Exercise during growth provides lifelong benefit to bone structure and strength: a case study

poster abstractExercise induces greatest gains in bone health during skeletal development, yet reduced bone strength is predominantly an age-related phenomenon. This dichotomy has raised the question of whether exercise-induced changes in bone health when young persist into late adulthood where they may have benefits on bone health and fracture risk. Previous work has suggested exercise-induced gains in bone mass are lost with aging; however, 1) exercise during growth predominantly influences bone structure rather than mass to increase bone strength and 2) mechanisms exist for the long-term maintenance of exercise effects on bone structure. The aim of the current case was to explore whether exercise-induced gains in bone structure and strength accrued when young persist lifelong. The subject was a 94-year-old former Major League Baseball (MLB) pitcher who played competitively for 20 years before ceasing play in 1955. Throwing athletes are a unique model to investigate the skeletal effects of exercise as: 1) the unilateral upper extremity loading associated with throwing enables the contralateral side to serve as an internal control site and 2) throwing athletes have large dominant-to-nondominant (D-to-ND) differences in midshaft humeral bone properties. Peripheral quantitative computed tomography slices of the subject’s dominant and nondominant humerii were taken at 50% humeral length, and D-to-ND percent differences in bone properties calculated and compared to those observed previously in non-throwing controls. Exercise when young had no lasting effects on D-to-ND difference in cortical bone mass or area; however, Dto-ND difference in total area was nearly 3-times that observed in controls. The maintenance of exercise effects on total area resulted from persistence of benefits on periosteal perimeter, with the loss of cortical bone mass and area benefits being due to greater endosteal expansion (perimeter). As a result of the maintenance of exercise-induced benefits on bone structure, D-to-ND difference in ability to resist torsional forces (polar moment of inertia) was nearly double that observed due to habitual loading associated with arm dominance in controls. The maintenance of exercise-induced benefits on bone structure in the current case, despite exercise ceasing 56 years ago, supports the hypothesis that exercise when young can have lasting benefits on bone strength independent of maintenance of bone mass effects. This question is being further explored in a cohort of 100 former MLB players and 100 matched controls

Regulatory Mechanisms in Bone Following Mechanical Loading

Bone responds with increased bone formation to mechanical loading, and the time course of bone formation after initiating mechanical loading is well characterized. However, the regulatory activities governing the loading-dependent changes in gene expression are not well understood. The goal of this study was to identify the time-dependent regulatory mechanisms that governed mechanical loading-induced gene expression in bone using a predictive bioinformatics algorithm. A standard model for bone loading in rodents was employed in which the right forelimb was loaded axially for three minutes per day, while the left forearm served as a non-loaded, contralateral control. Animals were subjected to loading sessions every day, with 24 hours between sessions. Ulnas were sampled at 11 time points, from 4 hours to 32 days after beginning loading. Using a predictive bioinformatics algorithm, we created a linear model of gene expression and identified 44 transcription factor binding motifs and 29 microRNA binding sites that were predicted to regulate gene expression across the time course. Known and novel transcription factor binding motifs were identified throughout the time course, as were several novel microRNA binding sites. These time-dependent regulatory mechanisms may be important in controlling the loading-induced bone formation process

Exercise Completed When Young Provides Lifelong Benefit to Cortical Bone Structure and Estimated Strength

poster abstractExercise induces greatest bone gains during growth, yet reduced bone strength is an age-related phenomenon. This raises the question of whether exercise-induced bone changes when young persist into adulthood. The current studies used Major/Minor League Baseball (MLB/MiLB) players to explore whether exercise-induced gains in humeral bone structure and strength accrued when young persist lifelong. MLB/MiLB players are a unique model as the unilateral upper extremity loading associated with throwing enables the contralateral side to serve as an internal control site and former MLB/MiLB players were consistently exposed to extreme loading reducing secular variations in exercise levels between generations. Dominant-to-nondominant (D-to-ND) differences in humeral cross-sectional properties in MLB/MiLB players were normalized to matched controls to correct for side-to-side differences due to elevated habitual loading associated with arm dominance. Exercise when young induced significant skeletal benefits, with active MLB/MiLB players having nearly double the estimated ability to resist torsion (polar moment of inertia, IP) in the humerus of their dominant arm. The cortical bone mass and area benefits of exercise observed in active MLB/MiLB players were lost in former MLB players following 40-49 years of detraining as a result of elevated medullary expansion and endocortical trabecularization. However, 42% of the total bone area benefit persisted following 50+ years of detraining and contributed to the maintenance of 24% of the benefit on IP. In MLB players who continued to exercise during aging, medullary expansion and endocortical trabecularization were reduced and there was maintenance of the cortical bone mass and area benefits of exercise. These cumulative data indicate: 1) the extreme plasticity of the growing skeleton to exercise; 2) that exercise when young has lifelong benefits on cortical bone size and estimated strength, but not bone mass, and; 3) exercise continued during aging maintains the bone mass benefits of exercise

Age-Related Changes in Proximal Humerus Bone Health in White Males

poster abstractThe proximal humerus is a common site for osteoporotic fracture during aging, accounting for up to 5% of fractures to the appendicular skeleton. While falls onto an outstretched hand are usually physically responsible for proximal humerus fractures, the ability of the underlying bone to resist applied loads must also play a role. Few studies have assessed proximal humerus bone health with aging. The aim of the current study was to explore age-related bone changes at the proximal humerus in men. A cross-sectional study design was used to assess peripheral quantitative computed tomography (pQCT)-derived bone properties of the proximal humerus in a cohort of 112 white males (age range = 30-85 yrs). A tomographic slice of the non-dominant upper extremity was acquired at 80% of humeral length proximal from its distal end—a location corresponding to the surgical neck of the humerus. Images were assessed for cortical (Ct.BMC) and trabecular (Tb.BMC) BMC, total (Tt.Ar), cortical (Ct.Ar) and medullary (Me.Ar) area, periosteal (Ps.Pm) and endosteal (Es.Pm) perimeter, cortical thickness (Ct.Th), and bone strength index for compression (BSIc). BSIc was calculated as the product of Tt.Ar and the square of total volumetric BMD. Data were plotted against age and linear regression lines assessed for their slope. Slopes were subsequently converted to percent change in the bone property per year. During aging, the proximal humerus expanded with Tt.Ar and Ps.Pm increasing at rates of 0.40%/yr and 0.19%/yr, respectively. However, Me.Ar (0.62%/yr) and Es.Pm (0.34%/yr) expanded at faster rates such that there was net loss of both Ct.BMC (-0.23%/yr) and Tb.BMC (-1.08%/yr). Also, the more rapid expansion of Me.Ar relative to Tt.Ar meant that Ct.Ar (-0.15%/yr) and Ct.Th (-0.34%/yr) both decreased with age. The net result of these mass and structural changes was progressive loss of bone strength with age, as indicated by a 0.44%/yr decline in BSIc. These data provide a picture of bone changes at the proximal humerus during aging. They suggest that between age 30 and 80 yrs, approximately 54% and 11% of Tb.BMC and Ct.BMC at the proximal humerus is lost, respectively. They also suggest that compressive strength of the proximal humerus declines by 22% between age 30 and 80 years. These declines in proximal humerus bone health have implications for fracture risk at this location during aging

The pore size of polycaprolactone scaffolds has limited influence on bone regeneration in an in vivo model

Bone tissue engineering scaffolds should be designed to optimize mass transport, cell migration, and mechanical integrity to facilitate and enhance new bone growth. Although many scaffold parameters could be modified to fulfill these requirements, pore size is an important scaffold characteristic that can be rigorously controlled with indirect solid freeform fabrication. We explored the effect of pore size on bone regeneration and scaffold mechanical properties using polycaprolactone (PCL) scaffolds designed with interconnected, cylindrical orthogonal pores. Three scaffold designs with unique microarchitectures were fabricated, having pore sizes of 350, 550, or 800 Μm. Bone morphogenetic protein-7 transduced human gingival fibroblasts were suspended in fibrin gel, seeded into scaffolds, and implanted subcutaneously in immuno-compromised mice for 4 or 8 weeks. We found that (1) modulus and peak stress of the scaffold/bone constructs depended on pore size and porosity at 4 weeks but not at 8 weeks, (2) bone growth inside pores depended on pore size at 4 weeks but not at 8 weeks, and (3) the length of implantation time had a limited effect on scaffold/bone construct properties. In conclusion, pore sizes between 350 and 800 Μm play a limited role in bone regeneration in this tissue engineering model. Therefore, it may be advantageous to explore the effects of other scaffold structural properties, such as pore shape, pore interconnectivity, or scaffold permeability, on bone regeneration when designing PCL scaffolds for bone tissue engineering. © 2009 Wiley Periodicals, Inc. J Biomed Mater Res, 2010Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/64538/1/32381_ftp.pd

Physical activity when young provides lifelong benefits to cortical bone size and strength in men

The skeleton shows greatest plasticity to physical activity-related mechanical loads during youth but is more at risk for failure during aging. Do the skeletal benefits of physical activity during youth persist with aging? To address this question, we used a uniquely controlled cross-sectional study design in which we compared the throwing-to-nonthrowing arm differences in humeral diaphysis bone properties in professional baseball players at different stages of their careers (n = 103) with dominant-to-nondominant arm differences in controls (n = 94). Throwing-related physical activity introduced extreme loading to the humeral diaphysis and nearly doubled its strength. Once throwing activities ceased, the cortical bone mass, area, and thickness benefits of physical activity during youth were gradually lost because of greater medullary expansion and cortical trabecularization. However, half of the bone size (total cross-sectional area) and one-third of the bone strength (polar moment of inertia) benefits of throwing-related physical activity during youth were maintained lifelong. In players who continued throwing during aging, some cortical bone mass and more strength benefits of the physical activity during youth were maintained as a result of less medullary expansion and cortical trabecularization. These data indicate that the old adage of “use it or lose it” is not entirely applicable to the skeleton and that physical activity during youth should be encouraged for lifelong bone health, with the focus being optimization of bone size and strength rather than the current paradigm of increasing mass. The data also indicate that physical activity should be encouraged during aging to reduce skeletal structural decay

The Cyprinodon variegatus genome reveals gene expression changes underlying differences in skull morphology among closely related species

Genes in durophage intersection set at 15 dpf. This is a comma separated table of the genes in the 15 dpf durophage intersection set. Given are edgeR results for each pairwise comparison. Columns indicating whether a gene is included in the intersection set at a threshold of 1.5 or 2 fold are provided. (CSV 13 kb

Tibial Loading Increases Osteogenic Gene Expression and Cortical Bone Volume in Mature and Middle-Aged Mice

There are conflicting data on whether age reduces the response of the skeleton to mechanical stimuli. We examined this question in female BALB/c mice of different ages, ranging from young to middle-aged (2, 4, 7, 12 months). We first assessed markers of bone turnover in control (non-loaded) mice. Serum osteocalcin and CTX declined significantly from 2 to 4 months (p<0.001). There were similar age-related declines in tibial mRNA expression of osteoblast- and osteoclast-related genes, most notably in late osteoblast/matrix genes. For example, Col1a1 expression declined 90% from 2 to 7 months (p<0.001). We then assessed tibial responses to mechanical loading using age-specific forces to produce similar peak strains (−1300 µε endocortical; −2350 µε periosteal). Axial tibial compression was applied to the right leg for 60 cycles/day on alternate days for 1 or 6 weeks. qPCR after 1 week revealed no effect of loading in young (2-month) mice, but significant increases in osteoblast/matrix genes in older mice. For example, in 12-month old mice Col1a1 was increased 6-fold in loaded tibias vs. controls (p = 0.001). In vivo microCT after 6 weeks revealed that loaded tibias in each age group had greater cortical bone volume (BV) than contralateral control tibias (p<0.05), due to relative periosteal expansion. The loading-induced increase in cortical BV was greatest in 4-month old mice (+13%; p<0.05 vs. other ages). In summary, non-loaded female BALB/c mice exhibit an age-related decline in measures related to bone formation. Yet when subjected to tibial compression, mice from 2–12 months have an increase in cortical bone volume. Older mice respond with an upregulation of osteoblast/matrix genes, which increase to levels comparable to young mice. We conclude that mechanical loading of the tibia is anabolic for cortical bone in young and middle-aged female BALB/c mice

Differential Gene Expression from Microarray Analysis Distinguishes Woven and Lamellar Bone Formation in the Rat Ulna following Mechanical Loading

Formation of woven and lamellar bone in the adult skeleton can be induced through mechanical loading. Although much is known about the morphological appearance and structural properties of the newly formed bone, the molecular responses to loading are still not well understood. The objective of our study was to use a microarray to distinguish the molecular responses between woven and lamellar bone formation induced through mechanical loading. Rat forelimb loading was completed in a single bout to induce the formation of woven bone (WBF loading) or lamellar bone (LBF loading). A set of normal (non-loaded) rats were used as controls. Microarrays were performed at three timepoints after loading: 1 hr, 1 day and 3 days. Confirmation of microarray results was done for a select group of genes using quantitative real-time PCR (qRT-PCR). The micorarray identified numerous genes and pathways that were differentially regulated for woven, but not lamellar bone formation. Few changes in gene expression were evident comparing lamellar bone formation to normal controls. A total of 395 genes were differentially expressed between formation of woven and lamellar bone 1 hr after loading, while 5883 and 5974 genes were differentially expressed on days 1 and 3, respectively. Results suggest that not only are the levels of expression different for each type of bone formation, but that distinct pathways are activated only for woven bone formation. A strong early inflammatory response preceded an increase in angiogenic and osteogenic gene expression for woven bone formation. Furthermore, at later timepoints there was evidence of bone resorption after WBF loading. In summary, the vast coverage of the microarray offers a comprehensive characterization of the early differences in expression between woven and lamellar bone formation