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To compare the independent influence of mechanical and non-mechanical factors on bone features, multiple regression analyses were performed between pQCT indicators of radius and tibia bone mass, mineralization, design and strength as determined variables, and age or time since menopause (TMP), body mass, bone length and regional muscles' areas as selected determinant factors, in Caucasian, physically active, untrained healthy men and pre- and post-menopausal women. In men and pre-menopausal women, the strongest influences were exerted by muscle area on radial features and by both muscle area and bone length on the tibia. Only for women, was body mass a significant factor for tibia traits. In men and pre-menopausal women, mass/design/strength indicators depended more strongly on the selected determinants than the cortical vBMD did (p<0.01-0.001 vs n.s.), regardless of age. However, TMP was an additional factor for both bones (p<0.01-0.001). The selected mechanical factors (muscle size, bone lengths) were more relevant than age/TMP or body weight to the development of allometrically-related bone properties (mass/design/strength), yet not to bone tissue 'quality' (cortical vBMD), suggesting a determinant, rather than determined role for cortical stiffness. While the mechanical impacts of muscles and bone levers on bone structure were comparable in men and pre-menopausal women, TMP exerted a stronger impact than allometric or mechanical factors on bone properties, including cortical vBMD.

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The pQCT-assessed Bone Strength Indices (BSI's, SSI) depend on the product of a 'quality' indicator, the cortical vBMD (vCtD), and a 'design' indicator, one of the cross-sectional moments of inertia or related variables (MIs) in long bones. As the MIs vary naturally much more than the vCtD and represent different properties, it could be that the variation of the indices might not reflect the relative mechanical impact of the variation of their determinant factors in different individuals or circumstances. To understand this problem, we determined the vCtD and MI's in tibia scans of 232 healthy men and pre- and post-MP women, expressed in SD of the means calculated for each group, and analyzed the independent influence of 1 SD unit of variation of each factor on that of the indices by multiple correlations. Results showed: 1. that the independent influence of the MIs on the indices was generally larger than that of the vCtD, and 2. that in post-MP women the influence of the vCtD was larger than it was in the other groups. This confirms the view that inter-individual variation of vCtD is comparatively small, and that mechanical competence of human bone is mostly determined by 'design' factors.

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Some pharmacologic effects on bone modeling may not be evident in studies of remodeling skeletons. This study analyzes some effects of olpadronate on cortical bone modeling and post-yield properties in femurs diaphyses (virtually only-modeling bones) of young rats by mid-diaphyseal pQCT scans and bending tests. We studied 20/22 male/female animals traetad orally with olpadronate (45-90 mg/kg/d, 3 months) and 8/9 untreated controls. Both OPD doses enhanced diaphyseal cross-sectional moments of inertia (CSMI) with no change in cortical vBMD and elastic modulus. Yield stiffness and strength were mildly increased. Post-yield strength, deflection and energy absorption were strikingly enhanced. Ultimate strength was enhanced mainly because of effects on bone mass/geometry and post-yield properties. The large improvement of post-yield properties could be explained by improvements in bone geometry. Improvements in bone mass/geometry over weight-bearing needs suggest an enhanced modeling-related response to mechanical stimuli. Effects on tissue microstructural factors (not measured) could not be excluded. Results reveal novel olpadronate effects on bone strength and toughness unrelated to tissue mineralization and stiffness, even at high doses. Further studies could establish whether this could also occur in modeling-remodeling skeletons. If so, they could counteract the negative impact of anti-remodeling effects of bisphosphonates on bone strength.

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In a pQCT study of running-trained and untrained men and women we had shown that bone mass distribution along the tibia was adapted to the usage-derived stress pattern. To study the possible association between the efficiency of diaphyseal design and bone material stiffness, we extend the analysis of the same sample to correlate pQCT indicators of the distribution (CSMIs), mass (BMC), and density (vBMD) of cortical bone tissue as descriptors of "distribution/mass" (d/m) or "distribution/quality" (d/q) relationships. The d/m and d/c curves followed positive (exponential) and negative (hyperbolic-like) equations, respectively. Distribution curves of r coefficients throughout the bone were all bell-shaped, reaching a maximum towards the mid-diaphysis. The CSMIs and BMC were higher, and vBMD was lower in men than women and in runners than non-runners. The d/m relationships were described by unique curves for all groups while d/q relationships were better adjusted to separate curves for men and women. Results support that: 1. diaphyseal design reflects the relative influence of bending/torsion stress along the bones, tending to minimize bone mass; 2. there is a trade-off between cortical bone "quality" and distribution; 3. d/m and d/q relationships are related to bone mechanical environment, and 4. d/q relationships are affected by sex.

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New concepts and methods of study in bone biomechanics defy the prevailing idea that bone strength is determined by a systemically-controlled "mineralized mass" which grows until reaching a peak and then is lost at individually-specific rates. In case of bones, "mass" represents actually the substratum of a structure, the stiffness of which does not depend on the mass, but on the intrinsic stiffness and the spatial distribution of the mineralized material. A feed-back system called "bone mechanostat" seems to orient the osteoblastic and osteoclastic processes of bone, modeling and remodeling, according to the sensing by osteocytes of strains caused in the structure by mechanical usage of the skeleton, in specific directions as determined principally by the customary contractions of regional muscles and impact forces. The endocrine-metabolic systems, crucial for the normal skeletal development, modulate the work of osteocytes, blasts and clasts in a systemic way (i.e., not related to a specific direction of the stimuli). Therefore, they tend actually to interact with, rather than contribute to, the biomechanical control of bone structure. Furthermore, no feed-back loop enabling a cybernetic relationship of those systems with bone is known. Instead of passively letting hormones regulate their "mass" in order to optimize their strength, bones would actively self-regulate their architecture following an anisotropic pattern in order to optimize their stiffness (the only known variable to be ever controlled in the skeleton) and strength "despite of" the endocrine systems. Three practical questions derive from those ideas: 1. Osteoporoses are not "intense osteopenias" but "osteopenic fragilities". 2. The diagnosis of osteopenia could be solved densitometrically; but that of bone fragility is a biomechanical problem which requires auxiliary resources for evaluating the stiffness and the spatial distribution of the mineralized material. 3. Osteopenias and osteoporoses should be on time evaluated as related to the mass or strength of the regional muscles, respectively, in order to differentiate between the "primary" (intrinsic lesion of the mechanostat) or "secondary" (systemic) etiologies and the biomechanical origin (disuse) in each case, with important therapeutic implications.

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A whole-body DXA study of 1450 healthy Caucasian individuals [Bone 22 (1998) 683] found that mineral mass, either crude (BMC) or statistically adjusted to fat mass (FM-adjusted BMC), correlated linearly with lean mass (LM, proportional to muscle mass). The results showed similar slopes but decreasing intercepts (ordinate values) in the order: pre-MP women > men > post-MP women > children. This supports the hypothesis that sex hormones influence the control of bone status by muscle strength in all species. Now we further study those relationships in 2512 healthy Hispanic adults (307 men, 753 pre-MP women, 1452 post-MP women), including separate determinations in their upper and lower limbs. The slopes of the BMC or FM-adjusted BMC vs. LM relationships were parallel in all the studied regions. However, region-related differences were found between the ordinates of the curves. In the whole body, the crude-BMC/LM relationships showed the same ordinate differences as previously observed. In the lower limbs, those differences were smaller in magnitude but highly significant, showing the order: pre-MP women > men = post-MP women. In the upper limbs, the decreasing ordinate order was: men > pre-MP women > post-MP women. After fat adjustment of the BMC, order in both limbs was: men > pre-MP women > post-MP women. Parallelism of the curves was maintained in all cases. LM had a larger independent influence on these results than FM, body weight, or age. The parallelism of the curves supports the idea that a common biomechanical control of bones by muscles occurs in humans. Results suggest that sex-hormone-associated differences in DXA-assessed muscle-bone proportionality in humans could vary according to the region studied. This could be related to the different weight-bearing nature of the musculoskeletal structures studied. Besides the obvious anthropometric associations, FM would exert a mechanical effect as a component of body weight, evident in the lower limbs, while muscle contractions would induce a more significant, dynamical effect in both lower and upper limbs. Muscles seem to exert a larger influence than FM, body weight, and age on BMC in the whole body and lower limbs, regardless of the gender and reproductive status of the individual. The muscle-bone relationships studied may provide a rationale for a future differential diagnosis between disuse-related and other types of osteopenia.

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Three different regions of interest (ROIs) were defined in pQCT scans (XCT-3000 machine, Stratec, Germany) taken at the tibial mid-diaphyses of 12 pre-menopausal (pre-MP) and 12 post-menopausal (post-MP) women who were otherwise normal, according to the volumetric bone mineral density (vBMD) value of their corresponding pixels (voxels) as assessed by their respective attenuation values. They were classified as "low-vBMD" (LD-ROI, with a vBMD of 200-400 mg/cm(3)), corresponding chiefly to trabecular-subcortical bone; "medium-vBMD" (MD-ROI, vBMD = 400-800 mg/cm(3)), corresponding mainly to porous cortical bone or cortical-subcortical bone, and "high-vBMD" (HD-ROI, vBMD higher than 800 mg/cm(3)), corresponding to dense cortical bone. The fraction of the total cross-sectional bone area covered by the HD-ROI was 16% higher, and that covered by the MD-ROI 20% lower, in pre-MP than post-MP women. No differences concerning the LDROIs were found. A close, linearly negative relationship was found between the MD- and HD-ROI fractions in all the women together, with no inter-group differences in slope. The Stress-Strain Index (an indicator of the torsional stiffness and strength of the whole bones that involved both the vBMD and the spatial disposition of the HD bone in the cross-section - torsional moment of inertia -) correlated linearly and positively with the cross-sectional area of the HD-ROI, with a higher slope for pre-MP than post-MP women. Qualitatively, a. post-MP women showed a significantly more prevalent discontinuity of the voxels in the HD-ROI than pre-MP women, and b. the tendency of LD-ROIs to accumulate along the mechanically lesseffective (antero-posterior) axis of the image - a characteristic of pre-MP bones - was visually less evident in post-MP bones. These features describe non-invasively some changes induced by menopause in the human tibia that may be critical for defining the skeletal condition and to monitor the effects of treatments addressed either to protect or to improve mechanically the bone structure, beyond the possibilities of standard densitometry.

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

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Previous studies with standard densitometry (DXA) have suggested that the bone mass is strongly dependent on the muscle mass in the species, following a similar relationship at any age and sex hormones or related factors potentiate that relationship. Studies with pQCT indicated that the surplus bone mass per unit of muscle mass previously observed in premenopausal women would be stored in skeletal regions with relatively little mechanical relevance, thus avoiding remotion through mechanically oriented remodelling by the bone mechanostat. Scanning the distal radius with pQCT has also showed a highly significant, linear relationship between SSI of the distal radius and the dynamometric maximal bending moment of the forearm in normal men and women. In order to investigate similar relationships in regions that are inaccessible to pQCT, we used spinal radiographs and axial QCT. This study affords additional evidence to the previous references concerning the direct, significant impact of the regional muscle strength on the determination of the tomographic indicators of bone mechanical quality and their indirect repercussion of the skeletal condition (curvature of the spine).

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The mineral, lean, and fat contents of the human body may be not only allometrically but also functionally associated. This report evaluates the influence of muscle mass on bone mass and its age-related changes by investigating these and other variables in both genders in the different stages of reproductive life. We have analyzed the dual-energy X-ray absorptiometry (DEXA)-determined whole-body mineral content (TBMC), lean body mass (LBM), and fat body mass data (FBM) of 778 children and adolescents of both genders, aged 2-20 years [previously reported in Bone 16(Suppl.): 393S-399S; 1995], and of 672 age-matched men and women, aged 20-87 years. Bone mass (as assessed by TBMC) was found to be closely and linearly associated with muscle mass (as reflected by LBM) throughout life. This relationship was similar in slope and intercept in prepubertal boys and girls. However, while keeping the same slope of that relationship (50-54 g increase in TBMC per kilogram LBM): (1) both men and women stored more mineral per unit of LBM within the reproductive period than before puberty (13%-29% and 33%-58%, respectively); (2) women stored more mineral than age-matched men with comparable LBM (17%-29%) until menopause; and (3) postmenopausal women had lower values of bone mineral than premenopausal women, similar to those of men with comparable LBM. Men showed no age effect on the TBMC/LBM relationship after puberty. Multiple regression analyses showed that not only the LBM, but also the FBM and body height (but not body weight), influenced the TBMC, in that decreasing order of determining power. However, neither the FBM nor body height could explain the pre/postpubertal and the gender-related differences in the TBMC/LBM relationship. Accordingly: (1) calculated TBMC/LBM and FBM-adjusted TBMC/LBM ratios were lower in girls and boys from 2-4 years of age until puberty; (2) thereafter, females rapidly reached significantly higher ratios than age-matched men until menopause; and (3) then, ratios for women and age-matched men tended to equalize. A biomechanical explanation of those differences is suggested. Sex hormones or related factors could affect the threshold of the feedback system that controls bone remodeling to adapt bone structure to the strains derived from customary mechanical usage in each region of the skeleton (bone "mechanostat"). Questions concerning whether the mineral accumulation in women during the reproductive period is related or not to an eventual role in pregnancy or lactation, or whether the new bone is stored in mechanically optimal or less optimal regions of the skeleton, are open to discussion.

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Two lines of mice divergently selected from the control strain (CBi) against the positive phenotypic correlation between body weight (b.w.) and tail (skeletal) length were obtained (CBi/C: high weight, short tail; CBi/L: low weight, long tail). The selected animals showed a different relationship between body and skeletal masses. To compare the adequacy between biomass and load-bearing ability of the skeleton, and to describe the eventual role of bone mechanostat in the production of these changes, cross-sectional and bending properties of both femur diaphyses were determined in CBi, CBi/C, and CBi/L adult mice of both genders. Cortical bone material quality (elastic modulus) was reduced in the selected lines (p < 0.001), significantly less in CBi/C than in CBi/L. In contrast, cross-sectional design (b.w.-adjusted values of moment of inertia, CSMI) was largely improved (p < 0.001), significantly more in CBi/C than in CBi/L. These effects determined a greater stiffness and strength in CBi/C than in CBi/L or CBi weight-paired mice. The elevations of the negative regression lines between elastic modulus and CSMI ("distribution/quality" curves) decreased in the order CBi/C > CBi/L > CBi. Data show that selection improved diaphyseal stiffness and strength in CBi/C animals because of an architectural overcompensation for the reduced bone material quality. Therefore, an inadequate control of long-bone architectural design as a function of the mechanical quality of cortical bone and b.w. bearing could have been induced in that line. Assuming bone mechanostatic regulation to be genetically programmed, some of the corresponding biological determinants should be transmitted independently, because artificial selection separately affected material quality and architectural design. The possibility of transmission of an inadequate mechanostatic function (inability to adapt bone modeling to bone material quality as a function of the biomass to be supported) was also shown, as some genotypes could express architectural modifications that largely exceed bone material quality deterioration.

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Bone mechanical competence (stiffness, strength) at organ level is determined by mechanical quality (intrinsic stiffness) and spatial distribution (macro-architecture) of bone material in cortical tissue (in every bone) and trabecular network (in vertebral bodies). These properties are inter-related and controlled according to mechanical usage by a feed-back mechanism known as mechanostat. Therefore, the effects on bone fragility of any treatment should be evaluated concerning the way they may have affected bone material or geometric properties as well as the mechanostatical interactions between them. Standard densitometry does not provide the necessary data, but some alternative methodologies (as peripheral quantitative computed tomography, pQCT) are being developed to complement or even substitute SPA, DPA or DXA determinations. Bisphosphonate (BP) effects on bone biomechanics have been studied only in animal models. Many sources of variation of results (type of compound, dose, mode of administration, species, race, sex, age, age since menopause, type of bone, remodeling ability of the skeleton, endocrine-metabolic status, interactions with other treatments, etc.) have been reported. In general terms, BPs are beneficial concerning cortical bone strength in purely modeling species (rodents) and trabecular strength in remodeling mammals (dogs, baboons). This positive action at organ level depends on independent improvements in bone macro-architecture (mainly affected by bone modeling) and material stiffness (chiefly affected by bone composition and remodeling). On one hand, bone macro-architecture has been positively affected by BPs in normal (not in ovariectomy (OX), steroid- or disuse-induced osteopenic) animals. On the other, bone material quality has been improved in the latter but not in the former. Mechanostatic interrelationships have been differently affected according to the compound employed. Results reported by ours and other laboratories concerning the three derivatives available nowadays in Argentina were reviewed and summarized. Pamidronate improved small rodents' cortical bone strength and geometric properties at low doses but impaired mineralization, material properties and strength at toxic doses. In normal, remodeling animals it improved mechanical properties in vertebral bodies but not in long bones. It also prevented the negative impact of OX-, steroid- or disuse-induced osteopenia in rats by improving bone material properties without affecting normal mechanostatic interrelationships. Olpadronate exerted positive effects on long-bone strength at any dose in normal rats and mice by improving cross-sectional properties and preserving both mineralization and material properties. These effects were highly dependent upon bone deformability, body weight, and mechanical usage of the limb as an evidence of an anabolic interaction induced on bone modeling and mechanostatic interrelationships. This compound also prevented the OX- or disuse-induced impairment in rat cortical long-bone strength and recovered rat cortical bone when given since 3 months after OX by improving only bone material quality. No interaction with bone mechanostat was detected in these studies. Alendronate effects on bone biomechanics in normal rats and dogs were positive only in long treatments. They were highly dependent on body weight of the animals, hence a positive interaction with bone mechanostat should be hypothesized. It also prevented the negative impact of OX in rat femurs by improving cortical material quality with no effect on cross-sectional properties, i.e., exerting an anti-catabolic interaction with bone mechanostat. The effects of all the three compounds were found positive for bone health, yet their mechanisms of action varied with type of bone and subject condition. A striking dissociation between (positive) effects on bone strength and (variable) effects on bone stiffness was repeatedly observed in these studies. Also an enla

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Bisphosphonates regulate bone turnover by inhibiting osteoclastic bone resorption. Due to their pharmacodynamic and pharmacokinetic characteristics, bisphosphonates have a special pharmacotoxicological profile related to their high degree of specificity: low or non-existent distribution in soft tissues and strong affinity for calcified tissues. Some general conclusions may be drawn from the pre-clinical toxicological studies, whose main aim is to identify the toxicity target organ/s and estimate the safety margins of a "prospective therapeutic agent" in laboratory animals. They are based on our own results and on data from the available literature as regards various bisphosphonates: Alendronate, Clodronate, Etidronate, Olpadronate and Pamidronate. Generally, very high doses of bisphosphonates are required to produce in different levels and incidence various extra-skeletical toxic side effects: local reaction, hypocalcemia (and its consequences on the cardiovascular system and the possibility of tetany), affection of the dental structures and renal dysfunction. Most of side effects may be related to the low solubility in biological fluids, the formation of calcium complexes, the potent inhibitory effect of endogenous or induced bone resorption as well as to its main excretion pathway. Some other side effects (on the eye, lungs and liver), may be related to repeated excessive high doses. A safety margin of 200 to 300 : 1 between the "toxic" and "pharmacological" doses may be estimated if the total quantity of Olpadronate given to various animal species in toxicological studies and in pharmacodynamic experimental models (osteopenias due to estrogen deprivation or immobilization and retinoid-induced hypercalcemia) is considered. If the toxic doses in animals are related to the highest doses suggested for human beings, then the ratio increases from 300 to 1000 : 1 depending on the pathology and the route of administration. As regards their effect on the bone, experimental data with the new bisphosphonates suggest a significant dissociation between pharmacologically active doses and those ones producing defective mineralization. The excessive inhibition of bone remodelling, due to the use of high doses in normal animals, is the natural consequence of the pharmacological effect of this family of compounds. A bisphosphonate's toxic potential effect on bone should not be evaluated in normal animals but in particular situations with a high bone turnover. Furthermore, the doses should be adjusted in order to regulate the magnitude of bone remodelling inhibition so as to take it to a normal level without totally suppressing it. Potency, safety margins, doses and proper administration schemes, should be considered as key elements for the optimum use of the therapeutic potentiality of these compounds.

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Cross-sectional moment of inertia (CSMI) and volumetric cortical bone mineral density (vCtBMD) were assessed by peripheral quantitative computed tomography (pQCT) at femur midshafts from 103 Wistar female rats receiving 0 (n = 12) or 15-1000 mu g/kg/day sc of dexamethasone (n = 46) from 5 to 9 weeks of age, or 0 or 80 mg/kg 3/wk of AI(OH)(3) IP (n = 23,22) from 4 to 10 months of age. A bone strength index (BSI), calculated as the product CSMI x vCtBMD, was found to closely correlate (r = 0.94, R(2) = 0.89, p < 0.001) with the actual, mechanically tested bending breaking force of all bones. Correlation and determination coefficients obtained were higher than those usually reported employing different long-bone strength predictive formulae. The curve approached the origin and was linear throughout the wide range of CSMI, vCtBMD and BSI achieved because of age- and treatment-induced differences, showing a very low standard error of the estimate. Instead, different curve slopes and/or intercepts were found in separate analysis between data from each of the experiments when breaking force was correlated with CSMI or vCtBMD alone, or with the DEXA-assessed BMD of the mechanically assayed bone portion. Results suggest that noninvasive assessment of the BSI by means of pQCT technology provides an original tool for a precise and accurate estimation of long-bone bending strength that can be advantageously applied in crosssectional as well as longitudinal, in vivo studies employing animal models.

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Six-month old rats chronically submitted to right hindlimb immobilization (IM) with mechanical overload (OL) of the left leg were treated 1 month later with 200 micrograms/kg/d of hPTH(1-38) for 15 or 75 days. Peripheral quantitative computed tomography (pQCT) scans and bending tests showed that hPTH increased cortical mass and volumetric BMD (vCtBMD) in both legs. However, elastic modulus of cortical bone and diaphyseal load-bearing capacity were improved only in OL bones. Improvement of diaphyseal strength was attributable to that of cortical bone quality, yet a stronger mechanostatic response of cortical modeling to bone material quality was also observed in treated OL bones. Data support hPTH(1-38) use for improving cortical bone mass and strength and point out a physical activity interaction with therapeutic results.

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An anabolic effect of hPTH(1-38) (s.c. doses of 200 micrograms/kg/d during 75 days) on trabecular and cortical bone mass is tomographically described in the metaphyseal region of immobilized rat femurs using pQCT technology, in agreement with previous histomorphometrical studies of the proximal tibial metaphyses. Correlations between pQCT and histomorphometrical data showed that this effect derived from a stimulation of endosteal and trabecular bone modeling that induced a transference from trabecular to cortical bone mass. Loss of effects after withdrawal, resulting from a stimulation of bone remodeling, could be total or partially prevented by subsequent s.c. injections of risedronate (5 micrograms/kg/2/wk), 17-B-estradiol (10 micrograms/kg/d) or calcitonin (10 micrograms/kg/d) given during 60 days, in this order of effectiveness. The preventive potency was proportionally related to the reduction induced in histomorphometric indices of bone resorption.

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As part of a safety-assessment study, doses of 8, 40, and 200 mg/kg per day, 6 days per week, of sodium olpadronate (dimethyl-APD, Me2-APD) were given by gavage to 10-week-old male and female rats during 27 weeks. Only the 200 mg/kg per day dose provoked toxic effects and a meaningful growth depression, regardless of the animal gender. In male animals, doses of 40 or 200 mg/kg per day improved strength, stiffness, and cross-sectional moment of inertia (CSMI) of femur diaphyses despite the toxic effects observed at the highest dose. Changes in bone mechanical properties were a consequence of those induced in CSMI. Regression analyses showed a treatment-induced improvement in bone modeling (as assessed by CSMI) for the same level of bone material stiffness (as expressed by calculated values of elastic modulus). The high dependency of results on body mass bearing suggested that these effects were exerted through an increase in the efficiency of bone mechanostat. Strikingly, they were not evident in female rats. If not related to a lower bone bioavailability of bisphosphonates in female rats as described by others, this phenomenon may have reflected: (1) their a smaller biomass; and/or (2) a less effective mechanostatic regulation of bone architecture derived from a higher bone material stiffness related to male animals. An increase of BMD with a predominance toward the distal region was observed in all femurs studied. This effect, unrelated to the observed changes in mechanical properties, seems to express a lack of remodeling of primary cartilage or bone tissue.

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The biomechanical repercussion of the corticoid-induced osteopenia (a severe consequence of long-term glucocorticoid therapy) was studied in cortical bone of small rodents. Growing rats receiving 12.5-3200 micrograms/kg/d of betamethasone (BMS) s.c. for 20 days suffered a log-dose related impairment in body weight gain and in mechanical (fracture load, bending stiffness) and cross-sectional properties (area, moment of inertia) of femur diaphyses. No changes in bone material properties (ability to stand stress, elastic modulus, energy absorption per unit volume) were observed. At variance with the biphasic dose-response curves (positive effects at low-medium doses, negative at high doses) previously obtained with cortisol in a similar model, only negative effects on every variable studied were observed in this experiment. Results suggest that BMS effects on cortical bone biomechanics derived mainly or completely from those induced on bone geometry (biomechanical correlate of corticoid-induced osteopenia) in the assayed conditions. Data are compatible with a BMS-induced change in the setpoint of bone mechanostat. Correlation of bone geometric and biomechanical data with body weight gain showed that the anti-anabolic effects of BMS on bone were proportionally less intense than those exerted on the whole biomass.

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In previous studies with cortisol, betamethasone and oxazacort we attributed glucocorticoid effects on bone biomechanics to changes in bone mass and geometry rather than to an action on bone material properties. In this experiment, groups of 7 rats each received subcutaneous doses of 15.6, 31.2, 62.5, 125, 250, 500 or 1000 micrograms/kg per day of dexamethasone (DMS) and an additional 14 animals were controlled untreated for 4 weeks. Their fresh femurs were then scanned by peripheral quantitative computerized tomography (pQCT; XCT-960, Stratec, Germany) at the midshaft and submitted to three-point bending tests. In consonance with our earlier investigations, a significant, log-dose-related reduction in bone load-bearing capacity was observed, associated with an impairment in bone geometric properties (cross-sectional area and moment of inertia) and in body weight gain. However, the pQCT-assessed volumetric mineral density of cortical bone (vCtBMD; regarded as a material quality indicator in terms of mineralization) was significantly reduced by DMS following a dose-response relationship. Furthermore, a direct association was detected between vCtBMD and diaphyseal load-bearing capacity and stiffness. In contrast with our previous approach, data suggests that, apart from changes in bone geometric properties, glucocorticoid effects on bone material quality--as assessed by vCtBMD changes in this study--seem also to play a significant role in the determination of their biomechanical consequences.

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A compensation for differences in bone material quality by bone geometric properties in femora from two different strains of rats was previously shown by us. A feedback mechanism controlling the mechanical properties of the integrated bones was then proposed, in accordance with Frost's mechanostat theory. Evidence of such a system is now offered by the finding of a negative correlation between the modeling-dependent cross-sectional architecture (moment of inertia) and the mineral-dependent stiffness (elastic modulus) of bone material in the femoral diaphyses of 45 normal Wistar rats of different sexes, ages, and sizes. The strength and stiffness of the integrated diaphyses were found to depend on both cross-sectional inertia and body weight, not on bone mineral density. These findings are interpreted as supporting the hypothesis that the architectural efficiency of diaphyseal cross-sectional design resulting from the spatial orientation of bone modeling during growth is optimized as a function of the body weight-dependent bone strain history, within the constraints imposed by bone stiffness. Results suggest a modulating role of biomass, related to the system set point determination, and explain the usually observed lack of a direct correlation between mineral density and strength or stiffness of long bones in studies of geometrically inhomogeneous populations.

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