Structural differences contributing to sex-specific associations between FN BMD and whole-bone strength for adult White women and men.

Hip areal BMD (aBMD) is widely used to identify individuals with increased fracture risk. Low aBMD indicates low strength, but this association differs by sex with men showing greater strength for a given aBMD than women. To better understand the structural basis giving rise to this sex-specific discrepancy, cadaveric proximal femurs from White female and male donors were imaged using nano-CT and loaded in a sideways fall configuration to assess strength. FN pseudoDXA images were generated to identify associations among structure, aBMD, and strength that differ by sex. Strength correlated significantly with pseudoDXA aBMD for females (R2 = 0.468, P < .001) and males (R2 = 0.393, P < .001), but the elevations (y-intercepts) of the linear regressions differed between sexes (P < .001). Male proximal femurs were 1045 N stronger than females for a given pseudoDXA aBMD. However, strength correlated with pseudoDXA BMC for females (R2 = 0.433, P < .001) and males (R2 = 0.443, P < .001) but without significant slope (P = .431) or elevation (P = .058) differences. Dividing pseudoDXA BMC by FN-width, total cross-sectional area, or FN-volume led to significantly different associations between strength and the size-adjusted BMC measures for women and men. Three structural differences were identified that differentially affected aBMD and strength for women and men: First, men had more bone mass per unit volume than women; second, different cross-sectional shapes resulted in larger proportions of bone mass orthogonal to the DXA image for men than women; and third, men and women had different proportions of cortical and trabecular bone relative to BMC. Thus, the proximal femurs of women were not smaller versions of men but were constructed in fundamentally different manners. Dividing BMC by a bone size measure was responsible for the sex-specific associations between hip aBMD and strength. Thus, a new approach for adjusting measures of bone mass for bone size and stature is warranted.

Perspective: A multi-trait integrative approach to understanding the structural basis of bone fragility for pediatric conditions associated with abnormal bone development.

Bone development is a highly orchestrated process that establishes the structural basis of bone strength during growth and functionality across the lifespan. This developmental process is generally robust in establishing mechanical function, being adaptable to many genetic and environmental factors. However, not all factors can be fully accommodated, leading to abnormal bone development and lower bone strength. This can give rise to early-onset bone fragility that negatively impacts bone strength across the lifespan. Current guidelines for assessing bone strength include measuring bone mineral density, but this does not capture the structural details responsible for whole bone strength in abnormally developing bones that would be needed to inform clinicians on how and when to treat to improve bone strength. The clinical consequence of not operationalizing how altered bone development informs decision making includes under-detection and missed opportunities for early intervention, as well as a false positive diagnosis of fragility with possible resultant clinical actions that may actually harm the growing skeleton. In this Perspective, we emphasize the need for a multi-trait, integrative approach to better understand the structural basis of bone growth for pediatric conditions with abnormal bone development. We provide evidence to showcase how this approach might reveal multiple, unique ways in which bone fragility develops across and within an array of pediatric conditions that are associated with abnormal bone development. This Perspective advocates for the development of new translational research aimed at informing better ways to optimize bone growth, prevent fragility fractures, and monitor and treat bone fragility based on the child's skeletal needs.

Associations Among Hip Structure, Bone Mineral Density, and Strength Vary With External Bone Size in White Women.

Bone mineral density (BMD) is heavily relied upon to reflect structural changes affecting hip strength and fracture risk. Strong correlations between BMD and strength are needed to provide confidence that structural changes are reflected in BMD and, in turn, strength. This study investigated how variation in bone structure gives rise to variation in BMD and strength and tested whether these associations differ with external bone size. Cadaveric proximal femurs (n = 30, White women, 36-89+ years) were imaged using nanocomputed tomography (nano-CT) and loaded in a sideways fall configuration to assess bone strength and brittleness. Bone voxels within the nano-CT images were projected onto a plane to create pseudo dual-energy X-ray absorptiometry (pseudo-DXA) images consistent with a clinical DXA scan. A validation study using 19 samples confirmed pseudo-DXA measures correlated significantly with those measured from a commercially available DXA system, including bone mineral content (BMC) (R 2  = 0.95), area (R 2  = 0.58), and BMD (R 2  = 0.92). BMD-strength associations were conducted using multivariate linear regression analyses with the samples divided into narrow and wide groups by pseudo-DXA area. Nearly 80% of the variation in strength was explained by age, body weight, and pseudo-DXA BMD for the narrow subgroup. Including additional structural or density distribution information in regression models only modestly improved the correlations. In contrast, age, body weight, and pseudo-DXA BMD explained only half of the variation in strength for the wide subgroup. Including bone density distribution or structural details did not improve the correlations, but including post-yield deflection (PYD), a measure of bone material brittleness, did increase the coefficient of determination to more than 70% for the wide subgroup. This outcome suggested material level effects play an important role in the strength of wide femoral necks. Thus, the associations among structure, BMD, and strength differed with external bone size, providing evidence that structure-function relationships may be improved by judiciously sorting study cohorts into subgroups. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Sex and External Size Specific Limitations in Assessing Bone Health From Adult Hand Radiographs.

Morphological parameters measured for the second metacarpal from hand radiographs are used clinically for assessing bone health during growth and aging. Understanding how these morphological parameters relate to metacarpal strength and strength at other anatomical sites is critical for providing informed decision-making regarding treatment strategies and effectiveness. The goals of this study were to evaluate the extent to which 11 morphological parameters, nine of which were measured from hand radiographs, relate to experimentally measured whole-bone strength assessed at multiple anatomical sites and to test whether these associations differed between men and women. Bone morphology and strength were assessed for the second and third metacarpals, radial diaphysis, femoral diaphysis, and proximal femur for 28 white male donors (18-89 years old) and 35 white female donors (36-89+ years old). The only morphological parameter to show a significant correlation with strength without a sex-specific effect was cortical area. Dimensionless morphological parameters derived from hand radiographs correlated significantly with strength for females, but few did for males. Males and females showed a significant association between the circularity of the metacarpal cross-section and the outer width measured in the mediolateral direction. This cross-sectional shape variation contributed to systematic bias in estimating strength using cortical area and assuming a circular cross-section. This was confirmed by the observation that use of elliptical formulas reduced the systematic bias associated with using circular approximations for morphology. Thus, cortical area was the best predictor of strength without a sex-specific difference in the correlation but was not without limitations owing to out-of-plane shape variations. The dependence of cross-sectional shape on the outer bone width measured from a hand radiograph may provide a way to further improve bone health assessments and informed decision making for optimizing strength-building and fracture-prevention treatment strategies. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Divergent mechanical properties of older human male femora reveal unique combinations of morphological and compositional traits contributing to low strength.

Bone strength is generally thought to decline with aging and prior work has compared traits between younger and older cohorts to identify the structural and compositional changes that contribute to fracture risk with age. However, for men, the majority of individuals do not fracture a bone in their lifetime. While fracture occurrence is multifactorial, the absence of fracture in the majority of males suggests that some individuals maintain bone strength or do not lose enough strength to fracture, whereas others do lose strength with aging. Consequently, not all structural and material changes observed with age may lead to strength-decline. We propose that consideration of different subgroups of older individuals will provide a more precise understanding of which structural and material changes directly contribute to strength-decline. We identified subgroups using latent profile analysis (LPA), which is a clustering-based algorithm that takes multiple continuous variables into account. Human cadaveric male femoral diaphyses (n = 33, 26-89 years) were subjected to whole bone and tissue-level mechanical tests. Morphological traits, porosity, and cortical tissue mineral density (Ct.TMD) were obtained, as were measures of enzymatic cross-links and the advanced glycation end product, pentosidine (PEN). A univariate analysis first identified a younger cohort (YNG, n = 11) and older cohort (n = 22). LPA was then conducted using three mechanical traits (whole bone strength, tissue-level strength, and tissue-level post-yield strain), resulting in a further stratification of the older group into two similarly aged groups (p = 0.558), but one with higher (OHM, n = 16) and another with lower mechanical properties (OLM, n = 6). The OLM group exhibited lower whole bone strength (p = 0.016), tissue-level strength (p < 0.001), and tissue-level post-yield strain (p < 0.001) compared to the YNG group. Meanwhile, the OHM only exhibited significantly lower tissue-level post-yield strain (p < 0.001), compared to the YNG group. Between the two older groups, the OHM group exhibited higher whole bone strength (p = 0.037), tissue-level strength (p = 0.006), and tissue-level post-yield strain (p = 0.012) than the OLM group. Probing the morphological and compositional relationships among the three groups, both OHM and OLM exhibited increased PEN content (p < 0.001, p = 0.008 respectively) and increased Log(cortical pore score) relative to YNG (p = 0.003, p < 0.001 respectively). Compared to the OHM group, the OLM also exhibited increased marrow area (p = 0.049), water content (p = 0.048), and decreased Ct.TMD (p = 0.005). The key traits that were unique to the OLM group compared to YNG were decreased Ct.TMD (p < 0.001) and increased Log(porosity) (p = 0.002). There were many properties that differed between the younger and older groups, but not all were associated with reduced mechanical properties, highlighting the relative importance of certain age-related traits such as porosity, Ct.TMD, water content, and marrow area that were unique to the OLM group. Overall, this work supports the hypothesis that there are subgroups of men showing different strength-decline trajectories with aging and establishes a basis for refining our understanding of which age-related changes are directly contributing to decreased strength.

Region-specific associations among tissue-level mechanical properties, porosity, and composition in human male femora.

Region-specific differences in age-related bone remodeling are known to exist. We therefore hypothesized that the decline in tissue-level strength and post-yield strain (PYS) with age is not uniform within the femur, but is driven by region-specific differences in porosity and composition. Four-point bending was conducted on anterior, posterior, medial, and lateral beams from male cadaveric femora (n = 33, 18-89 yrs of age). Mid-cortical porosity, composition, and mineralization were assessed using nano-computed tomography (nanoCT), Raman spectroscopy, and ashing assays. Traits between bones from young and elderly groups were compared, while multivariate analyses were used to identify traits that predicted strength and PYS at the regional level. We show that age-related decline in porosity and mechanical properties varied regionally, with highest positive slope of age vs. Log(porosity) found in posterior and anterior bone, and steepest negative slopes of age vs. strength and age vs. PYS found in anterior bone. Multivariate analyses show that Log(porosity) and/or Raman 1246/1269 ratio explained 46-51% of the variance in strength in anterior and posterior bone. Three out of five traits related to Log(porosity), mineral crystallinity, 1246/1269, mineral/matrix ratio, and/or hydroxyproline/proline (Hyp/Pro) ratio, explained 35-50% of the variance in PYS in anterior, posterior and lateral bones. Log(porosity) and Hyp/Pro ratio alone explained 13% and 19% of the variance in strength and PYS in medial bone, respectively. The predictive performance of multivariate analyses was negatively impacted by pooling data across all bone regions, underscoring the complexity of the femur and that the use of pooled analyses may obscure underlying region-specific differences.

Excess healthcare spending associated with fractures among adults with cerebral palsy.

BACKGROUND: Fractures represent a triple threat to adults with cerebral palsy (CP): common, accumulate early in adulthood, and are consequential to health. An economic evaluation of fractures in CP is needed to highlight priorities for allocating resources to clinical and public health programs aimed at preventing fractures and their disease sequela. OBJECTIVE: To identify short-term healthcare costs associated with fractures among adults with CP. METHODS: A retrospective cohort study was performed using Optum's de-identified Clinformatics® Data Mart Database from 01/01/2011-12/31/2017. The primary cohort included adults ≥ 18 years old with CP with an incident fracture (CP+Fx), and cost estimates were compared with: CP without fractures (CPw/oFx) and without CP+Fx (w/oCP+Fx). A difference-in-difference (DiD) analysis compared the change in pharmacy and medical costs between cohorts from the one-year baseline period through the one-year post-index period in three-month quarters. RESULTS: CP+Fx (n = 855) had higher mean costs in the baseline and follow-up periods compared with CPw/oFx (n = 5667) and w/oCP+Fx (n = 588,042). The first post-index quarter DiD estimate suggests that CP+Fx accumulated an excess $6462 (95%CI = $3810-$9021) compared with w/oCP+Fx and $17,197 (95%CI = $14,418-$19,833) compared with CPw/oFx. The CP+Fx cohort had higher DiD estimates in the other follow-up quarters, but they were not statistically significant compared with CPw/oFx. When stratified by fracture site, vertebral column fractures for CP+Fx vs. w/oCP+Fx accumulated an excess $25,226 (95%CI = $12,639-$37,417). CONCLUSIONS: Fractures, especially of the vertebral column, were associated with high healthcare costs among adults with CP. Studies are needed to identify cost-effective opportunities to utilize available resources to prevent fractures and their costly sequela for CP.

State of the mineralized tissue comprising the femoral ACL enthesis in young women with an ACL failure.

Despite poor graft integration among some patients that undergo an anterior cruciate ligament (ACL) reconstruction, there has been little consideration of the bone quality into which the ACL femoral tunnel is drilled and the graft is placed. Bone mineral density of the knee decreases following ACL injury. However, trabecular and cortical architecture differences between injured and non-injured femoral ACL entheses have not been reported. We hypothesize that injured femoral ACL entheses will show significantly less cortical and trabecular mass compared with non-injured controls. Femoral ACL enthesis explants from 54 female patients (13-25 years) were collected during ACL reconstructive surgery. Control explants (n = 12) were collected from seven donors (18-36 years). Injured (I) femoral explants differed from those of non-injured (NI) controls with significantly less (p ≤ 0.001) cortical volumetric bone mineral density (vBMD) (NI: 736.1-867.6 mg/cm3 ; I: 451.2-891.9 mg/cm3 ), relative bone volume (BV/TV) (NI: 0.674-0.867; I: 0.401-0.792) and porosity (Ct.Po) (NI: 0.133-0.326; I: 0.209-0.600). Injured explants showed significantly less trabecular vBMD (p = 0.013) but not trabecular BV/TV (p = 0.314), thickness (p = 0.412), or separation (p = 0.828). We found significantly less cortical bone within injured femoral entheses compared to NI controls. Lower cortical and trabecular bone mass within patient femoral ACL entheses may help explain poor ACL graft osseointegration outcomes in the young and may be a contributor to the osteolytic phenomenon that often occurs within the graft tunnel following ACL reconstruction.

Clinical bone health among adults with cerebral palsy: moving beyond assessing bone mineral density alone.

AIM: To understand associations among bone mineral density (BMD), bone mineral content (BMC), and bone area, and their association with fractures in adults with cerebral palsy (CP). METHOD: This retrospective cohort study included 78 adults with CP with a hip dual energy X-ray absorptiometry (DXA) from 1st December 2012 to 3rd May 2021 performed at the University of Michigan. Data-driven logistic regression techniques identified which, if any, DXA-derived bone traits (e.g. age/sex/ethnicity-based z-scores) were associated with fracture risk by sex and severity of CP. BMC-area associations were examined to study the structural mechanisms of fragility. RESULTS: Femoral neck area was associated with lower age-adjusted odds ratios (ORs) of fracture history (OR 0.72; 95% confidence interval [CI] 0.49-1.06; p=0.098), while higher BMD was associated with higher odds of incident fracture (OR 3.08; 95% CI 1.14-8.33; p=0.027). Females with fracture had lower area than females without fracture but similar BMC, whereas males with fracture had larger area and higher BMC than males without fracture. The paradoxical BMD-fracture association may be due to artificially elevated BMD from BMC-area associations that differed between females and males (sex interaction, p˂0.05): males had higher BMC at lower area values and lower BMC at higher area values compared to females. INTERPRETATION: BMD alone may not be adequate to evaluate bone strength for adults with CP. Further research into associations (or integration) between BMC and area is needed.

Nanoscale hybrid implant surfaces and Osterix-mediated osseointegration.

Endosseous implant surface topography directly affects adherent cell responses following implantation. The aim of this study was to examine the impact of nanoscale topographic modification of titanium implants on Osterix gene expression since this gene has been reported as key factor for bone formation. Titanium implants with smooth and nanoscale topographies were implanted in the femurs of Osterix-Cherry mice for 1-21 days. Implant integration was evaluated using scanning electron microscopy (SEM) to evaluate cell adhesion on implant surfaces, histology, and nanotomography (NanoCT) to observe and quantify the formed bone-to-implant interface, flow cytometry to quantify of Osterix expressing cells in adjacent tissues, and real-time PCR (qPCR) to quantify the osteoinductive and osteogenic gene expression of the implant-adherent cells. SEM revealed topography-dependent adhesion of cells at early timepoints. NanoCT demonstrated greater bone formation at nanoscale implants and interfacial osteogenesis was confirmed histologically at 7 and 14 days for both smooth and nanosurface implants. Flow cytometry revealed greater numbers of Osterix positive cells in femurs implanted with nanoscale versus smooth implants. Compared to smooth surface implants, nanoscale surface adherent cells expressed higher levels of Osterix (Osx), Alkaline phosphatase (Alp), Paired related homeobox (Prx1), Dentin matrix protein 1 (Dmp1), Bone sialoprotein (Bsp), and Osteocalcin (Ocn). In conclusion, nanoscale surface implants demonstrated greater bone formation associated with higher levels of Osterix expression over the 21-day healing period with direct evidence of surface-associated gene regulation involving a nanoscale-mediated osteoinductive pathway that utilizes Osterix to direct adherent cell osteoinduction.

Bringing Mechanical Context to Image-Based Measurements of Bone Integrity.

PURPOSE OF REVIEW: Image-based measurements of bone integrity are used to estimate failure properties and clinical fracture risk. This paper (1) reviews recent imaging studies that have enhanced our understanding of the mechanical pathways to bone fracture and (2) discusses the influence that inter-individual differences in image-based measurements may have on the clinical assessment of fracture risk RECENT FINDINGS: Increased tissue mineralization is associated with improved bone strength but reduced fracture toughness. Trabecular architecture that is important for fatigue resistance is less important for bone strength. The influence of porosity on bone failure properties is heavily dependent on pore location and size. The interaction of various characteristics, such as bone area and mineral content, can further complicate their influence on bone failure properties. What is beneficial for bone strength is not always beneficial for bone toughness or fatigue resistance. Additionally, given the large amount of imaging data that is clinically available, there is a need to develop effective translational strategies to better interpret non-invasive measurements of bone integrity.

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

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.

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

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, P < .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.

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

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 P < 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 P < 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.

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

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; n = 1777); (2) CP without NTFx (CP w/o NTFx; n = 12,933); (3) without CP and with NTFx (w/o CP + NTFx; n = 433,560); and (4) without CP and without NTFx (w/o CP w/o NTFx; n = 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.

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

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 (R2 = 0.50, p = 0.002), tissue-level post-yield strain (R2 = 0.75, p < 0.001) and borderline significance for whole bone strength (R2 = 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; R2 = 0.75), tissue-level strength (Age, Ct.TMD, Log(DHLNL/HLNL); R2 = 0.56), and post-yield strain (Age, Log(Pyrrole), Ct.Area; R2 = 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.

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

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.

Elevated fracture risk for adults with neurodevelopmental disabilities.

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.