The dynamics of bone structure development during pubertal growth

The pubertal growth spurt is a time of rapid changes in bone length, mass and structure, followed by the cessation of longitudinal growth. The two best studied anatomical areas in this respect are the metaphyses and the diaphyses of peripheral long bones. A model is presented here in which the speed of longitudinal growth and the resulting age gradient in metaphyseal bone are key factors in explaining the high incidence of distal radius fractures during puberty. As growth in length accelerates, the age of the bone structural elements at a given distance to the growth plate decreases, leaving less time for cortical thickening through trabecular coalescence. This leads to a discrepancy between stagnant metaphyseal bone strength and increasing mechanical requirements in the case of accidents. In comparison to the metaphysis, diaphyseal bone develops more in line with the increasing mechanical requirements, presumably because the bone formation rates needed for diaphyseal growth in width are only a fraction of the apposition rates in the metaphysis. It remains largely unexplored how local and systemic signals are integrated to achieve site-specific changes in bone structure.     

Time course for bone formation with long-term external mechanical loading.

Increased mechanical loading of bone with the rat tibia four-point bending device stimulates bone formation on periosteal and endocortical surfaces. With long-term loading cell activity diminishes, and it has been reported that early gains in bone size may reverse. This study examined the time course for bone cellular and structural response after 6, 12, and 18 wk of loading at 1,200-1, 700 microstrain (muepsilon). Bone formation rates, measured by histomorphometry, were compared within groups, between loaded and contralateral nonloaded tibiae, and between weeks. Formation surface, mineral apposition rate, and bone formation rate on periosteal and endocortical surfaces were elevated after 6 wk of loading. By 12 wk of loading, periosteal and endocortical formation surface and endocortical mineral apposition rates were elevated. By 18 wk of loading, periosteal adaptation appeared complete, whereas endocortical mineral apposition rate remained elevated. No periosteal resorption was observed. Average thickness of new bone formed, from baseline to collection, was greater in loaded than nonloaded tibiae by week 6 and was maintained through week 18. Early increases in bone formation result in periosteal apposition of new bone that persists after formation ceases.     

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.     

Skeletal tissue and transforming growth factor beta

Normal skeletal growth results from a balance between the processes of bone matrix synthesis and resorption. These activities are regulated by both systemic and local factors. Bone turnover is dynamic, and skeletal growth must be maintained throughout life. Although many growth promoters are associated with bone matrix, it is enriched particularly with transforming growth factor beta (TGF-beta) activity. Experimental evidence indicates that TGF-beta regulates replication and differentiation of mesenchymal precursor cells, chondrocytes, osteoblasts, and osteoclasts. Recent studies further suggest that TGF-beta activity in skeletal tissue may be controlled at multiple levels by other local and systemic agents. Consequently, the intricate mechanisms by which TGF-beta regulates bone formation are likely to be fundamental to understanding the processes of skeletal growth during development, maintenance of bone mass in adult life, and healing subsequent to bone 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.     

Periosteal biaxial residual strains correlate with bone specific growth rates in chick embryos

It has been proposed that periosteal residual tensile strains influence periosteal bone apposition and endochondral ossification. The role of bone growth rates on the development of residual strains is not well known. This study examined the relationships between specific growth rate and residual strains in chick tibiotarsi. We measured length and circumference during embryonic days 11-20 using microCT. Bones grew faster in length, with longitudinal and circumferential specific growth rates decreasing from 17 to 9% and 14 to 8% per day, respectively. To calculate residual strains, opening dimensions of incisions through the periosteum were analysed using finite element techniques. Results indicate that Poisson's ratio for an isotropic material model is between 0 and 0.04. For the model with Poisson's ratio 0.03, longitudinal and circumferential residual strains decreased from 46.2 to 29.3% and 10.6 to 3.9%, respectively, during embryonic days 14-20. Specific growth rates and residual strains were positively correlated (p<0.05).     

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.     

Bone remodelling and tumour grade modifications induced by interactions between bone and swarm rat chondrosarcoma

Chondrosarcoma is currently defined as a malignant cartilage tumour arising de novo or within a pre-existing benign cartilage tumour. Chondrosarcoma can be surgically resected, but all grades have significant rates of local recurrence. The purpose of the present study was to develop an animal intraosseous chondrosarcoma model simulating the progression of human chondrosarcoma and elucidating its behaviour and biology. An intraosseous Swarm rat model was designed to assess interactions between bone and chondrosarcoma. A comparison of tumour grading was carried out according to transplantation site. The effects of chondrosarcoma cells (SRC cells) on the mineralisation capacities of osteoblasts and on osteoclast differentiation were studied in relation to modifications observed in vivo at the cellular level. Transplantation of Swarm rat chondrosarcoma within bone marrow or contiguous to induced periosteal lesions led to extensive bone remodelling with trabecular bone rarefaction and periosteal apposition. Transplantation in close contact to bone but without any periosteal lesion had no effect on bone, suggesting that bone healing factors interact with tumour development. With the intramedullary model, the development of tumours of different grade confirms that bone environment is an important factor in malignancy. A decrease of bone nodule formation was noted after cocultures of SRC cells with rat bone marrow, but there was no modification of osteoclast differentiation after cultures of total rabbit bone cells with SRC cells. These data reveal the importance of interactions between bone environment and tumour in inducing bone remodelling and variations in tumour malignancy.     

Ontogenetic modelling of the petrous part of the temporal bone in man

The inner and the outer layers of the petrous part of the temporal bone (p.p.t.b.) become definitive until the sixth intrauterine month. Therefore, the growth and modelling of the p.p.t.b. are subsequently achieved by apposition of the periosteal outer layer. Periosteal apposition takes place in the form of plates appearing successively. The author identified seven such plates concentrated around the canals passing through the p.p.t.b. and describes them in fetuses, premature infants and adults. Periosteal ossification may cause compression of nerves passing through the p.p.t.b. thus inducing the onset of Ménière's disease. The anatomical peculiarities determined by the periosteal bone must be thoroughly known to permit high-accuracy surgical interventions at the p.p.t.b. level.     

Increased formation and decreased resorption of bone in mice with elevated vitamin D receptor in mature cells of the osteoblastic lineage.

The microarchitecture of bone is regulated by complex interactions between the bone-forming and resorbing cells, and several compounds regulate both actions. For example, vitamin D, which is required for bone mineralization, also stimulates bone resorption. Transgenic mice overexpressing the vitamin D receptor solely in mature cells of the osteoblastic bone-forming lineage were generated to test the potential therapeutic value of shifting the balance of vitamin D activity in favor of bone formation. Cortical bone was 5% wider and 15% stronger in these mice due to a doubling of periosteal mineral apposition rate without altered body weight or calcium homeostatic hormone levels. A 20% increase in trabecular bone volume in transgenic vertebrae was also observed, unexpectedly associated with a 30% reduction in resorption surface rather than greater bone formation. These findings indicate anabolic vitamin D activity in bone and identify a previously unknown pathway from mature osteoblastic cells to inhibit osteoclastic bone resorption, counterbalancing the known stimulatory action through immature osteoblastic cells. A therapeutic approach that both stimulates cortical anabolic and inhibits trabecular resorptive pathways would be ideal for treatment of osteoporosis and other osteopenic disorders.     

Local Mechanical Stimuli Regulate Bone Formation and Resorption in Mice at the Tissue Level

Bone is able to react to changing mechanical demands by adapting its internal microstructure through bone forming and resorbing cells. This process is called bone modeling and remodeling. It is evident that changes in mechanical demands at the organ level must be interpreted at the tissue level where bone (re)modeling takes place. Although assumed for a long time, the relationship between the locations of bone formation and resorption and the local mechanical environment is still under debate. The lack of suitable imaging modalities for measuring bone formation and resorption in vivo has made it difficult to assess the mechanoregulation of bone three-dimensionally by experiment. Using in vivo micro-computed tomography and high resolution finite element analysis in living mice, we show that bone formation most likely occurs at sites of high local mechanical strain (p<0.0001) and resorption at sites of low local mechanical strain (p<0.0001). Furthermore, the probability of bone resorption decreases exponentially with increasing mechanical stimulus (R² = 0.99) whereas the probability of bone formation follows an exponential growth function to a maximum value (R² = 0.99). Moreover, resorption is more strictly controlled than formation in loaded animals, and ovariectomy increases the amount of non-targeted resorption. Our experimental assessment of mechanoregulation at the tissue level does not show any evidence of a lazy zone and suggests that around 80% of all (re)modeling can be linked to the mechanical micro-environment. These findings disclose how mechanical stimuli at the tissue level contribute to the regulation of bone adaptation at the organ level.     

Cellular and molecular aspects of muscle growth,adaptation and ageing

Although major advances have been made over the past few decades in prosthetic dentistry, deterioration in oral function and altered facial appearance are still common accompaniments of ageing. Molecular biology methods now allow us to understand these age-related changes at the level of gene expression. Muscle loss as well as bone loss still present major problems, the magnitude of which increases as the age profile of our society changes. Both muscle and bone tissue respond to mechanical signals for which bone depends on muscle and for muscle, stretch has been shown to be important as it induces protein synthesis and an increase in girth as well as length of the muscle fibres. The latter involves the production of more sarcomeres in series so that the jaw muscles adapt to a new functional length following changes in vertical dimension of occlusion. It also determines the postural position of the lower jaw. In our investigations into the control of muscle mass we have recently cloned a growth factor which is expressed in exercised and/or overloaded muscles. This comes in two forms: an autocrine or local form and a paracrine or systemic form. Both growth factors influence muscle growth markedly and it is probable that the systemic type is also involved in maintenance of bone. The discovery of these growth factors provides the mechanisms by which mechanical signals are transduced into chemical signals that in turn regulate gene expression and protein synthesis.     

Continuing periosteal apposition. I: Documentation, hypotheses, and interpretation

Continuing periosteal apposition (CPA) of small amounts of new lamellar bone, leading to absolutely larger size, has been identified in a number of adult cranial and postcranial bones. This paper reviews 42 studies published since 1964 that have found both significant and nonsignificant age-related change in various skeletal size dimensions, e.g., length, diameter, width, and area. Also considered are four hypotheses that have, or may be, postulated for the occurrence of CPA. To date, however, these hypotheses (cohort effect, mechanical compensation, bone repair and/or mechanical response potential, and heterochrony) have not been rigorously tested, hence remain speculative. An important interpretive problem that befalls the investigation of CPA is its small effect size (i.e., the magnitude of change between observations), since most studies have restricted sample sizes. This problem is illustrated by power analysis of three reviewed studies that reported nonsignificant age-related change. The analysis indicates that these studies had very little likelihood of finding a statistically significant result, i.e., a low probability of rejecting the null hypothesis stipulating no size change with age. This finding has implications for interpreting CPA and for distinguishing between the statistical and biological significance of this phenomenon.     

Bone and bone marrow disruption by endocrine-active substances

Bone is a multifaceted dynamic tissue, involved in mobility, mineral metabolism, and mesenchymal or stromal and hematopoietic progenitor or stem cells breading. Recently, an endocrine role has been attributed to bone due to its ability to produce at least two hormones (osteocalcin and fibroblast growth factor 23) and to participate directly or indirectly in leptin, insulin, estrogens, and serotonin signaling; regulation; and action. Also, bearing in mind the enormous amounts of substances secreted by the different bone marrow cell types, it becomes understandable the contribution of bone tissue to systemic homeostasis. Besides, bone is a well-known estrogen-responsive tissue, reacting to environmental influences. Thus, it has been coined as a critical target of environmental xenoestrogens, known as endocrine-disrupting chemicals (EDCs). The exposure to EDCs results to disruption or imbalance of the systemic hormonal regulation of the skeleton including bone modeling and remodeling, local hormones, and cytokine or chemokine release. The present report highlights the harmful EDCs effects on bone tissue and provides up-to-date information of xenoestrogen action on proliferation, maturation, and homing of bone marrow inhabitants.     

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.     

Modeling of bone adaptative behavior based on cells activities

Bone remodeling occurs in an adult’s skeleton to adapt its architecture to external loadings. This involves bone resorption by osteoclasts cells followed by formation of new bone by osteoblasts cells. During bone remodeling, osteoclasts and osteoblasts interact with each other by expressing autocrine and paracrine factors that regulate cells’ population. Therefore, changes in bone density depend on the amount of each acting cell population. The aim of this paper is to propose a model for the bone remodeling process, which takes into account the opposite activity of both types of cells. For this purpose, a system of differential equations, proposed by Komarova et al. (Bone 33:206–215, 2003), is introduced to describe bone cell interactions using parameters which characterize the autocrine and paracrine factors. Such equations allow us to determine how the autocrine and paracrine factors vary in response to an external stimulus. It is assumed that an equilibrium state can be obtained for values of stimulus near to some reference quantity. Far from this value, unbalanced activity of osteoblasts and osteoclasts is observed, which leads to bone apposition or resorption. The proposed model has been implemented into the finite element software ABAQUS to analyze the qualitative response of a bone structure when subjected to certain mechanical loadings. Obtained results are satisfactory and in accordance with the expected bone remodeling behavior.     

Skeletal growth in early and late Neolithic foragers from the Cis‐Baikal region of Eastern Siberia

Skeletal growth is explored between Early Neolithic (EN) (8000 to 6800 BP) and Late Neolithic (LN) (6000 to 5200 BP) foragers from the Cis‐Baikal region of Eastern Siberia. Previous studies suggest that increased systemic stress and smaller adult body size characterize the EN compared to LN. On this basis, greater evidence for stunting and wasting is expected in the EN compared to LN. Skeletal growth parameters assessed here include femoral and tibial lengths, estimated stature and body mass, femoral midshaft cortical thickness, total bone thickness, and medullary width. Forward selection was used to fit polynomial lines to each skeletal growth parameter relative to dental age in the pooled samples, and standardized residuals were compared between groups using t tests. Standardized residuals of body mass and femoral length were significantly lower in the EN compared to LN sample, particularly from late infancy through early adolescence. However, no significant differences in the standardized residuals for cortical thickness, medullary width, total bone thickness, tibial length, or stature were found between the groups. Age ranges for stunting in femoral length and wasting in body mass are consistent with environmental perturbations experienced at the cessation of breast feeding and general resource insecurity in the EN compared to LN sample. Differences in relative femoral but not tibial length may be associated with age‐specific variation in growth‐acceleration for the distal and proximal limb segments. Similarity in cortical bone growth between the two samples may reflect the combined influences of systemic and mechanical factors on this parameter. Am J Phys Anthropol 153:377–386, 2014. © 2013 Wiley Periodicals, Inc.     

High-impact exercise and growing bone: relation between high strain rates and enhanced bone formation.

We investigated whether high-impact drop jumps could increase bone formation in the middiaphyseal tarsometatarsus of growing rooster. Roosters were designated as sedentary controls (n = 10) or jumpers (n = 10). Jumpers performed 200 drop jumps per day for 3 wk. The mechanical milieu of the tarsometatarsus was quantified via in vivo strain gauges. Indexes of bone formation and mechanical parameters were determined in each of twelve 30 degrees sectors subdividing the middiaphyseal cortex. Compared with baseline walking, drop jumping produced large peak strain rates (+740%) in the presence of moderately increased peak strain magnitudes (+30%) and unaltered strain distributions. Bone formation rates were significantly increased by jump training at periosteal (+40%) and endocortical surfaces (+370%). Strain rate was significantly correlated with the specific sites of increased formation rates at endocortical but not at periosteal surfaces. Previously, treadmill running did not enhance bone growth in this model. Comparing the mechanical milieus produced by running and drop jumps revealed that jumping significantly elevated only peak strain rates. This further emphasized the sensitivity of immature bone to high strain rates.     

Age-dependent cortical bone loss in women from 18th and early 19th century London

Age-dependent cortical bone loss was investigated in an earlier British population. The study sample comprised female skeletons from the 18th/19th century crypt at Christ Church, Spitalfields, London. Bone loss was monitored using metacarpal radiogrammetry. Age at death was known exactly from coffin plates. Results indicated that peak cortical thickness was less than in modern subjects. Continuing periosteal apposition was evident throughout adulthood, and the rate of increase in metacarpal diameter resembled that in modern subjects. Bone loss from the endosteal surface was evident from the fifth decade onwards, and this outstripped the rate of subperiosteal gain so that there was a net loss of cortical bone with age. Cortical bone loss occurred at a similar rate to that in modern subjects. In contrast to modern populations, there was no evidence that loss of cortical bone was associated with increased propensity to fracture. The present results, together with those previously published for a British medieval skeletal assemblage, suggest that patterns of cortical bone loss in women have remained unchanged over at least the last millennium in Britain. Given the great changes in lifestyle which have occurred during this period, this suggests that lifestyle factors may be rather less important than is sometimes asserted in influencing the severity of osteoporosis, at least as far as loss of cortical bone is concerned.