No effect of risedronate on articular cartilage damage in the Dunkin Hartley guinea pig model of osteoarthritis.

OBJECTIVES: To investigate whether treatment with a bisphosphonate would influence the subchondral bone plate stiffness and the development of cartilage damage in Dunkin Hartley guinea pigs, which develop osteoarthritis (OA) spontaneously. METHOD: Fifty-six 3-month-old male Dunkin Hartley guinea pigs were randomized into a baseline group and six groups receiving either the bisphosphonate risedronate (30 µg/kg) or vehicle five times a week for 6, 12, or 24 weeks. The medial condyle of the right stifle joint was investigated by histology, using the Osteoarthritis Research Society International (OARSI) score, along with static and dynamic histomorphometry. The subchondral bone plate of the left tibia was tested mechanically with indentation testing. Degradation products of C-terminal telopeptides of type II collagen (CTX-II) were measured in serum. RESULTS: The OARSI score did not differ between risedronate-treated and control animals at any time point. The fraction of bone surfaces covered with osteoclasts (Oc.S/BS) was significantly suppressed in risedronate-treated animals at all time points, as were the fractions of mineralizing surfaces (MS/BS) and osteoid-covered surfaces (OS/BS), and also serum CTX-II. This was accompanied by a significant increase in the epiphyseal content of calcified tissue and in the thickness of the subchondral bone plate. However, this did not result in a stiffer subchondral bone at any time point. DISCUSSION: The risedronate treatment inhibited osteoclastic resorption of calcified cartilage in the primary spongiosa under the epiphyseal growth plate, explaining the risedronate-mediated decrease in CTX-II. Moreover, the serum CTX-II level was not related to the OA-induced articular cartilage degradation seen in this model. CONCLUSIONS: Risedronate did not influence the OARSI score and subchondral plate stiffness, but decreased serum CTX-II in Dunkin Hartley guinea pigs.

Relationship between articular cartilage damage and subchondral bone properties and meniscal ossification in the Dunkin Hartley guinea pig model of osteoarthritis.

OBJECTIVES: To describe the age-related changes of articular cartilage, subchondral bone morphology, and stiffness. Furthermore, to investigate whether subchondral bone histological and mechanical properties and meniscal histological properties are related to articular cartilage damage in the Dunkin Hartley guinea pig model of osteoarthritis (OA). METHODS: Forty male Dunkin Hartley guinea pigs aged 2, 6, 9, and 12 months were studied. The right stifle joints and the left menisci were embedded undecalcified and the tibial articular cartilage and subchondral bone and the menisci were examined using histology. The stiffness of the left tibial subchondral bone was determined with indentation testing. RESULTS: The Osteoarthritis Research Society International (OARSI) grade of the osteoarthritic cartilage lesions of the medial (p < 0.001) and lateral (p < 0.001) condyle and the ossification of the medial (p < 0.001) and lateral (p < 0.001) meniscus increased significantly with age and was significantly more pronounced at the medial condyle than at the lateral condyle. The grade of the osteoarthritic cartilage lesions was significantly correlated (r = 0.78, p < 0.001) with the meniscal ossification, weakly correlated (r = 0.34, p < 0.007) with the subchondral bone plate thickness, and not correlated with the subchondral bone density (r = -0.010, p = 0.94) and the subchondral bone stiffness (r = -0.13, p = 0.30). CONCLUSION: The meniscal ossification observed in Dunkin Hartley guinea pigs may play an important role in the pathogenesis of OA in these animals.

The anabolic effect of PTH on bone is attenuated by simultaneous glucocorticoid treatment.

Glucocorticoids (GC) are used for the treatment of a wide spectrum of diseases because of their potent anti-inflammatory and immunosuppressive effects, and they are serious and common causes of secondary osteoporosis. Administration of intermittent parathyroid hormone (PTH) may induce formation of new bone and may counteract the bone loss induced by GC treatment. Effects of simultaneous PTH and GC treatment were investigated on bone biomechanics, static and dynamic histomorphometry, and bone metabolism. Twenty-seven-month-old female rats were divided randomly into the following groups: baseline, vehicle, PTH, GC, and PTH + GC. PTH (1-34) 25 mug/kg and GC (methylprednisolone) 2.5 mg/kg were injected subcutaneously each day for a treatment period of 8 weeks. The rats were labeled with fluorochromes 3 times during the experiment. Bone sections were studied by fluorescence microscopy. The PTH injections resulted in a 5-fold increase in cancellous bone volume. At the proximal tibia, PTH induced a pronounced formation of new cancellous bone which originated from the endocortical bone surfaces and from thin trabeculae. Formation and modeling of connections between trabeculae were observed. Similar but less pronounced structural changes were seen in the PTH + GC group. The compressive strength of the cancellous bone was increased by 6-fold in the PTH group compared with the vehicle group. GC partially inhibited the increase in compressive strength induced by PTH. Concerning cortical bone, PTH induced a pronounced increase in the endocortical bone formation rate (BFR) and a smaller increase in periosteal BFR. The combination of PTH + GC resulted in a partial inhibition of the PTH-induced increase in bone formation. Serum-osteocalcin was increased by 65% in the PTH group and reduced by 39% in the GC group. The pronounced anabolic effect of PTH injections on the endocortical and trabecular bone surfaces and less pronounced anabolic effect on periosteal surfaces were partially inhibited, but not prevented, by simultaneous GC treatment in old rats. Both cortical and cancellous bone possessed full mechanical competence after treatment with PTH + GC.

Dietary supplementation with methionine and homocysteine promotes early atherosclerosis but not plaque rupture in ApoE-deficient mice.

Hyperhomocysteinemia is an independent risk factor for atherothrombosis. However, causality is unproven, and it remains unknown whether hyperhomocysteinemia promotes atherosclerosis, plaque rupture, and/or thrombosis. We evaluated the short- and long-term effects of hyperhomocysteinemia on plaque size and structure in 99 atherosclerosis-prone apolipoprotein E-deficient mice. Hyperhomocysteinemia was induced by methionine (Met) or homocysteine (HcyH) supplementation: low Met (+11 g Met/kg food), high Met (+33 g Met/kg food), low HcyH (0.9 g HcyH/L drinking water), and high HcyH (1.8 g HcyH/L drinking water). Met and HcyH supplementation significantly raised plasma total homocysteine levels by 4- to 16-fold above those observed in mice fed a control diet (up to 146.1 micromol/L). Compared with controls, aortic root plaque size was significantly larger in supplemented groups after 3 months (56% and 173% larger in high-Met and high-HcyH, respectively) but not after 12 months. Hyperhomocysteinemia was associated with an increase in the amount of collagen in plaques after both 3 and 12 months. Mechanical testing of the tail tendons revealed no weakening of collagen after 12 months of hyperhomocysteinemia. Many plaques in both control and supplemented mice appeared rupture prone morphologically, but all aortic root plaques and all but 1 coronary plaque had an intact surface without rupture or thrombosis. Thus, diet-induced hyperhomocysteinemia promotes early atherosclerosis and plaque fibrosis but does not, even in the long term, weaken collagen or induce plaque rupture.

The giraffe kidney tolerates high arterial blood pressure by high renal interstitial pressure and low glomerular filtration rate.

BACKGROUND: The tallest animal on earth, the giraffe (Giraffa camelopardalis) is endowed with a mean arterial blood pressure (MAP) twice that of other mammals. The kidneys reside at heart level and show no sign of hypertension-related damage. We hypothesized that a species-specific evolutionary adaption in the giraffe kidney allows normal for size renal haemodynamics and glomerular filtration rate (GFR) despite a MAP double that of other mammals. METHODS: Fourteen anaesthetized giraffes were instrumented with vascular and bladder catheters to measure glomerular filtration rate (GFR) and effective renal plasma flow (ERPF). Renal interstitial hydrostatic pressure (RIHP) was assessed by inserting a needle into the medullary parenchyma. Doppler ultrasound measurements provided renal artery resistive index (RI). Hormone concentrations as well as biomechanical, structural and histological characteristics of vascular and renal tissues were determined. RESULTS: GFR averaged 342 ± 99 mL min(-1) and ERPF 1252 ± 305 mL min(-1) . RIHP varied between 45 and 140 mmHg. Renal pelvic pressure was 39 ± 2 mmHg and renal venous pressure 32 ± 4 mmHg. A valve-like structure at the junction of the renal and vena cava generated a pressure drop of 12 ± 2 mmHg. RI was 0.27. The renal capsule was durable with a calculated burst pressure of 600 mmHg. Plasma renin and AngII were 2.6 ± 0.5 mIU L(-1) and 9.1 ± 1.5 pg mL(-1) respectively. CONCLUSION: In giraffes, GFR, ERPF and RI appear much lower than expected based on body mass. A strong renal capsule supports a RIHP, which is >10-fold that of other mammals effectively reducing the net filtration pressure and protecting against the high MAP.

Long-term exercise of young and adult female rats: effect on femoral neck biomechanical competence and bone structure.

The present study was designed to examine the effect of exercise on femoral neck bone structure and strength in female rats after 4 and 10 months of exercise. Female Fischer rats aged 2 months were exercised for 4 h a day, 5 days a week on a motor-driven treadmill the speed of which was gradually increased until a daily distance of 2 km was reached. The training level was maintained for 4 months (n = 15) and 10 months (n = 15). Sedentary age-matched rats served as controls (n = 30). At death the proximal third of both femora was obtained from each rat. The left femoral neck was tested in a materials-testing machine, and the right was used for either trabecular bone mass measurement (BV/TV) or scanning electron microscopy (SEM). Biomechanical testing revealed a significant training-induced increase in femoral neck bone strength after 4 months of exercise, which although not accelerated was preserved after 10 months of exercise. Histologic investigation revealed a significant training-induced increase in BV/TV, accounted for by a significantly smaller proportion of marrow space. No difference in cortical area was found. Both histology and SEM revealed a tendency to an earlier closure of the growth line in the exercised animals. However, the exercised animals aged 6 months had a significantly increased total femoral length compared with the sedentary rats. No difference was found in total femoral length between sedentary and exercised rats aged 12 months. On the basis of this study, it is concluded that exercise has a positive effect on femoral neck bone strength.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the skeletal effects of combined mild dietary calcium restriction and ovariectomy in Sinclair S-1 minipigs: a pilot study.

A pilot study was conducted to investigate the combined effects of ovariectomy (OVX) with preceding and concomitant mild dietary calcium restriction on the minipig skeleton. Minipigs 4 months old were fed diets containing 0.9, 0.75, or 0.5% calcium (Ca). At 10 months, the 0.75 and 0.5% pigs were OVX and the 0.9% were either sham operated or OVX. All pigs were maintained on their respective diets for an additional 6 months. Excised lumbar vertebrae and long bones were evaluated by densitometry and histomorphometry, and vertebral cancellous bone samples were tested biomechanically. In pigs fed the 0.9% Ca diet, OVX alone effected decreases of 6% in vertebral bone mineral density (BMD), 15% in trabecular bone volume (BV/TV), and 13% in trabecular number (Tb.N), an increase of 15% in trabecular separation (Tb.Sp), and a nonsignificant increase (p < 0.056) in vertebral cancellous final erosion depth (F.E.De) compared with the 0.9% Ca sham-operated group. Decreasing dietary Ca to 0.5% in combination with OVX effected an 8% reduction in vertebral BMD that was not associated with any significant alterations in parameters of vertebral cancellous bone microstructure or remodeling compared with the 0.9% Ca sham-operated pigs. Increases in serum PTH noted in the 0.5% Ca OVX group were generally paralleled by increases in calcitriol. In OVX pigs fed a diet containing 0.75% Ca, a 10% reduction in vertebral BMD was observed. This was associated with significant increases in F.E.De and vertebral marrow star volume (Ma.St.V) compared with the 0.9% Ca sham-operated pigs and the other OVX groups. In addition, Tb.Sp was increased and Tb.N decreased compared with the 0.9% Ca sham-operated pigs. Increases in serum PTH in this group were not accompanied by increases in calcitriol. Midradial and midfemoral BMD values were reduced in the 0.75 and 0.5% Ca OVX groups compared with the 0.9% Ca sham-operated pigs. Histomorphometric analyses of cortical bone suggested the reduction in cortical bone mass in the 0.75% Ca OVX group may have been largely due to net loss on the endocortical surface versus possible failure to accrue bone in the 0.5% Ca OVX group. Ash density and biomechanical parameters for vertebral cancellous bone decreased progressively in the 0.9% sham-operated, 0.9% Ca OVX, and 0.75% Ca OVX groups and then increased in the 0.5% Ca OVX group. After normalization for bone mass (ash), mechanical changes were still apparent, particularly for the 0.75% Ca OVX group compared with other OVX groups, reflecting that structural changes had taken place in the trabecular network.(ABSTRACT TRUNCATED AT 400 WORDS)

The effect on vertebral bone mass and strength of long term treatment with antiresorptive agents (estrogen and calcitonin), human parathyroid hormone-(1-38), and combination therapy, assessed in aged ovariectomized rats.

The aim of the study was to assess the long term effect of the antiresorptive agents estrogen and salmon calcitonin, the anabolic drug PTH, and combination therapy on vertebral bone mass and bone biomechanical competence in aged osteopenic ovariectomized (OVX) rats. Seventy-nine 1-yr-old retired breeder Wistar rats were randomized into seven groups: 1) sham-operated, 2) OVX, 3) OVX plus estrogen, 4) OVX plus salmon calcitonin, 5) OVX plus human (h) PTH-(1-38), 6) OVX plus hPTH-(1-38) and estrogen, and finally, 7) OVX plus hPTH-(1-38) and calcitonin. Treatment regimens were initiated 8 weeks after ovariectomy and continued for 24 weeks. Whole body bone mass was measured by dual photon absorptiometry at intervals of 4 weeks and at death. Changes in spinal bone mass (BMC), biomechanical competence, and structure were assessed from the lumbar vertebral bodies. The results revealed a protective effect of both estrogen and calcitonin on ovariectomy-induced loss of whole body bone mass, but only estrogen had a significant effect on spinal BMC. hPTH-(1-38) monotherapy increased vertebral bone mass (BMC and ash content), size, and biomechanical parameters 20-80% over OVX levels. A more rapid effect on vertebral bone mass was seen when hPTH-(1-38) was combined with estrogen or salmon calcitonin. The study has shown that in aged OVX osteopenic rats, hPTH-(1-38) therapy increases vertebral bone mass and bone quality and also maintains trabecular connectivity. Both estrogen and calcitonin reduce the ovariectomy-induced bone loss, but cannot restore bone mass to sham-operated levels. On the basis of this study, it is concluded that PTH therapy seems to hold promise in the management of postmenopausal and age-related osteoporosis.

The anabolic effects of human parathyroid hormone (hPTH) on rat vertebral body mass are also reflected in the quality of bone, assessed by biomechanical testing: a comparison study between hPTH-(1-34) and hPTH-(1-84).

PTH has a proven anabolic effect on bone mass, as has been shown in several animal models and treatment regimens. The aim of this study was to ascertain whether the positive effect on bone mass is also reflected in the quality of bone formed. The study was performed in a rat model using human PTH (hPTH). One hundred and twenty male Wistar rats, divided into 10 groups, were given either hPTH-(1-34) or hPTH-(1-84) in daily sc doses. Dose levels ranged from 0.11-3.00 nmol/100 g BW.day for a period of 30 days. At death all six lumbar vertebrae were obtained from each rat. A combination of methods was applied to these vertebral bodies in order to ascertain the effect of hPTH on vertebral bone volume, density, trabecular structure, and biomechanical competence. The results revealed a dose-dependent increase in total volume, dry weight, ash weight, and trabecular bone volume. Also, a dose-dependent increase in load values could be demonstrated. The increase in bone strength remained significant after normalization for both cross-sectional area and bone mass. This indicates that the increase in bone size and bone mass was not achieved at the expense of the quality of the bone present. When the two treatments were administered at the same molar dose level, no difference between hPTH-(1-34) and hPTH-(1-84) was revealed. On the basis of this study, it is concluded that PTH could prove to be a promising treatment in the management of osteopenic states.

Thermal stability of reconstituted collagen fibrils. Shrinkage characteristics upon in vitro maturation.

Thermal stability measured as area shrinkage without tension during heating was determined for membranes of collagen fibrils reconstituted from solutions of highly purified rat skin collagens. Shrinkage in per cent of area at 25 degrees C and shrinkage temperature were quantitated in a standardized way and determined as a function of in vitro maturation time for 11 to 104 days after aggregation for the collagen membranes. Similar to reports on intact rat skin, shrinkage temperature remained constant and shrinkage per cent declined with a rate decreasing with time during maturation. Solubility in water at 80 degrees C for 2 hours was 95-96% and remained unchanged for the maturation time (about 2 months) studied. The decreased shrinkage reflecting a lower degree of collapse is ascribed to an increasing thermal stability of the membranes during maturation. Development of heat-stable bonds in the reconstituted collagen fibrils is taken up to be amenable to this increased stability. Similarity in changes of shrinkage characteristics during in vivo and in vitro maturation indicates that maturation changes in reconstituted collagen fibrils reflect those occurring in intact collagen during in vivo aging.

Mechanical properties of native and reconstituted rat tail tendon collagen upon maturation in vitro.

Native and reconstituted rat tail tendon collagen were tested mechanically after in vitro maturation by incubation. The mechanical strength of the native tendons increased upon incubation and attained maximum strength values similar to those of tendons matured and aged in vivo. This finding indicates that the same stabilizing process occurs both in vivo and in vitro. However, the mechanical strength values similar to those of tendons matured and aged in vivo. This finding indicates that the same stabilizing process occurs both in vivo and in vitro. However, the mechanical strength increased at an initial higher rate in vitro than in vivo. The mechanical strength of fibrils reconstituted from purified tail tendon collagen increased during incubation in air as previously reported for fibrils prepared from skin collagen. Fibrils prepared from tail tendon and skin collagen shared common mechanical and thermal stability characteristics upon the incubation. However, distinct qualitative mechanical characteristics for fibrils of the two collagens were found. These characteristics showed a resemblance to those of the respective source tissues. The results indicate that the same process is responsible for the gain in mechanical strength of native tissues and reconstituted collagen fibrils. Thus, reconstituted collagen fibrils seem a useful model for studying mechanical stability changes during maturation of collagen.

Insulin-like growth factor I as a predictor of cortical bone mass in a long-term study of ovariectomized and estrogen-treated rats.

The relationship between serum insulin-like growth factor I (IGF-I) and cortical bone mass, formation and resorption and length of bone in a long-term experiment on intact, ovariectomized and estrogen-treated/substituted rats was studied by using multiple linear regression analysis. The study comprised intact rats killed at 2, 6, 9, 12, 15, and 24 months of age, rats ovariectomized 6 months old and killed at 9, 12, 15, and 24 months of age, and intact and ovariectomized rats treated with a low dose of estrogen for 8 months before they were killed at 24 months of age. Serum IGF-I, bone length and total, subperiosteal and subendocortical bone mass in mid-diaphyseal cross sections of the femur were determined. Changes in the latter two variables, respectively, represent the net result of subperiosteal bone formation and subendocortical bone resorption. Multiple linear regression analysis showed that IGF-I was a positive determinant of cortical bone mass and subperiosteal bone formation. In aged rats, IGF-I was also a positive determinant of bone length, whereas IGF-I was not found to be a determinant of subendocortical bone resorption. The analyses showed that long-term treatment of aged rats with a low dose of estrogen had a dual effect on cortical bone by inhibiting subperiosteal formation and subendocortical resorption. The results revealed a relationship between endogenous circulating IGF-I and local anabolic actions of the growth factor in bones. Thus, IGF-I may be a valuable serum marker of cortical bone formation and length of long bones when considering estrogen-depleted and estrogen-treated rats.

Biomechanical competence of vertebral trabecular bone in relation to ash density and age in normal individuals.

Cylindrical trabecular bone samples from the central part of the first lumbar vertebral body were obtained from 42 normal people (27 females and 15 males) aged 15-87 years and analyzed by a compression test in either vertical or horizontal direction. Maximum stress, maximum stiffness, energy absorption capacity, and strain at maximum stress (compressibility) were calculated from the load-deformation curves. The ash density of the samples was measured after incineration. From age 20 to 80 years, the decline (P less than 0.01) in ash density was 48-50% compared to a 75-80% decrease (P less than 0.001) in vertical stress, stiffness, and energy absorption capacity. Qualitatively similar age-related changes (P less than 0.01) were observed by horizontal compression, but the absolute values were smaller. In both directions, highly significant positive correlations (P less than 0.01) were observed between the biomechanical properties and ash density stress, stiffness and energy absorption capacity still showed significant decreases with age (P less than 0.01). The vertical maximum strain values, which increased (P less than 0.05) with age, were inversely related to the other biomechanical variables (P less than 0.05) and to the ash density (P less than 0.05). It is concluded from the study that the biomechanical competence of vertebral trabecular bone depends not only on bone mass (ash density) but also on the continuity of the trabecular lattice, which changes with increasing age.

The effect of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats.

Ovariectomy has a proven pronounced effect on bone mass, as has been shown in several animal models and in clinical studies. The aim of this study was to investigate the effect of ovariectomy on both vertebral bone mass and biomechanical competence. The study was performed on a long-term mature rat model. One hundred and five, three-month-old female Wistar rats were randomized into seven groups. One group was killed at the start of the study and was used as a baseline group. Three groups were ovariectomized and followed for one, three, or six months after the operation. Three groups were sham-operated and followed for the same periods. At death, three lumbar vertebrae were obtained from each rat, and changes in bone mass (ash content, trabecular bone volume (TBV)), bone structure, and biomechanical competence were assessed from these vertebrae. The results revealed an age-related (three-nine months) increase in bone mass and biomechanical competence in the sham-operated control groups. In the ovariectomized groups, an age-related decrease in TBV was disclosed. The ash content remained constant, whereas the biomechanical parameters--after an initial increase--showed decreasing values with age in the ovariectomized groups. When age-matched control and ovariectomized rats were compared, an increasing difference in both bone mass and bone biomechanical competence was disclosed. The study has shown that ovariectomy has a pronounced effect not only on vertebral bone mass, but also on bone quality, and that this mature rat model forms an excellent basis for evaluating potential therapeutic regimens for the treatment of osteoporosis.

The effect of long-term exercise on vertebral and femoral bone mass, dimensions, and strength--assessed in a rat model.

The rat model has previously been used to test the effect of ovariectomy and of PTH administration on vertebral bone mass, size, and biomechanical competence. In this study, we used the same "biomechanical rat model" to assess the effect of long-term exercise on vertebral bone mass and quality and also on femoral bone mass, dimensions, and strength. Sixty female Fischer rats were randomized into four groups. Two groups were exercised for 5 days a week on a treadmill with a running distance of 2 km per day. The exercise program was initiated at the age of 2 months. The two exercise groups were investigated after 4 and 10 months. Two sedentary groups (observed for 4 and 10 months) served as controls. At death, three lumbar vertebral bodies (L4-L6) and the left femur were obtained from each rat, and changes in bone mass (ash density, trabecular bone volume [BV/TV]), bone size, and biomechanical competence were assessed. The results revealed an age-related (4-10 months) increase in vertebral bone mass and strength. The additional effect of exercise on the vertebral bodies was an increase in cross-sectional area and bone biomechanical competence. In the femoral bone specimens, an age-related increase in bone mass, size, and strength was also disclosed, and while exercise by itself had no significant influence on biomechanical parameters it did reduce cortical-endosteal bone resorption. The study has demonstrated an anabolic effect of a light exercise regimen on both femoral cortical bone and vertebral bodies (mainly trabecular bone).(ABSTRACT TRUNCATED AT 250 WORDS)

Thermal stability of cortical bone collagen in relation to age in normal individuals and in individuals with osteopetrosis.

The thermal stability of cortical bone collagen was determined in iliac crest biopsies obtained from 41 normal individuals (21 women aged 20-96 years and 20 men aged 21-84 years) and 8 individuals with autosomal dominant osteopetrosis type I (4 women and 4 men aged 17-63 years). The cortical bone was decalcified and the bone matrix was cut into 80-microns-thick freeze sections parallel to the bone surface. Circular specimens punched out from the sections were used for determination of area shrinkage during gradual heating and shrinkage temperature, Ts (representing the temperature for 50% of the area shrinkage). In normal men, Ts was not found to decrease until the age of 60-65 years, but was markedly decreased in the elderly individuals. In normal women, Ts varied considerably throughout the age range tested, without relationship to age. In contrast to age-matched controls, Ts decreased with age in men with osteopetrosis, whereas Ts in affected women was neither related to age nor different from the highly variable values found in age-matched normal women. Previous findings in rats indicate that Ts decreases with the chronological age of the bone collagen. The present results agree with these findings, which imply that a reduction in turnover rate of bone results in an increasing age and a reduced Ts of the constituent collagen. Following this assumption, the turnover rate of bone seems to be more variable in women than in men and reduced in osteopetrotic men.(ABSTRACT TRUNCATED AT 250 WORDS)

The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength--assessed in a sexually mature, ovariectomized rat model.

The aim of the study was to determine the effect of parathyroid hormone (PTH), the antiresorptive agents estrogen and bisphosphonate (risedronate), and also the combination of PTH with these antiresorptive drugs on femoral cortical bone mass, dimensions and strength in a sexually mature, ovariectomized rat model. A total of 138, 3-month-old Sprague-Dawley rats were randomized into seven groups: 1--sham operated (control); 2--ovariectomized (OVX); 3--OVX plus estrogen; 4--OVX plus bisphosphonate (risedronate [NE]; 5--OVX plus hPTH (1-34); 6--OVX plus hPTH (1-34) and estrogen; 7--OVX plus hPTH (1-34) and risedronate. Treatment regimens were initiated 4 weeks after OVX and were continued for 5 and 15 weeks for each treatment group. Changes in bone mass (ash content), cross-sectional area, cortical thickness and dimensions and bone strength were assessed in middiaphyseal, femoral specimens. The results revealed that ovariectomy had no effect on cortical bone mass and biomechanical competence. OVX rats treated with estrogen and also OVX rats treated with risedronate showed no significant difference from either OVX or control groups. After only 5 weeks of treatment, hPTH monotherapy increased ash content, cross-sectional area, cortical thickness and compressive bone strength (load) significantly. After 15 weeks of treatment, OVX rats treated with PTH monotherapy or PTH in combination with risedronate showed identical load-values. These values were significantly higher than those seen in both control and OVX rats. However, PTH in combination with estrogen failed to augment cortical bone strength over control or OVX levels after therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of short-term alendronate treatment on the three-dimensional microstructural, physical, and mechanical properties of dog trabecular bone.

The bisphosphonate, alendronate, is well known for its potent inhibition of osteoclast-mediated bone resorption. It has been used clinically for the treatment of osteoporosis and has also recently been used to reduce osteolysis around prostheses in a canine revision model of implant loosening (femoral condyle). In this study, the effects of alendronate on trabecular bone properties were assessed in dogs at an oral dose of 0.5 mg/kg per day over a 12 week period, and compared with control dogs. Cubic cancellous bone specimens were produced from lumbar vertebrae (L-1 and L-2) and bilateral proximal humeri. These specimens were scanned using a high-resolution microcomputed tomography (micro-CT) system. From accurate data sets, three-dimensional microstructural properties were calculated and physical and mechanical properties were determined. Treatment with alendronate increased bone volume fraction by 9.5%, 7.7%, 7.4%, and 18.4%, respectively, in L-1, L-2, humeral greater tuberosity, and humeral head trabecular bone. In the lumbar vertebrae, the alendronate-treated trabeculae were thicker and lower in bone surface-to-volume ratio. In the greater tuberosity, the alendronate-treated trabeculae were thicker, lower in bone surface-to-volume ratio, and less anisotropic. In the humeral head, the alendronate-treated trabeculae were thicker, less anisotropic, lower in surface density, and showed decreased trabecular separation. Alendronate significantly increased apparent density and collagen density in the lumbar vertebrae and humeral heads, and significantly decreased collagen concentration in the vertebrae. In the lumbar vertebrae, Young's modulus in the cephalocaudal direction, ultimate stress, and failure energy were significantly increased in the alendronate-treated group. The changes in mechanical properties in the humeral head trabecular bone were similar to those seen in the lumbar vertebrae. Our results demonstrate that alendronate increases the mechanical properties of healthy canine trabecular bone after short-term treatment. The physical and microstructural changes of trabecular bone are consistent with the significantly increased mechanical properties.

Additional weight-bearing during exercise is more important than duration of exercise for anabolic stimulus of bone: a study of running exercise in female rats.

Mechanical loading is necessary for maintenance of skeletal integrity, but the most effective type, intensity, and duration of exercise are not known. In vivo experiments have indicated that the strain generated by the stimulus is more important than the duration of the stimulus. To elucidate this question, we studied 5-month-old female Wistar rats exercised on a motor-driven exercise belt for 17 weeks, 5 days per week (average velocity 20 m/min). Group 1 served as controls, group 2 was trained for 30 min, group 3 was trained for 30 min with a 50-g backpack, and group 4 was trained for 15 min with a 50-g backpack. Total body bone mineral content (BMC), bone mass of the lower extremities (LEBMC), total body lean soft-tissue mass (LSTM), and total body fat-tissue mass (FTM) were measured by dual-energy absorptiometry (DXA) at 0, 6, and 17 weeks. The BMC increased more in group 4 than in controls (15% vs. 8%, p < 0.03). In the other two intervention groups, no significant increases of total body BMC occurred compared with controls, although a trend was observed (12%). The LEBMC increased significantly in all exercising groups after 17 weeks, being 16% in group 2, 15% in group 3, and 20% in group 4, compared with 6% in controls (p < 0.05). The increase in LSTM after 6 weeks was most pronounced in group 3, at 20%, compared with 10% in the control group (p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium-restricted ovariectomized Sinclair S-1 minipigs: an animal model of osteopenia and trabecular plate perforation.

The ovariectomized rat model has now been generally accepted as a useful model for screening different therapeutic agents, but there is a major requirement to identify reliable large animal models for osteoporosis research. In this study, the calcium restricted, ovariectomized minipig has been thoroughly investigated in order to define a large animal model with trabecular and cortical bone remodeling which would be reliable for further testing of agents that had shown promise of efficacy during the screening procedure. Twenty six female, 4-month old minipigs were randomized into four groups and fed either normal diet (0.90% calcium (Ca.)) or diet with restricted calcium content (0.75%, 0.50%). At the age of ten months, 3 groups were ovariectomized (OVX) while one group on normal diet was shamoperated. The groups were followed for six months after the operation. At death, bone mass was determined by densitometry and by ashing. Additionally, biomechanical competence was assessed in trabecular bone cores from the vertebral bodies. Finally, histomorphometry (static and dynamic parameters) and structural analyses (star volume) were performed on the vertebral bodies. The study revealed an OVX-related decline of 6% in vertebral bone mineral density (BMD) and a decline of 15% in trabecular bone volume (BV/TV). In contrast, a 15% increase in mean trabecular plate separation (Tb.Sp.) and a small increase in marrow space star volume (Ma. Star V.) were detected. The structural changes became more pronounced when OVX was combined with mild Ca. restriction (0.75% Ca.) with an increase in Ma. Star V. to 164%.(ABSTRACT TRUNCATED AT 250 WORDS)