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.     

The importance of mechanical loading in bone biology and medicine

This paper discusses the premise that the skeleton is primarily a mechanical organ, and reviews the reasons that mechanical factors play a major role in bone biology. It begins by considering three basic observations: (1) Galileo's observation that bone proportions become more robust as the species' overall size increases; (2) da Vinci's observation that larger structures are inherently weaker than smaller structures subjected to the same stress; and (3) the general observation that each unit of bone mass provides structural support for about 15 units of soft tissue organ mass. Together, these observations lead to the concept that it can be advantageous to minimize bone mass, consistent with constraints on other factors. This premise is discussed here in relation to the phenomenon of bone remodeling, which is seen to serve two purposes: the adjustment of bone mass and geometry to maintain peak bone strains at their maximum tolerable values, and the continual removal of fatigue damage produced at those strain levels. Finally, it is observed that bone remodeling apparently originated approximately 250 million years ago when the first vertebrates of substantial size became weight-bearing on land, suggesting that mechanical forces associated with weight-bearing were instrumental in the evolution of bone remodeling.     

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)     

A mechanistic model for internal bone remodeling exhibits different dynamic responses in disuse and overload

Bone is a dynamic tissue which, through the process of bone remodeling in the mature skeleton, renews itself during normal function and adapts to mechanical loads. It is, therefore, important to understand the effect of remodeling on the mechanical function of bone, as well as the effect of the inherent time lag in the remodeling process. In this study, we develop a constitutive model for bone remodeling which includes a number of relevant mechanical and biological processes and use this model to address differences in the remodeling behavior as a volume element of bone is placed in disuse or overload. The remodeling parameters exhibited damped oscillatory behavior as the element was placed in disuse, with the amplitude of the oscillations increasing as the severity of disuse increased. In overload situations, the remodeling parameters exhibited critically sensitive behavior for loads beyond a threshold value. These results bear some correspondence to experimental findings, suggesting that the model may be useful when examining the importance of transient responses for bone in disuse, and for investigating the role fatigue damage removal plays in preventing or causing stress fractures. In addition, the constitutive algorithm is currently being employed in finite element simulations of bone adaptation to predict important features of the internal structure of the normal femur, as well as to study bone diseases and their treatment.     

Covariation between forelimb muscle anatomy and bone shape in an Australian scratch-digging marsupial: Comparison of morphometric methods

The close association between muscle and bone is broadly intuitive; however, details of the covariation between the two has not been comprehensively studied. Without quantitative understanding of how muscle anatomy influences bone shape, it is difficult to draw conclusions of the significance of many morphological traits of the skeleton. In this study, we investigated these relationships in the Quenda (Isoodon fusciventer), a scratch-digging marsupial. We quantified the relationships between forelimb muscle anatomy and bone shape for animals representing a range of body masses (124–1,952 g) using two-block partial least square analyses. Muscle anatomy was quantified as muscle mass and physiological cross-sectional area (PCSA), and we used two morphometric methods to characterize bone shape: seven indices of linear bone proportions, and landmarks analysis. Bone shape was significantly correlated with body mass, reflecting allometric bone growth. Of the seven bone indices, only shoulder moment index (SMI) and ulna robustness index (URI) showed a significant covariation with muscle anatomy. Stronger relationships between muscle anatomy and forelimb bone shape were found using the landmark coordinates: muscle mass and PCSA were correlated with the geometric shape of the scapula, humerus, and third metacarpal, but to a lesser extent with shape of the ulna. Overall, our data show that landmark coordinates are more sensitive than bone indices to capturing shape changes evident throughout ontogeny, and is therefore a more appropriate method to investigate covariation with forelimb muscle anatomy. Single-species studies investigating ontogeny require refined methods to accurately develop understanding of the important relationships between muscle force generation and bone shape remodeling. Landmark analyses provide such a method.     

Biology of RANK,RANKL, and osteoprotegerin

The discovery of the receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) system and its role in the regulation of bone resorption exemplifies how both serendipity and a logic-based approach can identify factors that regulate cell function. Before this discovery in the mid to late 1990s, it had long been recognized that osteoclast formation was regulated by factors expressed by osteoblast/stromal cells, but it had not been anticipated that members of the tumor necrosis factor superfamily of ligands and receptors would be involved or that the factors involved would have extensive functions beyond bone remodeling. RANKL/RANK signaling regulates the formation of multinucleated osteoclasts from their precursors as well as their activation and survival in normal bone remodeling and in a variety of pathologic conditions. OPG protects the skeleton from excessive bone resorption by binding to RANKL and preventing it from binding to its receptor, RANK. Thus, RANKL/OPG ratio is an important determinant of bone mass and skeletal integrity. Genetic studies in mice indicate that RANKL/RANK signaling is also required for lymph node formation and mammary gland lactational hyperplasia, and that OPG also protects arteries from medial calcification. Thus, these tumor necrosis factor superfamily members have important functions outside bone. Although our understanding of the mechanisms whereby they regulate osteoclast formation has advanced rapidly during the past 10 years, many questions remain about their roles in health and disease. Here we review our current understanding of the role of the RANKL/RANK/OPG system in bone and other tissues.     

Optimal principle of bone structure

Bone modeling and remodeling is an optimization process where no agreement has been reached regarding a unified theory or model. We measured 384 pieces of bone in vivo by 64-slice CT and discovered that the bone's center of mass approximately superposes its centroid of shape. This phenomenon indicates that the optimization process of non-homogeneous materials such as bone follows the same law of superposition of center of mass and centroid of shape as that of homogeneous materials. Based upon this principle, an index revealing the relationship between the center of mass and centroid of shape of the compact bone is proposed. Another index revealing the relationship between tissue density and distribution radius is followed. Applying these indexes to evaluate the strength of bone, we have some new findings.     

Why bones bend but don't break

The musculoskeletal system is adept at dissipating potentially damaging energy that could accelerate fracture consequent to multiple loading cycles. Microstructural damage reduces bone's residual properties, but prevents high stresses within the material by dissipating energy that can lead to eventual failure. Thus skeletal microdamage can be viewed as an adaptive process to prevent bone failure by dissipating energy. Because a damaged bone has reduced strength and stiffness, it must be repaired, so bone has evolved a system of self-repair that relies on microdamage-stimulated signaling mechanisms. When repair cannot occur quickly enough, low energy stress fractures can occur. The regulating effects of muscle also prevent failure by controlling where high stresses occur. Acting synergistically, muscle forces dissipate energy by appropriately regulating accelerations and decelerations of the limbs during movement. When muscles become fatigued, these functions are constrained, larger amounts of energy are imparted to bone, increasing the likelihood of microstructural damage and fracture. Thus, healthy bones are maintained by the ability of the musculoskeletal system to dissipate the energy through synergistic muscular activity and through the maintenance of microstructural and material properties that allow for crack initiation, but also for their repair.     

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.     

An expanded overview of postmenopausal osteoporosis

Why is the incidence of osteoporotic fracture so much higher in women than in men? The dominant medical view holds that the exaggerated skeletal fragility and fracture risk of postmenopausal women solely reflects the loss of bone following withdrawal of endogenous estrogen. Indeed, an enormous amount of research in this area has attempted to understand the rise in fractures after menopause in terms of the impact of estrogen lack on bone remodeling. Recent insights suggest that this simple view does not offer an adequate explanation for the greater susceptibility of older women to fracture compared to that of men. It seems more reasonable to view bone health as a lifelong process, reflecting the contributions and influences of myriad events occurring throughout life to skeletal acquisition and maintenance. Only recently has the medical community recognized that the amount of bone present at skeletal maturity makes a powerful contribution to lifelong skeletal status. A second area that must be incorporated into discussions of this topic relates to bone size and geometry. Women's bones are inherently smaller than those of men. A bone's strength is determined by its size as well as by its material properties. In boys, pubertal increases in the cortical thickness of long bones are achieved by (testosterone-dependent) periosteal apposition. By contrast, increased cortical thickness in girls reflects bone expansion into the medullary space, with little or no periosteal apposition, suggesting an inhibitory effect of estrogen on the latter process. Consequently, at skeletal maturity, men have wider bones of greater mechanical competence. Although estrogen is generally held to be skeletally protective, this aspect of its actions may actually render women more susceptible to some fractures. In later life, men may lose even more bone from appendicular sites than do women, but men show much greater concomitant increases in periosteal apposition than women, permitting them to maintain a relatively favorable mechanical profile. These several findings are based on cross-sectional observations of relatively few individuals and therefore require confirmation in prospective longitudinal studies. The degree to which gender-related differences in later life skeletal adaptation reflects a bone's mechanical or metabolic environment has been frequently discussed but still awaits experimental confirmation.     

On the role of bone damage in calcium homeostasis

Bone serves as the reservoir of some minerals including calcium. If calcium is needed anywhere in the body, it can be removed from the bone matrix by resorption and put back into the blood flow. During bone remodelling the resorbed tissue is replaced by osteoid which gets mineralized very slowly. Then, calcium homeostasis is controlled by bone remodelling, among other processes: the more intense is the remodelling activity, the lower is the mineral content of bone matrix. Bone remodelling is initiated by the presence of microstructural damage. Some experimental evidences show that the fatigue properties of bone are degraded and more microdamage is accumulated due to the external load as the mineral content increases. That damage initiates bone remodelling and the mineral content is so reduced. Therefore, this process prevents the mineral content of bone matrix to reach very high (non-physiological) values. A bone remodelling model has been used to simulate this regulatory process. In this model, damage is an initiation factor for bone remodelling and is estimated through a fatigue algorithm, depending on the macroscopic strain level. Mineral content depends on bone remodelling and mineralization rate. Finally, the bone fatigue properties are defined as dependent on the mineral content, closing the interconnection between damage and mineral content. The remodelling model was applied to a simplified example consisting of a bar under tension with an initially heterogeneous mineral distribution. Considering the fatigue properties as dependent on the mineral content, the mineral distribution tends to be homogeneous with an ash fraction within the physiological range. If such dependance is not considered and fatigue properties are assumed constant, the homogenization is not always achieved and the mineral content may rise up to high non-physiological values. Thus, the interconnection between mineral content and fatigue properties is essential for the maintenance of bone's structural integrity as well as for the calcium homeostasis.     

Role of calcitonin gene-related peptide in bone repair after cyclic fatigue loading

Background

Calcitonin gene related peptide (CGRP) is a neuropeptide that is abundant in the sensory neurons which innervate bone. The effects of CGRP on isolated bone cells have been widely studied, and CGRP is currently considered to be an osteoanabolic peptide that has effects on both osteoclasts and osteoblasts. However, relatively little is known about the physiological role of CGRP in-vivo in the skeletal responses to bone loading, particularly fatigue loading.

Methodology/Principal Findings

We used the rat ulna end-loading model to induce fatigue damage in the ulna unilaterally during cyclic loading. We postulated that CGRP would influence skeletal responses to cyclic fatigue loading. Rats were fatigue loaded and groups of rats were infused systemically with 0.9% saline, CGRP, or the receptor antagonist, CGRP_8–37, for a 10 day study period. Ten days after fatigue loading, bone and serum CGRP concentrations, serum tartrate-resistant acid phosphatase 5b (TRAP5b) concentrations, and fatigue-induced skeletal responses were quantified. We found that cyclic fatigue loading led to increased CGRP concentrations in both loaded and contralateral ulnae. Administration of CGRP_8–37 was associated with increased targeted remodeling in the fatigue-loaded ulna. Administration of CGRP or CGRP_8–37 both increased reparative bone formation over the study period. Plasma concentration of TRAP5b was not significantly influenced by either CGRP or CGRP_8–37 administration.

Conclusions

CGRP signaling modulates targeted remodeling of microdamage and reparative new bone formation after bone fatigue, and may be part of a neuronal signaling pathway which has regulatory effects on load-induced repair responses within the skeleton.     

Skeletal adaptations during mammalian reproduction

Remarkable changes occur in the mammalian skeleton prior to, during and after the reproductive cycle. Skeletal changes occur with ovarian maturation and initiation of menses and estrus in adolescence, which may result in a greater accumulation of skeletal mineral in the female vs the male skeleton. There is also some evidence to suggest an excess skeletal mass in young female experimental animals. In early pregnancy, growth, modeling and perhaps suppressed remodeling promote the accumulation of calcium. Some changes may also occur with the transition from pituitary to placental control of the pregnancy. In later pregnancy, an increase in bone turnover appears to coincide with fetal skeletal mineralization. Rapid and important changes occur in the skeleton and mineral metabolism in the transition from pregnancy to lactation as the mammary gland rather than the uterus draws on the maternal calcium stores. Lactational demands are met at least partially by a temporary demineralization of the skeleton, which is associated with increased bone modeling and remodeling. Endochondral growth almost ceases during lactation, but envelope-specific bone modeling and remodeling are greatly increased. This is generally associated with a loss of skeletal mass and density, more apparent at sites with less of a mechanical role (e.g. central metaphysis regions and the endocortical envelope). The post-lactational period is profoundly anabolic with substantial increases in bone formation, but blunted resorption at almost all skeletal envelopes. Skeletal mass is increased during this period and it is associated with improved skeletal mechanical properties. There are several important observations. 1) The nulliparous animal appears to have an excess skeletal mass to perhaps compensate for maternal metabolic inefficiency of the first reproductive cycle. 2) Changes in growth, modeling and remodeling occur at different times and at different skeletal envelopes during the reproductive cycle. These site-specific, temporal changes appear to be adaptations that facilitate the use of skeletal mineral while preserving mechanical competence. 3) After the first reproductive cycle, modeling and remodeling optimize the existing skeletal mass into a structure that better accommodates the prevailing mechanical environment. 4) The post-lactational period is profoundly anabolic and may provide new strategies for preservation of skeletal mass when reproductive capacity ceases.     

Bone material properties and mineral matrix contributions to fracture risk or age in women and men

The strength of bone is related to its mass and geometry, but also to the physical properties of the tissue itself. Bone tissue is composed primarily of collagen and mineral, each of which changes with age, and each of which can be affected by pharmaceutical treatments designed to prevent or reverse the loss of bone. With age, there is a decrease in collagen content, which is associated with an increased mean tissue mineralization, but there is no difference in cross-link levels compared to younger adult bone. In osteoporosis, however, there is a decrease in the reducible collagen cross-links without an alteration in collagen concentration; this would tend to increase bone fragility. In older people, the mean tissue age (MTA) increases, causing the tissue to become more highly mineralized. The increased bone turnover following menopause may reduce global MTA, and would reduce overall tissue mineralization. Bone strength and toughness are positively correlated to bone mineral content, but when bone tissue becomes too highly mineralized, it tends to become brittle. This reduces its toughness, and makes it more prone to fracture from repeated loads and accumulated microcracking. Most approved pharmaceutical treatments for osteoporosis suppress bone turnover, increasing MTA and mineralization of the tissue. This might have either or both of two effects. It could increase bone volume from refilling of the remodeling space, reducing the risk for fracture. Alternatively, the increased MTA could increase the propensity to develop microcracks, and reduce the toughness of bone, making it more likely to fracture. There may also be changes in the morphology of the mineral crystals that could affect the homogeneity of the tissue and impact mechanical properties. These changes might have large positive or negative effects on fracture incidence, and could contribute to the paradox that both large and small increases in density have about the same effect on fracture risk. Bone mineral density measured by DXA does not discriminate between density differences caused by volume changes, and those caused by changes in mineralization. As such, it does not entirely reflect material property changes in aging or osteoporotic bone that contribute to bone's risk for fracture.     

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.     

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.     

Hormonal aspects of the muscle-bone unit

Osteoporotic fractures are the result of low density and especially inferior bone quality (microarchitecture) caused by both internal (genes, hormones) and external (life style) influences. Bone mechanosensors are extremely important for the overall integrity of the skeleton, because in response to mechanical load they activate its modeling, resulting in an increase in bone density and strength. The largest physiological loads are caused by muscle contractions. Bone mass in adult men has a closer relationship to muscle mass than is case in women. The sexual differences in the relationship between bone and muscle mass are also apparent in children. Based on the mechanostatic theory, the muscle-bone unit has been defined as a functional system whose components are under the common control of the hormones of the somatotropin-IGF-I axis, sexual steroids, certain adipose tissue hormones and vitamin D. The osteogenic effects of somatotropin-IGF-I system are based on the stimulation of bone formation, as well as increase in muscle mass. Moreover, somatotropin decreases the bone mechanostat threshold and reinforces the effect of physical stress on bone formation. The system, via the muscle-bone unit, plays a significant role in the development of the childhood skeleton as well as in its stability during adulthood. The muscle and bone are also the targets of androgens, which increase bone formation and the growth of muscle mass in men and women, independently of IGF-I. The role of further above-mentioned hormones in regulation of this unified functional complex is also discussed.     

Electromyographic models to assess muscle fatigue

Muscle fatigue is a common experience in daily life. Many authors have defined it as the incapacity to maintain the required or expected force, and therefore, force, power and torque recordings have been used as direct measurements of muscle fatigue. In addition, the measurement of these variables combined with the measurement of surface electromyography (sEMG) recordings (which can be measured during all types of movements) during exercise may be useful to assess and understand muscle fatigue. Therefore, there is a need to develop muscle fatigue models that relate changes in sEMG variables with muscle fatigue. However, the main issue when using conventional sEMG variables to quantify fatigue is their poor association with direct measures of fatigue. Therefore, using different techniques, several authors have combined sets of sEMG parameters to assess muscle fatigue. The aim of this paper is to serve as a state-of-the-art summary of different sEMG models used to assess muscle fatigue. This paper provides an overview of linear and non-linear sEMG models for estimating muscle fatigue, their ability to assess power loss and their limitations due to neuromuscular changes after a training period.     

Functional strain in bone tissue as an objective, and controlling stimulus for adaptive bone remodelling

The skeleton consists of a series of elements with a variety of functions. In locations where shape or protection are of prime importance the bone's architecture is achieved during growth under direct genetic control. In locations where resistance to repetitive loading is important only the general form of the bone will be achieved as a result of growth alone, the remaining characteristics result from functional adaptation. This mechanism ensures that bone architecture is modelled and remodelled until prevailing strains match those genetically prescribed for that location. For this match to be established, and subsequently maintained, bone cells must be able to 'assess' feedback derived directly or indirectly from the functional strains produced within the tissue. These strains are therefore the objective of functionally adaptive remodelling, and the stimulus for its control. Evans was the first person to refer to the recording of functional strains from gauges attached to bone in vivo. This technique has allowed quantitative investigations on bone's normal functional strain environment, and its adaptive response to changes in its state of strain. Recent investigations have extended to the immediate effects of dynamic strains on the structure of the bone matrix, and the biochemical behaviour of the resident bone cells. Such studies should reveal the mechanism by which strains within the matrix are transduced into the biochemical signals by which adaptive remodelling is controlled.     

From mechanostat theory to development of the "Functional Muscle-Bone-Unit"

Bone densitometric data are often difficult to interpret in children and adolescents because of large inter- and intraindividual variations in bone size. Here, we propose a functional approach to bone densitometry that addresses two questions: is bone strength normally adapted to the largest physiological loads, that is, muscle force? Is muscle force adequate for body size? The theoretical background for this approach is provided by the mechanostat theory, which proposes that bones adapt their strength to keep the strain caused by physiological loads close to a set point. Because the largest physiological loads are caused by muscle contractions, there should be a close relationship between bone strength and muscle force or size. The proposed two-step diagnostic algorithm requires a measure of muscle force or size and a measure of bone mineral content (BMC) at a corresponding location. The results can be combined into four diagnostic groups. In the first situation, muscle force or size is adequate for height. If the skeleton is adapted normally to the muscle system, the result is interpreted as "normal". If it is lower than expected for muscle force or size, a "primary bone defect" is diagnosed. In the second situation, muscle force or size is too low for height. Even if the skeleton is adapted adequately to the decreased mechanical challenge, this means that bone mass and presumably strength are still too low for body height. Therefore, a "secondary bone defect" is diagnosed. It is hoped that the more detailed insights thus gained could help to devise targeted strategies for the prevention and treatment of pediatric bone diseases.