Size, structure and gender: lessons about fracture risk

The differences in age-related fracture risks among men and women must reflect gender differences in the relevant variables. We are concerned here with gender differences in structural variables that relate to the size and shape of bones. As children grow, their bones grow in diameter through periosteal modeling. Studies show that radial growth is driven by mechanical forces and is not just "genetically programmed". Moving bone mass farther from the center of the diaphysis makes it more effective in resisting bending and twisting forces, and disproportionately so in comparison to changes in bone mass. Gender differences in long bone structure appear to arise because the bone cells of males and females function in different hormonal environments which affect their responses to mechanical loading. In girls, bone formation on the metacarpal periosteal surface essentially stops at puberty, and is replaced by formation on the endosteal surface, reducing endosteal diameter until about age 20. Bone strength is 60% greater in male metacarpals than in those of females because bone is added periosteally in boys and endosteally in girls. At menopause endosteal resorption resumes, accompanied by slow periosteal apposition, weakening cortical structure. Similar phenomena occur in such critical regions as the femoral neck. Another fundamental gender difference in skeletal development is that whole body bone mineral content increases in linear proportion to lean body mass throughout skeletal maturation in boys, but in girls there is a distinct increase in the slope of this relationship at puberty, when estrogen rises. Frost's hypothesis is that this reflects an effect of estrogen on bone's mechanostat set point, and this is increasingly supported by data showing that estrogen and mechanical strain act through a common pathway in osteoblast-like cells. If Frost's hypothesis is correct, the mechanostat is set for maximal effect of mechanical loading on bone gain during the 2-3 years preceding menarche. During the childbearing years, the set point is at an intermediate level, and at menopause, it shifts again to place the skeleton into the metabolic equivalent of a disuse state. The most direct approach to resolving this problem would be to simulate the putative effect of estrogen on the set point itself.     

A novel method to 'exercise' rats: making rats rise to erect bipedal stance for feeding - raised cage model

We employed a novel method to exercise rats: making them rise to bipedal stance for feeding using raised cages. We studied its effects on the skeletons of 6 and 10-month-old intact or orchidectomized (ORX) rats. Body and hindlimb muscle weights, tibial BMC and periosteal cortical bone formation increased after housing in raised cages, but more so in 6-month-old animals than in 10-month-old ones. In 6-month-old orchidectomized rats, raised cages partially prevented ORX-induced bone loss by stimulating periosteal cortical bone (TX) formation and decreased bone resorption next to marrow. In 10-month-old male orchidectomized rats, raised cages also decreased the endosteal and trabecular bone resorption, but not enough to prevent completely ORX-induced net bone losses. Because the osteogenic effects of raised cages alone were only partial, we also studied the interaction between raised cage and prostaglandin E(2) (PGE(2)) in 10-month-old retired female breeders. When treated with combined raised cage and PGE(2), both cortical (TX) and trabecular bone mass of the proximal tibial metaphysis and lumbar vertebral body increased over either raised cages or PGE(2) treatment alone, that was accompanied by dramatic increased bone formation at periosteal and endosteal surfaces. Thus making rats rise to erect bipedal stance for feeding helps to prevent bone loss after orchidectomy; it amplifies the anabolic effects of PGE(2), and it provides an inexpensive, non-invasive and reliable way to increase mechanical loading of certain bones of the rat skeleton.     

Continuing periosteal apposition. II: The significance of peak bone mass, strain equilibrium, and age-related activity differentials for mechanical compensation in human tubular bones

It is generally presumed that compensation for the reduction of bone strength by progressive endosteal bone loss in adults is provided by continuing periosteal apposition (CPA) of new lamellar bone. However, the appropriate magnitude of compensatory bone growth, and the parameters that operate to determine that magnitude, are unknown. This paper examines the mechanical compensation hypothesis in a series of right-circular tubular bone analogues. Under this hypothesis, the stated objective of CPA is maintenance of the cross-sectional geometric properties of the element. These include the second and polar moments of area, as well as the cortical area of the section (I, J, and CA, respectively). This study assumes that, as resorption and apposition proceed, geometric change is isometric (shape preserving). The analysis suggests that for a given rate of endosteal bone loss (the stimulus), the magnitude of periosteal growth (the response) required to maintain geometric strength is determined by the maximum ratio (CT0) of the radial distances from the section centroid to the endosteal and periosteal surfaces (i.e., cortical thickness prior to the onset of progressive endosteal bone loss, or peak bone mass). The analysis also indicates that, for any given individual, the amount of compensatory periosteal gain required may be very small. This is particularly true for individuals having a large CT0 and for whom the magnitude of dynamic loading imparted to the skeleton declines with advancing age. This finding is illustrated in a model that relates concepts of bone surface remodeling equilibria and age-related activity differentials.     

Alfacalcidol prevents age-related bone loss and causes an atypical pattern of bone formation in aged male rats

The current study was designed to investigate the skeletal effects of alfacalcidol in aged rats. Eighteen-month-old male rats were treated with 0, 0.1, or 0.2 microg/kg/d of alfacalcidol by daily oral gavage, 5 days/week for 12 weeks. At the beginning of the treatments, one group of rats was euthanized to serve as a baseline control. At the end of the study, the second lumbar vertebrae and the right tibial diaphysess were processed for bone histomorphometric analysis. The fourth lumbar vertebrae were subjected to strength testing. The control group of rats at 21 months of age had decreased serum testosterone levels and decreased cancellous bone mass associated with increased bone turnover on the trabecular surface. The older rats had increased bone turnover on the endocortical surface and decreased bone formation on the periosteal surface compared with the 18-month group. In contrast, alfacalcidol treatment increased cancellous and cortical bone mass in aged male rats. Trabecular bone resorption was decreased whereas bone formation was maintained or increased in the rats treated with alfacalcidol. In addition, endocortical bone formation was decreased whereas periosteal bone formation was increased in the rats treated with alfacalcidol compared with vehicle-treated rats. Marrow trabecular bone area was increased by alfacalcidol treatment in tibial diaphyses. Furthermore, bone strength of the lumbar vertebral body was increased after alfacalcidol treatment. An atypical pattern of bone formation on endosteal bone surfaces was seen in the rats treated with alfacalcidol. The atypical bone formation is characterized by small, focal packets of newly formed bone on trabecular and endocortical bone surfaces. This gave the appearance of the formation of "bone buds" emanating from trabecular surfaces. These bony outgrowths were mineralized and demonstrated significant fluorochrome label indicating recent mineralization. Also, lamellae of the bony buds did not run parallel to those of the trabecular plate to which they are attached. Arrest lines presented in most of the "bone buds". In summary, alfacalcidol treatment increased cancellous and cortical bone mass and improved bone strength, resulting in the prevention of age-related bone loss in aged male rats. An atypical pattern of bone formation observed in this study may be a result of minimodeling based bone formation stimulated by alfacalcidol treatment.     

A cellular solid model for modulus reduction due to resorption of trabeculae in bone

In osteoporotic trabecular bone, bone loss occurs by thinning and subsequent resorption of the trabeculae. In this study, we compare the effects of density reductions from uniform thinning of struts or from removal of struts in a random, open-cell, three-dimensional Voronoi structure. The results of this study, combined with those previous studies on other regular and random structures, suggest that the modulus and strength of trabecular bone are reduced more dramatically by density losses from resorption of trabeculae than by those from uniform thinning of trabeculae.     

Effect of circular motion exercise on bone modeling and bone mass in young rats: an animal model of isometric exercise

The aims of the study are to develop a non-invasive animal model of circular motion exercise and to evaluate the effect of this type of exercise on bone turnover in young rats. The circular motion exercise simulates isometric exercise using an orbital shaker that oscillates at a frequency of 50 Hz and is capable of speeds from 0-400 rpm. A cage is fixed on top of the shaker and the animals are placed inside. When the shaker is turned on, the oscillatory movement should encourage the animals to hold on to the cage and use various muscle forces to stabilize themselves. Rats at 8 weeks of age were trained on the shaker for 6 weeks and static and dynamic histomorphometric analyses were performed for the proximal tibial metaphysis and the tibial shaft. The exercise resulted in no significant effect on animal body weight, gastrocnemius muscle weight and femoral weight. Although the bone formation rate of cancellous and cortical periosteum was increased by the exercise, trabecular bone volume was decreased. The exercise increased periosteal and marrow perimeters and the cross-sectional diameter of cortical bone from medial to lateral without a significant increase in the cortical bone area. These results suggest that circular motion exercise under force without movement or additional weight loading will cause bone-modeling drift with an increase in bone turnover to reconstruct bone shape in adaptation to the demand in strength. Since there is no additional weight loading during circular motion exercise, the net mass of bone is not increased. The bone mass lost in trabecular bone could possibly be due to a re-distribution of mineral to the cortical bone.     

Subperiosteal gain and endosteal loss in protein-calorie malnutrition

Subperiosteal and medullary cavity diameters of 91 Guatemalan boys hospitalized with a diagnosis of protein-calorie malnutrition show a slight but significant increase in total width but a marked reduction at the endosteal surface, and in cortical area and percent cortical area, indicative of continuing subperiosteal apposition and a dramatic excess of endosteal resorption.     

Effects of age and occupation on cortical bone in a group of 18th-19th century British men

The effects of age and occupation on cortical bone in a group of adult males from the 18th-19th century AD skeletal collection from Christ Church Spitalfields, London, were investigated. Cortical bone was monitored using metacarpal radiogrammetry. Individual age at death was known exactly from coffin plates. Occupation for individuals was known from historical sources. Results showed that continued periosteal apposition was evident throughout adult life, but from middle age onwards this was outstripped by about 2:1 by endosteal resorption, so that there was net thinning of cortical bone. The rate of cortical thinning resembled that seen in modern European males. Cross-sectional properties, as measured by second moments of area, bore no relationship to occupation. The results may suggest that, firstly, patterns of loss of cortical bone have remained unchanged in males for at least two centuries in Britain, and secondly, that biomechanical analyses of metacarpal cortical bone may be rather insensitive indicators of intensity of manual activity.     

An algorithm for bone mechanoresponsiveness: implementation to study the effect of patient-specific cell mechanosensitivity on trabecular bone loss

The rate of bone loss is subject to considerable variation between individuals. With the 'mechanostat' model of Frost, genetic variations in bone mechanoresponsiveness are modelled by different mechanostat 'setpoints'--which may also change with age or disease. In this paper, the following setpoints are used: epsilonmin (strain below which resorption is triggered); epsilonmax (strain above which deposition occurs); omegacrit (microdamage-level above which damage-stimulated resorption occurs). To simulate decreased mechanosensitivity, epsilonmax is increased. Analyses carried out on a simplified model of a trabecula show that epsilonmax is a critical parameter: if it is higher in an individual (genetics) or increases (with age) the mass deficit each remodelling cycle increases. Furthermore, there is a value of epsilonmax above which trabecular perforation occurs, leading to rapid loss of bone mass. Maintaining bone cell mechanosensitivity could therefore be a therapeutic target for the prevention of osteoporosis.     

Simulation of vertebral trabecular bone loss using voxel finite element analysis

Trabecular bone loss in human vertebral bone is characterised by thinning and eventual perforation of the horizontal trabeculae. Concurrently, vertical trabeculae are completely lost with no histological evidence of significant thinning. Such bone loss results in deterioration in apparent modulus and strength of the trabecular core. In this study, a voxel-based finite element program was used to model bone loss in three specimens of human vertebral trabecular bone. Three sets of analyses were completed. In Set 1, strain adaptive resorption was modelled, whereby elements which were subject to the lowest mechanical stimulus (principal strain) were removed. In Set 2, both strain adaptive and microdamage mechanisms of bone resorption were included. Perforation of vertical trabeculae occurred due to microdamage resorption of elements with strains that exceeded a damage threshold. This resulted in collapse of the trabecular network under compression loading for two of the specimens tested. In Set 3, the damage threshold strain was gradually increased as bone loss progressed, resulting in reduced levels of microdamage resorption. This mechanism resulted in trabecular architectures in which vertical trabeculae had been perforated and which exhibited similar apparent modulus properties compared to experimental values reported in the literature. Our results indicate that strain adaptive remodelling alone does not explain the deterioration in mechanical properties that have been observed experimentally. Our results also support the hypothesis that horizontal trabeculae are lost principally by strain adaptive resorption, while vertical trabeculae may be lost due to perforation from microdamage resorption followed by rapid strain adaptive resorption of the remaining unloaded trabeculae.     

Ten years muscle-bone hypothesis: what have we learned so far?--almost a festschrift--

The importance of mechanical stimuli for bone is widely appreciated. Mechanostat theory proposes a negative feedback system to explain the adaptation of bone by homeostatic control of peak strains. However, no assumption is made as to which forces cause these strains. Biomechanical analyses suggest that the largest forces emerge from muscle contractions, rather than from body weight per se. Hence, the idea of a 'muscle-bone' unit emerged ten years ago, proposing that bones adapt to muscle strength. This muscle-bone hypothesis is well able to account for the accrual of bone mass and strength during childhood, and also to explain why certain types of exercise are able to prevent bone loss during immobilization. However, the hypothesis fails to explain why exercise becomes rather ineffective to increase bone strength after puberty. It is here proposed that joint size as a 'third agent' might solve the conundrum. More specifically, the assumptions are made that the peak forces determine joint size until the end of puberty, and that motor control limits joint reaction forces to critical limits during adulthood in order to prevent joint damage. Providing evidence in favour or against these conjectures will improve our understanding of the musculoskeletal system.     

Peak power and body mass as predictors of tibial bone strength in healthy male and female adults

Objective:The purpose of this study was to examine whether a non-invasive, muscular fitness field test was a better predictor of bone strength compared to body mass in healthy adults.Methods:Hierarchical multiple regression analyses were used to determine the amount of variance that peak power explained for tibial bone strength compared to body mass. Peak power was estimated from maximal vertical jump height using the Sayer’s equation. Peripheral quantitative computed tomography scans were used to assess bone strength measures.Results:Peak power (β=0.541, p<0.001) contributed more to the unique variance in bone strength index for compression (trabecular bone) compared to body mass (β=-0.102, p=0.332). For polar strength strain index (cortical bone), the beta coefficient for body mass remained significant (β=0.257, p<0.006), however peak power’s contribution was similar (β=0.213, p=0.051).Conclusion:Compared to body mass, peak power was a better predictor for trabecular bone strength but similar to body mass for cortical bone strength. These data provide additional support for the development of a vertical jump test as an objective, valid and reliable measure to monitor bone strength among youth and adult populations.     

Invited Review: Pathogenesis of osteoporosis.

Patients with fragility fractures may have abnormalities in bone structural and material properties such as larger or smaller bone size, fewer and thinner trabeculae, thinned and porous cortices, and tissue mineral content that is either too high or too low. Bone models and remodels throughout life; however, with advancing age, less bone is replaced than was resorbed within each remodeling site. Estrogen deficiency at menopause increases remodeling intensity: a greater proportion of bone is remodeled on its endosteal (inner) surface, and within each of the many sites even more bone is lost as more bone is resorbed while less is replaced, accelerating architectural decay. In men, there is no midlife increase in remodeling. Bone loss within each remodeling site proceeds by reduced bone formation, producing trabecular and cortical thinning. Hypogonadism in 20-30% of elderly men contributes to bone loss. In both sexes, calcium malabsorption and secondary hyperparathyroidism increase remodeling: more bone is removed from an ever-diminishing bone mass. As bone is removed from the endosteal envelope, concurrent bone formation on the periosteal (outer) bone surface during aging partly offsets bone loss and increases bone's cross-sectional area. Periosteal apposition is less in women than in men; therefore, women have more net bone loss because they gain less on the periosteal surface, not because they resorb more on the endosteal surface. More women than men experience fractures because their smaller skeleton incurs greater architectural damage and adapts less by periosteal apposition.     

Determination of the heterogeneous anisotropic elastic properties of human femoral bone: From nanoscopic to organ scale

Cortical bone is a multiscale composite material. Its elastic properties are anisotropic and heterogeneous across its cross-section, due to endosteal bone resorption which might affect bone strength. The aim of this paper was to describe a homogenization method leading to the estimation of the variation of the elastic coefficients across the bone cross-section and along the bone longitudinal axis. The method uses the spatial variations of bone porosity and of the degree of mineralization of the bone matrix (DMB) obtained from the analysis of 3-D synchrotron micro-computed tomography images. For all three scales considered (the foam (100 nm), the ultrastructure (5 μm) and the mesoscale (500 μm)), the elastic coefficients were determined using the Eshelby’s inclusion problem. DMB values were used at the scale of the foam. Collagen was introduced at the scale of the ultrastructure and bone porosity was introduced at the mesoscale. The pores were considered as parallel cylinders oriented along the bone axis. Each elastic coefficient was computed for different regions of interest, allowing an estimation of its variations across the bone cross-section and along the bone longitudinal axis. The method was applied to a human femoral neck bone specimen, which is a site of osteoporotic fracture. The computed elastic coefficients for cortical bone were in good agreement with experimental results, but some discrepancies were obtained in the endosteal part (trabecular bone). These results highlight the importance of accounting for the heterogeneity of cortical bone properties across bone cross-section and along bone longitudinal axis.     

Overview: animal models of osteopenia and osteoporosis

Prior to initiating a clinical trial in a post-menopausal osteoporosis study, it is reasonable to recommence the evaluation of treatment in the 9-month-old ovariectomized female rat. A female rat of this age has reached peak bone mass and can be manipulated to simulate clinical findings of post-menopausal osteoporosis. Ample time exists for experimental protocols that either prevent estrogen depletion osteopenia or restore bone loss after estrogen depletion. More time can be saved by acceleration of the development of the osteopenia by combining ovariectomized (OVX) plus immobilization (IM) models. Methods like serum biochemistry, histomorphometry and densitometry used in humans are applicable in rats. Like most animal models of osteopenia, the rat develops no fragility fractures, but mechanical testing of rat bones substitutes as a predictor of bone fragility. Recent studies have shown that the prevailing activity in cancellous and cortical bone of the sampling sites in rats is remodeling. The problems of dealing with a growing skeleton, the site specificity of the OVX and IM models, the lack of trabecular and Haversian remodeling and the slow developing cortical bone loss have been and can be overcome by adding beginning and pre-treatment controls and muscle mass measurements in all experimental designs, selecting cancellous bone sampling sites that are remodeling, concentrating the analysis of cortical bone loss to the peri-medullary bone and combining OVX and IM in a model to accelerate the development of both cancellous and cortical bone osteopenia. Not to be forgotten is the distal tibia site, an adult bone site with growth plate closure at 3 months and low trabecular bone turnover and architecture similar to human spongiosa. This site would be most challenging to the action of bone anabolic agents. Data about estrogen-deplete mice are encouraging, but the ovariectomized rat model suggests that developing an ovariectomized mouse model as an alternative is not urgent. Nevertheless, the mouse model has a place in drug development and skeletal research. In dealing with drug development, it could be a useful model because it is a much smaller animal requiring fewer drugs for screening. In skeletal research mice are useful in revealing genetic markers for peak bone mass and gene manipulations that affect bone mass, structure and strength. When the exciting mouse glucocorticoid-induced bone loss model of Weinstein and Manolagas is confirmed by others, it could be a significant breakthrough for that area of research. Lastly, we find that the information generated from skeletal studies of nonhuman primates has been most disappointing and recommend that these expensive skeletal studies be curtailed unless it is required by a regulatory agency for safety studies.     

Hormone replacement therapy improves distal radius bone structure by endocortical mineral deposition

Hormone replacement therapy (HRT) produces a small increase in bone mineral density (BMD) when measured by dual energy X-ray absorptiometry (DXA). The corresponding decrease in fracture risk is more impressive, implying that other factors that contribute to bone strength are favourably modified by HRT. We investigated, using peripheral quantitated computed tomography (pQCT), the changes produced by HRT in both the distribution of mineral between cortical and trabecular bone and the changes produced by HRT in the apparent structure of trabecular bone, expressed as average hole area and apparent connectivity. Twenty-one postmenopausal women starting HRT and 32 control women were followed for 2 years, with distal radius pQCT measurements every 6 months. HRT prevented the loss of total bone mass seen in controls (p < 0.02). HRT also produced an apparent rapid loss of trabecular bone mass within the first 6 months of the study (p < 0.02), with an associated rapid loss in the apparent connectivity (p = 0.034). Average hole area also increased but not to a statistically significant extent. Exogenous estrogen apparently fills small marrow pores close to the endocortical surface, such that the pQCT-defined boundary between trabecular and cortical bone is shifted in favour of cortical bone. Trabecular bone structure indices are adversely affected, as the central, poorly interconnected trabecular bone with greater than average marrow spaces constitutes a greater fraction of the remaining trabecular bone. This study suggests that the improvements in fracture risk resulting from HRT are explained by a reversal of net endocortical resorption of bone.     

The skeleton in primary hyperparathyroidism: a review focusing on bone remodeling, structure, mass, and fracture.

The mechanisms behind the influence of PHPT on the skeleton are closely connected with bone turnover. Throughout life, the skeleton is continuously renewed by bone remodeling, a process which serves the purpose of repairing damaged bone and adapting the skeleton to changes in physical load. In this process, old bone is removed by osteoclastic resorption and new bone is laid down by osteoblastic formation. Bone mass increases with growth in the first decades of life, and around the age of 30 years the peak bone mass is reached. Thereafter, as a result of mechanisms involving bone remodeling, a net bone loss is seen: 1) A reversible bone loss because of increase in the remodeling space, i.e., the amount of bone resorped but not yet reformed during the remodeling cycle. This mechanism leads to decrease in average trabecular thickness and cortical width, and to increase in cortical porosity. 2) An irreversible bone loss caused by negative bone balance, where the amount of bone formed by the osteoblasts is exceeded by the amount of bone resorbed by the osteoclasts at the same remodeling site. Consequently, progressive thinning of trabecular elements, reduced cortical width and increased cortical porosity is seen. 3) Finally, perforation of trabecular plates by deep resorption lacunae leads to complete irreversible removal of structural bone components. Parathyroid hormone, together with vitamin D, are the principal modulators in calcium homeostasis. The main actions of PTH are executed in bone and kidneys. In the kidneys, PTH increases the tubular re-absorption of calcium, thereby tending to increase serum calcium. PTH also induces increased conversion of 25(OH)-D to 1,25(OH)2-D. This last action, enhances intestinal calcium absorption and increased skeletal calcium mobilization, which further adds to the circulating calcium pool. In bone, the "acute" regulatory actions of PTH on serum calcium are probably accompliced via activation of osteocytes and lining cells. A second mechanism of PTH in bone is the regulation of bone remodeling. The action seems to be an increased recruitment from osteoblastic precursor cells and activation of mature osteoclasts. It is supposed that these responses are predominantly mediated indirectly through actions on osteoblast-like or nonosteoblast-like stromal cells, as osteoclasts themselves to not have PTH receptors. Bone metabolism and bone mass are studied by biochemical bone markers, bone histomorphometry, and densitometry. As bone markers and bone histomorphometry give information on bone metabolism from different points of view, these methods are preferably combined. Histomorphometry gives detailed information about bone turnover on cellular level, the whole remodeling sequence is described, and the bone balance can be calculated. However, they focus on a small volume, and may, therefore, not be representative for the whole skeleton. On the other hand, studies of bone markers supply general information about turnover in the whole skeleton, but they do not give facts on the bone turnover on the cellular or tissue level and bone balance. Bone densitometry is the principal method in studying bone mass, but valuable information concerning bone structure also comes from histomorphometry. Bone remodeling is considerably increased in PHPT. Studies of bone markers show increase in both resorptive and formative markers, and the increases seem to be of equivalent size. This is in agreement with histomorphometric findings and shows that the coupling between resorption and formation is preserved. By histomorphometry on iliac crest biopsies, trabecular bone remodeling is found increased by 50%, judged by the increase in activation frequency; a measure of how often new remodeling is initiated on the trabecular bone surface. In PHPT, such remodeling activity is repeated about once every year. Reconstruction of the whole remodeling sequence does not show major deviations in lengths of the resorptive and formative periods compared to normal. Furthermore, the amount of bone removed by the osteoclasts during the resorptive phase is matched by the amount of new bone formed by the osteoblasts leading to a bone balance very close to zero. Compared with trabecular bone, the turnover rate in cortical bone is considerably lower, around 10%. Remodeling of the cortical bone takes place at the endocortical, the pericortical, and the Haversian surfaces. Endocortical bone remodeling activities are very similar to trabecular remodeling activities with good correlation between individual parameters. Periosteal remodeling activity is negligible in PHPT, as it is in the normal state. Cortical porosity, which reflects the remodeling activity on the Haversian surface, is increased by 30-65% in PHPT. (ABSTRACT TRUNCATED)     

Mechanical, morphological and biochemical adaptations of bone and muscle to hindlimb suspension and exercise

The influences of weightbearing forces on the structural remodeling, matrix biochemistry, and mechanical characteristics of the rat tibia and femur and surrounding musculature were examined by means of a hindlimb suspension protocol and highly intensive treadmill running. Female, young adult, Sprague-Dawley rats were designated as either normal control, sedentary suspended, or exercise suspended rats. For 4 weeks, sedentary suspended rats were deprived of hindlimb-to-ground contact forces, while the exercise suspended rats experienced hindlimb ground reaction forces only during daily intensive treadmill training sessions. The suspension produced generalized atrophy of hindlimb skeletal muscles, with greater atrophy occurring in predominantly slow-twitch extensors and adductors, as compared with the mixed fiber-type extensors and flexors. Region-specific cortical thinning and endosteal resorption in tibial and femoral diaphyses occurred in conjunction with decrements in bone mechanical properties. Tibial and femoral regional remodeling was related to both the absence of cyclic bending strains due to normal weightbearing forces and the decrease in forces applied to bone by antigravity muscles. To a moderate extent, the superimposed strenuous running counteracted muscular atrophy during the suspension, particularly in the predominantly slow-twitch extensor and adductor muscles. The exercise did not, however, mitigate changes in bone mechanical properties and cross-sectional morphologies, and in some cases exacerbated the changes. Suspension with or without exercise did not alter the normal concentrations of collagen, phosphorus, and calcium in either tibia or femur.     

Immobilization and bone structure in humans

Long-term immobilization is known to result in substantial bone loss. The present review examined the existing evidence for deterioration of bone structure during long-term disuse in humans. Paralysis due to spinal cord injury, long-term exposure to microgravity in space or tightly restricted mobility during bed rest provide reasonable models to assess the influence of immobilization on bone structure. Expectedly, the duration of immobilisation was the major determinant of bone loss, but irrespective of whether the skeletal unloading was due to irrecoverable paralysis, long-term spaceflight or bed rest, the mean pattern of structural deterioration of bone, mainly manifest as substantial cortical thinning and trabecular bone loss, was quite similar. However, skeletal responses to disuse can be highly variable between individuals. Apparently the relative decline in individual’s bone loading in relation to loading prior to immobilization accounts for inter-individual variation.     

Effects of reproduction on sexual dimorphisms in rat bone mechanics

Osteoporosis most commonly affects postmenopausal women. Although men are also affected, women over 65 are 6 times more likely to develop osteoporosis than men of the same age. This is largely due to accelerated bone remodeling after menopause; however, the peak bone mass attained during young adulthood also plays an important role in osteoporosis risk. Multiple studies have demonstrated sexual dimorphisms in peak bone mass, and additionally, the female skeleton is significantly altered during pregnancy/lactation. Although clinical studies suggest that a reproductive history does not increase the risk of developing postmenopausal osteoporosis, reproduction has been shown to induce long-lasting alterations in maternal bone structure and mechanics, and the effects of pregnancy and lactation on maternal peak bone quality are not well understood. This study compared the structural and mechanical properties of male, virgin female, and post-reproductive female rat bone at multiple skeletal sites and at three different ages. We found that virgin females had a larger quantity of trabecular bone with greater trabecular number and more plate-like morphology, and, relative to their body weight, had a greater cortical bone size and greater bone strength than males. Post-reproductive females had altered trabecular microarchitecture relative to virgins, which was highly similar to that of male rats, and showed similar cortical bone size and bone mechanics to virgin females. This suggests that, to compensate for future reproductive bone losses, females may start off with more trabecular bone than is mechanically necessary, which may explain the paradox that reproduction induces long-lasting changes in maternal bone without increasing postmenopausal fracture risk.