On the strength-safety factor (SSF) for load-bearing skeletal organs

The strength of healthy postnatal mammalian load-bearing bones, growth plates, joints, fascia, ligaments and tendons exceeds the minimum strength needed to keep voluntary mechanical usage from breaking or rupturing them or from causing arthroses. Thus, they have a strength-safety factor (SSF). Some general features of the physiology in the Utah paradigm of skeletal physiology can explain two things: (i) Why load-bearing bones should have an SSF, (ii) and why its numerical value should approximately 6 in healthy young adult mammals. The number and kinds of studies and facts that revealed those two things for load-bearing bones do not yet exist for the extraosseous load-bearing organs that are made with cartilage and collagenous tissue. However, clinical-pathologic observations suggest the latter organs' SSFs should depend on features analogous to those that create SSFs for load-bearing bones. If so, the physiology on which bone's SSF depends could suggest directions for future studies of the SSF determinants of load-bearing extraosseous organs. Biomechanicians currently favor strain above stress when discussing biomechanical roles in the functional adaptations of bones to mechanical loading. However, an SSF is best expressed in stress terms, so a Table in this article provides corresponding strain/stress/unit-load values for bone's three important thresholds, and for its ultimate strength.     

The many adaptations of bone

Studies concerned with the "adaptations" in bones usually deal with modelling taking place during the individual's lifetime. However, many adaptations are produced over evolutionary time. This survey samples some adaptations of bone that may occur over both length scales, and tries to show whether short- or long-term adaptation is important. (a) Woven and lamellar bone. Woven bone is less mechanically competent than lamellar bone but is frequently found in bones that grow quickly. (b) Stress concentrations in bone. Bone is full of cavities that potentially may act as stress concentrators. Usually these cavities are oriented to minimise their stress-concentrating effect. Furthermore, the "flow" of lamellae round the cavities will still further reduce their stress-concentrating effect, but the elastic anisotropy of bone will, contrarily, tend to enhance it in normal loading situations. (c) Stiffness versus toughness. The mineral content of bone is the main determinant of differences in mechanical properties. Different bones have different mineral contents that optimise the mix of stiffness and toughness needed. (d) Synergy of whole bone architecture and material properties. As bone material properties change during growth the architecture of the whole bone is modified concurrently, to produce an optimum mechanical behaviour of the whole bone. (e) Secondary remodelling. The formation of secondary osteones in general weakens bone. Various suggestions that have been put forward to account for secondary remodelling: enabling mineral homeostasis; removing dead bone; changing the grain of the bone; taking out microcracks. (f) The hollowness of bones. It is shown how the degree of hollowness is adapted to the life of the animal.     

Growth hormone and osteoporosis: an overview of endocrinological and pharmacological insights from the Utah paradigm of skeletal physiology

Multidisciplinary advances in skeletal physiology offer a new paradigm for the effects of growth hormone (GH) and other agents on bone and osteoporosis. The still-evolving Utah paradigm of skeletal physiology supplements earlier ideas with later discovered roles of the skeleton's tissue-level 'nephron equivalents' and muscle strength in skeletal development, physiology and disorders. This article summarizes how these factors could influence the effects of GH on bone strength and bone 'mass', and the use of GH in the treatment of osteoporoses. Although the cellular and molecular biological mechanisms involved remain obscure, the associated cascades of cellular, genetic and biochemical processes and molecules should offer many opportunities to find or design agents that have medically useful effects on bone and muscle without giving rise to unwanted side-effects.     

Effect of rapamycin on bone mass and strength in the α2(I)‐G610C mouse model of osteogenesis imperfecta

Osteogenesis imperfecta (OI) is commonly caused by heterozygous type I collagen structural mutations that disturb triple helix folding and integrity. This mutant‐containing misfolded collagen accumulates in the endoplasmic reticulum (ER) and induces a form of ER stress associated with negative effects on osteoblast differentiation and maturation. Therapeutic induction of autophagy to degrade the mutant collagens could therefore be useful in ameliorating the ER stress and deleterious downstream consequences. To test this, we treated a mouse model of mild to moderate OI (α2(I) G610C) with dietary rapamycin from 3 to 8 weeks of age and effects on bone mass and mechanical properties were determined. OI bone mass and mechanics were, as previously reported, compromised compared to WT. While rapamycin treatment improved the trabecular parameters of WT and OI bones, the biomechanical deficits of OI bones were not rescued. Importantly, we show that rapamycin treatment suppressed the longitudinal and transverse growth of OI, but not WT, long bones. Our work demonstrates that dietary rapamycin offers no clinical benefit in this OI model and furthermore, the impact of rapamycin on OI bone growth could exacerbate the clinical consequences during periods of active bone growth in patients with OI caused by collagen misfolding mutations.     

A reconciliation of local and global models for bone remodeling through optimization theory

Remodeling rules with either a global or a local mathematical form have been proposed for load-bearing bones in the literature. In the local models, the bone architecture (shape, density) is related to the strains/energies sensed at any point in the bone, while in the global models, a criterion believed to be applicable to the whole bone is used. In the present paper, a local remodeling rule with a strain "error" form is derived as the necessary condition for the optimum of a global remodeling criterion, suggesting that many of the local error-driven remodeling rules may have corresponding global optimization-based criteria. The global criterion proposed in the present study is a trade-off between the cost of metabolic growth and use, mathematically represented by the mass, and the cost of failure, mathematically represented by the total strain energy. The proposed global criterion is shown to be related to the optimality criteria methods of structural optimization by the equivalence of the model solution and the fully stressed solution for statically determinate structures. In related work, the global criterion is applied to simulate the strength recovery in bones with screw holes left behind after removal of fracture fixation plates. The results predicted by the model are shown to be in good agreement with experimental results, leading to the conclusion that load-bearing bones are structures with optimal shape and property for their function.     

Material matters: a mechanostat-based perspective on bone development in osteogenesis imperfecta and hypophosphatemic rickets

This perspective paper presents a hypothesis that links abnormalities of bone material with densitometric findings in two congenital metabolic bone disorders, osteogenesis imperfecta type I (OI) and X-linked hypophosphatemic rickets (XLH). Analyses of iliac bone samples from OI patients have shown that material bone density is elevated and that the bone material is abnormally stiff in this disorder. Therefore, a given mechanical load on an OI bone will generate a smaller than normal deformation. This in turn should lead osteocytes, the putative mechanosensing cells, to systematically underestimate the prevailing mechanical forces. According to the mechanostat model, bone strength should then be adapted to the underestimated mechanical loads, which means that bone architecture and mass remain below requirements. Available densitometric studies are in accordance with this hypothesis. In XLH, a mild mineralization defect persists despite treatment. This mineralization defect should lead to soft bone material. In analogy to the above model for OI, mechanical loads should be overestimated, resulting in increased densitometric parameters of bone strength. Indeed, lumbar spine areal bone mineral density is usually elevated in such patients.     

四川自贡大山铺中侏罗世蜀龙和峨眉龙长骨骨组织结构的初步研究

通过对四川自贡大山铺恐龙动物群中两种主要蜥脚类恐龙—李氏蜀龙和天府峨眉龙肱骨和尺骨的骨组织结构观察,并与我国晚白垩世的几种恐龙长骨进行对比,结果发现:1)恐龙的长骨都具有快速的后生生长速率;2)恐龙的生长方式属于非限定生长,即在成年后并不停止生长;3)不同类型的恐龙到了成年以后,其骨沉积速率可能有较大差异;4)不同类型的恐龙在长骨的生长改建过程中,骨组织内部的重吸收作用有较大差异;5)生长轮结构在不同部位的骨骼中或在骨骼的生长发育过程中可能也有较大差异。     

Palaeohistology of the bones of pterosaurs (Reptilia: Archosauria): anatomy, ontogeny, and biomechanical implications

Thin sections from long bones of specimens representing pterosaurs ranging from the Early Jurassic to the latest Cretaceous provide a profile of bone histology across a range of sizes, skeletal elements, growth stages, and phylogenetic positions. Most pterosaur bone is fibro-lamellar, organized in an unusual way that suggests high growth rates through ontogeny. Fibro-lamellar deposits are finished by a relatively abrupt deceleration or cessation of growth represented by lamellar, poorly vascularized subperiosteal bone in what appear to be adults. Pterosaurs had the thinnest bone walls of any tetrapods; they complemented high rates of periosteal deposition with almost equally high rates of endosteal erosion. Pterosaurs show a great variety of histologic features that include articular calcified cartilage, sub-chondral bone plates, trabecular bone struts and related internal supports, and secondary deposition and remodeling of bone. They remodeled their bones internally by (1) depositing endosteal bone coatings on the inner cortex and over struts of pre-existing internal bone, (2) secondarily filling bone spaces, and (3) Haversian reworking. The construction of these struts reflects both developmental patterns of bone construction and biomechanical function. Alternating plywood-like layers of bone, heretofore undescribed in tetrapods, provided strength, as did the obliquely oriented system of reticular blood vessels in the bones. The distribution and ontogenetic features of pterosaur bone tissues, when combined with other evidence, suggest generally high growth rates, high metabolic levels, altricial birth, and extended parental care.     

Molecular and Mesoscale Mechanisms of Osteogenesis Imperfecta Disease in Collagen Fibrils

Osteogenesis imperfecta (OI) is a genetic disorder in collagen characterized by mechanically weakened tendon, fragile bones, skeletal deformities, and in severe cases, prenatal death. Although many studies have attempted to associate specific mutation types with phenotypic severity, the molecular and mesoscale mechanisms by which a single point mutation influences the mechanical behavior of tissues at multiple length scales remain unknown. We show by a hierarchy of full atomistic and mesoscale simulation that OI mutations severely compromise the mechanical properties of collagenous tissues at multiple scales, from single molecules to collagen fibrils. Mutations that lead to the most severe OI phenotype correlate with the strongest effects, leading to weakened intermolecular adhesion, increased intermolecular spacing, reduced stiffness, as well as a reduced failure strength of collagen fibrils. We find that these molecular-level changes lead to an alteration of the stress distribution in mutated collagen fibrils, causing the formation of stress concentrations that induce material failure via intermolecular slip. We believe that our findings provide insight into the microscopic mechanisms of this disease and lead to explanations of characteristic OI tissue features such as reduced mechanical strength and a lower cross-link density. Our study explains how single point mutations can control the breakdown of tissue at much larger length scales, a question of great relevance for a broad class of genetic diseases.     

Curvature, length, and cross-sectional geometry of the femur and humerus in anthropoid primates

The aims of this study were to describe the curvature of anthropoid limb bones quantitatively, to determine how limb bone curvature scales with body mass, and to discuss how bone curvature influences static measures of bone strength. Femora and humeri in six anthropoid genera of Old World monkeys, New World monkeys, and gibbons were used. Bone length, curvature, and cross-sectional properties were incorporated into the analysis. These variables were obtained by a new method using three-dimensional morphological data reconstructed from consecutive CT images. This method revealed the patterns of curvature of anthropoid limb bones. Log-transformed scaling analyses of the characters revealed that bone length and especially bone curvature strongly reflected taxonomic/locomotor differences. As compared with Old World monkeys, New World monkeys and gibbons in particular have a proportionally long and less curved femur and humerus relative to body mass. It is also revealed that the section modulus relative to body mass varies less between taxonomic/locomotor groups in anthropoids. Calculation of theoretical bending strengths implied that Old World monkeys achieve near-constant bending strength in accordance with the tendency observed in general terrestrial mammals. Relatively shorter bone length and larger A-P curvature of Old World monkeys largely contribute to this uniformity. Bending strengths in New World monkeys and gibbons were, however, a little lower under lateral loading and extremely stronger and more variable under axial loading as compared with Old World monkeys, due to their relative elongated and weakly curved femora and humeri. These results suggest that arboreal locomotion, including quadrupedalism and suspension, requires functional demands quite dissimilar to those required in terrestrial quadrupedalism.     

Muscle-bone properties after prolonged voluntary wheel running in a mouse model of dominant severe osteogenesis imperfecta

Objective:The objective of the current study is to assess the effect of a seven-week voluntary wheel running intervention on muscles and bones properties in a mouse model mimicking dominant severe osteogenesis imperfecta (OI).Methods:Female wild-type (WT) and OI (Col1a1^Jrt/+) mice either performed voluntarily wheel-running exercise for 7-weeks or remained sedentary. Running distance and speed, forelimb grip strength, isolated muscle force and fatigability as well as bone morphology and mechanical properties were assessed.Results:We demonstrate that female WT and OI mice voluntarily performed exercise, although OI mice exercised less than WT littermates. The exercise regimen increased soleus muscle masses in WT and OI but increased relative grip strength in WT mice only. Specific muscle force and fatigability were similar between WT and OI mice and did not improve with exercise. Furthermore, the exercise regimen did not improve the femoral architectural and biomechanical properties in OI mice.Conclusion:Our study suggests that voluntary wheel running is not appropriate to assess the effects of exercise in a mouse model of OI. Findings from exercising OI mice model studies may not necessarily be transferable to humans.     

Analysis of biomechanical effects on bone and on the muscle-bone interactions in small animal models

Animal models are suitable to study many aspects of bone structure and strength. This article reviews some general principles of current bone biomechanics and describes the scope of the available methodology for biomechanical studies of the musculoskeletal system employing those models. The analysis comprises bone and muscle "mass" indicators provided by standard densitometry (DEXA); bone 'mass', 'apparent density', geometry or architectural design and strength and muscle strength indicators that can be determined by peripheral quantitative computed tomography (pQCT), and bone material and structural (whole-bone) properties than can be directly assessed by destructive mechanical tests. Some novel interrelationships that can be investigated that way are discussed, namely, 1. the pathogenetic analysis of the effects on whole-bone strength, 2. the discrimination between mineralization and microstructural factors as determinants of changes in the bone material or structural properties, 3. the evaluation of the interaction of a treatment with the ability of bone 'mechanostat' to optimize the bone architectural design by 'distribution / mass' and 'distribution / quality' curves, and 4. the analysis of effects on the musclebone interactions for a differential diagnosis between 'physiological' or 'disuse' and 'true' osteopenias and osteoporoses.     

The Effect of Naturally Occurring Chronic Kidney Disease on the Micro-Structural and Mechanical Properties of Bone

Chronic kidney disease (CKD) is a growing public health concern worldwide, and is associated with marked increase of bone fragility. Previous studies assessing the effect of CKD on bone quality were based on biopsies from human patients or on laboratory animal models. Such studies provide information of limited relevance due to the small size of the samples (biopsies) or the non-physiologic CKD syndrome studied (rodent models with artificially induced CKD). Furthermore, the type, architecture, structure and biology of the bone of rodents are remarkably different from human bones; therefore similar clinicopathologic circumstances may affect their bones differently. We describe the effects of naturally occurring CKD with features resembling human CKD on the skeleton of cats, whose bone biology, structure and composition are remarkably similar to those of humans. We show that CKD causes significant increase of resorption cavity density compared with healthy controls, as well as significantly lower cortical mineral density, cortical cross-sectional area and cortical cross-sectional thickness. Young''s modulus, yield stress, and ultimate stress of the cortical bone material were all significantly decreased in the skeleton of CKD cats. Cancellous bone was also affected, having significantly lower trabecular thickness and bone volume over total volume in CKD cats compared with controls. This study shows that naturally occurring CKD has deleterious effects on bone quality and strength. Since many similarities exist between human and feline CKD patients, including the clinicopathologic features of the syndrome and bone microarchitecture and biology, these results contribute to better understanding of bone abnormalities associated with CKD.     

Remnant Woven Bone and Calcified Cartilage in Mouse Bone: Differences between Ages/Sex and Effects on Bone Strength

IntroductionMouse models are used frequently to study effects of bone diseases and genetic determinates of bone strength. Murine bones have an intracortical band of woven bone that is not present in human bones. This band is not obvious under brightfield imaging and not typically analyzed. Due to the band’s morphology and location it has been theorized to be remnant bone from early in life. Furthermore, lamellar and woven bone are well known to have differing mechanical strengths. The purpose of this study was to determine (i) if the band is from early life and (ii) if the woven bone or calcified cartilage contained within the band affect whole bone strength.

Woven Bone Origin Studies

In twelve to fourteen week old mice, doxycycline was used to label bone formed prior to 3 weeks old. Doxycycline labeling and woven bone patterns on contralateral femora matched well and encompassed an almost identical cross-sectional area. Also, we highlight for the first time in mice the presence of calcified cartilage exclusively within the band. However, calcified cartilage could not be identified on high resolution cone-beam microCT scans when examined visually or by thresholding methods.

Mechanical Strength Studies

Subsequently, three-point bending was used to analyze the effects of woven bone and calcified cartilage on whole bone mechanics in a cohort of male and female six and 13 week old Balb/C mice. Three-point bending outcomes were correlated with structural and compositional measures using multivariate linear regression. Woven bone composed a higher percent of young bones than older bones. However, calcified cartilage in older bones was twice that of younger bones, which was similar when normalized by area. Area and/or tissue mineral density accounted for >75% of variation for most strength outcomes. Percent calcified cartilage added significant predictive power to maximal force and bending stress. Calcified cartilage and woven bone could have more influence in genetic models where calcified cartilage percent is double our highest value.     

Effect of altered occlusal function on transseptal ligament and new bone thicknesses in the periodontium of the rat

Alteration of tooth function is assumed to change stress/strain on the adjacent alveolar bone and its mucoperiosteum, producing changes in morphology similar to those described for other load-bearing bones. The present study suggested that crestal alveolar bone and its mucoperiosteum respond differently to stress/strain than load-bearing bones in other locations, possibly due to differences in the mechanism of bone loading by muscles and teeth. Occlusal hypofunction was initiated by extraction of agonist teeth; the contralateral teeth were placed in hyperfunction by the surgery. Untreated animals were also studied. 3H-proline was injected, animals were killed 1-5 weeks later, and the thicknesses of new bone and transseptal ligament were measured. After 5 weeks of altered function, total thickness (new bone + transseptal ligament) was similar in untreated and in hypofunctional and hyperfunctional situations; however, a new ratio between transseptal ligament and new bone thicknesses was established. Occlusal force was negatively correlated with new bone and positively correlated with transseptal ligament thickness; both thicknesses were statistically correlated in each functional situation (P less than 0.001). Hyperfunction resulted in increased transseptal ligament thickness, but decreased new bone thickness as compared to untreated controls (P less than 0.001). In contrast, hypofunction resulted in an increased new bone thickness, but a decreased transseptal ligament thickness (P less than 0.001). Tissue responses assure appropriate support for the teeth in each functional situation.     

Investigating histomorphological variations in human cranial bones through ontogeny

Through ontogeny, human cranial vault bones undergo differentiation in terms of their shape, size and tissue maturation. This differentiation is visible at both the macroscopic and microscopic levels. Preliminary data from a histological and compartmentalisation exploratory analysis of individuals with different ages suggest differences in the modelling and remodelling patterns through ontogeny. Child vault bones are primarily composed of avascular lamellar bone (largely vascularised), late juvenile or adolescent bones present the largest extension of mineralised areas (highly remodelled) and the lowest vascularisation (diploe is highly reduced), and the adult present highly vascularised bone in which the diploe is again largely extended. During childhood, the existence of an avascular lamellar bone promotes the sealing of the cranium bones surfaces whereas adult vault bones seem to become opened ectocranially due to the remodelling. We discuss the possibility that both effects could be related with the head thermoregulation.     

Molecular Consequences of the SERPINH1/HSP47 Mutation in the Dachshund Natural Model of Osteogenesis Imperfecta

Osteogenesis imperfecta (OI) is a heritable connective tissue disease characterized by bone fragility and increased risk of fractures. Up to now, mutations in at least 18 genes have been associated with dominant and recessive forms of OI that affect the production or post-translational processing of procollagen or alter bone homeostasis. Among those, SERPINH1 encoding heat shock protein 47 (HSP47), a chaperone exclusive for collagen folding in the ER, was identified to cause a severe form of OI in dachshunds (L326P) as well as in humans (one single case with a L78P mutation). To elucidate the disease mechanism underlying OI in the dog model, we applied a range of biochemical assays to mutant and control skin fibroblasts as well as on bone samples. These experiments revealed that type I collagen synthesized by mutant cells had decreased electrophoretic mobility. Procollagen was retained intracellularly with concomitant dilation of ER cisternae and activation of the ER stress response markers GRP78 and phospho-eIF2α, thus suggesting a defect in procollagen processing. In line with the migration shift detected on SDS-PAGE of cell culture collagen, extracts of bone collagen from the OI dog showed a similar mobility shift, and on tandem mass spectrometry, the chains were post-translationally overmodified. The bone collagen had a higher content of pyridinoline than control dog bone. We conclude that the SERPINH1 mutation in this naturally occurring model of OI impairs how HSP47 acts as a chaperone in the ER. This results in abnormal post-translational modification and cross-linking of the bone collagen.     

Bisphosphonate treatment in the oim mouse model alters bone modeling during growth

Osteogenesis imperfecta (OI) is a heritable disease, which results from an abnormal amount or structure of Type I collagen. Bisphosphonates, a class of synthetic antiresorptive drugs, used in osteoporosis management, are also used to decrease fracture incidence and improve quality of life in children with OI. In this study, we used the oim mouse to test the hypotheses that pamidronate treatment during active growth (1) produces larger, stronger, stiffer long bone diaphyses without altering bone material properties, and (2) negatively impacts longitudinal bone growth. Our results indicate that femoral cross-sectional moment of inertia in the distal metaphysis tended to increase with pamidronate treatment and that the treated bones are thicker and structurally stiffer, but shorter than their control-dose counterparts.     

The healing of facial bone fractures by the process of secondary union

The mechanism of healing of facial bone fractures was investigated in a rabbit model. Twelve New Zealand white rabbits underwent surgically induced fractures of the right infraorbital rim and fracture ostectomies (4 to 5 mm) of the left infraorbital rim. Animals were sacrificed 2, 4, and 8 weeks postfracture. Bone, including periosteum, obtained from each fracture or fracture osteoctomy site was divided longitudinally for hematoxylin and eosin staining, fluorescent microscopy, microangiography, and microradiography. Sequential fluorochrome labels of oxytetracycline (30 mg/kg), alizarin complexone (30 mg/kg), DCAF (20 mg/kg), and xylenol orange (90 mg/kg) were administered 24 hours preoperatively and at 1, 2, 4, and 8 weeks postfracture. All fracture and fracture ostectomy sites demonstrated vascular ingrowth, mineralization, and woven bone formation by 2 to 4 weeks postoperatively, beginning with a cartilage precursor. Subsequently, the woven bone was replaced with remodeled lamellar bone, resulting in complete bony healing by 8 weeks postoperatively. These steps were substantiated by microscopic, microradiographic, and radiologic examination of the specimens. This study demonstrates that fractures of the facial bones in a rabbit model heal by a process of new bone formation that resembles secondary union in endochondral bones.     

Prolyl 3-Hydroxylase 1 Null Mice Display Abnormalities in Fibrillar Collagen-rich Tissues Such as Tendons,Skin, and Bones

Osteogenesis imperfecta (OI) is a skeletal disorder primarily caused by mutations in the type I collagen genes. However, recent investigations have revealed that mutations in the genes encoding for cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1 (P3H1) can cause a severe, recessive form of OI. These reports show minimal 3-hydroxylation of key proline residues in type I collagen as a result of CRTAP or P3H1 deficiency and demonstrate the importance of P3H1 and CRTAP to bone structure and development. P3H1 and CRTAP have previously been shown to form a stable complex with cyclophilin B, and P3H1 was shown to catalyze the 3-hydroxylation of specific proline residues in procollagen I in vitro. Here we describe a mouse model in which the P3H1 gene has been inactivated. Our data demonstrate abnormalities in collagen fibril ultrastructure in tendons from P3H1 null mice by electron microscopy. Differences are also seen in skin architecture, as well as in developing limbs by histology. Additionally bone mass and strength were significantly lower in the P3H1 mice as compared with wild-type littermates. Altogether these investigations demonstrate disturbances of collagen fiber architecture in tissues rich in fibrillar collagen, including bone, tendon, and skin. This model system presents a good opportunity to study the underlying mechanisms of recessive OI and to better understand its effects in humans.