Publications by authors named "Leanne M Ward"

65 Publications

Patient-Reported Outcomes from a Randomized, Active-Controlled, Open-Label, Phase 3 Trial of Burosumab Versus Conventional Therapy in Children with X-Linked Hypophosphatemia.

Calcif Tissue Int 2021 Jan 23. Epub 2021 Jan 23.

Department of Medicine and Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.

Changing to burosumab, a monoclonal antibody targeting fibroblast growth factor 23, significantly improved phosphorus homeostasis, rickets, lower-extremity deformities, mobility, and growth versus continuing oral phosphate and active vitamin D (conventional therapy) in a randomized, open-label, phase 3 trial involving children aged 1-12 years with X-linked hypophosphatemia. Patients were randomized (1:1) to subcutaneous burosumab or to continue conventional therapy. We present patient-reported outcomes (PROs) from this trial for children aged ≥ 5 years at screening (n = 35), using a Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire and SF-10 Health Survey for Children. PROMIS pain interference, physical function mobility, and fatigue scores improved from baseline with burosumab at weeks 40 and 64, but changed little with continued conventional therapy. Pain interference scores differed significantly between groups at week 40 (- 5.02, 95% CI - 9.29 to - 0.75; p = 0.0212) but not at week 64. Between-group differences were not significant at either week for physical function mobility or fatigue. Reductions in PROMIS pain interference and fatigue scores from baseline were clinically meaningful with burosumab at weeks 40 and 64 but not with conventional therapy. SF-10 physical health scores (PHS-10) improved significantly with burosumab at week 40 (least-squares mean [standard error] + 5.98 [1.79]; p = 0.0008) and week 64 (+ 5.93 [1.88]; p = 0.0016) but not with conventional therapy (between-treatment differences were nonsignificant). In conclusion, changing to burosumab improved PRO measures, with statistically significant differences in PROMIS pain interference at week 40 versus continuing with conventional therapy and in PHS-10 at weeks 40 and 64 versus baseline.Trial registration: ClinicalTrials.gov NCT02915705.
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http://dx.doi.org/10.1007/s00223-020-00797-xDOI Listing
January 2021

Glucocorticoid-Induced Osteoporosis: Why Kids Are Different.

Authors:
Leanne M Ward

Front Endocrinol (Lausanne) 2020 16;11:576. Epub 2020 Dec 16.

The Ottawa Pediatric Bone Health Research Group, The Children's Hospital of Eastern Ontario Genetic and Metabolic Bone Disease Clinic, University of Ottawa, Ottawa, ON, Canada.

Glucocorticoids (GC) are an important risk factor for bone fragility in children with serious illnesses, largely due to their direct adverse effects on skeletal metabolism. To better appreciate the natural history of fractures in this setting, over a decade ago the Canadian eroid-associated steoporosis in the ediatric opulation ("") Consortium launched a 6 year, multi-center observational cohort study in GC-treated children. This study unveiled numerous key clinical-biological principles about GC-induced osteoporosis (GIO), many of which are unique to the growing skeleton. This was important, because most GIO recommendations to date have been guided by adult studies, and therefore do not acknowledge the pediatric-specific principles that inform monitoring, diagnosis and treatment strategies in the young. Some of the most informative observations from the STOPP study were that vertebral fractures are the hallmark of pediatric GIO, they occur early in the GC treatment course, and they are frequently asymptomatic (thereby undetected in the absence of routine monitoring). At the same time, some children have the unique, growth-mediated ability to restore normal vertebral body dimensions following vertebral fractures. This is an important index of recovery, since spontaneous vertebral body reshaping may preclude the need for osteoporosis therapy. Furthermore, we now better understand that children with poor growth, older children with less residual growth potential, and children with ongoing bone health threats have less potential for vertebral body reshaping following spine fractures, which can result in permanent vertebral deformity if treatment is not initiated in a timely fashion. Therefore, pediatric GIO management is now predicated upon early identification of vertebral fractures in those at risk, and timely intervention when there is limited potential for spontaneous recovery. A single, low-trauma long bone fracture can also signal an osteoporotic event, and a need for treatment. Intravenous bisphosphonates are currently the recommended therapy for pediatric GC-induced bone fragility, typically prescribed to children with limited potential for medication-unassisted recovery. It is recognized, however, that even early identification of bone fragility, combined with timely introduction of intravenous bisphosphonate therapy, may not completely rescue the osteoporosis in those with the most aggressive forms, opening the door to novel strategies.
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http://dx.doi.org/10.3389/fendo.2020.00576DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772619PMC
December 2020

Advances in the Bone Health Assessment of Children.

Endocrinol Metab Clin North Am 2020 12;49(4):613-636

The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada.

The last 2 decades have seen tremendous growth in understanding the clinical characteristics of various childhood bone disorders, their mechanisms and natural histories, and their responses to treatment. In this review, the authors describe advances in bone assessment techniques for children. In addition, they provide their skeletal site-specific applications, underscore the principles that are relevant to the biology of the growing child, show how these methods assist in the diagnosis and management of pediatric bone diseases, and highlight how these techniques have shed light on bone development and underlying disease mechanisms.
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http://dx.doi.org/10.1016/j.ecl.2020.07.005DOI Listing
December 2020

Long-Term Follow-up of Hypophosphatemic Bone Disease Associated With Elemental Formula Use: Sustained Correction of Bone Disease After Formula Change or Phosphate Supplementation.

Clin Pediatr (Phila) 2020 Oct 15;59(12):1080-1085. Epub 2020 Jul 15.

Yale University, New Haven, CT, USA.

In this article, we describe the long-term outcomes of children who were previously reported to have developed hypophosphatemic bone disease in association with elemental formula use. An extended chart review allowed for an updated report of 34 children with regard to severity/duration of bone disease, extent of recovery, and time to correction using radiology reports and biochemical data. After implementation of formula change and/or phosphate supplementation, we found that serum phosphorus concentration increased and serum alkaline phosphatase activity decreased in all patients, normalizing by 6.6 ± 4.0 (mean ± SD) months following diagnosis. The decrease in serum alkaline phosphatase from diagnosis to the time of correction was moderately correlated with the concurrent increase in serum phosphorus ( = 0.48, < .05). Age at diagnosis significantly correlated with time to resolution ( = 0.51, = .01). This study supports the earlier report that bone disease associated with hypophosphatemia during elemental formula use responds to formula change and/or phosphate supplementation.
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http://dx.doi.org/10.1177/0009922820941097DOI Listing
October 2020

New developments in the management of achondroplasia.

Wien Med Wochenschr 2020 Apr 6;170(5-6):104-111. Epub 2020 Mar 6.

Departments of Paediatrics and Surgery, University of Ottawa, Ottawa, Canada.

Achondroplasia is the most common form of disproportionate short stature. A dominantly inherited FGFR3 mutation permanently activates the fibroblast growth factor receptor 3 (FGFR3) and its downstream mitogen-activated protein kinase (MAPK) signalling pathway. This inhibits chondrocyte differentiation and puts a break on growth plate function, in addition to causing serious medical complications such as foramen magnum and spinal stenosis and upper airway narrowing. A great deal has been learned about complications and consequences of FGFR3 activation and management guidance is evolving aimed to reduce the increased mortality and morbidity in this condition, particularly deaths from spinal cord compression and sleep apnoea in infants and small children. To date, no drugs are licensed for treatment of achondroplasia. Here, we report on the various substances in the drug development pipeline which target elements in molecular disease mechanism such as FGF (fibroblast growth factor) ligands, FGFR3, MAPK signalling as well as the C‑type natriuretic peptide receptor NPR‑B (natriuretic peptide receptor B).
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http://dx.doi.org/10.1007/s10354-020-00741-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7098936PMC
April 2020

A Contemporary View of the Definition and Diagnosis of Osteoporosis in Children and Adolescents.

J Clin Endocrinol Metab 2020 05;105(5)

Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, The Children's Hospital of Philadelphia and the University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

The last 2 decades have seen growing recognition of the need to appropriately identify and treat children with osteoporotic fractures. This focus stems from important advances in our understanding of the genetic basis of bone fragility, the natural history and predictors of fractures in chronic conditions, the use of bone-active medications in children, and the inclusion of bone health screening into clinical guidelines for high-risk populations. Given the historic focus on bone densitometry in this setting, the International Society for Clinical Densitometry published revised criteria in 2013 to define osteoporosis in the young, oriented towards prevention of overdiagnosis given the high frequency of extremity fractures during the growing years. This definition has been successful in avoiding an inappropriate diagnosis of osteoporosis in healthy children who sustain long bone fractures during play. However, its emphasis on the number of long bone fractures plus a concomitant bone mineral density (BMD) threshold ≤ -2.0, without consideration for long bone fracture characteristics (eg, skeletal site, radiographic features) or the clinical context (eg, known fracture risk in serious illnesses or physical-radiographic stigmata of osteoporosis), inappropriately misses clinically relevant bone fragility in some children. In this perspective, we propose a new approach to the definition and diagnosis of osteoporosis in children, one that balances the role of BMD in the pediatric fracture assessment with other important clinical features, including fracture characteristics, the clinical context and, where appropriate, the need to define the underlying genetic etiology as far as possible.
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http://dx.doi.org/10.1210/clinem/dgz294DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7121121PMC
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

Local Tumor Recurrence and Escape from Suppression of Bone Resorption With Denosumab Treatment in Two Adolescents With Giant Cell Tumors of Bone.

JBMR Plus 2019 Sep 18;3(9):e10196. Epub 2019 Jun 18.

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

Giant cell tumors of bone (GCTB) may be difficult to resect because of size or location. We describe two adolescents who were treated with denosumab and followed for tumoral and biochemical responses. Denosumab was effective in achieving sufficient regression to allow surgical resection and in preserving peritumor cortical bone. Reactivation of bone resorption markers was noted while the patients were receiving monthly denosumab. One patient suffered a local tumor recurrence. Denosumab was safe in enabling surgical resection of GCTB. However, the effect was transient, with an escape of resorption markers and tumor recurrence. © 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/jbm4.10196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6808219PMC
September 2019

The Utility of DXA Assessment at the Forearm, Proximal Femur, and Lateral Distal Femur, and Vertebral Fracture Assessment in the Pediatric Population: 2019 ISCD Official Position.

J Clin Densitom 2019 Oct - Dec;22(4):567-589. Epub 2019 Jul 10.

Division of GI, Hepatology and Nutrition, The Children's Hospital of Philadelphia, Department of Pediatrics, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA. Electronic address:

Dual-energy X-ray absorptiometry (DXA) is widely used in the evaluation of bone fragility in children. Previous recommendations emphasized total body less head and lumbar spine DXA scans for clinical bone health assessment. However, these scan sites may not be possible or optimal for all groups of children with conditions that threaten bone health. The utility of DXA scans of the proximal femur, forearm, and radius were evaluated for adequacy of reference data, precision, ability of predict fracture, and applicability to all, or select groups of children. In addition, the strengths and limitations of vertebral fracture assessment by DXA were evaluated. The new Pediatric Positions provide guidelines on the use of these additional measures in the assessment of skeletal health in children.
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http://dx.doi.org/10.1016/j.jocd.2019.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010480PMC
July 2020

Burosumab versus conventional therapy in children with X-linked hypophosphataemia: a randomised, active-controlled, open-label, phase 3 trial.

Lancet 2019 06 16;393(10189):2416-2427. Epub 2019 May 16.

Department of Pediatrics, University of California, San Francisco, San Francisco, CA, USA.

Background: X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment. We compared the efficacy and safety of continuing conventional therapy, consisting of oral phosphate and active vitamin D, versus switching to burosumab, a fully human monoclonal antibody against FGF23, in paediatric X-linked hypophosphataemia.

Methods: In this randomised, active-controlled, open-label, phase 3 trial at 16 clinical sites, we enrolled children with X-linked hypophosphataemia aged 1-12 years. Key eligibility criteria were a total Thacher rickets severity score of at least 2·0, fasting serum phosphorus lower than 0·97 mmol/L (3·0 mg/dL), confirmed PHEX (phosphate-regulating endopeptidase homolog, X-linked) mutation or variant of unknown significance in the patient or a family member with appropriate X-linked dominant inheritance, and receipt of conventional therapy for at least 6 consecutive months for children younger than 3 years or at least 12 consecutive months for children older than 3 years. Eligible patients were randomly assigned (1:1) to receive either subcutaneous burosumab starting at 0·8 mg/kg every 2 weeks (burosumab group) or conventional therapy prescribed by investigators (conventional therapy group). Both interventions lasted 64 weeks. The primary endpoint was change in rickets severity at week 40, assessed by the Radiographic Global Impression of Change global score. All patients who received at least one dose of treatment were included in the primary and safety analyses. The trial is registered with ClinicalTrials.gov, number NCT02915705.

Findings: Recruitment took place between Aug 3, 2016, and May 8, 2017. Of 122 patients assessed, 61 were enrolled. Of these, 32 (18 girls, 14 boys) were randomly assigned to continue receiving conventional therapy and 29 (16 girls, 13 boys) to receive burosumab. For the primary endpoint at week 40, patients in the burosumab group had significantly greater improvement in Radiographic Global Impression of Change global score than did patients in the conventional therapy group (least squares mean +1·9 [SE 0·1] with burosumab vs +0·8 [0·1] with conventional therapy; difference 1·1, 95% CI 0·8-1·5; p<0·0001). Treatment-emergent adverse events considered possibly, probably, or definitely related to treatment by the investigator occurred more frequently with burosumab (17 [59%] of 29 patients in the burosumab group vs seven [22%] of 32 patients in the conventional therapy group). Three serious adverse events occurred in each group, all considered unrelated to treatment and resolved.

Interpretation: Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy.

Funding: Ultragenyx Pharmaceutical and Kyowa Kirin International.
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http://dx.doi.org/10.1016/S0140-6736(19)30654-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7179969PMC
June 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

236th ENMC International Workshop Bone protective therapy in Duchenne muscular dystrophy: Determining the feasibility and standards of clinical trials Hoofddorp, The Netherlands, 1-3 June 2018.

Neuromuscul Disord 2019 03 12;29(3):251-259. Epub 2019 Jan 12.

MRC Centre for Neuromuscular Disease and Division of Neuropathology, UCL Institute of Neurology, National Hospital for Neurology and Neurosurgery, London, UK.

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http://dx.doi.org/10.1016/j.nmd.2019.01.002DOI Listing
March 2019

Growth, pubertal development, and skeletal health in boys with Duchenne Muscular Dystrophy.

Curr Opin Endocrinol Diabetes Obes 2019 02;26(1):39-48

Division of Endocrinology and Diabetes, Golisano Children's Hospital, University of Rochester Medical Centre, Rochester, New York, USA.

Purpose Of Review: Glucocorticoid therapy is currently the most widely used treatment for Duchenne muscular dystrophy (DMD), having consistently shown to prolong ambulation by 2 years, reduce the frequency of scoliosis, and improve cardiorespiratory function. Among the most frequent side effects of glucocorticoids are fractures due to osteoporosis, linear growth retardation or arrest, and pubertal delay, the subjects of this review.

Recent Findings: The diagnosis of osteoporosis has shifted in recent years away from a bone mineral density-centric to a fracture-focused approach, with particular emphasis on early vertebral fracture identification (one of the key triggers for osteoporosis intervention). Delayed puberty should be addressed in an age-appropriate manner, with numerous options available for sex steroid replacement. Growth impairment, however, is a more challenging complication of glucocorticoid-treated DMD, one that is most likely best addressed through growth-sparing therapies that target the dystrophinopathy.

Summary: With glucocorticoid prescription an increasingly prevalent component of DMD care, early attention to management of osteoporosis and delayed puberty are important components of multidisciplinary and anticipatory care. The treatment of short stature remains controversial, with no accepted therapy currently available to over-ride the toxic effects of glucocorticoids on the growth axis.
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http://dx.doi.org/10.1097/MED.0000000000000456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402320PMC
February 2019

Skeletal Morbidity in Children and Adolescents during and following Cancer Therapy.

Horm Res Paediatr 2019 27;91(2):137-151. Epub 2018 Nov 27.

Department of Pediatrics, The Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada.

Skeletal abnormalities are common in children and adolescents diagnosed and treated for a malignancy. The spectrum ranges from mild pain to debilitating osteonecrosis and fractures. In this review, we summarize the impact of cancer therapy on the developing skeleton, provide an update on therapeutic strategies for prevention and treatment, and discuss the most recent advances in musculoskeletal research. Early recognition of skeletal abnormalities and strategies to optimize bone health are essential to prevent long-term skeletal sequelae and diminished quality of life in childhood cancer survivors.
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http://dx.doi.org/10.1159/000494809DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6536370PMC
December 2019

Obesity and Endocrine Management of the Patient With Duchenne Muscular Dystrophy.

Pediatrics 2018 10;142(Suppl 2):S43-S52

Department of Pediatrics, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa, Ontario, Canada; and

Duchenne muscular dystrophy (DMD) is associated with an increased risk of endocrine complications due to the effects of prolonged glucocorticoid therapy as well as progressive muscle weakness. Categories of complications include obesity and its comorbidities, short stature, pubertal delay, and adrenal insufficiency. Obesity prevention is important for long-term management of patients with DMD. Preventing glucocorticoid-induced weight gain fosters patient mobility, ease of transfer, and reduces sleep-disordered breathing. Metabolic complications from obesity (glucose intolerance, dyslipidemia) also can be avoided. Short stature and pubertal delay may negatively affect self-esteem and peer relationships, and careful monitoring of growth and pubertal development can allow anticipatory counseling. Adrenal insufficiency, a potentially life-threatening complication associated with prolonged glucocorticoid use, must be recognized so as to allow prompt treatment. In this article, we provide a summary of current guidance to ensure comprehensive endocrine management is followed in patients with DMD.
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http://dx.doi.org/10.1542/peds.2018-0333FDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6460463PMC
October 2018

Bone Health and Osteoporosis Management of the Patient With Duchenne Muscular Dystrophy.

Pediatrics 2018 10;142(Suppl 2):S34-S42

Golisano Children's Hospital, School of Medicine and Dentistry, University of Rochester, Rochester, New York.

Duchenne muscular dystrophy is associated with an increased risk of bone fragility due to the adverse effects of prolonged glucocorticoid therapy and progressive muscle weakness on bone strength. Osteoporosis manifests clinically as low-trauma long-bone and vertebral fractures (VFs), with VFs frequent, particularly in those treated with glucocorticoid therapy. It is increasingly recognized that bone pain, medical complications of osteoporosis (such as fat embolism syndrome), and the potential for permanent, fracture-induced loss of ambulation can be mitigated with timely bone health surveillance and management. This includes periodic spine radiographs for VF detection because VFs can be asymptomatic in their early phases and thereby go undetected in the absence of monitoring. With this article, we provide a comprehensive review of the following 4 phases of bone health management: (1) bone health monitoring, which is used to identify early signs of compromised bone health; (2) osteoporosis stabilization, which is aimed to mitigate back pain and interrupt the fracture-refracture cycle through bone-targeted therapy; (3) bone health maintenance, which has the goal to preserve the clinical gains realized during the stabilization phase through ongoing bone-targeted therapy; and (4) osteoporosis therapy discontinuation, which places those who are eligible for discontinuation of osteoporosis treatment back on a health monitoring program. In the course of reviewing these 4 phases of management, we will discuss the criteria for diagnosing osteoporosis, along with detailed recommendations for osteoporosis intervention including specific drugs, dose, length of therapy, contraindications, and monitoring of treatment efficacy and safety.
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http://dx.doi.org/10.1542/peds.2018-0333EDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6442478PMC
October 2018

An Introduction to the Duchenne Muscular Dystrophy Care Considerations.

Pediatrics 2018 10;142(Suppl 2):S1-S4

Department of Pediatrics, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio.

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http://dx.doi.org/10.1542/peds.2018-0333BDOI Listing
October 2018

Impact of Vertebral Fractures and Glucocorticoid Exposure on Height Deficits in Children During Treatment of Leukemia.

J Clin Endocrinol Metab 2019 02;104(2):213-222

University of Ottawa, Ottawa, Ontario, Canada.

Objective: To assess the effect of vertebral fractures (VF) and glucocorticoid (GC) exposure on height deficits in children during treatment of acute lymphoblastic leukemia (ALL).

Methods: Children with ALL treated without cranial radiation therapy (n = 160; median age, 5.1 years; 58.1% male) were followed prospectively for 6 years. Spinal deformity index (SDI) was used to quantify VF status.

Results: Baseline height z score ± SD was 0.3 ± 1.2. It fell by 0.5 ± 0.4 in the first 6 months for boys and by 0.4 ± 0.4 in the first 12 months for girls (P < 0.01 for both) and then subsequently recovered. The prevalence of VF peaked at 1 year (17.6%). Among those with VF, median SDI rose from 2 [interquartile range (IQR): 1, 7] at baseline to 8 (IQR: 1, 8) at 1 year. A mixed model for repeated measures showed that height z score declined by 0.13 (95% CI: 0.02 to 0.24; P = 0.02) for each 5-unit increase in SDI during the previous 12 months. Every 10 mg/m2 increase in average daily GC dose (prednisone equivalent) in the previous 12 months was associated with a height z score decrement of 0.26 (95% CI: 0.20 to 0.32; P < 0.01).

Conclusions: GC likely plays a major role in the observed height decline during therapy for ALL. Because only a minority of children had VF, fractures could not have contributed significantly to the height deficit in the entire cohort but may have been important among the subset with VF.
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http://dx.doi.org/10.1210/jc.2018-01083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6291659PMC
February 2019

Phase IIa trial in Duchenne muscular dystrophy shows vamorolone is a first-in-class dissociative steroidal anti-inflammatory drug.

Pharmacol Res 2018 10 13;136:140-150. Epub 2018 Sep 13.

University of Pittsburgh and Department of Veterans Affairs Medical Center, Pittsburgh, PA, USA. Electronic address:

We report a first-in-patient study of vamorolone, a first-in-class dissociative steroidal anti-inflammatory drug, in Duchenne muscular dystrophy. This 2-week, open-label Phase IIa multiple ascending dose study (0.25, 0.75, 2.0, and 6.0 mg/kg/day) enrolled 48 boys with Duchenne muscular dystrophy (4 to <7 years), with outcomes including clinical safety, pharmacokinetics and pharmacodynamic biomarkers. The study design included pharmacodynamic biomarkers in three contexts of use: 1. Secondary outcomes for pharmacodynamic safety (insulin resistance, adrenal suppression, bone turnover); 2. Exploratory outcomes for drug mechanism of action; 3. Exploratory outcomes for expanded pharmacodynamic safety. Vamorolone was safe and well-tolerated through the highest dose tested (6.0 mg/kg/day) and pharmacokinetics of vamorolone were similar to prednisolone. Using pharmacodynamic biomarkers, the study demonstrated improved safety of vamorolone versus glucocorticoids as shown by reduction of insulin resistance, beneficial changes in bone turnover (loss of increased bone resorption and decreased bone formation only at the highest dose level), and a reduction in adrenal suppression. Exploratory biomarkers of pharmacodynamic efficacy showed an anti-inflammatory mechanism of action and a beneficial effect on plasma membrane stability, as demonstrated by a dose-responsive decrease in serum creatine kinase activity. With an array of pre-selected biomarkers in multiple contexts of use, we demonstrate the development of the first dissociative steroid that preserves anti-inflammatory efficacy and decreases steroid-associated safety concerns. Ongoing extension studies offer the potential to bridge exploratory efficacy biomarkers to clinical outcomes.
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http://dx.doi.org/10.1016/j.phrs.2018.09.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6218284PMC
October 2018

Bone Morbidity and Recovery in Children With Acute Lymphoblastic Leukemia: Results of a Six-Year Prospective Cohort Study.

J Bone Miner Res 2018 08 22;33(8):1435-1443. Epub 2018 May 22.

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

Osteoporotic fractures are a significant cause of morbidity in acute lymphoblastic leukemia (ALL). Our objective was to determine the incidence and predictors of fractures and recovery from osteoporosis in pediatric ALL over 6 years following glucocorticoid initiation. Vertebral fractures (VF) and vertebral body reshaping were assessed on annual spine radiographs, low-trauma non-VF were recorded at regular intervals and spine bone mineral density (BMD) was captured every 6 months for 4 years and then annually. A total of 186 children with ALL were enrolled (median age 5.3 years; range, 1.3 to 17.0 years). The cumulative fracture incidence was 32.5% for VF and 23.0% for non-VF; 39.0% of children with VF were asymptomatic. No fractures occurred in the sixth year and 71.3% of incident fractures occurred in the first 2 years. Baseline VF, cumulative glucocorticoid dose, and baseline lumbar spine (LS) BMD Z-score predicted both VF and non-VF. Vertebral body reshaping following VF was incomplete or absent in 22.7% of children. Those with residual vertebral deformity following VF were older compared to those without (median age 8.0 years at baseline [interquartile range {IQR}, 5.5 to 9.4] versus 4.8 years [IQR, 3.6 to 6.2], p = 0.04) and had more severe vertebral collapse (median maximum spinal deformity index 3.5 [IQR, 1.0 to 8.0] versus 0.5 [IQR, 0.0 to 1.0], p = 0.01). VF and low LS BMD Z-score at baseline as well as glucocorticoid exposure predicted incident VF and non-VF. Nearly 25% of children had persistent vertebral deformity following VF, more frequent in older children, and in those with more severe collapse. These results suggest the need for trials addressing interventions in the first 2 years of chemotherapy, targeting older children and children with more severe vertebral collapse, because these children are at greatest risk for incident VF and subsequent residual vertebral deformity. © 2018 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3447DOI Listing
August 2018

Anabolic Therapy for the Treatment of Osteoporosis in Childhood.

Curr Osteoporos Rep 2018 06;16(3):269-276

Department of Pediatrics, Faculty of Medicine, McGill University, and Shriners Hospital for Children, 1003 Boulevard Décarie, Montréal, Québec, H4A 0A9, Canada.

Purpose Of Review: Numerous forms of osteoporosis in childhood are characterized by low bone turnover (for example, osteoporosis due to neuromuscular disorders and glucocorticoid exposure). Anti-resorptive therapy, traditionally used to treat osteoporosis in the young, is associated with further reductions in bone turnover, raising concerns about the long-term safety and efficacy of such therapy. These observations have led to increasing interest in the role of anabolic therapy to treat pediatric osteoporosis.

Recent Findings: While growth hormone and androgens appears to be relatively weak anabolic modulators of bone mass, emerging therapies targeting bone formation pathways (anti-transforming growth factor beta antibody and anti-sclerostin antibody) hold considerable promise. Teriparatide remains an attractive option that merits formal study for patients post-epiphyseal fusion, although it must be considered that adult studies have shown its effect is blunted when administered following bisphosphonate therapy. Mechanical stimulation of bone through whole body vibration therapy appears to be much less effective than bisphosphonate therapy for treating osteoporosis in children. New anabolic therapies which target important pathways in skeletal metabolism merit further study in children, including their effects on fracture risk reduction and after treatment discontinuation.
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http://dx.doi.org/10.1007/s11914-018-0434-zDOI Listing
June 2018

Severe vitamin D deficiency: A persistent yet preventable problem among Canadian youth.

Paediatr Child Health 2017 Mar 30;22(1):43-44. Epub 2017 Mar 30.

The Hospital for Sick Children, University of Toronto, Toronto, Ontario.

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http://dx.doi.org/10.1093/pch/pxw006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5804700PMC
March 2017

Diagnosis and management of Duchenne muscular dystrophy, part 3: primary care, emergency management, psychosocial care, and transitions of care across the lifespan.

Lancet Neurol 2018 05 2;17(5):445-455. Epub 2018 Feb 2.

Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, and University of Ottawa, Ottawa, ON, Canada.

Improvements in the function, quality of life, and longevity of patients with Duchenne muscular dystrophy (DMD) have been achieved through a multidisciplinary approach to management across a range of health-care specialties. In part 3 of this update of the DMD care considerations, we focus on primary care, emergency management, psychosocial care, and transitions of care across the lifespan. Many primary care and emergency medicine clinicians are inexperienced at managing the complications of DMD. We provide a guide to the acute and chronic medical conditions that these first-line providers are likely to encounter. With prolonged survival, individuals with DMD face a unique set of challenges related to psychosocial issues and transitions of care. We discuss assessments and interventions that are designed to improve mental health and independence, functionality, and quality of life in critical domains of living, including health care, education, employment, interpersonal relationships, and intimacy.
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http://dx.doi.org/10.1016/S1474-4422(18)30026-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902408PMC
May 2018

Diagnosis and management of Duchenne muscular dystrophy, part 2: respiratory, cardiac, bone health, and orthopaedic management.

Lancet Neurol 2018 04 3;17(4):347-361. Epub 2018 Feb 3.

Division of Endocrinology and Metabolism, Children's Hospital of Eastern Ontario, and University of Ottawa, Ottawa, ON, Canada.

A coordinated, multidisciplinary approach to care is essential for optimum management of the primary manifestations and secondary complications of Duchenne muscular dystrophy (DMD). Contemporary care has been shaped by the availability of more sensitive diagnostic techniques and the earlier use of therapeutic interventions, which have the potential to improve patients' duration and quality of life. In part 2 of this update of the DMD care considerations, we present the latest recommendations for respiratory, cardiac, bone health and osteoporosis, and orthopaedic and surgical management for boys and men with DMD. Additionally, we provide guidance on cardiac management for female carriers of a disease-causing mutation. The new care considerations acknowledge the effects of long-term glucocorticoid use on the natural history of DMD, and the need for care guidance across the lifespan as patients live longer. The management of DMD looks set to change substantially as new genetic and molecular therapies become available.
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http://dx.doi.org/10.1016/S1474-4422(18)30025-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5889091PMC
April 2018

Diagnosis and management of Duchenne muscular dystrophy, part 1: diagnosis, and neuromuscular, rehabilitation, endocrine, and gastrointestinal and nutritional management.

Lancet Neurol 2018 03 3;17(3):251-267. Epub 2018 Feb 3.

Division of Endocrinology and Diabetes, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, NY, USA.

Since the publication of the Duchenne muscular dystrophy (DMD) care considerations in 2010, multidisciplinary care of this severe, progressive neuromuscular disease has evolved. In conjunction with improved patient survival, a shift to more anticipatory diagnostic and therapeutic strategies has occurred, with a renewed focus on patient quality of life. In 2014, a steering committee of experts from a wide range of disciplines was established to update the 2010 DMD care considerations, with the goal of improving patient care. The new care considerations aim to address the needs of patients with prolonged survival, to provide guidance on advances in assessments and interventions, and to consider the implications of emerging genetic and molecular therapies for DMD. The committee identified 11 topics to be included in the update, eight of which were addressed in the original care considerations. The three new topics are primary care and emergency management, endocrine management, and transitions of care across the lifespan. In part 1 of this three-part update, we present care considerations for diagnosis of DMD and neuromuscular, rehabilitation, endocrine (growth, puberty, and adrenal insufficiency), and gastrointestinal (including nutrition and dysphagia) management.
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http://dx.doi.org/10.1016/S1474-4422(18)30024-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869704PMC
March 2018

Rickets.

Nat Rev Dis Primers 2017 Dec 21;3:17101. Epub 2017 Dec 21.

South African Medical Research Council-Wits Developmental Pathways for Health Research Unit, Department of Paediatrics, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg 2194, South Africa.

Rickets is a bone disease associated with abnormal serum calcium and phosphate levels. The clinical presentation is heterogeneous and depends on the age of onset and pathogenesis but includes bowing deformities of the legs, short stature and widening of joints. The disorder can be caused by nutritional deficiencies or genetic defects. Mutations in genes encoding proteins involved in vitamin D metabolism or action, fibroblast growth factor 23 (FGF23) production or degradation, renal phosphate handling or bone mineralization have been identified. The prevalence of nutritional rickets has substantially declined compared with the prevalence 200 years ago, but the condition has been re-emerging even in some well-resourced countries; prematurely born infants or breastfed infants who have dark skin types are particularly at risk. Diagnosis is usually established by medical history, physical examination, biochemical tests and radiography. Prevention is possible only for nutritional rickets and includes supplementation or food fortification with calcium and vitamin D either alone or in combination with sunlight exposure. Treatment of typical nutritional rickets includes calcium and/or vitamin D supplementation, although instances infrequently occur in which phosphate repletion may be necessary. Management of heritable types of rickets associated with defects in vitamin D metabolism or activation involves the administration of vitamin D metabolites. Oral phosphate supplementation is usually indicated for FGF23-independent phosphopenic rickets, whereas the conventional treatment of FGF23-dependent types of rickets includes a combination of phosphate and activated vitamin D; an anti-FGF23 antibody has shown promising results and is under further study.
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http://dx.doi.org/10.1038/nrdp.2017.101DOI Listing
December 2017

Growth and weight gain in children with juvenile idiopathic arthritis: results from the ReACCh-Out cohort.

Pediatr Rheumatol Online J 2017 Aug 22;15(1):68. Epub 2017 Aug 22.

From British Columbia Children's Hospital and University of British Columbia, Vancouver, Canada.

Background: With modern treatments, the effect of juvenile idiopathic arthritis (JIA) on growth may be less than previously reported. Our objective was to describe height, weight and body mass index (BMI) development in a contemporary JIA inception cohort.

Methods: Canadian children newly-diagnosed with JIA 2005-2010 had weight and height measurements every 6 months for 2 years, then yearly up to 5 years. These measurements were used to calculate mean age- and sex-standardized Z-scores, and estimate prevalence and cumulative incidence of growth impairments, and the impact of disease activity and corticosteroids on growth.

Results: One thousand one hundred forty seven children were followed for median 35.5 months. Mean Z-scores, and the point prevalence of short stature (height < 2.5th percentile, 2.5% to 3.4%) and obesity (BMI > 95th percentile, 15.8% to 16.4%) remained unchanged in the whole cohort. Thirty-three children (2.9%) developed new-onset short stature, while 27 (2.4%) developed tall stature (>97.5th percentile). Children with systemic arthritis (n = 77) had an estimated 3-year cumulative incidence of 9.3% (95%CI: 4.3-19.7) for new-onset short stature and 34.4% (23-49.4) for obesity. Most children (81.7%) received no systemic corticosteroids, but 1 mg/Kg/day prednisone-equivalent maintained for 6 months corresponded to a drop of 0.64 height Z-scores (0.56-0.82) and an increase of 0.74 BMI Z-scores (0.56-0.92). An increase of 1 in the 10-cm physician global assessment of disease activity maintained for 6 months corresponded to a drop of 0.01 height Z-scores (0-0.02).

Conclusions: Most children in this modern JIA cohort grew and gained weight as children in the general population. About 1 in 10 children who had systemic arthritis, uncontrolled disease and/or prolonged corticosteroid use, had increased risk of growth impairment.
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http://dx.doi.org/10.1186/s12969-017-0196-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5567720PMC
August 2017

Proceedings of a Parent Project Muscular Dystrophy Bone Health Workshop: Morbidity due to osteoporosis in DMD: The Path Forward May 12-13, 2016, Bethesda, Maryland, USA.

Neuromuscul Disord 2018 01 15;28(1):64-76. Epub 2017 May 15.

Indiana Center for Musculoskeletal Health, Departments of Anatomy and Cell Biology and Orthopaedic Surgery, Indiana University, Indianapolis, IN, USA.

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http://dx.doi.org/10.1016/j.nmd.2017.05.012DOI Listing
January 2018

Increased bone matrix mineralization in treatment-naïve children with inflammatory bowel disease.

Bone 2017 Dec 10;105:50-56. Epub 2017 Jul 10.

Children's Hospital of Eastern Ontario (CHEO) Research Institute, Ottawa, Ontario, Canada; Department of Paediatrics, University of Ottawa, Canada.

Inflammatory bowel disease (IBD) affects many organ systems including the skeleton. In children with IBD, bone mineral density (BMD) and bone turnover are frequently low. Disturbances in bone mineralization density distribution (BMDD) are linked to alterations in bone material strength; however, BMDD has not previously been reported in children with chronic inflammatory disorders. The aim of this study was to characterize BMDD based on quantitative backscatter electron imaging in cancellous (Cn.) and cortical (Ct.) compartments from trans-iliac biopsy samples from a cohort of 20 treatment-naïve children at the time of their IBD diagnosis (12 males, mean age 14.5±2.3years). The outcomes were compared to pediatric reference BMDD data and correlation with revisited biochemical and histomorphometric outcomes was analyzed. BMDD in treatment-naïve children with IBD was shifted toward higher calcium concentrations compared to reference: (i) In cancellous bone, the most frequent calcium concentration (Cn.CaPeak+2.8%, p=0.004) and the portion of highly mineralized bone (Cn.CaHigh+52%, p=0.009) were increased. (ii) In cortical bone, the mineralization heterogeneity (Ct.CaWidth+17.0%, p=0.001) and Ct.CaHigh (+30.4%, p=0.006) were increased. (iii) Furthermore, significant correlations with serum alkaline phosphatase (ALP), bone-specific alkaline phosphatase (bsALP), and urinary crosslinked N-telopeptide of type I collagen (uNTX) were observed: the higher CaMean (the average calcium concentration), CaPeak and CaHigh, the lower were ALP, bsALP, and uNTX (p-value from <0.001 to 0.05). Children with treatment-naïve IBD have decreased bone turnover leading to a higher bone matrix mineralization density, findings which may contribute to compromised bone strength.
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http://dx.doi.org/10.1016/j.bone.2017.07.011DOI Listing
December 2017

Diagnosis and Management of Osteopetrosis: Consensus Guidelines From the Osteopetrosis Working Group.

J Clin Endocrinol Metab 2017 09;102(9):3111-3123

Department of Pediatrics, Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, Torrance, California 90502.

Background: Osteopetrosis encompasses a group of rare metabolic bone diseases characterized by impaired osteoclast activity or development, resulting in high bone mineral density. Existing guidelines focus on treatment of the severe infantile forms with hematopoietic cell transplantation (HCT) but do not address the management of patients with less severe forms for whom HCT is not the standard of care. Therefore, our objective was to develop expert consensus guidelines for the management of these patients.

Methods: A modified Delphi method was used to build consensus among participants of the Osteopetrosis Working Group, with responses to an anonymous online survey used to identify areas of agreement and conflict and develop a follow-up survey. The strength of recommendations and quality of evidence was graded using the Grading of Recommendations Assessment, Development and Evaluation system.

Results: Consensus was found in the areas of diagnosis, monitoring, and treatment. We recommend relying on characteristic radiographic findings to make the diagnosis and found that genetic testing adds important information by identifying mutations associated with unique disease complications. We recommend ongoing monitoring for changes in mineral metabolism and other complications, including cranial nerve impingement, anemia, leukopenia, and dental disease. We suggest that calcitriol should not be used in high doses and instead recommend symptom-based supportive therapy for disease complications because noninfantile osteopetrosis has no effective treatment.

Conclusions: Scarcity of published studies on osteopetrosis reduce the ability to develop evidence-based guidelines for the management of these patients. Expert opinion-based guidelines for this rare condition are nevertheless important to enable improved care.
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http://dx.doi.org/10.1210/jc.2017-01127DOI Listing
September 2017