Systematic Evaluation of Skeletal Mechanical Function

Many genetic and environmental perturbations lead to measurable changes in bone morphology, matrix composition, and matrix organization. Here, straightforward biomechanical methods are described that can be used to determine whether a genetic or environmental perturbation affects bone strength. A systematic method is described for evaluating how bone strength is altered in the context of morphology and tissue‐level mechanical properties, which are determined in large part from matrix composition, matrix organization, and porosity. The methods described include computed tomography, whole‐bone mechanical tests (bending and compression), tissue‐level mechanical tests, and determination of ash content, water content, and bone density. This strategy is intended as a first step toward screening mice for phenotypic effects on bone and establishing the associated biomechanical mechanism by which function has been altered, and can be conducted without a background in engineering. The outcome of these analyses generally provides insight into the next set of experiments required to further connect cellular perturbation with functional change. Curr. Protoc. Mouse Biol. 3:39‐67 © 2013 by John Wiley & Sons, Inc.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/143805/1/cpmo130027.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

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

Topiramate for cocaine dependence during methadone maintenance treatment: A randomized controlled trial

BackgroundDual dependence on opiate and cocaine occurs in about 60% of patients admitted to methadone maintenance and negatively impacts prognosis (Kosten et al. 2003. Drug Alcohol Depend. 70, 315). Topiramate (TOP) is an antiepileptic drug that may have utility in the treatment of cocaine dependence because it enhances the GABAergic system, antagonizes the glutamatergic system, and has been identified by NIDA as one of only a few medications providing a "positive signal" warranting further clinical investigation. (Vocci and Ling, 2005. Pharmacol. Ther. 108, 94).MethodIn this double-blind controlled clinical trial, cocaine dependent methadone maintenance patients (N=171) were randomly assigned to one of four groups. Under a factorial design, participants received either TOP or placebo, and monetary voucher incentives that were either contingent (CM) or non-contingent (Non-CM) on drug abstinence. TOP participants were inducted onto TOP over 7 weeks, stabilized for 8 weeks at 300 mg daily then tapered over 3 weeks. Voucher incentives were supplied for 12 weeks, starting during the fourth week of TOP induction. Primary outcome measures were cocaine abstinence (Y/N) as measured by thrice weekly urinalysis and analyzed using Generalized Estimating Equations (GEE) and treatment retention. All analyses were intent to treat and included the 12-week evaluation phase of combined TOP/P treatment and voucher intervention period.ResultsThere was no significant difference in cocaine abstinence between the TOP vs. P conditions nor between the CM vs. Non-CM conditions. There was no significant TOP/CM interaction. Retention was not significantly different between the groups.ConclusionTopiramate is not efficacious for increasing cocaine abstinence in methadone patients