Gustavo Cointry

Bone Quality Parameters of the Distal Radius as Assessed by pQCT in Normal and Fractured Women

Abstract. The aim of this study was to test the ability of some indicators of different aspects of bone quality (assessed by peripheral quantitative computed tomography in the distal radius) to discriminate between fractured and nonfractured individuals. The study compared 214 women aged 45–85 years, free of any bone-affecting treatment, of whom 107 had suffered a Colles” fracture in the previous 6 months and 107 did not. The determinations included bone tissue or mineral “mass” indicators (trabecular, cortical and total volumetric mineral content, cortical bone area); bone “density” estimates (trabecular, cortical and total volumetric mineral density), and the Cartesian (rectangular) and polar moments of inertia as influences of cross-sectional architecture on resistance to bending and torsional loads, respectively. The influences of body height, weight and age on the tomographic indicators were minimized by adjusting the data according to the partial coefficients of multiple stepwise regressions. The adjusted values of all the indicators were lower in fractured than in nonfractured groups. The prevalence of fractures was directly related to the actual values of the indicators, rather than the age or body habitus of the individuals. The significance of these differences between the assessed indicators decreased in the following order: trabecular “mass” > trabecular “density” > cortical or total “mass” > cortical architecture > total or cortical “density” indicators. Within the same type of bone, the tissue or mineral “mass” indicators performed better than the “density” indicators. The cortical bone density did not give useful information, probably because of technical difficulties. Odds-ratios and receiver-operating characteristic (ROC) analyses confirmed those features. The selected “cut-off” values of the indicators as determined by the ROC curves (very close to those determined by the inflexion points of the logistic reression curves) may indicate reference limits to detect persons at risk of fracture according to the type of information provided by each variable. These results show that these tomographic indicators discriminate well between fractured and nonfractured individuals, and should be suitable to assess how total, cortical and trabecular bone strength in the distal radius could affect different kinds of strength regardless of the age or body habitus of the individual. Their ability to estimate fracture risk from different biomechanical points of view should be assessed by adequately designed, prospective studies.

Structural analysis of the human tibia by tomographic (pQCT) serial scans

This study analyses the evaluation of tomographic indicators of tibia structure, assuming that the usual loading pattern shifts from uniaxial compression close to the heel to a combined compression, torsion and bending scheme towards the knee. To this end, pQCT scans were obtained at 5% intervals of the tibia length (S5–S95 sites from heel to knee) in healthy men and women (10/10) aged 20–40 years. Indicators of bone mass [cortical area, cortical/total bone mineral content (BMC)], diaphyseal design (peri/endosteal perimeters, cortical thickness, circularity, bending/torsion moments of inertia – CSMIs), and material quality [(cortical vBMD (bone mineral density)] were determined. The longitudinal patterns of variation of these measures were similar between genders, but male values were always higher except for cortical vBMD. Expression of BMC data as percentages of the minimal values obtained along the bone eliminated those differences. The correlative variations in cortical area, BMC and thickness, periosteal perimeter and CSMIs along the bone showed that cortical bone mass was predominantly associated with cortical thickness toward the mid‐diaphysis, and with bone diameter and CSMIs moving more proximally. Positive relationships between CSMIs (y) and total BMC (x) showed men’s values shifting to the upper‐right region of the graph and women’s values shifting to the lower‐left region. Total BMC decayed about 33% from S5 to S15 (where minimum total BMC and CSMI values and variances and maximum circularity were observed) and increased until S45, reaching the original S5 value at S40. The observed gender‐related differences reflected the natural allometric relationships. However, the data also suggested that men distribute their available cortical mass more efficiently than women. The minimum amount and variance of mass indicators and CSMIs, and the largest circularity observed at S15 reflected the assumed adaptation to compression pattern at that level. The increase in CSMIs (successively for torsion, A–P bending, and lateral bending), the decrease in circularity values and the changes in cortical thickness and periosteal perimeter toward the knee described the progressive adaptation to increasing torsion and bending stresses. In agreement with the biomechanical background, the described relationships: (i) identify the sites at which some changes in tibial stresses and diaphyseal structure take place, possibly associated with fracture incidence; (ii) allow prediction of mass indicators at any site from single determinations; (iii) establish the proportionality between the total bone mass at regions with highly predominant trabecular and cortical bone of the same individual, suitable for a specific evaluation of changes in trabecular mass; and (iv) evaluate the ability of bone tissue to self‐distribute the available cortical bone according to specific stress patterns, avoiding many anthropometric and gender‐derived influences.

Structural analysis of the human tibia in men with spinal cord injury by tomographic (pQCT) serial scans

Spinal cord injury (SCI), as a primarily neurological disorder that causes muscular atrophy, is well known to be associated with sub-lesional bone losses. These losses are more pronounced from epiphyseal than from diaphyseal regions. We hypothesized that this discrepancy may be explained by anatomical variation in endocortical circumference. Nine men who had attracted SCI 9 to 32 (mean 21.4) years prior to study inclusion were matched to able bodied control (Ctrl) people by age, height and weight. Serial scans by peripheral quantitative computed tomography were obtained from the tibia at steps corresponding to 5%-steps of the tibias length (s05 to s95, from distal to the proximal end of the tibia). As expected, SCI people had lower total bone mineral content (vBMC.tot) than able bodied control people (P<0.001 at all sites). This group difference (DeltavBMC.tot) was more pronounced at the distal and proximal tibia than in the shaft (P<0.001), and it amounted to 51% at s05, to 22% at s40, and to 47% at s95. Both endocortical and periosteal circumference were better predictors of DeltavBMC.tot (R(2)=0.98 and R(2)=0.97, respectively; P<0.001 in both cases) than vBMC.tot (R(2)=0.58, P<0.001), suggesting that anatomical variation in geometry, rather than in bone mass can explain differential rates of bone loss after SCI. Moreover, the s04:s38 ratio in vBMC.tot was found to be 1.00 (95% confidence interval: 0.95-1.05) in the Ctrl group, and 0.63 in the SCI group (P<0.001, 95% confidence interval: 0.54-0.68). These findings offer a rationale to account for the discrepancy between epiphyseal and diaphyseal bone losses following SCI. The suggestion is that the bone adaptive responses involved are limited in time, and that the reduced surface:volume ratio constitutes a limit within the available time window, in particular in the diaphysis. Finally, the drastically reduced s04:s38 vBMC.tot ratio observed in the SCI group in this study provides a rationale to scrutinize this Capozza index also in other studies as a general indicator of immobilisation-induced bone loss.

Association between low lean body mass and osteoporotic fractures after menopause

Objective: This study evaluated dual-energy x-ray absorptiometry-assessed whole-body bone-muscle relationship (bone mineral content/lean mass [BMC/LM]) as an indicator of its nonmechanical perturbations (ie, systemic) in pre- and postmenopausal women. A total of 3,205 women were studied, either healthy (no fracture [No Fx] groups, 1,035 premenopausal, 1,556 postmenopausal) or with recent fractures (Fx groups, 139 premenopausal, 475 postmenopausal) located at osteoporotic sites (hip, spine, long-bone metaphyses; Type II Fx, n = 386) or at other skeletal sites (Type I Fx, n = 228) to evaluate the impact of decreased muscle mass on fracture incidence before and after menopause. Design: SD-scored graphs of BMC/LM proportionality were obtained from the No Fx groups as normal references. Based on the reference BMC versus LM curves obtained from their respective No Fx pre- and postmenopausal controls, BMC-LM SD scores were calculated for all women with fractures. Results: BMC-LM SD scores in all premenopausal women with fractures and in Type I Fx postmenopausal women were similar to the reference. In contrast, SD scores in Type II Fx postmenopausal women were lower than the reference, especially in those with hip fractures. Except for Type II Fx postmenopausal women, all groups showed linear and similar BMC versus LM curves. Type II Fx postmenopausal women showed nonlinear relationships, with progressively decreasing BMC and BMC-LM SD scores as their LM decreased. Conclusions: Results suggest that both LM and BMC-LM SD scores can help to differentiate between systemic and mechanical (disuse-related) osteopenia/osteoporosis after menopause. Low LM values or BMC-LM SD scores seem to constitute additional fracture risk factors beyond those usually detected in premenopausal women or in women with other types of fractures. This application of dual-energy x-ray absorptiometry technology may lead to more effective diagnosis and treatment at low cost.

Analysis of the Structure and Strength of Bones in Celiac Disease Patients

OBJECTIVE:The aim of this study was to gain insight into the pathogenesis of bone mass loss and weakening affecting patients with celiac disease, according to the new concepts of bone structure/strength and muscle/bone interrelationships.METHODS:We studied serum variables and tomographic indicators of bone structure and strength and regional muscle masses in a series of patients at diagnosis and after 1 yr on a gluten-free diet and in gender- and age-matched controls.RESULTS:At diagnosis, serum levels of calcium and vitamin D were low, and indicators of parathyroid hormone activity and bone formation and resorption were increased. All these parameters were normalized by treatment. Peripheral quantitative CT scans of the distal radius revealed that cortical bone was generally more affected than trabecular bone. The cross-sectional area (CSA) and the volumetric mineral content and density of cortical bone (indicators of cortical tissue mass and mechanical quality), and moments of inertia (CSMI, indicator of the bone architectural design) were in the lower end of normal range in men, and below that in 50% of women. In men, the CSMI/CSA ratio (indicator of the architectural efficiency of distribution of the available cortical tissue) was lower than expected and remained unchanged after treatment. In women, the baseline ratio was normal, but both the ratio and the CSMI were low at diagnosis and normalized after treatment. Both baseline values and the treatment-induced changes of cortical and trabecular bone in the radius and the axis (L3) correlated inversely with serum parathyroid hormone levels. Baseline values or changes in the mineral content of the vertebral bone correlated with the CSA of psoas and spine-extensor muscles. Multiple regression analyses showed that metabolic and mechanical parameters were independent determinants of different aspects of the vertebral bone weakening.CONCLUSIONS:Our results show that bone weakening in celiac disease might result from both 1) a metabolic disturbances of bone remodeling affecting trabecular and cortical bone masses and the mechanical quality of the bone material, and 2) a reduction of muscle strength impairing the modeling-dependent optimization of bone architectural design and mass of cortical bone. Dietary treatment seems to correct almost exclusively the metabolically induced disturbances, which were predominant in women.

Biomechanical impact of aluminum accumulation on the pre- and post-yield behavior of rat cortical bone.

In order to analyze the effects on whole-bone behavior of aluminum accumulation, 14 rats, aged 90 days, received i.p. doses of 27 mg/day of elemental Al, as Al(OH)3, during 26 weeks, while 14 rats remained as controls. Their femur diaphyses were studied tomographically by peripheral quantitative computed tomography (pQCT) and mechanically tested in bending. The load/deformation curves obtained allowed distinction between effects observed during the linearly elastic (Hookean) and nonlinear (non-Hookean, or plastic) behaviors of bones before and after the yield point, respectively. Treatment reduced the cortical bone mineralization (volumetric bone mineral density [BMD], −2%; P < 0.01), with a negative impact on the bending stiffness (Young’s elastic modulus) and the yield stress of cortical bone (−18% and −13%; P < 0.05). Despite the absence of any cortical mass increase (cross-sectional area), improved spatial distribution of cortical tissue concerning anterior-posterior bending stress (cross-sectional moment of inertia, 10%; P < 0.05) occurred through a modulation of modeling drifts. Up to the yield point, neither the structural strength (load supported), the strain, nor the structural stiffness (load/deformation ratio) of the diaphyses were affected. This suggests an adaptive response of bone geometry to the impairment of bone material stiffness. However, Al intoxication significantly reduced the ultimate load and the post-yield fraction of that load (−6% and −27%; P < 0.05). This suggests that the proposed, adaptive response could have improved bone design so as to make it adequate for maintaining a normal pre-yield diaphyseal stiffness and strength according to the bone mechanostat theory, but not so as to provide complete protection of the diaphyseal post-yield (and ultimate) strength. Although a relative inhibition of bone formation could not be discarded, an Al-induced impairment of the bone ability to resist loads beyond the yield point could have caused the unusual disparity observed between effects on bone (elastic) stiffness and (ultimate) strength. In addition, to explain the unusual finding, these results suggest that little-studied microstructural factors (spatial arrangement of elements within the mineralized tissue) affecting the post-yield behavior of cortical bone, regardless of bone mineralization in these and other conditions, ought to be further investigated in specifically designed studies as a novel, promising resource in skeletal research.

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.

Absorptiometric assessment of muscle-bone relationships in humans: reference, validation, and application studies.

This report summarizes some preliminary absorptiometric (DXA, QCT/pQCT) studies from our laboratory, supporting the following assumptions. 1. InHomo sapiens at all ages, natural proportionality between DXA-assessed bone mineral mass (bone mineral content, BMC) and muscle mass (lean mass, LM) of the whole body or limbs is specific for ethnicity, gender, and reproductive status, but not for body weight, height, or body mass index. 2. This proportionality is sensitive to many kinds of endocrine-metabolic perturbations. 3. Percentilized or Z-scored charts of the BMC/LM correlations as determined in large samples of healthy individuals can provide a diagnostic reference for evaluating proportionality in different conditions. 4. Employing exclusively DXA, this methodology can be applied to discriminate between “disuse-related” and “metabolic” osteopenias based on the finding of normal or low BMC/LM percentiles or Z-scores respectively, with important therapeutic and monitoring implications.

Novel experimental effects on bone material properties and the pre- and postyield behavior of bones may be independent of bone mineralization

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 theeSS 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 mineralization 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 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.

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.