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Bae E, Sim SY, Park SJ, Kim SE, Kim S, Kim SH, Cho WK, Cho KS, Jung MH, Suh BK, Ahn MB. Bone-Specific Alkaline Phosphatase as a Complementary Diagnostic Marker for the Assessment of Children and Adolescents with Secondary Osteoporosis. Diagnostics (Basel) 2025; 15:630. [PMID: 40075877 PMCID: PMC11898864 DOI: 10.3390/diagnostics15050630] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Revised: 02/22/2025] [Accepted: 03/03/2025] [Indexed: 03/14/2025] Open
Abstract
Background/Objective: With increasing cases of osteoporosis in children and adolescents, the need for timely diagnosis, management, and follow-up has become important. This study aimed to determine whether bone turnover markers (BTMs), particularly serum bone-specific alkaline phosphatase (BsALP) and serum C-telopeptide of collagen type 1 (CTx), accurately reflect BMD. Methods: In this retrospective study, 280 post-puberty males and females who were previously diagnosed with hemato-oncologic, rheumatic, gastrointestinal, and endocrinologic diseases at a single tertiary care center were reviewed. The association between the lumbar spine bone mineral density (LSBMD) Z-scores and BTMs, such as BsALP and CTx, were assessed. The LSBMD was measured in the anterior-posterior direction using DXA, and BTMs were determined using the blood samples obtained. Results: Of the 280 patients, 95 were male (33.9%), and the mean age was 15.4 ± 2.07 years. With multivariate regression analysis, LSBMD Z-scores and BsALP showed a negative correlation with p < 0.007, while CTx was not statistically significant. The logistic regression models showed that after adjusting for underlying diseases and sex, as BsALP increased, the probability of LSBMD Z-score being ≤-2 increased with an odds ratio of 1.043 (p = 0.048). When comparing BTMs with vertebral fracture while adjusting for underlying diseases and sex, as BsALP increased, the probability of vertebral fracture increased with an odds ratio of 1.035 (p = 0.005). Conclusions: The positive correlation between BsALP and LSBMD Z-scores being ≤-2, as well as with vertebral fracture after adjusting for underlying diseases and sex, suggests the possible application of BsALP as a predictor of bone health in patients.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Moon Bae Ahn
- Department of Pediatrics, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (E.B.); (S.Y.S.); (S.J.P.); (S.E.K.); (S.K.); (S.-H.K.); (W.K.C.); (K.S.C.); (M.H.J.); (B.-K.S.)
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2
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Sen P, Uday S. Bone Health in Paediatric Inflammatory Bowel Disease. Diagnostics (Basel) 2025; 15:580. [PMID: 40075827 PMCID: PMC11899547 DOI: 10.3390/diagnostics15050580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2024] [Revised: 02/17/2025] [Accepted: 02/22/2025] [Indexed: 03/14/2025] Open
Abstract
Paediatric inflammatory bowel disease (IBD) is often complicated by bone loss resulting in an increased risk of fractures and impaired quality of life. Underlying inflammation, nutritional deficiencies and glucocorticoid therapy are some of the factors contributing to secondary osteoporosis in IBD. Optimising nutrition, dietary supplementation and timely screening are essential in preventing bone loss. Bisphosphonate therapy remains the cornerstone of medical management of osteoporosis. This review explores the various mechanisms contributing towards poor bone health in IBD and the recent advances in diagnostic and preventive approaches along with updates in management strategies.
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Affiliation(s)
- Proteek Sen
- Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham B4 6NH, UK;
| | - Suma Uday
- Department of Endocrinology and Diabetes, Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham B4 6NH, UK;
- Department of Metabolism and Systems Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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3
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Rossi A, Simeoli C, Pivonello R, Salerno M, Rosano C, Brunetti B, Strisciuglio P, Colao A, Parenti G, Melis D, Derks TGJ. Endocrine involvement in hepatic glycogen storage diseases: pathophysiology and implications for care. Rev Endocr Metab Disord 2024; 25:707-725. [PMID: 38556561 PMCID: PMC11294274 DOI: 10.1007/s11154-024-09880-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/23/2024] [Indexed: 04/02/2024]
Abstract
Hepatic glycogen storage diseases constitute a group of disorders due to defects in the enzymes and transporters involved in glycogen breakdown and synthesis in the liver. Although hypoglycemia and hepatomegaly are the primary manifestations of (most of) hepatic GSDs, involvement of the endocrine system has been reported at multiple levels in individuals with hepatic GSDs. While some endocrine abnormalities (e.g., hypothalamic‑pituitary axis dysfunction in GSD I) can be direct consequence of the genetic defect itself, others (e.g., osteopenia in GSD Ib, insulin-resistance in GSD I and GSD III) may be triggered by the (dietary/medical) treatment. Being aware of the endocrine abnormalities occurring in hepatic GSDs is essential (1) to provide optimized medical care to this group of individuals and (2) to drive research aiming at understanding the disease pathophysiology. In this review, a thorough description of the endocrine manifestations in individuals with hepatic GSDs is presented, including pathophysiological and clinical implications.
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Affiliation(s)
- Alessandro Rossi
- Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
- Department of Translational Medicine, Section of Pediatrics, University of Naples "Federico II", Naples, Italy.
| | - Chiara Simeoli
- Dipartmento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, University of Naples "Federico II", Naples, Italy
| | - Rosario Pivonello
- Dipartmento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, University of Naples "Federico II", Naples, Italy
| | - Mariacarolina Salerno
- Department of Translational Medicine, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Carmen Rosano
- Department of Translational Medicine, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Barbara Brunetti
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Section of Pediatrics, University of Salerno, Baronissi, Italy
| | - Pietro Strisciuglio
- Department of Translational Medicine, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
| | - Annamaria Colao
- Dipartmento di Medicina Clinica e Chirurgia, Sezione di Endocrinologia, Diabetologia ed Andrologia, University of Naples "Federico II", Naples, Italy
| | - Giancarlo Parenti
- Department of Translational Medicine, Section of Pediatrics, University of Naples "Federico II", Naples, Italy
- Telethon Institute of Genetics and Medicine, Pozzuoli, Italy
| | - Daniela Melis
- Department of Medicine, Surgery and Dentistry "Scuola Medica Salernitana", Section of Pediatrics, University of Salerno, Baronissi, Italy
| | - Terry G J Derks
- Section of Metabolic Diseases, Beatrix Children's Hospital, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
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Ma J, Siminoski K, Jaremko JL, Koujok K, Matzinger MA, Shenouda N, Wilson N, Cheng M, Alos N, Atkinson S, Cummings EA, Ho J, Rodd C, Sbrocchi AM, Stein R, Barr R, Cairney E, Dix DB, Fernandez CV, Grant R, Halton J, Israels S, Laverdière C, Lewis VA, Cabral DA, Huber A, Houghton K, Jurencak R, Lang B, Larché M, LeBlanc CMA, Miettunen P, Roth J, Scuccimarri R, Bell L, Blydt-Hansen T, Filler G, Feber J, Phan V, Smit K, Rauch F, Ward LM. Vertebral Body Reshaping after Fractures: An Important Index of Recovery in Glucocorticoid-Treated Children. J Clin Endocrinol Metab 2024; 109:e1225-e1237. [PMID: 37843393 DOI: 10.1210/clinem/dgad611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/20/2023] [Accepted: 10/12/2023] [Indexed: 10/17/2023]
Abstract
PURPOSE In this 6-year study we identified factors associated with spontaneous vertebral body reshaping in glucocorticoid (GC)-treated children with leukemia, rheumatic disorders, and nephrotic syndrome. METHODS Subjects were 79 children (mean age 7.4 years) who had vertebral fracture (VF) evaluation on lateral spine radiographs at least 1 year after VF detection. VF were graded using the modified Genant semiquantitative method and fracture burden for individuals was quantified using the spinal deformity index (SDI; sum of grades from T4 to L4). RESULTS Sixty-five children (82.3%) underwent complete vertebral body reshaping (median time from VF detection to complete reshaping 1.3 years by Cox proportional hazard modeling). Of 237 VF, the majority (83.1%) ultimately reshaped, with 87.2% reshaping in the thoracic region vs 70.7% in the lumbar region (P = .004). Cox models showed that (1) every g/m2 increase in GC exposure in the first year after VF detection was associated with a 19% decline in the probability of reshaping; (2) each unit increase in the SDI at the time of VF detection was associated with a 19% decline in the probability of reshaping [hazard ratio (HR) = 0.81; 95% confidence interval (CI) = 0.71, 0.92; P = .001]; (3) each additional VF present at the time of VF detection reduced reshaping by 25% (HR = 0.75; 95% CI = 0.62, 0.90; P = .002); and (4) each higher grade of VF severity decreased reshaping by 65% (HR = 0.35; 95% CI = 0.21, 0.57; P < .001). CONCLUSION After experiencing a VF, children with higher GC exposure, higher SDI, more severe fractures, or lumbar VF were at increased risk for persistent vertebral deformity.
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Affiliation(s)
- Jinhui Ma
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON L8S 4L8, Canada
| | - Kerry Siminoski
- Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, AB T6G 2B7, Canada
| | - Jacob L Jaremko
- Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, AB T6G 2B7, Canada
| | - Khaldoun Koujok
- Department of Radiology, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Mary Ann Matzinger
- Department of Radiology, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Nazih Shenouda
- Department of Radiology, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Nagwa Wilson
- Department of Radiology, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Megan Cheng
- Faculty of Health Sciences, McMaster University, Hamilton, ON L8N 3Z5, Canada
| | - Nathalie Alos
- Département de pédiatrie, Université de Montréal, Montréal, QC H3T 1C5, Canada
| | - Stephanie Atkinson
- Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Elizabeth A Cummings
- Department of Pediatrics, Dalhousie University/IWK Health, Halifax, NS B3K 6R8, Canada
| | - Josephine Ho
- Department of Pediatrics, University of Calgary, Calgary, AB T3B 6A8, Canada
| | - Celia Rodd
- Department of Pediatrics and Child Health, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Anne Marie Sbrocchi
- Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Robert Stein
- Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5W9, Canada
| | - Ronald Barr
- Department of Pediatrics, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Elizabeth Cairney
- Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5W9, Canada
| | - David B Dix
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada
| | - Conrad V Fernandez
- Department of Pediatrics, Dalhousie University/IWK Health, Halifax, NS B3K 6R8, Canada
| | - Ronald Grant
- Department of Pediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada
| | - Jacqueline Halton
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Sara Israels
- Department of Pediatrics and Child Health, Children's Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, MB R3T 2N2, Canada
| | - Caroline Laverdière
- Département de pédiatrie, Université de Montréal, Montréal, QC H3T 1C5, Canada
| | - Victor A Lewis
- Department of Pediatrics, University of Calgary, Calgary, AB T3B 6A8, Canada
| | - David A Cabral
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada
| | - Adam Huber
- Department of Pediatrics, Dalhousie University/IWK Health, Halifax, NS B3K 6R8, Canada
| | - Kristin Houghton
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada
| | - Roman Jurencak
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Bianca Lang
- Department of Pediatrics, Dalhousie University/IWK Health, Halifax, NS B3K 6R8, Canada
| | - Maggie Larché
- Department of Medicine, McMaster University, Hamilton, ON L8S 4K1, Canada
| | - Claire M A LeBlanc
- Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Paivi Miettunen
- Department of Pediatrics, University of Calgary, Calgary, AB T3B 6A8, Canada
| | - Johannes Roth
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
- Department of Pediatrics, Kantonsspital Luzern, 6004 Luzern, Switzerland
| | - Rosie Scuccimarri
- Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Lorraine Bell
- Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Tom Blydt-Hansen
- Department of Pediatrics, University of British Columbia, Vancouver, BC V6H 3V4, Canada
| | - Guido Filler
- Department of Pediatrics, Schulich School of Medicine and Dentistry, Western University, London, ON N6A 5W9, Canada
| | - Janusz Feber
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Véronique Phan
- Département de pédiatrie, Université de Montréal, Montréal, QC H3T 1C5, Canada
| | - Kevin Smit
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
| | - Frank Rauch
- Department of Pediatrics, Faculty of Medicine and Health Sciences, McGill University, Montreal, QC H3G 2M1, Canada
| | - Leanne M Ward
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Faculty of Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada
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Ward LM. A practical guide to the diagnosis and management of osteoporosis in childhood and adolescence. Front Endocrinol (Lausanne) 2024; 14:1266986. [PMID: 38374961 PMCID: PMC10875302 DOI: 10.3389/fendo.2023.1266986] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 10/18/2023] [Indexed: 02/21/2024] Open
Abstract
Osteoporosis in childhood distinguishes itself from adulthood in four important ways: 1) challenges in distinguishing otherwise healthy children who have experienced fractures due to non-accidental injury or misfortunate during sports and play from those with an underlying bone fragility condition; 2) a preponderance of monogenic "early onset" osteoporotic conditions that unveil themselves during the pediatric years; 3) the unique potential, in those with residual growth and transient bone health threats, to reclaim bone density, structure, and strength without bone-targeted therapy; and 4) the need to benchmark bone health metrics to constantly evolving "normal targets", given the changes in bone size, shape, and metabolism that take place from birth through late adolescence. On this background, the pediatric osteoporosis field has evolved considerably over the last few decades, giving rise to a deeper understanding of the discrete genes implicated in childhood-onset osteoporosis, the natural history of bone fragility in the chronic illness setting and associated risk factors, effective diagnostic and monitoring pathways in different disease contexts, the importance of timely identification of candidates for osteoporosis treatment, and the benefits of early (during growth) rather than late (post-epiphyseal fusion) treatment. While there has been considerable progress, a number of unmet needs remain, the most urgent of which is to move beyond the monotherapeutic anti-resorptive landscape to the study and application of anabolic agents that are anticipated to not only improve bone mineral density but also increase long bone cross-sectional diameter (periosteal circumference). The purpose of this review is to provide a practical guide to the diagnosis and management of osteoporosis in children presenting to the clinic with fragility fractures, one that serves as a step-by-step "how to" reference for clinicians in their routine clinical journey. The article also provides a sightline to the future, emphasizing the clinical scenarios with the most urgent need for an expanded toolbox of effective osteoporosis agents in childhood.
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Affiliation(s)
- Leanne M. Ward
- Department of Pediatrics, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
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Bouman K, Dittrich ATM, Groothuis JT, van Engelen BGM, Zweers-van Essen H, de Baaij-Daalmeyer A, Janssen MCH, Erasmus CE, Draaisma JMT, Voermans NC. Bone quality in LAMA2-related muscular dystrophy and SELENON-related congenital myopathy, a one-year prospective natural history study. Neuromuscul Disord 2024; 34:105-113. [PMID: 38160563 DOI: 10.1016/j.nmd.2023.11.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 11/09/2023] [Accepted: 11/26/2023] [Indexed: 01/03/2024]
Abstract
Fragility fractures are frequently reported in neuromuscular diseases and negatively influence functional prognosis, quality of life and survival. In LAMA2-related muscular dystrophy (LAMA2-MD) and SELENON(SEPN1)-related congenital myopathy (SELENON-RM) cross-sectional and prospective natural history studies on bone quality and fragility long bone fractures (LBFs) are lacking. We therefore aim to systematically assess bone quality and provide recommendations for clinical care. We performed a one-year prospective natural history study in 21 LAMA2-MD and 10 SELENON-RM patients including a standardized fracture history and bone quality assessment through dual energy Xray absorptiometry scan (DEXA-scan) and/or bone health index (BHI). Ninety percent of the LAMA2-MD and SELENON-RM patients showed low bone quality. Eight (38%) LAMA2-MD and five (50%) SELENON-RM patients had a history of fragility LBFs. During the one-year follow-up period, one LAMA2-MD patient (female, 3 years) experienced a fragility LBF of the right humerus. We found no difference in bone mineral density between baseline and one-year follow-up. Based on general international guidelines for osteoporosis, we advise adequate vitamin D and calcium intake, and standardized clinical follow-up through a DEXA-scan or BHI in all LAMA2-MD and SELENON-RM patients. On indication, patients should be referred to the pediatrics or internal medicine for consideration of additional treatments.
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Affiliation(s)
- Karlijn Bouman
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Anne T M Dittrich
- Department of Pediatrics, Radboud Institute for Health Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jan T Groothuis
- Department of Rehabilitation, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Baziel G M van Engelen
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Heidi Zweers-van Essen
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Anja de Baaij-Daalmeyer
- Department of Gastroenterology and Hepatology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Mirian C H Janssen
- Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Corrie E Erasmus
- Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Jos M T Draaisma
- Department of Pediatrics, Radboud Institute for Health Sciences, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Nicol C Voermans
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands
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Blum AGR, Russo TDH, Nogueira RJN. Dual x-ray absorptiometry monitoring in pediatric short bowel syndrome: an integrative review. REVISTA PAULISTA DE PEDIATRIA : ORGAO OFICIAL DA SOCIEDADE DE PEDIATRIA DE SAO PAULO 2023; 42:e2023064. [PMID: 38126603 PMCID: PMC10742346 DOI: 10.1590/1984-0462/2024/42/2023064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 09/03/2023] [Indexed: 12/23/2023]
Abstract
OBJECTIVE To analyze the bone health of pediatric patients with short bowel syndrome intestinal failure (SBS-IF). DATA SOURCE An integrative literature review was performed using the data published in the MEDLINE-PubMed and Scientific Electronic Library Online (SciELO) databases between January 2010 and April 2021, and through a manual search of the reference lists of relevant studies. Studies were included if they assessed bone mineral density by the Dual X-Ray Absorptiometry (DXA) technique, incorporated pediatric patients (up to 20 years of age) with SBS under parenteral nutrition (PN) and were written in English. Eleven primary sources met the inclusion criteria for this study. DATA SYNTHESIS Pediatric patients with SBS-IF under long-term parenteral nutrition experienced frequent changes in bone metabolism, leading to osteoporotic fractures and growth failure. These patients have deficiencies in multiple nutrients, such as calcium, magnesium, phosphorus, and vitamin D. Consequently, there are variations in the secretion and regulation of the parathyroid hormone. In addition, the pharmacotechnical limitations related to calcium and phosphorus in the PN solution, use of glucocorticoids, and difficulty performing physical activity are risk factors for the development of metabolic bone disease in pediatric patients with SBS-IF. CONCLUSIONS Low bone mineral density was associated with a high risk of developing osteoporosis, fractures, and growth deficiency in pediatric patients with SBS-IF on PN therapy in the long term.
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8
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Chin SM, Unnold-Cofre C, Naismith T, Jansen S. The actin-bundling protein, PLS3, is part of the mechanoresponsive machinery that regulates osteoblast mineralization. Front Cell Dev Biol 2023; 11:1141738. [PMID: 38089885 PMCID: PMC10711096 DOI: 10.3389/fcell.2023.1141738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 11/07/2023] [Indexed: 02/01/2024] Open
Abstract
Plastin-3 (PLS3) is a calcium-sensitive actin-bundling protein that has recently been linked to the development of childhood-onset osteoporosis. Clinical data suggest that PLS3 mutations lead to a defect in osteoblast function, however the underlying mechanism remains elusive. To investigate the role of PLS3 in bone mineralization, we generated MC3T3-E1 preosteoblast cells that are stably depleted of PLS3. Analysis of osteogenic differentiation of control and PLS3 knockdown (PLS3 KD) cells showed that depletion of PLS3 does not alter the first stage of osteoblast mineralization in which a collagen matrix is deposited, but severely affects the subsequent mineralization of that matrix. During this phase, osteoblasts heavily rely on mechanosensitive signaling pathways to sustain mineral deposition in response to increasing stiffness of the extracellular matrix (ECM). PLS3 prominently localizes to focal adhesions (FAs), which are intricately linked to mechanosensation. In line with this, we observed that depletion of PLS3 rendered osteoblasts unresponsive to changes in ECM stiffness and showed the same cell size, FA lengths and number of FAs when plated on soft (6 kPa) versus stiff (100 kPa) substrates in contrast to control cells, which showed an increased in each of these parameters when plated on 100 kPa substrates. Defective cell spreading of PLS3 KD cells on stiff substrates could be rescued by expression of wildtype PLS3, but not by expression of three PLS3 mutations that were identified in patients with early onset osteoporosis and that have aberrant actin-bundling activity. Altogether, our results show that actin-bundling by PLS3 is part of the mechanosensitive mechanism that promotes osteoblast mineralization and thus begins to elucidate how PLS3 contributes to the development of bone defects such as osteoporosis.
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Affiliation(s)
| | | | | | - Silvia Jansen
- Department of Cell Biology and Physiology, Washington University in St. Louis, Saint Louis, MO, United States
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9
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Park SJ, Yoo JW, Ahn MB. Case Report and Literature Review: Bisphosphonate, Sirolimus, and Atenolol Treatment in a 4-Year-Old Child Diagnosed with Gorham-Stout Disease. Pharmaceuticals (Basel) 2023; 16:1504. [PMID: 37895975 PMCID: PMC10610495 DOI: 10.3390/ph16101504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 10/12/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
We report a 4-year-old with Gorham-Stout disease (GSD) who was treated with a combination of bisphosphonate, sirolimus, and atenolol. A previously healthy 4-year-old girl presented with back pain after falling on her back 2 months prior. Thoracolumbar spine X-ray revealed diffuse compression spinal fractures in T9-L2. Magnetic resonance imaging (MRI) confirmed multiple compression fractures at T9-L5 and revealed a paraspinal mass along the T1-L1 level. Based on clinical, radiological, and histopathological findings, Gorham-Stout disease was diagnosed. Treatment with sirolimus (0.5 mg twice daily, 1.6 mg/m2) was initiated and intravenous bisphosphonate (pamidronate, 1 mg/kg for 3 days, total 3 mg/kg every 4 months) was added for back pain; she had immediate improvement in back pain. After 9 months with this treatment, she had a mild increase in paraspinal lymphangiomatosis and aggravation in T9-L5 compression fractures; atenolol was administered. The patient underwent 11 months of combination treatment with bisphosphonate, sirolimus, and atenolol, and MRI showed mild degree of reduction in the paraspinal lesions at L1-L5. The patient is currently in stable condition with no back pain or side effects. The triple combination treatment with bisphosphonate, sirolimus, and atenolol may be helpful in stabilizing the disease course of GSD.
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Affiliation(s)
- Su Jin Park
- Divison of Endocrinology, Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jae Won Yoo
- Division of Hematology and Oncology, Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Moon Bae Ahn
- Divison of Endocrinology, Department of Pediatrics, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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10
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Granild-Jensen JB, Møller-Madsen B, Rackauskaite G, Farholt S, Søndergaard C, Sørensen TH, Vestergaard ET, Langdahl BL. Zoledronate Increases Bone Mineral Density in Nonambulant Children With Cerebral Palsy: A Randomized Controlled Trial. J Clin Endocrinol Metab 2023; 108:2840-2851. [PMID: 37235798 DOI: 10.1210/clinem/dgad299] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2023] [Revised: 05/15/2023] [Accepted: 05/23/2023] [Indexed: 05/28/2023]
Abstract
CONTEXT Zoledronate appears to reduce fracture rates in children with cerebral palsy (CP), but no previous randomized, controlled trial has been performed to compare the effect of zoledronate to placebo in children with CP. OBJECTIVE To investigate the effect of zoledronate on bone mineral density (BMD) Z-scores in children with nonambulant CP in a randomized, controlled, double-blind trial. METHODS Nonambulant children with CP (5 to 16 years of age) were randomized 1:1 to receive 2 doses of zoledronate or placebo at a 6-month interval. BMD Z-score changes at the lumbar spine and the lateral distal femur (LDF) were calculated from dual-energy x-ray absorptiometry scans. Monitoring included weight, bone age, pubertal staging, knee-heel length, adverse events, biochemical markers, and questionnaires. RESULTS Twenty-four participants were randomized and all completed the study. Fourteen were assigned to zoledronate. The mean lumbar spine BMD Z-score increased 0.8 SD (95% CI: 0.4; 1.2) in the zoledronate group, which was significant when compared to 0.0 SD (95% CI: -0.3; 0.3) in the placebo group. Similarly, the LDF BMD Z-scores increased more in the zoledronate group. Severe acute phase symptoms affected 50% of the patients in the zoledronate group but were reported exclusively after the first dose. Growth parameters were similar in both groups. CONCLUSION Zoledronate for 12 months increased BMD Z-scores significantly without affecting growth, but first-dose side effects were common and considerable. Studies into lower first doses and long-term outcomes are needed.
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Affiliation(s)
- Jakob Bie Granild-Jensen
- Department of Child and Youth, Randers Regional Hospital, 8930 Randers, Denmark
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
| | - Bjarne Møller-Madsen
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
- Department of Children's Orthopedics (www.dpor.dk), Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Gija Rackauskaite
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Stense Farholt
- Centre for Rare Diseases - Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Charlotte Søndergaard
- Department of Pediatrics and Adolescent Medicine, Gødstrup Regional Hospital, 7400 Herning, Denmark
| | - Tine Høg Sørensen
- Department of Pediatrics and Adolescent Medicine, Aalborg University Hospital, 9000 Aalborg, Denmark
| | - Esben Thyssen Vestergaard
- Department of Pediatrics and Adolescent Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
| | - Bente Lomholt Langdahl
- Department of Clinical Medicine, Aarhus University, 8200 Aarhus N, Denmark
- Department of Endocrinology and Internal Medicine, Aarhus University Hospital, 8200 Aarhus N, Denmark
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11
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He S, Zhang Y, Tan C, Tan W, Yin B. Inverted U-shaped relationships between bone mineral density and VCTE-quantified degree of hepatic steatosis in adolescents: Evidence from the NHANES. PLoS One 2023; 18:e0286688. [PMID: 37294745 PMCID: PMC10256176 DOI: 10.1371/journal.pone.0286688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 05/20/2023] [Indexed: 06/11/2023] Open
Abstract
INTRODUCTION There may be inaccuracies in hepatic steatosis in past research assessing the relationship between bone metabolism and liver steatosis. The goal of the current research was to look at the associations between bone mineral density (BMD) and the hepatic steatosis and fibrosis as detected by vibration-controlled transient elastography (VCTE) in teenagers in the United States. METHODS Weighted multiple linear regression models and smoothed curve fitting were used to investigate the association between BMD and the degree of hepatic steatosis and fibrosis in adolescents. RESULTS In 829 adolescents aged 12-19 years we found a negative association between total BMD and CAP (controlled attenuation parameter) [-32.46 (-58.98, -9.05)] and a significant positive association between lumbar BMD and LSM (liver stiffness measurement) [1.35 (0.19, 2.51)]. The inverted U-shaped relationships were founded between total BMD, lumbar BMD, pelvis BMD, and CAP with inflection points of 221.22 dB/m, 219.88 dB/m, and 216.02 dB/m, respectively. CONCLUSIONS In adolescents, higher BMD is significantly associated with lower levels of hepatic steatosis and higher levels of liver stiffness.
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Affiliation(s)
- Shengmao He
- Department of Hand and Foot Surgery, The Affiliated Second Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Yun Zhang
- Department of Traumatic and Pediatric Orthopedics, The Affiliated Second Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Caixia Tan
- Department of Traumatic and Pediatric Orthopedics, The Affiliated Second Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Wenfu Tan
- Department of Traumatic and Pediatric Orthopedics, The Affiliated Second Hospital, Hengyang Medical School, University of South China, Hengyang, China
| | - Bingliang Yin
- Department of Hand and Foot Surgery, The Affiliated Second Hospital, Hengyang Medical School, University of South China, Hengyang, China
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12
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Dittrich ATM, Janssen EJM, Geelen J, Bouman K, Ward LM, Draaisma JMT. Diagnosis, Follow-Up and Therapy for Secondary Osteoporosis in Vulnerable Children: A Narrative Review. APPLIED SCIENCES 2023; 13:4491. [DOI: 10.3390/app13074491] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
Abstract
By definition, children constitute a vulnerable population, especially when they are chronically ill and/or disabled. A characteristic of chronically ill and disabled children is that they also suffer from indirect effects of their disease, such as immobilization, chronic inflammation, reduced time outdoors in the sun, osteotoxic effects of disease-targeted therapy (like glucocorticoids), and poor nutrition. All these factors may lead to bone fragility due to secondary osteoporosis, a co-morbidity that may be overlooked in the context of serious underlying diseases. The ultimate goal of osteoporosis diagnosis and monitoring in this setting is the early identification, prevention, and treatment of low-trauma long bone and vertebral fractures; indeed, vertebral fractures are a frequently under-diagnosed manifestation of overt bone fragility in this context. Efforts to prevent first-ever fractures are also meritorious, including encouragement of weight-bearing activities, optimization of nutritional status, including calcium and vitamin D supplementation, and the diagnosis and treatment of delayed growth and puberty; however, these conservative measures may be insufficient in those at high risk. Numerous natural history studies have shown that vertebral fractures are more common than non-vertebral (i.e., long bone) fractures in at-risk children. Not surprisingly, the cornerstone of secondary osteoporosis monitoring is lateral spine imaging for the early detection of vertebral collapse. Although dual-energy x-ray absorptiometry (DXA) is the gold standard to measure bone mineral density, digital X-ray radiogrammetry may be used as a surrogate measure of bone strength if dual-energy x-ray absorptiometry is not available. In the event that preventive measures fail, treatment with bisphosphonates may be appropriate. Typically, treatment with intravenous bisphosphonates is reserved for children with overt bone fragility and limited potential for spontaneous recovery. However, there is increasing attention to very high-risk children, such as boys with Duchenne muscular dystrophy, who may benefit from bisphosphonate therapy prior to first-ever fractures (given their high fracture frequency and essentially absent potential for spontaneous recovery). This article provides a contemporary overview of the definition and diagnosis of osteoporosis in children with chronic illness, along with the approach to monitoring those at risk and the evidence for currently recommended intervention strategies.
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Affiliation(s)
- Anne T. M. Dittrich
- Department of Pediatrics, Radboudumc Amalia Children’s Hospital, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Etienne J. M. Janssen
- Department of Pediatrics, Radboudumc Amalia Children’s Hospital, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
- Department of Pediatrics, Maastricht University Medical Centre, 6229 HX Maastricht, The Netherlands
| | - Joyce Geelen
- Department of Pediatrics, Radboudumc Amalia Children’s Hospital, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Karlijn Bouman
- Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behavior, Amalia Children’s Hospital, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
| | - Leanne M. Ward
- The Department of Pediatrics, University of Ottawa, Ottawa, ON K1H 8L1, Canada
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada
| | - Jos M. T. Draaisma
- Department of Pediatrics, Radboudumc Amalia Children’s Hospital, Radboud Institute for Health Sciences, Radboud University Medical Center, 6525 GA Nijmegen, The Netherlands
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13
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Valenzuela Riveros LF, Long J, Bachrach LK, Leonard MB, Kent K. Trabecular Bone Score (TBS) Varies with Correction for Tissue Thickness Versus Body Mass Index: Implications When Using Pediatric Reference Norms. J Bone Miner Res 2023; 38:493-498. [PMID: 36779634 DOI: 10.1002/jbmr.4786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 01/20/2023] [Accepted: 01/25/2023] [Indexed: 02/14/2023]
Abstract
Trabecular bone score (TBS) derived from secondary analysis of lumbar spine dual-energy X-ray absorptiometry (DXA) scans improves fracture prediction independent of bone mineral density (BMD) in adults. The utility of TBS to assess fracture risk in younger patients has not been established because pediatric norms have been lacking. Robust TBS reference data from the Bone Mineral Density in Childhood Study (BMDCS) have been published. TBS values for the BMDCS study were derived using an algorithm that accounts for tissue thickness (TBSTH ) rather than the commercially available algorithm that adjusts for body mass index (BMI; TBSBMI ). We examined the magnitude of differences in TBSTH and TBSBMI in a cohort of 189 healthy youth. TBS values using both algorithms increased with age and pubertal development in a similar pattern. However, TBSBMI values were systematically and significantly higher than TBSTH (mean = 0.06, p < 0.0001). The difference between calculated TBSBMI and TBSTH was not uniform. Differences were greater at lower TBS values, in males, in older individuals, in those at later Tanner stages, and in those with a greater BMI Z-score. These systematic differences preclude the development of a simple formula to allow conversion of TBSBMI to TBSTH "equivalents." Because of these systematic differences in these two algorithms, using an individual's TBSBMI to calculate a Z-score using the BMDCS TBSTH reference values results in a falsely higher TBS Z-score (differences mean = 0.73, interquartile range [IQR] = 0.3 to 1.6). Until TBSTH software for Hologic DXA equipment becomes commercially available, BMDCS TBS reference norms should not be used. © 2023 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
| | - Jin Long
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA
| | - Laura K Bachrach
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA
| | - Mary B Leonard
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA
| | - Kyla Kent
- Department of Pediatrics, Stanford School of Medicine, Stanford, CA, USA
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Madhuchani D, Seneviratne SN, Ward LM. Bone health in childhood and adolescence: an overview on dual-energy X-ray absorptiometry scanning, fracture surveillance and bisphosphonate therapy for low-middle-income countries. Front Endocrinol (Lausanne) 2023; 14:1082413. [PMID: 37139332 PMCID: PMC10150014 DOI: 10.3389/fendo.2023.1082413] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Accepted: 02/16/2023] [Indexed: 05/05/2023] Open
Abstract
Bone accrual in childhood determines bone health in later life. Loss of bone strength in early life can lead to increased morbidity and reduced quality of life in childhood and adolescence. Increased availability of assessment tools and bisphosphonate therapy, together with increased awareness on the significance of fracture history and risk factors, have led to greater opportunities, to improve detection and optimize management of children and adolescents with bone fragility globally, including those in lower resource settings. Bone mineral density z-scores and bone mineral content are surrogate measures of bone strength, which can be measured by dual-energy X-ray absorptiometry (DXA), in growing individuals. DXA can aid in the diagnosis and management of primary and secondary bone fragility disorders in childhood. DXA helps evaluate children with clinically significant fractures, and monitor those with bone fragility disorders, or at high risk for compromised bone strength. Obtaining DXA images can however be challenging, especially in younger children, due to difficulty in positioning and movement artefacts, while paediatric DXA interpretation can be confounded by effects of growth and puberty. Furthermore, access to DXA facilities as well as appropriate paediatric reference norms and expertise for interpretation, may not be easily available especially in lower resource settings. Pediatric bone experts are now placing increasing emphasis on the fracture phenotype and clinical context to diagnose osteoporosis over bone mineral density (BMD) by DXA. Low trauma vertebral fractures are now recognized as a hallmark of bone fragility, and spinal fracture surveillance by either conventional lateral thoracolumbar radiographs or vertebral fracture assessment by DXA is gaining increasing importance in diagnosing childhood osteoporosis, and initiating bone protective therapy. Furthermore, it is now understood that even a single, low-trauma long bone fracture can signal osteoporosis in those with risk factors for bone fragility. Intravenous bisphosphonate therapy is the mainstay of treatment for childhood bone fragility disorders. Other supportive measures to improve bone strength include optimizing nutrition, encouraging weight bearing physical activity within the limits of the underlying condition, and treating any associated endocrinopathies. With this paradigm shift in childhood osteoporosis evaluation and management, lack of DXA facilities to assess BMD at baseline and/or provide serial monitoring is not a major barrier for initiating IV bisphosphonate therapy in children in whom it is clinically indicated and would benefit from its use. DXA is useful, however, to monitor treatment response and optimal timing for treatment discontinuation in children with transient risk factors for osteoporosis. Overall, there is lack of awareness and paucity of guidelines on utilizing and adopting available resources to manage paediatric bone disorders optimally in lower-resource settings. We provide an evidence-based approach to the assessment and management of bone fragility disorders in children and adolescents, with appropriate considerations for lower resource settings including LMIC countries.
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Affiliation(s)
| | - Sumudu Nimali Seneviratne
- Department of Paediatrics, Faculty of Medicine, University of Colombo, Colombo, Sri Lanka
- *Correspondence: Sumudu Nimali Seneviratne,
| | - Leanne M. Ward
- Department of Pediatrics, University of Ottawa and Division of Endocrinology, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
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15
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Bouman K, Groothuis JT, Doorduin J, van Alfen N, Udink ten Cate FE, van den Heuvel FM, Nijveldt R, Kamsteeg EJ, Dittrich AT, Draaisma JM, Janssen MC, van Engelen BG, Erasmus CE, Voermans NC. SELENON-Related Myopathy Across the Life Span, a Cross-Sectional Study for Preparing Trial Readiness. J Neuromuscul Dis 2023; 10:1055-1074. [PMID: 37807786 PMCID: PMC10657684 DOI: 10.3233/jnd-221673] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/11/2023] [Indexed: 10/10/2023]
Abstract
BACKGROUND SELENON(SEPN1)-related myopathy (SELENON-RM) is a rare congenital neuromuscular disease characterized by proximal and axial muscle weakness, spinal rigidity, scoliosis and respiratory impairment. No curative treatment options exist, but promising preclinical studies are ongoing. Currently, natural history data are lacking, while selection of appropriate clinical and functional outcome measures is needed to reach trial readiness. OBJECTIVE We aim to identify all Dutch and Dutch-speaking Belgian SELENON-RM patients, deep clinical phenotyping, trial readiness and optimization of clinical care. METHODS This cross-sectional, single-center, observational study comprised neurological examination, functional measurements including Motor Function Measurement 20/32 (MFM-20/32) and accelerometry, questionnaires, muscle ultrasound, respiratory function tests, electro- and echocardiography, and dual-energy X-ray absorptiometry. RESULTS Eleven patients with genetically confirmed SELENON-RM were included (20±13 (3-42) years, 73% male). Axial and proximal muscle weakness were most pronounced. The mean MFM-20/32 score was 71.2±15.1%, with domain 1 (standing and transfers) being most severely affected. Accelerometry showed a strong correlation with MFM-20/32. Questionnaires revealed impaired quality of life, pain and problematic fatigue. Muscle ultrasound showed symmetrically increased echogenicity in all muscles. Respiratory function, and particularly diaphragm function, was impaired in all patients, irrespective of the age. Cardiac assessment showed normal left ventricular systolic function in all patients but abnormal left ventricular global longitudinal strain in 43% of patients and QRS fragmentation in 80%. Further, 80% of patients showed decreased bone mineral density on dual-energy X-ray absorptiometry scan and 55% of patients retrospectively experienced fragility long bone fractures. CONCLUSIONS We recommend cardiorespiratory follow-up as a part of routine clinical care in all patients. Furthermore, we advise vitamin D supplementation and optimization of calcium intake to improve bone quality. We recommend management interventions to reduce pain and fatigue. For future clinical trials, we propose MFM-20/32, accelerometry and muscle ultrasound to capture disease severity and possibly disease progression.
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Affiliation(s)
- Karlijn Bouman
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
- Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Amalia Children’s Hospital, Radboud university medical center, Nijmegen, The Netherlands
| | - Jan T. Groothuis
- Department of Rehabilitation, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Jonne Doorduin
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Nens van Alfen
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Floris E.A. Udink ten Cate
- Department of Pediatric cardiology, Amalia Children’s Hospital, Radboud university medical center, Nijmegen, The Netherlands
| | | | - Robin Nijveldt
- Department of Cardiology, Radboud university medical center, Nijmegen, The Netherlands
| | - Erik-Jan Kamsteeg
- Department of Human Genetics, Radboud university medical center, Nijmegen, The Netherlands
| | - Anne T.M. Dittrich
- Department of Pediatrics, Radboud Institute for Health Sciences, Amalia Children’s Hospital, Radboud university medical center, Nijmegen, The Netherlands
| | - Jos M.T. Draaisma
- Department of Pediatrics, Radboud Institute for Health Sciences, Amalia Children’s Hospital, Radboud university medical center, Nijmegen, The Netherlands
| | - Mirian C.H. Janssen
- Department of Internal Medicine, Radboud university medical center, Nijmegen, The Netherlands
| | - Baziel G.M. van Engelen
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
| | - Corrie E. Erasmus
- Department of Pediatric Neurology, Donders Institute for Brain, Cognition and Behaviour, Amalia Children’s Hospital, Radboud university medical center, Nijmegen, The Netherlands
| | - Nicol C. Voermans
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud university medical center, Nijmegen, The Netherlands
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16
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Li D, Ou J, Zeng Y, Hou L, Yuan Y, Luo Z. Bibliometric study on clinical research of osteoporosis in adolescents. Front Public Health 2023; 11:1041360. [PMID: 36908434 PMCID: PMC9992876 DOI: 10.3389/fpubh.2023.1041360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Accepted: 02/06/2023] [Indexed: 02/24/2023] Open
Abstract
Objective Focusing on the theme of "osteoporosis-related research in adolescents," a systematic visualization of the developmental lineage, current research status, hot spots, and trends of adolescent osteoporosis was conducted to provide a reference for subsequent related research, clinical diagnosis, and treatment. Method The Web of Science core database was used as the data source to retrieve the relevant literature and the bibliometrics method. An online bibliometric platform, CiteSpace, and VOSviewer software were used to conduct co-occurrence analysis on the authors, scientific research institutions, national cooperation, keywords, and funding sources to draw the relevant knowledge map. Result A total of 1,199 publications from the Web of Science core database were included in this study. The number of published adolescent osteoporosis (AOP) studies has shown an upward trend over the past 29 years, with the United States being the major contributor to the field with the highest number of publications (291, 24.3%) and the highest number of citations (12,186). The international collaboration map shows that the United States is the country most focused on international collaborative exchanges, with the closest collaboration between the United States and Canada. The most influential research institutions and authors are Children's Hospital and Rauch F. the United States is the primary funding source for this research area. Research hotspots were mainly focused on "bone density," "osteoporosis," and "children." Conclusion These knowledge maps review the research hotpots in adolescent osteoporosis research over time, analyze and summarize the research process over the past 29 years, and predict future research directions.
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Affiliation(s)
- Dingshuang Li
- Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Jingxi Ou
- Acupuncture and Rehabilitation Clinical School of Guangzhou University of Traditional Chinese Medicine, Guangzhou, China
| | - Yang Zeng
- Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Lei Hou
- Department of Science and Education Section, Foshan Hospital of Traditional Chinese Medicine, Foshan, Guangdong, China
| | - Yu Yuan
- Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
| | - Zhiyuan Luo
- Eighth Clinical Medical College of Guangzhou University of Chinese Medicine, Foshan, Guangdong, China
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17
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Safety and Efficacy of Alendronate to Treat Osteopenia in Children During Therapy for Acute Lymphoblastic Leukemia: A Retrospective Cohort Study of Sequential Outcomes. J Pediatr Hematol Oncol 2022; 45:200-206. [PMID: 36729669 DOI: 10.1097/mph.0000000000002606] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 11/07/2022] [Indexed: 02/03/2023]
Abstract
BACKGROUND Low bone mineral density is encountered in children with acute lymphoblastic leukemia (ALL) before, during, and after treatment. Prior experience with alendronate, an oral bisphosphonate, demonstrated high tolerability and evident clinical efficacy. However, concerns have been expressed about the long-term safety and utility of such agents in children. PROCEDURE Sixty-nine children with ALL received alendronate for a mean of 87 weeks after dual-energy x-ray absorptiometry. Dual-energy x-ray absorptiometry was repeated following the completion of alendronate, and 5 to 9 years later in a subgroup of 32 children. Lumbar spine areal bone mineral density (LS aBMD) Z scores were obtained. RESULTS The mean LS aBMD Z score rose from -1.78 to-0.47 (P <0.0001). There was a modest median loss of LS aBMD subsequently in the 32 subjects on long-term follow-up. Almost 80% (N=172) of the children remain in continuous complete remission at a mean of 14.5 years from diagnosis. Of those who received alendronate, which was almost uniformly well tolerated, 7/69 (10.3%) relapsed compared with 19/89 (21.3%) who did not receive the drug. DISCUSSION Alendronate appears to be well tolerated and moderately effective in osteopenic children with ALL. Whether it offers protection against relapse of leukemia needs further study.
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Grimbly C, Escagedo PD, Jaremko JL, Bruce A, Alos N, Robinson ME, Konji VN, Page M, Scharke M, Simpson E, Pastore YD, Girgis R, Alexander RT, Ward LM. Sickle cell bone disease and response to intravenous bisphosphonates in children. Osteoporos Int 2022; 33:2397-2408. [PMID: 35904681 PMCID: PMC9568449 DOI: 10.1007/s00198-022-06455-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 05/28/2022] [Indexed: 11/30/2022]
Abstract
UNLABELLED Children with sickle cell disease (SCD) have the potential for extensive and early-onset bone morbidity. This study reports on the diversity of bone morbidity seen in children with SCD followed at three tertiary centers. IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications. INTRODUCTION To evaluate bone morbidity and the response to intravenous (IV) bisphosphonate therapy in children with SCD. METHODS We conducted a retrospective review of patient records from 2003 to 2019 at three Canadian pediatric tertiary care centers. Radiographs, magnetic resonance images, and computed tomography scans were reviewed for the presence of avascular necrosis (AVN), bone infarcts, and myositis. IV bisphosphonates were offered for bone pain management. Bone mineral density was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS Forty-six children (20 girls, 43%) had bone morbidity at a mean age of 11.8 years (SD 3.9) including AVN of the femoral (17/46, 37%) and humeral (8/46, 17%) heads, H-shaped vertebral body deformities due to endplate infarcts (35/46, 76%), and non-vertebral body skeletal infarcts (15/46, 32%). Five children (5/26, 19%) had myositis overlying areas of AVN or bone infarcts visualized on magnetic resonance imaging. Twenty-three children (8/23 girls) received IV bisphosphonate therapy. They all reported significant or complete resolution of bone pain. There were no reports of sickle cell hemolytic crises, pain crises, or stroke attributed to IV bisphosphonate therapy. CONCLUSION Children with SCD have the potential for extensive and early-onset bone morbidity. In this series, IV bisphosphonates were effective for bone pain analgesia and did not trigger sickle cell complications.
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Affiliation(s)
- C Grimbly
- Department of Pediatrics, University of Alberta, 4-584 Edmonton Clinic Health Academy, 11405 - 87 Ave, Edmonton, AB, T6G 2R7, Canada.
- Women's and Children's Health Research Institute, Alberta, Canada.
| | - P Diaz Escagedo
- Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montreal, Montreal, QC, Canada
| | - J L Jaremko
- Department of Radiology & Diagnostic Imaging, University of Alberta, Edmonton, AB, Canada
| | - A Bruce
- Department of Pediatrics, University of Alberta, 4-584 Edmonton Clinic Health Academy, 11405 - 87 Ave, Edmonton, AB, T6G 2R7, Canada
- Women's and Children's Health Research Institute, Alberta, Canada
| | - N Alos
- Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montreal, Montreal, QC, Canada
| | - M E Robinson
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - V N Konji
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - M Page
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - M Scharke
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - E Simpson
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
| | - Y D Pastore
- Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine, Université de Montreal, Montreal, QC, Canada
| | - R Girgis
- Department of Pediatrics, University of Alberta, 4-584 Edmonton Clinic Health Academy, 11405 - 87 Ave, Edmonton, AB, T6G 2R7, Canada
- Women's and Children's Health Research Institute, Alberta, Canada
| | - R T Alexander
- Department of Pediatrics, University of Alberta, 4-584 Edmonton Clinic Health Academy, 11405 - 87 Ave, Edmonton, AB, T6G 2R7, Canada
- Women's and Children's Health Research Institute, Alberta, Canada
| | - L M Ward
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
- The Ottawa Pediatric Bone Health Research Group, Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
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19
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Abstract
Osteoporosis is a major public health problem with serious long-term complications. In children, the definition of osteoporosis is not only based on densitometric criteria but also takes into account vertebral and long bone fragility fractures. Several factors, such as long-term high-dose steroids, chronic inflammation, malnutrition, immobility, lack of sex steroids, and medication can reduce bone density and increase the risk for fragility fractures when left untreated. Also, genetic conditions can predispose to primary bone fragility disorders, with osteogenesis imperfecta being the most common. Furthermore, since the growing skeleton is at an increased rate of bone remodeling, the ability to heal long bone fractures and reshape vertebral fractures differentiates children from adults. The scope of this chapter is to review the risk factors of osteoporosis and fragility fractures and describe the commonest causes of primary and secondary osteoporosis and their management in children and young adults.
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Affiliation(s)
- Sophia D Sakka
- Department of Endocrinology and Diabetes, Evelina London Children's Hospital, London, UK; GKT School of Medical Education, King's College London, UK; Department of Endocrinology, Metabolism and Diabetes, First Department of Paediatrics, Athens University Medical School, 'Aghia Sophia Children's Hospital', Athens, Greece.
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20
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Wu Z, Feng Z, Zhu X, Dai Z, Min K, Qiu Y, Yi L, Xu L, Zhu Z. Identification of a novel splicing mutation and genotype-phenotype correlations in rare PLS3-related childhood-onset osteoporosis. Orphanet J Rare Dis 2022; 17:247. [PMID: 35752817 PMCID: PMC9233774 DOI: 10.1186/s13023-022-02380-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Accepted: 06/06/2022] [Indexed: 11/16/2022] Open
Abstract
Background X-linked early-onset osteoporosis, caused by mutations in plastin3 (PLS3), is an extremely rare disease characterized by low bone mineral density (BMD) and recurrent osteoporotic fractures. There is limited information on genetic and phenotypic spectrum, as well as genotype–phenotype correlations of the disease. Moreover, whether decreased PLS3 levels were also involved in osteoporosis among subjects without PLS3 pathogenic mutations remains unknown. Methods Whole-exome sequencing and bidirectional Sanger sequencing were performed for screening and validation of pathogenic mutations. Serum biochemical parameters and clinical information of the subjects were retrospectively collected. ELISA and online datasets were utilized to investigate the association between PLS3 expression and BMD. Results We identified a novel splicing mutation (c.892-2A > G) which led to the skipping of exon 9 in a family with X-linked early-onset osteoporosis. Scoliosis represents a potential new phenotype in the patients harboring PLS3 mutations, which may be corrected by brace treatment. Genotype–phenotype analysis reveals that there was no significant difference in BMD z-scores between different types of reported mutations including this study (p = 0.5). There is a marginally significant negative correlation between age and BMD z-score (p = 0.059, r = − 0.30). The conditions of osteoporosis in all patients were improved after bisphosphonates therapy, with mean BMD z-score increased from − 2.9 to − 0.57 (p < 0.0001). Serum PLS3 levels in adolescents and adults without PLS3 pathogenic mutations but representing osteoporosis were also evaluated, while no association was found between bone mineral density and PLS3 levels (p > 0.05). Conclusions Our findings expanded the mutation and phenotype spectrum of the rare disease and highlights the importance of early diagnosis and early treatment with bisphosphonates. More reports of cases with PLS3 mutation and function studies of the gene are warranted to understand genotype–phenotype correlations. Supplementary Information The online version contains supplementary material available at 10.1186/s13023-022-02380-z.
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Affiliation(s)
- Zhichong Wu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Zhenhua Feng
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Xiufen Zhu
- Osteoporosis and Metabolic Bone Disease Center, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Zhicheng Dai
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Kaixing Min
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Yong Qiu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Long Yi
- Jiangsu Key Laboratory of Molecular Medicine, School of Medicine, Nanjing University, Nanjing, China
| | - Leilei Xu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China.,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China
| | - Zezhang Zhu
- Division of Spine Surgery, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China. .,Joint Scoliosis Research Center of The Chinese University of Hong Kong and Nanjing University, Nanjing & Hong Kong, China.
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21
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Di Marcello F, Di Donato G, d’Angelo DM, Breda L, Chiarelli F. Bone Health in Children with Rheumatic Disorders: Focus on Molecular Mechanisms, Diagnosis, and Management. Int J Mol Sci 2022; 23:ijms23105725. [PMID: 35628529 PMCID: PMC9143357 DOI: 10.3390/ijms23105725] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/13/2022] [Accepted: 05/19/2022] [Indexed: 02/04/2023] Open
Abstract
Bone is an extremely dynamic and adaptive tissue, whose metabolism and homeostasis is influenced by many different hormonal, mechanical, nutritional, immunological and pharmacological stimuli. Genetic factors significantly affect bone health, through their influence on bone cells function, cartilage quality, calcium and vitamin D homeostasis, sex hormone metabolism and pubertal timing. In addition, optimal nutrition and physical activity contribute to bone mass acquisition in the growing age. All these factors influence the attainment of peak bone mass, a critical determinant of bone health and fracture risk in adulthood. Secondary osteoporosis is an important issue of clinical care in children with acute and chronic diseases. Systemic autoimmune disorders, like juvenile idiopathic arthritis, can affect the skeletal system, causing reduced bone mineral density and high risk of fragility fractures during childhood. In these patients, multiple factors contribute to reduce bone strength, including systemic inflammation with elevated cytokines, reduced physical activity, malabsorption and nutritional deficiency, inadequate daily calcium and vitamin D intake, use of glucocorticoids, poor growth and pubertal delay. In juvenile arthritis, osteoporosis is more prominent at the femoral neck and radius compared to the lumbar spine. Nevertheless, vertebral fractures are an important, often asymptomatic manifestation, especially in glucocorticoid-treated patients. A standardized diagnostic approach to the musculoskeletal system, including prophylaxis, therapy and follow up, is therefore mandatory in at risk children. Here we discuss the molecular mechanisms involved in skeletal homeostasis and the influence of inflammation and chronic disease on bone metabolism.
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22
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Fu Y, Wang G, Liu J, Li M, Dong M, Zhang C, Xu R, Liu X. Stimulant use and bone health in US children and adolescents: analysis of the NHANES data. Eur J Pediatr 2022; 181:1633-1642. [PMID: 35091797 DOI: 10.1007/s00431-021-04356-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/16/2021] [Accepted: 12/17/2021] [Indexed: 11/03/2022]
Abstract
UNLABELLED Stimulants have become the most popular psychopharmacologic drugs used in therapy for attention-deficit/hyperactivity disorder (ADHD). Childhood and adolescence are crucial periods for optimizing bone health to prevent osteoporosis-related fractures in old age. However, controversy remains regarding the relationship between stimulant use and bone health. The present study was designed to examine the bone mineral content (BMC) and bone mineral density (BMD) of 5472 individuals aged 8-16 years with or without stimulant use based on National Health and Nutrition Examination Survey (NHANES) 2011-2018 data and to further assess the association between stimulant use and bone health. Among these, 284 (5.2%) participants were using stimulants. In analyses stratified by sex, the BMC and BMD at the level of the lumbar spine, pelvis, and total body were generally lower among stimulant users than among nonusers in males (all P < 0.001), while the differences were not statistically significant in females. In multivariable linear regression models, the increasing range of BMCs and BMDs with age was lower in participants using stimulants than in those not using stimulants after fully adjusting for potential confounding factors. Compared to participants not using stimulants, stimulant use ≥ 3 months was associated with significantly lower BMCs [lumbar spine: β = - 1.35, (95% CI: - 2.56, - 0.14); pelvis: β = - 9.06, (95% CI: - 15.21, - 2.91); and total: β = - 52.96, (95% CI: - 85.87, - 20.04)] and BMDs [pelvis: β = - 0.03, (95% CI: - 0.04, - 0.01), total: β = - 0.01, (95% CI: - 0.02, - 0.00)]. CONCLUSIONS Children and adolescents using stimulants exhibited reductions in BMC and BMD at the lumbar spine, pelvis, and total body compared to those who were not using stimulants, especially among males. WHAT IS KNOWN • Childhood and adolescence are crucial periods for optimizing bone health to prevent osteoporosis-related fractures in old age. • Controversy remains regarding the relationship between stimulant use and bone health. WHAT IS NEW • The bone mineral content and bone mineral density at the level of the lumbar spine, pelvis, and total body were generally lower among stimulant users than among nonusers in males, while the differences were not statistically significant in females. • Body mass index and serum alkaline phosphatase may be predictors for loss of bone mineral content and bone mineral density in stimulant users.
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Affiliation(s)
- Yanan Fu
- Department of Medical Engineering, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Guan Wang
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China.,NHC Key Laboratory of Otorhinolaryngology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Junhui Liu
- School of Medicine, Shandong University, No. 44 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Meng Li
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Meng Dong
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Chen Zhang
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Rui Xu
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China
| | - Xinjie Liu
- Department of Pediatrics, Qilu Hospital of Shandong University, No. 107 West Wenhua Road, Jinan, Shandong Province, 250012, China.
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23
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Petkovic MJ, Tran HA, Ebeling PR, Zengin A. Osteoporosis management and falls prevention in patients with haemophilia: Review of haemophilia guidelines. Haemophilia 2022; 28:388-396. [PMID: 35290707 PMCID: PMC9310867 DOI: 10.1111/hae.14540] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2021] [Revised: 02/21/2022] [Accepted: 02/25/2022] [Indexed: 12/22/2022]
Abstract
INTRODUCTION Patients with haemophilia (PWH) have a high prevalence of osteoporosis, falls and fractures at all ages. The role of haemophilia itself may contribute to low bone mineral density (BMD) due to coagulation factor deficiency. Guidelines for the management of osteoporosis, fracture and fall risk may help to reduce fracture and fall risk, and delay osteoporosis onset. AIM We aim to review current haemophilia guidelines regarding osteoporosis prevention, screening, diagnosis and management, and fall prevention. METHOD A database search (Ovid MEDLINE) revealed two haemophilia guidelines (World and British) published within the last ten years. Local Australian haemophilia guidelines were identified through a manual search. RESULTS All haemophilia guidelines were found to contain inadequate recommendations for osteoporosis management and fall prevention due to a lack of evidence in the literature. CONCLUSION Further studies are required to assess the trajectory of bone health in PWH, the mechanism of bone loss in PWH, and the effectiveness of weight-bearing exercises, interventions for fall prevention, screening programmes, and use of anti-osteoporosis medications in PWH across the lifecourse.
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Affiliation(s)
- Madison J Petkovic
- Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Huyen A Tran
- Australian Centre for Blood Diseases, Monash University, Melbourne, Australia.,Clinical Haematology Department, Alfred Hospital, Thrombosis & Haemostasis Unit, Melbourne, Australia
| | - Peter R Ebeling
- Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
| | - Ayse Zengin
- Department of Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
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24
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Höppner J, Steff K, Lobert F, Heyer CM, Hauffa BP, Grasemann C. Rhizomelia and Impaired Linear Growth in a Girl with Juvenile Paget Disease: The Natural History of the Condition. Horm Res Paediatr 2022; 94:151-158. [PMID: 34261073 DOI: 10.1159/000517164] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2020] [Accepted: 05/10/2021] [Indexed: 11/19/2022] Open
Abstract
In ultra-rare bone diseases, information on growth during childhood is sparse. Juvenile Paget disease (JPD) is an ultra-rare disease, characterized by loss of function of osteoprotegerin (OPG). OPG inhibits osteoclast activation via the receptor activator of nuclear factor-κB (RANK) pathway. In JPD, overactive osteoclasts result in inflammatory-like bone disease due to grossly elevated bone resorption. Knowledge on the natural history of JPD, including final height and growth, is limited. Most affected children receive long-term antiresorptive treatment, mostly with bisphosphonates, to contain bone resorption, which may affect growth. In this study, we report the follow-up of height, growth velocity, and skeletal maturation in a 16-year-old female patient with JPD. The patient was treated with cyclic doses of pamidronate starting at 2.5 years of age and with 2 doses of denosumab at the age of 8 years, when pamidronate was paused. In the following years, a sustainable decline in a height z-score and a stunted pubertal growth spurt; despite appropriate maturation of the epiphyseal plates of the left hand, the proximal right humerus and both femora were observed. Whether this reflects the growth pattern in JPD or might be associated to the antiresorptive treatments is unclear, since there is very limited information available on the effect of bisphosphonates and denosumab on growth and the growth plate in pediatric patients. Studies are needed to understand the natural history of an ultra-rare bone disease and to assess the effects of antiresorptive treatment on the growing skeleton.
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Affiliation(s)
- Jakob Höppner
- Center for Rare Diseases Ruhr CeSER, Ruhr-University Bochum and Witten/Herdecke University, Bochum, Germany
| | - Katja Steff
- Department of Pediatrics II, University Hospital Essen and University of Duisburg-Essen, Essen, Germany.,Department of Pediatrics, St. Vinzenz -Hospital Dinslaken, Dinslaken, Germany
| | - Felix Lobert
- Technische Universität Dresden, Dresden, Germany
| | - Christoph M Heyer
- Institute of Pediatric Radiology, St.-Josef Hospital Bochum, Ruhr-University Bochum, Bochum, Germany
| | - Berthold P Hauffa
- Department of Pediatrics II, University Hospital Essen and University of Duisburg-Essen, Essen, Germany
| | - Corinna Grasemann
- Center for Rare Diseases Ruhr CeSER, Ruhr-University Bochum and Witten/Herdecke University, Bochum, Germany.,Department of Pediatrics, St.-Josef Hospital Bochum, Ruhr-University Bochum, Bochum, Germany
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25
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Ciancia S, van Rijn RR, Högler W, Appelman-Dijkstra NM, Boot AM, Sas TCJ, Renes JS. Osteoporosis in children and adolescents: when to suspect and how to diagnose it. Eur J Pediatr 2022; 181:2549-2561. [PMID: 35384509 PMCID: PMC9192469 DOI: 10.1007/s00431-022-04455-2] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2022] [Revised: 03/18/2022] [Accepted: 03/21/2022] [Indexed: 02/07/2023]
Abstract
UNLABELLED Early recognition of osteoporosis in children and adolescents is important in order to establish an appropriate diagnosis of the underlying condition and to initiate treatment if necessary. In this review, we present the diagnostic work-up, and its pitfalls, of pediatric patients suspected of osteoporosis including a careful collection of the medical and personal history, a complete physical examination, biochemical data, molecular genetics, and imaging techniques. The most recent and relevant literature has been reviewed to offer a broad overview on the topic. Genetic and acquired pediatric bone disorders are relatively common and cause substantial morbidity. In recent years, there has been significant progress in the understanding of the genetic and molecular mechanistic basis of bone fragility and in the identification of acquired causes of osteoporosis in children. Specifically, drugs that can negatively impact bone health (e.g. steroids) and immobilization related to acute and chronic diseases (e.g. Duchenne muscular dystrophy) represent major risk factors for the development of secondary osteoporosis and therefore an indication to screen for bone mineral density and vertebral fractures. Long-term studies in children chronically treated with steroids have resulted in the development of systematic approaches to diagnose and manage pediatric osteoporosis. CONCLUSIONS Osteoporosis in children requires consultation with and/or referral to a pediatric bone specialist. This is particularly relevant since children possess the unique ability for spontaneous and medication-assisted recovery, including reshaping of vertebral fractures. As such, pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children. WHAT IS KNOWN • Both genetic and acquired pediatric disorders can compromise bone health and predispose to fractures early in life. • The identification of children at risk of osteoporosis is essential to make a timely diagnosis and start the treatment, if necessary. WHAT IS NEW • Pediatricians have an opportunity to improve bone mass accrual and musculoskeletal health in osteoporotic children and children at risk of osteoporosis. • We offer an extensive but concise overview about the risk factors for osteoporosis and the diagnostic work-up (and its pitfalls) of pediatric patients suspected of osteoporosis.
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Affiliation(s)
- Silvia Ciancia
- Department of Pediatrics, Subdivision of Endocrinology, Erasmus University Medical Center, Sophia Children's Hospital, Rotterdam, The Netherlands.
| | - Rick R. van Rijn
- grid.7177.60000000084992262Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
| | - Wolfgang Högler
- grid.9970.70000 0001 1941 5140Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz, Austria
| | - Natasha M. Appelman-Dijkstra
- grid.10419.3d0000000089452978Department of Internal Medicine, Subdivision of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Annemieke M. Boot
- grid.4830.f0000 0004 0407 1981Department of Pediatrics, Subdivision of Endocrinology, University Medical Center Groningen, Beatrix Children’s Hospital, University of Groningen, Groningen, The Netherlands
| | - Theo C. J. Sas
- grid.416135.40000 0004 0649 0805Department of Pediatrics, Subdivision of Endocrinology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands ,Diabeter, Center for Pediatric and Adult Diabetes Care and Research, Rotterdam, The Netherlands
| | - Judith S. Renes
- grid.416135.40000 0004 0649 0805Department of Pediatrics, Subdivision of Endocrinology, Erasmus University Medical Center, Sophia Children’s Hospital, Rotterdam, The Netherlands
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26
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Ambrosio MR, Aliberti L, Gagliardi I, Franceschetti P, Zatelli MC. Bone health in adolescence. Minerva Obstet Gynecol 2021; 73:662-677. [PMID: 34905874 DOI: 10.23736/s2724-606x.20.04713-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Adolescence is a fundamental period for the formation of the skeleton, because is the stage in which bones grow more in both size and strength, laying a solid foundation for the future health of the skeleton. Any condition interfering with optimal peak bone mass accrual can increase fracture risk later in life. Up to 80% of peak bone mass is genetically determined while the remaining 20% is modulated by environmental factors that, if deleterious, may result in low bone mineral density (BMD) and an increased risk of fracture. The preferred test to assess bone health is dual-energy x-ray absorptiometry (spine or total body less head) using Z scores instead of T scores, even though in short stature or growth delay, should be used the height Z-score. The correction of risk factors is the first treatment for low BMD in children and adolescents. It's necessary having a correct lifestyle for preserving bone health: a proper nutrition, an adequate physical weight-bearing activity and avoidance of alcohol intake and tobacco smoke. Bisphosphonates could be used in children who sustained osteoporotic fractures, impairing quality of life, when spontaneous recovery is low for the persistence of osteoporosis risk factors. This clinical review discusses factors affecting bone health during childhood and adolescence and deals with diagnosis and treatment of low bone mass or osteoporosis in this age group.
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Affiliation(s)
- Maria R Ambrosio
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy -
| | - Ludovica Aliberti
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Irene Gagliardi
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
| | - Paola Franceschetti
- Operative Unit of Endocrinology and Metabolic Diseases, Department of Oncology and Specialty Medicine, Ferrara University Hospital, Ferrara, Italy
| | - Maria C Zatelli
- Section of Endocrinology and Internal Medicine, Department of Medical Sciences, University of Ferrara, Ferrara, Italy
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27
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Barr RD, Inglis D, Athale U, Jaworski M, Farncombe T, Gordon CL. Bone health in long-term survivors of pediatric acute lymphoblastic leukemia. An assessment by peripheral quantitative computed tomography. Pediatr Blood Cancer 2021; 68:e29218. [PMID: 34264535 DOI: 10.1002/pbc.29218] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Revised: 05/28/2021] [Accepted: 06/11/2021] [Indexed: 11/11/2022]
Abstract
BACKGROUND Loss of bone mineral is a common concomitant of the treatment of acute lymphoblastic leukemia (ALL) due mainly to chemotherapy, especially with corticosteroids. Osteopenia/osteoporosis may be encountered long into survivorship. Measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry is limited to two-dimensionality and cannot distinguish trabecular from cortical bone. METHODS A sample of 74 subjects, ages 13.5-38.3 years more than 10 years from diagnosis, underwent peripheral quantitative computed tomography (pQCT) at metaphyseal (trabecular bone) and diaphyseal (cortical bone) sites in the radius and tibia. pQCT provides three-dimensional assessment of bone geometry, density, and architecture. RESULTS Average values in multiple metrics were similar to those in healthy individuals, but deficits in both trabecular and cortical bones were revealed by lower Z scores using an ethnically comparable sample of healthy individuals. Connectivity, a measure of bone architecture and a surrogate measure of bone strength, was lower in females than males. Survivors of standard-risk ALL had greater connectivity in and more compact trabecular bone than high-risk survivors who had received more intensive osteotoxic chemotherapy. There were no statistically significant differences in any of the metrics at any of the sites between subjects who had or had not a history of fracture, cranial irradiation, or use of a bisphosphonate. CONCLUSIONS These long-term survivors of ALL have somewhat compromised bone health, but data in comparable healthy populations are limited. Longitudinal studies in larger and more ethnically diverse cohorts will provide greater insight into bone health in this vulnerable population.
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Affiliation(s)
- Ronald D Barr
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Dean Inglis
- Canadian Longitudinal Study on Aging, Department of Health Research Methods, Evidence and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Uma Athale
- Department of Pediatrics, McMaster University, Hamilton, Ontario, Canada
| | - Maciej Jaworski
- Department of Biochemistry, RadioImmunology and Experimental Medicine, The Children's Memorial Health Institute, Warsaw, Poland
| | - Troy Farncombe
- Department of Nuclear Medicine, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
| | - Christopher L Gordon
- Department of Nuclear Medicine, Hamilton Health Sciences Corporation, Hamilton, Ontario, Canada
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28
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Ward LM, Choudhury A, Alos N, Cabral DA, Rodd C, Sbrocchi AM, Taback S, Padidela R, Shaw NJ, Hosszu E, Kostik M, Alexeeva E, Thandrayen K, Shenouda N, Jaremko JL, Sunkara G, Sayyed S, Aftring RP, Munns CF. Zoledronic Acid vs Placebo in Pediatric Glucocorticoid-induced Osteoporosis: A Randomized, Double-blind, Phase 3 Trial. J Clin Endocrinol Metab 2021; 106:e5222-e5235. [PMID: 34228102 DOI: 10.1210/clinem/dgab458] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Glucocorticoids (GCs) prescribed for chronic pediatric illnesses are associated with osteoporotic fractures. OBJECTIVE This study aims to determine the efficacy and safety of intravenous (IV) zoledronic acid (ZA) compared with placebo to treat pediatric GC-induced osteoporosis (GIO). METHODS Children aged 5 to 17 years with GIO were enrolled in this multinational, randomized, double-blind, placebo-controlled phase 3 trial (ClinicalTrials.gov NCT00799266). Eligible children were randomly assigned 1:1 to 6 monthly IV ZA 0.05 mg/kg or IV placebo. The primary end point was the change in lumbar spine bone mineral density z score (LSBMDZ) from baseline to month 12. Incident fractures and safety were assessed. RESULTS Thirty-four children were enrolled (mean age 12.6 ± 3.4 years [18 on ZA, 16 on placebo]), all with low-trauma vertebral fractures (VFs). LSBMDZ increased from -2.13 ± 0.79 to -1.49 ± 1.05 on ZA, compared with -2.38 ± 0.90 to -2.27 ± 1.03 on placebo (least squares means difference 0.41 [95% CI, 0.02-0.81; P = .04]); when corrected for height z score, the least squares means difference in LBMDZ was 0.75 [95% CI, 0.27-1.22; P = .004]. Two children on placebo had new low-trauma VF vs none on ZA. Adverse events (AEs) were reported in 15 of 18 children (83%) on ZA, and in 12 of 16 (75%) on placebo, most frequently within 10 days after the first infusion. There were no deaths or treatment discontinuations due to treatment-emergent AEs. CONCLUSION LSBMDZ increased significantly on ZA compared with placebo over 1 year in children with GIO. Most AEs occurred after the first infusion.
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Affiliation(s)
- Leanne M Ward
- Children's Hospital of Eastern Ontario and The University of Ottawa, Ottawa, Ontario, Canada
| | | | | | - David A Cabral
- British Columbia Children's Hospital, Vancouver, British Columbia, Canada
| | - Celia Rodd
- Montréal Children's Hospital, Montréal, Quebec H4A 3J1, Canada
| | | | - Shayne Taback
- Winnipeg Children's Hospital, Winnipeg, Manitoba, Canada
| | - Raja Padidela
- Department of Pediatric Endocrinology, Royal Manchester Children's Hospital and Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK
| | - Nick J Shaw
- Birmingham Children's Hospital, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK
| | - Eva Hosszu
- 2nd Department of Pediatrics, Faculty of Medicine, Semmelweis University, Budapest, Hungary
| | - Mikhail Kostik
- Saint- Petersburg State Pediatric Medical University of the MoH, St Petersburg, Russia
| | - Ekaterina Alexeeva
- Federal State Autonomous Institution "National Medical Research Center of Children's Health" of the Ministry of Health of the Russian Federation, Moscow, Russia
- Federal State Autonomous Educational Institution of Higher Education, I.M. Sechenov First Moscow State Medical University of the Ministry of Health of the Russian Federation, Moscow, Russia
| | - Kebashni Thandrayen
- Department of Pediatrics, Chris Hani Baragwanath Academic Hospital, Faculty of Health Sciences, University of Witwatersrand, Braamfontein, Johannesburg, South Africa
| | - Nazih Shenouda
- Children's Hospital of Eastern Ontario and The University of Ottawa, Ottawa, Ontario, Canada
| | - Jacob L Jaremko
- Stollery Children's Hospital and The University of Alberta, Edmonton, Alberta, Canada
| | | | | | - R Paul Aftring
- Novartis Pharmaceuticals Corp; East Hanover, New Jersey, USA
| | - Craig F Munns
- Children's Hospital at Westmead, Sydney, Westmead, New South Wales 2145, Australia and Discipline of Paediatrics & Child Health, University of Sydney, Sydney, NSW, Australia
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Lim A, Simm PJ, James S, Lee SLK, Zacharin M. Outcomes of Zoledronic Acid Use in Paediatric Conditions. Horm Res Paediatr 2021; 93:442-452. [PMID: 33508822 DOI: 10.1159/000512730] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Accepted: 10/29/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Limited evidence is available concerning experience with use of zoledronic acid (ZA) and treatment for conditions other than primary bone fragility. MATERIALS AND METHODS A retrospective review of all Royal Children Hospital patients who had been administered at least 1 dose of intravenous ZA from 2002 to 2015 was undertaken. RESULTS The audit included 309 children with 228 being treated for bone fragility conditions. Of the 228, 68 had height-adjusted lumbar spine bone mineral density Z-scores available over up to a 5-year period, and median increases were +2.0 SD (median absolute deviation = 0.9) (N = 36, p value for median increase of at least 0.5 in Z-score <0.001), for patients with osteogenesis imperfecta or other primary bone fragility disorders, +1.0 SD (0.9) (N = 14, p = 0.029), for immobility conditions, +0.5 SD (0.7) (N = 10, p = 0.399), and for glucocorticoid-induced secondary osteoporosis, +0.7 SD (0.6) (N = 8, p = 0.015). 81/309 children were treated for bone abnormality indications (e.g., avascular necrosis [AVN], fibrous dysplasia, and bone cysts). Of 39 with AVN, outcome data were available for 33, with joint integrity maintained for 24/33 from 6 to 24 months after last ZA, subjective reports (22/28) of reduced pain. Reduction in bone lesion size was seen in 2/4 patients with bone cysts within 12 months of ZA commencement. DISCUSSION/CONCLUSION This is the largest cohort of reported outcomes of ZA use in a paediatric population. Results demonstrate a good efficacy profile and associated improved bone density for osteoporotic conditions and stabilization of non-traumatic AVN with a low rate of joint collapse.
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Affiliation(s)
- Angelina Lim
- Hormone Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Centre for Medicine Use and Safety, Monash University, Melbourne, Victoria, Australia.,Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Peter J Simm
- Hormone Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Simon James
- School of Information Technology, Deakin University, Melbourne, Victoria, Australia
| | - Samantha Lai-Ka Lee
- Hormone Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.,Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria, Australia
| | - Margaret Zacharin
- Hormone Research, Murdoch Children's Research Institute, Melbourne, Victoria, Australia, .,Department of Endocrinology, Royal Children's Hospital, Melbourne, Victoria, Australia,
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Velentza L, Zaman F, Sävendahl L. Bone health in glucocorticoid-treated childhood acute lymphoblastic leukemia. Crit Rev Oncol Hematol 2021; 168:103492. [PMID: 34655742 DOI: 10.1016/j.critrevonc.2021.103492] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/05/2021] [Accepted: 09/08/2021] [Indexed: 12/30/2022] Open
Abstract
Glucocorticoids (GCs) are widely used in the treatment of childhood acute lymphoblastic leukemia (ALL), but their long-term use is also associated with bone-related morbidities. Among others, growth deficit, decreased bone mineral density (BMD) and increased fracture rate are well-documented and severely impact quality of life. Unfortunately, no efficient treatment for the management of bone health impairment in patients and survivors is currently available. The overall goal of this review is to discuss the existing data on how GCs impair bone health in pediatric ALL and attempts made to minimize these side effects.
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Affiliation(s)
- Lilly Velentza
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
| | - Farasat Zaman
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - Lars Sävendahl
- Division of Pediatric Endocrinology, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden; Pediatric Endocrinology Unit, Karolinska University Hospital, Stockholm, Sweden
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Ma J, Siminoski K, Wang P, Jaremko JL, Koujok K, Matzinger MA, Shenouda N, Lentle B, Alos N, Cummings EA, Ho J, Houghton K, Miettunen PM, Scuccimarri R, Rauch F, Ward LM. The Accuracy of Incident Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches. J Bone Miner Res 2021; 36:1255-1268. [PMID: 33784410 DOI: 10.1002/jbmr.4294] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Revised: 02/26/2021] [Accepted: 03/16/2021] [Indexed: 12/23/2022]
Abstract
Vertebral fractures are clinically important sequelae of a wide array of pediatric diseases. In this study, we examined the accuracy of case-finding strategies for detecting incident vertebral fractures (IVF) over 2 years in glucocorticoid-treated children (n = 343) with leukemia, rheumatic disorders, or nephrotic syndrome. Two clinical situations were addressed: the prevalent vertebral fracture (PVF) scenario (when baseline PVF status was known), which assessed the utility of PVF and low lumbar spine bone mineral density (LS BMD; Z-score <-1.4), and the non-PVF scenario (when PVF status was unknown), which evaluated low LS BMD and back pain. LS BMD was measured by dual-energy X-ray absorptiometry, vertebral fractures were quantified on spine radiographs using the modified Genant semiquantitative method, and back pain was assessed by patient report. Forty-four patients (12.8%) had IVF. In the PVF scenario, both low LS BMD and PVF were significant predictors of IVF. Using PVF to determine which patients should have radiographs, 11% would undergo radiography (95% confidence interval [CI] 8-15) with 46% of IVF (95% CI 30-61) detected. Sensitivity would be higher with a strategy of PVF or low LS BMD at baseline (73%; 95% CI 57-85) but would require radiographs in 37% of children (95% CI 32-42). In the non-PVF scenario, the strategy of low LS BMD and back pain produced the highest specificity of any non-PVF model at 87% (95% CI 83-91), the greatest overall accuracy at 82% (95% CI 78-86), and the lowest radiography rate at 17% (95% CI 14-22). Low LS BMD or back pain in the non-PVF scenario produced the highest sensitivity at 82% (95% CI 67-92), but required radiographs in 65% (95% CI 60-70). These results provide guidance for targeting spine radiography in children at risk for IVF. © 2021 American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Jinhui Ma
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Kerry Siminoski
- Department of Radiology and Diagnostic Imaging and Department of Internal Medicine, University of Alberta, Edmonton, Canada
| | - Peiyao Wang
- Faculty of Science, McMaster University, Hamilton, Canada
| | - Jacob L Jaremko
- Department of Radiology and Diagnostic Imaging, University of Alberta, Edmonton, Canada
| | - Khaldoun Koujok
- Department of Medical Imaging, University of Ottawa, Ottawa, Canada
| | | | - Nazih Shenouda
- Department of Medical Imaging, University of Ottawa, Ottawa, Canada
| | - Brian Lentle
- Department of Radiology, University of British Columbia, Vancouver, Canada
| | - Nathalie Alos
- Department of Pediatrics, Université de Montréal, Montréal, Canada
| | | | - Josephine Ho
- Department of Pediatrics, University of Calgary, Calgary, Canada
| | - Kristin Houghton
- Department of Pediatrics, University of British Columbia, Vancouver, Canada
| | | | | | - Frank Rauch
- Department of Pediatrics, McGill University, Montreal, Canada
| | - Leanne M Ward
- Department of Pediatrics, University of Ottawa, Ottawa, Canada
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- Canadian Pediatric Bone Health Working Group, Ottawa, Canada
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Biosimilar Interchangeability and Emerging Treatment Strategies for Inflammatory Bowel Diseases: A Commentary. GASTROENTEROLOGY INSIGHTS 2021. [DOI: 10.3390/gastroent12030026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
This commentary summarizes a collection of key references published within the last ten years, and identifies pharmacologic research directions to improve treatment access and success through greater biosimilar or “follow-on” biologic utilization combined with other targeted small molecule agents that possess unique pathophysiologic mechanisms for inflammatory bowel diseases (IBD) in adult and pediatric patients. Since they are not identical to the originator or reference biologic agent, all biosimilars are not generically equivalent. However, in the US and other countries, they are considered therapeutically interchangeable if the manufacturer has demonstrated no clinically meaningful differences from the reference product. Comparisons of different clinical initiation and switching scenarios are discussed with reference to interchangeability, immunogenicity, nocebo effect, cost effectiveness, and time courses for discontinuation rates.
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Yoon JH, Choi Y, Lee Y, Yoo HW, Choi JH. Efficacy and safety of intravenous pamidronate infusion for treating osteoporosis in children and adolescents. Ann Pediatr Endocrinol Metab 2021; 26:105-111. [PMID: 34218632 PMCID: PMC8255864 DOI: 10.6065/apem.2040150.075] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/16/2020] [Accepted: 09/09/2020] [Indexed: 11/22/2022] Open
Abstract
PURPOSE Osteoporosis is a skeletal disorder characterized by reduced bone mass that results in increased risk of fractures. Pediatric osteoporosis can be caused by monogenic diseases, chronic diseases, and/or their treatment. This study was performed to investigate the effect of pamidronate infusion on osteoporosis in children and adolescents. METHODS This study included 13 unrelated pediatric patients (10 males and 3 females) whose bone mineral density (BMD) z-score was <-2.0. Pamidronate was administered intravenously at a dosage of 1 mg/kg for 3 consecutive days every 4 months. Clinical and biochemical findings were reviewed retrospectively. The BMD values of the lumbar spine and femoral neck were assessed by dual energy x-ray absorptiometry at baseline and annually. RESULTS The underlying diseases were immobilization (62%), inflammatory bowel disease (23%), protein-losing enteropathy (8%), and idiopathic juvenile osteoporosis (8%). The mean age at the start of treatment was 12.7±4.3 years. Duration of treatment ranged from 12-50 months. The baseline height-standard deviation score (SDS) and weight-SDS were -2.01±2.08 and -2.60±1.62, respectively. The lumbar spine BMD z-scores improved significantly after 1 year of pamidronate treatment, but the femoral neck BMD z-scores did not. However, both z-scores had significantly increased by the end of treatment. CONCLUSION This study demonstrated that pamidronate treatment increased BMD in pediatric patients with osteoporosis with no significant adverse events. Further studies are required to better define the long-term efficacy and safety of pamidronate therapy in a large number of pediatric patients.
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Affiliation(s)
- Ji-Hee Yoon
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Yunha Choi
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Yena Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Jin-Ho Choi
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea,Address for correspondence: Jin-Ho Choi Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-Gil, SongpaGu, Seoul 05505, Korea
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Chun LF, Yu EL, Sawh MC, Bross C, Nichols J, Polgreen L, Knott C, Schlein A, Sirlin CB, Middleton MS, Kado DM, Schwimmer JB. Hepatic Steatosis is Negatively Associated with Bone Mineral Density in Children. J Pediatr 2021; 233:105-111.e3. [PMID: 33545191 PMCID: PMC8154638 DOI: 10.1016/j.jpeds.2021.01.064] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2020] [Revised: 01/12/2021] [Accepted: 01/27/2021] [Indexed: 11/28/2022]
Abstract
OBJECTIVE To evaluate the relationship between hepatic steatosis and bone mineral density (BMD) in children. In addition, to assess 25-hydroxyvitamin D levels in the relationship between hepatic steatosis and BMD. STUDY DESIGN A community-based sample of 235 children was assessed for hepatic steatosis, BMD, and serum 25-hydroxyvitamin D. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction (MRI-PDFF). BMD was measured by whole-body dual-energy x-ray absorptiometry. RESULTS The mean age of the study population was 12.5 years (SD 2.5 years). Liver MRI-PDFF ranged from 1.1% to 40.1% with a mean of 9.3% (SD 8.5%). Across this broad spectrum of hepatic fat content, there was a significant negative relationship between liver MRI-PDFF and BMD z score (R = -0.421, P < .001). Across the states of sufficiency, insufficiency, and deficiency, there was a significant negative association between 25-hydroxyvitamin D and liver MRI-PDFF (P < .05); however, there was no significant association between vitamin D status and BMD z score (P = .94). Finally, children with clinically low BMD z scores were found to have higher alanine aminotransferase (P < .05) and gamma-glutamyl transferase (P < .05) levels compared with children with normal BMD z scores. CONCLUSIONS Across the full range of liver MRI-PDFF, there was a strong negative relationship between hepatic steatosis and BMD z score. Given the prevalence of nonalcoholic fatty liver disease and the critical importance of childhood bone mineralization in protecting against osteoporosis, clinicians should prioritize supporting bone development in children with nonalcoholic fatty liver disease.
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Affiliation(s)
- Lauren F. Chun
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California
| | - Elizabeth L. Yu
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California,Department of Gastroenterology, Rady Children’s Hospital, San Diego, California
| | - Mary Catherine Sawh
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California,Department of Gastroenterology, Rady Children’s Hospital, San Diego, California
| | - Craig Bross
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California
| | - Jeanne Nichols
- Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California,Graduate School of Public Health, San Diego State University, San Diego, California
| | - Lynda Polgreen
- Department of Pediatrics, The Lundquist Institute for Biomedical Innovation at Harbor-UCLA Medical Center, Torrance, California
| | - Cynthia Knott
- Altman Clinical and Translational Research Institute, School of Medicine, University of California San Diego School of Medicine, Ja Jolla, California
| | - Alexandra Schlein
- Liver Imaging Group, Department of Radiology, University of California San Diego School of Medicine, La Jolla, California
| | - Claude B. Sirlin
- Liver Imaging Group, Department of Radiology, University of California San Diego School of Medicine, La Jolla, California
| | - Michael S. Middleton
- Liver Imaging Group, Department of Radiology, University of California San Diego School of Medicine, La Jolla, California
| | - Deborah M. Kado
- Department of Family Medicine and Public Health, University of California San Diego, La Jolla, California,Department of Internal Medicine, University of California San Diego, La Jolla, California
| | - Jeffrey B. Schwimmer
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, University of California San Diego School of Medicine, La Jolla, California,Department of Gastroenterology, Rady Children’s Hospital, San Diego, California
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Ward LM. Part 2: When Should Bisphosphonates Be Used in Children with Chronic Illness Osteoporosis? Curr Osteoporos Rep 2021; 19:289-297. [PMID: 34146247 DOI: 10.1007/s11914-021-00672-0] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/12/2021] [Indexed: 11/30/2022]
Abstract
PURPOSE OF REVIEW Part 1 of this review on secondary osteoporosis of childhood was devoted to understanding which children should undergo bone health monitoring, when to label a child with osteoporosis in this setting, and how best to monitor in order to identify early, rather than late, signs of bone fragility. In Part 2 of this review, we discuss the next critical step in deciding which children require bisphosphonate therapy. This involves distinguishing which children have the potential to undergo "medication-unassisted" recovery from secondary osteoporosis, obviating the need for bisphosphonate administration, from those who require anti-resorptive therapy in order to recover from osteoporosis. RECENT FINDINGS Unlike children with primary osteoporosis such as osteogenesis imperfecta, where the potential for recovery from osteoporosis without medical therapy is limited, many children with secondary osteoporosis can undergo complete recovery in the absence of bisphosphonate intervention. Over the last decade, natural history studies have unveiled the spectrum of this recovery, which spans overt deterioration (i.e., incident vertebral and non-vertebral fractures and declines in bone mineral density (BMD)), to spectacular reclamation of BMD, and complete restoration of normal vertebral dimensions after spine fractures. The fact that reshaping of vertebral bodies following fractures is growth-dependent underscores the need to identify and treat those at risk for permanent vertebral deformity in a timely fashion. The decision to treat a child with a bisphosphonate hinges on distinguishing bone fragility from typical childhood fractures, and determining the potential for medication-unassisted recovery following an osteoporotic fragility fracture. While improvements in BMD are a well-known sign of recovery, restitution of bone structure is also a key indicator of recuperation, one that is unique to childhood, and that plays a pivotal role in the decision to intervene or not.
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Affiliation(s)
- Leanne M Ward
- University of Ottawa, Ottawa, Canada.
- The Ottawa Pediatric Bone Health Research Group, The CHEO Pediatric Genetic and Metabolic Bone Disease Clinic, The Children's Hospital of Eastern Ontario (CHEO), Room 250H, 401 Smyth Road, Ottawa, Ontario, K1H 8L1, Canada.
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Abstract
PURPOSE OF THE REVIEW Underlying conditions which adversely affect skeletal strength are one of the most common reasons for consultations in pediatric bone health clinics. The diseases most frequently linked to fragility fractures include leukemia and other cancers, inflammatory disorders, neuromuscular disease, and those treated with osteotoxic drugs (particularly glucocorticoids). The decision to treat a child with secondary osteoporosis is challenged by the fact that fractures are frequent in childhood, even in the absence of risk factors. Furthermore, some children have the potential for medication-unassisted recovery from osteoporosis, obviating the need for bisphosphonate therapy. RECENT FINDINGS Over the last decade, there have been important advances in our understanding of the skeletal phenotypes, fracture frequencies, and risk factors for bone fragility in children with underlying disorders. With improved knowledge about the importance of fracture characteristics in at-risk children, there has been a shift away from a bone mineral density (BMD)-centric definition of osteoporosis in childhood, to a fracture-focused approach. As a result, attention is now drawn to the early identification of fragility fractures, which includes asymptomatic vertebral collapse. Furthermore, even a single, long bone fracture can represent a major osteoporotic event in an at-risk child. Fundamental biological principles of bone strength development, and the ways in which these go awry in chronic illnesses, form the basis for monitoring and diagnosis of osteoporosis in children with underlying conditions. Overall, the goal of monitoring is to identify early, rather than late, signs of osteoporosis in children with limited potential to undergo medication-unassisted recovery. These are the children who should undergo bisphosphonate therapy, as discussed in part 1 (monitoring and diagnosis) and part 2 (recovery and the decision to treat) of this review.
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Affiliation(s)
- Leanne M Ward
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada.
- The Ottawa Pediatric Bone Health Research Group, The CHEO Pediatric Genetic and Metabolic Bone Disease Clinic, The Children's Hospital of Eastern Ontario (CHEO), Room 250H, 401 Smyth Road, Ottawa, ON, K1H 8L1, Canada.
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Testini V, Eusebi L, Tupputi U, Carpagnano FA, Bartelli F, Guglielmi G. Metabolic Bone Diseases in the Pediatric Population. Semin Musculoskelet Radiol 2021; 25:94-104. [PMID: 34020471 DOI: 10.1055/s-0040-1722566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
Bone plays an important role in regulating mineral balance in response to physiologic needs. In addition, bone is subject to a continuous remodeling process to maintain healthy bone mass and growth. Metabolic bone diseases are a heterogeneous group of diseases caused by abnormalities of bone mass, mineral structure homeostasis, bone turnover, or bone growth. In pediatrics, several significant advances have been made in recent years in the diagnosis of metabolic bone diseases (e.g., osteogenesis imperfecta, hyperparathyroidism, rickets, renal osteodystrophy, pediatric osteoporosis, and osteopetrosis). Imaging is fundamental in the diagnosis of these pathologies.
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Affiliation(s)
- Valentina Testini
- Department of Clinical and Experimental Medicine, Foggia University School of Medicine, Foggia, Italy
| | - Laura Eusebi
- Radiology Unit, "Carlo Urbani" Hospital, Jesi, Italy
| | - Umberto Tupputi
- Department of Clinical and Experimental Medicine, Foggia University School of Medicine, Foggia, Italy
| | - Francesca Anna Carpagnano
- Department of Clinical and Experimental Medicine, Foggia University School of Medicine, Foggia, Italy
| | | | - Giuseppe Guglielmi
- Department of Clinical and Experimental Medicine, Foggia University School of Medicine, Foggia, Italy.,Radiology Unit, Barletta University Campus UNIFG, "Dimiccoli" Hospital, Barletta, Italy
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Diemar SS, Lylloff L, Rønne MS, Møllehave LT, Heidemann M, Thuesen BH, Johannesen J, Schou AJ, Husby S, Wedderkopp N, Mølgaard C, Jørgensen NR. Reference intervals in Danish children and adolescents for bone turnover markers carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP). Bone 2021; 146:115879. [PMID: 33561588 DOI: 10.1016/j.bone.2021.115879] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 01/20/2021] [Accepted: 02/03/2021] [Indexed: 12/13/2022]
Abstract
PURPOSE Bone turnover markers (BTM) are gaining ground in clinical practice but to fully use their potential there is a need for establishing valid reference intervals (RI). Consequently, the purpose of the study was to establish general RI as well as suggested clinical RI for carboxy-terminal cross-linked telopeptide of type I collagen (β-CTX), pro-collagen type I N-terminal propeptide (PINP), osteocalcin (OC) and bone-specific alkaline phosphatase (bone ALP) in children and adolescents. METHOD BTM were measured on Danish children and adolescents participating in the CHAMPS-study DK. A total of 762 participants were included (8-18 years, 50.4% girls) contributing a total of 1410 study visits. The RI was calculated based on 2-years age spans. Participants with biochemical signs of metabolic bone disease were excluded. RESULTS The differences in RI between age groups clearly reflect changes in growth with an initial increase in BTM, greatest in boys, and a subsequent decrease most pronounced in girls. β-CTX and PINP are markers most affected by these changes, compared to OC and bone ALP. The suggested clinical 95% RI included participants with vitamin D insufficiency but no biochemical signs of metabolic bone disease which did not markedly alter the RI. CONCLUSION RI for β-CTX, PINP, OC and bone ALP varies with age and sex. β-CTX and PINP which reflect bone resorption and formation processes are mostly affected by these changes. We suggest a set of clinically applicable 95% RI for the four BTM to heighten the usefulness and generalizability of the RI.
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Affiliation(s)
- Sarah Seberg Diemar
- Department of Clinical Biochemistry, Rigshospitalet, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark.
| | - Louise Lylloff
- Department of Clinical Biochemistry, Regional Hospital West Jutland, Gl. Landevej 61, 7400 Herning, Denmark
| | - Maria Sode Rønne
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Kløvervænget 23C, 5000 Odense, Denmark
| | - Line Tang Møllehave
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark
| | - Malene Heidemann
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Kløvervænget 23C, 5000 Odense, Denmark
| | - Betina Heinsbæk Thuesen
- Center for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Nordre Fasanvej 57, 2000 Frederiksberg, Denmark
| | - Jesper Johannesen
- Department of Children and Adolescents, Copenhagen University Hospital Herlev, Borgmester Ib Juuls Vej 1, 2730 Herlev, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
| | - Anders J Schou
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Kløvervænget 23C, 5000 Odense, Denmark
| | - Steffen Husby
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Kløvervænget 23C, 5000 Odense, Denmark; Clinical Institute, University of Southern Denmark, Campusvej 55, 5000 Odense, Denmark
| | - Niels Wedderkopp
- Research Unit for Exercise Epidemiology, Centre of Research in Childhood Health, Department of Regional Health Research, University of Southern Denmark, Campusvej 55, 5000 Odense, Denmark; Department of Orthopaedics, Hospital of Southwest Jutland, Finsensgade 35, 6700 Esbjerg, Denmark
| | - Christian Mølgaard
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Kløvervænget 23C, 5000 Odense, Denmark; Clinical Institute, University of Southern Denmark, Campusvej 55, 5000 Odense, Denmark; Department of Nutrition, Exercise and Sports, University of Copenhagen, Nørre Allé 51, 2200 Copenhagen, Denmark
| | - Niklas Rye Jørgensen
- Department of Clinical Biochemistry, Rigshospitalet, Valdemar Hansens Vej 1-23, 2600 Glostrup, Denmark; Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark
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Sies NS, Zaini AA, de Bruyne JA, Jalaludin MY, Nathan AM, Han NY, Thavagnanam S. Obstructive sleep apnoea syndrome (OSAS) as a risk factor for secondary osteoporosis in children. Sci Rep 2021; 11:3193. [PMID: 33542317 PMCID: PMC7862364 DOI: 10.1038/s41598-021-82605-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Accepted: 01/19/2021] [Indexed: 11/20/2022] Open
Abstract
Repetitive hypoxia seen in obstructive sleep apnoea syndrome (OSAS) may affect bone metabolism increasing the risk for secondary osteoporosis. This study investigates the association between OSAS in children and secondary osteoporosis. This cross-sectional study included 150 children aged 10–17 years: 86 with OSAS and 64 with no OSAS. OSAS was confirmed by polysomnography. Quantitative ultrasound (QUS) of calcaneum measuring speed of sound (SoS) and broadband ultrasound attenuation (BUA) were collected. Other parameters collected including bone profile, vitamin D levels, physical activity scoring and dietary calcium intake. Majority were male and Malay ethnicity. OSAS children were mostly obese (84%) and 57% had moderate to severe OSAS. Most had lower physical activities scores. Mean (SD) phosphate and Alkaline phosphatase were lower in OSA children compared to controls: PO4, p = 0.039 and ALP, p < 0.001. Using both single and multivariate analysis, children with OSAS had a lower mean SoS value, p < 0.001 and p = 0.004 respectively after adjusting for age, BMI and bone profile. Children with OSAS had lower SoS suggesting risk for secondary osteoporosis. QUS calcaneus is a non-invasive, feasible tool and can be used to screen risk of osteoporosis in children. Further bone mineral density assessment is needed in these groups of children to confirm diagnosis of osteoporosis.
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Affiliation(s)
- Nur Syazwin Sies
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia
| | - Azriyanti Anuar Zaini
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.,University Malaya Paediatric and Child Health Research Group, University of Malaya, Kuala Lumpur, Malaysia
| | - Jessie Anne de Bruyne
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.,University Malaya Paediatric and Child Health Research Group, University of Malaya, Kuala Lumpur, Malaysia
| | - Muhammad Yazid Jalaludin
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.,University Malaya Paediatric and Child Health Research Group, University of Malaya, Kuala Lumpur, Malaysia
| | - Anna Marie Nathan
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.,University Malaya Paediatric and Child Health Research Group, University of Malaya, Kuala Lumpur, Malaysia
| | - Ng Yit Han
- Public Health Unit, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
| | - Surendran Thavagnanam
- Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia. .,University Malaya Paediatric and Child Health Research Group, University of Malaya, Kuala Lumpur, Malaysia. .,Department of Paediatrics, Royal London Hospital, London, UK.
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40
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Wu Z, Yuan Y, Tian J, Long F, Luo W. The associations between serum trace elements and bone mineral density in children under 3 years of age. Sci Rep 2021; 11:1890. [PMID: 33479410 PMCID: PMC7820346 DOI: 10.1038/s41598-021-81501-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 01/05/2021] [Indexed: 12/31/2022] Open
Abstract
We examined the associations of age and serum magnesium, iron, lead, copper, and zinc levels with bone mineral density (BMD) in 2412 children under 3 years of age in order to find a tool to monitor BMD in children without the use of expensive imaging techniques. One-way ANOVA and chi-square tests were used to determine the associations of age and serum trace elements with BMD. Multivariable logistic regression analysis was used to test the correlation of five serum trace elements with BMD after adjustments for potential confounding factors in children under 3 years of age. Significant associations between age and four serum trace elements and BMD were found. Compared to the group with the lowest serum levels detected, the adjusted odds ratio (OR) for the incidence of normal bone mineral density in the third magnesium concentration tertile, the third iron concentration tertile, the fifth copper concentration quintile, the third zinc concentration quintile, and the fifth zinc concentration quintile were 1.30 (95% confidence interval (CI) 1.02–1.67), 1.43 (95% CI 1.11–1.84), 1.42 (95% CI 1.04–1.94), 1.46 (95% CI 1.05–2.04), and 1.48 (95% CI 1.06–2.06), respectively. However, there was no significant correlation between serum lead level and BMD in this study. Age and serum magnesium, iron, copper, and zinc levels are positively associated with BMD in children under 3 years old.
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Affiliation(s)
- Ziyi Wu
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Yuhao Yuan
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Jian Tian
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Feng Long
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Wei Luo
- Department of Orthopaedics, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Guss CE, McAllister A, Gordon CM. DXA in Children and Adolescents. J Clin Densitom 2021; 24:28-35. [PMID: 32111573 DOI: 10.1016/j.jocd.2020.01.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/17/2020] [Accepted: 01/21/2020] [Indexed: 12/27/2022]
Abstract
DXA plays a critical role in assessing skeletal health and disease, as well as, fat and muscle status in children and adolescents. Quality DXA requires training, expertise and attention to details, as in adults, but there are key differences in performing and interpretations in children. These include choice of measurement site, skills required, reference data and software, and considerations for indications and underlying disorders to facilitate correct interpretation. The International Society for Clinical Densitometry (ISCD) has been pivotal in establishing official positions and training for people who are interested in performing or interpreting such examinations, and guiding clinicians who may request such studies. However training in the performance and interpretation of scans of individuals with more complex needs falls outside the scope of this review, and consideration should be given to refer such examinations to a specialist pediatric DXA unit. Others may be scanned and reported by those with expertise in densitometry, as long as due diligence is paid to standard quality procedures, as well as knowledge of the special circumstances and training required for this field. In this invited review we outline some of these considerations, highlight key messages, and provide some appropriate references to help guide clinicians, technologists and scientists involved or interested in DXA use in children and adolescents.
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Affiliation(s)
- Carly E Guss
- Boston Children's Hospital, Division of Adolescent/Young Adult Medicine, Boston, MA, USA; Boston Children's Hospital, Division of Endocrinology, Boston, MA, USA; Harvard Medical School, Department of Pediatrics, Boston, MA, USA.
| | | | - Catherine M Gordon
- Boston Children's Hospital, Division of Adolescent/Young Adult Medicine, Boston, MA, USA; Boston Children's Hospital, Division of Endocrinology, Boston, MA, USA; Harvard Medical School, Department of Pediatrics, Boston, MA, USA; DXA Center and Bone Health Program, Boston, MA, USA
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42
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Khalatbari H, Binkovitz LA, Parisi MT. Dual-energy X-ray absorptiometry bone densitometry in pediatrics: a practical review and update. Pediatr Radiol 2021; 51:25-39. [PMID: 32857206 DOI: 10.1007/s00247-020-04756-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 05/13/2020] [Accepted: 06/15/2020] [Indexed: 12/18/2022]
Abstract
The assessment of pediatric bone mineral content and density is an evolving field. In this manuscript we provide a practical review and update on the interpretation of dual-energy X-ray absorptiometry (DXA) in pediatrics including historical perspectives as well as a discussion of the recently published 2019 Official Position Statements of the International Society of Clinical Densitometry (ISCD) that apply to children.
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Affiliation(s)
- Hedieh Khalatbari
- Department of Radiology, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way NE, Seattle, WA, 98105, USA.
| | - Larry A Binkovitz
- Department of Radiology, Divisions of Pediatric Radiology and Nuclear Medicine, Mayo Clinic Graduate School of Medicine, Rochester, MN, USA
| | - Marguerite T Parisi
- Department of Radiology, Seattle Children's Hospital, University of Washington School of Medicine, 4800 Sand Point Way NE, Seattle, WA, 98105, USA.,Department of Pediatrics, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, USA
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Abstract
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 STeroid-associated Osteoporosis in the Pediatric Population ("STOPP") 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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Affiliation(s)
- Leanne M. Ward
- 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
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Edouard T, Guillaume-Czitrom S, Bacchetta J, Sermet-Gaudelus I, Dugelay E, Martinez-Vinson C, Salles JP, Linglart A. Guidelines for the management of children at risk of secondary bone fragility: Expert opinion of a French working group. Arch Pediatr 2020; 27:393-398. [PMID: 32921532 DOI: 10.1016/j.arcped.2020.07.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2019] [Accepted: 07/30/2020] [Indexed: 11/30/2022]
Abstract
The current French national guidelines were elaborated by a working group consisting of experts in the field of pediatric endocrinology, rheumatology, hepatogastroenterology, nephrology, and pneumology. A systematic search was undertaken of the literature published between 2008 and 2018 and indexed in PubMed. The recommendations developed were then validated by an external evaluation group comprising representatives from the various highly specialized fields in pediatrics, representatives of the societies and groups supporting the development of the guidelines, and representatives of different healthcare professions. The objective of these guidelines was to detail the current optimal management of children at risk of secondary bone fragility.
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Affiliation(s)
- T Edouard
- Unité d'endocrinologie, maladies osseuses et génétique, centre de référence des maladies rares du calcium et du phosphate, filière OSCAR, ERN BOND, hôpital des Enfants, CHU de Toulouse, 330, avenue de Grande-Bretagne, TSA 70034, 31059 Toulouse cedex 9, France.
| | - S Guillaume-Czitrom
- AP-HP, médecine des adolescents, GHU Bicêtre Paris-Saclay, 94270 Le Kremlin-Bicêtre cedex, France
| | - J Bacchetta
- Service de néphrologie, rhumatologie et dermatologie pédiatrique, centre de référence des maladies rares du calcium et du phosphate, filière OSCAR, CHU de Lyon, 69677 Bron cedex, France
| | | | - E Dugelay
- Service de gastroentérologie et hépatologie pédiatrique, CHU Robert-Debré, 75019 Paris, France
| | - C Martinez-Vinson
- Service de gastroentérologie et hépatologie pédiatrique, CHU Robert-Debré, 75019 Paris, France
| | - J P Salles
- Unité d'endocrinologie, maladies osseuses et génétique, centre de référence des maladies rares du calcium et du phosphate, filière OSCAR, ERN BOND, hôpital des Enfants, CHU de Toulouse, 330, avenue de Grande-Bretagne, TSA 70034, 31059 Toulouse cedex 9, France
| | - A Linglart
- AP-HP, endocrinologie et diabète de l'enfant, centre de référence des maladies rares du calcium et du phosphate, filière OSCAR, GHU Bicêtre Paris-Saclay, 94270 Le Kremlin-Bicêtre cedex, France
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45
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Martínez de Zabarte Fernández JM, Ros Arnal I, Peña Segura JL, García Romero R, Rodríguez Martínez G. Bone health impairment in patients with cerebral palsy. Arch Osteoporos 2020; 15:91. [PMID: 32556612 DOI: 10.1007/s11657-020-00753-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Accepted: 05/06/2020] [Indexed: 02/03/2023]
Abstract
UNLABELLED Bone health problems may be related to the nutritional deficit in pediatric patients with cerebral palsy. It is common to find asymptomatic vertebral fractures when they have low bone mineral density. Fat mass deficit could be related to a lower bone mineral density and a higher risk of vertebral fractures. OBJECTIVES To study the bone health of patients with CP and its relationship with neurological and nutritional status. PURPOSE Cerebral palsy (CP) is the most common cause of motor disability in pediatric age. METHODS Cross-sectional, observational, descriptive, and analytical study in which patients with CP between 4 and 5 years with Gross Motor Function Classification System (GMFCS) grades III-IV-V were included. It was carried out: survey, anthropometric study, bioimpedanciometry (BIA), and bone densitometry. Patients with low bone mineral density (BMD Z score less than - 2.0) underwent lumbar radiography looking for vertebral fractures to be diagnosed with osteoporosis. RESULTS Total sample: 51 patients (51.0% women). Mean age: 11.0 ± 0.5 years. BMD Z score average: - 2.1 (95% CI - 2.5, - 1.7). BMD Z score according to GMFCS: grade III - 1.6 (- 2.2; - 1.), grade IV - 1.6 (- 2.4; - 0.9), grade V - 3.1 (- 3.9, - 2.2) (p = 0.013). Bone health classification according to the International Society for Clinical Densitometry was: 47.1% normal, 52.9% low BMD. Relationship between low BMD and low fat mass (p = 0.030) and low cell mass (p = 0.040) was found. Prevalence of vertebral fractures in lumbar radiography: 25.9%, increasing as the degree of neurological involvement. Vertebral fractures were found in 5/13 GMFCS grade V, 2/6 GMFCS grade IV, and 0/10 GMFCS grade III. CONCLUSIONS Bone health in the pediatric population with CP is compromised in relation to the degree of neurological involvement and nutritional status. Those patients with moderate-severe cerebral palsy and low BMD seem to present an increased risk of fracture.
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Affiliation(s)
| | - Ignacio Ros Arnal
- Paediatric Gastroenterology and Nutrition Unit, Miguel Servet University Hospital, Zaragoza, Spain
| | | | - Ruth García Romero
- Paediatric Gastroenterology and Nutrition Unit, Miguel Servet University Hospital, Zaragoza, Spain
| | - Gerardo Rodríguez Martínez
- Aragon Health Research Institute, Maternal and Child Health Network (SAMID), RETICS ISCIII, Zaragoza University, Zaragoza, Spain
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46
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Al-Agha AE, Kabli YO, AlBeiruty MG, Daftardar HE, Alkhattabi SZ, Badauod WM, Bamousa WA. Quantitative ultrasound screening of bone mineral density on children with short stature. Saudi Med J 2020; 41:597-601. [PMID: 32518925 PMCID: PMC7502949 DOI: 10.15537/smj.2020.6.25126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Objectives: To assess bone mineral density (BMD) of children with short stature using quantitative ultrasound (QUS) and compare it to children with normal height. Methods: We conducted a descriptive, cross-sectional controlled study between May 2018 and February 2019 at various pediatric clinics in Jeddah, Saudi Arabia. In total, 219 children were included: 100 had short stature, and 119 were of normal height. Data were collected from one-on-one interviews, and BMD was measured using quantitative ultrasound. Results: Children with short stature had significantly lower BMD z-scores than children with normal height (p<0.05). The use of vitamin D supplements was related to higher BMD z-scores in children with short stature (p<0.05). A significant association was found between higher BMD z-scores, and both age (p=0.05) and height (p=0.02). Through a further division of children with short stature into those with and those without growth hormone deficiencies, we show that growth hormone deficiency was positively associated with lower BMD z-scores; however, the p-value was 0.06. Conclusions: Compared with children of normal height, those with short stature had lower BMD. Height, vitamin D supplementation, and age were all significantly correlated with higher BMD, while growth hormone deficiency was correlated with lower BMD.
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Affiliation(s)
- Abdulmoein E Al-Agha
- Department of Pediatrics, King Abdulaziz University Hospital, Jeddah, Kingdom of Saudi Arabia. E-mail.
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Sato D, Takahata M, Ota M, Fukuda C, Hasegawa T, Yamamoto T, Amizuka N, Tsuda E, Okada A, Hiruma Y, Fujita R, Iwasaki N. Siglec-15-targeting therapy protects against glucocorticoid-induced osteoporosis of growing skeleton in juvenile rats. Bone 2020; 135:115331. [PMID: 32217159 DOI: 10.1016/j.bone.2020.115331] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Revised: 03/12/2020] [Accepted: 03/23/2020] [Indexed: 02/06/2023]
Abstract
Effective treatment of juvenile osteoporosis, which is frequently caused by glucocorticoid (GC) therapy, has not been established due to limited data regarding the efficacy and adverse effects of antiresorptive therapies on the growing skeleton. We previously demonstrated that sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) targeting therapy, which interferes with osteoclast terminal differentiation in the secondary, but not primary, spongiosa, increased bone mass without adverse effects on skeletal growth, whereas bisphosphonate, a first-line treatment for osteoporosis, increased bone mass but impaired long bone growth in healthy growing rats. In the present study, we investigated the efficacy of anti-Siglec-15 neutralizing antibody (Ab) therapy against GC-induced osteoporosis in a growing rat model. GC decreased bone mass and deteriorated mechanical properties of bone, due to a disproportionate increase in bone resorption. Both anti-Siglec-15 Ab and alendronate (ALN) showed protective effects against GC-induced bone loss by suppressing bone resorption, which was more pronounced with anti-Siglec-15 Ab treatment, possibly due to a reduced negative impact on bone formation. ALN induced histological abnormalities in the growth plate and morphological abnormalities in the long bone metaphysis but did not cause significant growth retardation. Conversely, anti-Siglec-15 Ab did not show any negative impact on the growth plate and preserved normal osteoclast and chondroclast function at the primary spongiosa. Taken together, these results suggest that anti-Siglec-15 targeting therapy could be a safe and efficacious prophylactic therapy for GC-induced osteoporosis in juvenile patients.
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Affiliation(s)
- Dai Sato
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Masahiko Takahata
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan.
| | - Masahiro Ota
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Chie Fukuda
- Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Tomoka Hasegawa
- Hokkaido University, Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Sapporo, Japan
| | - Tomomaya Yamamoto
- Hokkaido University, Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Sapporo, Japan
| | - Norio Amizuka
- Hokkaido University, Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Sapporo, Japan
| | - Eisuke Tsuda
- Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Akiko Okada
- Specialty Medicine Research Laboratories I, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Yoshiharu Hiruma
- Pharmacovigilance Department, Daiichi Sankyo Co., Ltd., Tokyo, Japan
| | - Ryo Fujita
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
| | - Norimasa Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo 060-8638, Japan
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Manousaki D, Kämpe A, Forgetta V, Makitie RE, Bardai G, Belisle A, Li R, Andersson S, Makitie O, Rauch F, Richards JB. Increased Burden of Common Risk Alleles in Children With a Significant Fracture History. J Bone Miner Res 2020; 35:875-882. [PMID: 31914204 DOI: 10.1002/jbmr.3956] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/11/2019] [Accepted: 12/14/2019] [Indexed: 12/22/2022]
Abstract
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 × 10-5 ). The gSOS of 78 individuals with suspected Mendelian osteoporosis was even lower (-0.76 SD, p = 5.3 × 10-10 ). 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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Affiliation(s)
- Despoina Manousaki
- Lady Davis Institute for Medical Research, Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Canada.,Department of Human Genetics, McGill University, Montreal, Canada
| | - Anders Kämpe
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden
| | - Vincenzo Forgetta
- Lady Davis Institute for Medical Research, Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Canada
| | - Riikka E Makitie
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.,Folkhälsan Institute of Genetics, Helsinki, Finland.,Molecular Endocrinology Laboratory, Department of Medicine, Hammersmith Campus, Imperial College London, London, UK
| | - Ghalib Bardai
- McGill University, Ingram School of Nursing, and Shriners Hospitals for Children, Montreal, Canada
| | | | - Rui Li
- McGill Genome Center, McGill University, Montreal, Canada
| | - Sture Andersson
- Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Outi Makitie
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.,Folkhälsan Institute of Genetics, Helsinki, Finland.,Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Frank Rauch
- McGill University, Ingram School of Nursing, and Shriners Hospitals for Children, Montreal, Canada
| | - J Brent Richards
- Lady Davis Institute for Medical Research, Centre for Clinical Epidemiology, Jewish General Hospital, McGill University, Montreal, Canada.,Department of Human Genetics, McGill University, Montreal, Canada.,Department of Medicine, Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Canada.,Department of Twin Research and Genetic Epidemiology, King's College London, London, UK
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49
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Garrido C, Bardón-Cancho EJ, Fajardo-Sánchez VDLÁ, Cascón-Pérez-Teijón ME, García-Morín M, Cela E. Evaluation of the effectiveness of prophylactic oral vitamin D (cholecalciferol) in children with sickle cell disease. Bone 2020; 133:115228. [PMID: 31972313 DOI: 10.1016/j.bone.2020.115228] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Revised: 12/23/2019] [Accepted: 01/08/2020] [Indexed: 01/20/2023]
Abstract
BACKGROUND Vitamin D (25(OH)D) deficiency has become an emerging public health problem due to its influence on skeletal and extraskeletal diseases. Bone health in patients with sickle cell disease (SCD) is especially compromised and they are more likely to have 25(OH)D deficiency than the general population. Despite this, there is little information on the efficacy of vitamin D3 (vitD3) prophylaxis and its role in improving bone mineral density (BMD) in this population. PROCEDURES A prospective, longitudinal, single-center study was conducted with 136 children with SCD monitored at a tertiary referral hospital for SCD. Demographic, clinical and management data, 25(OH)D levels and bone densitometries (DXA) were collected. RESULTS Eighty patients were included. There are significant differences between the means of each of 25(OH)D levels as a function of whether the patient started prophylactic treatment as an infant or not (35.71 vs. 27.89 ng/ml, respectively [p = .014]). In multivariate analysis, 800 IU daily dose was shown as a protective factor (p = .044) to reach optimal blood levels (≥30 ng/ml). According to Kaplan-Meier curves, patients younger than 10 years reached optimal levels earlier than older (p = .002), as well as those who were not being treated with hydroxyurea (p = .039). CONCLUSIONS VitD3 prophylaxis is a safe practice in SCD. It is important to start this prophylactic treatment when the child is an infant. The daily regimen with 800 IU could be more effective for reaching levels ≥30 ng/ml, and, especially in preadolescent and adolescent patients, we should raise awareness about the importance of good bone health.
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Affiliation(s)
- Carmen Garrido
- Pediatric Hematology Unit, "Hospital General Universitario Gregorio Marañón", Facultad de Medicina, Universidad Complutense de Madrid, Spain; Instituto Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
| | - Eduardo J Bardón-Cancho
- Pediatric Hematology Unit, "Hospital General Universitario Gregorio Marañón", Facultad de Medicina, Universidad Complutense de Madrid, Spain; Instituto Investigación Sanitaria Gregorio Marañón, Madrid, Spain.
| | | | - María Elena Cascón-Pérez-Teijón
- Musculoskeletal Section, Radiodiagnosis Department, "Hospital General Universitario Gregorio Marañón", Profesora asociada Facultad de Medicina, Universidad Complutense de Madrid, Spain.
| | - Marina García-Morín
- Pediatric Hematology Unit, "Hospital General Universitario Gregorio Marañón", Facultad de Medicina, Universidad Complutense de Madrid, Spain; Instituto Investigación Sanitaria Gregorio Marañón, Madrid, Spain
| | - Elena Cela
- Pediatric Hematology Unit, "Hospital General Universitario Gregorio Marañón", Facultad de Medicina, Universidad Complutense de Madrid, Spain; Instituto Investigación Sanitaria Gregorio Marañón, Madrid, Spain; Instituto Nacional de Investigación Biomédica en Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, Madrid, Spain.
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Ma J, Siminoski K, Wang P, Alos N, Cummings EA, Feber J, Halton J, Ho J, Houghton K, Lang B, Miettunen PM, Scuccimarri R, Jaremko JL, Koujok K, Lentle B, Matzinger MA, Shenouda N, Rauch F, Ward LM. The Accuracy of Prevalent Vertebral Fracture Detection in Children Using Targeted Case-Finding Approaches. J Bone Miner Res 2020; 35:460-468. [PMID: 31742768 DOI: 10.1002/jbmr.3922] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 11/07/2019] [Accepted: 11/11/2019] [Indexed: 01/06/2023]
Abstract
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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Affiliation(s)
- Jinhui Ma
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada
| | - Kerry Siminoski
- Department of Radiology and Diagnostic Imaging and Department of Internal Medicine, University of Alberta, Edmonton, AB, Canada
| | - Peiyao Wang
- Faculty of Science, McMaster University, Hamilton, ON, Canada
| | - Nathalie Alos
- Department of Pediatrics, Universite de Montreal, Montreal, QC, Canada
| | | | - Janusz Feber
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
| | | | - Josephine Ho
- Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | - Kristin Houghton
- Department of Pediatrics, University of British Columbia, Vancouver, BC, Canada
| | - Bianca Lang
- Department of Pediatrics, Dalhousie University, Halifax, NS, Canada
| | - Paivi M Miettunen
- Department of Pediatrics, University of Calgary, Calgary, AB, Canada
| | | | - Jacob L Jaremko
- Department of Radiology & Diagnostic Imaging, University of Alberta, Edmonton, AB, Canada
| | - Khaldoun Koujok
- Department of Medical Imaging, University of Ottawa, Ottawa, ON, Canada
| | - Brian Lentle
- Department of Radiology, University of British Columbia, Vancouver, BC, Canada
| | | | - Nazih Shenouda
- Department of Medical Imaging, University of Ottawa, Ottawa, ON, Canada
| | - Frank Rauch
- Department of Pediatrics, McGill University, Montreal, QC, Canada
| | - Leanne M Ward
- Department of Pediatrics, University of Ottawa, Ottawa, ON, Canada
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- Canadian Pediatric Bone Health Working Group, Ottawa, ON, Canada
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