Mechanical Implications of Estrogen Supplementation in Early Postmenopausal Women

Department of Radiology, University of Pennsylvania, Philadelphia, PA 19104, USA.
Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research (Impact Factor: 6.59). 06/2010; 25(6):1406-14. DOI: 10.1002/jbmr.33
Source: PubMed

ABSTRACT Whereas the structural implications of drug intervention are well established, there are few data on the possible mechanical consequences of treatment. In this work we examined the changes in elastic and shear moduli (EM and SM) in a region of trabecular bone in the distal radius and distal tibia of early postmenopausal women on the basis of MRI-based micro-finite-element (microFE) analysis. Whole-section axial stiffness (AS) encompassing both trabecular and cortical compartments was evaluated as well. The study was conducted on previously acquired high-resolution images at the two anatomic sites. Images were processed to yield a 3D voxel array of bone-volume fraction (BVF), which was converted to a microFE model of hexahedral elements in which tissue modulus was set proportional to voxel BVF. The study comprised 65 early postmenopausal women (age range 45 to 55 years), of whom 32 had chosen estrogen supplementation (estradiol group); the remainder had not (control group). Subjects had been scanned at baseline and 12 and 24 months thereafter. At the distal tibia, EM and SM were reduced by 2.9% to 5.5% in the control group (p < .05 to <.005), but there was no change in the estradiol subjects. AS decreased 3.9% (4.0%) in controls (p < .005) and increased by 5.8% (6.2%) in estradiol group subjects (p < .05) at 12 (24) months. At the distal radius, EM and SM changes from baseline were not significant, but at both time points AS was increased in estradiol group subjects and decreased in controls (p < .005 to <.05), albeit by a smaller margin than at the tibia. EM and SM were strongly correlated with BV/TV (r(2) = 0.44 to 0.92) as well as with topologic parameters expressing the ratio of plates to rods (r(2) = 0.45 to 0.82), jointly explaining up to 96% of the variation in the mechanical parameters. Finally, baseline AS was strongly correlated between the two anatomic sites (r(2) = 0.58), suggesting that intersubject variations in the bone's mechanical competence follows similar mechanisms. In conclusion, the results demonstrate that micro-MRI-based microFE models are suited for the study of the mechanical implications of antiresorptive treatment. The data further highlight the anabolic effect of short-term estrogen supplementation.

Download full-text


Available from: Felix W Wehrli, Jan 09, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Osteoporotic and age-related fractures are a significant public health problem. The current standard of osteoporosis assessment via bone mineral density has been shown to be inadequate for fracture risk predictions highlighting the importance of material composition and structural design of bone in determining skeletal fragility. Bone is a hierarchical material that derives its fracture resistance from various mechanisms that act at length scales ranging from nano- to macroscale. Recent research efforts have focussed on the understanding of bone fracture based on this hierarchical structure to provide a more reliable assessment of fracture risk. Understanding the function, contribution and interaction of each length scale to bone toughness is a crucial step to develop new strategies for fracture risk assessment, fracture prevention, and development of therapeutic interventions for disease and age-related changes in bone. This review presents a hierarchical perspective of bone toughness ranging from nano- to macroscale and reports on the current state of knowledge in the areas of experimental and computational approaches to bone fracture.
    International Materials Reviews 06/2014; 59(5):245-263. DOI:10.1179/1743280414Y.0000000031 · 6.55 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Context: Severe deficiencies of testosterone (T) and growth hormone (GH) are associated with low bone mineral density (BMD) and increased fracture risk. Replacement of T in hypogonadal men improves several bone parameters. Replacement of GH in GH-deficient men improves BMD. Objective: To determine if T and GH treatment together improves the structural and mechanical parameters of bone more than T alone in men with hypopituitarism. Design: Randomized, prospective, two-year study. Subjects: Thirty-two men with severe deficiencies of T and GH due to panhypopituitarism. Intervention: Subjects were randomized to receive T alone (n=15) or T+GH (n=17) for two years. Main outcome measures: MicroMRI-derived structural (bone volume fraction and trabecular thickness) and mechanical (axial stiffness, a measure of bone strength) properties of the distal tibia at baseline and after one and two years of treatment. Results Treatment with T and GH did not affect bone volume fraction, thickness or axial stiffness differently from T alone. T treatment in all subjects for two years increased trabecular bone volume fraction by 9.6% (P<0.0001), trabecular thickness by 2.6% (P<0.001), and trabecular axial stiffness by 9.8% (P<0.001). In contrast, testosterone treatment in all subjects significantly increased cortical thickness by 2.4% (P<0.01) but decreased cortical bone volume fraction by -4.7% (P<0.01) and cortical axial stiffness by -6.9% (P<0.01). Conclusion: Combined T and GH treatment of men with hypopituitarism for two years did not improve the measured structural or mechanical parameters of the distal tibia more than T alone. However, testosterone significantly increased the structural and mechanical properties of trabecular bone but decreased most of these properties of cortical bone, illustrating the potential importance of assessing trabecular and cortical bone separately in future studies of the effect of testosterone on bone.
    The Journal of Clinical Endocrinology and Metabolism 01/2014; 99(4):jc20133665. DOI:10.1210/jc.2013-3665 · 6.31 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Commercially available recombinant human bone morphogenetic protein 2 (rhBMP2) has demonstrated efficacy in bone regeneration, but not without significant side effects. In this study, we utilize rhBMP2 encapsulated in PLGA microspheres (PLGA-rhBMP2) placed in a rabbit cranial defect model to test whether low-dose, sustained, delivery can effectively induce bone regeneration. rhBMP2 was encapsulated in 15% poly (lactic-co-glycolic acid), using a double emulsion, solvent extraction/evaporation technique, and its release kinetics and bioactivity were tested. Two critical-size defects (10mm) were created in the calvarium of New Zealand White rabbits (5-7 mos of age, M/F) and filled with a collagen scaffold containing one of four groups: 1) no implant, 2) collagen scaffold only, 3) PLGA-rhBMP2(0.1ug/implant), or 4) free rhBMP2 (0.1ug/implant). After 6 weeks, the rabbits were sacrificed and defects were analyzed by µCT, histology, and finite element analysis. RhBMP2 delivered via bioactive PLGA microspheres resulted in higher volumes and surface area coverage of new bone than an equal dose of free rhBMP2 by µCT and histology (p=0.025, 0.025). FEA indicated that the mechanical competence using the regional elastic modulus did not differ with rhBMP2 exposure (p=0.70). PLGA-rhBMP2 did not demonstrate heterotopic ossification, craniosynostosis, or seroma formation. Sustained delivery via PLGA microspheres can significantly reduce the rhBMP2 dose required for de novo bone formation. Optimization of the delivery system may be a key to reduce the risk for recently reported rhBMP2 related adverse effects. Animal Study.
    Plastic and Reconstructive Surgery 03/2014; 134(1). DOI:10.1097/PRS.0000000000000287 · 3.33 Impact Factor