Publications by authors named "Karl J Jepsen"

95 Publications

The effect of age when initiating anti-seizure medication therapy on fragility fracture risk for children with epilepsy.

Bone 2021 Aug 5;149:115996. Epub 2021 May 5.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

Background: Anti-seizure medication (ASM) is necessary to manage epilepsy and often prescribed to children and adolescents, but can lead to iatrogenic effects, including bone fragility by altering bone metabolism. Disrupting bone metabolism during crucial developmental stages could have a lasting adverse effect on bone health. Therefore, the objective of this propensity score-matched, observational cohort study was to determine if age when initiating ASM therapy across developmental stages (from pre- to post-puberty) for individuals with epilepsy was associated with an increased risk of fragility fracture.

Methods: Data from 01/01/2011 to 12/31/2018 were extracted from Optum Clinformatics® Data Mart. Children aged 4-21 years at baseline with at least 5 years of continuous health plan enrollment were included to allow for a 1-year baseline and 4-years of follow-up. The primary group of interest included new ASM users (i.e., treatment naïve) with epilepsy. The comparison group, no ASM users without epilepsy, was matched 1:14 to new ASM users with epilepsy for demographics and baseline fracture. To provide a proxy for developmental stages, age was categorized as 4-6 (pre-puberty), 7-10 (early puberty), 11-13 (mid-puberty), 14-17 (late puberty), and 18-21 (post-puberty). Crude incidence rate (IR; per 1000 person years) and IR ratio (IRR and 95% confidence intervals [CI]) were estimated for non-trauma fracture (NTFx) for up to 4-years of follow-up.

Results: Prior to stratifying by age group, the crude NTFx IR (95% CI) of 20.6 (16.5-24.8) for new ASM users with epilepsy (n = 1205) was 34% higher (IRR = 1.34; 95% CI = 1.09-1.66) than the crude NTFx IR (95% CI) of 15.4 (14.4-16.3) for no ASM users without epilepsy. The groups exhibited a different pattern of NTFx incidence with age, with new ASM users showing a more dramatic increase and peaking at 11-13 years, then decreasing with the older age groups. The crude IR and IRR were elevated for new ASM users with epilepsy compared to no ASM users without epilepsy for each age group (10% to 55% higher), but was only statistically significant for 11-13 years (IRR = 1.55; 95% CI = 1.02-2.36).

Conclusions: Children with epilepsy initiating ASM therapy may be vulnerable to fragility fracture, especially when initiating ASM around the time of puberty. Clinicians should be aware of this age-related association and consider age-appropriate adjunct bone fragility therapies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2021.115996DOI Listing
August 2021

Presence of Neovascularization in Torn Plantar Plates of the Lesser Metatarsophalangeal Joints.

Foot Ankle Int 2021 Feb 9:1071100721990038. Epub 2021 Feb 9.

Department of Orthopaedic Surgery, University of Michigan Health System, Ann Arbor, MI, USA.

Background: Recent surgical techniques have focused on anatomic repair of lesser toe metatarsophalangeal (MTP) plantar plate tears, yet it remains unknown whether the plantar plate has the biological capacity to heal these repairs. Therefore, a better understanding of the plantar plate vasculature in response to injury may provide further insight into the potential for healing after anatomic plantar plate repair. Recently, a study demonstrated that the microvasculature of the normal plantar plate is densest at the proximal and distal attachments. The purpose of this study was to compare the intact plantar plate microvasculature network to the microvasculature network of plantar plates in the presence of toe deformity using similar perfusion and nano-computed tomographic (CT) imaging methods.

Methods: Seven fresh-frozen human cadaveric lower extremities with lesser toe deformities including hammertoe or crossover toe were perfused using a barium solution. The soft tissues of each foot were counterstained with phosphomolybdic acid (PMA). Then using nano-CT imaging, the second through fourth toe metatarsophalangeal joints of 7 feet were imaged. These images were then reconstructed, plantar plate tears were identified, and 11 toes remained. The plantar plate microvasculature for these 11 toes was analyzed, and calculation of vascular density along the plantar plate was performed. Using analysis of variance (ANOVA), this experimental group was compared to a control group of 35 toes from cadaveric feet without deformity and the vascular density compared between quartiles of plantar plate length proximal to distal. A power analysis was performed, determining that 11 experimental toes and 35 control toes would be adequate to provide 80% power with an alpha of 0.05.

Results: Significantly greater vascular density (vascular volume/tissue volume) was found along the entire length of the plantar plate for the torn plantar plates compared to intact plantar plates (ANOVA, < .001). For the first quartile of length (proximal to distal), the vascular density for the torn plantar plates was 0.365 (SD 0.058) compared to 0.281 (SD 0.036) for intact plantar plates; in the second quartile it was 0.300 (SD 0.044) vs 0.175 (SD 0.025); third quartile it was 0.326 (SD 0.051) vs 0.117 (SD 0.015); and fourth (most distal) quartile was 0.600 (SD 0.183) vs 0.319 (SD 0.082).

Conclusion: Torn plantar plates showed increased vascular density throughout the length of the plantar plate with an increase in density most notable in the region at or just proximal to the attachment to the proximal phalanx. Our analysis revealed that torn plantar plates exhibit neovascularization around the site of a plantar plate tear that does not exist in normal plantar plates.

Clinical Relevance: The clinical significance of the increased vascularity of torn plantar plates is unknown at this time. However, the increase in vasculature may suggest that the plantar plate is a structure that is attempting to heal.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1071100721990038DOI Listing
February 2021

The respiratory disease burden of non-traumatic fractures for adults with cerebral palsy.

Bone Rep 2020 Dec 27;13:100730. Epub 2020 Oct 27.

Department of Physical Medicine and Rehabilitation, University of Michigan, Ann Arbor, MI, USA.

Background: Individuals with cerebral palsy (CP) are vulnerable to non-trauma fracture (NTFx) and premature mortality due to respiratory disease (RD); however, very little is known about the contribution of NTFx to RD risk among adults with CP. The purpose of this study was to determine if NTFx is a risk factor for incident RD and if NTFx exacerbates RD risk in the adult CP population.

Methods: Data from 2011 to 2016 Optum Clinformatics® Data Mart and a random 20% sample Medicare fee-for-service were used for this retrospective cohort study. Diagnosis codes were used to identify adults (18+ years) with and without CP, NTFx, incident RD at 3-, 6-, 12-, and 24-month time points (pneumonia, chronic obstructive pulmonary disease, interstitial/pleura disease), and comorbidities. Crude incidence rates per 100 person years of RD were estimated. Cox regression estimated hazard ratios (HR and 95% confidence interval [CI]) for RD measures, comparing: (1) CP and NTFx (CP + NTFx); (2) CP without NTFx (CP w/o NTFx); (3) without CP and with NTFx (w/o CP + NTFx); and (4) without CP and without NTFx (w/o CP w/o NTFx) after adjusting for demographics and comorbidities.

Results: The crude incidence rate was elevated for CP + NTFx vs. CP w/o NTFx and w/o CP + NTFx for each RD measure. After adjustments, the HR was elevated for CP + NTFx vs. CP w/o NTFx for pneumonia and interstitial/pleura disease at all time points (all  < 0.05), but not chronic obstructive pulmonary disease (e.g., 24-month HR = 1.07; 95%CI = 0.88-1.31). The adjusted HR was elevated for CP + NTFx vs. w/o CP + NTFx for pneumonia at all time points, interstitial/pleura disease at 12- and 24-month time points, and chronic obstructive pulmonary disease at 24-months (all  < 0.05). There is evidence of a time-dependent effect of NTFx on pneumonia and interstitial/pleura disease for CP + NTFx as compared to CP w/o NTFx.

Conclusions: Study findings suggest that NTFx is a risk factor for incident RD, including pneumonia and interstitial/pleura disease, among adults with CP and that NTFx exacerbates RD risk for adults with vs. without CP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bonr.2020.100730DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645631PMC
December 2020

External bone size identifies different strength-decline trajectories for the male human femora.

J Struct Biol 2020 12 21;212(3):107650. Epub 2020 Oct 21.

Department of Biomedical Engineering, College of Engineering, University of Michigan, MI, USA; Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA. Electronic address:

Understanding skeletal aging and predicting fracture risk is increasingly important with a growing elderly population. We hypothesized that when categorized by external bone size, the male femoral diaphysis would show different strength-age trajectories which can be explained by changes in morphology, composition and collagen cross-linking. Cadaveric male femora were sorted into narrow (n = 15, 26-89 years) and wide (n = 15, 29-82 years) groups based upon total cross-sectional area of the mid-shaft normalized to bone length (Tt.Ar/Le) and tested for whole bone strength, tissue-level strength, and tissue-level post-yield strain. Morphology, cortical TMD (Ct.TMD), porosity, direct measurements of enzymatic collagen cross-links, and pentosidine were obtained. The wide group alone showed significant negative correlations with age for tissue-level strength (R = 0.50, p = 0.002), tissue-level post-yield strain (R = 0.75, p < 0.001) and borderline significance for whole bone strength (R = 0.14, p = 0.108). Ct.TMD correlated with whole bone and tissue-level strength for both groups, but pentosidine normalized to enzymatic cross-links correlated negatively with all mechanical properties for the wide group only. The multivariate analysis showed that just three traits for each mechanical property explained the majority of the variance for whole bone strength (Ct.Area, Ct.TMD, Log(PEN/Mature; R = 0.75), tissue-level strength (Age, Ct.TMD, Log(DHLNL/HLNL); R = 0.56), and post-yield strain (Age, Log(Pyrrole), Ct.Area; R = 0.51). Overall, this highlights how inter-individual differences in bone structure, composition, and strength change with aging and that a one-size fits all understanding of skeletal aging is insufficient.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jsb.2020.107650DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7744353PMC
December 2020

The mortality burden of non-trauma fracture for adults with cerebral palsy.

Bone Rep 2020 Dec 7;13:100725. Epub 2020 Oct 7.

Department of Orthopaedic Surgery, University of Michigan, 1540 E Hospital Dr., Ann Arbor, MI 48109, United States of America.

Background: Individuals with cerebral palsy (CP) manifest skeletal fragility problems early in life, are vulnerable to non-trauma fracture (NTFx), and have a high burden of premature mortality. No studies have examined the contribution of NTFx to mortality among adults with CP. The purpose of this study was to determine if NTFx is a risk factor for mortality among adults with CP and if NTFx exacerbates mortality risk compared to adults without CP.

Methods: Data from 2011 to 2016 Optum Clinformatics® Data Mart and a random 20% sample Medicare fee-for-service were used for this retrospective cohort study. Diagnosis codes were used to identify adults (18+ years) with and without CP, NTFx, and pre-NTFx comorbidities. Crude mortality rates per 100 person years were estimated. Cox regression estimated hazard ratios (HR and 95% confidence interval [CI]) for mortality, comparing: (1) CP and NTFx (CP + NTFx;  = 1777); (2) CP without NTFx (CP w/o NTFx;  = 12,933); (3) without CP and with NTFx (w/o CP + NTFx;  = 433,560); and (4) without CP and without NTFx (w/o CP w/o NTFx;  = 6.8 M) after adjusting for demographics and pre-NTFx comorbidities.

Results: The 3-, 6-, and 12-month crude mortality rates were highest among CP + NTFx (12-month mortality rate = 6.80), followed by w/o CP + NTFx (12-month mortality rate = 4.91), CP w/o NTFx (12-month mortality rate = 2.15), and w/o CP w/o NTFx (12-month mortality rate = 0.49). After adjustments, the mortality rate was elevated for CP + NTFx for all time points compared to CP w/o NTFx (e.g., 12-month HR = 1.61; 95%CI = 1.29-2.01), w/o CP + NTFx (e.g., 12-month HR = 1.49; 95%CI = 1.24-1.80), and w/o CP w/o NTFx (e.g., 12-month HR = 5.33; 95%CI = 4.42-6.44). There were site-specific effects (vertebral column, lower extremities) on 12-month mortality.

Conclusions: NTFx is associated with an increase of 12-month mortality risk among adults with CP and compared to adults without CP. Findings suggest that NTFx may be a robust risk factor for mortality among adults with CP.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bonr.2020.100725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7560646PMC
December 2020

Loss of BMP signaling mediated by BMPR1A in osteoblasts leads to differential bone phenotypes in mice depending on anatomical location of the bones.

Bone 2020 08 1;137:115402. Epub 2020 May 1.

Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, MI, USA. Electronic address:

Bone morphogenetic protein (BMP) signaling in osteoblasts plays critical roles in skeletal development and bone homeostasis. Our previous studies showed loss of function of BMPR1A, one of the type 1 receptors for BMPs, in osteoblasts results in increased trabecular bone mass in long bones due to an imbalance between bone formation and bone resorption. Decreased bone resorption was associated with an increased mature-to-immature collagen cross-link ratio and mineral-matrix ratios in the trabecular compartments, and increased tissue-level biomechanical properties. Here, we investigated the bone mass, bone composition and biomechanical properties of ribs and spines in the same genetically altered mouse line to compare outcomes by loss of BMPR1A functions in bones from different anatomic sites and developmental origins. Bone mass was significantly increased in both cortical and trabecular compartments of ribs with minimal to modest changes in compositions. While tissue-levels of biomechanical properties were not changed between control and mutant animals, whole bone levels of biomechanical properties were significantly increased in association with increased bone mass in the mutant ribs. For spines, mutant bones showed increased bone mass in both cortical and trabecular compartments with an increase of mineral content. These results emphasize the differential role of BMP signaling in osteoblasts in bones depending on their anatomical locations, functional loading requirements and developmental origin.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2020.115402DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7354232PMC
August 2020

Low-Trauma Fracture Increases 12-Month Incidence of Cardiovascular Disease for Adults With Cerebral Palsy.

J Orthop Res 2020 04 11;38(4):803-810. Epub 2019 Nov 11.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan.

Individuals with cerebral palsy (CP) have poor skeletal and cardiovascular health. However, no studies have examined if skeletal fragility enhances cardiovascular disease (CVD) risk for this population. The purpose of this study was to determine whether adults with CP have higher 12-month CVD incidence following a low-trauma fracture compared with adults without CP. Data, from the Optum Clinformatics® Data Mart, were extracted from adults (18+ years) that sustained a low-trauma fracture between 01/01/2012 and 12/31/2016. The primary outcome measure was incident CVD within 12 months following a low-trauma fracture. Cox proportional hazards regression models were used to compare 12-month incident CVD with adjustment for sociodemographics and chronic disease comorbidities. Mean age (SD) at baseline was 54.7 (18.9) for adults with CP (n = 1,025, 43.3% men) and 60.4 (19.7) for adults without CP (n = 460,504, 33.7% men). During the follow-up, 121 adults with CP (11.8%, mean age [SD] = 63.9 [16.3]) and 45,330 adults without CP (9.8%, mean age [SD] = 74.5 [11.9]) developed CVD. In the fully adjusted model, adults with CP had higher 12-month post-fracture CVD incidence (hazard ratio [HR] = 1.63; 95% confidence interval [CI] = 1.37-1.95). When the outcome was stratified by CVD subtype, adults with CP had higher 12-month post-fracture incidence of ischemic heart disease (HR = 1.45; 95% CI = 1.09-1.92), heart failure (HR = 1.68; 95% CI = 1.22-2.31), and cerebrovascular disease (HR = 1.96; 95% CI = 1.54-2.50). Study findings suggest that among adults with CP, low-trauma fracture may enhance 12-month CVD incidence compared with adults without CP. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:803-810, 2020.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jor.24515DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065336PMC
April 2020

Elevated fracture risk for adults with neurodevelopmental disabilities.

Bone 2020 01 24;130:115080. Epub 2019 Oct 24.

Department of Physical Medicine and Rehabilitation, University of Michigan, 325 E. Eisenhower, Ann Arbor, MI 48108, USA; Institute for Healthcare Policy and Innovation, University of Michigan, 2800 Plymouth Rd., Ann Arbor, MI 48109, USA.

Background: Fracture is a high-burden condition that accelerates unhealthful aging and represents a considerable economic burden. Adults with neurodevelopmental disabilities (NDDs) may be susceptible for fracture at younger ages compared to adults without NDDs; and yet, very little is known about the burden of fracture for these underserved populations. The purpose of this study was to determine the sex-stratified prevalence of all-cause fracture among adults with NDDs, as compared to adults without NDDs, and if comorbidity of NDDs is associated with greater risk of fracture.

Methods: Data from 2016 were extracted from Optum Clinformatics® Data Mart (private insurance) and a random 20% sample from Medicare fee-for-service (public insurance). ICD-10-CM diagnosis codes were used to identify adults with NDDs, including intellectual disabilities, autism spectrum disorders, and cerebral palsy. Age-standardized prevalence of any fracture and fracture by anatomical location was compared between adults with and without NDDs, and then for adults with 1 NDD vs. 2 and 3 NDDs.

Results: Adults with intellectual disabilities (n=69,456), autism spectrum disorders (n=21,844), and cerebral palsy (n=29,255) had a higher prevalence of any fracture compared to adults without NDDs (n=8.7 million). For women, it was 8.3%, 8.1%, and 8.5% vs. 3.5%, respectively. For men, it was 6.6%, 5.9%, and 6.7% vs. 3.0%, respectively. Women with NDDs had a higher prevalence of fracture of the head/neck, thoracic, lumbar/pelvis, upper extremities, and lower extremities compared to women without NDDs. A similar pattern was observed for men, except for no difference for lumbar/pelvis for all NDDs and thoracic for autism spectrum disorders. For women and men, increasing comorbidity of NDDs was associated with a higher prevalence of any fracture: 1 NDD (women, 7.7%; men, 5.7%); 2 NDDs (women, 9.4%; men, 7.2%); all 3 NDDs (women, 11.3%; men, 13.7%).

Conclusions: Study findings suggest that adults with NDDs have an elevated prevalence of fracture compared to adults without NDDs, with the fracture risk being higher with greater numbers of comorbid NDD conditions for most anatomical locations. Our study findings indicate a need for earlier screening and preventive services for musculoskeletal frailty for adults with NDDs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2019.115080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065344PMC
January 2020

The effect of low-trauma fracture on one-year mortality rate among privately insured adults with and without neurodevelopmental disabilities.

Bone 2019 12 5;129:115060. Epub 2019 Sep 5.

Department of Orthopaedic Surgery, University of Michigan, 1540 E Hospital Dr., Ann Arbor, MI 48109, United States of America.

Background: Individuals with neurodevelopmental disabilities (NDDs) have poor development and preservation of skeletal health throughout the lifespan, and are especially vulnerable to low-trauma fracture and post-fracture health complications. However, no studies have examined if adults with NDDs have greater post-fracture mortality risk compared to adults without NDDs. The purpose of this study was to determine whether adults with NDDs have greater 12-month mortality rates following a low-trauma fracture compared to adults without NDDs.

Methods: Data from 2011 to 2017 was leveraged from Optum Clinformatics® Data Mart; a nationwide claims database from a single private payer in the U.S. Data were extracted from adults (18+ years) with and without NDDs that sustained a low-trauma fracture between 01/01/2012-12/31/2016, as well as pre-fracture chronic diseases (i.e., cardiovascular diseases, cerebrovascular diseases, diabetes, chronic obstructive pulmonary diseases, cancer). Mortality rate was estimated for adults with and without NDDs, and the mortality rate ratio (RR) and 95% confidence interval (CI) was calculated. Cox regression was used to estimate hazard ratio (HR) and 95% CI for 1-, 3-, 6-, and 12-month post-fracture mortality rates between adults with and without NDDs after adjusting for age, sex, race, U.S. region, and pre-fracture chronic diseases.

Results: Mean age (SD) at baseline was 56.7 (20.6) for adults with NDDs (n = 3749; 45.2% men) and 63.9 (19.2) for adults without NDDs (n = 585,910; 34.4% men). During the 12-month follow-up period, 182 adults with NDDs (mean age [SD] = 69.8 [14.7]; 46.2% men) and 25,456 adults without NDDs (mean age [SD] = 78.9 [9.8]; 38.3% men) died. Crude mortality rate was not different between adults with and without NDDs for any time points (e.g., 12-months: 5.40 vs. 4.96 per 100 person years; RR = 1.09; 95% CI = 0.94-1.26); however, it was greater for adults with intellectual disabilities compared to adults without NDDs (RR = 1.46; 95% CI = 1.23-1.79). After adjustments, adults with NDDs had greater post-fracture mortality rates for 3-, 6-, and 12-month time points (e.g., 12-months: HR = 1.46; 95% CI = 1.27-1.69). When stratified by the type of NDD, adults with intellectual disabilities and adults with autism spectrum disorders, but not adults with cerebral palsy, had greater 12-month post-fracture mortality risk. When stratified by fracture location, lower extremities were associated with greater crude mortality rate (RR = 1.69; 95% CI = 1.22-2.35) and adjusted mortality risk (HR = 2.41; 95% CI = 1.73-3.35), while upper extremities were associated with greater adjusted mortality risk (HR = 1.76; 95% CI = 1.23-2.50) for adults with vs. without NDDs.

Conclusions: Among privately insured adults with NDDs, low-trauma fracture is associated with greater mortality risk within 1 year of the fracture event, even after adjusting for pre-fracture chronic diseases. Study findings suggest the need for earlier fracture prevention strategies and improved post-fracture healthcare management.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bone.2019.115060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065338PMC
December 2019

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

PLoS One 2019 4;14(4):e0214520. Epub 2019 Apr 4.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan, United States of America.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0214520PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6448823PMC
December 2019

Strain-specific differences in the development of bone loss and incidence of osteonecrosis following glucocorticoid treatment in two different mouse strains.

J Orthop Translat 2019 Jan 27;16:91-101. Epub 2018 Jul 27.

Center for Musculoskeletal Health, Department of Internal Medicine, University of California Davis Medical Center, Sacramento, CA, United States.

Objective: Glucocorticoids (GCs) are commonly prescribed as treatment for chronic inflammatory diseases. Prolonged use of GCs is a common cause of atraumatic osteonecrosis (ON) and secondary osteoporosis. Currently, there is no effective treatment for this disease; therefore, a reliable animal model would be useful to study both the pathology and novel treatment strategies for patients with the disease. The aim of this study was to establish a validated, reproducible model of GC-induced ON and bone loss in two different mouse strains (BALB/c and C57BL/6).

Methods: Seven-week-old male BALB/c ( = 32) and male C57BL/6 mice ( = 32) were randomised into placebo or GC groups and treated with daily 4 mg/L oral dexamethasone in drinking water for 90 days. Study outcome measures included histologic assessment of ON of the distal femur, bone mass and mechanical strength of tibia and lumbar vertebral body, osteoclast number, biochemical measure of bone formation and bone marrow fat quantitation.

Results: GC-induced ON lesions were observed in the distal femur in 47% of the male BALB/c mice and 25% of the male C57BL/6 mice. GC treatment decreased the trabecular bone volume and serum pro-collagen type 1N-protease (P1NP) in BALB/c mice compared with the placebo ( < 0.05) and reduced tibial bone strength in both BALB/c and C57BL/6 mice. GC-treated BALB/c mice had significantly greater marrow fat levels compared to the placebo group.

Conclusion: GC-induced ON was more prevalent in the male BALB/c mice compared to the male C57BL/6 mice. GC treatment significantly reduced bone mass, bone formation measured by P1NP, bone strength and increased marrow fat levels in male BALB/c mice. Therefore, the use of male BALB/c mice strain is recommended for both diagnostic and therapeutic studies for the prevention and treatment of ON and bone loss following prolonged treatment with GCs.

The Translational Potential Of This Article: GCs are commonly used to treat patients with various chronic inflammatory diseases, and this is associated with both the development of ON and bone loss. Our study confirmed that the BALB/c mouse strain treated for 90 days with GC may be useful for developing novel treatments for ON.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jot.2018.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6350024PMC
January 2019

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

J Bone Miner Res 2019 05 4;34(5):825-837. Epub 2019 Feb 4.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

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 (R = 0.565, p = 0.001), but not narrow (R = 0.0004, p = 0.944) subgroup showed a significant negative correlation between strength and age. Significant positive correlations between age and robustness (R = 0.269, p = 0.048), cortical area (Ct.Ar; R = 0.356, p = 0.019), and the mineral/matrix ratio (MMR; R = 0.293, p = 0.037) were observed for narrow, but not wide radii (robustness: R = 0.015, p = 0.217; Ct.Ar: R = 0.095, p = 0.245; MMR: R = 0.086, p = 0.271). Porosity increased with age for the narrow (R = 0.556, p = 0.001) and wide (R = 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536328PMC
May 2019

Microvasculature of the Plantar Plate Using Nano-Computed Tomography.

Foot Ankle Int 2019 Apr 19;40(4):457-464. Epub 2018 Dec 19.

1 Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

Background:: Lesser toe plantar plate attenuation or disruption is being increasingly implicated in a variety of common clinical conditions. A multitude of surgical techniques and devices have been recently developed to facilitate surgical repair of the plantar plate. However, the microvascular anatomy, and therefore the healing potential in large part, has not been defined. We investigated the microvasculature of the plantar plate by employing a novel technique involving microvascular perfusion and nano-computed tomography (nano-CT) imaging.

Methods:: Twelve human adult cadaveric lower extremities were amputated distal to the knee. The anterior and posterior tibial arteries were perfused with a barium solution. The soft tissues of each foot were then counterstained with phosphomolybdic acid (PMA). The second through fourth toe metatarsophalangeal (MTP) joints of 12 feet were imaged with nano-CT at 14-micron resolution. Images were then reconstructed for analysis of the plantar plate microvasculature and calculation of the vascular density along the length of the plantar plate.

Results:: A microvascular network extends from the surrounding soft tissues at the attachments of the plantar plate on both the metatarsal and proximal phalanx. The midsubstance of the plantar plate appears to be relatively hypovascular. Analysis of the vascular density along the length of the plantar plate demonstrated a consistent trend with increased vascular density at approximately the proximal 29% and distal 22% of the plantar plate.

Conclusion:: There is a vascular network extending from the surrounding soft tissues into the proximal and distal attachments of the plantar plate.

Clinical Relevance:: The hypovascular midportion of the plantar plate may play an important role in the underlying pathoanatomy and pathophysiology of this area. These findings may have significant clinical implications for the reparative potential of this region and the surgical procedures currently described to accomplish anatomic plantar plate repair.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1177/1071100718816292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443423PMC
April 2019

The relationship between whole bone stiffness and strength is age and sex dependent.

J Biomech 2019 01 26;83:125-133. Epub 2018 Nov 26.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Accurately estimating whole bone strength is critical for identifying individuals that may benefit from prophylactic treatments aimed at reducing fracture risk. Strength is often estimated from stiffness, but it is not known whether the relationship between stiffness and strength varies with age and sex. Cadaveric proximal femurs (44 Male: 18-78 years; 40 Female: 24-95 years) and radial (36 Male: 18-89 years; 19 Female: 24-95 years) and femoral diaphyses (34 Male: 18-89 years; 19 Female: 24-95 years) were loaded to failure to evaluate how the stiffness-strength relationship varies with age and sex. Strength correlated significantly with stiffness at all sites and for both sexes, as expected. However, females exhibited significantly less strength for the proximal femur (58% difference, p < 0.001). Multivariate regressions revealed that stiffness, age and PYD were significant negative independent predictors of strength for the proximal femur (Age: M: p = 0.005, F: p < 0.001, PYD: M: p = 0.022, F: p = 0.025), radial diaphysis (Age: M = 0.055, PYD: F = 0.024), and femoral diaphysis (Age: M: p = 0.014, F: p = 0.097, PYD: M: p = 0.003, F: p = 0.091). These results indicated that older bones tended to be significantly weaker for a given stiffness than younger bones. These results suggested that human bones exhibit diminishing strength relative to stiffness with aging and with decreasing PYD. Incorporating these age- and sex-specific factors may help to improve the accuracy of strength estimates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jbiomech.2018.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338331PMC
January 2019

Differential Adaptive Response of Growing Bones From Two Female Inbred Mouse Strains to Voluntary Cage-Wheel Running.

JBMR Plus 2018 May 12;2(3):143-153. Epub 2018 Feb 12.

Department of Orthopaedic Surgery University of Michigan Ann Arbor MI USA.

The phenotypic response of bones differing in morphological, compositional, and mechanical traits to an increase in loading during growth is not well understood. We tested whether bones of two inbred mouse strains that assemble differing sets of traits to achieve mechanical homeostasis at adulthood would show divergent responses to voluntary cage-wheel running. Female A/J and C57BL6/J (B6) 4-week-old mice were provided unrestricted access to a standard cage-wheel for 4 weeks. A/J mice have narrow and highly mineralized femora and B6 mice have wide and less mineralized femora. Both strains averaged 2 to 9.5 km of running per day, with the average-distance run between strains not significantly different (= 0.133). Exercised A/J femora showed an anabolic response to exercise with the diaphyses showing a 2.8% greater total area (Tt.Ar,  = 0.06) and 4.7% greater cortical area (Ct.Ar,  = 0.012) compared to controls. In contrast, exercised B6 femora showed a 6.2% ( < 0.001) decrease in Tt.Ar ( < 0.001) and a 6.7% decrease in Ct.Ar (= 0.133) compared to controls, with the femora showing significant marrow infilling (= 0.002). These divergent morphological responses to exercise, which did not depend on the daily distance run, translated to a 7.9% (= 0.001) higher maximum load (ML) for exercised A/J femora but no change in ML for exercised B6 femora compared to controls. A consistent response was observed for the humeri but not the vertebral bodies. This differential outcome to exercise has not been previously observed in isolated loading or forced treadmill running regimes. Our findings suggest there are critical factors involved in the metabolic response to exercise during growth that require further consideration to understand how genotype, exercise, bone morphology, and whole-bone strength interact during growth. © 2018 The Authors. is published by Wiley Periodicals, Inc. on behalf of the American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbm4.10032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6124195PMC
May 2018

The challenges of diagnosing osteoporosis and the limitations of currently available tools.

Clin Diabetes Endocrinol 2018 29;4:12. Epub 2018 May 29.

1Division of Metabolism, Endocrinology & Diabetes, Department of Internal Medicine, University of Michigan, Ann Arbor, MI USA.

Dual-energy X-ray absorptiometry (DXA) was the first imaging tool widely utilized by clinicians to assess fracture risk, especially in postmenopausal women. The development of DXA nearly coincided with the availability of effective osteoporosis medications. Although osteoporosis in adults is diagnosed based on a T-score equal to or below - 2.5 SD, most individuals who sustain fragility fractures are above this arbitrary cutoff. This incongruity poses a challenge to clinicians to identify patients who may benefit from osteoporosis treatments. DXA scanners generate 2 dimensional images of complex 3 dimensional structures, and report bone density as the quotient of the bone mineral content divided by the bone area. An obvious pitfall of this method is that a larger bone will convey superior strength, but may in fact have the same bone density as a smaller bone. Other imaging modalities are available such as peripheral quantitative CT, but are largely research tools. Current osteoporosis medications increase bone density and reduce fracture risk but the mechanisms of these actions vary. Anti-resorptive medications (bisphosphonates and denosumab) primarily increase endocortical bone by bolstering mineralization of endosteal resorption pits and thereby increase cortical thickness and reduce cortical porosity. Anabolic medications (teriparatide and abaloparatide) increase the periosteal and endosteal perimeters without large changes in cortical thickness resulting in a larger more structurally sound bone. Because of the differences in the mechanisms of the various drugs, there are likely benefits of selecting a treatment based on a patient's unique bone structure and pattern of bone loss. This review retreats to basic principles in order to advance clinical management of fragility fractures by examining how skeletal biomechanics, size, shape, and ultra-structural properties are the ultimate predictors of bone strength. Accurate measurement of these skeletal parameters through the development of better imaging scanners is critical to advancing fracture risk assessment and informing clinicians on the best treatment strategy. With this information, a "treat to target" approach could be employed to tailor current and future therapies to each patient's unique skeletal characteristics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40842-018-0062-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5975657PMC
May 2018

Endocrine-disrupting chemicals, epigenetics, and skeletal system dysfunction: exploration of links using bisphenol A as a model system.

Environ Epigenet 2018 Apr 26;4(2):dvy002. Epub 2018 Apr 26.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI 48109, USA.

Early life exposures to endocrine-disrupting chemicals (EDCs) have been associated with physiological changes of endocrine-sensitive tissues throughout postnatal life. Although hormones play a critical role in skeletal growth and maintenance, the effects of prenatal EDC exposure on adult bone health are not well understood. Moreover, studies assessing skeletal changes across multiple generations are limited. In this article, we present previously unpublished data demonstrating dose-, sex-, and generation-specific changes in bone morphology and function in adult mice developmentally exposed to the model estrogenic EDC bisphenol A (BPA) at doses of 10 μg (lower dose) or 10 mg per kg bw/d (upper dose) throughout gestation and lactation. We show that F1 generation adult males, but not females, developmentally exposed to bisphenol A exhibit dose-dependent reductions in outer bone size resulting in compromised bone stiffness and strength. These structural alterations and weaker bone phenotypes in the F1 generation did not persist in the F2 generation. Instead, F2 generation males exhibited greater bone strength. The underlying mechanisms driving the EDC-induced physiological changes remain to be determined. We discuss potential molecular changes that could contribute to the EDC-induced skeletal effects, with an emphasis on epigenetic dysregulation. Furthermore, we assess the necessity of intact sex steroid receptors to mediate these effects. Expanding future assessments of EDC-induced effects to the skeleton may provide much needed insight into one of the many health effects of these chemicals and aid in regulatory decision making regarding exposure of vulnerable populations to these chemicals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/eep/dvy002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5920333PMC
April 2018

Bone robusticity in two distinct skeletal dysplasias diverges from established patterns.

J Orthop Res 2017 11 4;35(11):2392-2396. Epub 2017 May 4.

Hospital for Special Surgery, 535 East 70th Street, New York, New York, 10021.

Achondroplasia (ACH) is a heritable disorder of endochondral bone formation characterized by disproportionate short stature. Osteogenesis imperfecta (OI) is a heritable bone and connective tissue disorder characterized by bone fragility. To investigate bone morphology of these groups, we retrospectively reviewed 169 de-identified bone age films from 20 individuals with ACH, 39 individuals with OI and 37 age- and sex-matched controls (matched to historical measurements from the Bolton-Brush Collection). We calculated robustness (Tt.Ar/Le) and relative cortical area (Ct.Ar/Tt.Ar) from measurements of the second metacarpal, which reflect overall bone health. Relative cortical area (RCA) is a significant predictor of fracture risk and correlates with robustness at other sites. Individuals with OI had RCH values above and robustness values below that of the control population. Bisphosphonate treatment did not significantly impact either robustness or RCA. In contrast to that reported in the unaffected population, there was no sexual dimorphism found in OI robustness or relative cortical area. We suggest that the underlying collagen abnormalities in OI override sex-specific effects. Individuals with ACH had robustness values above and RCA values below that of the control population. Sexual dimorphism was found in ACH robustness and RCH values.

Clinical Significance: Identifies morphologic trends in two distinct skeletal dysplasia populations (OI and ACH) to better understand development of bone robusticity and slenderness in humans. Understanding these patterns of bone morphology is important to predict how individuals will respond to treatment and to increase treatment effect. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2392-2396, 2017.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jor.23543DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7368882PMC
November 2017

Canalization Leads to Similar Whole Bone Mechanical Function at Maturity in Two Inbred Strains of Mice.

J Bone Miner Res 2017 May 27;32(5):1002-1013. Epub 2017 Feb 27.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, MI, USA.

Previously, we showed that cortical mineralization is coordinately adjusted to mechanically offset external bone size differences between A/J (narrow) and C57BL/6J (wide) mouse femora to achieve whole bone strength equivalence at adulthood. The identity of the genes and their interactions that are responsible for establishing this homeostatic state (ie, canalization) remain unknown. We hypothesize that these inbred strains, whose interindividual differences in bone structure and material properties mimic that observed among humans, achieve functional homeostasis by differentially adjusting key molecular pathways regulating external bone size and mineralization throughout growth. The cortices of A/J and C57BL/6J male mouse femora were phenotyped and gene expression levels were assessed across growth (ie, ages 2, 4, 6, 8, 12, 16 weeks). A difference in total cross-sectional area (p < 0.01) and cortical tissue mineral density were apparent between mouse strains by age 2 weeks and maintained at adulthood (p < 0.01). These phenotypic dissimilarities corresponded to gene expression level differences among key regulatory pathways throughout growth. A/J mice had a 1.55- to 7.65-fold greater expression among genes inhibitory to Wnt pathway induction, whereas genes involved in cortical mineralization were largely upregulated 1.50- to 3.77-fold to compensate for their narrow diaphysis. Additionally, both mouse strains showed an upregulation among Wnt pathway antagonists corresponding to the onset of adult ambulation (ie, increased physiological loads). This contrasts with other studies showing an increase in Wnt pathway activation after functionally isolated, experimental in vivo loading regimens. A/J and C57BL/6J long bones provide a model to develop a systems-based approach to identify individual genes and the gene-gene interactions that contribute to trait differences between the strains while being involved in the process by which these traits are coordinately adjusted to establish similar levels of mechanical function, thus providing insight into the process of canalization. © 2017 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413428PMC
May 2017

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

J Bone Miner Res 2017 Jun 30;32(6):1218-1228. Epub 2017 Jan 30.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

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 age-related changes in bone traits also depend on external bone size. We analyzed hip dual-energy X-ray absorptiometry images acquired longitudinally over 14 years for 198 midlife women transitioning through menopause. The 14-year change in bone mineral content (BMC, R  = 0.03, p = 0.015) and bone area (R  = 0.13, p = 0.001), but not areal bone mineral density (aBMD, R  = 0.00, p = 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 14-year changes in BMC and bone area on baseline bone area remained significant after adjusting for race/ethnicity, postmenopausal hormone use, the 14-year change in weight, and baseline aBMD, weight, height, and age. Women were sorted into tertiles using the baseline bone area-height residuals. The 14-year change in BMC (p = 0.009) and bone area (p = 0.001) but not aBMD (p = 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 strength-decline trajectories remains to be determined. © 2017 American Society for Bone and Mineral Research.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.3082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5466474PMC
June 2017

Spontaneous destructive periodontitis and skeletal bone damage in transgenic mice carrying a human shared epitope-coding allele.

RMD Open 2016 1;2(2):e000349. Epub 2016 Dec 1.

Departments of Internal Medicine , University of Michigan , Ann Arbor, Michigan , USA.

Objective: Shared epitope (SE)-coding alleles are associated with bone erosion in several diseases, including rheumatoid arthritis (RA) and periodontal disease (PD), but the underlying mechanism is unknown. We have recently identified the SE as an osteoclast-activating ligand. To better understand the biological effects of the SE in vivo, here we sought to determine whether it can facilitate spontaneous bone damage in naïve mice.

Methods: 3-month old naïve transgenic mice that carry the human SE-coding allele , or a SE-negative allele were studied Bone tissues were analysed by micro-CT, and the tooth-supporting tissues were studied by histology, immunohistochemistry and immunofluorescence. Serum biomarkers were determined by ELISA.

Results: Transgenic mice expressing the SE-coding 01 allele, but not mice carrying the SE-negative allele , showed spontaneous PD associated with interleukin (IL)-17 overabundance and periostin disruption. Mandibular bone volumetric and mineralisation parameters were significantly lower in SE-positive mice, and alveolar bone resorption was significantly increased in these mice. SE-positive mice also had more slender tibiae, and their marrow, cortical and total areas were lower than those of SE-negative mice. Additionally, significantly increased serum IL-17, tumour necrosis factor-α and osteoprotegrin levels were found in SE-positive mice, while their receptor activator of nuclear factor κ-B ligand levels were significantly lower.

Conclusions: A human SE-coding allele increases the propensity to spontaneous bone-destructive periodontal inflammation and skeletal bone damage in transgenic mice. These findings provide new insights into the previously documented but poorly understood association of the SE with accelerated bone erosion in RA and several other human diseases.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/rmdopen-2016-000349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5133411PMC
December 2016

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

Womens Midlife Health 2016;2. Epub 2016 Mar 7.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI 48109-2029, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s40695-016-0016-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5035036PMC
March 2016

Bone structure and function in male C57BL/6 mice: Effects of a high-fat Western-style diet with or without trace minerals.

Bone Rep 2016 Dec;5:141-149

Department of Pathology, The University of Michigan, Ann Arbor, Michigan 48109.

Purpose: Osteoporosis occurs in both women and men, but most of what we know about the condition comes from studies in females. The present study examined bone structure and function over an 18-month period in male C57BL/6 mice maintained on either a rodent chow diet (AIN76A) or a high-fat, Western-style diet (HFWD). Effects of mineral supplementation were assessed in both diets.

Methods: Trabecular and cortical bone structure in femora and vertebrae were assessed by micro-CT analysis. Following this, bone stiffness and strength measurements were made. Finally, bone levels of several cationic trace elements were quantified, and serum biomarkers of bone metabolism evaluated.

Results: Bone loss occurred over time in both diets but was more rapid and extensive in mice on the HFWD. Dietary mineral supplementation reduced bone loss in both diets and increased bone stiffness in the femora and bone stiffness and strength in the vertebrae. Bone content of strontium was increased in response to mineral supplementation in both diets.

Conclusions: Bone loss was more severe in mice on the HFWD and mineral supplementation mitigated the effects of the HFWD. In comparison to previous findings with female C57BL/6 mice, the present studies indicate that males are more sensitive to diet and benefited from a healthy diet (AIN76A), while females lost as much bone on the healthy diet as on the HFWD. Male mice benefited from mineral supplementation, just as females did in the previous study.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bonr.2016.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4920365PMC
December 2016

Patterns of strain and the determination of the safe arc of motion after subscapularis repair--A biomechanical study.

J Orthop Res 2016 Mar 18;34(3):518-24. Epub 2015 Sep 18.

Department of Orthopaedic Surgery, University of Michigan, Ann Arbor, Michigan.

This study characterizes the strain patterns and safe arcs for passive range of motion (ROM) in the superior and inferior subscapularis tendon in seven cadaveric shoulders, mounted for controlled ROM, after deltopectoral approach to the glenohumeral joint, including tenotomy of the subscapularis tendon 1 cm medial to its insertion on the lesser tuberosity. The tenotomy was repaired with end-to-end suture in neutral rotation. Strain patterns were measured during passive ROM in external rotation (ER), ER with 30° abduction (ER+30), abduction, and forward flexion in the scapular plane (SP) before and after surgery. Percentages were calculated from 35 trials corresponding to five trials of each motion across seven specimens. With ER of 0-30°, 89% of trials of superior subscapularis tendon and 100% of trials of inferior subscapularis tendon achieved strains >3%, with very similar patterns noted in ER+30. In abduction of 0-90°, 5.8% of trials of superior and 85.3% of trials of inferior tendon achieved >3% strain. With passive ROM in SP, 26.5% of trials reached 3% strain in superior tendon compared to 100% in inferior tendon. Strain patterns in abduction and SP differed significantly (p < 0.001). Selective tenotomy and repair of the superior subscapularis tendon with open reparative or reconstructive shoulder procedures, when feasible, may be favorable for protected early passive ROM and rehabilitation postoperatively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jor.23045DOI Listing
March 2016

Region-specific variation in the properties of skeletal adipocytes reveals regulated and constitutive marrow adipose tissues.

Nat Commun 2015 Aug 6;6:7808. Epub 2015 Aug 6.

Departments of Molecular and Integrative Physiology and Internal Medicine, University of Michigan, Ann Arbor, Michigan 48105, USA.

Marrow adipose tissue (MAT) accumulates in diverse clinical conditions but remains poorly understood. Here we show region-specific variation in MAT adipocyte development, regulation, size, lipid composition, gene expression and genetic determinants. Early MAT formation in mice is conserved, whereas later development is strain dependent. Proximal, but not distal tibial, MAT is lost with 21-day cold exposure. Rat MAT adipocytes from distal sites have an increased proportion of monounsaturated fatty acids and expression of Scd1/Scd2, Cebpa and Cebpb. Humans also have increased distal marrow fat unsaturation. We define proximal 'regulated' MAT (rMAT) as single adipocytes interspersed with active haematopoiesis, whereas distal 'constitutive' MAT (cMAT) has low haematopoiesis, contains larger adipocytes, develops earlier and remains preserved upon systemic challenges. Loss of rMAT occurs in mice with congenital generalized lipodystrophy type 4, whereas both rMAT and cMAT are preserved in mice with congenital generalized lipodystrophy type 3. Consideration of these MAT subpopulations may be important for future studies linking MAT to bone biology, haematopoiesis and whole-body metabolism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/ncomms8808DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4530473PMC
August 2015

Editorial Comment: Symposium: Sex Differences in Musculoskeletal Disease and Science.

Clin Orthop Relat Res 2015 Aug;473(8):2474-8

Department of Orthopedic Surgery, University of Michigan, Ann Arbor, MI, USA.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11999-015-4368-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488225PMC
August 2015

Establishing biomechanical mechanisms in mouse models: practical guidelines for systematically evaluating phenotypic changes in the diaphyses of long bones.

J Bone Miner Res 2015 Jun;30(6):951-66

Department of Biomedical Engineering and Sibley School of Mechanical & Aerospace Engineering, Cornell University, Ithaca, NY, USA.

Mice are widely used in studies of skeletal biology, and assessment of their bones by mechanical testing is a critical step when evaluating the functional effects of an experimental perturbation. For example, a gene knockout may target a pathway important in bone formation and result in a "low bone mass" phenotype. But how well does the skeleton bear functional loads; eg, how much do bones deform during loading and how resistant are bones to fracture? By systematic evaluation of bone morphological, densitometric, and mechanical properties, investigators can establish the "biomechanical mechanisms" whereby an experimental perturbation alters whole-bone mechanical function. The goal of this review is to clarify these biomechanical mechanisms and to make recommendations for systematically evaluating phenotypic changes in mouse bones, with a focus on long-bone diaphyses and cortical bone. Further, minimum reportable standards for testing conditions and outcome variables are suggested that will improve the comparison of data across studies. Basic biomechanical principles are reviewed, followed by a description of the cross-sectional morphological properties that best inform the net cellular effects of a given experimental perturbation and are most relevant to biomechanical function. Although morphology is critical, whole-bone mechanical properties can only be determined accurately by a mechanical test. The functional importance of stiffness, maximum load, postyield displacement, and work-to-fracture are reviewed. Because bone and body size are often strongly related, strategies to adjust whole-bone properties for body mass are detailed. Finally, a comprehensive framework is presented using real data, and several examples from the literature are reviewed to illustrate how to synthesize morphological, tissue-level, and whole-bone mechanical properties of mouse long bones.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/jbmr.2539DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4794979PMC
June 2015

How Does Bone Strength Compare Across Sex, Site, and Ethnicity?

Clin Orthop Relat Res 2015 Aug;473(8):2540-7

Department of Orthopaedic Surgery, University of Michigan, 109 Zina Pitcher Place, Room 2148 BSRB, Ann Arbor, MI, 48109, USA,

Background: The risk of fragility fractures in the United States is approximately 2.5 times greater among black and white women compared with their male counterparts. On average, men of both ethnicities have wider bones of greater cortical mass compared with the narrower bones of lower cortical mass among women. However, it remains uncertain whether the low cortical area observed in the long bones of women is consistent with their narrower bone diameter or if their cortical area is reduced beyond that which is expected for the sex differences in body size and external bone size.

Questions/purposes: We asked (1) do black and white women consistently have narrower bones of less strength across long bones compared with black and white men; and (2) do all long bones of black and white women have reduced cortical area compared with black and white men?

Methods: Peripheral quantitative CT was used to quantify bone strength and cross-sectional morphology from the major long bones of 125 white and 115 black adult men and women (20-35 years of age). Regression analyses were used to test for differences in bone strength and cortical area after for adjusting for either body size, bone size, or both.

Results: After adjusting bone strength for body size, regression analyses showed that black women had lower bone strength compared with black men (women: mean=298.7-25,522 mg HA mm4, 95% confidence interval [CI], 270-27,692 mg HA mm4; men: mean = 381.6-30,945 mg HA mm4, 95% CI, 358.2-32,853 mg HA mm4; percent difference=12%-38%, p=0.06-0.0001). Similarly, white women also had lower bone strength compared with white men (women: mean=229.5-22,892 mg HA mm4, 95% CI, 209.3-24,539 mg HA mm4; men: mean=314.3-29,986 mg HA mm4, 95% CI, 297.3-31,331 mg HA mm4; percent difference=27%-49%, p=0.0001). All long bones of women for both ethnicities showed lower cortical area compared with men. After accounting for both body size and external bone size, black women (women: mean=43.25-357.70 mm2, 95% CI, 41.45-367.52 mm2; men: mean=48.06-400.10 mm2, 95% CI, 46.67-408.72; percent difference=6%-25%, p=0.02-0.0001) and white women (women: mean=38.53-350.10 mm2, 95% CI, 36.99-359.80 mm2; men: mean=42.06-394.30 mm2, 95% CI, 40.95-402.10 mm2; percent difference=6%-22%, p=0.02-0.0001) were shown to have lower cortical area than their male counterparts. Therefore, the long bones of women are not only more slender than those of men, but also show a reduced cortical area that is 6% to 25% greater than expected for their external size, depending on the bone being considered.

Conclusions: The long bones of females are not just a more slender version of male long bones. Women have less cortical area than expected for their body size and bone size, which in part explains their reduced bone strength when compared with the more robust bones of men.

Clinical Relevance: The outcome of this assessment may be clinically important for the development of diagnostics and treatment regimens used to combat fractures. Future work should look at how the relationship among parameters reported here translates to the more fracture-prone metaphyseal regions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11999-015-4229-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488216PMC
August 2015

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

Clin Orthop Relat Res 2015 Aug;473(8):2530-9

Department of Orthopaedic Surgery, University of Michigan, 109 Zina Pitcher Place, Room 2001 BSRB, Ann Arbor, MI, 48109, USA,

Background: The twofold greater lifetime risk of fracturing a bone for white women compared with white men and black women has been attributed in part to differences in how the skeletal system accumulates bone mass during growth. On average, women build more slender long bones with less cortical area compared with men. Although slender bones are known to have a naturally lower cortical area compared with wider bones, it remains unclear whether the relatively lower cortical area of women is consistent with their increased slenderness or is reduced beyond that expected for the sex-specific differences in bone size and body size. Whether this sexual dimorphism is consistent with ethnic background and is recapitulated in the widely used mouse model also remains unclear.

Questions/purposes: We asked (1) do black women build bones with reduced cortical area compared with black men; (2) do white women build bones with reduced cortical area compared with white men; and (3) do female mice build bones with reduced cortical area compared with male mice?

Methods: Bone strength and cross-sectional morphology of adult human and mouse bone were calculated from quantitative CT images of the femoral midshaft. The data were tested for normality and regression analyses were used to test for differences in cortical area between men and women after adjusting for body size and bone size by general linear model (GLM).

Results: Linear regression analysis showed that the femurs of black women had 11% lower cortical area compared with those of black men after adjusting for body size and bone size (women: mean=357.7 mm2; 95% confidence interval [CI], 347.9-367.5 mm2; men: mean=400.1 mm2; 95% CI, 391.5-408.7 mm2; effect size=1.2; p<0.001, GLM). Likewise, the femurs of white women had 12% less cortical area compared with those of white men after adjusting for body size and bone size (women: mean=350.1 mm2; 95% CI, 340.4-359.8 mm2; men: mean=394.3 mm2; 95% CI, 386.5-402.1 mm2; effect size=1.3; p<0.001, GLM). In contrast, female and male femora from recombinant inbred mouse strains showed the opposite trend; femurs from female mice had a 4% larger cortical area compared with those of male mice after adjusting for body size and bone size (female: mean=0.73 mm2; 95% CI, 0.71-0.74 mm2; male: mean=0.70 mm2; 95% CI, 0.68-0.71 mm2; effect size=0.74; p=0.04, GLM).

Conclusions: Female femurs are not simply a more slender version of male femurs. Women acquire substantially less mass (cortical area) for their body size and bone size compared with men. Our analysis questions whether mouse long bone is a suitable model to study human sexual dimorphism.

Clinical Relevance: Identifying differences in the way bones are constructed may be clinically important for developing sex-specific diagnostics and treatment strategies to reduce fragility fractures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s11999-015-4184-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488191PMC
August 2015