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Tuompo S, Mäkitie RE, Nieminen MT. Craniofacial fibrous dysplasia: A review of current literature. Bone 2025; 192:117377. [PMID: 39681203 DOI: 10.1016/j.bone.2024.117377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 12/05/2024] [Accepted: 12/13/2024] [Indexed: 12/18/2024]
Abstract
INTRODUCTION Fibrous dysplasia (FD) is a rare genetic disease, in which normal bone is replaced by fibro-osseus tissue. Disease severity varies greatly from single monostotic lesions to widespread polyostotic disease. Craniofacial lesions are common and, due to the complex anatomy, can cause several disabling symptoms and local extra-skeletal complications. Since relatively rare, reported cases of craniofacial FD (CFD), specifically, are few and the appropriate management remains incompletely defined. METHODOLOGY We performed a systematic literature review following the PRISMA guidelines for articles considering CFD in the years 2010-2023. The search was conducted in the PubMed and OVID Medline libraries. Altogether 193 articles were retrieved and reviewed. RESULTS Overall, the clinical presentation of CFD is highly variable depending on site and extent of lesion, with pain, deformity or impairment of function being most common. Diagnoses are often incidental and primarily based on CT imaging, while more extensive imaging, genetic studies and lesion biopsies are reserved for unclear cases. Asymptomatic patients are suitable for observation, while symptomatic or widespread disease may require more active approach with medical or surgical treatment. Follow-up is encouraged in all patients to observe possible lesion reactivation, late-stage complications and, though rarely, malignant transformation. Management should be individually tailored with a multidisciplinary team and wholesome consideration of individual needs. CONCLUSIONS This review provides an updated discussion on craniofacial FD with focus on improved understanding of disease pathophysiology, appropriate line of surgical management, and new potential means of medical treatment.
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Affiliation(s)
- Sara Tuompo
- Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, POBox 263, FI-00029 HUS Helsinki, Finland
| | - Riikka E Mäkitie
- Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, POBox 263, FI-00029 HUS Helsinki, Finland; Faculty of Medicine, Haartmaninkatu 8, P.O. Box 63, 00014, University of Helsinki, Helsinki, Finland
| | - Mikko T Nieminen
- Department of Otorhinolaryngology - Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, POBox 263, FI-00029 HUS Helsinki, Finland.
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Schmitt L, Theiler-Schwetz V, Sadoghi P, Trummer C, Pilz S. Rebound hypercalcemia after denosumab cessation during follow-up after surgical treatment for parathyroid carcinoma: case report and literature review. ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e240035. [PMID: 39529981 PMCID: PMC11554368 DOI: 10.20945/2359-4292-2024-0035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2024] [Accepted: 06/13/2024] [Indexed: 11/16/2024]
Abstract
Denosumab is a potent antiresorptive medication, commonly used in the treatment of osteoporosis, as well as in a variety of other diseases. Potential adverse rebound effects after its cessation include a loss in bone mineral density and an increased risk of osteoporotic fractures. Hypercalcemia is a less frequently reported rebound phenomenon after denosumab discontinuation, that may pose a diagnostic challenge to physicians as a rare non-parathyroid hormone (PTH) dependent cause of hypercalcemia. In our case, a 47-year-old male presented with rebound hypercalcemia after denosumab cessation during follow-up after surgical treatment for parathyroid carcinoma. This non-PTH-dependent hypercalcemia resolved after re-initiation of denosumab. We performed a systematic literature review on rebound hypercalcemia after denosumab cessation and identified 52 individual patient cases. Children appear to be more prone to developing rebound hypercalcemia, which could be attributed to their higher baseline bone turnover, underlying conditions, or denosumab dosage regimens. In most cases, patients initially presented with acute and often severe symptoms of hypercalcemia that occur from 1.75 to 9 months after denosumab cessation (4 to 9 months in adults). Most effective treatment approaches to sufficiently decrease serum calcium levels were bisphosphonates or re-administration of denosumab. A watch and wait strategy may be sufficient in asymptomatic cases, which are less common and probably underdiagnosed. Subsequent antiresorptive treatment after denosumab cessation, which is a common practice in osteoporosis treatment, may reduce the risk of rebound hypercalcemia. As denosumab is a frequently used drug in patients with advanced malignant diseases and rebound hypercalcemia with low PTH levels may raise the suspicion for skeletal metastases, awareness of this rebound effect may be for particular relevance in such settings.
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Affiliation(s)
- Lisa Schmitt
- Medical University of GrazDivision of Endocrinology and DiabetologyDepartment of Internal MedicineGrazAustriaDivision of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Verena Theiler-Schwetz
- Medical University of GrazDivision of Endocrinology and DiabetologyDepartment of Internal MedicineGrazAustriaDivision of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Patrick Sadoghi
- Medical University of GrazDepartment of Orthopaedics and TraumaGrazAustriaDepartment of Orthopaedics and Trauma, Medical University of Graz, Graz, Austria
| | - Christian Trummer
- Medical University of GrazDivision of Endocrinology and DiabetologyDepartment of Internal MedicineGrazAustriaDivision of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Stefan Pilz
- Medical University of GrazDivision of Endocrinology and DiabetologyDepartment of Internal MedicineGrazAustriaDivision of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
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Kim HJ, Yoon PW, Yoon JY, Kim H, Choi YJ, Park S, Moon JK. Discrepancies in ChatGPT's Hip Fracture Recommendations in Older Adults for 2021 AAOS Evidence-Based Guidelines. J Clin Med 2024; 13:5971. [PMID: 39408030 PMCID: PMC11477870 DOI: 10.3390/jcm13195971] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2024] [Revised: 10/05/2024] [Accepted: 10/07/2024] [Indexed: 10/20/2024] Open
Abstract
Background: This study aimed to assess the reproducibility and reliability of Chat-Based GPT (ChatGPT)'s responses to 19 statements regarding the management of hip fractures in older adults as adopted by the American Academy of Orthopaedic Surgeons' (AAOS) evidence-based clinical practice guidelines. Methods: Nineteen statements were obtained from the 2021 AAOS evidence-based clinical practice guidelines. After generating questions based on these 19 statements, we set a prompt for both the GPT-4o and GPT-4 models. We repeated this process three times at 24 h intervals for both models, producing outputs A, B, and C. ChatGPT's performance, the intra-ChatGPT reliability, and the accuracy rates were assessed to evaluate the reproducibility and reliability of the hip fracture-related guidelines. Regarding the strengths of the recommendation compared with the 2021 AAOS guidelines, we observed accuracy of 0.684, 0.579, and 0.632 for outputs A, B, and C, respectively. Results: The precision was 0.740, 0.737, and 0.718 in outputs A, B, and C, respectively. For the reliability of the strengths of the recommendation, the Fleiss kappa was 0.409, indicating a moderate level of agreement. No statistical differences in the strengths of the recommendation were observed in outputs A, B, and C between the GPT-4o and GPT-4 versions. Conclusion: ChatGPT may be useful in providing guidelines for hip fractures but performs poorly in terms of accuracy and precision. However, hallucinations remain an unresolved limitation associated with using ChatGPT to search for hip fracture guidelines. The effective utilization of ChatGPT as a patient education tool for the management of hip fractures should be addressed in the future.
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Affiliation(s)
- Hong Jin Kim
- Department of Orthopaedic Surgery, Kyung-in Regional Military Manpower Administration, Suwon 16440, Republic of Korea;
- Department of Orthopedic Surgery, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea; (H.K.); (S.P.)
| | - Pil Whan Yoon
- Department of Orthopaedic Surgery, Seoul Now Hospital, Anyang-si 14058, Republic of Korea; (P.W.Y.); (J.Y.Y.)
| | - Jae Youn Yoon
- Department of Orthopaedic Surgery, Seoul Now Hospital, Anyang-si 14058, Republic of Korea; (P.W.Y.); (J.Y.Y.)
| | - Hyungtae Kim
- Department of Orthopedic Surgery, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea; (H.K.); (S.P.)
| | - Young Jin Choi
- Department of Orthopedic Surgery, Chung Goo Sung Sim Hospital, Seoul 03330, Republic of Korea;
| | - Sangyoon Park
- Department of Orthopedic Surgery, Inje University Sanggye Paik Hospital, Seoul 01757, Republic of Korea; (H.K.); (S.P.)
| | - Jun-Ki Moon
- Department of Orthopaedic Surgery, Chung-Ang University Hospital, Seoul 06973, Republic of Korea
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Voermans NC, Dittrich ATM, Liguori S, Panicucci C, Moretti A, Weber DR, Ward LM. 274th ENMC international workshop: recommendations for optimizing bone strength in neuromuscular disorders. Hoofddorp, The Netherlands, 19-21 January 2024. Neuromuscul Disord 2024; 43:1-13. [PMID: 39173540 DOI: 10.1016/j.nmd.2024.07.009] [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: 06/17/2024] [Revised: 07/22/2024] [Accepted: 07/23/2024] [Indexed: 08/24/2024]
Abstract
The 274th ENMC workshop for optimizing bone strength in neuromuscular disorders (NMDs) was held on January 19-21, 2024. The group of participants included experts in the fields of bone health and neuromuscular medicine along with the patient voice. Bone strength represents a crucial aspect of the management of pediatric and adult patients with NMDs. Bone strength may be compromised due to different pathophysiologic mechanisms, including disrupted bone-muscle "cross-talk", loss of biomechanical loading, nutritional insufficiency, inadequate weight-bearing physical activity, muscle weakness and/or immobility, and drug treatment. While for Duchenne muscular dystrophy recommendations for evaluation and treatment of bone strength have been published, evidence on bone strength in other hereditary and acquired NMDs is scarce. Enhanced knowledge is needed to understand the development and maintenance of bone strength in patients with NMDs. This workshop aimed to develop a strategy to improve bone strength and thus prevent fractures in patients with NMDs.
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Affiliation(s)
- Nicol C Voermans
- Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands.
| | - Anne T M Dittrich
- Department of Pediatrics, Radboud University Medical Center, Radboudumc Amalia Children's Hospital, Nijmegen, the Netherlands
| | - Sara Liguori
- Department of Medical and Surgical Specialties and Dentistry, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy; Department of Mental and Physical Health and Preventive Medicine, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - Chiara Panicucci
- Centre of Translational and Experimental Myology, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Antimo Moretti
- Department of Medical and Surgical Specialties and Dentistry, University of Campania "Luigi Vanvitelli", 80138 Naples, Italy
| | - David R Weber
- Division of Endocrinology, Children's Hospital of Philadelphia and Perelman School of Medicine at the University of Pennsylvania Philadelphia, PA, USA
| | - Leanne M Ward
- Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
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Soloviova M, Beltrán-Vargas JC, Castro LFD, Belmonte-Beitia J, Pérez-García VM, Caballero M. A Mathematical Model for Fibrous Dysplasia: The Role of the Flow of Mutant Cells. Bull Math Biol 2024; 86:108. [PMID: 39007985 DOI: 10.1007/s11538-024-01336-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2024] [Accepted: 06/26/2024] [Indexed: 07/16/2024]
Abstract
Fibrous dysplasia (FD) is a mosaic non-inheritable genetic disorder of the skeleton in which normal bone is replaced by structurally unsound fibro-osseous tissue. There is no curative treatment for FD, partly because its pathophysiology is not yet fully known. We present a simple mathematical model of the disease incorporating its basic known biology, to gain insight on the dynamics of the involved bone-cell populations, and shed light on its pathophysiology. We develop an analytical study of the model and study its basic properties. The existence and stability of steady states are studied, an analysis of sensitivity on the model parameters is done, and different numerical simulations provide findings in agreement with the analytical results. We discuss the model dynamics match with known facts on the disease, and how some open questions could be addressed using the model.
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Affiliation(s)
- Mariia Soloviova
- Department of Mathematics, Mathematical Oncology Laboratory (MOLAB), Universidad de Castilla-La Mancha, Avda. Camilo José Cela 3, Ciudad Real, 13071, Spain.
| | - Juan C Beltrán-Vargas
- Department of Mathematics, Mathematical Oncology Laboratory (MOLAB), Universidad de Castilla-La Mancha, Avda. Camilo José Cela 3, Ciudad Real, 13071, Spain
| | - Luis Fernandez de Castro
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, Department of Health and Human Services, National Institutes of Health, Bethesda, MD, USA
| | - Juan Belmonte-Beitia
- Department of Mathematics, Mathematical Oncology Laboratory (MOLAB), Universidad de Castilla-La Mancha, Avda. Camilo José Cela 3, Ciudad Real, 13071, Spain
| | - Víctor M Pérez-García
- Department of Mathematics, Mathematical Oncology Laboratory (MOLAB), Universidad de Castilla-La Mancha, Avda. Camilo José Cela 3, Ciudad Real, 13071, Spain
| | - Magdalena Caballero
- Department of Mathematics, Universidad de Córdoba, Campus de Rabanales, Córdoba, 14071, Spain
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Chen Y, Fang C, Yang Z, Qiu G, Tang S. Hypercalcemia in children induced by denosumab: a case report and an analysis of the FDA adverse event reporting system database. Expert Opin Drug Saf 2024:1-12. [PMID: 39007894 DOI: 10.1080/14740338.2024.2379446] [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: 01/24/2024] [Accepted: 05/22/2024] [Indexed: 07/16/2024]
Abstract
BACKGROUND The potential risks of denosumab on pediatric patients have raised concerns about its safety. This article aims to analyze the adverse effects of denosumab in minors, with a specific focus on hypercalcemia. RESEARCH DESIGN AND METHODS A case study involving a child was analyzed. The OpenVigil 2.1 was utilized to extract adverse event data from the FAERS database, focusing on denosumab as the primary suspect drug in pediatric patients. The study also reviewed published cases of children developing hypercalcemia after discontinuing denosumab. RESULTS The incidence of denosumab induced hypercalcemia in individuals under 18 years old is significantly higher than the overall incidence. The signal value for hypercalcemia was higher in the male group and was highest in the adolescent group. Hypercalcemia usually appeared approximately 4 months after denosumab discontinuation. Males had a higher peak blood calcium level. Patients aged 0-11 years had a higher average peak serum calcium compared to aged 12-17 years. CONCLUSIONS This study highlights the risk of hypercalcemia after discontinuation of denosumab in minors, with young age and male gender identified as potential high-risk factors. These findings offer valuable safety warnings and preventative measures for the secure administration of this drug in pediatric populations.
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Affiliation(s)
- Yiyu Chen
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chuxuan Fang
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhiyong Yang
- Department of PICU, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guosheng Qiu
- Department of PICU, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shuangyi Tang
- Department of Pharmacy, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Liu J, Lin X, Sun L, Zhang Q, Jiang Y, Wang O, Xing X, Xia W, Li M. Safety and Efficacy of Denosumab in Children With Osteogenesis Imperfecta-the First Prospective Comparative Study. J Clin Endocrinol Metab 2024; 109:1827-1836. [PMID: 38198649 PMCID: PMC11180505 DOI: 10.1210/clinem/dgad732] [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: 09/01/2023] [Indexed: 01/12/2024]
Abstract
CONTEXT Denosumab is a potential therapeutic agent for osteogenesis imperfecta (OI), but its efficacy and safety remain unclear in children with OI. OBJECTIVE We aimed to investigate the effects of denosumab on bone mineral density (BMD), spinal morphometry, and safety in children with OI compared with zoledronic acid. METHODS In this prospective study, 84 children or adolescents with OI were randomized to receive denosumab subcutaneous injection every 6 months or zoledronic acid intravenous infusion once. Changes of BMD and its Z-score, vertebral shape, serum levels of calcium and bone turnover biomarkers were assessed during the 1-year treatment. RESULTS After 12 months of treatment, BMD at the lumbar spine, femoral neck, and total hip significantly increased by 29.3%, 27.8%, and 30.2% in the denosumab group, and by 32.2%, 47.1%, and 41.1% in the zoledronic acid group (all P < .001 vs baseline). Vertebral height and projection area significantly increased after denosumab and zoledronic acid treatment. Rebound hypercalcemia was found to be a common and serious side effect of denosumab, of which 14.3% reached hypercalcemic crisis. Rebound hypercalcemia could be alleviated by switching to zoledronic acid treatment. CONCLUSION Treatment with denosumab or zoledronic acid is beneficial in increasing BMD and improving the spinal morphometry of children with OI. However, denosumab should be used with caution in pediatric patients with OI because of its common and dangerous side effect of rebound hypercalcemia. The appropriate dosage and dosing interval of denosumab need to be further explored in children with OI.
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Affiliation(s)
- Jiayi Liu
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoyun Lin
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Lei Sun
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Qian Zhang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Yan Jiang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Ou Wang
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Xiaoping Xing
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Weibo Xia
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
| | - Mei Li
- Department of Endocrinology, Key Laboratory of Endocrinology, National Health and Family Planning Commission, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China
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Liu X, Xie Y, Tang J, Zhong J, Lan D. Hypercalcemia in Children Following a Discontinuation of Denosumab Therapy: A Case Report and Literature Review. Clin Pediatr (Phila) 2024; 63:750-754. [PMID: 37594083 DOI: 10.1177/00099228231194427] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 08/19/2023]
Affiliation(s)
- Xu Liu
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Yanshu Xie
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jing Tang
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jingzi Zhong
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Dan Lan
- Department of Pediatrics, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Vilos I, Nieminen MT, Mäkitie RE. Fibrous dysplasia of the head and neck in Southern Finland: a retrospective study on clinical characteristics, diagnostics, and treatment. Eur Arch Otorhinolaryngol 2024; 281:3189-3195. [PMID: 38564011 PMCID: PMC11065911 DOI: 10.1007/s00405-024-08595-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024]
Abstract
PURPOSE Fibrous dysplasia (FD) is a rare genetic disease with benign bone tumors. FD can affect one (monostotic FD) or multiple bones (polyostotic FD), with craniofacial lesions being common. Because of its rarity, there are only few clinical reports on FD in the head and neck region and its clinical characteristics remain incompletely defined. This study aimed to determine patient demographics, symptoms, diagnostics, and given treatment in patients with FD of the head and neck in a Finnish population. METHODS A retrospective review on all patients diagnosed with or treated for FD of the head and neck at the Helsinki University Hospital during 2005-2020. RESULTS In total 74 patients were identified; 54% were male and the mean age 45 years. Overall 95% had monostotic FD. Mandibula and maxilla were the most common anatomic sites. Majority of patients had symptoms, most commonly pain and lesion growth, and 49% had extra-skeletal symptoms. For all, diagnosis was primarily based on imaging findings, biopsies were obtained from 41%. Altogether 54 patients (73%) were managed by observation only, 20 patients (27%) received treatment; ten bisphosphonates, six surgery and four both. CONCLUSION Although highly variable in its clinical manifestations, head and neck FD lesions are often symptomatic and impose risk for extra-skeletal complications. Treatment is often conservative but should be individually tailored. Future studies are encouraged to better define the disease characteristics and hopefully offer new treatment possibilities.
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Affiliation(s)
- Isabella Vilos
- Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, HUS, Kasarmikatu 11-13, 00029, Helsinki, Finland
| | - Mikko T Nieminen
- Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, HUS, Kasarmikatu 11-13, 00029, Helsinki, Finland
| | - Riikka E Mäkitie
- Department of Otorhinolaryngology, Head and Neck Surgery, Helsinki University Hospital and University of Helsinki, HUS, Kasarmikatu 11-13, 00029, Helsinki, Finland.
- Faculty of Medicine, University of Helsinki, Helsinki, Finland.
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Lung H, Wentworth KL, Moody T, Zamarioli A, Ram A, Ganesh G, Kang M, Ho S, Hsiao EC. Wnt pathway inhibition with the porcupine inhibitor LGK974 decreases trabecular bone but not fibrosis in a murine model with fibrotic bone. JBMR Plus 2024; 8:ziae011. [PMID: 38577521 PMCID: PMC10994528 DOI: 10.1093/jbmrpl/ziae011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/22/2023] [Accepted: 01/08/2024] [Indexed: 04/06/2024] Open
Abstract
G protein-coupled receptors (GPCRs) mediate a wide spectrum of physiological functions, including the development, remodeling, and repair of the skeleton. Fibrous dysplasia (FD) of the bone is characterized by fibrotic, expansile bone lesions caused by activating mutations in GNAS. There are no effective therapies for FD. We previously showed that ColI(2.3)+/Rs1+ mice, in which Gs-GPCR signaling was hyper-activated in osteoblastic cell lineages using an engineered receptor strategy, developed a fibrotic bone phenotype with trabecularization that could be reversed by normalizing Gs-GPCR signaling, suggesting that targeting the Gs-GPCR or components of the downstream signaling pathway could serve as a promising therapeutic strategy for FD. The Wnt signaling pathway has been implicated in the pathogenesis of FD-like bone, but the specific Wnts and which cells produce them remain largely unknown. Single-cell RNA sequencing on long-bone stromal cells of 9-wk-old male ColI(2.3)+/Rs1+ mice and littermate controls showed that fibroblastic stromal cells in ColI(2.3)+/Rs1+ mice were expanded. Multiple Wnt ligands were up- or downregulated in different cellular populations, including in non-osteoblastic cells. Treatment with the porcupine inhibitor LGK974, which blocks Wnt signaling broadly, induced partial resorption of the trabecular bone in the femurs of ColI(2.3)+/Rs1+ mice, but no significant changes in the craniofacial skeleton. Bone fibrosis remained evident after treatment. Notably, LGK974 caused significant bone loss in control mice. These results provide new insights into the role of Wnt and Gs-signaling in fibrosis and bone formation in a mouse model of Gs-GPCR pathway overactivation.
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Affiliation(s)
- Hsuan Lung
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
- Department of Dentistry, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan
- School of Dentistry, Institute of Oral Medicine, College of Medicine, National Cheng Kung University, Tainan 701, Taiwan
| | - Kelly L Wentworth
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Department of Medicine, Division of Endocrinology and Metabolism, University of California, Zuckerberg San Francisco General Hospital, San Francisco, CA 94143, United States
| | - Tania Moody
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
| | - Ariane Zamarioli
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Department of Orthopaedics and Anesthesiology, Ribeirao Preto Medical School, University of Sao Paulo, Sao Paulo (SP) 14049-900, Brazil
| | - Apsara Ram
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
| | - Gauri Ganesh
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
| | - Misun Kang
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
| | - Sunita Ho
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
| | - Edward C Hsiao
- Department of Medicine, Division of Endocrinology and Metabolism, The Institute for Human Genetics, and the Eli and Edythe Broad Institute for Regeneration Medicine, University of California, San Francisco, CA 94143, United States
- Oral and Craniofacial Sciences Graduate Program, School of Dentistry, University of California, San Francisco, CA 94143, United States
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Michel Z, Raborn LN, Spencer T, Pan KS, Martin D, Roszko KL, Wang Y, Robey PG, Collins MT, Boyce AM, de Castro LF. Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia. Cells 2024; 13:774. [PMID: 38727310 PMCID: PMC11083355 DOI: 10.3390/cells13090774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2024] [Revised: 04/24/2024] [Accepted: 04/26/2024] [Indexed: 05/13/2024] Open
Abstract
Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.
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Affiliation(s)
- Zachary Michel
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA; (Z.M.); (K.S.P.); (A.M.B.)
| | - Layne N. Raborn
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 207, Bethesda, MD 20892, USA; (L.N.R.); (T.S.); (K.L.R.); (M.T.C.)
| | - Tiahna Spencer
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 207, Bethesda, MD 20892, USA; (L.N.R.); (T.S.); (K.L.R.); (M.T.C.)
| | - Kristen S. Pan
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA; (Z.M.); (K.S.P.); (A.M.B.)
| | - Daniel Martin
- Genomics and Computational Biology Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Kelly L. Roszko
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 207, Bethesda, MD 20892, USA; (L.N.R.); (T.S.); (K.L.R.); (M.T.C.)
| | - Yan Wang
- Mass Spectrometry Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Pamela G. Robey
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA;
| | - Michael T. Collins
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 207, Bethesda, MD 20892, USA; (L.N.R.); (T.S.); (K.L.R.); (M.T.C.)
| | - Alison M. Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA; (Z.M.); (K.S.P.); (A.M.B.)
| | - Luis Fernandez de Castro
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 207, Bethesda, MD 20892, USA; (L.N.R.); (T.S.); (K.L.R.); (M.T.C.)
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12
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Vanderniet JA, Szymczuk V, Högler W, Beck-Nielsen SS, Uday S, Merchant N, Crane JL, Ward LM, Boyce AM, Munns CF. Management of RANKL-mediated Disorders With Denosumab in Children and Adolescents: A Global Expert Guidance Document. J Clin Endocrinol Metab 2024; 109:1371-1382. [PMID: 38041865 PMCID: PMC11031248 DOI: 10.1210/clinem/dgad657] [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: 06/08/2023] [Revised: 11/07/2023] [Accepted: 11/09/2023] [Indexed: 12/04/2023]
Abstract
CONTEXT Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. OBJECTIVE This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. PARTICIPANTS Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. EVIDENCE Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. CONCLUSION Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.
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Affiliation(s)
- Joel A Vanderniet
- Sydney Medical School, Faculty of Medicine and Health, The University of Sydney and Institute of Endocrinology and Diabetes, The Children’s Hospital at Westmead, Sydney, NSW 2145, Australia
| | - Vivian Szymczuk
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20814, USA
| | - Wolfgang Högler
- Department of Paediatrics and Adolescent Medicine, Johannes Kepler University Linz, Linz 4020, Austria
| | - Signe S Beck-Nielsen
- Centre for Rare Diseases, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus N DK-8200, Denmark
| | - Suma Uday
- Department of Endocrinology and Diabetes, Birmingham Women's and Children's Hospital and Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TG, UK
| | - Nadia Merchant
- Division of Endocrinology and Diabetes, Children's National Hospital, Washington, DC 20010, USA
| | - Janet L Crane
- Department of Pediatrics and Department of Orthopedic Surgery, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Leanne M Ward
- Department of Pediatrics, University of Ottawa and Division of Endocrinology, Children's Hospital of Eastern Ontario, Ottawa, Ontario K1H 8L1, Canada
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20814, USA
| | - Craig F Munns
- Child Health Research Centre and Mayne Academy of Paediatrics, University of Queensland, Brisbane, QLD 4101, Australia
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13
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Palmisano B, Farinacci G, Campolo F, Tavanti C, Stefano A, Donsante S, Ippolito E, Giannicola G, Venneri MA, Corsi A, Riminucci M. A pathogenic role for brain-derived neurotrophic factor (BDNF) in fibrous dysplasia of bone. Bone 2024; 181:117047. [PMID: 38331308 DOI: 10.1016/j.bone.2024.117047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 01/10/2024] [Accepted: 02/06/2024] [Indexed: 02/10/2024]
Abstract
Brain derived neurotrophic factor (BDNF) is a neurotrophin, expressed in the central nervous system and in peripheral tissues, that is regulated by the Gsα/cAMP pathway. In bone, it regulates osteogenesis and stimulates RANKL secretion and osteoclast formation in osteolytic tumors such as Multiple Myeloma. Fibrous dysplasia (FD) of bone is a rare genetic disease of the skeleton caused by gain-of-function mutations of the Gsα gene in which RANKL-dependent enhanced bone resorption is a major cause of bone fragility and clinical morbidity. We observed that BDNF transcripts are expressed in human FD lesions. Specifically, immunolocalization studies performed on biopsies obtained from FD patients revealed the expression of BDNF in osteoblasts and, to a lower extent, in the spindle-shaped cells within the fibrous tissue. Therefore, we hypothesized that BDNF can play a role in the pathogenesis of FD by stimulating RANKL secretion and bone resorption. To test this hypothesis, we used the EF1α-GsαR201C mouse model of the human disease (FD mice). Western blot analysis revealed a higher expression of BDNF in bone segments of FD mice compared to WT mice and the immunolabeling pattern within mouse FD lesions was similar to that observed in human FD. Treatment of FD mice with a monoclonal antibody against BDNF reduced the fibrous tissue along with the number of osteoclasts and osteoblasts within femoral lesions. These results reveal BDNF as a new player in the pathogenesis of FD and a potential molecular mechanism by which osteoclastogenesis may be nourished within FD bone lesions. They also suggest that BDNF inhibition may be a new approach to reduce abnormal bone remodeling in FD.
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Affiliation(s)
- Biagio Palmisano
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Giorgia Farinacci
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Federica Campolo
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Chiara Tavanti
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Alessia Stefano
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Samantha Donsante
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Ernesto Ippolito
- Department of Orthopaedic Surgery, University of Rome Tor Vergata, 00133 Rome, Italy
| | - Giuseppe Giannicola
- Department of Anatomical, Histological, Medico Legal and Orthopaedic Sciences, Sapienza University of Rome, 00161 Rome, Italy
| | - Mary Anna Venneri
- Department of Experimental Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, 00161 Rome, Italy.
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Akintoye SO, Adisa AO, Okwuosa CU, Mupparapu M. Craniofacial disorders and dysplasias: Molecular, clinical, and management perspectives. Bone Rep 2024; 20:101747. [PMID: 38566929 PMCID: PMC10985038 DOI: 10.1016/j.bonr.2024.101747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 02/27/2024] [Accepted: 02/29/2024] [Indexed: 04/04/2024] Open
Abstract
There is a wide spectrum of craniofacial bone disorders and dysplasias because embryological development of the craniofacial region is complex. Classification of craniofacial bone disorders and dysplasias is also complex because they exhibit complex clinical, pathological, and molecular heterogeneity. Most craniofacial disorders and dysplasias are rare but they present an array of phenotypes that functionally impact the orofacial complex. Management of craniofacial disorders is a multidisciplinary approach that involves the collaborative efforts of multiple professionals. This review provides an overview of the complexity of craniofacial disorders and dysplasias from molecular, clinical, and management perspectives.
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Affiliation(s)
- Sunday O. Akintoye
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States of America
| | - Akinyele O. Adisa
- University of Ibadan and University College Hospital Ibadan, Ibadan, Nigeria
| | - Chukwubuzor U. Okwuosa
- Department of Oral Pathology & Oral Medicine, University of Nigeria Teaching Hospital, Ituku-Ozalla, Nigeria
| | - Mel Mupparapu
- Department of Oral Medicine, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA, United States of America
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15
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Michel Z, Raborn LN, Spencer T, Pan K, Martin D, Roszko KL, Wang Y, Robey PG, Collins MT, Boyce AM, de Castro Diaz LF. Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.23.581225. [PMID: 38529507 PMCID: PMC10962707 DOI: 10.1101/2024.02.23.581225] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/27/2024]
Abstract
Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.
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Affiliation(s)
- Zachary Michel
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Layne N. Raborn
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Tiahna Spencer
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Kristen Pan
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Daniel Martin
- Genomics and Computational Biology Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Kelly L. Roszko
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Yan Wang
- Mass Spectrometry Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Pamela G. Robey
- Skeletal Biology Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Michael T. Collins
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Alison M. Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
| | - Luis Fernandez de Castro Diaz
- Skeletal Diseases and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD
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16
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Moon JK, Park J, Yoo Y, Yoon JY, Lee S, Yoon PW. The efficacy of Denosumab in the treatment of femoral head osteonecrosis: a retrospective comparative study. Sci Rep 2024; 14:4140. [PMID: 38374383 PMCID: PMC10876926 DOI: 10.1038/s41598-024-54685-7] [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: 10/12/2023] [Accepted: 02/15/2024] [Indexed: 02/21/2024] Open
Abstract
The present study aimed to compare clinical and radiological differences of ONFH patients who were treated with denosumab, and a control group. A total of 178 patients (272 hips) with symptomatic, nontraumatic ONFH were divided into a denosumab group (98 patients, 146 hips) and a control group (80 patients, 126 hips). Patients in the denosumab group received a 60 mg subcutaneous dose of denosumab every 6 months. For the clinical assessments, Harris hip scores (HHS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) were evaluated. Plain radiographs and MRI were performed before and a minimum of 1 year after administration of denosumab, which were evaluated for radiological results including femoral head collapse (≥ 2 mm) and volume change of necrotic lesion. Femoral head collapse occurred in 36 hips (24.7%) in the denosumab group, and 48 hips (38.1%) in the control group, which was statistically significant (P = 0.012). Twenty-three hips (15.8%) in the denosumab group and 29 hips (23%) in the control group required THA, which showed no significant difference (P = 0.086). At the final follow-up, 71.9% of hips in the denosumab group had a good or excellent HHS compared with 48.9% in the control group, showing a significant difference (P = 0.012). The denosumab group showed a significantly higher rate of necrotic lesion volume reductions compared with the control group (P < 0.001). Denosumab can significantly reduce the volume of necrotic lesions and prevent femoral head collapse in patients with ARCO stage I or II ONFH.
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Affiliation(s)
- Jun-Ki Moon
- Department of Orthopaedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Jinyong Park
- Department of Orthopedic Surgery, Asan Medical Center, Seoul, South Korea
| | - Yisack Yoo
- Department of Orthopaedic Surgery, Chung-Ang University Hospital, Chung-Ang University College of Medicine, Seoul, South Korea
| | - Jae Youn Yoon
- Department of Orthopedic Surgery, Seoul Now Hospital, 372, Simin-Daero, Dongan-gu, Seoul, South Korea
| | - Sunhyung Lee
- Department of Orthopedic Surgery, Seoul National University Boramae Medical Center, Seoul, South Korea
| | - Pil Whan Yoon
- Department of Orthopedic Surgery, Seoul Now Hospital, 372, Simin-Daero, Dongan-gu, Seoul, South Korea.
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17
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Gun ZH, Arif A, Boyce AM. Fibrous dysplasia in children and its management. Curr Opin Endocrinol Diabetes Obes 2024; 31:60-66. [PMID: 38010041 DOI: 10.1097/med.0000000000000847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2023]
Abstract
PURPOSE OF REVIEW The purpose of this review is to provide a comprehensive overview into the diagnosis and management of fibrous dysplasia (FD) in children. RECENT FINDINGS FD is a mosaic disorder arising from somatic Gα s variants, leading to impaired osteogenic cell differentiation. Fibro-osseous lesions expand during childhood and reach final disease burden in early adulthood. The mainstay of treatment focuses on surgical correction of skeletal deformities, physiatric care, and medical management of associated hyperfunctioning endocrinopathies. Bisphosphonates may be helpful to treat bone pain, but do not alter lesion quality or progression. Emerging evidence suggests that the RANKL inhibitor denosumab may be effective in improving lesion activity and mineralization, however further studies are needed to determine the potential utility of this and other novel therapies, particularly in children with FD. SUMMARY Management of children with FD has unique challenges related to skeletal growth and age-related lesion progression. Inclusion of children in clinical research is critical to develop effective treatment strategies to treat FD lesions and prevent their development.
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Affiliation(s)
- Zubeyir Hasan Gun
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health
- Pediatric Endocrinology Inter-Institute Training Program, National Institute of Child Health and Development, National Institutes of Health, Bethesda, Maryland, USA
| | - Aleena Arif
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health
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18
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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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19
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Phung K, Crabtree N, Connolly AM, Furlong P, Hoffman EP, Jackowski SA, Jayash SN, Johnson A, Koujok K, Munns CF, Niks E, Rauch F, Schrader R, Turner C, Vroom E, Weber DR, Wong BL, Guglieri M, Ward LM, Wong SC. Moving Beyond the 2018 Minimum International Care Considerations for Osteoporosis Management in Duchenne Muscular Dystrophy (DMD): Meeting Report from the 3rd International Muscle-Bone Interactions Meeting 7th and 14th November 2022. J Neuromuscul Dis 2024; 11:233-252. [PMID: 37980681 PMCID: PMC10789336 DOI: 10.3233/jnd-230176] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/17/2023] [Indexed: 11/21/2023]
Affiliation(s)
- Kim Phung
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Nicola Crabtree
- Birmingham Women’s and Children’s NHS Foundation Trust, Birmingham, United Kingdom
| | - Anne M. Connolly
- Nationwide Children’s Hospital, Ohio State University, Columbus, OH, USA
| | - Pat Furlong
- Parent Project Muscular Dystrophy, Washington, DC, USA
| | - Eric P. Hoffman
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences Binghamton University, State University of New York, Binghamton, NY, USA
| | - Stefan A. Jackowski
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Soher Nagi Jayash
- Roslin institute, University of Edinburgh, Edinburgh, United Kingdom
| | | | - Khaldoun Koujok
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Craig F. Munns
- Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
- Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia
- Department of Endocrinology and Diabetes, Queensland Children’s Hospital, Brisbane, QLD, Australia
| | - Erik Niks
- Leiden University Medical Center, Leiden, The Netherlands
| | - Frank Rauch
- Shriners Hospital for Children, Montreal, QC, Canada
| | | | | | | | | | | | | | - Leanne M. Ward
- Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada
| | - Sze Choong Wong
- Correspondence to: Dr. Sze Choong Wong, Department of Paediatric Endocrinology, Royal Hospital for Children, 1345 Govan Road, Glasgow G51 4TF United Kingdom. Tel.: +44 141 451 5841; E-mail:
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20
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Schreuder WH, Meijer EB, Cleven AHG, Edelenbos E, Klop C, Schreurs R, de Jong RT, van Maarle MC, Horsthuis RBG, de Lange J, van den Berg H. Efficacy and Toxicity of Calcitonin Treatment in Children with Cherubism: A Single-Center Cohort Study. J Bone Miner Res 2023; 38:1822-1833. [PMID: 37823782 DOI: 10.1002/jbmr.4922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2023] [Revised: 09/19/2023] [Accepted: 10/06/2023] [Indexed: 10/13/2023]
Abstract
Cherubism is a rare autosomal dominant disease characterized by expansile osteolytic jawbone lesions. The effect and safety of off-label calcitonin treatment during the progressive phase of the disease are not well described. In this retrospective study, we present data on the radiological response and adverse effects of subcutaneously administered calcitonin in a cohort of nine cherubism children (three female, six male). Two of the nine patients underwent two separate treatment courses with a significant off-treatment interval in between; therefore, a total of 11 treatment courses with a mean duration of 17.9 months (range <1 to 35, SD 10.8) were studied. To measure the response, the cumulative volume of cherubism lesions was calculated from available three-dimensional imaging. The primary outcome was the change in the volume of lesions during calcitonin treatment and only assessed for the eight treatment courses with a minimal duration of 6 months. A statistically significant reduction in the mean cumulative volume of lesions was seen regardless of treatment duration. Average volume reduction was highest in the first half year of treatment, with a gradual, ongoing reduction thereafter. For the secondary outcome, the change in the cumulative volume of lesions after treatment cessation was assessed for the seven treatment courses with follow-up imaging available. After six of these seven treatment courses, the cumulative volume increased again but remained undoubtedly smaller than the initial volume at the start of therapy. Adverse effects were assessed for all 11 treatment courses and occurred in 73% of them. Most adverse effects were mild and low grade, with the most severe being one grade 3 symptomatic hypocalcemia requiring hospitalization and early treatment termination. Calcitonin treatment seems effective and tolerable in treating actively progressing cherubism in children. However, further research is required to better understand the pharmacological treatment of cherubism, including also other drugs, dosing, and protocols. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Willem H Schreuder
- Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Centers Location AMC and Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
- Department of Head and Neck Surgery and Oncology, Antoni van Leeuwenhoek, Netherlands Cancer Center, Amsterdam, the Netherlands
| | - Ethan B Meijer
- Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Centers Location AMC and Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
| | - Arjen H G Cleven
- Department of Pathology, University Medical Center Groningen, Groningen, the Netherlands
| | - Esther Edelenbos
- Department of Pediatric Oncology, Amsterdam University Medical Centers Location AMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Cornelis Klop
- Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Centers Location AMC and Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
| | - Ruud Schreurs
- Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Centers Location AMC and Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
| | - Renate T de Jong
- Department of Internal Medicine, Endocrine section, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, the Netherlands
| | - Merel C van Maarle
- Department of Clinical Genetics, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands
| | - Roy B G Horsthuis
- Department of Oral and Maxillofacial Surgery, Ziekenhuisgroep Twente, Almelo and Medisch Spectrum Twente, Enschede, the Netherlands
| | - Jan de Lange
- Department of Oral and Maxillofacial Surgery, Amsterdam University Medical Centers Location AMC and Academic Center for Dentistry Amsterdam, University of Amsterdam, Amsterdam, the Netherlands
| | - Henk van den Berg
- Department of Pediatric Oncology, Amsterdam University Medical Centers Location AMC, University of Amsterdam, Amsterdam, the Netherlands
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21
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Kim HY, Shim JH, Heo CY. A Rare Skeletal Disorder, Fibrous Dysplasia: A Review of Its Pathogenesis and Therapeutic Prospects. Int J Mol Sci 2023; 24:15591. [PMID: 37958575 PMCID: PMC10650015 DOI: 10.3390/ijms242115591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Revised: 10/16/2023] [Accepted: 10/23/2023] [Indexed: 11/15/2023] Open
Abstract
Fibrous dysplasia (FD) is a rare, non-hereditary skeletal disorder characterized by its chronic course of non-neoplastic fibrous tissue buildup in place of healthy bone. A myriad of factors have been associated with its onset and progression. Perturbation of cell-cell signaling networks and response outputs leading to disrupted building blocks, incoherent multi-level organization, and loss of rigid structural motifs in mineralized tissues are factors that have been identified to participate in FD induction. In more recent years, novel insights into the unique biology of FD are transforming our understandings of its pathology, natural discourse of the disease, and treatment prospects. Herein, we built upon existing knowledge with recent findings to review clinical, etiologic, and histological features of FD and discussed known and potential mechanisms underlying FD manifestations. Subsequently, we ended on a note of optimism by highlighting emerging therapeutic approaches aimed at either halting or ameliorating disease progression.
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Affiliation(s)
- Ha-Young Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
| | - Jung-Hee Shim
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea;
- Department of Research Administration Team, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea
| | - Chan-Yeong Heo
- Interdisciplinary Program in Bioengineering, Seoul National University, Seoul 08826, Republic of Korea;
- Department of Plastic and Reconstructive Surgery, College of Medicine, Seoul National University, Seoul 03080, Republic of Korea
- Department of Plastic and Reconstructive Surgery, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea;
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22
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Pan KS, Taylor J, Szymczuk V, Boyce AM. Lesion Expansion in Gnathic Fibrous Dysplasia: Natural History, Indicators of Progression, and Response to Bisphosphonates. J Bone Miner Res 2023; 38:1465-1471. [PMID: 37477421 PMCID: PMC11063912 DOI: 10.1002/jbmr.4886] [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: 05/22/2023] [Revised: 06/27/2023] [Accepted: 07/15/2023] [Indexed: 07/22/2023]
Abstract
Fibrous dysplasia (FD) is characterized by expansile fibro-osseous lesions that may occur in association with endocrinopathies as part of McCune-Albright syndrome (MAS). Craniofacial FD is a significant source of morbidity and most commonly involves the gnathic bones. There is a critical need to understand the natural history and risk factors for gnathic FD progression to develop preventative trials and identify candidates for intervention. The purpose of this study was to characterize gnathic FD lesion expansion and to identify risk factors associated with lesion growth. Patients with gnathic FD and serial CT imaging were evaluated. Volumetric analyses of CT scans were performed using MIM Encore software. Generalized mixed model analysis was used to account for intra-subject correlation, with FD lesion volume as the dependent variable. In addition to age, effects of MAS-associated endocrinopathies, sex, disease severity, and bisphosphonate treatment were evaluated. A total of 104 total lesions in 52 patients were characterized longitudinally. Median age at initial scan was 8.8 years (range 3.4-18.8), and median age at final scan was 16.8 years (range 6.9-33.4 years). The median number of scans per subject was 4 (range 2-14). FD lesion volume increased with age (2.50 cm3 /yr, 95% confidence interval [CI] 1.95-3.04, p < 0.001). However, lesion expansion rate decreased over time (-0.05 cm3 /yr, 95% CI -0.07 to 0.04, p < 0.001). Mandibular lesions tended to expand at a greater rate than maxillary lesions (p < 0.001). Growth hormone excess was associated with accelerated expansion rate (p = 0.002). Other MAS-associated endocrinopathies, pubertal status, sex, weight, lesion density, disease severity, and bisphosphonate treatment were not associated with lesion volume or expansion. Gnathic FD lesion expansion is most rapid in younger children and declines as patients approach adulthood. The availability of quantitative natural history data will guide clinicians in identifying patients who are candidates for medical and surgical interventions and clinical trials for preventative therapies. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.
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Affiliation(s)
- Kristen S Pan
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
- Department of Plastic and Reconstructive Surgery, The Johns Hopkins Medical Institutions, Baltimore, MD, USA
| | - Jocelyn Taylor
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Vivian Szymczuk
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
- Pediatric Endocrinology Inter-Institute Training Program, National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, USA
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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23
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Tater J, Diajil AR. Immunohistochemical analysis of osteoclastic and osteoblastic activity in ossifying fibroma and juvenile ossifying fibroma: A comparative study. J Med Life 2023; 16:1369-1374. [PMID: 38107708 PMCID: PMC10719798 DOI: 10.25122/jml-2023-0126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 05/15/2023] [Indexed: 12/19/2023] Open
Abstract
Cemento-ossifying fibroma (COF) and juvenile ossifying fibroma (JOF) have been considered distinct entities within the category of fibro-osseous lesions. This study aimed to assess osteoblast and osteoclast activity in COF and JOF by investigating bone resorption markers, specifically receptor activator of nuclear factor-kB (RANK), RANK ligand (RANKL), and its inhibitor osteoprotegerin (OPG). A comparative analysis of these markers was performed on all lesions. Immunohistochemistry was employed to evaluate and quantify the expression of these biomarkers in a sample of 20 cases of cemento-ossifying fibroma (COF), 15 cases of psammomatoid juvenile ossifying fibroma (PsJOF), and 10 cases of trabecular juvenile ossifying fibroma (TrJOF). The expression of osteoprotegerin was significantly higher in cemento-ossifying fibroma (33.9±13.0) compared to trabecular juvenile ossifying fibroma (27.3±9.2) and psammatoid ossifying fibroma (25.2±14.9), with the COF showing the highest expression followed by the latter two (p=0.037). There was a higher percentage (80%) of stromal fibroblast cells that showed positive expression of RANKL in cemento-ossifying fibroma (COF) compared to psammomatoid juvenile ossifying fibroma (PsJOF) (33.3%) and trabecular juvenile ossifying fibroma (TrJOF) (30.0%) when considering a positive expression score of 3 (p=0.024). Cemento-ossifying fibroma demonstrated the highest expression of osteoprotegerin and RANKL-positive stromal fibroblast cells, followed by psammomatoid juvenile ossifying fibroma and trabecular juvenile ossifying fibroma. These findings provide valuable insights into the pathogenesis of these lesions.
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Affiliation(s)
- Jawaher Tater
- Department of Oral and Maxillofacial Pathology, College of Dentistry, University of Baghdad, Baghdad, Iraq
| | - Ameena Ryhan Diajil
- Department of Oral Medicine, College of Dentistry, University of Baghdad, Baghdad, Iraq
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24
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Trojani MC, Gensburger D, Bagouet F, Cortet B, Couture G, Marcelli C, Mehsen Cetre N, Breuil V, Chapurlat R. Denosumab use in bone fibrous dysplasia refractory to bisphosphonate: A retrospective multicentric study. Bone 2023; 174:116819. [PMID: 37301527 DOI: 10.1016/j.bone.2023.116819] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2022] [Revised: 05/29/2023] [Accepted: 06/06/2023] [Indexed: 06/12/2023]
Abstract
INTRODUCTION Increased RANKL expression is observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS). In one animal model of FD/MAS, the inhibition of RANKL reduced tumor volume. A beneficial effect of denosumab on pain in patients refractory to bisphosphonates has been reported, but without systematic quantification of pain improvement. This work describes the clinical experience of our group on the efficacy on pain of denosumab treatment, along with safety, in FD/MAS patients refractory to bisphosphonates. MATERIALS AND METHODS We have conducted a retrospective multicenter study in 6 academic rheumatology centers in France. We have collected patients and FD/MAS characteristics, duration of prior exposure to bisphosphonates, denosumab treatment modalities (dosage - administration regimen - number of courses); evolution of pain evaluated by Visual Analogic Scale (VAS). RESULTS 13 patients were included (10 women and 3 men) 45 years on average, 5 MAS, 4 monostotic and 4 polyostotic forms. The average duration post-diagnosis of FD/MAS was 25 years and the mean duration of prior exposure to bisphosphonates was 4.7 years. Pain could be analyzed in 7 patients, showing a significant improvement from a mean VAS of 7.8 to 2.9 (-4.9 points, p = 0.003). In one patient with fronto-orbital FD/MAS, a 30 % decrease in lesional volume, assessed by MRI, was observed within 6 months of treatment, that was sustained over the following 12 months. Treatment regimens were heterogeneous. No hypercalcemia was observed after treatment cessation and the clinical tolerance was good. DISCUSSION This study suggests that denosumab reduces pain in patients with DF/MAS refractory to bisphosphonates, and quantifies this improvement for the first time in a multicenter study. In our cohort, no patients who discontinued denosumab developed hypercalcemia and clinical tolerance was overall good. This study also provides encouraging data regarding lesion volume control. Further controlled studies are required to determine the place and modalities of the denosumab treatment of FD/MAS. CONCLUSION Denosumab significantly decreased pain in FD/MAS refractory to bisphosphonate. This study paves the way for a randomized clinical trial to validate and standardize the prescription of denosumab in FD/MAS.
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Affiliation(s)
- M C Trojani
- Department of Rheumatology, Nice University Hospital, Nice, France; Faculté de Médecine Nice, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, Université Côte d'Azur, CEDEX 2, 06107 Nice, France.
| | - D Gensburger
- INSERM UMR_S 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex O3, France
| | - F Bagouet
- INSERM UMR_S 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex O3, France
| | - B Cortet
- Department of Rheumatology, Lille University Hospital and ULR 4490, 59000 Lille, France
| | - G Couture
- Department of Rheumatology, Toulouse University Hospital and University Toulouse III, Toulouse, France
| | - C Marcelli
- Department of Rheumatology, Caen University Hospital, Caen, France
| | - N Mehsen Cetre
- Department of Rheumatology, Bordeaux University Hospital, Bordeaux, France
| | - V Breuil
- Department of Rheumatology, Nice University Hospital, Nice, France; Faculté de Médecine Nice, UMR E-4320 TIRO-MATOs CEA/DRF/Institut Joliot, Université Côte d'Azur, CEDEX 2, 06107 Nice, France
| | - R Chapurlat
- INSERM UMR_S 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex O3, France
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25
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Obermeier KT, Hartung JT, Hildebrandt T, Dewenter I, Smolka W, Hesse E, Fegg F, Otto S, Malenova Y, Abdullah A. Fibrous Dysplasia of the Jaw: Advances in Imaging and Treatment. J Clin Med 2023; 12:4100. [PMID: 37373793 DOI: 10.3390/jcm12124100] [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: 05/17/2023] [Revised: 06/12/2023] [Accepted: 06/15/2023] [Indexed: 06/29/2023] Open
Abstract
A total of 7% of all benign bone lesions are diagnosed as fibrous dysplasia (FD). The symptoms of FD of the jaw range from asymptomatic to dental anomalies, pain and facial asymmetry. Due to its resemblance to other fibro-osseous bone lesions, misdiagnosis often occurs and can lead to inadequate treatment. Particularly in the jaw, this lesion does not become quiescent during puberty, making fundamental knowledge about the diagnosis and treatment of FD crucial. Mutational analysis and nonsurgical approaches offer new diagnostic and therapeutic options. In this review, we examine the advances and the difficulties of the diagnosis and the various treatment modalities of FD of the jaw in order to capture the current scientific knowledge on this bone disease.
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Affiliation(s)
- Katharina Theresa Obermeier
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Jens Tobias Hartung
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Tim Hildebrandt
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Ina Dewenter
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Wenko Smolka
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Eric Hesse
- Institute of Musculoskeletal Medicine, University Hospital, LMU Munich, Fraunhoferstraße 20, 82152 Munich, Germany
- Musculoskeletal University Center Munich, University Hospital, LMU Munich, Fraunhoferstraße 20, 82152 Munich, Germany
| | - Florian Fegg
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Sven Otto
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Yoana Malenova
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
| | - Anusha Abdullah
- Department of Oral and Maxillofacial Surgery and Facial Plastic Surgery, Ludwig Maximilians University, 80337 Munich, Germany
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26
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Aslan SG, Tezel K, Ordu-Gökkaya NK. Fibrous dysplasia and McCune-Albright syndrome: A case report with review of literature on the rehabilitation approach. Turk J Phys Med Rehabil 2023; 69:252-256. [PMID: 37671385 PMCID: PMC10475905 DOI: 10.5606/tftrd.2023.8815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Accepted: 11/02/2021] [Indexed: 09/07/2023] Open
Abstract
McCune-Albright syndrome is classically defined by the clinical triad of fibrous dysplasia (FD) of the bone, café-au-lait macules, and endocrinopathies. We report the case of a 15-year-old male with a diagnosed with McCune Albright syndrome. McCune-Albright syndrome remains a diagnostic challenge, and delayed diagnosis may have significant consequences. Routine musculoskeletal screening along with other endocrinopathies should be kept in mind. The rehabilitation programs that provides significant improvement in their quality of life. The treatment of McCune-Albright syndrome is directed toward the specific symptoms that are apparent in each individual.
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Affiliation(s)
- Sefa Gümrük Aslan
- Department of Physical Medicine and Rehabilitation, University of Health Sciences Gülhane School of Medicine, Gaziler Physical Medicine and Rehabilitation Health Application and Research Center, Ankara, Türkiye
| | - Kutay Tezel
- Department of Physical Medicine and Rehabilitation, University of Health Sciences Gülhane School of Medicine, Gaziler Physical Medicine and Rehabilitation Health Application and Research Center, Ankara, Türkiye
| | - N. Kutay Ordu-Gökkaya
- Department of Physical Medicine and Rehabilitation, Ankara City Hospital, Ankara, Türkiye
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27
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Szymczuk V, Taylor J, Boyce AM. Craniofacial Fibrous Dysplasia: Clinical and Therapeutic Implications. Curr Osteoporos Rep 2023; 21:147-153. [PMID: 36849642 PMCID: PMC11087144 DOI: 10.1007/s11914-023-00779-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/13/2023] [Indexed: 03/01/2023]
Abstract
PURPOSE OF REVIEW This study aims to review diagnosis, potential complications, and clinical management in craniofacial fibrous dysplasia. RECENT FINDINGS Fibrous dysplasia (FD) is a rare mosaic disorder in which normal bone and marrow are replaced with expansile fibro-osseous lesions. Disease presents along a broad spectrum and may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). The craniofacial skeleton is one of the most commonly impacted areas in FD, and its functional and anatomical complexities create unique challenges for diagnosis and management. This review summarizes current approaches to diagnosis and management in FD/MAS, with emphasis on the clinical and therapeutic implications for the craniofacial skeleton.
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Affiliation(s)
- Vivian Szymczuk
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
- Pediatric Endocrinology Inter-Institute Training Program, National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, USA
| | - Jocelyn Taylor
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
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28
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de Castro LF, Michel Z, Pan K, Taylor J, Szymczuk V, Paravastu S, Saboury B, Papadakis GZ, Li X, Milligan K, Boyce B, Paul SM, Collins MT, Boyce AM. Safety and Efficacy of Denosumab for Fibrous Dysplasia of Bone. N Engl J Med 2023; 388:766-768. [PMID: 36812441 PMCID: PMC10015375 DOI: 10.1056/nejmc2214862] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/24/2023]
Affiliation(s)
| | | | | | | | | | | | | | | | - Xiaobai Li
- National Institutes of Health, Bethesda, MD
| | | | - Brendan Boyce
- University of Rochester Medical Center, Rochester, NY
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29
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Vanderniet JA, Tsinas D, Wall CL, Girgis CM, London K, Keane C, Briody J, Hibbert S, Poon M, Padhye B, Biggin A, Dalla-Pozza L, Gray RJ, Munns CF. Surgical Management and Denosumab for Aneurysmal Bone Cysts of the Spine in an Australian Tertiary Paediatric Centre. Calcif Tissue Int 2023; 112:592-602. [PMID: 36810677 DOI: 10.1007/s00223-023-01068-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Accepted: 01/30/2023] [Indexed: 02/23/2023]
Abstract
Aneurysmal bone cysts (ABC) are rare osteolytic, benign but often locally aggressive tumours of the long bones or vertebrae. For spinal ABC, surgical management, embolisation or sclerotherapy alone often carry high morbidity and/or high recurrence rates. Interruption of receptor activator of nuclear factor-kappa B ligand (RANKL) signalling holds promise as an effective therapeutic strategy for these tumours. We aimed to review the approach to surgical management and evaluate the efficacy and safety of denosumab for ABC of the spine in children. Retrospective review of 7 patients treated with denosumab using a standardised protocol for ABC of the spine in a tertiary paediatric centre. Surgical intervention was only conducted if there was spinal instability or significant neurological impairment. Denosumab 70 mg/m2 was given 4-weekly for at least 6 months, followed by 2 doses of zoledronate 0.025 mg/kg, aiming to prevent rebound hypercalcaemia. All patients achieved stability of the spine and resolution of neurological impairment, if present. Six patients achieved metabolic remission and have ceased denosumab without recurrence to date; the other showed clinical and radiological improvement without complete metabolic remission. Three patients developed symptomatic hypercalcaemia 5-7 months after cessation of denosumab, requiring additional bisphosphonate treatment. We present our algorithm for the surgical and medical management of paediatric spinal ABC. Denosumab produced a radiological and metabolic response in all patients, with complete remission in most. Follow-up time was not long enough to evaluate the endurance of response after cessation in some patients. Incidence of rebound hypercalcaemia in this paediatric cohort was high, prompting a change to our protocol.
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Affiliation(s)
- Joel A Vanderniet
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia.
| | - Dionysios Tsinas
- Department of Orthopaedics, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Christie-Lee Wall
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia
| | - Christian M Girgis
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Department of Endocrinology, Royal North Shore Hospital, Sydney, NSW, Australia
- Department of Diabetes and Endocrinology, Westmead Hospital, Sydney, NSW, Australia
| | - Kevin London
- Department of Nuclear Medicine, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Corinne Keane
- Department of Orthopaedics, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Julie Briody
- Department of Nuclear Medicine, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Sally Hibbert
- Department of Dentistry, The Children's Hospital at Westmead, Sydney, NSW, Australia
- Department of Paediatric Dentistry, Westmead Centre for Oral Health, Sydney, NSW, Australia
| | - Myra Poon
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia
| | - Bhavna Padhye
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Cancer Centre for Children, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Andrew Biggin
- Institute of Endocrinology and Diabetes, The Children's Hospital at Westmead, Locked Bag 4001, Westmead, Sydney, NSW, 2145, Australia
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
| | - Luciano Dalla-Pozza
- Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia
- Cancer Centre for Children, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Randolph J Gray
- Department of Orthopaedics, The Children's Hospital at Westmead, Sydney, NSW, Australia
| | - Craig F Munns
- Child Health Research Centre, The University of Queensland, Brisbane, QLD, Australia
- Mayne Academy of Paediatrics, The University of Queensland, Brisbane, QLD, Australia
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30
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Hung C, Shibli-Rahhal A. Denosumab Use in Adults With Fibrous Dysplasia: Case Reports and Review of the Literature. Endocr Pract 2022; 28:1196-1201. [PMID: 35952985 DOI: 10.1016/j.eprac.2022.07.012] [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: 05/22/2022] [Revised: 07/20/2022] [Accepted: 07/25/2022] [Indexed: 11/03/2022]
Abstract
OBJECTIVE In fibrous dysplasia (FD) of the bone, a gain-of-function mutation in the G-nucleotide binding protein alpha subunit results in constitutively active cyclic adenosine monophosphate. Downstream effects include formation of disorganized cortex and bone marrow fibrosis. Patients with FD experience bone pain and are at risk of fracture. Bisphosphonates are traditionally used to manage pain with mixed results. We sought to report denosumab use in patients with FD at our institution and summarized the existing literature on denosumab use in FD. METHODS We retrospectively identified patients with FD who were treated with denosumab at our institution, describing patient characteristics and outcomes. We reviewed the existing literature on denosumab use in patients with FD. RESULTS Patient 1 was diagnosed with FD at the age of 17 years and took bisphosphonates with initial improvement in pain. Pain eventually worsened; therefore, she received 4 doses of denosumab. Patient 2 was diagnosed with FD after a fall and was treated with bisphosphonates, reporting some initial improvement in bone pain. A few years later, the pain recurred, and he received 3 doses of denosumab. Both patients tolerated denosumab well but experienced no improvement in pain. On literature review, although some serious side effects were noted, patients experienced a decline in bone turnover markers, and most reported improvement in bone pain with denosumab. CONCLUSION Denosumab is a promising therapy for managing symptoms of FD. Further studies are needed to determine the optimal dose and duration of treatment. Its long-term effect on FD lesions remains unclear.
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Affiliation(s)
- Chermaine Hung
- Department of Internal Medicine, University of Iowa, Iowa City, Iowa
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31
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Szymczuk V, Taylor J, Michel Z, Sinaii N, Boyce AM. Skeletal Disease Acquisition in Fibrous Dysplasia: Natural History and Indicators of Lesion Progression in Children. J Bone Miner Res 2022; 37:1473-1478. [PMID: 35695414 DOI: 10.1002/jbmr.4618] [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: 03/15/2022] [Revised: 05/20/2022] [Accepted: 06/04/2022] [Indexed: 11/11/2022]
Abstract
Fibrous dysplasia (FD) is a rare mosaic disorder resulting in fractures, pain, and disability. Bone lesions appear during childhood and expand during skeletal growth. The rate at which FD lesions progress and the biochemical determinants of FD lesion formation have not been established, making it difficult to investigate and implement preventative therapies. The purpose of this study was to characterize FD lesion progression in children, and to identify clinical variables associated with progressive disease. Clinical data and imaging from an ongoing natural history study at the National Institutes of Health (NIH) were reviewed. 99m-Technetium methylene diphosphonate (99Tc-MDP) scans were used to determine Skeletal Burden Score (SBS), a validated quantitative scoring system. FD progression rate was determined by the change in the SBS in each patient per year. Thirty-one children had serial 99Tc-MDP scans, with a median age at first scan of 6 years (interquartile range [IQR] 4-8, range 2-10), and median follow-up 1.1 years (IQR 1.1-2.1, range 0.7-11.2). The median FD progression rate for the total group was 2.12 SBS units/year (IQR 0.81-2.94, range 0.05-7.81). FD progression rates were highest in children under age 8 years and declined with age (p = 0.03). Baseline disease severity was associated with subsequent disease progression (p = 0.009), with the highest FD progression rates in patients with moderate disease (baseline SBS 16-30), and lowest progression rates in those with severe disease (SBS ≥50). Serum levels of the bone formation marker osteocalcin were positively correlated with subsequent FD progression rate (p = 0.01, R = 0.58). There was no association between FD progression and baseline endocrinopathies, fractures, or surgery rates. FD lesions progress during childhood, particularly in younger children and those with moderate involvement. Osteocalcin may potentially serve as a biomarker for progressive disease. These findings may allow clinicians to investigate preventative therapies, and to identify children with FD who are candidates for early interventions. Published 2022. This article is a U.S. Government work and is in the public domain in the USA.
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Affiliation(s)
- Vivian Szymczuk
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.,Pediatric Endocrinology Inter-Institute Training Program, National Institute of Child Health and Development, National Institutes of Health, Bethesda, MD, USA
| | - Jocelyn Taylor
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Zachary Michel
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Ninet Sinaii
- Biostatistics and Clinical Epidemiology Service, Clinical Center, National Institutes of Health, Bethesda, MD, USA
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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32
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Wang R, Renouf DA. Rebound hypercalcemia post-denosumab cessation in metastatic breast cancer. Osteoporos Int 2022; 33:1625-1629. [PMID: 35286436 DOI: 10.1007/s00198-022-06369-z] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/02/2022] [Indexed: 11/25/2022]
Abstract
Denosumab delays and prevents skeletal related events in patients with malignancy-related bony metastases. Rarely, denosumab discontinuation can lead to rebound hypercalcemia in the setting of increased bone resorption. We describe the case of a 49-year-old breast cancer survivor who developed rebound hypercalcemia after cessation of long-term denosumab. She had been treated with 42 doses of denosumab between August 2013 and March 2020 and 8 months after her last dose of denosumab developed symptomatic hypercalcemia. Parathyroid hormone levels were suppressed, and active malignancy was excluded based on biochemical and radiological testing. She required treatment with intravenous bisphosphonates on three separate occasions in order to achieve long-term normalization of her hypercalcemia. Rebound hypercalcemia post-denosumab cessation is a rare but serious complication that clinicians should be aware of.
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Affiliation(s)
- R Wang
- Department of Diabetes and Endocrinology, Peninsula Health, 2 Hastings Road, Frankston, VIC, 3199, Australia.
| | - D A Renouf
- Department of Diabetes and Endocrinology, Peninsula Health, 2 Hastings Road, Frankston, VIC, 3199, Australia
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33
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Spencer TL, Watts L, Soni A, Pinedo-Villanueva R, Heegaard AM, Boyce AM, Javaid MK. Neuropathic-like Pain in Fibrous Dysplasia/McCune-Albright Syndrome. J Clin Endocrinol Metab 2022; 107:e2258-e2266. [PMID: 35262711 PMCID: PMC9113795 DOI: 10.1210/clinem/dgac120] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Pain is a major symptom in adults with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) and response to current treatments, including bisphosphonates and standard analgesics (nonsteroidal anti-inflammatory drugs and opiates) is unpredictable. No studies have explored whether the type of pain is variable in this patient group. OBJECTIVE To determine the frequency of neuropathic-like pain in patients with FD/MAS. DESIGN Retrospective, dual registry study. SETTING Community. PATIENTS FD/MAS online registries: the US-based Familial Dysautonomia Foundation (FDF) and the UK-based Rare and Undiagnosed Diseases (RUDY) study. INTERVENTION Subjects completed questionnaires to evaluate the presence of features of neuropathic-like pain (painDETECT) and the impact on sleep quality (Pittsburgh Sleep Quality Index) and mental health (Hospital Anxiety and Depression Scale). Descriptive statistics were used to characterize the prevalence and associated burden of neuropathic-like pain. MAIN OUTCOME MEASURES Incidence of neuropathic, nociceptive, and unclear pain. RESULTS Of 249 participants, one third experienced neuropathic-like pain. This group had statistically significantly (P < 0.001) worse mental well-being and sleep in comparison to those with predominately nociceptive pain. CONCLUSIONS Neuropathic-like pain is common in patients with FD/MAS and associated with worse quality of life. Evaluation of pain in patients with FD/MAS should include assessment of neuropathic-like pain to guide personalized approaches to treatment and inform future research.
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Affiliation(s)
- Tiahna L Spencer
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Laura Watts
- Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Campus, Du Cane Road, London, UK
| | - Anushka Soni
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Rafael Pinedo-Villanueva
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
| | - Anne-Marie Heegaard
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - M Kassim Javaid
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK
- Correspondence: Muhammad K. Javaid, PhD, Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, OX4 2UH, UK.
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34
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Chapurlat R, Gensburger D, Trolliet C, Rouanet S, Mehsen-Cetre N, Orcel P. Inhibition of IL-6 in the treatment of fibrous dysplasia of bone: The randomized double-blind placebo-controlled TOCIDYS trial. Bone 2022; 157:116343. [PMID: 35104665 DOI: 10.1016/j.bone.2022.116343] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2021] [Revised: 01/07/2022] [Accepted: 01/25/2022] [Indexed: 01/01/2023]
Abstract
Increased interleukin-6 (IL-6) has been observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS) and is possibly involved in the increased bone destruction and bone pain characterizing this disease. The TOCIDYS trial was a randomized, placebo-controlled, 1 year, cross-over, proof-of-concept trial, conducted in patients not responding to bisphosphonates, using monthly intra-venous tocilizumab (a monoclonal antibody to the IL-6 receptor) at 8 mg/kg or a matching placebo for 6 months. Over the following 6 months, they received tocilizumab if they first had placebo, and vice-versa. We measured change in serum CTX after 6 months of treatment, compared with baseline (primary endpoint). Other endpoints were the change in bone pain, change in P1NP, bone alkaline phosphatase, osteocalcin and ICTP, and variation of quality of life. The analysis relied on ANOVA, with sequence of treatment, period and treatment as factors and accounting for a potential carry-over effect. We have randomized 8 patients with FD/MAS in each sequence who all completed the first 6 months treatment period. During the second 6 months period, 3 patients stopped therapy, so the efficacy analysis set included 13 patients. We observed no significant change in serum CTX and other biochemical markers of bone turnover between the tocilizumab and placebo groups. There was no significant change in the level of bone pain on tocilizumab, although 3 patients had a sharp decrease in pain while on active drug, with progressive relapse on placebo for 2 of them, but with some degree of improvement in a few patients while on placebo. The SF-36 quality of life scale was not significantly changed. We conclude that tocilizumab does not decrease bone turnover in FD/MAS when administered in patients who fail to respond to bisphosphonates. Tocilizumab does not reduce bone pain in most patients, but a substantial effect in a subset cannot be ruled out in this trial powered for markers but not for pain.
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Affiliation(s)
- Roland Chapurlat
- INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France.
| | - Deborah Gensburger
- INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France
| | - Cédric Trolliet
- INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France
| | - Stéphanie Rouanet
- INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France
| | - Nadia Mehsen-Cetre
- INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France
| | - Philippe Orcel
- INSERM UMR 1033, Université Claude Bernard-Lyon 1, Hôpital E Herriot, 69437 Lyon cedex 03, France
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35
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Drug Treatment of Low Bone Mass and Other Bone Conditions in Pediatric Patients. Paediatr Drugs 2022; 24:103-119. [PMID: 35013997 DOI: 10.1007/s40272-021-00487-7] [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] [Accepted: 12/01/2021] [Indexed: 10/19/2022]
Abstract
Osteoporosis may affect young individuals, albeit infrequently. In childhood, bone mass increases, reaching its peak between the second and third decades; then, after a period of stability, it gradually declines. Several conditions, including genetic disorders, chronic diseases, and some medications, can have an impact on bone homeostasis. Diagnosis in young patients is based on the criteria defined by the International Society for Clinical Densitometry (ISCD), published in 2013. High risk factors should be identified and monitored. Often simple interventions aimed to eliminate the underlying cause, to minimize the negative bone effects linked to drugs, or to increase calcium and vitamin D intake can protect bone mass. However, in selected cases, pharmacological treatment should be considered. Bisphosphonates remain the main therapeutic agent for children with significant skeletal fragility and are also useful in a large number of other bone conditions. Denosumab, an anti-RANKL antibody, could become a potential alternative treatment. Clinical trials to evaluate the long-term effects and safety of denosumab in children are ongoing.
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36
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Liu Z, Yin Y, Wang Z, Xie L, Deng P, Wang D, Ji N, Zhao H, Han X, Chen Q, Chung CH, Bai D, Zhao X. RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia. Bone 2022; 156:116301. [PMID: 34952228 DOI: 10.1016/j.bone.2021.116301] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2021] [Revised: 11/07/2021] [Accepted: 12/13/2021] [Indexed: 02/08/2023]
Abstract
Fibrous dysplasia (FD) is a rare bone disease caused by GNAS mutation in skeletal stem cells, typically originating from and worsening in childhood. Till now, no cure for FD exists despite the well-recognized etiology. Studies have demonstrated that osteoclastogenesis hyperactivity is caused by elevated RANKL expression, making RANKL inhibition a potential therapy. Although a human monoclonal anti-RANKL antibody, denosumab, has been used in FD patients, the effects and mechanisms of RANKL inhibition for FD treatment require assessment. Denosumab is expensive and can only be injected. Therefore, formulating an oral-administered, cost-effective medicine is encouraged. In the current study, we evaluated the effects of a small-molecule RANKL inhibitor, AS2676293, on a transgenic FD mouse model. AS2676293 effectively suppressed osteoclastogenesis and halted FD progression. The pre-existing bone defects were primarily replaced by newly formed mineralized bone after two weeks of AS2676293 administration. The potent RANKL inhibitory effect and easier route of delivery make AS2676293 a promising target therapy of FD. Results from our study suggested that RANKL inhibition is effective in halting FD progression and promoting bone remineralization, which could benefit the patients with early onset of FD.
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Affiliation(s)
- Zhongyu Liu
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Yijia Yin
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Zheng Wang
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Liang Xie
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Peng Deng
- Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, School of Dentistry, UCLA, Los Angeles, CA 90095, USA
| | - Donghui Wang
- School of Materials Science and Engineering, Hebei University of Technology, Tianjin 300130, China
| | - Ning Ji
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Hang Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Xianglong Han
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Qianming Chen
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China
| | - Chun-Hsi Chung
- Department of Orthodontics, School of Dental Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Ding Bai
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
| | - Xuefeng Zhao
- State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, China.
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37
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Geels RES, Meier ME, Saikali A, Tsonaka R, Appelman-Dijkstra NM, Boyce AM. Long Bone Fractures in Fibrous Dysplasia/McCune-Albright Syndrome: Prevalence, Natural History, and Risk Factors. J Bone Miner Res 2022; 37:236-243. [PMID: 34668234 PMCID: PMC9548190 DOI: 10.1002/jbmr.4463] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 02/03/2023]
Abstract
Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare bone and endocrine disorder arising along a broad spectrum. Long-bone fractures are a common, painful, and potentially disabling complication. However, fracture prevalence and risk factors have not been well-established, making it difficult to predict which patients are at risk for a severe course. Clinical and imaging data were reviewed from two large, well-phenotyped cohorts (National Institutes of Health [NIH] in the United States and the Leiden University Medical Center [LUMC] in the Netherlands) to identify long-bone fractures at FD sites. Skeletal burden score was quantified using bone scintigraphy. Multiple linear regressions were performed to identify clinical associations with fractures. A total of 419 patients were included (186 NIH, 233 LUMC); 194 (46%) had MAS endocrinopathies. Median age at last follow-up was 30.2 years (range 3.2-84.6, interquartile range [IQR] 25.5), and median skeletal burden score was 16.6 (range 0-75, IQR 33). A total of 48 (59%) patients suffered one or more lifetime fracture (median 1, range 0-70, IQR 4). Median age at first fracture was 8 years (range 1-76, IQR 10). Fracture rates peaked between 6 and 10 years of age and decreased thereafter. Lifetime fracture rate was associated with skeletal burden score (β = 0.40, p < 0.01) and MAS hyperthyroidism (β = 0.22, p = 0.01). Younger age at first fracture was associated with skeletal burden score (β = -0.26, p = 0.01) and male sex (β = -0.23, p = 0.01). Both skeletal burden score >25 and age at first fracture ≤7 years were associated with a higher total number of lifetime fractures (median 4, range 1-70, IQR 5 versus median 1, range 1-13, IQR 1) (p < 0.01). In conclusion, higher skeletal burden score and MAS hyperthyroidism are associated with long-bone fractures in FD/MAS. Both skeletal burden score ≥25 and age at first fracture ≤7 years are associated with a higher lifetime long-bone fracture risk and may predict a more severe clinical course. These results may allow clinicians to identify FD/MAS patients at risk for severe disease who may be candidates for early therapeutic interventions. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
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Affiliation(s)
- Raya E S Geels
- Department of Medicine, Division of Endocrinology, Centre for Bone Quality, Leiden University Medical Centre, Leiden, The Netherlands
| | - Maartje E Meier
- Department of Medicine, Division of Endocrinology, Centre for Bone Quality, Leiden University Medical Centre, Leiden, The Netherlands.,Department of Orthopedic Surgery, Leiden University Medical Centre, Leiden, The Netherlands
| | - Amanda Saikali
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Roula Tsonaka
- Department of Medical Statistics and Bioinformatics, Einthovenweg, Leiden University Medical Center, Leiden, The Netherlands
| | - Natasha M Appelman-Dijkstra
- Department of Medicine, Division of Endocrinology, Centre for Bone Quality, Leiden University Medical Centre, Leiden, The Netherlands
| | - Alison M Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
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38
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Hopkins C, de Castro LF, Corsi A, Boyce A, Collins MT, Riminucci M, Heegaard AM. Fibrous dysplasia animal models: A systematic review. Bone 2022; 155:116270. [PMID: 34875396 DOI: 10.1016/j.bone.2021.116270] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 11/22/2021] [Accepted: 11/25/2021] [Indexed: 12/09/2022]
Abstract
BACKGROUND Fibrous dysplasia (FD) is a rare genetic bone disorder resulting in an overproduction of cAMP leading to a structurally unsound tissue, caused by a genetic mutation in the guanine nucleotide-binding protein gene (GNAS). In order to better understand this disease, several animal models have been developed with different strategies and features. OBJECTIVE Conduct a systematic review to analyze and compare animal models with the causative mutation and features of FD. METHODS A PRISMA search was conducted in Scopus, PubMed, and Web of Science. Studies reporting an in vivo model of FD that expressed the causative mutation were included for analysis. Models without the causative mutation, but developed an FD phenotype and models of FD cell implantation were included for subanalysis. RESULTS Seven unique models were identified. The models were assessed and compared for their face validity, construct validity, mosaicism, and induction methods. This was based on the features of clinical FD that were reported within the categories of: macroscopic features, imaging, histology and histomorphometry, histochemical and cellular markers, and blood/urine markers. LIMITATIONS None of the models reported all features of FD and some features were only reported in one model. This made comparing models a challenge, but indicates areas where further research is necessary. CONCLUSION The benefits and disadvantages of every model were assessed from a practical and scientific standpoint. While all published reports lacked complete data, the models have nonetheless informed our understanding of FD and provided meaningful information to guide researchers in bench and clinical research.
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Affiliation(s)
- Chelsea Hopkins
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Luis Fernandez de Castro
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Alessandro Corsi
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Alison Boyce
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Michael T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - Mara Riminucci
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Anne-Marie Heegaard
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark.
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Abstract
INTRODUCTION Fibrous dysplasia (FD) is a rare bone disease that is associated with various endocrine conditions, such as McCune Albright syndrome. It manifests as abnormal osteolysis, multiple fractures, or deformities that are reported during disease course. The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) pathway is upregulated in FD and can be targeted with denosumab, a blocking monoclonal antibody. AREAS COVERED Preclinical and clinical data on the scientific rationale for using denosumab in FD and on the efficacy and safety of this therapy for this condition have been reviewed, in addition to other therapies. EXPERT OPINION Denosumab is a potential therapeutic agent against FD. A combined synergic approach involving theranostics might increase its therapeutic potential.
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Affiliation(s)
- Bogdan Huzum
- University of Medicine and Pharmacy Grigore T Popa, Iasi, Romania
| | - Sabina Antoniu
- Department of Medicine II-Nursing/Palliative Care, University of Medicine and Pharmacy Grigore T Popa, Iasi, Romania
| | - Raluca Dragomir
- Department of Anesthesiology and Oral Surgery, Faculty of Dental Medicine, University of Medicine and Pharmacy Grigore T Popa, Iasi, Romania
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40
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Ikuta K, Sakai T, Koike H, Ito K, Imagama S, Nishida Y. Successful treatment with denosumab for pelvic fibrous dysplasia: A case report and review of the literature. Medicine (Baltimore) 2021; 100:e28138. [PMID: 34889277 PMCID: PMC8663861 DOI: 10.1097/md.0000000000028138] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 11/17/2021] [Indexed: 12/16/2022] Open
Abstract
RATIONALE Fibrous dysplasia is a rare disorder that results in fractures, pain, and disability and can affect any bone in the body. The treatment of symptomatic fibrous dysplasia is determined based on the affected bones. Although some lesions are often too extensive for surgical procedures, there are currently no effective or recommended medical treatments available for them. PATIENT CONCERNS A 27-year-old woman developed right buttock pain and was diagnosed with a bone tumor in the right ilium. Clinical images revealed an expansive osteolytic lesion with thinning of the cortex and cystic change from the acetabulum to the sacroiliac joint. DIAGNOSIS An incisional biopsy was performed, and the lesion was diagnosed as cystic fibrous dysplasia. Occasional osteoclast-like giant cells and woven bone were observed. The patient had no evidence of polyostotic lesions or findings of McCune-Albright syndrome. Biochemical blood test results showed no obvious abnormal values, except for an increase in serum tartrate-resistant acid phosphatase 5b to 459 mU/dL. INTERVENTIONS Since surgical treatment appeared to be challenging, she was treated with denosumab with decreased dose-intensity schedules. OUTCOMES The administration of denosumab caused osteosclerosis within the lesion, resulting in the elimination of bone pain. The patient received denosumab treatment for 18 months. Pain relief and lesion radiodensity were maintained for 9 months after denosumab discontinuation. The serum level of tartrate-resistant acid phosphatase 5b was measured to monitor the response to denosumab, which was suppressed during denosumab treatment. LESSONS We described successful denosumab treatment in a patient with cystic fibrous dysplasia (FD) who maintained efficacy for 9 months after treatment. Although the use of denosumab in fibrous dysplasia is currently off-label, our experience with this patient supports the potential of denosumab therapy for patients for whom surgical treatment is challenging.
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Affiliation(s)
- Kunihiro Ikuta
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan
| | - Tomohisa Sakai
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan
| | - Hiroshi Koike
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan
| | - Kan Ito
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan
| | - Shiro Imagama
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan
| | - Yoshihiro Nishida
- Department of Orthopedic Surgery, Nagoya University Graduate School and School of Medicine, 65 Tsurumai, Showa, Nagoya, Japan
- Department of Rehabilitation, Nagoya University Hospital, 65 Tsurumai, Showa, Nagoya, Japan
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41
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Kaur H, Mohanty S, Kochhar GK, Iqbal S, Verma A, Bhasin R, Kochhar AS. Comprehensive management of malocclusion in maxillary fibrous dysplasia: A case report. World J Clin Cases 2021; 9:10671-10680. [PMID: 35005000 PMCID: PMC8686154 DOI: 10.12998/wjcc.v9.i34.10671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 07/14/2021] [Accepted: 10/20/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Fibrous dysplasia (FD) is a developmental hamartomatous bone disease characterized by a blend of fibrous and osseous entities. Though rarely malignant, the tumor can vary from being small and asymptomatic, to a fairly large sized lesion, progressing gradually, compromising occlusion and facial esthetics. Treatment approach depends on the stage of skeletal maturity. It primarily involves surgical management for stabilizing the disease process. Post-surgical comprehensive dental treatment is necessary for restoring form and function of the jaws and teeth. This article describes comprehensive orthodontic management of severe malocclusion in a surgically operated case of FD maxilla.
CASE SUMMARY A 19-year female presented with a chief complaint of excessive gingival display when smiling. Dental history included swelling of gums around the upper right front teeth, diagnosed at the age of 15 as FD of the right anterior maxillary segment and treated with surgical recontouring of the dysplastic bone. The clinical and radiological examinations showed adequate post-surgical healing. The surgically treated dysplastic area presented with right canting of the maxillary anterior occlusal plane. The maxillary teeth were torqued palatally, with the root of the right maxillary canine exposed clinically. We discuss sequential management of the associated malocclusion with comprehensive fixed orthodontics, along with special precautions taken to prevent reactivation of the quiescent and healed lesion.
CONCLUSION The adequate healing of fibro-dysplastic bone post-surgery must be allowed before initiating orthodontic tooth movement in the dysplastic bone. Periodic follow-ups are needed to monitor stability of occlusion and any relapse of the lesion.
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Affiliation(s)
- Harneet Kaur
- Department of Orthodontics and Dentofacial Orthopaedics, Faculty of Dentistry, Jamia Millia Islamia, Delhi 110025, Delhi, India
| | - Sujata Mohanty
- Department of Oral and Maxillofacial Surgery, Maulana Azad Institute of Dental Sciences, Delhi 110002, Delhi, India
| | - Gulsheen Kaur Kochhar
- Department of Pediatric and Preventive Dentistry, National Dental College and Hospital, Derabassi 140507, Punjab, India
| | - Shahid Iqbal
- Faculty of Dentistry, Jamia Millia Islamia, Delhi 110025, Delhi, India
| | - Anjali Verma
- Department of Oral and Maxillofacial Surgery, Maulana Azad Institute of Dental Sciences, Delhi 110002, Delhi, India
| | - Ritasha Bhasin
- Faculty of Dentistry, University of Toronto, Toronto M5G1G6, Ontario, Canada
| | - Anuraj Singh Kochhar
- Department of Orthodontics and Dentofacial Orthopaedics, Faculty of Dentistry, University of Toronto, Toronto M5G0C1, Ontario, Canada
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Hypercalcemia following discontinuation of denosumab therapy: A systematic review. Bone Rep 2021; 15:101148. [PMID: 34825020 PMCID: PMC8605220 DOI: 10.1016/j.bonr.2021.101148] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/02/2021] [Accepted: 11/07/2021] [Indexed: 01/19/2023] Open
Abstract
Denosumab is a monoclonal antibody that has been approved to treat osteoporosis, skeletal metastasis, and giant cell tumor of bone in skeletally mature patients. Due to its potential adverse effects on normal bone growth, its use has not yet been approved in skeletally immature patients; however, the use of this agent in such patients with overt or dysregulated bone resorptive conditions has been explored in recent years. While most studies have proven the effectiveness of denosumab in controlling the progression of various disorders in skeletally immature patients, they have also revealed that refractory hypercalcemia often follows the discontinuation of denosumab treatment, raising a concern over the use of this agent in these patients. Thus, this study was designed to better understand the pathology of this condition through a systematic review of the published literature. Our analysis suggests that this condition has a potential male predisposition, that there is a correlation between the duration of denosumab treatment and patient age, and that this condition often occurs within 3 months after the last administration of denosumab in skeletally immature patients but is significantly less likely in adults. These results may further underscore that high bone formation and bone turnover rates are critically associated with hypercalcemia after the discontinuation of denosumab. In contrast, given that not all skeletally immature patients develop hypercalcemia, it is probable that other unidentified factors are involved in the pathology of this condition.
Rebound hypercalcemia often follows denosumab cessation in juveniles. Although relatively rare, rebound hypercalcemia can occur in adults. Rebound hypercalcemia may have a male predisposition in juveniles. Treatment duration of denosumab required to trigger hypercalcemia correlates with age. Onset of hypercalcemia is significantly earlier in juveniles than in adults.
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Maximen J, Robin F, Tronchot A, Rossetti A, Ropars M, Guggenbuhl P. Denosumab in the management of Aneurysmal bone cyst. Joint Bone Spine 2021; 89:105260. [PMID: 34481945 DOI: 10.1016/j.jbspin.2021.105260] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Accepted: 08/24/2021] [Indexed: 11/19/2022]
Abstract
BACKGROUND Aneurysmal bone cyst (ABC) is a benign, locally aggressive tumour that arises predominantly in long bones and spine. Following the encouraging results of denosumab use in Giant Cell Tumors (GCT) and the histological similarities between ABC and GCT, the interest on the role of denosumab in the therapeutic arsenal of the most advanced ABC is growing. The purpose of this literature review is to investigate the current state of knowledge about the use of denosumab in ABCs. METHODS A literature research was conducted through PUBMED, COCHRANE and GOOGLE SCHOLAR using the keywords "aneurysmal bone cyst" AND "denosumab". Seventeen articles were included. RESULTS A total of 43 cases were reported in the literature. There were 23 males, 20 females. The mean age was 15,9±8,1 year. Pain relief and neurological improvement were rapid and sustained. Radiological assessment showed ossification and/or volume reduction in 36/39 patients. Eight patients (18,6%) presented a recurrence after or during denosumab therapy of whom 7 were adults. Adverse events occurred in 11 patients, 5 of them were admitted to the intensive care unit due to hypercalcemia. CONCLUSION Denosumab use in non-surgical ABCs has shown a positive impact in pain and neurological symptoms. The oncological outcome remains unclear with a recurrence rate of 18,6% during/after denosumab therapy, mostly in adults. However, regarding the potential clinical benefits, its use might be discussed in the most advanced cases. Further research and clinical trials are mandatory to precise its belonging in the therapeutic arsenal.
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Affiliation(s)
- Julien Maximen
- Department of Orthopedic surgery, Pontchaillou University Hospital, 2, rue Henri Le Guilloux, 35033 Rennes, France.
| | - François Robin
- Inserm, Univ Rennes, INRA, Rheumatology department CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), 35000 Rennes, France
| | - Alexandre Tronchot
- Department of Orthopedic surgery, Pontchaillou University Hospital, 2, rue Henri Le Guilloux, 35033 Rennes, France
| | - Adrien Rossetti
- Department of Orthopedic surgery, Pontchaillou University Hospital, 2, rue Henri Le Guilloux, 35033 Rennes, France
| | - Mickaël Ropars
- Department of Orthopedic surgery, Pontchaillou University Hospital, 2, rue Henri Le Guilloux, 35033 Rennes, France
| | - Pascal Guggenbuhl
- Inserm, Univ Rennes, INRA, Rheumatology department CHU Rennes, Institut NUMECAN (Nutrition Metabolisms and Cancer), 35000 Rennes, France
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Samieirad S, Momtaz MM, Mohtasham N, Mohammadzadeh F, Ebrahimzadeh N, Tohidi E. Surgical Treatment of Fibrous dysplasia in the Maxillary Bone of a 12 Year-Old Girl: A Case Report. World J Plast Surg 2021; 10:126-133. [PMID: 34912679 PMCID: PMC8662688 DOI: 10.29252/wjps.10.3.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Revised: 09/03/2021] [Accepted: 09/23/2021] [Indexed: 10/31/2022] Open
Abstract
Fibrous dysplasia is a rare bony disorder with recurrent character distinguished by abnormal fibro-osseous tissue. One or more bones may be involved in this lesion; however, the maxilla is the most commonly affected bone in the maxillofacial region. Here, we present an interesting case of a surgically treated 12-year-old adult female patient with a diagnosis of craniofacial fibrous dysplasia (CFD) in the maxillary bone with an invasive expansion to the orbital bone who was referred to the Department of Oral and Maxillofacial, Mashhad Dental School, Mashhad, Iran, in Apr 2021. The patient was treated under general anesthesia by the surgical recontouring and bone shaving of the tumor. Several factors should be considered in choosing the best treatment such as pathological features of the lesion, patient's age, and risk of recurrence. However, surgical treatment, in this case, was beneficial to help the patient resuming a normal life. There is no published report describing bone recontouring and shaving management in an invasive case of craniomaxillofacial FD before the age of skeletal maturity due to the psychological effect of the deformity.
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Affiliation(s)
- Sahand Samieirad
- Oral and Maxillofacial Diseases Research Center, Mashhad University of medical sciences, Mashhad, Iran
| | - Mohammad Mehdi Momtaz
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Science, Mashhad, Iran
| | - Nooshin Mohtasham
- Oral and Maxillofacial Diseases Research Center, Mashhad University of medical sciences, Mashhad, Iran
| | - Farzaneh Mohammadzadeh
- Student Research Committee, Faculty of Dentistry, Mashhad University of Medical Science, Mashhad, Iran
| | - Niloofar Ebrahimzadeh
- Student Research Committee, Faculty of Dentistry, Zahedan University of Medical Science, Zahedan, Iran
| | - Elahe Tohidi
- Oral and Maxillofacial Diseases Research Center, Mashhad University of medical sciences, Mashhad, Iran
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Raborn LN, Burke AB, Ebb DH, Collins MT, Kaban LB, Boyce AM. Denosumab for craniofacial fibrous dysplasia: duration of efficacy and post-treatment effects. Osteoporos Int 2021; 32:1889-1893. [PMID: 33772327 DOI: 10.1007/s00198-021-05895-6] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/16/2021] [Indexed: 10/21/2022]
Abstract
Denosumab has been advocated as a potential treatment for the rare skeletal disorder fibrous dysplasia (FD); however, there is limited data to support safety and efficacy, particularly after drug discontinuation. We report a case of successful treatment of aggressive craniofacial FD with denosumab, highlighting novel insights into the duration of efficacy, surrogate treatment markers, and discontinuation effects. A 13-year-old girl presented with persistent pain and expansion of a maxillary FD lesion, which was not responsive to repeated surgical procedures or bisphosphonates. Pre-treatment biopsy showed high RANKL expression and localization with proliferation markers. Denosumab therapy was associated with improved pain, decreased bone turnover markers, and increased lesion density on computed tomography scan. During 3.5 years of treatment, the patient developed increased non-lesional bone density, and after denosumab discontinuation, she developed hypercalcemia managed with bisphosphonates. Pain relief and lesion stability continued for 2 years following treatment, and symptom recurrence coincided with increased bone turnover markers and decreased lesion density back to pre-treatment levels. This case highlights the importance of considering the duration of efficacy when treating patients with FD and other nonresectable skeletal neoplasms that require long-term management.
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Affiliation(s)
- L N Raborn
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - A B Burke
- Oral and Maxillofacial Surgery, University of Washington School of Dentistry, Seattle, WA, USA
| | - D H Ebb
- Department of Pediatric Hematology Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - M T Collins
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA
| | - L B Kaban
- Department of Oral & Maxillofacial Surgery, Massachusetts General Hospital, Harvard School of Dental Medicine, Boston, MA, USA
| | - A M Boyce
- Skeletal Disorders and Mineral Homeostasis Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
- Metabolic Bone Disorders Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, 30 Convent Drive, Building 30, Room 228, MSC 4320, Bethesda, MD, 20892-4320, USA.
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Pagnotti GM, Thompson WR, Guise TA, Rubin CT. Suppression of cancer-associated bone loss through dynamic mechanical loading. Bone 2021; 150:115998. [PMID: 33971314 PMCID: PMC10044486 DOI: 10.1016/j.bone.2021.115998] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 04/30/2021] [Accepted: 05/03/2021] [Indexed: 02/06/2023]
Abstract
Patients afflicted with or being treated for cancer constitute a distinct and alarming subpopulation who exhibit elevated fracture risk and heightened susceptibility to developing secondary osteoporosis. Cancer cells uncouple the regulatory processes central for the adequate regulation of musculoskeletal tissue. Systemically taxing treatments to target tumors or disrupt the molecular elements driving tumor growth place considerable strain on recovery efforts. Skeletal tissue is inherently sensitive to mechanical forces, therefore attention to exercise and mechanical loading as non-pharmacological means to preserve bone during treatment and in post-treatment rehabilitative efforts have been topics of recent focus. This review discusses the dysregulation that cancers and the ensuing metabolic dysfunction that confer adverse effects on musculoskeletal tissues. Additionally, we describe foundational mechanotransduction pathways and the mechanisms by which they influence both musculoskeletal and cancerous cells. Functional and biological implications of mechanical loading at the tissue and cellular levels will be discussed, highlighting the current understanding in the field. Herein, in vitro, translational, and clinical data are summarized to consider the positive impact of exercise and low magnitude mechanical loading on tumor-bearing skeletal tissue.
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Affiliation(s)
- G M Pagnotti
- University of Texas - MD Anderson Cancer Center, Department of Endocrine, Neoplasia and Hormonal Disorders, Houston, TX, USA.
| | - W R Thompson
- Indiana University, Department of Physical Therapy, Indianapolis, IN, USA
| | - T A Guise
- University of Texas - MD Anderson Cancer Center, Department of Endocrine, Neoplasia and Hormonal Disorders, Houston, TX, USA
| | - C T Rubin
- Stony Brook University, Department of Biomedical Engineering, Stony Brook, NY, USA
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Meier ME, Clerkx SN, Winter EM, Pereira AM, van de Ven AC, van de Sande MAJ, Appelman-Dijkstra NM. Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study. J Bone Miner Res 2021; 36:1729-1738. [PMID: 34076303 PMCID: PMC8518724 DOI: 10.1002/jbmr.4380] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 04/29/2021] [Accepted: 05/22/2021] [Indexed: 12/14/2022]
Abstract
Denosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (RANKL)-mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of Dmab discontinuation in FD/MAS. Thirty-seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) treatment, were included. Health records were screened for pain scores, side effects, and bone turnover markers (BTMs) (calcium, alkaline phosphatase [ALP], procollagen 1 N-terminal propeptide [P1NP], and β-crosslaps [B-CTX, also termed β-C-terminal telopeptide]) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median (interquartile range [IQR]). BTMs normalized in two-thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow-up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response, and multiple injections. Further studies on the safety of Dmab and withdrawal are needed and ongoing. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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Affiliation(s)
- Maartje E Meier
- Department of Orthopaedic Surgery, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Stance N Clerkx
- Department of Orthopaedic Surgery, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Elizabeth M Winter
- Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Alberto M Pereira
- Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Annenienke C van de Ven
- Department of Internal Medicine, Division of Endocrinology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Michiel A J van de Sande
- Department of Orthopaedic Surgery, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
| | - Natasha M Appelman-Dijkstra
- Department of Internal Medicine, Division of Endocrinology, Center for Bone Quality, Leiden University Medical Center, Leiden, The Netherlands
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Mamedova E, Kolodkina A, Vasilyev EV, Petrov V, Belaya Z, Tiulpakov A. Successful Use of Denosumab for Life-Threatening Hypercalcemia in a Pediatric Patient with Primary Hyperparathyroidism. Horm Res Paediatr 2021; 93:272-278. [PMID: 32998142 DOI: 10.1159/000510625] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 08/03/2020] [Indexed: 11/19/2022] Open
Abstract
INTRODUCTION Primary hyperparathyroidism (PHPT) is rare and usually symptomatic in children. There is no approved medication to lower serum calcium levels in this patient group. Denosumab is used in adult patients with osteoporosis and hyperparathyroidism. To our knowledge, only 1 case of denosumab treatment in a child with severe PHPT has been reported to date. CASE PRESENTATION A 16-year-old female was referred to our clinic with symptoms including pathologic fractures, nausea, emesis, and progressive weight loss. At admission, her serum total calcium was 4.17 mmol/L (reference range 2.15-2.55), parathyroid hormone 2,151 pg/mL (15-65), and phosphate 1.07 mmol/L (1.45-1.78). Due to potentially life-threatening hypercalcemia, denosumab 60 mg subcutaneously was administered after obtaining informed consent. Serum calcium levels were reduced within 12 h of injection and the patient's condition rapidly improved, which allowed genetic testing to be done prior to surgery. A heterozygous mutation in the CDC73 gene was revealed, and a parathyroidectomy was performed on day 22 after denosumab administration. Morphological examination revealed solitary parathyroid adenoma. After surgery, hypocalcemia developed requiring high doses of alfacalcidol and calcium supplements. CONCLUSION Our case supports the previous observations in adults that denosumab can be safely and effectively used as a preoperative treatment in patients with PHPT and severe hypercalcemia and shows that it may be used in pediatric patients.
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Affiliation(s)
- Elizaveta Mamedova
- Department of Neuroendocrinology and Bone Diseases, Endocrinology Research Centre, Moscow, Russian Federation
| | - Anna Kolodkina
- Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russian Federation
| | - Evgeny V Vasilyev
- Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russian Federation
| | - Vasiliy Petrov
- Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russian Federation
| | - Zhanna Belaya
- Department of Neuroendocrinology and Bone Diseases, Endocrinology Research Centre, Moscow, Russian Federation
| | - Anatoly Tiulpakov
- Department and Laboratory of Inherited Endocrine Disorders, Endocrinology Research Centre, Moscow, Russian Federation,
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Surgical Treatment of Fibrous dysplasia in the Maxillary Bone of a 12 Year-Old Girl: A Case Report. World J Plast Surg 2021. [DOI: 10.52547/wjps.10.3.126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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PV S, Jain RS, Agarwal J. Denosumab-Induced Proximal Myopathy in a Child. JOURNAL OF PEDIATRIC NEUROLOGY 2021. [DOI: 10.1055/s-0041-1729738] [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
AbstractDenosumab, a fully humanized monoclonal antibody, has been used for the treatment of osteoporosis, in complications resulting from bone metastatic disease and in giant cell tumor in both adults and skeletally mature adolescents. Denosumab is an inhibitor of the receptor activator of nuclear factor kappa-B ligand and belongs to a new class of antiresorptive medications. We report a unique case of myopathy in a 13-year-old boy prescribed denosumab for enchondromatosis. The boy presented with hypovitaminosis D, elevated parathyroid hormone, suppressed alkaline phosphatase, hypocalcemia, and hypophosphatemia after a single dose of denosumab. Our case points to altered calcium–vitamin D homeostasis induced by denosumab. Myopathy associated with denosumab has not been described previously in children. Early recognition of myopathy and adequate supplementation with calcium–vitamin D may ensure a more favorable clinical outcome.
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Affiliation(s)
- Sripadma PV
- Department of Neurology, SMS Medical College and Hospital, Jaipur, Rajasthan, India
| | - Rajendra S Jain
- Department of Neurology, SMS Medical College and Hospital, Jaipur, Rajasthan, India
| | - Jitesh Agarwal
- Department of Neurology, SMS Medical College and Hospital, Jaipur, Rajasthan, India
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