Publications by authors named "Frank Rauch"

228 Publications

Health-related quality of life in adults with osteogenesis imperfecta.

Clin Genet 2021 Feb 12. Epub 2021 Feb 12.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.

Patient-reported outcome measures (PROMs) are increasingly utilized as endpoints in clinical trials. The Short Form Health Survey-12 (SF-12v2) is a generic PROM for adults. We sought to evaluate the validity of SF-12v2 in adults with osteogenesis imperfecta (OI). Physical and mental health-related quality of life (HRQoL) were assessed in a large cohort of adults in a multicenter, observational, natural history study. Physical HRQoL scores were correlated with the Gillette Functional Assessment Questionnaire (GFAQ). We calculated sample sizes required in clinical trials with crossover and parallel-group designs to detect clinically meaningful changes in physical HRQoL. Three hundred and two adults with OI types I, III, and IV were enrolled. Physical HRQoL scores in the study population were lower than population norms. Physical HRQoL scores moderately correlated with GFAQ for OI types I and IV. We found no correlations between mental and physical HRQoL. From a clinical trial readiness perspective, we show that SF-12v2 reliably measures physical function in adults with OI and can be utilized in crossover trials to detect meaningful physical HRQoL changes with small sample sizes. This study shows that SF-12v2 can be used to measure changes in physical HRQoL in response to interventions in OI.
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http://dx.doi.org/10.1111/cge.13939DOI Listing
February 2021

Multisite longitudinal calibration of HR-pQCT scanners and precision in osteogenesis imperfecta.

Bone 2021 Feb 6:115880. Epub 2021 Feb 6.

Research Centre, Shriners Hospital for Children-Canada, Montreal, Canada; Department of Pediatric Surgery, McGill University, Montreal, Canada; Department of Biomedical Engineering, McGill University, Montreal, Canada. Electronic address:

Background: For high-resolution peripheral quantitative computed tomography (HR-pQCT) to be used in longitudinal multi-center studies to assess disease and treatment effects, data must be aggregated across multiple timepoints and scanners. This requires an understanding of the factors contributing to scanner precision, and multi-scanner cross-calibration procedures, especially for clinical populations with severe phenotypes, like osteogenesis imperfecta (OI).

Methods: To address this, we first evaluated single- and multi-center short- and long-term precision errors of standard HR-pQCT parameters. Two imaging phantoms were circulated among 13 sites (7 XtremeCT and 6 XtremeCT2) and scanned in triplicate at 3 timepoints/site. Additionally, duplicate in vivo radial and tibial scans were acquired in 29 individuals with OI. Secondly, we investigated subject- and scanner-related factors that contribute to precision errors using regression analysis. Thirdly, we proposed a reference site selection criterion for multisite cross-calibration and demonstrated the external validity of phantom-based calibrations.

Results: Our results show excellent short-term single-site precision in both phantoms (CV %  < 0.5%) and in density, microarchitecture and finite element parameters of OI participants (CV %  = 0.75 to 1.2%). In vivo reproducibility significantly improved with (i) cross sectional area image registration versus no registration and (ii) scans with no motion artifacts. While reproducibility was similar across OI subtypes and anatomical sites, XtremeCT2 scanners achieved ~2.5% better precision than XtremeCT for trabecular parameters. Finally, we demonstrate that multisite longitudinal precision errors resulting from inconsistencies between scanners can be partially corrected through scanner cross-calibration.

Conclusions: This study is the first to assess long-term reproducibility and cross-calibration in a study using first and second generation HR-pQCT scanners. The results presented in this context provide timely guidelines for future use of this powerful clinical imaging modality in multi-center longitudinal clinical trials.
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http://dx.doi.org/10.1016/j.bone.2021.115880DOI Listing
February 2021

Effects of treatment with a bone-targeted prostaglandin E2 receptor 4 agonist C3 (Mes-1007) in a mouse model of severe osteogenesis imperfecta.

Bone 2021 Apr 29;145:115867. Epub 2021 Jan 29.

Shriners Hospital for Children-Canada, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada. Electronic address:

Objective: Osteogenesis imperfecta (OI) is a heritable bone fragility disorder that is usually caused by mutations affecting collagen type I synthesis in osteoblasts. Bisphosphonates are widely used to decrease fracture rate but are only partially effective. Bone anabolic compounds, such as prostaglandin E2 receptor 4 (EP4) agonists may be an alternative treatment approach. Here we assessed the effect of Mes-1007, a novel bone-targeted EP4 agonist in Jrt mice, a model of severe OI.

Study Design: Experimental study.

Results: Male 8-week old wild type (WT) and OI mice were randomly assigned to 4 weeks of three intraperitoneal injections per week with Mes-1007 (25 mg per kg body mass), phosphate-buffered saline, zoledronate (5 μg per kg), or a combination treatment of zoledronate and Mes-1007. Treatment with Mes-1007 alone did not lead to higher trabecular bone volume per tissue volume (BV/TV) in the distal femur or lumbar vertebra 4 in either WT or OI mice. Treatment with zoledronate alone was associated with a significant increase in distal femur and vertebra BV/TV in both genotypes. In zoledronate-treated WT and OI mice, Mes-1007 increased bone formation rate in vertebral trabecular bone and had an additive effect on BV/TV. Vertebral BV/TV in OI mice that received zoledronate or Mes-1007/zoledronate combination treatment was similar to untreated WT mice (p = 0.25). At the femoral midshaft, Mes-1007/zoledronate combination treatment increased cortical thickness in both genotypes and led to higher periosteal diameter in OI mice. Three-point bending tests of femurs showed that Mes-1007/zoledronate combination treatment increased the stiffness, load at yield and maximal load in WT but not in OI mice.

Conclusion: Dosing Mes-1007 in combination with zoledronate improved the bone properties in a manner that is consistent with a mechanism of action of EP4 agonists on bone and additive to effects of anti-resorptives typified by zoledronate.
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http://dx.doi.org/10.1016/j.bone.2021.115867DOI Listing
April 2021

Burosumab for the Treatment of Tumor-Induced Osteomalacia.

J Bone Miner Res 2020 Dec 18. Epub 2020 Dec 18.

Yale University School of Medicine, New Haven, CT, USA.

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..
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http://dx.doi.org/10.1002/jbmr.4233DOI Listing
December 2020

Prevalence of SARS-CoV-2 infections in a pediatric orthopedic hospital.

Paediatr Anaesth 2021 02 11;31(2):247-248. Epub 2020 Nov 11.

Shriners Hospital for Children - Canada, Montreal, QC, Canada.

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http://dx.doi.org/10.1111/pan.14047DOI Listing
February 2021

Treatment response to long term antiresorptive therapy in osteogenesis imperfecta type VI: does genotype matter?

J Pediatr Endocrinol Metab 2020 Dec 8;33(12):1617-1624. Epub 2020 Oct 8.

Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey.

Objectives: Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel mutations, who show great variation in their treatment response to bisphosphonates.

Case Presentation: The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead.

Conclusion: transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.
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http://dx.doi.org/10.1515/jpem-2020-0260DOI Listing
December 2020

Giving Children With Osteogenesis Imperfecta a Voice: Participatory Approach for the Development of the Interactive Assessment and Communication Tool Sisom OI.

J Med Internet Res 2020 09 22;22(9):e17947. Epub 2020 Sep 22.

Ingram School of Nursing, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC, Canada.

Background: Children with osteogenesis imperfecta (OI) experience acute and chronic symptoms that expose them to physical, mental, and social challenges. Empowering these children by involving them in their care can help them to cope with OI. Sisom is an interactive assessment and communication tool designed to help children aged 6-12 years with chronic illnesses express their symptoms. This tool has not yet been adapted to the unique needs of OI.

Objective: The aim of this study was to develop a Sisom OI paper prototype by seeking the perspectives of end users.

Methods: A participatory approach was adopted to develop the prototype overseen by an expert panel of 9 clinicians at a university-affiliated pediatric hospital. Purposive sampling was used to recruit 12 children with OI who were aged 6-12 years. The study was carried out over the course of 3 feedback cycles. Data were deductively interpreted using content analysis techniques.

Results: Overall, 64% (57/89) of the Sisom symptoms were deemed relevant for inclusion in Sisom OI, with 42% (37/89) directly incorporated and 22% (20/89) incorporated with changes. In total, 114 symptoms were used to create the prototype, of which 57 were newly generated. The relevant symptoms addressed children's thoughts and feelings about hospitalization and their wishes for participation in their own care. The new symptoms addressed fractures, body image, and social isolation related to difficulties with accessibility and intimidation.

Conclusions: Once developed, Sisom OI will offer clinicians an innovative and child-centered approach to capture children's perspectives on their condition.
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http://dx.doi.org/10.2196/17947DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7539168PMC
September 2020

Assessment of longitudinal bone growth in osteogenesis imperfecta using metacarpophalangeal pattern profiles.

Bone 2020 11 27;140:115547. Epub 2020 Jul 27.

Shriners Hospital for Children and McGill University, Montreal, Quebec, Canada. Electronic address:

Objective: Osteogenesis imperfecta (OI) is commonly associated with short stature, but it is unclear whether this is exclusively secondary to fractures and bone deformities or whether there is a primary defect in longitudinal bone growth. As metacarpal and phalangeal bones are rarely affected by fractures and deformities, any length deficits in these bones should reflect a direct disease effect on longitudinal growth. This study therefore assessed the relationship of hand bone length with clinical OI type and genotype.

Study Design: Prospective study.

Results: The length of all 19 tubular hand bones were measured in 144 individuals (age 6 to 57 years; 68 female) who had OI caused by COL1A1 or COL1A2 variants. Measurements of bone length were converted to z-scores using published reference data. Bone length was mostly normal in OI type I but was significantly decreased in OI types III and IV. Mean hand bone length z-score (i.e., the average length z-score of all 19 bones of a hand) was -0.2 for OI type I, -2.9 for OI type III and -1.2 for OI type IV. Mean hand bone length z-score was positively associated with height z-score (r = 0.65, P < 0.001). Regarding genotype-phenotype correlations, mean hand bone length z-score was close to 0 in individuals with COL1A1 mutations leading to haploinsufficiency but were significantly lower in the presence of mutations leading to triple-helical glycine substitutions in either the alpha 1 or alpha 2 chain of collagen type I.

Conclusion: COL1A1 and COL1A2 mutations affect bone growth not only by inducing fractures and bone deformities, but also through longitudinal growth deficits in bones that do not fracture or deform.
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http://dx.doi.org/10.1016/j.bone.2020.115547DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7502481PMC
November 2020

Predicting ambulatory function at skeletal maturity in children with moderate to severe osteogenesis imperfecta.

Eur J Pediatr 2021 Jan 28;180(1):233-239. Epub 2020 Jul 28.

Shriners Hospital for Children, 1003 Decarie Boulevard, Montreal, Quebec, Canada.

Maximizing ambulation is a key treatment aim in moderate to severe osteogenesis imperfecta (OI). Here we investigated which early clinical characteristics predicted ambulation function at skeletal maturity. We assessed Bleck ambulation scores in 88 individuals with OI at 5 to 6 years of age and again at final height (at 15 to 24 years of age). At 5 to 6 years of age, 33 (38%) children were non-ambulators, 32 (36%) were fully independent ambulators, and 23 (26%) had intermediate ambulation skills. At skeletal maturity, 58% of the study participants had the same mobility level as at first assessment. The ability to ambulate independently at skeletal maturity was predicted by independent ambulation at 5 to 6 years (odds ratio [OR] 22.6, 95% confidence interval [CI] 4.9-105; P < 0.001), height z score at 5 to 6 years (OR 3.1, CI 1.6-6.3; P = 0.001) and weight z score at 5 to 6 years (OR 0.44, CI 0.19-0.99; P = 0.04).Conclusion: Independent ambulation at 5 to 6 years was the main determinant of independent ambulation at skeletal maturity. This highlights the importance of maximizing ambulation in children below 5 years of age. What is Known: •walking ability varies markedly between OI types. The highest level of mobility was found in OI type I, the lowest in OI type III who require mobility aids; intermediate levels were reported for OI type IV. • OI type is a key predictor of ultimate ability to ambulate, whereas the timing of developmental milestones was not associated with walking ability What is New: • overall key predictors of mobility function at skeletal maturity were mobility status and height z-score at 5-6 years of age • Childrenwho were non-ambulators at 5 to 6 years of age had a higher chance of having better mobility at skeletal maturity if they had good upper extremity function, as expressed in the PEDI Self Care Score.
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http://dx.doi.org/10.1007/s00431-020-03754-wDOI Listing
January 2021

Malocclusion traits and oral health-related quality of life in children with osteogenesis imperfecta: A cross-sectional study.

J Am Dent Assoc 2020 Jul;151(7):480-490.e2

Background: The incidence of malocclusion is higher among people with osteogenesis imperfecta (OI) than the general population, and treatment options are limited due to the weak structure of bones and teeth. Focusing on those malocclusion traits that might have a high impact on a patient's oral health-related quality of life (OHRQoL) is warranted.

Methods: A total of 138 children and adolescents with OI were examined for malocclusion traits. OHRQoL was measured using age-specific versions (8 through 10 years and 11 through 14 years) of the Child Perceptions Questionnaire (CPQ), considering the following domains: oral symptoms, functional limitation, emotional well-being, and social well-being. Higher scores implied worse OHRQoL. Multivariable ordinal logistic regression was used to estimate the association between malocclusion traits and OHRQoL.

Results: Among children aged 8 through 10 years (n = 56), the CPQ and its constituent domain scores were relatively similar between those with malocclusion (higher scores) and those without. In the adolescent (n = 82) group aged 11 through 14 years; however, those with posterior crossbite (odds ratio, 5.01; 95% confidence interval, 1.40 to 12.41) or open bite (odds ratio, 3.21; 95% confidence interval, 1.21 to 10.23) experienced statistically significantly higher degrees of functional limitations (a higher functional limitation score) than those without.

Conclusions: Adolescents with OI and posterior open bites or crossbites have substantial self-reported functional limitations and worse oral symptoms, which warrants additional investigation and therapeutic trials in an attempt to improve the malocclusion. In addition, the authors found that the CPQ can be a useful tool in a clinical trial of orthodontic interventions in OI.
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http://dx.doi.org/10.1016/j.adaj.2020.03.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7360479PMC
July 2020

Bone densities and bone geometry in children and adolescents with arthrogryposis.

Bone 2020 08 25;137:115454. Epub 2020 May 25.

Shriners Hospital for Children, Montreal, Quebec, Canada; Department of Pediatrics, McGill University, Montreal, Quebec, Canada. Electronic address:

Objective: To describe bone densitometry results using lumbar spine dual-energy X-ray absorptiometry and forearm peripheral quantitative computed tomography (pQCT) in children with arthrogryposis multiplex congenita (AMC).

Study Design: Prospective study.

Results: Lumbar spine areal bone mineral density (BMD) was measured in 58 participants (mean age 6.8 years, range 1 month to 19.7 years; 26 males). The diagnostic subgroup was Amyoplasia in 27 participants, distal arthrogryposis (unclassified, n = 13; type 2A, n = 1; type 2B, n = 2; type 8, n = 2) in 18 patients, an unclassified form of arthrogryposis in 6 patients, and a syndromic form of arthrogryposis in 7 patients. The mean lumbar spine areal BMD was -0.4 (SD: 1.5) which was significantly below 0 (p < 0.05, one-sample t-test). The mean lumbar spine bone mineral apparent density z-score (+0.4 [SD: 1.4]), a measure that is largely independent of bone size, was not significantly different from 0 (P > 0.05). A subset of 22 patients aged 6 years or older (mean age 10.9 years, 11 males) had forearm pQCT analysis. Mean z-scores for trabecular and cortical volumetric BMD at the radius were similar to healthy controls. Radius periosteal bone circumference and bone mineral content were appropriate for height. These densitometric results did not differ between patients with Amyoplasia or individuals with other diagnoses.

Conclusions: Low areal BMD in children and adolescents with AMC reflects their smaller bone size rather than a specific bone mass deficit. These data do not suggest that children and adolescents with AMC in general require regular monitoring by bone densitometry unless there are specific clinical concerns.
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http://dx.doi.org/10.1016/j.bone.2020.115454DOI Listing
August 2020

Exploring the Perceived Self-management Needs of Young Adults With Osteogenesis Imperfecta.

Clin Nurse Spec 2020 May/Jun;34(3):99-106

Author Affiliations: McGill University, Ingram School of Nursing (Mss Michalovic and Anderson and Drs Rauch and Tsimicalis); and Shriners Hospitals for Children (Ms Thorstad and Drs Rauch and Tsimicalis), Montreal, Quebec, Canada.

Purpose: To explore the perceived self-management needs of young adults with osteogenesis imperfecta (OI) with the goal of optimizing the self-management and transitional care services.

Methods: A qualitative descriptive study was performed with young adults diagnosed with OI. Two semistructured interviews were conducted before and after their first appointment with a nurse practitioner in the adult healthcare settings (a new partnership initiated by the pediatric hospital). Data were transcribed and descriptively analyzed.

Results: Seven participants with OI types I, III, and IV were interviewed. Ages ranged from 23 to 34 years, and years since discharge from the pediatric hospital ranged from 3 to 10. Four themes emerged including (1) dropped in the jungle, with no one to call; (2) they do not know how to treat me; (3) I feel like I'm going to get back in the loop; and (4) self-managing what I know, how I know.

Conclusions: Similar to other childhood-onset conditions, adolescents and young adults with OI require education and mentorship, and clinicians in the adult healthcare system need to be prepared and supported to receive them. Collective efforts are needed to improve the self-management and transitional care needs for young adults with OI.
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http://dx.doi.org/10.1097/NUR.0000000000000517DOI Listing
April 2020

Bone Disease in Patients with Ehlers-Danlos Syndromes.

Curr Osteoporos Rep 2020 04;18(2):95-102

Shriners Hospital for Children, 1003 Boulevard Decarie, Montreal, Québec, Canada.

Purpose Of Review: To summarize the bone findings, mainly bone mass and fracture risk, in Ehlers-Danlos syndromes (EDS).

Recent Findings: Low bone mineral density and fractures seem to be frequent in some of the rare EDS types (kyphoscoliotic, arthrochalasia, spondylodysplastic, and classic-like EDS). For the more prevalent hypermobile and classic EDS types, some case-control studies found mildly decreased bone mineral density, but it was not clear that fracture rates were increased. Nevertheless, abnormalities in vertebral shape seem to be common in classical and hypermobile EDS types. In a cohort of individuals with EDS followed since birth, no fractures were observed during infancy. Bone mineral density varies widely among the different types of EDS, and vertebral abnormalities seem to be common in classical and hypermobile EDS. It might be justified to perform spine radiographs and bone mineral density assessments in newly diagnosed EDS.
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http://dx.doi.org/10.1007/s11914-020-00568-5DOI Listing
April 2020

Musculoskeletal phenotype in two unrelated individuals with a recurrent nonsense variant in SGMS2.

Bone 2020 05 3;134:115261. Epub 2020 Feb 3.

Shriners Hospital for Children - Canada, McGill University, Montreal, QC, Canada.

Heterozygous mutations in the gene encoding the sphingomyelin synthase 2, SGMS2, have recently been linked to childhood-onset osteoporosis and skeletal dysplasia. One nonsense variant at position c.148C>T (p.Arg50*) has been associated with mild bone fragility with or without cranial sclerosis. Here we assessed the effect of the SGMS2 p.Arg50* variant in two unrelated probands with childhood-onset osteoporosis and their unaffected family members. We found that the p.Arg50* variant was associated with phenotypic variability, ranging from absence of a bone phenotype to severe vertebral compression fractures and low lumbar spine areal bone mineral density (BMD) as measured by dual energy x-ray absorptiometry. Peripheral quantitative computed tomography of the radius and tibia in the two probands revealed low cortical volumetric BMD and reduced cortical thickness. In addition, both probands were obese and suffered from muscle function deficits compared to sex- and age-matched controls. Long-term bisphosphonate treatment was associated with reshaping of previously compressed vertebral bodies.
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http://dx.doi.org/10.1016/j.bone.2020.115261DOI Listing
May 2020

Increased Burden of Common Risk Alleles in Children With a Significant Fracture History.

J Bone Miner Res 2020 05 28;35(5):875-882. Epub 2020 Jan 28.

Lady Davis Institute for Medical Research, Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Canada.

Extreme presentations of common disease in children are often presumed to be of Mendelian etiology, but their polygenic basis has not been fully explored. We tested whether children with significant fracture history and no osteogenesis imperfecta (OI) are at increased polygenic risk for fracture. A childhood significant fracture history was defined as the presence of low-trauma vertebral fractures or multiple long bone fractures. We generated a polygenic score of heel ultrasound-derived speed of sound, termed "gSOS," which predicts risk of osteoporotic fracture. We tested if individuals from three cohorts with significant childhood fracture history had lower gSOS. A Canadian cohort included 94 children with suspected Mendelian osteoporosis, of which 68 had negative OI gene panel. Two Finnish cohorts included 59 children with significant fracture history and 22 with suspected Mendelian osteoporosis, among which 18 had no OI. After excluding individuals with OI and ancestral outliers, we generated gSOS estimates and compared their mean to that of a UK Biobank subset, representing the general population. The average gSOS across all three cohorts (n = 131) was -0.47 SD lower than that in UK Biobank (n = 80,027, p = 1.1 × 10 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10 ). Among the 131 individuals with a significant fracture history, we observed 8 individuals with gSOS below minus 2 SD from the mean; their mean lumbar spine DXA-derived bone mineral density Z-score was -1.7 (SD 0.8). In summary, children with significant fracture history but no OI have an increased burden of common risk alleles. This suggests that a polygenic contribution to disease should be considered in children with extreme presentations of fracture. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3956DOI Listing
May 2020

The Accuracy of Prevalent Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches.

J Bone Miner Res 2020 03 17;35(3):460-468. Epub 2019 Dec 17.

Canadian Pediatric Bone Health Working Group, Ottawa, ON, Canada.

Due to concerns about cumulative radiation exposure in the pediatric population, it is not standard practice to perform spine radiographs in most conditions that predispose to vertebral fracture (VF). In this study we examined the accuracy of two clinical predictors, back pain and lumbar spine bone mineral density (LS BMD), to derive four case-finding paradigms for detection of prevalent VF (PVF). Subjects were 400 children at risk for PVF (leukemia 186, rheumatic disorders 135, nephrotic syndrome 79). Back pain was assessed by patient report, LS BMD was measured by dual-energy X-ray absorptiometry, and PVF were quantified on spine radiographs using the modified Genant semiquantitative method. Forty-four patients (11.0%) had PVF. Logistic regression analysis between LS BMD and PVF produced an odds ratio (OR) of 1.9 (95% confidence interval [CI], 1.5 to 2.5) per reduction in Z-score unit, an area under the receiver operating characteristic curve of 0.70 (95% CI, 0.60 to 0.79), and an optimal BMD Z-score cutoff of -1.6. Case identification using either low BMD alone (Z-score < -1.6) or back pain alone gave similar results for sensitivity (55%, 52%, respectively), specificity (78%, 81%, respectively), positive predictive value (PPV; 24%, 25%, respectively), and negative predictive value (NPV; 93%, 93%, respectively). The paradigm using low BMD plus back pain produced lower sensitivity (32%), higher specificity (96%), higher PPV (47%), and similar NPV (92%). The approach using low BMD or back pain had the highest sensitivity (75%), lowest specificity (64%), lowest PPV (20%), and highest NPV (95%). All paradigms had increased sensitivities for higher fracture grades. Our results show that BMD and back pain history can be used to identify children with the highest risk of PVF so that radiography can be used judiciously. The specific paradigm to be applied will depend on the expected PVF rate and the clinical approach to the use of radiography. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3922DOI Listing
March 2020

A de novo frameshift FGFR1 mutation extending the protein in an individual with multiple epiphyseal dysplasia and hypogonadotropic hypogonadism without anosmia.

Eur J Med Genet 2020 Apr 9;63(4):103784. Epub 2019 Oct 9.

Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine Hospital, University of Montreal, Montreal, Canada. Electronic address:

Multiple epiphyseal dysplasia (MED) is a genetically and clinically heterogeneous disease with both dominant and recessive inheritance. Eight different genes are known to cause the disease but in 15% of cases of MED, no mutation is found. Fibroblast growth factor receptor 1 (FGFR1) is a crucial regulator of bone formation and when mutated, can cause diseases with skeletal manifestations; nevertheless, MED has not been described in individuals with FGFR1 mutations. In this report, we describe a proband with MED and congenital normosmic hypogonadotropic hypogonadism (HH). DNA analysis showed a de novo frameshift variant in FGFR1 likely explaining the HH (p.Arg852Thrfs*165). No other mutation was found after a large gene sequencing panel, exome sequencing and an array CGH, except for a variant of unknown significance in FBN1 (rs755375255), but there were no features of a disease associated with FBN1 mutations and this variant is found a few times in population databases. We thus discuss the possibility that MED might be a new skeletal feature associated with FGFR1 mutations.
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http://dx.doi.org/10.1016/j.ejmg.2019.103784DOI Listing
April 2020

Arachidonic acid exacerbates diet-induced obesity and reduces bone mineral content without impacting bone strength in growing male rats.

J Nutr Biochem 2019 11 15;73:108226. Epub 2019 Aug 15.

School of Human Nutrition, McGill University, 21111 Lakeshore Road, Ste-Anne-de-Bellevue, QC, Canada H9X 3V9. Electronic address:

Long-chain polyunsaturated fatty acids modulate bone mass and adipocyte metabolism. Arachidonic acid (AA, C20:4 n-6) is elevated in obesity and postulated to stimulate bone resorption. This study aimed to determine the effect of AA on bone mass, quality, and adiposity in diet-induced obesity during growth. Male Sprague-Dawley rats (n=42, 4-week) were randomized into groups fed a control diet (CTRL, AIN-93G), high-fat diet (HFD, 35% kcal fat) or HFD + AA (1% w/w diet) for 6 weeks. Body composition, bone mineral density and microarchitecture were measured using dual-energy X-ray absorptiometry and micro-computed tomography. Red blood cell fatty acid profile was measured with gas chromatography. Group differences were evaluated using repeated measures two-way analysis of variance with Tukey-Kramer post hoc testing. Total energy intake did not differ among diet groups. At week 6, HFD + AA had significantly greater body fat % (12%), body weight (6%) and serum leptin concentrations (125%) than CTRL, whereas visceral fat (mass and %, assessed with micro-computed tomography) was increased in both HFD and HFD + AA groups. HFD + AA showed reduced whole body bone mineral content and femur mid-diaphyseal cortical bone cross-sectional area than HFD and CTRL, without impairment in bone strength. Contrarily, HFD + AA had greater femur metaphyseal trabecular vBMD (35%) and bone volume fraction (5%) compared to controls. Inclusion of AA elevated leptin concentrations in male rats. The early manifestations of diet-induced obesity on bone mass were accelerated with AA. Studies of longer duration are needed to clarify the effect of AA on peak bone mass following growth cessation.
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http://dx.doi.org/10.1016/j.jnutbio.2019.108226DOI Listing
November 2019

Osteogenesis Imperfecta: New Perspectives From Clinical and Translational Research.

JBMR Plus 2019 Aug 20;3(8):e10174. Epub 2019 Feb 20.

Shriners Hospital for Children Montreal Quebec Canada.

Osteogenesis imperfecta (OI) is a monogenic bone fragility disorder that usually is caused by mutations in one of the two genes coding for collagen type I alpha chains, or . Mutations in at least 18 other genes can also lead to an OI phenotype. As genetic testing is more widely used, mutations in these genes are also more frequently discovered in individuals who have a propensity for fractures, but who do not have other typical clinical characteristics of OI. Intravenous bisphosphonate therapy is still the most widely used drug treatment approach. Preclinical studies in OI mouse models have shown encouraging effects when the antiresorptive effect of a bisphosphonate was combined with bone anabolic therapy using a sclerostin antibody. Other novel experimental treatment approaches include inhibition of transforming growth factor beta signaling with a neutralizing antibody and the inhibition of myostatin and activin A by a soluble activin receptor 2B. © 2019 The Authors. published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715783PMC
August 2019

Novel ActRIIB ligand trap increases muscle mass and improves bone geometry in a mouse model of severe osteogenesis imperfecta.

Bone 2019 11 13;128:115036. Epub 2019 Aug 13.

Department of Pediatrics, McGill University, Montreal, Quebec, Canada; Shriners Hospital for Children-Canada, Montreal, Quebec, Canada. Electronic address:

Osteogenesis imperfecta (OI) caused by mutations affecting the extracellular matrix protein collagen type I is characterized by fragile bones and low muscle mass and function. Activin A and myostatin, members of the TGF-β superfamily, play a key role in the control of muscle mass and in muscle-bone communication. Here we investigated activin A/myostatin signaling in a mouse model of severe dominant OI, Col1a1mouse, and the effect of activin A/myostatin inhibition by a soluble activin receptor IIB receptor, ACE-2494, on bones and muscles in 8-week old mice. Compared to wild type mice, Col1a1mice had elevated TGF-β signaling in bone and muscle tissue. ACE-2494 treatment of wild type mice resulted in significantly increased muscle mass, bone length, bone mass as well as improved bone mechanical properties. However, treatment of Col1a1mice with ACE-2494 was associated with significant gain in muscle mass, significantly improved bone length and bone geometry, but no significant treatment effect was found on bone mass or bone mechanical properties. Thus, our data indicate that activin A/myostatin neutralizing antibody ACE-2494 is effective in stimulating muscle mass, bone length and diaphyseal bone growth but does not correct bone mass phenotype in a mouse model ofdominant OI.
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http://dx.doi.org/10.1016/j.bone.2019.115036DOI Listing
November 2019

Mineralized tissues in hypophosphatemic rickets.

Pediatr Nephrol 2020 10 8;35(10):1843-1854. Epub 2019 Aug 8.

Shriners Hospital for Children and McGill University, 1003 Boulevard Decarie, Montreal, Québec, H4A 0A9, Canada.

Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized ("periosteocytic lesions"), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated.
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http://dx.doi.org/10.1007/s00467-019-04290-yDOI Listing
October 2020

Burosumab Improved Histomorphometric Measures of Osteomalacia in Adults with X-Linked Hypophosphatemia: A Phase 3, Single-Arm, International Trial.

J Bone Miner Res 2019 12 1;34(12):2183-2191. Epub 2019 Oct 1.

Division of Pediatric Nephrology, University of California, San Francisco, CA, USA.

In adults with X-linked hypophosphatemia (XLH), excess FGF23 impairs renal phosphate reabsorption and suppresses production of 1,25-dihydroxyvitamin D, resulting in chronic hypophosphatemia and persistent osteomalacia. Osteomalacia is associated with poor bone quality causing atraumatic fractures, pseudofractures, delayed fracture healing, and bone pain. Burosumab is a fully human monoclonal antibody against FGF23. UX023-CL304 is an ongoing, open-label, single-arm, phase 3 study investigating the efficacy of subcutaneous burosumab, 1.0 mg/kg administered every 4 weeks, in improving osteomalacia in adults with XLH who have not been treated for at least 2 years before enrollment. The primary endpoint was improvement in osteoid volume/bone volume assessed by transiliac bone biopsies obtained at baseline and week 48. Additional assessments included serum phosphorus, markers of bone turnover, fracture/pseudofracture healing, and safety. Fourteen subjects enrolled, 13 completed 48 weeks, and 11 completed paired biopsies. All osteomalacia-related histomorphometric measures improved significantly at week 48 (mean percent change: osteoid volume/bone volume, -54%, osteoid thickness, -32%, osteoid surface/bone surface, -26%, [median] mineralization lag time, -83%). Mean serum phosphorus concentration averaged across the mid-point of the dose cycle between weeks 0 and 24 was 3.3 mg/dL, a 50% increase from 2.2 mg/dL at baseline. Markers of bone formation and resorption increased at week 48 (least squares [LS] mean increase: P1NP, +77%; CTx, +36%; both p < 0.0001). All subjects had one or more treatment-emergent adverse event (AE). Most AEs were mild to moderate in severity. Two subjects experienced serious AEs (migraine; paresthesia) that were unrelated to treatment and resolved. Eleven subjects had 18 biopsy procedure-related AEs: 14 for pain, two for itch, and one each for headache and bandage irritation. No deaths or incidents of hyperphosphatemia occurred. In conclusion, by normalizing phosphate homeostasis, burosumab significantly improved osteomalacia in adults with XLH, which likely explains the improved fracture healing and amelioration of skeletal complications. © 2019 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3843DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6916280PMC
December 2019

Osteogenesis Imperfecta: Skeletal Outcomes After Bisphosphonate Discontinuation at Final Height.

J Bone Miner Res 2019 12 26;34(12):2198-2204. Epub 2019 Aug 26.

Shriners Hospital for Children, Montreal, Canada.

Intravenous cyclical bisphosphonates are widely used to treat children with moderate to severe osteogenesis imperfecta (OI). Bisphosphonates are often discontinued when growth is completed, but subsequent skeletal changes have not been studied in detail. We assessed 31 patients (22 females) with OI who had started intravenous bisphosphonates (either pamidronate or zoledronic acid) before 13 years of age, were treated for at least 2 years (range 4.7-15.7 years), and discontinued treatment after completion of growth, when their age ranged from 13.4 to 20.0 years (mean 16.4 years). At 4 years after treatment discontinuation, lumbar spine areal bone mineral density (BMD) had increased by 4% (p < 0.05). Peripheral quantitative computed tomography of the radius showed a decrease in trabecular volumetric BMD at the distal metaphysis of 19% but an increase in cortical volumetric BMD of 4% (p < 0.05 for both). None of the patients sustained a new vertebral compression fracture during follow-up. The proportion of patients with new long-bone fractures was higher in the 2 years before treatment discontinuation than in the last 2 years of follow-up (42% and 16%, respectively; p < 0.05). © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3833DOI Listing
December 2019

Cone-Beam Computed Tomography of Osteogenesis Imperfecta Types III and IV: Three-Dimensional Evaluation of Craniofacial Features and Upper Airways.

JBMR Plus 2019 Jun 7;3(6):e10124. Epub 2019 Feb 7.

Faculty of Dentistry McGill University Montreal Canada.

This cross-sectional study investigated the natural history of craniofacial deformities in osteogenesis imperfecta (OI) and determined the impact of three-dimensional (3D) analysis on diagnosis and treatment planning in orthodontics and orthognathic surgery in comparison to conventional two-dimensional (2D) cephalometric examination. 3D images of the craniofacial complex were acquired during 1 calendar year using cone-beam computed tomography (CBCT) from a cohort of 41 individuals (aged 11 to 35 years; 28 females) with OI type III ( = 13) or IV ( = 28). 3D evaluation of the craniocervical junction and upper airways was conducted using InVivo. 2D lateral cephalogram was constructed, traced, and examined using the University of Western Ontario analysis (Dolphin). Quantitative and qualitative parameters were compared between OI type III and type IV groups (unpaired test) and the unaffected population (-score). 3D evaluation revealed a high prevalence of craniocervical abnormalities, craniofacial asymmetries, and nasal septum deviation in both OI groups. Mean airway dimensions were comparable to the non-affected population norms, except for 5 individuals who had insufficient airway dimensions. In 2D, the maxilla was retrognathic and hypoplastic, and the mandibular position was convergent with respect to the face, resulting in mandibular prognathism and face height reduction. The 2D trends were more pronounced in OI type III, whereas the 3D craniocervical and airway abnormalities were common in both types. This study illustrates the prevalence of craniofacial and airway anomalies in OI that occur along with facial deformities are not associated with postcranial phenotype and OI type, are apparent only in 3D evaluation, and are likely to influence treatment strategy. For OI patients, a team effort involving a dentist, orthodontist, neurologist, and ear-nose-throat (ENT) practitioner is recommended for successful management of craniofacial deformities.
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http://dx.doi.org/10.1002/jbm4.10124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6636768PMC
June 2019

Management of bone disease in cystinosis: Statement from an international conference.

J Inherit Metab Dis 2019 09 5;42(5):1019-1029. Epub 2019 Aug 5.

Department of Pediatric Kidney, Liver and Metabolic Diseases, Hannover Medical School, Hannover, Germany.

Cystinosis is an autosomal recessive storage disease due to impaired transport of cystine out of lysosomes. Since the accumulation of intracellular cystine affects all organs and tissues, the management of cystinosis requires a specialized multidisciplinary team consisting of pediatricians, nephrologists, nutritionists, ophthalmologists, endocrinologists, neurologists' geneticists, and orthopedic surgeons. Treatment with cysteamine can delay or prevent most clinical manifestations of cystinosis, except the renal Fanconi syndrome. Virtually all individuals with classical, nephropathic cystinosis suffer from cystinosis metabolic bone disease (CMBD), related to the renal Fanconi syndrome in infancy and progressive chronic kidney disease (CKD) later in life. Manifestations of CMBD include hypophosphatemic rickets in infancy, and renal osteodystrophy associated with CKD resulting in bone deformities, osteomalacia, osteoporosis, fractures, and short stature. Assessment of CMBD involves monitoring growth, leg deformities, blood levels of phosphate, electrolytes, bicarbonate, calcium, and alkaline phosphatase, periodically obtaining bone radiographs, determining levels of critical hormones and vitamins, such as thyroid hormone, parathyroid hormone, 25(OH) vitamin D, and testosterone in males, and surveillance for nonrenal complications of cystinosis such as myopathy. Treatment includes replacement of urinary losses, cystine depletion with oral cysteamine, vitamin D, hormone replacement, physical therapy, and corrective orthopedic surgery. The recommendations in this article came from an expert meeting on CMBD that took place in Salzburg, Austria, in December 2016.
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http://dx.doi.org/10.1002/jimd.12134DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7379238PMC
September 2019

A Multicenter Observational Cohort Study to Evaluate the Effects of Bisphosphonate Exposure on Bone Mineral Density and Other Health Outcomes in Osteogenesis Imperfecta.

JBMR Plus 2019 May 7;3(5):e10118. Epub 2019 Jan 7.

Hospital for Special Surgery Dept of Orthopedic Surgery New York NY USA.

Osteogenesis imperfecta (OI) is characterized by low bone mass and bone fragility. Using data from a large cohort of individuals with OI from the Osteogenesis Imperfecta Foundation's linked clinical research centers, we examined the association between exposure to bisphosphonate (BPN) treatment (past or present) and lumbar spine (LS) areal bone mineral density (aBMD), fractures, scoliosis, and mobility. From 466 individuals, we obtained 1394 participant-age LS aBMD data points. Though all OI subtypes were examined, primary analyses were restricted to type I OI (OI-1). Using linear regression, we constructed expected OI-1 LS aBMD-for-age curves from the data from individuals who had never received BPN. LS aBMD in those who had been exposed to BPN was then compared with the computed expected aBMD. BPN exposure in preadolescent years (age <14 years) was associated with a LS aBMD that was 9% more than the expected computed values in BPN-naïve individuals ( < 0.01); however, such association was not observed across all ages. Exposure to i.v. BPN and treatment duration >2 years correlated with LS aBMD in preadolescent individuals. BPN exposure also had a significant association with non-aBMD clinical outcome variables. Logistic regression modeling predicted that with BPN exposure, a 1-year increase in age would be associated with an 8.2% decrease in fracture probability for preadolescent individuals with OI-1, compared with no decrease in individuals who had never received any BPN ( < 0.05). In preadolescent individuals with OI-1, a 0.1 g/cm increase in LS aBMD was associated with a 10.6% decrease in scoliosis probability, compared with a 46.8% increase in the BPN-naïve group ( < 0.01). For the same changes in age and LS aBMD in preadolescent individuals, BPN exposure was also associated with higher mobility scores ( < 0.01), demonstrating that BPN treatment may be associated with daily function. © 2018 The Authors. Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6524673PMC
May 2019

Identification of genetic variants associated with skeletal muscle function deficit in childhood acute lymphoblastic leukemia survivors.

Pharmgenomics Pers Med 2019 11;12:33-45. Epub 2019 Apr 11.

Department of Medicine, University of Montreal, Montreal, QC, Canada.

Although 80% of childhood acute lymphoblastic leukemia (ALL) cases are cured with current treatment protocols, exposure to chemotherapeutics or radiation therapy during a vulnerable period of child development has been associated with a high frequency of late adverse effects (LAE). Previous observations suggest important skeletal muscle size, density and function deficits in ALL survivors. Given that only a fraction of all patients will suffer from this particular complication, we investigated whether it could be predicted by genetic markers.  We analysed associations between skeletal muscle force (Fmax) and power (Pmax) and germline genetic variants from 1039 genes derived through whole-exome sequencing. Top-ranking association signals retained after correction for multiple testing were confirmed through genotyping, and further analysed through stratified analyses and multivariate models.  Our results show that skeletal muscle function deficit is associated with two common single nucleotide polymorphisms (SNPs) (rs2001616=0.0002 (Pmax) and rs41270041, =0.02 (Fmax)) and two rare ones located in the gene =0.001 (Pmax)). These associations were further modulated by sex, body mass index and risk groups, which reflected glucocorticoid dose and radiation therapy (≤0.02).  Occurrence of muscle function deficit in childhood ALL is thus strongly modulated by variations in the and genes, which could lead to personalized prevention strategies in childhood ALL survivors.
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http://dx.doi.org/10.2147/PGPM.S192924DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6489684PMC
April 2019

Mendelian bone fragility disorders.

Bone 2019 09 27;126:11-17. Epub 2019 Apr 27.

Shriners Hospital for Children, Montreal, Quebec, Canada. Electronic address:

Mendelian bone fragility disorders are caused by genetic variants that can be inherited in an autosomal dominant, autosomal recessive or X-linked manner and have a large detrimental effect on bone strength. As a rule, the more damaging the genetic defect is, the earlier the first fracture will occur, typically during bone development. This review focusses on conditions where bone fragility is the most conspicuous characteristic, of which osteogenesis imperfecta (OI) is the best-known disorder. The large majority of individuals with an OI phenotype have disease-causing dominant variants in COL1A1 or COL1A2, the genes coding for collagen type I. Interestingly, large sequencing databases indicate that there are about 10 times more carriers of COL1A1/COL1A2 variants that should lead to OI than there are individuals with a diagnosis of OI. It is possible that at least some of these variants lead to incomplete OI phenotypes and are diagnosed as osteoporosis during adulthood. Apart from mutations affecting collagen type I production, biallelic mutations in LRP5 and WNT1 can cause very rare and severe bone fragility disorders. Heterozygous pathogenic variants in these genes are much more common and can cause the clinical picture of primary osteoporosis. As sequencing studies are more widely performed in adults with bone fragility disorders, evidence is emerging that what appears as primary osteoporosis in fact can be due to mutations in bona fide OI genes. The distinction between OI and primary osteoporosis is therefore likely to blur in future.
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http://dx.doi.org/10.1016/j.bone.2019.04.021DOI Listing
September 2019

The Bone Phenotype and Pain Response to Pamidronate in Tyrosine Kinase Inhibitor-Treated Chronic Myelogenous Leukemia.

J Endocr Soc 2019 May 11;3(5):857-864. Epub 2019 Mar 11.

Pediatric Bone Health Clinical Research Program, Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.

Tyrosine kinase inhibitors (TKIs) have been linked to bone pain and linear growth attenuation in children with TKI-treated chronic myelogenous leukemia (CML). We describe the skeletal phenotype in an 11-year-old boy with chronic bone pain due to TKI-treated CML, including his response to intravenous (IV) pamidronate. This boy was diagnosed with Philadelphia chromosome-positive CML at 4 years of age. He was treated with imatinib for 3 years, followed by dasatinib for 4 years. At age 11 years, he was seen in a bone health clinic with a 4-year history of leg pains that necessitated regular nonsteroidal anti-inflammatory drugs (NSAIDS) and downward crossing of height percentiles (from the 25th to fifth). The bone volume/tissue volume Z-score was +1.6 for a trans-iliac bone biopsy specimen, with an increase in trabecular number (Z-score, +3.1). Bone formation and resorption parameters on trabecular surfaces were within normal limits. Tibia volumetric bone mineral density (BMD) and bone geometry were normal by peripheral quantitative computed tomography, areal BMD Z-scores were average or above average at multiple skeletal sites by dual-energy x-ray absorptiometry, and tibia length Z-score was reduced (-2.3). Growth- and bone-related biochemical studies were unremarkable except a low serum alkaline phosphatase level. His bone pain resolved completely after 9 months of low-dose IV pamidronate. An increase in trans-iliac trabecular number and shortened tibia were the main skeletal features in this patient. Short-term IV pamidronate was effective for mitigating bone pain, allowing this boy to continue receiving dasatinib without the need for chronic NSAID therapy.
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http://dx.doi.org/10.1210/js.2018-00268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6462212PMC
May 2019

Identification of a single-nucleotide polymorphism within gene associated with bone morbidity in childhood acute lymphoblastic leukemia survivors.

Pharmacogenomics 2019 04 15;20(6):409-420. Epub 2019 Apr 15.

Sainte-Justine University Hospital Research Centre, Montreal, Quebec, H3T 1C5, Canada.

To identify genetic markers associated with late treatment-related skeletal morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). To this end, we measured the association between reduction in bone mineral density or vertebral fractures prevalence and variants from 1039 genes derived through whole exome sequencing in 242 childhood ALL survivors. Top-ranking variants were confirmed through genotyping, and further explored with stratified analyses and multivariable models. The minor allele of rs1944294 in gene was associated with bone geometrical parameter, trabecular cross-sectional area (p = 0.001). The association was modulated by radiation therapy (p = 0.001) and post-treatment time (p = 0.0002). The variant in gene is a potential novel risk factor of bone morbidity in survivors of childhood ALL.
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http://dx.doi.org/10.2217/pgs-2018-0169DOI Listing
April 2019