Collagen mutation and age contribute to differential craniofacial phenotypes in mouse models of osteogenesis imperfecta.

Craniofacial and dentoalveolar abnormalities are present in all types of osteogenesis imperfecta (OI). Mouse models of the disorder are critical to understand these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. The Brtl/+ and G610c/+ are moderately severe and mild-type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT-scanned heads of 3-wk-old, 3-mo-old, and 6-mo-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT (P < .05), whereas G610c/+ skulls are similar in length to their WT counterparts. The Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible (P < .05). By contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 mo (P < .05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars (P < .05), which are similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in the craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups.

Serum Titanium Levels Remain Elevated But Urine Titanium is Undetectable in Children With Early Onset Scoliosis Undergoing Growth-Friendly Surgical Treatment: A Prospective Study.

BACKGROUND: Elevated serum titanium levels have been found in patients with early onset scoliosis (EOS) treated with traditional growing rods (TGR), magnetically controlled growing rods (MCGR), and vertical expandable prosthetic titanium rib (VEPTR). No studies have investigated whether serum titanium remains persistently elevated and if titanium is excreted. Our purpose was to compare serum titanium levels in patients with EOS with growth-friendly instrumentation to age-matched controls and evaluate urine titanium and serial serum titanium levels in patients with EOS. METHODS: This was a prospective case-control study. Patients with EOS with TGR, MCGR, or VEPTR underwent urine titanium and serial serum titanium collection at a minimum 6-month interval. Control patients did not have a history of metal implant insertion and underwent serum titanium collection before fracture fixation. RESULTS: Twenty patients with EOS (6 TGR, 8 MCGR, and 6 VEPTR) and 12 controls were analyzed. The control group had no detectable serum titanium (0 ng/mL), whereas the patients with EOS had a median serum titanium of 4.0 ng/mL ( P < 0.001). Analysis of variance showed significantly higher median serum titanium levels in the MCGR and VEPTR groups than the TGR group at time point 1 (5.5 vs 6.0 vs 2.0 ng/mL, P = 0.01) and time point 2 (6.5 vs 7.5 vs 2.0 ng/mL, P < 0.001). Binary comparisons showed a significant difference in serum titanium level between TGR and MCGR (time point 1: P = 0.026, time point 2: P = 0.011) and TGR and VEPTR (time point 1: P = 0.035, time point 2: P = 0.003). However, there was no difference between MCGR and VEPTR (time point 1: P = 0.399, time point 2: P = 0.492) even though the VEPTR group had a longer duration of follow-up ( P = 0.001) and a greater number of lengthenings per patient at the first serum collection ( P = 0.016). No patients with EOS had detectable urine titanium. CONCLUSIONS: Patients with EOS treated with titanium alloy growth-friendly instrumentation had elevated serum titanium levels compared with age-matched controls that persisted over time with no evidence of renal excretion. Additional studies are necessary to assess for local and systemic accumulation of titanium and the significance of long-term exposure to titanium in growing children. LEVEL OF EVIDENCE: Level III, therapeutic.

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.

A Conceptual Approach for Examining Effects of the Adolescent Bone Marrow Milieu on MSC Phenotype.

Children with bone fragility often exhibit elevated bone marrow lipid levels, which may affect mesenchymal stem cell (MSC) differentiation potential and ultimately bone strength via cell-autonomous and/or non-cell-autonomous factors. Here, we use standard co-culture techniques to study biological effects of bone marrow cell-derived secretome on MSC. Bone marrow was collected during routine orthopedic surgery, and the entire marrow cell preparation, with or without red blood cell (RBC) reduction, was plated at three different densities. Conditioned medium (secretome) was collected after 1, 3, and 7 days. ST2 cells, a murine MSC line, were then cultured in the secretomes. Exposure to the secretomes was associated with reductions of up to 62% in MSC MTT outcomes that depended on the duration of secretome development, as well as marrow cell plating density. Reduced MTT values were not associated with diminished cell number and viability assessed using Trypan Blue exclusion. Expression of pyruvate dehydrogenase kinase 4 was modestly elevated, and ß-actin levels were transiently reduced in ST2 cells exposed to secretome formulations that had elicited maximal reductions in MTT outcomes. The findings from this study can inform the design of future experimental studies to examine contributions of cell-autonomous and non-cell-autonomous factors in the bone marrow to MSC differentiation potential, bone formation, and skeletal growth. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Policies, Practices, and Attitudes Related to Parental Leave for Practicing Pediatric Orthopaedic Surgeons.

BACKGROUND: Parental leave impacts family engagement, bonding, stress, and happiness. Because parental leave benefits are important to all surgeons regardless of sex, understanding parental leave practices in pediatric orthopaedic surgery is critical to promote equity within the profession and supporting balance in work and family life. The aim of this study was to survey pediatric orthopaedic surgeons about their knowledge of parental leave policies, attitudes towards parental leave, and their individual experiences taking leave. METHODS: A 34-question anonymous survey was distributed to the Pediatric Orthopaedic Society of North America membership. Eligible respondents were attending pediatric orthopaedic surgeons practicing in the United States or Canada. The survey gathered information about employer parental leave policies, perceptions about and experiences with parental leave while practicing as a surgeon, and demographic information about respondents. RESULTS: A total of 77 responses were completed and used for analysis. Most respondents were men (59.7%), <50 years old (67.5%), married (90.9%), and in urban communities (75.3%). A large majority were practicing in the United States (97.4%). Most respondents were unfamiliar with employer parental leave policies (maternity: 53.3%; paternity: 67.5%; and adoption: 85.7%). Those familiar with policies reported that employers offered 7 to 12 weeks for maternity leave (45.7%) and <1 week for paternity leave (50%) and adoption leave (45.5%). Most respondents believed 7 to 12 weeks should be offered for maternity leave (66.2%), 1 to 6 weeks for paternity leave (54.6%), and 7 to 12 weeks for adoption leave (46.8%). Many respondents reported taking 1 to 6 weeks of parental leave as a surgeon (53.3%) and that their colleagues were supportive of their parental leave (40.3%). CONCLUSIONS: Most pediatric orthopaedic surgeons were unfamiliar with parental leave benefits provided by employers. Respondents who were familiar with these policies believed that more parental leave should be provided, especially for men who may feel social pressure to take less time for leave. Although respondents reported that their work environments were supportive, this study identified opportunities for improvement to support surgeons who wish to balance parental experiences with work responsibilities. LEVEL OF EVIDENCE: Level V.

Post-fracture rehabilitation pathways and association with mortality among adults with cerebral palsy.

OBJECTIVE: Rehabilitation may mitigate the high mortality rates and health declines post-fracture for adults with cerebral palsy, but this is understudied. The objectives were to characterize the post-fracture rehabilitation pathways and identify their association with 1-year survival among adults with cerebral palsy. METHODS: A retrospective cohort study of adults with cerebral palsy with a fragility fracture with continuous health plan enrollment ≥1-year prior to and ≥1 day after their fracture date was performed using a random 20% Medicare fee-for-service dataset. Participants were categorized as a home discharge or inpatient rehabilitation admission post-fracture. For the home discharge cohort, weekly exposure to outpatient physical/occupational therapy (PT/OT) was examined up to 6-month post-fracture. Cox regression examined the association between time-varying PT/OTuse within 6-month post-fracture and mortality from 30 days to 1-year post-fracture before and after adjusting for confounders (e.g. medical complexity). RESULTS: Of 3598 adults with cerebral palsy with an incident fragility fracture, 74% were discharged home without inpatient rehabilitation; they were younger, but more medically complex compared to the 26% admitted to inpatient rehabilitation. Among the home discharge cohort (n = 2662), 43.1% initiated PT/OTwithin 6-month post-fracture, and cumulative PT/OTexposure post-fracture was associated with improved survival; for example, per 3 weeks of PT/OTexposure, the adjusted mortality rate was 40% lower (95% confidence interval (CI) = 0.41-0.89). CONCLUSIONS: Most adults with cerebral palsy with a fragility fracture were discharged home rather than to inpatient rehabilitation, and only 43.1% of that group initiated outpatient PT/OTwithin 6 months post-fracture. Receiving outpatient PT/OTwas associated with improved 1-year survival.

Post-Fracture Inpatient and Outpatient Physical/Occupational Therapy and Its Association with Survival among Adults with Cerebral Palsy.

Physical and/or occupational therapy (PT/OT) may improve post-fracture health and survival among adults with cerebral palsy (CP), but this has not been studied in the inpatient setting. The objective was to quantify the association between acute inpatient and outpatient PT/OT use with 1-year mortality among adults with CP. This was a retrospective cohort study of adults with CP with an incident fragility fracture admitted to an acute care or rehabilitation facility using a random 20% Medicare fee-for-service dataset. Acute care/rehabilitation PT/OT was measured as the average PT/OT cost/day for the length of stay (LOS). Weekly exposure to outpatient PT/OT was examined up to 6 months post-fracture. Cox regression examined the adjusted association between the interaction of acute care/rehabilitation average PT/OT cost/day and LOS with 1-year mortality. A separate Cox model added time-varying outpatient PT/OT. Of 649 adults with CP, average PT/OT cost/day was associated with lower mortality rate for LOS < 17 days (HR range = 0.78−0.93), and increased mortality rate for LOS > 27 days (HR ≥ 1.08) (all, p < 0.05). After acute care/rehabilitation, 44.5% initiated outpatient PT/OT, which was associated with lower mortality rate (HR = 0.52; 95% CI = 0.27−1.01). Post-fracture inpatient and outpatient PT/OT were associated with improved 1-year survival among adults with CP admitted to acute care/rehabilitation facilities.

Five-year risk of fracture and subsequent fractures among adults with cerebral palsy.

Background: Epidemiologic evidence documenting the incidence of fracture and subsequent fractures among adults with cerebral palsy (CP) is lacking, which could inform fracture prevention efforts. The objective was to characterize the 5-year rate of initial and subsequent fragility fractures among adults with CP. Methods: This retrospective cohort study used Medicare claims from 01/01/2008-12/31/2019 from adults ≥18 years old with CP (n = 44,239) and elderly ≥65 years old without CP (n = 2,176,463) as a comparison. The incidence rate (IR), IR ratio (IRR), and site distribution were estimated for the initial and subsequent fragility fractures over 5-years by sex and age. Results: The IR of fragility fracture at any site over the 5-year follow-up was similar for 18-30-year-old men with CP (IR = 5.2; 95%CI = 4.4-5.9) and 30-34-year-old women with CP (IR = 6.3; 95%CI = 5.3-7.2) compared to the same sex youngest-old (65-74 years old) without CP (IRR = 1.09 and 0.94, respectively, both P > 0.05), and increased with older age for those with CP. The number of fragility fractures and IR of subsequent fragility fractures was similar for young men and middle-aged women with CP compared to elderly without CP, and increased with older age for those with CP. The proportion of fragility fracture at the tibia/fibula decreased while the vertebral column and multiple simultaneous sites (most involved hip/lower extremities) increased with older age. Conclusion: Young and middle-aged adults with CP had similar-to-worse initial and subsequent fragility fracture profiles compared to the general elderly population- a well characterized group for bone fragility. Findings emphasize the need for fracture prevention efforts at younger ages for CP, possibly by ~5 decades younger.

Preoperative Patient Education and Smaller Prescription Quantity Reduce Opioid Use After Posterior Spinal Fusion for Adolescent Idiopathic Scoliosis: Results of a Prospective Study.

BACKGROUND: Most opioids prescribed postoperatively are unused. Leftover opioids are a major source of nonmedical opioid use among adolescents. Postoperative opioid use has also been associated with prescription quantity. Our purpose was to evaluate the effect of preoperative patient education and implementation of evidence-based prescribing guidelines on opioid use and pain level after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). METHODS: AIS patients aged 10 to 17 years undergoing PSF were prospectively enrolled [postintervention cohort (POST-INT)]. Previous data on 77 patients showed median consumption of 29 doses of oxycodone after PSF [preintervention cohort (PRE-INT)]. All eligible patients during the study period were discharged with 30 doses of oxycodone and standard nonopioid analgesics. Only study participants received education on postoperative pain control. Demographics, radiographic/surgical data, pain level, and patient-reported outcomes were collected. Requests for opioid refills were documented. RESULTS: Forty-nine patients were enrolled. POST-INT was divided into low (L, ≤8 doses), average (AVE, 9-25), and high (H, >25) opioid use groups. Demographics, radiographic/surgical data, pain level, and patient-reported outcomes were similar between the groups. However, there was a difference in days of oxycodone use, doses consumed in the first week, and leftover doses ( P <0.001). Comparison to the PRE-INT L (≤16 doses), AVE (17 to 42), and high (H, >42) use groups showed that POST-INT L and AVE consumed less oxycodone (L: P =0.002; AVE: P <0.001). Also, the overall POST-INT cohort had fewer mean days of oxycodone use (5.6 vs. 8.9, P <0.001) and doses used in the first week (14 vs. 23, P <0.001) compared with the PRE-INT cohort. Subanalysis showed fewer study participants requested and received an opioid refill [3/49 patients (6%)] compared with eligible patients who declined to participate, withdrew, or missed enrollment [8/35 patients (23%)] ( P =0.045). CONCLUSIONS: Preoperative patient education and smaller prescription quantity successfully reduced opioid use while maintaining excellent pain control after PSF for AIS. Setting expectations regarding postoperative pain management is critical, as nonstudy participants were significantly more likely to request an opioid refill. LEVEL OF EVIDENCE: Level II-therapeutic.

Are resident research projects correlated to future subspecialty choice in orthopaedic surgery? A ten-year retrospective review of a single centre's experience.

AIM: To determine (1) frequency of resident research projects being in the same orthopaedic subspecialty that they ultimately choose for fellowship and practice; (2) percentage of research projects that were published. METHODS: Resident Thesis Day programs were independently assessed by two reviewers from 2010 to 2020. Reviewers classified projects based on orthopaedic subspecialty: Spine, Joints, Trauma, Hand, Foot and Ankle, Sports, Pediatrics, Oncology, and Shoulder Elbow. Presenting residents' fellowship subspecialty, current practice specialty, and geographic state of current practice were collected using internet searches. Correlation of residents who completed a thesis day project in the same subspecialty as their fellowship and current practice was calculated. RESULTS: A total of 81 resident physicians, 11 (13.6%) female, were included. In the entire cohort, 50.6% did a thesis day project in a different field than their current or projected subspecialty. Of those who completed, or are currently completing fellowship, 33 (52.4%) did their thesis day project in the same subspecialty as their fellowship. Of the current residents who have matched into fellowship, 46.7% did a thesis day project in the same subspecialty. A total of 51 (63.0%) projects were published. CONCLUSION: The majority of resident research projects were published, and about 50% of orthopaedic residents went on to complete a fellowship and practice in the same subspecialty as their research project. As residents often spend a considerable amount of time and effort on their projects, these findings may help tailor resident education and research curriculums to focus more on research principles than specific orthopedic content.

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.

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.

Fracture characteristics by age, sex, and ambulatory status among individuals with cerebral palsy: a descriptive study.

PURPOSE: To evaluate clinically relevant fracture characteristics by age, sex, and ambulatory status among individuals with cerebral palsy. METHODS: Fracture location, energy of fracture, and activities that lead to a fracture were assessed among a clinic-based sample of children (0-17 years; n = 57) and adults (18-70 years; n = 58) with cerebral palsy that sustained a fracture by sex and gross motor function classification system (GMFCS) I-III vs. IV/V. RESULTS: Proportion of fractures that were low-energy was 67-99% for children and 69-84% for adults. ∼2/3rds of fractures were at the lower extremities, with the distal femur being the most common site for children (44%) and the foot/ankle for adults (40%); however, there were age, sex, and ambulatory effects, such that 43% of adults GMFCS IV/V and 32% of women had a distal femur fracture. GMFCS I-III were more likely to fracture from functionally complex activities, while GMFCS IV/V were more likely to fracture from wheelchair/transfers/limb-stuck and incidental findings. CONCLUSIONS: The majority of fractures were low-energy and occurred in the lower extremities, with effects by age, sex, and GMFCS. Activities that led to a fracture also differed by age and GMFCS, which can be used to design fracture prevention interventions in addition to bolstering skeletal mass and architecture.Implications for rehabilitationSkeletal fragility is a major problem for individuals with cerebral palsy (CP) across the lifespan leading to an increased risk of fragility fractures.Rehabilitation is a prime clinical intervention to prevent fractures from occurring and improving post-fracture healing and function; yet, effective rehabilitation interventions require knowledge of fracture characteristics, such as where fractures are occurring and the activities that lead to the fracture event specific to individuals with CP.Using a clinic-based sample of 0-70 year olds with CP, we describe salient fracture characteristics based on age, sex, and ambulatory status to enhance translation into clinical and rehabilitation practice.

Gabapentin and intrathecal morphine combination therapy results in decreased oral narcotic use and more consistent pain scores after posterior spinal fusion for adolescent idiopathic scoliosis.

BACKGROUND: Gabapentin and intravenous patient-controlled analgesia (PCA) can reduce postoperative pain scores, postoperative opioid use, and time to completing physical therapy compared to PCA alone after posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS). Gabapentin combined with intrathecal morphine has not been studied. The primary purpose of this retrospective study was to evaluate whether perioperative gabapentin and intrathecal morphine provide more effective pain control than intrathecal morphine alone after PSF for AIS. METHODS: Patients aged 11 to 18 years who underwent PSF for AIS were identified. Patients who received intrathecal morphine only (ITM group) were matched by age and sex to patients who received intrathecal morphine and perioperative gabapentin (ITM+GABA group). The ITM+GABA group received gabapentin preoperatively and for up to 2 days postoperatively. Both groups received oxycodone and the same non-narcotic adjuvant medications. RESULTS: Our final study group consisted of 50 patients (25 ITM, 25 ITM+GABA). The ITM+GABA group had significantly lower mean total oxycodone consumption during the hospitalization (0.798 vs 1.036 mg/kg, P<0.015). While the ITM group had a lower mean pain score between midnight and 8 am on POD 1 (2.4 vs 3.7, P=0.026), pain scores were significantly more consistent throughout the postoperative period in ITM+GABA group. The ITM+GABA group experienced less nausea/vomiting (52% vs 84%, P=0.032) and pruritus (44% vs 72%, P=0.045). Time to physical therapy discharge and length of hospital stay were similar. CONCLUSION: Addition of gabapentin resulted in reduced oral opioid consumption and more consistent postoperative pain scores after PSF for AIS. The patients who received intrathecal morphine and gabapentin also experienced a lower rate of nausea/vomiting and pruritus. TRIAL REGISTRATION: All data was collected retrospectively from chart review, with institutional IRB approval. Trial registration is not applicable.

Effect of levetiracetam and oxcarbazepine on 4-year fragility fracture risk among prepubertal and pubertal children with epilepsy.

OBJECTIVE: The objective of this study was to determine whether two commonly prescribed antiseizure medications (ASMs), levetiracetam (LEV) and oxcarbazepine (OXC), were associated with an increased risk of fragility fracture in children with epilepsy when initiating therapy during a crucial period of bone development, namely, pre- and midpuberty. METHODS: Claims data from January 1, 2009 to December 31, 2018 were extracted from the Optum Clinformatics Data Mart. Children aged 4-13 years at baseline with at least 5 years of continuous health plan enrollment were included to allow for a 1-year baseline (e.g., pre-ASM exposure) and 4 years of follow-up. Children with epilepsy who were ASM naïve were grouped based on whether ASM treatment initiation included LEV or OXC. The comparison group included children without epilepsy and without ASM exposure. Crude incidence rate (IR; n per 1000 person-years) and IR ratio (IRR; with 95% confidence interval [CI]) were estimated for nontrauma fracture (NTFx), a claims-based proxy for fragility fracture, for up to 4 years of follow-up. Cox proportional hazards regression estimated the hazard ratio (HR; with 95% CI) after adjusting for demographic variables, motor impairment, and baseline fracture. RESULTS: The crude IR (95% CI) of NTFx was 21.5 (21.2-21.8) for non-ASM-users without epilepsy (n = 271 346), 19.8 (12.3-27.2) for LEV (n = 358), and 34.4 (21.1-47.7) for OXC (n = 203). Compared to non-ASM-users, the crude IRR of NTFx was similar for LEV (IRR = .92, 95% CI = .63-1.34) and elevated for OXC (IRR = 1.60, 95% CI = 1.09-2.35); the crude IRR of NTFx was elevated for OXC compared to LEV (IRR = 1.74, 95% CI = 1.02-2.99). The findings were consistent after adjusting for covariates, except when comparing OXC to LEV (HR = 1.71, 95% CI = .99-2.93), which was marginally statistically insignificant (p = .053). SIGNIFICANCE: Initiating OXC, but not LEV, therapy among 4-13-year-olds with epilepsy is associated with an elevated risk of fragility fracture. Studies are needed to determine whether these children could benefit from adjunct bone fragility therapies.

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.

Critical periods of bone health across the lifespan for individuals with cerebral palsy: Informing clinical guidelines for fracture prevention and monitoring.

BACKGROUND: Skeletal fragility is a major burden for individuals with cerebral palsy (CP), but little is known clinically about when to prevent fractures or monitor bone health for this population. Critical periods of bone health (CPBH) are important windows for intervention to augment bone growth or mitigate bone loss. However, CPBH from the general population may not align with the needs or timing of skeletal fragility for individuals with CP. The objective of this study was to identify discrepancies when evaluating individuals with CP using CPBH across the lifespan from the general population, and propose new CP-specific CPBH. METHODS: Data from 2016 administrative claims databases were used, including the Optum's De-identified Clinformatics® Data Mart Database and a random 20% sample of the Medicare fee-for-service database from the Centers for Medicare and Medicaid Services. Sex-stratified fracture prevalence was compared between individuals with and without CP across the lifespan starting at 2 years of age using age groups to capture important stages of development and 3-4-year age bands in adulthood (up to >80 years). Sex-specific CPBH from the general population included: rapid bone accrual, peak bone mass, menopause, and elderly. RESULTS: There were 23,861 individuals with CP and 9,976,161 individuals without CP. CPBH from the general population did not align with the timing of skeletal fragility for CP. For example, fractures were rare and decreased throughout the CPBH of peak bone mass for males without CP, but males with CP had a greater relative fracture risk (2.9-5.6-fold higher) and a substantially increased rate of fracture (CP-slope 14× higher than non-CP-slope). For females with CP, fracture risk was increased by 18-21 years, with additional inflection points (e.g., decade before menopause and again by 57-60 years). For males with CP, fracture risk in mid-life exhibited a pattern similar to elderly males without CP. CONCLUSIONS: This study identified discrepancies in evaluating fracture risk for individuals with CP if using established CPBH from the general population. We therefore propose new CP- and sex-specific CPBH for fracture monitoring and prevention.

Higher pedicle screw density does not improve curve correction in Lenke 2 adolescent idiopathic scoliosis.

PURPOSE: Higher pedicle screw density posterior spinal fusion (PSF) constructs have not been shown to result in improved curve correction in Lenke 1 and 5 adolescent idiopathic scoliosis (AIS) but do increase cost. The purpose of this study questioned whether higher screw density constructs improved curve correction and maintenance of correction in Lenke 2 AIS. Secondary goals were to identify predictive factors for correction and postoperative magnitude of curves in Lenke 2 AIS. METHODS: We identified patients 11 to 17 years old who underwent primary PSF for Lenke 2 AIS between 2007 and 2017 who had minimum follow-up of 2 years. Demographic and radiographic data were collected to perform regression and elimination analysis. RESULTS: Thirty patients (21 females, 9 males) were analyzed. Average age and SD at time of surgery was 14.0 ± 1.8 years (range, 11-17 years), and median follow-up was 2.8 years (IQR 2.1-4.0 years). Implant density did not predict final postoperative curve magnitude. Predictors of final postoperative curve magnitude were sex and preoperative curve magnitude. Predictors of percentage of correction of major curve were sex and age at the time of surgery. Predictors of final postoperative thoracic kyphosis were sex and percent flexibility preop. Females had lower final postoperative major curve magnitude, a higher percent curve correction, and lower postoperative thoracic kyphosis. CONCLUSIONS: Increased implant density is not predictive of postoperative curve magnitude in Lenke 2 AIS. Predictors of postoperative curve magnitude are sex and preoperative curve magnitude. LEVEL OF EVIDENCE: Level III, retrospective observational.

The Effect of Osteoporosis Medication on Risk Attenuation of Non-Trauma Fracture Among Adults with Cerebral Palsy: A Propensity Score-Matched Observational Study.

PURPOSE: The efficacy of osteoporosis medication on reducing the risk of non-trauma fracture (NTFx) among adults with cerebral palsy (CP) has not been comprehensively investigated. There are many logistical and biological factors that may reduce this efficacy, and therefore requires attention. The purpose of this propensity score-matched, observational cohort study was to determine if osteoporosis medication was associated with NTFx risk attenuation among adults with CP and compared to adults without CP. MATERIALS AND METHODS: Data from 07/01/2011 to 09/30/2015 were extracted from Optum Clinformatics® Data Mart. Claims identified adults (≥18 years), CP, osteoporosis medication, pre-index NTFx (6-months), and post-index NTFx (12-months). CP without osteoporosis medication (CPMeds-) and without CP with Meds (non-CPMeds+; reflects "background" population) served as controls and were matched (6:1 ratio) to adults with CP with Meds (CPMeds+; n=306). The Meds groups were further stratified by the initiation of their medication as new users or consistent users. Changes in the prevalence of NTFx from pre- to post-index periods were examined with risk ratios (RR) and the change was compared among groups using the ratio of the RR (RRR) via difference-in-difference analysis. RESULTS: New users with CP had: a larger risk attenuation of any NTFx compared to CPMeds- (RRR=0.39; 95% CI=0.22-0.71), which was consistent for vertebral column/hip and lower extremities; a larger risk attenuation for NTFx of the lower extremities compared to consistent users with CP (RRR=0.22; 95% CI=0.05-0.93); and a similar risk attenuation of any NTFx compared to new users without CP (RRR=0.81; 95% CI=0.45-1.43), which was consistent for vertebral column/hip and lower extremities. CONCLUSION: The findings suggest that osteoporosis medication is associated with clinically meaningful risk attenuation of NTFx, especially for new users with CP.

Intersite reliability of vertebral bone marrow lipidomics-derived lipid composition among children with varying degrees of bone fragility undergoing routine orthopedic surgery.

BACKGROUND: Lipidomics, a branch of metabolomics, is an attractive technique to characterize bone marrow lipid composition, which may be associated with skeletal acquisition and homeostasis. However, the reliability of lipidomics-derived lipid composition of the bone marrow is unknown, especially for pediatric populations with bone fragility. The purpose of this study was to evaluate the intersite reliability and standard error of measurement (SEM) of vertebral bone marrow lipid composition at the thoracic (T11/T12) and lumbar (L1/L2) spine determined by targeted lipidomics among children with varying degrees of bone fragility undergoing routine orthopedic surgery. METHODS: Children aged between 12 and 19 years of age, with a confirmed diagnosis of adolescent idiopathic scoliosis or neuromuscular scoliosis and cerebral palsy, and undergoing routine posterior spinal fusion surgery at our institution were initially included in this study. Transpedicular vertebral body bone marrow samples were taken from thoracic (T) or lumbar (L) vertebrae. Further inclusion criteria involved having bone marrow extracted from both T11 and T12 (n = 24) or L1 and L2 (n = 19). Lipid composition was measured using a targeted lipidomics technique and examined as the saturated, monounsaturated, and polyunsaturated index and as individual fatty acids. Relative and absolute test-retest reliability was assessed using the intraclass correlation coefficient (ICC) and SEM. RESULTS: For the T11/T12 analysis: the ICC and SEM were 0.59 and 1.7% for the saturated index, 0.31 and 6.2% for the monounsaturated index, and 0.44 and 6.1% for the polyunsaturated index; the ICC showed a considerable range for individual fatty acids from 0.07 (fatty acid 20:2) to 0.82 (15:0) with 62.1% of the fatty acids having poor reliability (i.e., ICC < 0.50). For the L1/L2 analysis: the ICC and SEM were 0.50 and 2.4% for the saturated index, -0.12 and 6.0% for the monounsaturated index, and 0.00 and 4.9% for the polyunsaturated index; the ICC showed a considerable range for individual fatty acids from -0.34 (18:1_n-9) to 0.88 (15:0 and 18:3_n-3) with 79.3% of the fatty acids having poor reliability. CONCLUSIONS: The intersite test-retest reliability was poor-to-moderate for index measures and generally poor for individual fatty acids for the thoracic and lumbar spine. At this time, it is not recommended to pool bone marrow adipose tissue across vertebral sites for bone marrow adiposity research or clinical monitoring for pediatric populations with bone fragility.