Brief communication: The effects of disuse on the mechanical properties of bone: What unloading tells us about the adaptive nature of skeletal tissue

The intricate link between load environment and skeletal health is exemplified by the severe osteopenia that accompanies prolonged periods of immobilization, frequently referred to as disuse osteoporosis. Investigating the effects disuse has on the structural properties of bone provides a unique opportunity to better understand how mechanical loads influence the adaptation and maintenance of skeletal tissue. Here, we report results from an examination of multiple indicators of bone metabolism (e.g., mean osteon density, mean osteon size, bone mass, and bone area distribution) within the major long bones of individuals with distinct activity level differences. Results are based on a sample comprising two subjects that suffered from long‐term quadriplegia and 28 individuals of comparable age that had full limb mobility. Although limited in sample size, our findings suggest bones associated with long‐term disuse have lower osteon densities and larger osteon areas compared to individuals of normal mobility, reflecting dramatically lower remodeling rates potentially related to reduced strain levels. Moreover, immobilized skeletal elements demonstrate a reduced percentage of cortical area present resulting from endosteal resorption. Differences between mobility groups in the percentage of cortical area present and bone distribution of all skeletal elements, suggests bone modeling activity is negligible in the unloaded adult skeleton. Additional histomorphometric comparisons reveal potential intraskeletal differences in bone turnover rates suggesting remodeling rates are highest within the humeri and femora. Addition of more immobilized individuals in the future will allow for quantitative statistical analyses and greater consideration of human variation within and between individuals. Am J Phys Anthropol 2012. © 2012 Wiley Periodicals, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94522/1/22150_ftp.pd

Moving toward a prevention strategy for osteoporosis by giving a voice to a silent disease

Abstract A major unmet challenge in developing preventative treatment programs for osteoporosis is that the optimal timing of treatment remains unknown. In this commentary we make the argument that the menopausal transition (MT) is a critical period in a woman’s life for bone health, and that efforts aimed at reducing fracture risk later in life may benefit greatly from strategies that treat women earlier with the intent of keeping bones strong as long as possible. Bone strength is an important parameter to monitor during the MT because engineering principles can be applied to differentiate those women that maintain bone strength from those women that lose bone strength and are in need of early treatment. It is critical to understand the underlying mechanistic causes for reduced strength to inform treatment strategies. Combining measures of strength with data on how bone structure changes during the MT may help differentiate whether a woman is losing strength because of excessive bone resorption, insufficient compensatory bone formation, trabeculae loss, or some combination of these factors. Each of these biomechanical mechanisms may require a different treatment strategy to keep bones strong. The technologies that enable physicians to differentially diagnose and treat women in a preventive manner, however, have lagged behind the development of prophylactic treatments for osteoporosis. To take advantage of these treatment options, advances in preventive treatment strategies for osteoporosis may require developing new technologies with imaging resolutions that match the pace by which bone changes during the MT and supplementing a woman's bone mineral density (BMD)-status with information from engineering-based analyses that reveal the structural and material changes responsible for the decline in bone strength during the menopausal transition.http://deepblue.lib.umich.edu/bitstream/2027.42/134529/1/40695_2016_Article_16.pd

Gene Expression Profile and Acute Gene Expression Response to Sclerostin Inhibition in Osteogenesis Imperfecta Bone

Sclerostin antibody (SclAb) therapy has been suggested as a novel therapeutic approach toward addressing the fragility phenotypic of osteogenesis imperfecta (OI). Observations of cellular and transcriptional responses to SclAb in OI have been limited to mouse models of the disorder, leaving a paucity of data on the human OI osteoblastic cellular response to the treatment. Here, we explore factors associated with response to SclAb therapy in vitro and in a novel xenograft model using OI bone tissue derived from pediatric patients. Bone isolates (approximately 2 mm3) from OI patients (OI type III, type III/IV, and type IV, n = 7; non‐OI control, n = 5) were collected to media, randomly assigned to an untreated (UN), low‐dose SclAb (TRL, 2.5 μg/mL), or high‐dose SclAb (TRH, 25 μg/mL) group, and maintained in vitro at 37°C. Treatment occurred on days 2 and 4 and was removed on day 5 for TaqMan qPCR analysis of genes related to the Wnt pathway. A subset of bone was implanted s.c. into an athymic mouse, representing our xenograft model, and treated (25 mg/kg s.c. 2×/week for 2/4 weeks). Implanted OI bone was evaluated using μCT and histomorphometry. Expression of Wnt/Wnt‐related targets varied among untreated OI bone isolates. When treated with SclAb, OI bone showed an upregulation in osteoblast and osteoblast progenitor markers, which was heterogeneous across tissue. Interestingly, the greatest magnitude of response generally corresponded to samples with low untreated expression of progenitor markers. Conversely, samples with high untreated expression of these markers showed a lower response to treatment. in vivo implanted OI bone showed a bone‐forming response to SclAb via μCT, which was corroborated by histomorphometry. SclAb induced downstream Wnt targets WISP1 and TWIST1, and elicited a compensatory response in Wnt inhibitors SOST and DKK1 in OI bone with the greatest magnitude from OI cortical bone. Understanding patients’ genetic, cellular, and morphological bone phenotypes may play an important role in predicting treatment response. This information may aid in clinical decision‐making for pharmacological interventions designed to address fragility in OI. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/2/jbm410377_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/156449/1/jbm410377.pd

Femoral Neck External Size but not aBMD Predicts Structural and Mass Changes for Women Transitioning Through Menopause

The impact of adult bone traits on changes in bone structure and mass during aging is not well understood. Having shown that intracortical remodeling correlates with external size of adult long bones led us to hypothesize that ageâ related changes in bone traits also depend on external bone size. We analyzed hip dualâ energy Xâ ray absorptiometry images acquired longitudinally over 14 years for 198 midlife women transitioning through menopause. The 14â year change in bone mineral content (BMC, R2â =â 0.03, pâ =â 0.015) and bone area (R2â =â 0.13, pâ =â 0.001), but not areal bone mineral density (aBMD, R2â =â 0.00, pâ =â 0.931) correlated negatively with baseline femoral neck external size, adjusted for body size using the residuals from a linear regression between baseline bone area and height. The dependence of the 14â year changes in BMC and bone area on baseline bone area remained significant after adjusting for race/ethnicity, postmenopausal hormone use, the 14â year change in weight, and baseline aBMD, weight, height, and age. Women were sorted into tertiles using the baseline bone areaâ height residuals. The 14â year change in BMC (pâ =â 0.009) and bone area (pâ =â 0.001) but not aBMD (pâ =â 0.788) differed across the tertiles. This suggested that women showed similar changes in aBMD for different structural and biological reasons: women with narrow femoral necks showed smaller changes in BMC but greater increases in bone area compared to women with wide femoral necks who showed greater losses in BMC but without large compensatory increases in bone area. This finding is opposite to expectations that periosteal expansion acts to mechanically offset bone loss. Thus, changes in femoral neck structure and mass during menopause vary widely among women and are predicted by baseline external bone size but not aBMD. How these different structural and mass changes affect individual strengthâ decline trajectories remains to be determined. © 2017 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/137625/1/jbmr3082.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/137625/2/jbmr3082_am.pd

External Bone Size Is a Key Determinant of Strength‐Decline Trajectories of Aging Male Radii

Given prior work showing associations between remodeling and external bone size, we tested the hypothesis that wide bones would show a greater negative correlation between whole‐bone strength and age compared with narrow bones. Cadaveric male radii (n = 37 pairs, 18 to 89 years old) were evaluated biomechanically, and samples were sorted into narrow and wide subgroups using height‐adjusted robustness (total area/bone length). Strength was 54% greater (p < 0.0001) in wide compared with narrow radii for young adults (<40 years old). However, the greater strength of young‐adult wide radii was not observed for older wide radii, as the wide (R2 = 0.565, p = 0.001), but not narrow (R2 = 0.0004, p = 0.944) subgroup showed a significant negative correlation between strength and age. Significant positive correlations between age and robustness (R2 = 0.269, p = 0.048), cortical area (Ct.Ar; R2 = 0.356, p = 0.019), and the mineral/matrix ratio (MMR; R2 = 0.293, p = 0.037) were observed for narrow, but not wide radii (robustness: R2 = 0.015, p = 0.217; Ct.Ar: R2 = 0.095, p = 0.245; MMR: R2 = 0.086, p = 0.271). Porosity increased with age for the narrow (R2 = 0.556, p = 0.001) and wide (R2 = 0.321, p = 0.022) subgroups. The wide subgroup (p < 0.0001) showed a significantly greater elevation of a new measure called the Cortical Pore Score, which quantifies the cumulative effect of pore size and location, indicating that porosity had a more deleterious effect on strength for wide compared with narrow radii. Thus, the divergent strength–age regressions implied that narrow radii maintained a low strength with aging by increasing external size and mineral content to mechanically offset increases in porosity. In contrast, the significant negative strength–age correlation for wide radii implied that the deleterious effect of greater porosity further from the centroid was not offset by changes in outer bone size or mineral content. Thus, the low strength of elderly male radii arose through different biomechanical mechanisms. Consideration of different strength–age regressions (trajectories) may inform clinical decisions on how best to treat individuals to reduce fracture risk. © 2019 American Society for Bone and Mineral Research.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149566/1/jbmr3661_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149566/2/jbmr3661.pd

Women Build Long Bones With Less Cortical Mass Relative to Body Size and Bone Size Compared With Men

INTRODUCTION: Zoning ordinances enacted under state enabling laws and home rule charters of municipalities are customarily entitled to a presumption that they were validly enacted, are within the powers delegated to the locality by the state, and are reasonable in effect. This presumption makes an exercise of the zoning power more easily defensible; one attacking the ordinance must show that it was passed incorrectly, or is beyond the scope of municipal authority, or is unreasonable, capricious or arbitrary in effect. Zoning officials have possessed this initial advantage in any litigation since the landmark decision of Village of Euclid v. Ambler Realty Co. in 1926. In this opinion, the first to uphold zoning in the United States Supreme Court, Justice Sutherland wrote for the majority

Biorhythms, deciduous enamel thickness, and primary bone growth in modern human children: a test of the Havers-Halberg Oscillation hypothesis

Across mammalian species, the periodicity with which enamel layers form (Retzius periodicity) in permanent teeth corresponds with average body mass and the pace of life history. According to the Havers-Halberg Oscillation hypothesis (HHO), Retzius periodicity (RP) is a manifestation of a biorhythm that is also expressed in lamellar bone. Potentially, these links provide a basis for investigating aspects of a species’ biology from fossilized teeth. Here, we tested intra-specific predictions of this hypothesis on skeletal samples of human juveniles. We measured daily enamel growth increments to calculate RP in deciduous molars (n=25). Correlations were sought between RP, molar average and relative enamel thickness (AET, RET), and the average amount of primary bone growth (n=7) in humeri of age-matched juveniles. Results show a previously un-described relationship between RP and enamel thickness. Reduced major axis regression reveals RP is significantly and positively correlated with AET and RET, and scales isometrically. The direction of the correlation was opposite to HHO predictions as currently understood for human adults. Juveniles with higher RPs and thicker enamel had increased primary bone formation, which suggests a coordinating biorhythm. However, the direction of the correspondence was again, opposite to predictions. Next, we compared RP from deciduous molars to new data for permanent molars, and to previously published values. The lowermost RP of four and five days in deciduous enamel extends below the lowermost RP of six days in permanent enamel. A lowered range of RP values in deciduous enamel implies that the underlying biorhythm might change with age. Our results develop the intra-specific HHO hypothesis

Data from: Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth

Administration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5 – 8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined

Data from: Differential changes in bone strength of two inbred mouse strains following administration of a sclerostin-neutralizing antibody during growth

Administration of sclerostin-neutralizing antibody (Scl-Ab) treatment has been shown to elicit an anabolic bone response in growing and adult mice. Prior work characterized the response of individual mouse strains but did not establish whether the impact of Scl-Ab on whole bone strength would vary across different inbred mouse strains. Herein, we tested the hypothesis that two inbred mouse strains (A/J and C57BL/6J (B6)) will show different whole bone strength outcomes following sclerostin-neutralizing antibody (Scl-Ab) treatment during growth (4.5 – 8.5 weeks of age). Treated B6 femurs showed a significantly greater stiffness (S) (68.8% vs. 46.0%) and maximum load (ML) (84.7% vs. 44.8%) compared to A/J. Although treated A/J and B6 femurs showed greater cortical area (Ct.Ar) similarly relative to their controls (37.7% in A/J and 41.1% in B6), the location of new bone deposition responsible for the greater mass differed between strains and may explain the greater whole bone strength observed in treated B6 mice. A/J femurs showed periosteal expansion and endocortical infilling, while B6 femurs showed periosteal expansion. Post-yield displacement (PYD) was smaller in treated A/J femurs (-61.2%, p < 0.001) resulting in greater brittleness compared to controls; an effect not present in B6 mice. Inter-strain differences in S, ML, and PYD led to divergent changes in work-to-fracture (Work). Work was 27.2% (p = 0.366) lower in treated A/J mice and 66.2% (p < 0.001) greater in treated B6 mice relative to controls. Our data confirmed the anabolic response to Scl-Ab shown by others, and provided evidence suggesting the mechanical benefits of Scl-Ab administration may be modulated by genetic background, with intrinsic growth patterns of these mice guiding the location of new bone deposition. Whether these differential outcomes will persist in adult and elderly mice remains to be determined

8-week-Old AJ and C57BL6J Morphologic, Mechanic, and Histomorphometric Raw Data

Please see Methods section of manuscript for trait abbreviations and measures from which raw values were derived