Fibula: The Forgotten Bone-May It Provide Some Insight On a Wider Scope for Bone Mechanostat Control?

The human fibula responds to its mechanical environment differently from the tibia accordingly with foot usage. Fibula structure is unaffected by disuse, and is stronger concerning lateral bending in soccer players (who evert and rotate the foot) and weaker in long-distance runners (who jump while running) with respect to untrained controls, along the insertion region of peroneus muscles. These features, strikingly associated to the abilities of the fibulae of predator and prey quadrupeds to manage uneven surfaces and to store elastic energy to jump, respectively, suggest that bone mechanostat would control bone properties with high selective connotations beyond structural strength.

Meagre effects of disuse on the human fibula are not explained by bone size or geometry.

Fibula response to disuse is unknown; we assessed fibula bone in spinal cord injury (SCI) patients and able-bodied counterparts. Group differences were smaller than in the neighbouring tibia which could not be explained by bone geometry. Differential adaptation of the shank bones may indicate previously unknown mechanoadaptive behaviours of bone. INTRODUCTION: The fibula supports only a small and highly variable proportion of shank compressive load (-8 to +19 %), and little is known about other kinds of stresses. Hence, whilst effects of habitual loading on tibia are well-known, fibula response to disuse is difficult to predict. METHODS: Therefore, we assessed fibular bone strength using peripheral quantitative computed tomography (pQCT) at 5 % increments from 5 to 90 % distal-proximal tibia length in nine participants with long-term spinal cord injury (SCI; age 39.2 ± 6.2 years, time since injury 17.8 ± 7.4 years), representing a cross-sectional model of long-term disuse and in nine able-bodied counterparts of similar age (39.6 ± 7.8 years), height and mass. RESULTS: There was no group difference in diaphyseal fibula total bone mineral content (BMC) (P = 0.22, 95 % CIs -7.4 % to -13.4 % and +10.9 % to +19.2 %). Site by group interactions (P < 0.001) revealed 27 and 22 % lower BMC in SCI at 5 and 90 % (epiphyseal) sites only. Cortical bone geometry differed at mid and distal diaphysis, with lower endocortical circumference and greater cortical thickness in SCI than able-bodied participants in this region only (interactions both P < 0.01). Tibia bone strength was also assessed; bone by group interactions showed smaller group differences in fibula than tibia for all bone parameters, with opposing effects on distal diaphysis geometry in the two bones (all Ps < 0.001). CONCLUSIONS: These results suggest that the structure of the fibula diaphysis is not heavily influenced by compressive loading, and only mid and distal diaphysis are influenced by bending and/or torsional loads. The fibula is less influenced by disuse than the tibia, which cannot satisfactorily be explained by differences in bone geometry or relative changes in habitual loading in disuse. Biomechanical study of the shank loading environment may give new information pertaining to factors influencing bone mechanoadaptation.

Suboptimal methotrexate use in rheumatoid arthritis patients in Italy: the MARI study.

OBJECTIVES: Methotrexate (MTX) is the first choice in the treatment of rheumatoid arthritis (RA), but the doses and regimens vary significantly. For this purpose, we conducted an observational study on the use of MTX for RA in Italy (MARI study). METHODS: The MARI study included 1,327 RA patients on MTX treatment for at least 12 months, at 60 Italian rheumatology units. Concomitant medications with corticosteroids, other DMARDs or biological therapies were recorded. The clinical assessment included the Disease Activity Score 28 (DAS28) and the serological positivity for the rheumatoid factor or for the anti-citrullinated protein antibodies. RESULTS: The included patients were treated with either oral (n=288) or parenteral (n=1039) MTX. Only 15.5% of the total number of the patients was on adequate MTX dose (i.e. ≥ 15 mg for the oral route of administration and >12 mg for the parenteral one). The initially established MTX dose was modified in 37.1% of the patients, for intolerance or clinical criteria. A DAS28 remission (DAS28 <2.6) was observed only in 58.5% of the cases, while 52.9% of the patients still presenting an active form of the disease were on suboptimal doses of MTX. CONCLUSIONS: The weekly dose of MTX prescribed for the treatment of RA is often suboptimal, even in conditions of inadequate control of the disease activity. The recommendations for the use of MTX in RA patients should take into account the efficacy and tolerability data derived from its use in real clinical practice.

Electrical charging effects on the sliding friction of a model nano-confined ionic liquid.

Recent measurements suggest the possibility to exploit ionic liquids (ILs) as smart lubricants for nano-contacts, tuning their tribological and rheological properties by charging the sliding interfaces. Following our earlier theoretical study of charging effects on nanoscale confinement and squeezout of a model IL, we present here molecular dynamics simulations of the frictional and lubrication properties of that model under charging conditions. First, we describe the case when two equally charged plates slide while being held together to a confinement distance of a few molecular layers. The shear sliding stress is found to rise strongly and discontinuously as the number of IL layers decreases stepwise. However, the shear stress shows, within each given number of layers, only a weak dependence upon the precise value of the normal load, a result in agreement with data extracted from recent experiments. We subsequently describe the case of opposite charging of the sliding plates and follow the shear stress when the charging is slowly and adiabatically reversed in the course of time, under fixed load. Despite the fixed load, the number and structure of the confined IL layers change with changing charge, and that in turn drives strong friction variations. The latter involves first of all charging-induced freezing of the IL film, followed by a discharging-induced melting, both made possible by the nanoscale confinement. Another mechanism for charging-induced frictional changes is a shift of the plane of maximum shear from mid-film to the plate-film interface, and vice versa. While these occurrences and results invariably depend upon the parameters of the model IL and upon its specific interaction with the plates, the present study helps identifying a variety of possible behavior, obtained under very simple assumptions, while connecting it to an underlying equilibrium thermodynamics picture.

Squeezout phenomena and boundary layer formation of a model ionic liquid under confinement and charging.

Electrical charging of parallel plates confining a model ionic liquid down to nanoscale distances yields a variety of charge-induced changes in the structural features of the confined film. That includes even-odd switching of the structural layering and charging-induced solidification and melting, with important changes of local ordering between and within layers, and of squeezout behavior. By means of molecular dynamics simulations, we explore this variety of phenomena in the simplest charged Lennard-Jones coarse-grained model including or excluding the effect a neutral tail giving an anisotropic shape to one of the model ions. Using these models and open conditions permitting the flow of ions in and out of the interplate gap, we simulate the liquid squeezout to obtain the distance dependent structure and forces between the plates during their adiabatic approach under load. Simulations at fixed applied force illustrate an effective electrical pumping of the ionic liquid, from a thick nearly solid film that withstands the interplate pressure for high plate charge to complete squeezout following melting near zero charge. Effective enthalpy curves obtained by integration of interplate forces versus distance show the local minima that correspond to layering and predict the switching between one minimum and another under squeezing and charging.

Analysis of the independent power of age-related, anthropometric and mechanical factors as determinants of the structure of radius and tibia in normal adults. A pQCT study.

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.

The pQCT 'Bone Strength Indices' (BSIs, SSI). Relative mechanical impact and diagnostic value of the indicators of bone tissue and design quality employed in their calculation in healthy men and pre- and post-menopausal women.

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.

Mineralization- and remodeling-unrelated improvement of the post-yield properties of rat cortical bone by high doses of olpadronate.

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.

pQCT-assessed relationships between diaphyseal design and cortical bone mass and density in the tibiae of healthy sedentary and trained men and women.

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.

Interrelationships between densitometric, geometric, and mechanical properties of rat femora: inferences concerning mechanical regulation of bone modeling.

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.

Interrelationships between geometric and mechanical properties of long bones from three rodent species with very different biomass: phylogenetic implications.

In femora from rats or mice, the area and moment of inertia (but not the wall-lumen ratio) of a diaphyseal section correlated with biomass and were determinants of the strength and stiffness of the integrated bone. In otter metacarpals, however, the geometric variable typically associated with body weight and mechanical ability of the integrated bone was the wall-lumen ratio (not the sectional moment of inertia). These differences may be associated with the meaningfulness of body density for natural selection in diving species like otters. A negative relationship between wall-lumen ratio and material modulus of elasticity in bones from the three species pointed out the impossibility of increasing diaphyseal thickness and stiffness at the same time. The results are compatible with the hypothesis that ecologic habits are selectively more important than phylogenetic relationships between species for the determination of bone mechanical properties in the upper vertebrates.

Mechanical validation of a tomographic (pQCT) index for noninvasive estimation of rat femur bending strength.

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.

Determination of femur structural properties by geometric and material variables as a function of body weight in rats. Evidence of a sexual dimorphism.

Femur diaphyses of male and female Wistar rats were densitometrically and biomechanically assayed. The BMD-dependent material properties were better in female than in male bones, but cross-section geometric properties were better in male femurs. As a result, mechanical properties of the integrated diaphyses were better in males, but differences disappeared after statistical adjustment of data to a common body weight. Results evidence a feed-back mechanism locally controlling the strain-dependent bone modelling and the corresponding cross-sectional design as related to bone stiffness, with a set-point adjusted to animal biomass. A sexual dimorphism of bone biomechanics is also described for the species.

Effects of large doses of olpadronate (dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs.

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.

Monophasic dose-response curves of betamethasone on geometric and mechanical properties of femur diaphyses in growing rats.

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.

A DXA study of muscle-bone relationships in the whole body and limbs of 2512 normal men and pre- and post-menopausal women.

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.

Dexamethasone effects on mechanical, geometric and densitometric properties of rat femur diaphyses as described by peripheral quantitative computerized tomography and bending tests.

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.

Long-bone biomechanics in mice selected for body conformation.

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.

Tomographic (pQCT) and biomechanical effects of hPTH(1-38) on chronically immobilized or overloaded rat femurs.

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.

Effects of on/off anabolic hPTH and remodeling inhibitors on metaphyseal bone of immobilized rat femurs. Tomographical (pQCT) description and correlation with histomorphometric changes in tibial cancellous bone.

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.