that the number of nodes, node to node, cortical to node, node to free end was reduced by ovariectomy. Treatment with minocycline attenuated the effect of ovariectomy on trabecular bone in aged animals. In contrast, cortical bone was not affected by ovariectomy or minocycline treatment. The effect of minocycline on bone turnover was also examined. Minocycline increased osteoid surface, mineralizing surface, mineral apposition rate, bone formation rate and reduced eroded surface. We have therefore concluded that the modest increase in bone mineral density and the improvement in the trabecular bone status noted in minocycline treated ovariectomized aged rats is likely due to an increase in bone formation coupled with a decrease in bone resorption.     

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。     

Histomorphometric analysis of bone mass and bone metabolism in growth hormone deficient adult men

Transiliac bone biopsies were obtained from 36 growth hormone (GH) deficient men (mean age ± SD, 28 ± 4 years), of which 13 had an isolated GH deficiency and 23 had partial or complete hypopituitarism. The latter group was adequately substituted for the pituitary hormone deficiencies other than GH. Static histomorphometry was compared with eight controls, and dynamic histomorphometry was compared with six healthy men matched for age. Mean trabecular bone volume was not decreased and bone volume was high (>30%) in ten patients. Osteoid thickness and mineralization lag time were slightly although not significantly higher than in controls. Osteoid surface, mineralizing surface and bone formation rate tended to be lower than in the controls. The eroded surface was significantly higher (p < 0.002) in the GH deficient patients. The results demonstrate that GH deficient patients do not show trabecular osteoporosis. The increased eroded surface together with normal to increased bone volume and bone surface suggests a prolonged reversal phase or a less sufficient coupling phenomenon.     

Normal bone particles are preferentially resorbed in the presence of osteocalcin-deficient bone particlesIn vivo

Summary In anin vivo model of osteoclastic bone resorption, we previously showed that osteocalcin-deficient bone particles (BPs), derived from warfarin-treated rats, were resorbed 50% as well as normal BPs and that they recruited fewer osteoclastic cells with decreased tartrate-resistant acid phosphatase (TRAP) activity. In order to determine the specificity of the resorption response, we evaluated the fate of implanted mixtures of normal and osteocalcin-deficient BPs. Normal and warfarin-treated donor rats were prelabeledin vivo with oxytetracycline to permit identification of BPs from either source. Normal, osteocalcin-deficient, and 50∶50 mixtures of BPs (either labeled or unlabeled) were implanted into normal rats and recovered 12 days later for enzymatic (TRAP) and nondecalcified histomorphometric analyses. The incorporated oxytetracycline had no signficant effect on resorption of bone particles. The recovered osteocalcin-deficient BPs were surrounded by fewer osteoclastic cells, were resorbed less, and contained less extractable TRAP activity than normal BPs. In mixed BP implants with normal and osteocalcin-deficient BPs, each type of bone particle elicited the same tissue response as when implanted separately. Remarkably, the different particles evoked dissimilar osteoclastic responses and were resorbed to different extents, even when adjacent within the same implant. These data suggest that osteocalcin may act as a substrate signal for resorption and that osteocalcin in the normal BPs does not influence the cellular response to adjacent osteocalcin-deficient BPs.     

糖皮质激素对肾小球疾病患者骨代谢影响因素的研究

目的　探讨长期应用糖皮质激素 (GC)治疗对肾小球疾病患者骨代谢影响的因素。方法　 2 0 7例肾小球疾病患者 ,应用常规剂量GC治疗 ,于治疗前及治疗后每隔 3～ 6个月 ,进行了 35 7例次腰椎和股骨近端骨密度 (BMD)、血钙、血磷和骨钙素浓度测定。结果　①用GC后骨钙素浓度明显降低 (P均 <0 0 0 5 ) ,但其不能预测BMD下降。②用药 15个月后男性各部位BMD均减少 (32 2～111 5 )mg/cm2 ,以L1 4和股骨粗隆更明显 (P均 <0 0 5 ) ,骨丢失率 3 3%～ 10 3% ;女性L1 4BMD均减少(4 3 8～ 76 0 )mg/cm2 ,以L1更明显 (P <0 0 5 ) ,骨丢失率 3 9%～ 7 9%。③年龄与各部位BMD变化呈负相关 ,但不影响GC造成的骨丢失。男性各部位、女性L1 4BMD减少与GC累计剂量和GC用药时间负相关。④用GC15个月 (GC累计剂量 10g以上 ) ,男性L1 4BMD正常的比例从 3/ 4至 3/ 5 ;女性L1和L2 BMD正常者从 3/ 4减少到 1/ 2。结论　长期口服糖皮激素导致与剂量和用药时间相关的腰椎和男性股骨粗隆骨丢失 ,年龄偏大和男性患者骨丢失更明显。     

Prostaglandin E2 receptor (EP4) selective agonist (ONO-4819.CD) accelerates bone repair of femoral cortex after drill-hole injury associated with local upregulation of bone turnover in mature rats

Prostaglandin E₂ (PGE₂) is essential for fracture healing. Systemic administration of EP4 ligands such as PGE₂ and other synthetic EP4 agonists appears to transduce anabolic signals by binding to receptor EP4. Therefore, the present study was designed to test whether administration of EP4 agonist accelerates the healing of drill-hole injury in the femoral diaphysis. After surgery, a total of 128 Wistar rats, at the age of 12 weeks, were assigned to basal control (n = 8), and three groups with respective doses of 0 (vehicle control), 10 (low-dose), and 30 (high-dose) μg/kg body weight of the agent were subcutaneously injected twice a day. Femoral specimens were obtained at 0, 5, 7, 14, 21, and 28 days. In EP4 agonist-treated groups, the total bone volume of the regenerating bone in the defect did not significantly differ, but the regenerated cortical bone volume measured by histomorphometry and cortical bone mineral content (Ct. BMC) by pQCT dose-dependently increased at 14 and 21 days compared to the control. In the high-dose group, the value of osteoclast surface significantly increased compared with that in the control at 14 days. Expression levels of osteocalcin and TRAP mRNAs in the injured tissue increased at 14 days. Expression levels of EP4, BMP-2, and RANKL mRNAs increased at 7 days in the high-dose group. The bone mineral values of the lumbar bone at 28 days, measured by DXA, did not differ in the three groups. These data indicated that systemic administration of EP4 agonist ONO-4819.CD accelerated cortical bone healing after drill-hole injury by upregulating the local turnover of the regenerating bone.