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Mechanical properties of rat cortical femur and tibia after long term treatment with biosynthetic human growth hormone
Abstract
The influence of biosynthetic human growth hormone (b-hGH) on female rat cortical femur and tibia was studied after administration of hormone doses of 0.16, 1.10, or 8.33 mg/kg body weight/day for 90 days. The mechanical properties, dimensions, real density, ash weight, and the mineral and collagen concentrations of the bones were measured. In both femur and tibia a positive linear relation was found between the dose of hormone and ultimate load, ultimate stiffness, energy absorption at ultimate load, load at failure, energy absorption at failure, and deflection at failure. In the femur a positive correlation between dose and deflection at ultimate load was also found. After normalizing the mechanical data for the dimensions of the bones, no differences were found in the hormone treated groups compared to placebo, except for the elastic modulus (Young's modulus), which was decreased in the femur in the group given 8.33 mg b-hGH. The mineral and collagen concentration were unaffected in both femur and tibia, whereas the real density was decreased in the femur. The growth-hormone-induced changes in the mechanical properties seem to be caused mainly by increased dimensions of the bones.
... T HE ADMINISTRATION of both parathyroid hormone (PTH) and growth hormone (GH) in rats increases diaphysial bone mass and enhances the mechanical strength of the bone. (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15) Labeling with fluorochromes during the PTH or GH treatment has shown that the PTH administration induces substantial bone formation at the endocortical surface of the diaphysis and limited bone formation at the periosteal surface. (2,8,16) GH injections, on the other hand, induce pronounced periosteal bone formation without influencing the endocortical surface. ...
... reason for the lack of response to the GH treatment could be the use of a GH dose that was too low. In dose-response studies, bone formation and mechanical strength have been found to remain unaffected at GH doses lower than 2 mg/kg per day, (9,27) whereas several investigations have reported the anabolic effect of GH treatment at GH doses in the range of 2-10 mg/kg per day. (9,11,14,27,28) In this experiment, the enhanced bone deposition caused by the treatments results in enhanced mechanical strength of the bone. ...
... In dose-response studies, bone formation and mechanical strength have been found to remain unaffected at GH doses lower than 2 mg/kg per day, (9,27) whereas several investigations have reported the anabolic effect of GH treatment at GH doses in the range of 2-10 mg/kg per day. (9,11,14,27,28) In this experiment, the enhanced bone deposition caused by the treatments results in enhanced mechanical strength of the bone. rhGH alone increases periosteal bone deposition, whereas PTH(1-34) alone increases endocortical bone deposition, both leading to enhanced mechanical strength of the bone. ...
The influence of combined parathyroid hormone (PTH) and growth hormone (GH) treatment on bone formation and mechanical strength was investigated in femoral middiaphysial cortical bone from 20-month-old ovariectomized (OVX) rats. The animals were OVX at 10 months of age, and at 18 months they were treated daily for 56 days with PTH(1-34) alone (60 μg/kg), recombinant human GH (rhGH) alone (2.7 mg/kg), or a combination of PTH(1-34) plus rhGH. Vehicle was given to OVX control rats. All animals were labeled at day 28 (calcein) and at day 49 (tetracycline) of the treatment period. PTH(1-34) alone gave rise to formation of a new zone of bone at the endocortical surface. rhGH alone caused substantial bone deposition at the periosteal surface without influencing the endocortical surface. Combined PTH(1-34) plus rhGH administration enhanced bone deposition at the periosteal surface to the same extent as that of rhGH alone. However, the combined treatment resulted in a more pronounced formation of new bone at the endocortical surface than was induced by PTH(1-34) alone. Both PTH(1-34) alone and rhGH alone increased the mechanical strength of the femoral diaphysis, and further increase in mechanical strength resulted from combined PTH(1-34) plus rhGH treatment. OVX by itself induced the characteristic increase in medullary cavity cross-sectional area and a minor decrease in the mechanical quality of the osseous tissue.
... In case of fractures or osteotomy, GH has shown also positive effects on the repair, as proven by Cacciafesta et al., 44 which have shown that in the animals treated with GH there is a significant increase almost doubling the volume of newformed bone as compared with the placebo group,Actually GH administration could be effective in the consolidation of hip fractures in humans. 45 Several authors have found an increase in cortical thickness after treatment with GH not only in normal rats, 46 but also in aged rats, 15,16 in ovariectomized rats, 23 and also in old ovariectomized rats 35,47 Accordingly, with Andreassen and Oxlund, 18 GH treatment does not seem to have effects on trabecular bone in absence of linear growth. ...
... Data obtained in the present study are consistent with previous ones showing improvements achieved by GH administration regarding biomechanical properties of the bone. 18,35,46 If we try to investigate the pathways by which GH is able to stimulate bone formation, it has been demonstrated that it is able to stimulate the differentiation from mesenchymal stem cells towards the osteoblast lineage, even in aged animals. 61 In addition, GH seems to modulate the activity of Runx2, a transcription factor that is needed for chondrocyte maturation and osteoblasts differentiation. ...
this study evaluate the beneficial effects of the treatment grow hormone on bone regeneration and osseointegration of dental implant surgeriesin elderly people. From a sample of 402 dentalimplants it was concluded that in all age and gender groups the reduction of the osseointegration time was quite significant.
... In old male rats, 80 days of GH treatment increased cortical bone formation mainly through increased subperiosteal bone formation (Andreassen et al. 1995). In young and in old rats, GH treatment increased cortical mechanical strength, mainly as a result of an increase in bone dimensions ( Jørgensen et al. 1991, Andreassen et al. 1995. In primates, GH but not insulin-like growth factor (IGF)-I given to female monkeys for 7 weeks increased bone formation as measured with mineral apposition rate, and the bone formation rate (Sass et al. 1997). ...
... However, the pQCT measurements of femurs in vitro revealed an unaffected cortical volumetric BMD and the measurements using Archimedes' principle showed an unchanged total femur and vertebra L6 volumetric BMD. Other studies have also shown that long-term GH treatment increases area BMD as measured by DXA (Yeh et al. 1994, Ohlsson et al. 1998), but the volumetric BMD (BMC/volume), as measured by Archimedes' principle or pQCT ( Jørgensen et al. 1991, Andreassen et al. 1995, Rosen et al. 1995, is unchanged. These findings could be explained by an overestimation of the increase in BMD by DXA. ...
Growth hormone (GH) is of importance for normal bone remodelling. A recent clinical study demonstrated that MK-677, a member of a class of GH secretagogues (GHSs), increases serum concentrations of biochemical markers of bone formation and bone resorption. The aim of the present study was to investigate whether the GHSs, ipamorelin (IPA) and GH-releasing peptide-6 (GHRP-6), increase bone mineral content (BMC) in young adult female rats. Thirteen-week-old female Sprague-Dawley rats were given IPA (0.5 mg/kg per day; n=7), GHRP-6 (0.5 mg/kg per day; n=8), GH (3.5 mg/kg per day; n=7), or vehicle administered continuously s.c. via osmotic minipumps for 12 weeks. The animals were followed in vivo by dual X-ray absorptiometry (DXA) measurements every 4th week. After the animals were killed, femurs were analysed in vitro by mid-diaphyseal peripheral quantitative computed tomography (pQCT) scans. After this, excised femurs and vertebrae L6 were analysed by the use of Archimedes' principle and by determinations of ash weights. All treatments increased body weight and total tibial and vertebral BMC measured by DXA in vivo compared with vehicle-treated controls. However, total BMC corrected for the increase in body weight (total BMC:body weight ratio) was unaffected. Tibial area bone mineral density (BMD, BMC/area) was increased, but total and vertebral area BMDs were unchanged. The pQCT measurements in vitro revealed that the increase in the cortical BMC was due to an increased cross-sectional bone area, whereas the cortical volumetric BMD was unchanged. Femur and vertebra L6 volumes were increased but no effect was seen on the volumetric BMDs as measured by Archimedes' principle. Ash weight was increased by all treatments, but the mineral concentration was unchanged. We conclude that treatment of adult female rats with the GHSs ipamorelin and GHRP-6 increases BMC as measured by DXA in vivo. The results of in vitro measurements using pQCT and Archimedes' principle, in addition to ash weight determinations, show that the increases in cortical and total BMC were due to an increased growth of the bones with increased bone dimensions, whereas the volumetric BMD was unchanged.
... Some investigators have studied the effects of GH on bone strength. Growth hormone was shown to increase bone strength in both young and old GH-sufficient rats, and this increase has been attributed almost solely to a larger bone size [23] [24]. In a rat model of osteoporosis, GH treatment was shown to reverse the loss of bone strength by increasing the ultimate stress and Young's modulus to normal levels [25]. ...
... The use of daily injections attempts to mimic the physiological release of GH, which occurs in a pulsatile manner with the largest peak release of GH occurring during sleep [29]. The dose (25 μg per mouse per day) was chosen as it is within the wide range of doses which stimulated growth in mice and rats [23] [24] [30]. Although recombinant human GH is often used to treat GH deficiency in animal experiments, antibody production can limit the efficacy of this treatment [31]. ...
Growth hormone (GH) deficiency is related to an increased fracture risk although it is not clear if this is due to compromised bone quality or a small bone size. We investigated the relationship between bone macrostructure, microarchitecture and mechanical properties in a GH-deficient (GHD) mouse model undergoing GH treatment commencing at an early (prepubertal) or late (postpubertal) time point. Microcomputed tomography images of the femur and L4 vertebra were obtained to quantify macrostructure and vertebral trabecular microarchitecture, and mechanical properties were determined using finite element analyses. In the GHD animals, bone macrostructure was 25 to 43% smaller as compared to the GH-sufficient (GHS) controls (P < 0.001). GHD animals had 20% and 19% reductions in bone volume ratio (BV/TV) and trabecular thickness (Tb.Th), respectively. Whole bone mechanical properties of the GHD mice were lower at the femur and vertebra (67% and 45% resp.) than the GHS controls (P < 0.001). Both early and late GH treatment partially recovered the bone macrostructure (15 to 32 % smaller than GHS controls) and the whole bone mechanical properties (24 to 43% larger than GHD animals) although there remained a sustained 27-52% net deficit compared to normal mice (P < 0.05). Importantly, early treatment with GH led to a recovery of BV/TV and Tb.Th with a concomitant improvement of trabecular mechanical properties. Therefore, the results suggest that GH treatment should start early, and that measurements of microarchitecture should be considered in the management of GHD.
... In contrast to PTH (1-34), treatment with GH as monotherapy was unable to counteract the BTX-induced loss of bone mass and deterioration of cortical morphology and trabecular microstructure. The general lack of skeletal protective effects of treatment with GH against disuse was somewhat surprising, as earlier studies in intact rodents have demonstrated increased bone mass and bone formation from treatment with GH (Andreassen, Jørgensen, Oxlund, Flyvbjerg, & Ørskov, 1995;Aspenberg, Hansson, & Thorngren, 1985;Jørgensen, Bak, & Andreassen, 1991;Rosen et al., 1995). However, the lack of effect of GH treatment is consistent with previous findings in GH-treated hypophysectomized hind limb unloaded rats and GHdeficient hind limb-unloaded dwarf rats treated with IGF-1 (Halloran et al., 1995;Sakata et al., 2003). ...
Animal models are fundamental to advance our knowledge of the underlying pathophysiology of bone loss and to study pharmaceutical countermeasures against it. The animal model of post-menopausal osteoporosis from ovariectomy is the most widely used preclinical approach to study skeletal deterioration. However, several other animal models exist, each with unique characteristics such as bone loss from disuse, lactation, glucocorticoid excess, or exposure to hypobaric hypoxia. The present review aimed to provide a comprehensive overview of these animal models to emphasize the importance and significance of investigating bone loss and pharmaceutical countermeasures from perspectives other than post-menopausal osteoporosis only. Hence, the pathophysiology and underlying cellular mechanisms involved in the various types of bone loss are different, and this might influence which prevention and treatment strategies are the most effective. In addition, the review sought to map the current landscape of pharmaceutical countermeasures against osteoporosis with an emphasis on how drug development has changed from being driven by clinical observations and enhancement or repurposing of existing drugs to today's use of targeted anti-bodies that are the result of advanced insights into the underlying molecular mechanisms of bone formation and resorption. Moreover, new treatment combinations or repurposing opportunities of already approved drugs with a focus on dabigatran, parathyroid hormone and abaloparatide, growth hormone, inhibitors of the activin signaling pathway, acetazolamide, zoledronate, and romosozumab are discussed. Despite the considerable progress in drug development, there is still a clear need to improve treatment strategies and develop new pharmaceuticals against various types of osteoporosis. The review also highlights that new treatment indications should be explored using multiple animal models of bone loss in order to ensure a broad representation of different types of skeletal deterioration instead of mainly focusing on primary osteoporosis from post-menopausal estrogen deficiency.
... Consequently, a proper approach enabling to investigate separately the effect of MGP on both structural and material properties of bone is required. In similar studies for different metabolic disorders, it has been reported that geometrical changes may dominate the changes in material properties [14][15][16] , while other studies have concluded to the exact opposite, emphasizing the crucial role of material changes rather than geometrical changes 17 . Such contradictory conclusions may partly come from the limitations described above concerning the exploitation of three-points bending tests results, and obviously depends on the metabolic change which is investigated in each study. ...
Matrix Gla protein (MGP) is mostly known to be a calcification inhibitor, as its absence leads to ectopic calcification of different tissues such as cartilage or arteries. MGP deficiency also leads to low bone mass and delayed bone growth. In the present contribution, we investigate the effect of MGP deficiency on the structural and material mechanical bone properties by focusing on the elastic response of femurs undergoing three-points bending. To this aim, biomechanical tests are performed on femurs issued from Mgp-deficient mice at 14, 21, 28, and 35 days of postnatal life and compared to healthy control femurs. µCT acquisitions enable to reconstruct bone geometries and are used to construct subject-specific finite element models avoiding some of the reported limitations concerning the use of beam-like assumptions for small bone samples. Our results indicate that MGP deficiency may be associated to differences in both structural and material properties of femurs during early stages of development. MGP deficiency appears to be related to a decrease in bone dimensions, compensated by higher material properties resulting in similar structural bone properties at P35. The search for a unique density-elasticity relationship based on calibrated bone mineral density (BMD) indicates that MGP deficiency may affect bone tissue in several ways, that may not be represented uniquely from the quantification of BMD. Despite of its limitation to elastic response, the present preliminary study reports for the very first time the mechanical skeletal properties of Mgp-deficient mice at early stages of development.
... Nevertheless, the delay in muscle and bone development in Hx rats affected bone geometry so severely that the structural stiffness and strength of the diaphyses were lower than normal. Only a single report of such type of effect on postyield bone strength in rats is known to us [34]. ...
In this article, we summarize the results of six different tomographic/biomechanical rat studies involving hypophysectomy (Hx), ovariectomy, treatment with rhGH, olpadronate, alendronate, and toxic doses of aluminum and the development of a genetic diabetes in the eSS strain. All these conditions induced some interesting and rarely reported effects on postyield bone strength. These effects were generally related neither to the degree of mineraliza-tion or the elastic modulus of the bone tissue nor to the preyield behavior of the bones. In two particular cases (Hx, eSS), the elastic modulus of bone tissue varied independently of its degree of mineralization. These results suggest the involvement of some microstructural factor(s) of bone tissue resistance to crack progression (a postyield feature of bone behavior), rather than to crack initiation (the yield-determining factor) in the corresponding mechanism. Changes in collagen or crystal structure may play that role. These changes are relevant to the mechanism of fracture production during plastic deformation, a feature of bone G.R. Cointry • R.F. Capozza • S. Feldman. N.M. Fracalossi. P. Reina • J.L. Ferretti ([]) Center for P-Ca Metabolism Studies G.R. Cointry and R.F. Capozza contributed equally to this work strength that might be independent from mineralization. Therefore, these changes might help to explain some effects of novel treatments on bone strength unrelated to bone mineralization. This questions the belief that the remaining bone mass in metabolic osteopenias is biologically and mechanically normal.
... Fig. 5 indicates that the elastic modulus of the rat bone beam in high vacuum is 4.98 ± 0.25 GPa, low vacuum is 5.24 ± 0.11 GPa and wet, in air is 5.22 ± 0.15 GPa and does not vary greatly over the time period examined. Previous mechanical testing on fully hydrated whole rat bone femur using 3-point bending configuration gives an elastic modulus of 5.12 ± 0.77 GPa (Kasra et al., 1997), 8.0 ± 0.4 GPa (Barengolts et al., 1993), 6.88 ± 0.31 GPa (Jorgensen et al., 1991), and 4.9 ± 0.4 GPa (Ejersted et al., 1993) which is similar to the calculated elastic modulus values in our work and indicates that the vacuum of the SEM chamber does not have an effect on elastic modulus of the samples over the time period investigated. Interestingly, the similarity between the elastic modulus of our relatively small bone volumes and whole bone testing suggests an effective transfer of stresses throughout the bone material, indicating that all bone components are not failing or slipping but are tightly bound to one another. ...
The lamellar unit is a critical component in defining the overall mechanical properties of bone. In this paper, micro-beams of bone with dimensions comparable to the lamellar unit were fabricated using focused ion beam (FIB) microscopy and mechanically tested in bending to failure using atomic force microscopy (AFM). A variation in the mechanical properties, including elastic modulus, strength and work to fracture of the micro-beams was observed and related to the collagen fibril orientation inferred from back-scattered scanning electron microscopy (SEM) imaging. Established mechanical models were further applied to describe the relationship between collagen fibril orientation and mechanical behaviour of the lamellar unit. Our results highlight the ability to measure mechanical properties of discrete bone volumes directly and correlate with structural orientation of collagen fibrils.
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... Compared to the epiphysis, metaphyseal bone also has much larger contact surface area with bone marrow, which can regulate the bone formation through dynamic remodeling [30]. Moreover, femurs and tibias have distinct geometrical and mechanical properties [31,32], which can also lead to their different phenotypic responses to PDIA3's actions. ...
1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3] is crucial for normal skeletal development and bone homeostasis. Protein disulfide isomerase family A, member 3 (PDIA3) mediates 1α,25(OH)2D3 initiated-rapid membrane signaling in several cell types. To understand its role in regulating skeletal development, we generated Pdia3-deficient mice and examined the physiologic consequence of Pdia3-disruption in embryos and Pdia3+/- heterozygotes at different ages. No mice homozygous for the Pdia3-deletion were found at birth nor were there embryos after E12.5, indicating that targeted disruption of the Pdia3 gene resulted in early embryonic lethality. Pdia3-deficiency also resulted in skeletal manifestations as revealed by µCT analysis of the tibias. In comparison to wild type mice, Pdia3 heterozygous mice displayed expanded growth plates associated with decreased tether formation. Histomorphometry also showed that the hypertrophic zone in Pdia3+/- mice was more cellular than seen in wild type growth plates. Metaphyseal trabecular bone in Pdia3+/- mice exhibited an age-dependent phenotype with lower BV/TV and trabecular numbers, which was most pronounced at 15 weeks of age. Bone marrow cells from Pdia3+/- mice exhibited impaired osteoblastic differentiation, based on reduced expression of osteoblast markers and mineral deposition compared to cells from wild type animals. Collectively, our findings provide in vivo evidence that PDIA3 is essential for normal skeletal development. The fact that the Pdia3+/- heterozygous mice share a similar growth plate and bone phenotype to nVdr knockout mice, suggests that PDIA3-mediated rapid membrane signaling might be an alternative mechanism responsible for 1α,25(OH)2D3's actions in regulating skeletal development.
... The reported homogeneous elastic modulus ranges orders of magnitude from over 130 MPa (Beaupied et al., 2006) to 1000 MPa (Nazarian et al., 2011). The elastic modulus values used in this study were determined by matching the force-displacement curves from the finite element model to the curves from the ex vivo femur loading and were the similar to previously reported values for rat femurs (Jorgensen et al., 1991). ...
Microdamage accumulates in bone due to repetitive or excessive mechanical loading, and accumulation of damage can lead to an increase in fracture susceptibility. Understanding the stress or strain criterion for damage formation would allow improved predictive modeling to better assess experimental results or evaluate training regimens. Finite element models coupled with three-dimensional measurements of damage were used to directly correlate damage formation to the local strain state in whole rat femora subjected to three-point bending fatigue. Images of accumulated damage from contrast-enhanced micro-CT were overlaid onto the calculated strain result to determine the strain associated with damage. Most microdamage accumulated in areas where the first principal strain exceeded 0.5%, but damage also occurred at lower strains when applied over sufficiently large volumes. As such, a single threshold strain was not a good predictor of damage. In order to capture the apparently stochastic nature of damage formation, a Weibull statistical model was applied. The model provided a good fit to the data, and a fit based on a subset of the data was able to predict the results in the remaining samples with an RMS error of 17%. These results demonstrate that damage formation is dependent on principal strain, but has a random component that is likely due to the presence of pores or flaws smaller than the resolution of the model that act as stress concentrations in bone.
... Homogenous populations of rats are available at low costs, but their bone physiology differs from humans. The organic bone matrix in humans consists to 90% of collagen, whereas in rats only 60% (Jorgensen et al. 1991). Cortical bone in rats consists of an inner layer of irregular oriented nonlamellar bone and an outer layer of concentric lamellar bone which occurs fi rst at the age of three months (Danielsen et al. 1993). ...
... Nevertheless, the delay in muscle and bone development in Hx rats affected bone geometry so severely that the structural stiffness and strength of the diaphyses were lower than normal. Only a single report of such type of effect on postyield bone strength in rats is known to us [34]. ...
In this paper we summarize the results of six different tomographic/biomechanical rat studies involving hypophysectomy (Hx), ovariectomy, treatment with rhGH, olpadronate, alendronate and toxic doses of aluminum, and the development of a genetic diabetes in the eSS strain. All these conditions induced some interesting and rarely reported effects on post-yield bone strength. These effects were generally neither related to the degree of mineralization or the elastic modulus of the bone tissue nor to the pre-yield behavior of the bones. In two particular cases (Hx, eSS) the elastic modulus of bone tissue varied independently of its degree of mineralization. These results suggest the involvement of some microstructural factor(s) of bone tissue resistance to crack progression (a post-yield feature of bone behavior), rather than to crack initiation (the yield-determining factor) in the corresponding mechanism. Changes in collagen or crystal structure may play that role. These changes are relevant to the mechanism of fracture production during plastic deformation, a feature of bone strength that might be independent from mineralization. Therefore, these changes might help to explain some effects of novel treatments on bone strength unrelated to bone mineralization. This questions the belief that the remaining bone mass in metabolic osteopenias is biologically and mechanically normal.
... In the rabbit femur, the range was 11-15 GPa Ayers et al., 1996). In mice and rats the ranges were 3-11 GPa and 7-8 GPa, respectively (Barengolts et al., 1993;Jorgensen et al., 1991;Wergedal et al., 2005). ...
The effective elastic modulus, yield strength, yield strain, ultimate strength, ultimate strain, strain energy density at yield and strain energy density at ultimate failure of femoral diaphyseal cortical bone were investigated on canine femurs. Four femurs representative of the canine population were selected from four statistically-determined clusters based on increasing size and weight comprising the Toy poodle (5kg), Poodle (12kg), German shorthaired pointer (25kg) and Doberman (50kg). The zones of interest were the lateral, medial, cranial, and caudal quadrants of the mid-diaphysis. Effective mechanical properties were measured using quasi-static three-point bending tests on strips. The averages±SD were 15.6±2.6GPa for effective elastic modulus, 174.3±32.1MPa for yield strength, 0.012±0.003 for yield strain, 251.0±49.1MPa for ultimate strength, 0.021±0.005 for ultimate strain, 10.7±4.0Jm(-3)×10(5) for strain energy density at Yield and 33.0±14.1Jm(-3)×10(5) for strain energy density at ultimate failure. Significant differences were found between dogs and the effective elastic modulus increased with breed weight and size (13.9GPa for the Toy poodle to 17.2GPa for the Doberman). The ultimate strength σ(u) and strain energy density at ultimate failure U(u) were significantly lower in the Toy poodle than in the Poodle and German shorthaired pointer indicating that the cortical bone material in the Toy poodle differed from that of the other dogs. Examination of the zones of interest revealed that the cranial quadrant showed the greatest stiffness, whereas strength was highest at the medial site. The caudal cortex was less stiff and strong than the cranial cortex.
... Fig. 5 indicates that the elastic modulus of the rat bone beam in high vacuum is 4.98 ± 0.25 GPa, low vacuum is 5.24 ± 0.11 GPa and wet, in air is 5.22 ± 0.15 GPa and does not vary greatly over the time period examined. Previous mechanical testing on fully hydrated whole rat bone femur using 3-point bending configuration gives an elastic modulus of 5.12 ± 0.77 GPa (Kasra et al., 1997), 8.0 ± 0.4 GPa (Barengolts et al., 1993), 6.88 ± 0.31 GPa (Jorgensen et al., 1991), and 4.9 ± 0.4 GPa (Ejersted et al., 1993) which is similar to the calculated elastic modulus values in our work and indicates that the vacuum of the SEM chamber does not have an effect on elastic modulus of the samples over the time period investigated. Interestingly, the similarity between the elastic modulus of our relatively small bone volumes and whole bone testing suggests an effective transfer of stresses throughout the bone material, indicating that all bone components are not failing or slipping but are tightly bound to one another. ...
The mechanical properties of rat bone at micron length scales have been evaluated as a function of environmental conditions using an in situ atomic force microscope (AFM) setup while observing using scanning electron microscopy (SEM). Focused ion beam fabricated rat bone cantilever samples were tested in both low and high vacuum conditions in the SEM as well as wet in air using the AFM to measure their elastic modulus. The elastic modulus of rat bone at micron length scales is shown to be independent of the environmental testing conditions and indicates water is bound to bone material even under relatively high vacuum conditions. Our work therefore shows how in situ mechanical testing of bone while observing using high resolution SEM can provide results similar to testing wet in air.
Sprouting angiogenesis plays a key role during bone regeneration. For example, insufficient early revascularization of the injured site can lead to delayed or non-healing. During sprouting, endothelial cells are known to be mechano-sensitive and respond to local mechanical stimuli. Endothelial cells interact and communicate mechanically with their surroundings, such as outer-vascular stromal cells, through cell-induced traction forces. In addition, external physiological loads act at the healing site, resulting in tissue deformations and impacting cellular arrangements. How these two distinct mechanical cues (cell-induced and external) impact angiogenesis and sprout patterning in early bone healing remains however largely unknown. Therefore, the aim of this study was to investigate the relative role of externally applied and cell-induced mechanical signals in driving sprout patterning at the onset of bone healing. To investigate cellular self-organisation in early bone healing, an in silico model accounting for the mechano-regulation of sprouting angiogenesis and stromal cell organization was developed. Computer model predictions were compared to in vivo experiments of a mouse osteotomy model stabilized with a rigid or a semirigid fixation system. We found that the magnitude and orientation of principal strains within the healing region can explain experimentally observed sprout patterning, under both fixation conditions. Furthermore, upon simulating the selective inhibition of either cell-induced or externally applied mechanical cues, external mechanical signals appear to overrule the mechanical communication acting on a cell-cell interaction level. Such findings illustrate the relevance of external mechanical signals over the local cell-mediated mechanical cues and could be used in the design of fracture treatment strategies for bone regeneration.
The presented work aims at describing some of the many applications of computational modelling (and finite element method in particular) in the field of biomechanics. More specifically, applications to the characterization of biological tissues and to the proposition of biosubstitutes will be detailed. This contribution starts with a snapshot of the numerous experimental and computational methods that have been developed in biomechanics to predict tissue behaviour and their interactions with their environment, or to propose repair solutions after an injury.
Some of my contributions in response to clinical issues (including bone reconstruction, bone tissue characterization, the proposition of ligament substitutes or the development of biomaterials for bone repair) are then detailed. In the reported work, a particular attention is paid to the confrontation of simulation results with experimental data in order to evaluate the validity of the proposed models.
Lastly, this contribution ends with the description of my future research project organized in two different axes: the first one concerns the characterization of soft fibrous tissues with original applications in the field of reproductive biomechanics, while the second on focuses on the in silico modelling and development of new bone substitutes. These research activities will be carried on in a highly multidisciplinary context, with constant connections to clinical applications.
Objectives:
The aim of this study was to assess whether growth hormone (GH) replacement therapy can enhance implant osseointegration.
Materials and methods:
A systematic literature search was conducted from 1982 to March 2016. A structured search using the keywords "growth hormone," "implants," and "osseointegration" was performed to identify preclinical and clinical in vivo controlled studies and was followed by a 2-phase search strategy. Initially, 31 potentially relevant articles were identified. After removal of duplicates and screening by title and abstract, 10 potential studies were included. Studies were assessed for bias and data were synthesized using a random-effects meta-analysis model.
Results:
All studies were preclinical animal trials, and the follow-up period ranged from 2 to 16 weeks. Seventy percent of the included studies reported an increase in bone-to-implant contact in animals receiving GH compared with controls. Meta-analysis showed a significant mean difference for bone to implant between GH groups versus controls (no GH supplementation) of 10.60% (95% confidence interval: 3.79%-17.41%) favoring GH administration.
Conclusion:
GH treatment seems to promote osseointegration around implants in preclinical studies; however, these findings must be assessed in highly controlled human clinical trials as a number of confounding factors may have influenced the outcomes of the included studies.
The management of osteoporotic fractures is multifactorial and pharmacological strategies consist of acute management of pain and complications resulting from the fractures rather than building up new, strong bone. This challenge to increase bone density can be achieved at a later stage after fracture healing has already occurred as this usually takes more than 5 years to be efficient. However osteoporotic patients with acute vertebral fractures have an increased risk for further new vertebral fractures at a given bone density level compared with those without prevalent fractures. Thus the management of patients with multiple acute vertebral fractures and very low bone density is the most difficult problem in osteoporosis.
Bone strength is the maximal load that can be applied before a fracture occurs. It is influenced by a number of different factors, such as mass, geometry, architecture, and intrinsic bone tissue quality (Figure 3.1). Bone tissue quality is related to microstructure, to the degree of mineralization, and to matrix characteristics, such as the orientation and chemical structure of the collagen fibers. The aim of antiosteoporotic treatments is to improve bone strength, and thus decrease the risk of fracture (Figure 3.2). In humans, the end point used to evaluate bone strength is fracture occurence; large numbers of patients are required to demonstrate significant reductions as a result of therapeutic intervention. Fracture is not only caused by decreased bone mineral mass, or alteration of the microarchitecture, but is also related to falls, which can occur as a result of loss of balance, inappropriate protective responses, or muscle weakness (Figure 3.3). Thus, careful and specific investigation in animal models to examine the effects of antiosteoporotic treatments on bone strength (Figure 3.4) and its determinants is of major importance.
Bone strength is determined by biomechanical parameters such as bone mass, size, shape and tissue quality. Many osteoporosis treatments build bone mass but also change tissue quality. Careful investigation of all determinants of bone strength should be considered in the pathophysiology of osteoporosis and consequently in the selection of proper antiosteoporotic treatment.
Bone is a dynamical, anisotropic, hierarchical, inhomogeneous and time-dependent biological material. At the micro and nano scales, their mechanical and structural characterizations are still being a challenging topic. Nanoindentation and Atomic Force Microscopy are used to assess the mechanical and morphological characteristics of cortical bones. Time-dependent, elastic and plastic mechanical properties were computed using the nanoindentation method proposed by (Mazeran et al., 2012). Experiments were performed on different species of bones for different conditions. Wistar rat femoral cortical bone was used to assess the evolution of the mechanical properties in a life span model (from growth to senescence). The variation of the mechanical properties with age was evidenced and their correlation with physico-chemical properties was established. Then, prediction equations were proposed to describe these behaviours. From these equations, it is possible to estimate an apparent maturation age for each mechanical property. Our findings suggest maturation age is earlier and growth rate are higher for elastic properties than for time-dependent mechanical properties. Time-dependent mechanical behaviour of Human femoral cortical bones were assessed considering its heterogeneity. Haversian systems with different apparent mineral content were identified by means of their apparent grey levels obtained from ESEM images. Results prove the mechanical heterogeneity of the Haversian systems and highlight the influence of the time-dependent mechanical properties in the anisotropic behaviour of bone. Bovine femoral cortical bone was used to quantify the mechanical and morphological effects of the demineralization process. Bone seems to have a quasi-isotropic mechanical behaviour after mineral loss. AFM images of the remaining organic components show that collagen fibrils are oriented in a possible privileged direction. According to our knowledge, few investigations have been performed simultaneously on mechanical, morphological and physico-chemical properties of bone. All these results provide a better understanding of the interactions of the collagen-mineral matrix, bone remodelling and their influence especially in the time-dependent mechanical response. Data reported in this work could be useful to develop and to improve multi-scale bone models and multi-scale constitutive laws for cortical bone.
Die Auswirkung der systemischen Applikation von 100µg/kg/KG rekombinantem speziesspezifischem Wachstumshormon (GH) über 26 Tage auf den Knochenumbau des Yucatan-Minischweins wurde an Wirbelkörpern, Beckenkämmen und Rippen histomorphometrisch untersucht. Der Einfluss der Distraktionsosteogenese auf die Mineralappositionsrate wurde ermittelt. 24 Tiere wurden an der linken Tibia osteotomiert, ein Fixateur externe wurde zur Distraktionsosteogenese von 2mm/d angelegt. 12 Tiere erhielten Wachstumshormon, 12 Placebo. Eine polychrome Fluoreszenzmarkierung wurde i.v. appliziert. Post mortem wurden Schnitte und Dünnschliffe der genannten Knochen angefertigt. Mittels Bildanalysesystem erfolgte die histomorphometrische Auswertung anhand der Parameter Knochendichte, Porosität, Trabekeldicke, Trabekelumbauparameter und Mineralappositionsrate (MAR). Signifikante Veränderungen durch Wachstumshormongabe konnten gezeigt werden. Unterschiede zwischen den Lokalisationen traten auf. So war die Knochendichte der GH-Tiere an Wirbelkörpern und Rippen signifikant geringer als in der Placebogruppe, kein signifikanter Unterschied zeigte sich am Beckenkamm. An allen 3 Lokalisationen war in der Wachstumshormongruppe eine signifikant erhöhte kortikale Porosität zu finden. Nur am Wirbelkörper waren die trabekuläre Knochendichte und die Trabekeldicke bei den GH-Tieren signifikant geringer als bei den Kontrolltieren. Die Knochenresorption war in der GH-Gruppe am Beckenkamm signifikant erhöht. Die Formation war bei den GH-Tieren sowohl iliakal als auch vertebral signifikant erhöht. Insgesamt ergab sich damit ein signifikant verminderter Anteil an ruhender Oberfläche bei den GH-Tieren. In ihrer Ausprägung waren diese Parameter zwischen Wirbel und Beckenkamm signifikant verschieden. Die MAR war in der GH-Gruppe signifikant höher als in der Placebogruppe, außerdem war sie während der Distraktionsphase signifikant höher als während der Konsolidierungsphase. Vergleicht man die Parameter mit Angaben aus der Literatur, kann bestätigt werden, dass die hier verwendeten Messmethoden geeignet sind, und dass das Yucatan-Minischwein ein geeignetes Modell zur Klärung von Fragestellungen der Knochenbiologie auch im Hinblick auf den Vergleich zum Menschen darstellt.
Osteoporosis is a disease known to promote bone fragility but the effect on the mechanical properties of bone material, which is independent of geometric effects, is particularly unclear. To address this problem, micro-beams of osteoporotic bone were prepared using focused ion beam microscopy and mechanically tested in compression using an atomic force microscope while observing them using in situ electron microscopy. This experimental approach was shown to be effective for measuring the subtle changes in the mechanical properties of bone material required to evaluate the effects of osteoporosis. Osteoporotic bone material was found to have lower elastic modulus and increased strain to failure when compared to healthy bone material, while the strength of osteoporotic and healthy bone was similar. Surprisingly, the increased strain to failure for osteoporotic bone material provided enhanced toughness relative to the control samples, suggesting that lowering of bone fragility due to osteoporosis is not defined by material performance. A mechanism is suggested based on these results and previous literature that indicates degradation of the organic material in osteoporosis bone is responsible for resultant mechanical properties.
The growth promoting effect of combined therapy with growth hormone (GH) and insulin-like growth factor-I (IGF-I) in normal rats is not known. We therefore investigated the efficacy of treatment with recombinant human (rh) GH and/or rhIGF-I on longitudinal bone growth and bone mass in intact, prepubertal, female Sprague-Dawley rats. RhGH was injected twice daily sc (5 mg/kg/d) and rhIGF-I continuously infused sc (2.2 or 4.4 mg/kg/d) for 28 days. Longitudinal bone growth was monitored by weekly x-rays of tibiae and nose-anus length measurements, and tibial growth plate histomorphology was analyzed. Bone mass was evaluated by peripheral quantitative computed tomography (pQCT). In addition, serum levels of IGF-I, rat GH, acid labile subunit (ALS), insulin-like growth factor binding protein-3 (IGFBP-3), 150-kDa ternary complex formation and markers of bone formation and degradation were measured. Monotherapy with rhGH was more effective than rhIGF-I (4.4 mg/kg/d) to increase tibia and nose-anus length while combined therapy did not further increase tibia, or nose-anus, lengths or growth plate height. In contrast, combined rhGH and rhIGF-I (4.4 mg/kg/d) therapy had an additive stimulatory effect on cortical bone mass vs. rhGH alone. Combined treatment with rhGH and rhIGF-I resulted in markedly higher serum IGF-I concentrations vs. rhGH alone but did not compromise the endogenous secretion of GH. We conclude that rhIGF-I treatment augments cortical bone mass but does not further improve bone growth in rhGH treated young, intact, female rats.
This eight-chapter monograph intends to present basic principles and applications of biomechanics in bone tissue engineering in order to assist tissue engineers in design and use of tissue-engineered products for repair and replacement of damaged/deformed bone tissues. Briefly, Chapter 1 gives an overall review of biomechanics in the field of bone tissue engineering. Chapter 2 provides detailed information regarding the composition and architecture of bone. Chapter 3 discusses the current methodologies for mechanical testing of bone properties (i.e., elastic, plastic, damage/fracture, viscoelastic/viscoplastic properties). Chapter 4 presents the current understanding of the mechanical behavior of bone and the associated underlying mechanisms. Chapter 5 discusses the structure and properties of scaffolds currently used for bone tissue engineering applications. Chapter 6 gives a brief discussion of current mechanical and structural tests of repair/tissue engineered bone tissues. Chapter 7 summarizes the properties of repair/tissue engineered bone tissues currently attained. Finally, Chapter 8 discusses the current issues regarding biomechanics in the area of bone tissue engineering.
Table of Contents: Introduction / Bone Composition and Structure / Current Mechanical Test Methodologies / Mechanical Behavior of Bone / Structure and Properties of Scaffolds for Bone Tissue Regeneration / Mechanical and Structural Evaluation of Repair/Tissue Engineered Bone / Mechanical and Structural Properties of Tissues Engineered/Repair Bone / Current Issues of Biomechanics in Bone Tissue Engineering
Several antiresorptive agents have been developed for the treatment of osteoporosis and bone disorders. Few agents have been introduced that stimulate bone formation. Treatment with parathyroid hormone induces, however, a potent increase in hip and lumbar bone mineral density (BMD) and is now available in some countries. The present review focuses on growth hormone (GH) / GH secretagogues (GHSs). GH/GHSs stimulates bone turnover, thereby increasing bone mass and density.
Objective—To determine the effect of recombinant canine somatotropin (STH) on radiographic, densitometric, and biomechanical aspects of bone healing using an unstable ostectomy gap model.
Study Design—After an ostectomy of the midshaft radius, bone healing was evaluated over an 8–week period in control dogs (n = 4) and dogs receiving recombinant canine STH (n = 4).
Animals or Sample Population—Eight sexually intact female Beagle dogs, 4 to 5 years old. Methods—Bone healing was evaluated by qualitative and quantitative evaluation of serial radiographs every 2 weeks. Terminal dual-energy x-ray absorptiometry and three-point bending biomechanical testing were also performed.
Results—Dogs receiving STH had more advanced radiographic healing of ostectomy sites. Bone area, bone mineral content, and bone density were two to five times greater at the ostectomy sites of treated dogs. Ultimate load at failure and stiffness were three and five times greater in dogs receiving STH.
Conclusions—Using the ostectomy gap model, recombinant canine STH enhanced the radiographic, densitometric, and biomechanical aspects of bone healing in dogs. Clinical Relevance—Dogs at risk for delayed healing of fractures may benefit from treatment with recombinant canine STH.
A refinement of the current ultrasonic elasticity technique was used to measure the orthotropic elastic properties of rat
cortical bone as well as to quantify changes in elastic properties, density, and porosity of the dwarf rat cortex after a
treatment with recombinant human growth hormone (rhGH). The ultrasonic elasticity technique was refined via optimized signal
management of high-frequency wave propagation through cubic cortical specimens. Twenty dwarf rats (37 days old) were randomly
assigned to two groups (10 rats each). The dwarf rat model (5–10% of normal GH) was given subcutaneous injections of either
rhGH or saline over a 14-day treatment period. Density was measured using Archimedes’ technique. Porosity and other microstructural
characteristics were also explored via scanning electron microscopy and image analysis. Statistical tests verified significant
decreases in corticla orthotropic Young’s (−26.7%) and shear (−16.7%) moduli and density (−2.42%) concomitant with an increase
in porosity (+125%) after rhGH treatments to the dwarf model (p<0.05). A change in material symmetry from orthotropy toward planar isotropy within the radial-circumferential plane after
GH treatments was also noted. These results demonstrate some alteration in bone properties at this time interval. Structural
implications of these changes throughout physiological loading regimens should be explored.
Bone regeneration has long been a major focus for tissue engineers and the importance of vascularization to the bone regeneration process has been well documented. Over the past decade, technological advances in the areas of stem cell biology, scaffold fabrication, and protein engineering have significantly enhanced our understanding of the interplay between vascularization and bone growth. This review, therefore, describes the commonly used models for investigating the complex interactions between osteoblastic cells and endothelial cells, evaluates the different tools utilized to investigate the relationship between vascularization and bone growth in vivo, and finally, summarizes possible areas of research related to therapeutic development.
The effects of a combination of mild exercise and GH injections on bone were studied in old female rats. Biosynthetic human GH, 2.7 mg/kg/day, was injected s.c. for 73 days. Exercised rats ran 8 m/min on a treadmill for 1 h/day. All rats (age 21 months old) were labeled with a tetracycline injection 56 days and a calcein injection 11 days before killing. The GH injections resulted in an 11-fold increase in femoral middiaphyseal bone formation rate and a 12% increase in cross-sectional area compared with the saline-injected group. The mild exercise doubled the mineralizing surface but did not influence the bone formation rate significantly. The combination of GH injections plus exercise, however, resulted in a further increase of 39% in bone formation rate, primarily at the anterolateral aspects, and an increase of 5% in cross-sectional area compared with the group injected with GH only. The femur ultimate breaking load was increased by 37% and the stiffness by 42% in the group injected with GH compared with the saline-injected group. Exercise alone did not influence the femur mechanical properties. The combination of GH injections plus exercise induced a 4% further increase in ultimate breaking load and 7% further increase in stiffness compared with the group injected with GH alone. The GH injections induced a 117% increase in serum insulin-like growth factor I. The GH-insulin-like growth factor I axis stimulates recruitment of osteoblast precursor cells, resulting in increased bone formation at the periosteal surface. GH injections and mild excercise in combination modulate and increase further the formation and strength of cortical bone in old female rats.
The aim of this study was to histologically evaluate the effect of using growth hormone (GH) around immediate dental implants in fresh extraction sockets.
Six mongrel dogs had had their lower right and left first premolars extracted. For the right side, the control side, implants were placed immediately. For the left sides, the study side, GH powder was placed in the socket and then immediate implant placement was done. Animals were killed at 2, 6, and 12 weeks after surgery, and histological sections were stained with hematoxylin and eosin, and trichrome stains, and observed under light microscopy for the newly formed bone.
Bone formation was obvious in both groups. But in study group, bone density had denser and well-oriented collagen fibers. An increase in bone response was observed with high local administration of GH. In the first phases of bone repair, the osteons were more organized; they were more organized by the 12th week.
The use of GH powder around dental implants placed immediately in fresh extraction sockets enhanced periimplant bone response.
Growth hormone (GH) has been found to increase the length, thickness and bending strength of rat femora. The present study was designed to investigate if glucocorticoid treatment or food restriction would interfere with the effect of exogenous GH on bone growth. Male rats treated with GH for 30 days experienced a weight gain of 30-35% and longitudinal and periosteal femoral growth. A dose-related increase in the bending strength of the femora was found and was explained by an increased thickness of the femora. In spite of a reduced real density, biomechanical competence was preserved after GH treatment. GH treatment combined with a relatively small dose of glucocorticoid, which in itself had no significant effect on bone growth and strength, reduced the stimulating effect of GH on body weight gain, femoral growth and strength. GH-treated rats that were food restricted, so as to limit their body weight gain to that of the saline group, experienced significant longitudinal and periosteal femoral growth. Bone strength, however, was not increased, which conforms to a reduced mineralization and increased porosity of the femora. Young's modulus (normalized bone stiffness) was significantly decreased in this group, probably as a result of decreased mineralization. Furthermore, the combination of GH treatment and food restriction resulted in a reduced apparent density indicating increased bone resorption.
The influence of growth hormone on bone formation, mechanical strength, and composition has been investigated in femur middiaphyseal cortical bone from 2-year-old male rats. The rats were given biosynthetic human growth hormone (bhGH) at 2.7 mg/kg/day in two daily injections for 20, 40, or 80 days, and all animals were killed 80 days after the start of bhGH administration. Control animals were given saline. All animals were labeled with tetracycline on days 41 and 69. Only in the bhGH-80-day group was subperiosteal tetracycline double labeling seen all around the femur diaphysis, and this pattern was found in all animals of the group. Double labeling subperiosteally at the posteromedial aspect was found in all animals of the experiment, but compared with the control group, a 400% and an 800% increase in mineral apposition rate was seen in the bhGH-40-day and bhGH-80-day groups, respectively. Light microscopy and polarization microscopy showed that this newly deposited bone was organized in the same concentric lammellae and had the same direction of the collagen fibers when compared with the surrounding bone formed before the start of bhGH injections. The cortical bone cross-sectional area was increased in the bhGH-40-day and bhGH-80-day groups. At the endosteum, scattered labeling was found in animals from all groups, and no differences in medullary cross-sectional areas were seen. The mechanical analysis revealed an increased mechanical strength of the whole diaphyseal bone after bhGH administration. When the data were corrected for dimensions of the diaphyseal bone, no differences in intrinsic mechanical properties of the bone tissue were found. No differences in apparent density of dry defatted bone, ash, and collagen were seen, whereas apparent density of dry defatted bone minus ash was decreased in all groups given bhGH. Correspondingly, a slight increase in ash concentrations of the bhGH-injected animals was seen. bhGH administration also increased the body weight, muscle mass, and total serum IGF-I and thyroxine concentrations.
Human growth hormone (hGH) and insulin-like growth factor I (IGF-I) both stimulate bone formation and have been proposed as therapeutic agents for osteoporosis. We examined the effect of hGH and IGF-I alone and in combination on bone size, bone mineral content (BMC), and bone mineral density (BMD) in 10- to 12-week old growing female Sprague-Dawley rats. Sixty rats were assigned to treatment with either placebo, hGH, IGF-I, or both for 4 weeks. After 4 weeks, the right femurs and tibias were excised, and ex vivo BMC and the area of the tibia and femur were measured by dual-energy X-ray absorptiometry (DXA); volume of these bones was measured by Archimedes' principle. In addition, proximal tibial bone density was measured directly by peripheral quantitative computerized tomography (pQCT). Bone length, area, and volume in all treated groups was greater than controls. Areal bone density by DXA (BMC/area) was higher in IGF-treated rats and lower in GH-treated rats than in controls. Volumetric bone density (BMC/volume) was lower in treated groups than in controls. Measurements by pQCT confirmed that true bone density was lower in all treated groups than in controls. We conclude that treatment with hGH or IGF-I increased bone size and mineral content but decreased bone density in growing rats. Because areal correction of BMC did not adequately correct for the increased bone volume in IGF-treated rats, results of areal bone density by DXA should be interpreted with caution when treatment causes a disparity in bone size between groups.
The effect of clodronate on healing of the fracture of osteopenic bone was studied in rats. A total of 165 female rats (14 +/- 1 weeks, 216 +/- 2 g) were divided into five fracture groups (n = 30), and a neurectomized group (n = 15). Osteopenia (op) was induced by right sciatic neurectomy 4 weeks before the fracture. Nonosteopenic (nop) rats were not operated. A closed prepinned diaphyseal fracture of the right femur was done by three-point bending method both to op and nop rats, and the left femur served as an unoperated control. All the fracture groups were divided into treatment (clodronate 10 mg/kg/day sc) and control (saline sc) groups, and the administration was continued throughout the study. The op rats were killed 2, 4, 8, and 12 weeks and nop rats 8 weeks after the fracture. Fracture healing was examined by x-ray and bone-bending strength. Neurectomy reduced bone strength (p < 0.01) at 4 weeks. Clodronate did not affect the bending strength of healing callus of op rats at 2, 4, 8, or 12 weeks after fracture, but reduced the strength of healing callus in nop rats (p < 0.05) at 8 weeks. Radiologic callus width increased in clodronate-treated groups both in op (8 and 12 weeks, p < 0.001) and nop rats (8 weeks, p < 0.05) when compared with saline-treated groups. Clodronate did not affect normal bone strength. In conclusion, clodronate did not affect the bending strength of op fracture nor the strength of the control bones. The remodeling of the fracture was delayed with clodronate.
Growing pigs were given subcutaneous (SC) injections of 40 micrograms porcine GH/kg body weight (BW) or its vehicle twice daily for 2 months. Animals were pair-fed with a diet containing 1.1% Ca, 0.6% P, and 1000 IU vitamin D3/kg. At slaughter, several bone characteristics including histomorphometric data (using double tetracycline labeling) were measured on tibia and metacarpals. GH accelerated growth, with greater (p < 0.01) tibial and metacarpal weights, greater tibial length (p < 0.01) and diameters (outside and inside, p < 0.01), and greater tibial ash weight (p < 0.02) in GH-treated pigs than in controls. The similar values of apparent bone density (weight/volume) and ash/bone volume or ash/dry matter in the two groups suggest adequate coupling between bone growth and mineralization in GH-treated pigs. Histomorphometric data for the distal metacarpal metaphysis indicated greater trabecular bone volume (p < 0.01), osteoblastic surface (p < 0.01), and mineral apposition rate (p < 0.05) in GH-treated pigs. The osteoclast surface, lacuna depth, and osteoid-related parameters in GH-treated and control pigs were similar. The plasma PTH of the two groups of pigs were similar throughout the experiment. These data and the elevated plasma alkaline phosphatase activity (p < 0.05) in GH-treated pigs suggest that GH specifically affects bone formation. GH had no effect on the plasma 25-OH vitamin D3 but 1,25(OH)2 vitamin D3 (calcitriol) was higher (p < 0.01) in treated pigs throughout the experiment. This suggests that calcitriol may help adapt bone mineralization to accelerated bone formation during growth hormone treatment.(ABSTRACT TRUNCATED AT 250 WORDS)
Epiphyseal growth plate cartilages from the proximal tibia of normal, hypophysectomized, and growth hormone (GH)-treated hypophysectomized rats were subjected to immunohistochemistry for detection of epidermal growth factor (EGF). In the normal growth plate, EGF was distributed mainly in the proliferative zone. Hypophysectomy resulted in considerable atrophy of the chondrocytes and the cartilage matrix (a decreased number of mature-type chondrocytes and a decreased ratio of proliferating to hypertrophic chondrocytes) and a significant diminution of EGF immunoreactivity. Treatment with GH reversed these effects of hypophysectomy, causing an increased thickness of the growth plate and EGF-reactive sites in all chondrocyte layers. The most intense immunostaining for EGF, however, was frequently seen in the nuclei of chondrocytes with flattened appearance. It appears that EGF could be incorporated or synthesized in chondrocytes having marked mitogenic activity. The present results, taken with previous data on EGF involvement in growth of cartilaginous tissue in vivo and in vitro, strongly suggest that EGF-immunoreactive chondrocytes are involved in cartilage proliferation and growth under the specific influence of GH.
To determine whether growth hormone administration would potentiate bone response to the stimulation of exercise, 80 female rats aged 14 months were divided into control (CON), ovine growth hormone administration (0.5 mg/kg daily) (GH), treadmill exercise (17 m/minute, 60 minutes daily) (EX), and GH+EX groups for 9 and 16 weeks. Static and dynamic histomorphometry were measured on the tibial shaft and (L-5) vertebral cortical bone. The periosteal and endocortical bone formation rate of the tibial shaft were higher in both EX and GH+EX than in the CON group in the 9-week study. There is a synergistic interaction between the two interventions in both cortical surfaces. After 16 weeks of study, the cortical bone area and periosteal bone formation rate were higher only in the EX than in the CON group. In the L-5 vertebra, the labeled surface on the periosteum was higher in the EX and the bone formation rate on the endocortical surface was higher in the GH than in the CON group. However, there was a negative interaction when the two interventions were combined. We conclude that a low-dose of growth hormone administration could initially potentiate long bone response to exercise. However, from the present study, long-term treatment with low-dose growth hormone administration does not enhance the increase in bone mass from exercise.
An anabolic effect on bone of intermittent parathyroid hormone (PTH) treatment has been found in patients with osteoporosis and also in experimental animals. Controversies exist, however, about whether the positive effect on the trabecular bone balance occurs at the expense of the cortical bone. We examined the biomechanical quality of cortical bone after intermittent treatment with different doses of PTH and, furthermore, compared the effects of PTH-(1-34) and PTH-(1-84). Groups of rats were treated with biosynthetic human PTH-(1-34) or PTH-(1-84), 1.1, 3.3, 10, or 30 nmol/kg/day for 30 days. No changes in the body weights and no changes in the lengths of the femora were observed after the PTH treatments. The biomechanical properties were analyzed by means of a materials-testing machine. A dose-related increase in the bending strength and stiffness of the femora was found, and this increase in mechanical strength corresponds with a 9-12% increase in the cross-sectional area of the femoral diaphyses. The deflection capability and energy absorption were not influenced by any of the PTH treatments. No differences were found between the effects of PTH-(1-34) or PTH-(1-84) on the biomechanical properties of the femora. Consequently, intermittent treatment with biosynthetic PTH-(1-34) or PTH-(1-84) increased the formation of cortical bone, and the biomechanical competence of the femora was found to be preserved.
Androgens have important effects on bone in vivo, possibly by direct activation of the androgen receptors in osteoblasts. To test this hypothesis, calcium homeostasis, bone mass, and bone turnover were evaluated in mature (4-month-old) androgen-resistant (testicular feminized, TFM) male rats. Data were compared with data from both female and male littermates of the same age and strain. Compared to normal males, TFM had similar serum testosterone, twofold higher estradiol and estrone, and sixfold higher androstenedione concentrations. Compared to normal females, TFM rats showed lower estradiol but also elevated concentrations of androstenedione and estrone. Despite similar free 1,25-(OH)2D3 concentrations, both TFM and male rats maintained higher serum calcium and phosphate concentrations than their female littermates. Serum IGF-I concentrations in TFM rats were decreased compared to male rats (-12%) or female rats (-27%). Serum osteocalcin concentrations, however, were twofold higher in TFM rats than in females but not significantly different from males. Femoral length, diameter, and cortical thickness were intermediate between those of males and females. The cancellous bone density of the femur and cancellous bone volume of the proximal metaphysis of the tibia, however, were not significantly different between groups. The ash weight of the tibia was also not significantly different, and the ash weight of the four distal lumbar vertebrae ranged between male and female values. Bone mechanical properties as measured by torsional strength and energy absorption of the femur were lower in TFM than in females but not different from males.(ABSTRACT TRUNCATED AT 250 WORDS)
It is known that growth hormone can induce accelerated bone turnover in GH deficient people as well as healthy elderly people. In this study we examined the effect of recombinant human GH (rhGH) on bone mineral mass and bone turnover in the presence of the bone resorption inhibiting agent, pamidronate. Effects on body composition were also studied.
Twenty-one post-menopausal osteoporotic women were treated with the bisphosphonate pamidronate during 12 months. During the initial 6 months rhGH (0.0675 IU/kg, 3 times/week) was administered in a placebo controlled fashion (10 vs 11 patients).
Bone mineral content (BMC) of the lumbar spine and femoral neck was measured with dual-energy X-ray absorptiometry and BMC of the distal and proximal forearm with single-photon absorptiometry. Body composition was measured with bioelectrical impedance and total body dual-energy X-ray absorptiometry. Serum IGF-I and biochemical indices of bone turnover were also measured.
The group treated with rhGH showed a two to three-fold increase in serum IGF-I levels. No effects on bone mineral mass were observed in the group treated with rhGH, either after the initial 6 months of treatment with rhGH or after the total period of 12 months. In women treated with pamidronate, however, a consistent increase of about 5% at the lumbar spine and somewhat less in the distal forearm was reached from 6 months onwards. In neither group was any change observed in BMC at the femoral neck or forearm. Compared to baseline, the biochemical measurements of bone turnover showed a decrease of about 50% in the pamidronate treated group, but this effect was blunted in the group additionally treated with rhGH. The body composition measurements showed clear effects of rhGH administration: a decrease in fat mass of about 5% and an increase in lean body mass of about 3%. However, these effects disappeared after the treatment with rhGH was stopped and both fat mass and lean body mass returned to initial values.
The present study suggests that treatment with rhGH blunted both the pamidronate induced accumulation of bone mineral mass and the reduction of biochemical markers of bone turnover. Furthermore, the positive effect of rhGH on body composition disappears completely after cessation of treatment with rhGH.
Ten-month-old lactating breeders were ovariectomized and kept on a low calcium diet. One month after ovariectomy, the rats were dosed once daily for 6 months with either a low dose of growth hormone (GH) (0.05 mg), a high dose of GH (1 mg), estrogen plus gestagen (E-G) [17 beta-estradiol (0.1 mg); norethisterone-acetate (0.05 mg)], or a combination of GH and E-G. Mechanical competence, apparent dry density, apparent ash density and ash concentration were measured in the fourth lumbar vertebral body. The reduced mechanical strength, ash density and ash concentration found in the vertebral body of ovariectomized animals were prevented by the high dose of GH alone, or in combination with E-G. E-G alone partly prevented the decline in ash density and ash concentration, but did not affect the reduced mechanical strength seen after ovariectomy. Only minor effects were observed after treatment with the low dose of GH, alone or in combination with E-G. In conclusion this study shows that GH administration prevents the decline in mechanical strength and bone mineral density seen in rats after ovariectomy.
The growth hormone (GH)-deficient dwarf rat was used to investigate recombinant human (rh) GH-induced bone formation and to determine whether rhGH facilitates simultaneous increases in bone formation and bone maturation during rapid growth. Twenty dwarf rats, 37 days of age, were randomly assigned to dwarf plus rhGH (GH; n = 10) and dwarf plus vehicle (n = 10) groups. The GH group received 1.25 mg rhGH/kg body wt two times daily for 14 days. Biochemical, morphological, and X-ray diffraction measurements were performed on the femur middiaphysis. rhGH stimulated new bone growth in the GH group, as demonstrated by significant increases (P < 0.05) in longitudinal bone length (6%), middiaphyseal cross-sectional area (20%), and the amount of newly accreted bone collagen (28%) in the total pool of middiaphyseal bone collagen. Cortical bone density, mean hydroxyapatite crystal size, and the calcium and collagen contents (microgram/mm3) were significantly smaller in the GH group (P < 0.05). Our findings suggest that the processes regulating new collagen accretion, bone collagen maturation, and mean hydroxyapatite crystal size may be independently regulated during rapid growth.
Areal bone mineral density (BMD) is a major determinant of bone strength and thereby of fracture risk. Other factors including trabecular microarchitecture and bone dimensions also contribute to bone strength. To investigate the relative importance for bone strength of BMD and bone dimensions, the relations between strength and the latter variables were evaluated under different experimental conditions in ovariectomized rats. Bone strength was assessed in compression and bending with measurement of BMD by dual-energy X-ray absorptiometry. Interventions were designed to increase trabecular BMD in rats with estrogen deficiency-induced bone loss (OVX) by treatment with pamidronate, an inhibitor of bone resorption, or to modify bone dimensions, particularly diameter, by administration of the growth factor IGF-I. In OVX rats, pamidronate treatment increased BMD with a commensurate increase in bone strength at the level of lumbar vertebrae and femoral neck (r = 0.789, p < 0.0001 and r = 0.535, p < 0.001, respectively). IGF-I increased the external diameter of midshaft tibia and femoral neck, which also correlated with bone strength (r = 0.678,p < 0.0001 and r = 0.507,p < 0.0002, respectively). Thus, both bone dimensions and BMD contributed to the determination of bone strength. In conclusion, adult rats with estrogen deficiency-induced bone loss represent a useful experimental model for investigating bone strength and its determinants such as BMD and external bone dimensions.
Summary The stiffness and strength of tape-reinforced composites have been calculated by using the finite-element method, simple model
theory and the von Mises-Hencky criterion. The tapes are assumed to be oriented uniaxially in both the longitudinal and transverse directions. According
to the theoretical calculations, substantial increases in two basic moduli and a transverse strength are possible with the
tape systems, as compared with the corresponding fiber systems. The calculations are based mainly on glassepoxy composites.
A somatomedin A preparation, when given at total doses of 14 and 70 U did not increase the longitudinal bone growth in hypophysectomized rats. Growth hormone (WHO) significantly increased the longitudinal bone growth.
Bony tissues, considered as a two phase composite system of HAP and collagen, are described as a family of Reuss solids where the soft matrix becomes stiffer as the hard filler is added until a maximum elastic modulus is reached. Polymeric elastic moduli increase with cross linking density and shortening of maximum cross link length in macromolecules. In some polymers like epoxy these are strongly affected by the solid filler. Close similarity is found between HAP-collagen and FAP-epoxy. The concept is supported from evidence found in chemistry, physical properties, hierarchal structure and mineralization characteristics of collagen. It is postulated that increased cross linking density is associated with increased HAP content and the HAP crystallites provide rigid bases for shortened links to stiffen the composite by reversible enzyme directed processes.
Blood samples were removed via chronic intra-atrial cannulae every 15 min in female rats during the estrous cycle, the last week of pregnancy, parturition and suckling. Growth hormone (GH) secretion during the estrous cycle is characterized by episodic release, occurring approximately once hourly. The surges in GH increase during the last 3-4 days of gestation, and rise to high levels during delivery and with suckling. Prolactin (PRL) shows minimal fluctuations during the estrous cycle, except for a prominent pulsatile surge during proestrus. PRL rises 4-6 h prior to parturition and declines during delivery. These studies provide a basis for further studies on the dynamics of GH and PRL secretion in the female rat.
The effect of different doses of biosynthetic human growth hormone on the mechanical properties of tibial fractures and intact bones was studied in a rat model; a three-point bending test was applied 40 days after fracturing. Ninety-day-old female rats received a daily dose of 0, 0.08, 0.4, 2.0, or 10 mg of growth hormone/kg body weight starting 1 week before fracture and continuing until mechanical testing. In the animals given 2.0 and 10 mg of hormone, the ultimate load sustained by the fractures, stiffness, and energy absorption at ultimate load increased, while the ultimate stress increased only in the latter groups. In the intact bones, ultimate load of the bones increased in the same groups, while stiffness and energy absorption at ultimate load increased only in the group given the highest dose of hormone.
Recombinant human growth hormone is more antigenic than pituitary preparations. Since GH antibodies interfere with radioimmunoassay of GH, we measured plasma free and total GH in patients with pituitary dwarfism with GH antibodies during treatment with a recombinant methionyl GH preparation. Plasma free GH was measured in the supernatant after polyethylene glycol precipitation. Total GH was measured after extracting plasma with acid-ethanol. In normal subjects, both free and total GH levels were similar to those measured in plasma by a direct conventional RIA. Peak free GH levels after administration of 4 IU methionyl GH to 3 normal subjects were 38.0, 30.7 and 13.2 micrograms/1, values similar to those measured in most of the patients with GH antibodies. All values were undetectable in one patient with a very high antibody titre. Total GH levels were similar to free GH levels in normal subjects. In patients with GH antibodies, total GH levels were high compared with their free levels, but similar to those assayed by conventional RIA. The patient with the highest antibody titre had total GH levels which were the lowest of those observed in the patients with GH antibodies in spite of having the highest GH levels measured by conventional RIA. The antibody in this particular case may have a high capacity and a high affinity. A relatively poor growth rate in this patient may be associated with the finding of undetectable free GH levels. Measurement of plasma free and total GH may be of value in examining GH dynamics and their relation to the clinical effectiveness of GH treatment in patients with GH antibodies.
To examine the relative effectiveness of GH-releasing hormone (GHRH) given either as multiple iv pulses or as a continuous iv infusion, we studied the GH response to a nearly equivalent total dose of GHRH-44 administered by both routes in a group of normal men. Further, in view of the pulsatile nature of GH secretion and its augmentation with sleep, we investigated whether a diurnal difference in GH release was present during chronic pulsatile administration of GHRH during day and night. Seven men received six GHRH pulses (1 microgram/kg, iv) at 2-h intervals during both day (0900-2100 h) and night (2100-0900 h), and four underwent nighttime placebo pulsing. Eight men received a daytime continuous GHRH infusion (0.15 microgram/kg X h for 5 h, followed by 0.75 microgram/kg X h for 5 h) and a separate 10-h placebo infusion. The GH response to a bolus dose of GHRH (1 microgram/kg, iv) was determined after both continuous GHRH and placebo infusions. No significant difference was found in the GH area response (mean +/- SEM) during total day and night GHRH pulsing periods (6095 +/- 1192 vs. 6506 +/- 1483 ng/min X ml; P = NS). GH secretion was blunted after the initial daytime GHRH pulse (P = 0.02), and only two of seven men had a GH increase after the second pulse; responsiveness was restored after the fourth pulse. In contrast, all subjects responded to the second nighttime GHRH pulse. During continuous GHRH infusions, GH secretion was unsustained and pulsatile. The incremental GH response to a single GHRH bolus dose was decreased after GHRH infusion compared to that after placebo (4.4 +/- 1.8 vs. 10.3 +/- 3.4 ng/ml; P less than 0.05). No difference was found in the total GH area response to a nearly equivalent dose of GHRH administered as either multiple pulses or continuous infusion followed by a single GHRH bolus dose. The apparent pulsatile nature of GH secretion during continuous GHRH infusion and the lack of a significant difference in the GH response to a nearly equivalent dose of GHRH administered as either multiple pulses or a continuous infusion suggest that GHRH need not be administered in a pulsatile manner to be an effective therapeutic agent for the stimulation of GH secretion in children with hypothalamic GHRH deficiency.
Stiffness of compact bone is found to be highly and nonlinearly dependent on its porosity, its complement, bone volume fraction and apparent density. Elastic modulus decreases as a power (0.55) of increasing porosity and increases both as a power of increasing bone tissue volume (10.92) and increasing apparent density (7.4). These data indicate that small changes in the amount or density of compact bone tissue exert a more pronounced influence on its stiffness than would similar changes in trabecular bone.
An ultrasonic technique was used to measure both the elastic modulus (Young's modulus) of trabecular bone material and the elastic modulus of the cancellous structure. The average trabecular modulus, measured on specimens obtained from three human and one bovine distal femora, was 13.0 GPa (S.D. 1.47) and 10.9 GPa (S.D. 1.57), respectively. On human specimens the structural elastic modulus was found to be related to the structural (apparent) density raised to the 1.88 power. The elastic modulus from the bovine specimens showed a more linear relationship with the density of the cancellous structure (density raised to the 1.57 power).
Biosynthetic human growth hormone was injected subcutaneously in rats for 90 days and in cynomolgus monkeys for 30 days. The daily doses were 0.5, 3.3 and 25 IU kg-1 (rats) and 0.3 and 15 IU kg-1 (monkeys). The growth hormone was tolerated well in both rats and monkeys. No drug related deaths occurred and all animals appeared to be normal and also behaved normally throughout the dosing period. Increased body weight gain, increased food utilisation and increased organ weights were seen in the rats in the high and intermediate dose groups. The higher doses of human growth hormone (3.3 and 25 IU kg-1) caused a glandular hyperplasia of the mammary gland in male and female rats with evidence of secretory activity. In the female monkeys secretory activity was seen without any sign of mammary gland hyperplasia. Mucification of the vaginal epithelium and stress induced prostatitis was observed in the rats. Additional treatment related changes in the rats were an increased haematopoietic activity in the spleen and an increase in the amounts of calcium and phosphate excreted in urine. An increase in fasting plasma glucose levels was seen in the male monkeys on the high dose level. The changes observed during the treatment periods presumably represent exaggerated pharmacological effects of the growth hormone.
• Slipped capital femoral (SCFE) occurs with greater frequency in children with growth hormone deficiency than in children in the general Population. This epidemiologic observation suggests that SCFE may be a complication of growth hormone deficiency, associated pituitary hormone deficiencies, growth hormone therapy, or a combination of these factors. To clarify the relationship of growth hormone treatment to SCFE, homologous growth hormone was administered to rats that were without growth hormone deficiency. This treatment was found to alter the material properties of the growth plate, increasing material stiffness and decreasing specific energyabsorptive capacity. Such material changes render the growth plate more susceptible to injury or separation. The observed effects of growth hormone on the growth plates of intact animals suggest that children without growth hormone deficiency who are treated with growth hormone may be at increased risk for growth plate separation. The experimental data also indicate that growth hormone treatment of children with this deficiency may contribute to the observed increased frequency of SCFE among these patients.
(AJDC 1987;141:497-501)
An automatic method for repetitive microsampling of blood from conscious animals was used to obtain detailed GH secretory profiles from normal female rats, which were compared with those in males and ovariectomized females. Female rats showed a highly variable GH secretory pattern, with sustained periods of low, almost continuous secretion, followed by very rapid bursts of high amplitude and short duration, occurring mostly at night. There was no clear relationship between the pattern of GH secretion and the phase of the oestrous cycle in rats continuously sampled over a 5-day period. In ovariectomized rats, the day:night difference was maintained, though the nocturnal GH surges were larger and of longer duration than in intact females. Male rats produced multicomponent GH bursts which continued unchanged throughout the day and night. This study shows for the first time that female rats switch to a rapid, highly pulsatile pattern of GH release at night, which can only be resolved by rapid blood sampling over extended periods in conscious undisturbed animals.
J. Endocr. (1987) 114, 399–407
The scarcity of purified somatomedin/insulin-like growth factor (SM/IGF) has prevented investigation of the mechanisms of SM/IGF action. Recently insulin-like growth factor I (IGF-I) has been synthesized by recombinant DNA technology. The availability of large quantities of the biosynthetic IGF-I made it possible to study its effects by administering 120 micrograms/day via s.c. implanted minipump to rats for 7 days. After this 7 day administration of IGF-I, the body weight increased to 197.6 +/- 3.5% of initial values; the value was significantly greater than that of the control (179.4 +/- 3.7% of initial values, P less than 0.01). The body length and tibial epiphyseal width in IGF-I-treated rats were also significantly increased over those of control rats. The weights of kidneys, liver, testes and pituitary in IGF-I-treated rats were greater than those in control rats as well. These results provide a first demonstration that IGF-I stimulates growth in normal rats in vivo, and suggest that IGF-I might be useful in the treatment of growth retardation.
The pituitary growth hormone (GH) responses during a 20-hour iv infusion of saline or human GH-releasing factor (hGRF-44) at 40 micrograms/h, followed by an iv bolus injection of hGRF at 2 micrograms/kg body weight, were studied in four normal adult men. During saline infusion only one or two pulses of plasma GH were observed. However, during hGRF infusion up to eight or ten pulses of GH were measured with an amplitude not different from that obtained during saline infusion. The mean +/- SEM integrated amount of GH secreted was 107 +/- 38.2 ng/ml.h in response to hGRF infusion, which was greater than the value of 25.4 +/- 3.5 ng/ml.h obtained during saline infusion. Plasma somatomedin-C also increased after hGRF infusion, but not after saline. After saline or hGRF infusion most of the subjects still responded to an iv bolus injection of the peptide (2 micrograms/kg). These results indicate that hGRF infusion augments GH secretion by increasing the number, but not the amplitude of GH pulses and that the infusion does not cause the pituitary somatotrophs to lose their capacity and ability to respond to hGRF subsequently.
Bone growth and remodelling was studied in rats after injection of growth hormone, melanocyte-stimulating hormone (alpha-MSH), and cortisone daily for 20 days with tetracycline as intravital marker. An increase of both longitudinal and periosteal growth with growth hormone was found. A decrease of both was found after a high cortisone dose. Lower cortisone doses seem to have stimulated periosteal growth. No effect of alpha-MSH was found.
Various fractions of hydroxyproline were determined in skin, femora, and humeri of DBA/2 mice treated for 2 weeks with one of three hormones: bovine growth hormone, anabolic steroid (17-β-hydroxy-17-α-methylandrostano[3,2-c]pyrazole), and cortisone acetate. The following fractions were studied: 0.15 M NaCl, 0.50 M NaCl, 0.50 M citrate, and total hydroxyproline. Since collagen is the only protein in the body containing hydroxyproline in significant amounts, this fractionation method allows an appraisal of the rates of synthesis, maturation, and breakdown of collagen. Growth hormone produced a significant increase in all extractable fractions and in the total hydroxyproline content of tissues studied. The action of anabolic steroid on hydroxyproline was generally comparable to that of growth hormone, but was less marked. Both total hydroxyproline and saline-extractable fractions were significantly reduced in skin and bone of cortisone-treated mice.
There is a considerable variation in the mineralization of bone; normal, non-pathological compact bone has ash masses ranging from 45 to 85% by mass. This range of mineralization results in an even greater range of mechanical properties. The Young modulus of elasticity can range from 4 to 32 GPa, bending strength from 50 to 300 MPa, and the work of fracture from 200 to 7000 Jm-2. It is not possible for any one type of bone to have high values for all three properties. Very high values of mineralization produce high values of Young modulus but low values of work of fracture (which is a measure of fracture toughness). Rather low values of mineralization are associated with high values of work of fracture but low values of Young modulus and intermediate values of bending strength. The reason for the high value for the Young modulus associated with high mineralization is intuitively obvious, but has not yet been rigorously modelled. The low fracture toughness associated with high mineralization may be caused by the failure of various crack-stopping mechanisms that can act when the mineral crystals in bone have not coalesced, but which become ineffective when the volume fraction of mineral becomes too high. The adoption of different degrees of mineralization by different bones, leading to different sets of mechanical properties, is shown to be adaptive in most cases studied, but some puzzles still remain.
The relationship between the ash content of rabbits' metatarsals and their modulus of elasticity, static strength, work to failure and impact strength was determined. Over the range of ash contents observed the static strength and the modulus of elasticity increased linearly with the ash content. The energy that could be absorbed by the bone material, in both static and dynamic loading, increased and then decreased with ash content. The highest values for energy absorption were roughly at the median value of ash. It is proposed that this value is the optimum value in life, because bones are usually broken by impact, and energy absorption is important in resisting impact. A short discussion of the reason for the rise and fall in energy absorption is given.
Starisrical methods m medicul research
- P Amitage
Amitage, P.: Berry. G. Starisrical methods m medicul research, Vol. 2. Oxford. Melbourne: Blackwell Scientific Publications: 1987;26+269.
Elastic modulus of trabecular bone material Modification of bone formation rate by growth hormone. melanocyte stimulating hormone. and cortisone in the normal rat
- R B Ashmann
- J Y Rho
Ashmann. R.B.: Rho, J.Y. Elastic modulus of trabecular bone material..I. Biomechunic~ 21:177-181; 1988. Aspenberg. P.: Hansson. L.I.; Thomgren, K.G. Modification of bone formation rate by growth hormone. melanocyte stimulating hormone. and cortisone in the normal rat. Acru Anar. 121:~~88; 1985. Orrhop. Stand. 52:605-613; 1981.
A textbook of biomedical engineering
- R M Kenedi
- Glasgow
- London
Kenedi, R.M. A textbook of biomedical engineering. Glasgow and London: Blackie & Sons; 1980;39-73.
The secretory pattern of growth hormone in the rat. Isaksson, 0
- R G Clark
Clark, R.G. The secretory pattern of growth hormone in the rat. Isaksson, 0.: Binder, C.: Hall, K.; Hb;kfeldt, B. (eds.), Growth hormone.