Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys

Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK) currently being developed as a once‐weekly treatment for osteoporosis. In this study, we evaluated the effects of ODN on bone turnover, bone mineral density (BMD), and bone strength in the lumbar spine of estrogen‐deficient, skeletally mature rhesus monkeys. Ovariectomized (OVX) monkeys were treated in prevention mode for 21 months with either vehicle, ODN 6 mg/kg, or ODN 30 mg/kg (p.o., q.d.) and compared with intact animals. ODN treatment persistently suppressed the bone resorption markers (urinary NTx [75% to 90%] and serum CTx [40% to 55%]) and the serum formation markers (BSAP [30% to 35%] and P1NP [60% to 70%]) versus vehicle‐treated OVX monkeys. Treatment with ODN also led to dose‐dependent increases in serum 1‐CTP and maintained estrogen deficiency–elevated Trap‐5b levels, supporting the distinct mechanism of CatK inhibition in effectively suppressing bone resorption without reducing osteoclast numbers. ODN at both doses fully prevented bone loss in lumbar vertebrae (L₁ to L₄) BMD in OVX animals, maintaining a level comparable to intact animals. ODN dose‐dependently increased L₁ to L₄ BMD by 7% in the 6 mg/kg group (p < 0.05 versus OVX‐vehicle) and 15% in the 30 mg/kg group (p < 0.05 versus OVX‐vehicle) from baseline. Treatment also trended to increase bone strength, associated with a positive and highly significant correlation (R = 0.838) between peak load and bone mineral content of the lumbar spine. Whereas ODN reduced bone turnover parameters in trabecular bone, the number of osteoclasts was either maintained or increased in the ODN‐treated groups compared with the vehicle controls. Taken together, our findings demonstrated that the long‐term treatment with ODN effectively suppressed bone turnover without reducing osteoclast number and maintained normal biomechanical properties of the spine of OVX nonhuman primates. © 2012 American Society for Bone and Mineral Research     

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.     

小鼠骨组织形态学特征及泼尼松对骨量及骨钙的影响

目的探讨小鼠骨组织形态学和小鼠骨钙含量的研究方法,并观察不同剂量的泼尼松对小鼠骨形态学及骨钙含量的影响.方法 24只昆明种♀小鼠,随机分为4组正常对照组,泼尼松低、中、高剂量组,对照组给予生理盐水,其余3组分别按泼尼松0.75、1.5、6.3 mg.kg-1@d-1灌胃给药,实验21 d后,眼眶放血,取右胫骨进行硬组织包埋切片,作骨组织形态计量学检测,取右股骨测骨钙含量.结果小鼠骨形态学与大鼠相似,但松质骨骨量个体差异大.形态学中骨量与骨钙含量有正相关(P＜0.05).对不同剂量泼尼松作用的检测表明低、高两剂量泼尼松对骨钙含量无明显影响,中剂量可增加骨钙含量(P＜0.05);骨形态计量学观察可见低、中剂量的泼尼松有增加骨量的趋势,中剂量差异有显著性(P＜0.05),高剂量泼尼松有减少骨量的趋势.中剂量增加松质骨表面双荧光强度(P＜0.05).结论小鼠骨形态学特征和骨钙含量有低的相关关系,泼尼松低的剂量可增加小鼠的骨钙含量、骨量和骨小梁表面荧光,当剂量增加时却有减少骨量和骨表面荧光的作用.提示测定药物对骨钙含量影响在一定程度上反映形态学中骨量的变化,提示若用高剂量泼尼松可致小鼠骨量减少模型.     

Histomorphometric study of trabecular channels in normal iliac bone

Summary Cancellous bone channels in the normal iliac crest have been studied histologically and by histomorphometry, and their biological role has been considered. Eighty percent of trabecular channels were typical osteons with the same structural and remodeling features as cortical osteons. The similarity of osteons in these two locations was corroborated by the comparability of morphometric features. The points of difference between osteons in the two types of bone were irregular configurations of trabecular osteons and marrow cells in the central canal in some. Since the number of trabecular osteons decreases with age, and since active trabecular resorption cavities were few in number, it is unlikely that additional osteons are formed in normal bone after the active modeling phase of bone growth. It is improbable that they make a significant contribution to bone remodeling since their number decreases with age, and since the available surface of trabecular channels for remodeling is extremely small. However, it is probable that they aid the intraosseous microcirculation and mineral exchange in thick trabecula and bifurcations, where they are mainly located. The demarcation curves at the 95% confidence interval, which suggest the normal range for numbers of channels, was calculated from the scatter diagram against bone area.     

A nonhuman primate model of age-related bone loss: a longitudinal study in male and premenopausal female rhesus monkeys

Aging is associated with gradual bone loss in men and premenopausal women, with an accelerated rate of loss after menopause in women. Although many studies have investigated bone loss due to surgically induced estrogen depletion, little is known regarding normal age-related changes in bone mass in animal models. We used dual-energy X-ray absorptiometry (DXA) to measure bone mineral density (BMD), bone mineral content (BMC), and projected area (PA) at four skeletal sites over 4 years in 20 premenopausal female (8-23 years) and 29 male (8-27 years) rhesus monkeys (Macaca mulatta). Forearm BMD declined with age in both male and female monkeys. Lean mass was positively associated with BMD at all sites in males and with the distal radius in females. Serum osteocalcin declined and urinary cross-links increased with age in males but not females. Serum 25-hydroxyvitamin D concentrations decreased with age in females, and a similar trend was observed in males. In conclusion, an age-related decline in forearm BMD was observed in male and female rhesus monkeys. Total body BMC declined over time in older females, with a similar trend in males. Changes in markers of bone turnover with age were also observed in male monkeys. The results of this longitudinal study suggest that the rhesus monkey is a potential model for age-related changes in the human skeleton.     

Growth and maturation of mandibular bone in otherwise totally immobilized rhesus monkeys

The effects of 14 days of total postcranial body immobilization (in plaster casts) on the mineralization rate and on the maturation of matrix and mineral moieties in the rhesus jaw were studied by tetracycline labeling and by density gradient methods, respectively. Immobilization did not alter the rates of periosteal and endosteal mineralization in the dense cortical bone from the lingular region of the jaw, but it did impair mineralization in osteonal bone. Osteons that continued to show radial closure did so at a normal rate. In the more trabecular cortex (premolar region) in young monkeys (3-6 kg body weight), immobilization impaired bone mineralization, as shown by lower ratios of calcium and inorganic phosphorus to hydroxyproline (Ca/HO-Pr;Pi/HO-Pr), and it reduced the rate at which the newly formed bone and mineral moieties matured. In older monkeys (6-10 kg body weight) immobilization did not alter Ca/HO-Pr and Pi/HO-Pr ratios or impair tissue maturation. These changes tended to normalize within 7 to 14 days after decasting.     

Relationship between vitamin D status and bone mineralization,mass, and metabolism in children with osteogenesis imperfecta: Histomorphometric study

The effect of low vitamin D levels in children with bone fragility disorders has not been examined in detail. In this study, we evaluated the relationship between vitamin D status and parameters of skeletal mineralization, mass, and metabolism in a group of pediatric osteogenesis imperfecta (OI) patients. This retrospective study consisted of 71 patients with a diagnosis of OI type I, III, or IV (ages 1.4 to 17.5 years; 36 girls) who had not received bisphosphonate treatment before iliac bone biopsy. Serum 25‐hydroxyvitamin D [25(OH)D] levels ranged from 13 to 103 nmol/L and were less than 50 nmol/L in 37 patients (52%). None of the OI patients had radiologic signs of rickets or fulfilled the histomorphometric criteria for the diagnosis of osteomalacia (ie, elevated results for both osteoid thickness and mineralization lag time). Serum 25(OH)D levels were negatively correlated with age and serum parathyroid hormone levels but were not correlated with any parameter of bone mineralization (ie, osteoid thickness, mineralization lag time, or bone‐formation rate per bone surface) or bone mass (ie, lumbar spine areal bone mineral density, iliac bone volume per tissue volume, or iliac cortical width). We found no evidence that serum 25(OH)D levels in the range from 13 to 103 nmol/L were associated with measures of bone mineralization, metabolism, or mass in children with OI. © 2011 American Society for Bone and Mineral Research     

Histomorphometric study of alveolar bone turnover in orthodontic tooth movement

Selected histomorphometric parameters were measured in alveolar bone adjacent to rat molars treated with a 40gram tipping force designed to tip the molar mesially and with a sham procedure. Undecalcified parasagittal sections of teeth and surrounding tissues were prepared for static and dynamic histomorphometry at 1, 3, 5, 7, 10, and 14 days. Initial tooth displacement was assessed by measuring differences between groups in the widths of the day-1 periodontal ligaments (PDL) at various vertical locations and correlating these using linear regression analysis. All parameters were measured in the alveolar bone adjacent to four quadrants around the teeth (mesial-distal; occlusalapical). Means and standard errors for each parameter in each group were calculated and compared for time- and group-specific differences using ANOVA and pairwise comparisons with Scheffe's multiple comparison tests. In shamtreated rats, bone resorption predominated on the distal alveolar surface, but significant surface-related differences between mesial and distal surfaces in bone formation were not demonstrated. Time-specific effects in bone resorption were not evident on either surface in the shams. These findings suggested that molar distal drift in the sham rat is facilitated by resorption in the distal alveolar bone. PDL width changes in orthodontically-treated rats were greatest in the mesial occlusal half of the root and decayed linearly toward the apex indicating that the greater initial tooth displacement occurred in the occlusal half of the root surface. Histomorphometric parameters of alveolar bone turnover were also seen to be greater in these locations, suggesting that these processes were sensitive to the increased tooth displacement. In orthodontically-treated rats, the total paradental alveolar bone and both pressure (mesial) and tension (distal) surfaces experienced a wave of resorption that lasted for four days, was preceded by an activation period of two days, and was followed by a wave of formation that persisted until the end of the experiment (14 days). The relative balance between bone formation and resorption waves was location-specific, with formation predominant on the tension side and resorption predominant on the pressure. These findings are consistent with the conclusion that pressure and tension initiate similar bone turnover events, and that bone deposition or removal is controlled by the degree of balance between the relative amounts of bone formation and resorption that occur at these sites.     

猴下颌角截骨术后咬肌组织学及酶组织化学变化的实验研究

目的 观察下颌角截骨术后咬肌组织学与酶组织化学的变化.方法 将12只成年雌性恒河猴随机分为三组,每组4只.各组经口内随机行一侧下颌角截骨术,另一侧作为对照.分别于术后3、6、12个月切取咬肌标本进行大体标本观察,HE染色和NADH染色观察.结果 术后咬肌发生一定程度萎缩,以术后3个月最为明显;术后12个月时有明显恢复;术侧咬肌Ⅰ型肌纤维平均横截面积和构成百分比均明显减小.Ⅱ型肌纤维的构成在术后各个时期均明显增加,其横截面积在术后3个月时,明显小于对照侧,但在术后6和12个月时,与对照侧相比无明显差别.结论 下颌角截骨术后,咬肌体积与镜下组织结构会发生适应性改建.这种变化与术后咬肌附着位置和咀嚼功能的变化有关.     

Bone formation and bone resorption in failed total joint arthroplasties: Histomorphometric analysis with histochemical and immunohistochemical technique

To elucidate the reactions of bone around aseptically loosened total joint arthroplasties, 24 interface tissues with adjacent bone were obtained in 17 revision operations (11 hips and six knees). The morphology of the bone surface next to the interface membrane was investigated with histochemical and immunohistochemical techniques and then histomorphometrically analysed. One-third of the total bone surface, 32.69 ± 5.16% (mean ± SE) (n = 24), showed positive alkaline phosphatase activity. The bone surface in contact with the cells positive for CD11b (a macrophage marker) amounted to 19.33 ± 5.16% (n = 24). The proportion of the osteoclastic bone resorption estimated by vitronectin receptor expression was 7.67 ± 1.82% (n = 21). Tissues retrieved from the sites where radiographic evidence of osteolysis was present (n = 12) had a significantly larger extent of the bone surface in contact with CD11b-positive cells than did the tissues from areas without osteolysis (n = 12, p = 0.0067, Mann-Whitney U test), whereas no significant difference was observed in the extent of osteoclastic bone resorption. These data demonstrate that active bone formation, regarded as a repair process, is the most common feature even in revised cases. They also highlight the role played by macrophages, not as cells producing inflammatory mediators that could activate osteoclasts, but as cells primarily responsible for the bone loss in osteolytic lesions.     

Spermatic granuloma of vas deferens after vasectomy in rhesus monkeys and men Light and electron microscopic study

Spermatic granuloma of the vas deferens is a common complication of vasectomy which has received scant morphologic study. This study investigated the light and electron microscopic structure of such granulomas detected in rhesus monkeys (Macaca mulatta) and man after various modes of vasectomy and postoperative periods. Unilateral experimental vasectomy in monkeys was performed by either silk ligation or clasp occlusion; in 4 of 13 ligated animals and 5 of 5 clasp vasectomized animals granulomas developed at the site of fasectomy. In man, portions of the vas deferens were excised adjacent to the site of vasectomy preparatory to vasovasostomy. Of 5 patients studied, unilateral spermatic granulomas developed in 3. Such granulomas in both monkey and man were characterized by (1) masses of sperm surrounded by epithelioid cells and connective tissue, and (2) multiple epithelial-lined channels which often contained sperm and spermiophages. In both species, fine structural characteristics of the epithelium lining such channels closely resembled those of the principal cells of the normal vas. Spermiophagic cells included macrophages, epithelioid cells, and, in the monkey only, neutrophils. Lymphocytic invasion was a common feature of the human granulomas but was found only occasionally in the monkey granulomas. As a greater number of granulomas are studied in humans and monkeys, it is hoped that the processes underlying granuloma formation and the role of such granulomas in the development of complications after vasectomy will be clarified.     

The effect of ovariectomy on spine bone mineral density in rhesus monkeys

As part of a study on the effects of hormones on uterine biology and estrogen metabolism, 12 normal female rhesus (Macaca mulatta) monkeys were ovariectomized, and treated intermittently with estradiol and progesterone. In order to determine whether there were changes in bone density as a result of ovariectomy despite the hormone therapy, spine bone mineral density (BMD) was measured by dual-photon absorptiometry. The mean +/- SE time from ovariectomy was 26 +/- 3 months, the mean estrogen treatment time was 3.5 +/- 0.4 months and the mean time from last hormonal treatment was 4.1 +/- 0.6 months. In these 12 monkeys aged 7.7 +/- 0.2 years, the mean spine BMD, 0.825 +/- 0.008 g/cm2, was significantly less, p = 0.0011, than the spine BMD, 0.863 +/- 0.007 g/cm2, in 12 intact female rhesus of similar age, 7.6 +/- 0.1 years and weight. Ovariectomy in female rhesus monkeys results in a relatively rapid diminution of spine BMD which is not prevented by intermittent hormonal replacement. This species may be an excellent model for studies of human osteoporosis.     

Histomorphometric study of bone reactions during orthodontic tooth movement in rats

The biological response to orthodontic tooth movement has generally focused on reactions within the periodontal ligament (PDL), whereas less attention has been paid to the behavior of neighboring bone. The purpose of the study was to describe the influence of orthodontic force on bone surrounding the displaced tooth and the adjacent, untreated teeth. Bone changes in relation to treatment time and different sites were investigated. A mesial tipping of the left maxillary first molar was obtained from 54 adult male Wistar rats. Oxytetracycline was injected subcutaneously 48 h before killing, which took place after 4, 7, or 14 days. The maxilla was fixed in paraformaldehyde and embedded undecalcified in methylmethacrylate. A set of thick horizontal sections was taken from the cervical, intermediate, and apical levels of the roots. The sections were microradiographed and analyzed microscopically under bright-field and fluorescent illumination. Bone fraction and PDL width was measured using a Zeiss Videoplan device equipped with an overlay system. New bone formation was detected by oxytetracycline labels. The analysis showed a consistent, significant decrease of the alveolar bone fraction around both displaced and adjacent teeth at all treatment times. Apposition, indicated by the tetracycline uptake, was found on the periosteal side of the treated hemimaxilla and, after 14 days, also on the surface toward which the tooth was moving and around the adjacent teeth. These results suggest that a time rather than a space relationship exists between bone resorption and formation and that the whole hemimaxilla reacts to the mechanical challenge, resembling the regional acceleratory phenomenon (RAP) observed in other circumstances.     

Bone and muscle mass after hip rearthroplasty: Controlled CT study of 12 patients

The cortical bone mineral density (BMD), bone volume, bone mass and muscle volume of the thigh and the cancellous BMD of the distal femur and proximal tibia were quantified by computed tomography (QCT) in 12 patients after hip rearthroplasty due to prosthetic loosening following arthroplasty for arthrosis. Both legs were scanned and the operated side was compared with the healthy side. A control group, 12 patients, had had unilateral hip arthroplasty without subsequent rearthroplasty. There was a 19 percent decrease in bone mass and 13 percent decrease in muscle volume in the middle femur, compared to the contralateral side, in the patients who had undergone rearthroplasty, and a reduction of 9 percent for the same variables in the control group. There was also a more marked osteopenia in the reoperated extremity in the distal femur and proximal tibia compared to the unoperated side     

Changes in vertebral bone marrow fat and bone mass after gastric bypass surgery: A pilot study

Bone marrow fat may serve a metabolic role distinct from other fat depots, and it may be altered by metabolic conditions including diabetes. Caloric restriction paradoxically increases marrow fat in mice, and women with anorexia nervosa have high marrow fat. The longitudinal effect of weight loss on marrow fat in humans is unknown. We hypothesized that marrow fat increases after Roux-en-Y gastric bypass (RYGB) surgery, as total body fat decreases. In a pilot study of 11 morbidly obese women (6 diabetic, 5 nondiabetic), we measured vertebral marrow fat content (percentage fat fraction) before and 6 months after RYGB using magnetic resonance spectroscopy. Total body fat mass declined in all participants (mean ± SD decline 19.1 ± 6.1 kg or 36.5% ± 10.9%, p < 0.001). Areal bone mineral density (BMD) decreased by 5.2% ± 3.5% and 4.1% ± 2.6% at the femoral neck and total hip, respectively, and volumetric BMD decreased at the spine by 7.4% ± 2.8% (p < 0.001 for all). Effects of RYGB on marrow fat differed by diabetes status (adjusted p = 0.04). There was little mean change in marrow fat in nondiabetic women (mean + 0.9%, 95% CI − 10.0 to + 11.7%, p = 0.84). In contrast, marrow fat decreased in diabetic women (− 7.5%, 95% CI − 15.2 to + 0.1%, p = 0.05). Changes in total body fat mass and marrow fat were inversely correlated among nondiabetic (r = − 0.96, p = 0.01) but not diabetic (r = 0.52, p = 0.29) participants. In conclusion, among those without diabetes, marrow fat is maintained on average after RYGB, despite dramatic declines in overall fat mass. Among those with diabetes, RYGB may reduce marrow fat. Thus, future studies of marrow fat should take diabetes status into account. Marrow fat may have unique metabolic behavior compared with other fat depots.     

Effect of exercise on tibial and lumbar vertebral bone mass in mature osteopenic rats: Bone histomorphometry study

The effect of moderate running exercise on tibial and lumbar vertebral bone mass was examined in mature osteopenic rats by bone histomorphometry. Ten 37-week-old female Wistar rats, with bone loss resulting from being fed a relatively low-calcium diet for 14 weeks after ovariectomy at the age of 23 weeks, were randomly divided into two groups of five animals each; control and exercise groups. The exercise consisted of treadmill running at 12 m/min for 1 h per day on 5 days per week for 12 weeks. During the exercise period, all animals were fed a standard calcium diet. After 12 weeks of exercise, bone histomorphometry was evaluated for cancellous bone (secondary spongiosa) of the proximal tibia and the fourth lumbar vertebra and for cortical bone of the tibial shaft. The findings suggested that in the mature osteopenic rat, there was a beneficial effect of moderate running exercise with adequate calcium intake on bone mass only in a weight-bearing long bone, the tibia. The mechanism for increased bone mass appeared to be both decreased bone resorption and increased bone formation in cancellous bone and increased bone formation in cortical bone. Received for publication on Dec. 18, 1997; accepted on April 2, 1998     

Enhanced bone mass and physical fitness in prepubescent footballers

Not much is known about the osteogenic effects of sport activities before puberty. We tested the hypothesis that football (soccer) participation is associated with enhanced bone mineral content (BMC) and areal density (BMD) in prepubertal boys. One hundred four healthy white boys (9.3 +/- 0.2 years, Tanner stages I-II) participated in this study: 53 footballers and 51 controls. The footballers devoted at least 3 h per week to participation in football, while the controls did not perform in any kind of regular physical activity other than that programmed during the compulsory physical education courses. Bone variables were measured by dual-energy X-ray absorptiometry. The maximal leg extension isometric force in the squat position with knees bent at 90 degrees and the peak force, mean power, and height jumped during vertical jumps were assed with a force plate. Additionally, 30-m running speed, 300-m run (anaerobic capacity), and 20-m shuttle-run tests (maximal aerobic power) were also performed. Compared to the controls, the footballers attained better results in the physical fitness test and had lower body mass (-10%, P < 0.05) due to a reduced percentage of body fat (4% less, P < 0.05). The footballers exhibit enhanced trochanteric BMC (+17%, P < 0.001). Likewise, femoral and lumbar spine BMD were also greater in the football players (P 相似文献   

Bone mass following physical activity in young years: a mean 39-year prospective controlled study in men

Summary

This is a study on exercise-associated bone mineral density (BMD) which in men is maintained three decades after cessation of sports. In this prospective controlled cohort study active athletes had a BMD Z-score of 1.0 and after 39 years 0.5 to 1.2 depending on the measured region), using the same single-photon absorptiometry device, dual X-ray absorptiometry (DXA), and peripheral computed tomography (pQCT).

Introduction

The aims of this study were to prospectively evaluate BMD changes in male athletes from activity into long-term retirement and to simultaneously evaluate other bone traits.

Methods

Bone mineral density (grams per square centimeter) was measured in 46 male athletes with a mean age of 22 years (range, 15–40) by using the same single-photon absorptiometry device, both at active career and a mean of 39 years (range, 38–40) later when they had long-term retired. At follow-up, BMD was also evaluated by DXA and pQCT. Twenty-four non-athletic males of similar age served as controls. Between-group differences are presented as means with 95 % confidence intervals.

Results

The active athletes (baseline) had a BMD Z-score of 1.0 (0.7, 1.4) in the femoral condyles. The retired athletes (follow-up) had a BMD Z-score of 0.5 to 1.2 depending on the measuring technique and the measured region. The tibial cortical area Z-score at follow-up was 0.8 (0.5, 1.2) and the tibial strength index Z-score 0.7 (0.4, 1.0). There were no changes in BMD Z-scores from activity to retirement, neither when estimated by the same device in different regions [? Z-score ?0.3 (?0.8, 0.2)] nor in the same region with different devices [? Z-score 0.0 (?0.4, 0.4)]. The benefits remained after adjustments for anthropometrics and lifestyle. No correlation was seen with years since retirement.

Conclusions

Exercise-associated high BMD in young years seems, in men, to be maintained three decades after cessation of high-level physical activity.