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Calcium & Bone Metabolism
Effect of Vitamin D Supplementation on Risk of Fractures and Falls According to Dosage and Interval: A Meta-Analysis
Sung Hye Kong, Han Na Jang, Jung Hee Kim, Sang Wan Kim, Chan Soo Shin
Endocrinol Metab. 2022;37(2):344-358.   Published online April 25, 2022
DOI: https://doi.org/10.3803/EnM.2021.1374
  • 10,406 View
  • 384 Download
  • 25 Web of Science
  • 26 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Although recent studies comparing various dosages and intervals of vitamin D supplementation have been published, it is yet to be elucidated whether there is an appropriate dose or interval to provide benefit regarding fracture risk. We aimed to assess the published evidence available to date regarding the putative beneficial effects of vitamin D supplements on fractures and falls according to various dosages and intervals.
Methods
We performed a meta-analysis of randomized controlled studies reporting associations between vitamin D supplementation and the risks of fractures and falls in PubMed, EMBASE, and Cochrane library. Studies with supplements of ergocalciferol or calcitriol, those with a number of event ≤10, or those with a follow-up duration of less than 6 months were also excluded.
Results
Thirty-two studies were included in the final analysis. Vitamin D supplementation with daily dose of 800 to 1,000 mg was associated with lower risks of osteoporotic fracture and fall (pooled relative risk [RR], 0.87; 95% confidence interval [CI], 0.78 to 0.97 and RR, 0.91; 95% CI, 0.85 to 0.98), while studies with <800 or >1,000 mg/day did not. Also, among intervals, daily administration of vitamin D was associated with the reduced risk of falls, while intermittent dose was not. Also, patients with vitamin D deficiency showed a significant risk reduction of falls after vitamin D supplementation.
Conclusion
Daily vitamin D dose of 800 to 1,000 IU was the most probable way to reduce the fracture and fall risk. Further studies designed with various regimens and targeted vitamin D levels are required to elucidate the benefits of vitamin D supplements.

Citations

Citations to this article as recorded by  
  • Ukrainian Consensus on Diagnosis and Management of Vitamin D Deficiency in Adults
    Nataliia Grygorieva, Mykola Tronko, Volodymir Kovalenko, Serhiy Komisarenko, Tetiana Tatarchuk, Ninel Dedukh, Mykola Veliky, Serhiy Strafun, Yulia Komisarenko, Andrii Kalashnikov, Valeria Orlenko, Volodymyr Pankiv, Oleg Shvets, Inna Gogunska, Svitlana Reg
    Nutrients.2024; 16(2): 270.     CrossRef
  • Vitamin D Supplementation: A Review of the Evidence Arguing for a Daily Dose of 2000 International Units (50 µg) of Vitamin D for Adults in the General Population
    Pawel Pludowski, William B. Grant, Spyridon N. Karras, Armin Zittermann, Stefan Pilz
    Nutrients.2024; 16(3): 391.     CrossRef
  • Clinical Characteristics and Outcomes of Limb Fractures in Saudi Children
    Lamia Aldhbiban, Fai Alhoshan, Raghad Alomari, Shahad A Almatrafi, Yousef Alanazi, Samir Alsayegh, Haifa Y Alfaraidi, Ayman H Jawadi, Fahad N Aljuraibah
    Cureus.2024;[Epub]     CrossRef
  • The interplay of rheumatoid arthritis and osteoporosis: exploring the pathogenesis and pharmacological approaches
    Nikhil Gupta, Navjot Kanwar, Anchal Arora, Kavin Khatri, Abhinav Kanwal
    Clinical Rheumatology.2024; 43(5): 1421.     CrossRef
  • The multi-faceted nature of age-associated osteoporosis
    A.E. Smit, O.C. Meijer, E.M. Winter
    Bone Reports.2024; 20: 101750.     CrossRef
  • Vitamin D Deficiency in Patients With Low-Energy Hip Fractures in Accordance With the Mediterranean Paradox
    Christos Konstantinidis, Ourania Psoma, Christos Kotsias, Vasileios Panagiotopoulos , Sotiris Plakoutsis, Dimitrios Tsiampas, Dimitrios Vardakas, Dimitrios Giotis
    Cureus.2024;[Epub]     CrossRef
  • Effect of vitamin D, calcium, or combined supplementation on fall prevention: a systematic review and updated network meta-analysis
    Long Tan, Ruiqian He, Xiaoxue Zheng
    BMC Geriatrics.2024;[Epub]     CrossRef
  • Analysis of medication treatment for women with osteoporosis: A real-world retrospective study from Chinese tertiary grade A hospital
    Xiaolei Liu, Zhenling Zhu, Xianli Wang
    Bone Reports.2024; 21: 101778.     CrossRef
  • New insights into dairy management and the prevention and treatment of osteoporosis: The shift from single nutrient to dairy matrix effects—A review
    Kaili Wang, Xu Zhao, Sijia Yang, Xiaoxi Qi, Aili Li, Wei Yu
    Comprehensive Reviews in Food Science and Food Safety.2024;[Epub]     CrossRef
  • The Importance of Vitamin K and the Combination of Vitamins K and D for Calcium Metabolism and Bone Health: A Review
    Jan O. Aaseth, Trine Elisabeth Finnes, Merete Askim, Jan Alexander
    Nutrients.2024; 16(15): 2420.     CrossRef
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    Gianpaolo Voltan, Nicola Veronese
    International Journal of Bone Fragility.2024; 4(1): 2.     CrossRef
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    Amy Y. Sato, Meloney Cregor, Kevin McAndrews, Charles A. Schurman, Eric Schaible, Jennifer Shutter, Punit Vyas, Bhawana Adhikari, Monte S. Willis, Marjan Boerma, Tamara Alliston, Teresita Bellido
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  • Vitamin D levels and bone mineral density: a prospective cross-sectional analysis of young orthopedic trauma patients at a rural United States trauma center
    Michael Booth, Kenneth Sabacinski, Colleen Watkins, Erin Butcho, Emilie Kramer, Lukas Meadows, Michelle A. Bramer
    Journal of Trauma and Injury.2024; 37(4): 276.     CrossRef
  • Association of vitamin and/or nutritional supplements with fall among patients with diabetes: A prospective study based on ACCORD and UK Biobank
    Lingfang He, Tianqi Ma, Guogang Zhang, Xunjie Cheng, Yongping Bai
    Frontiers in Nutrition.2023;[Epub]     CrossRef
  • Vitamin D and Calcium in Osteoporosis, and the Role of Bone Turnover Markers: A Narrative Review of Recent Data from RCTs
    Gavriela Voulgaridou, Sousana K. Papadopoulou, Paraskevi Detopoulou, Despoina Tsoumana, Constantinos Giaginis, Foivi S. Kondyli, Evgenia Lymperaki, Agathi Pritsa
    Diseases.2023; 11(1): 29.     CrossRef
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    Yaohui Yu, Yudan Wang, Xiaoli Hou, Faming Tian
    Frontiers in Public Health.2023;[Epub]     CrossRef
  • Can Nutrition Contribute to a Reduction in Sarcopenia, Frailty, and Comorbidities in a Super-Aged Society?
    Sadao Yoshida, Ryo Shiraishi, Yuki Nakayama, Yasuko Taira
    Nutrients.2023; 15(13): 2991.     CrossRef
  • Safety Profile of Vitamin D in Italy: An Analysis of Spontaneous Reports of Adverse Reactions Related to Drugs and Food Supplements
    Valentina Maggini, Giada Crescioli, Ilaria Ippoliti, Eugenia Gallo, Francesca Menniti-Ippolito, Adelaide Chiaravalloti, Vittorio Mascherini, Roberto Da Cas, Simona Potenza, Giulia Gritti, Maria Galiulo, Laura Sottosanti, Alfredo Vannacci, Niccolò Lombardi
    Journal of Clinical Medicine.2023; 12(14): 4726.     CrossRef
  • Cholecalciferol Use Is Associated With a Decreased Risk of Incident Morphometric Vertebral Fractures in Acromegaly
    Sabrina Chiloiro, Stefano Frara, Irene Gagliardi, Antonio Bianchi, Antonella Giampietro, Margherita Medici, Agnese Allora, Luigi di Filippo, Maria Rosaria Ambrosio, Alfredo Pontecorvi, Maria Chiara Zatelli, Laura De Marinis, Andrea Giustina
    The Journal of Clinical Endocrinology & Metabolism.2023; 109(1): e58.     CrossRef
  • Proceedings of the 2023 Santa Fe Bone Symposium: Progress and Controversies in the Management of Patients with Skeletal Diseases
    E. Michael Lewiecki, Teresita Bellido, John P. Bilezikian, Jacques P. Brown, Azeez Farooki, Christopher S. Kovacs, Brendan Lee, William D. Leslie, Michael R. McClung, Mark L. Prasarn, Deborah E. Sellmeyer
    Journal of Clinical Densitometry.2023; 26(4): 101432.     CrossRef
  • Diagnosis, prevention and treatment of vitamin D deficiency in adults: Ukrainian experts consensus statement
    N.V. Grygorieva, M.D. Tronko, V.M. Kovalenko, S.V. Komisarenko, T.F. Tatarchuk, N.V. Dedukh, M.M. Veliky, S.S. Strafun, Y.I. Komisarenko, A.V. Kalashnikov, V.L. Orlenko, V.I. Pankiv, O.V. Shvets, I.V. Gogunska, S.I. Regeda
    PAIN, JOINTS, SPINE.2023; 13(2): 60.     CrossRef
  • Serum 25-Hydroxyvitamin D Level Is Negatively Associated with Fatigue in Elderly Maintenance Hemodialysis Patients
    Menglin Pang, Lin Chen, Na Jiang, Mengmeng Jiang, Baofeng Wang, Lili Wang, Xiao-yan Jia
    Kidney and Blood Pressure Research.2023; 48(1): 231.     CrossRef
  • Vitamin D for Clinical Diseases in Women: An Indispensable Factor in Medicine and Dentistry
    Dario Calafiore, Leonzio Fortunato, Mario Migliario
    Journal of Clinical Medicine.2022; 11(11): 3104.     CrossRef
  • Malnutrition in Older Adults—Effect on Falls and Fractures: A Narrative Review
    Malgorzata Kupisz-Urbanska, Ewa Marcinowska-Suchowierska
    Nutrients.2022; 14(15): 3123.     CrossRef
  • Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group
    Thierry Chevalley, Maria Luisa Brandi, Kevin D. Cashman, Etienne Cavalier, Nicholas C. Harvey, Stefania Maggi, Cyrus Cooper, Nasser Al-Daghri, Oliver Bock, Olivier Bruyère, Mario Miguel Rosa, Bernard Cortet, Alfonso J. Cruz-Jentoft, Antonio Cherubini, Bes
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    Hadeel Anwar Alsarraje, *Liqaa Khalel Alhyali
    International Journal of Research in Medical Sciences and Technology.2022; 14(01): 127.     CrossRef
Close layer
Calcium & Bone Metabolism
Development of a Spine X-Ray-Based Fracture Prediction Model Using a Deep Learning Algorithm
Sung Hye Kong, Jae-Won Lee, Byeong Uk Bae, Jin Kyeong Sung, Kyu Hwan Jung, Jung Hee Kim, Chan Soo Shin
Endocrinol Metab. 2022;37(4):674-683.   Published online August 5, 2022
DOI: https://doi.org/10.3803/EnM.2022.1461
  • 6,054 View
  • 250 Download
  • 23 Web of Science
  • 22 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Since image-based fracture prediction models using deep learning are lacking, we aimed to develop an X-ray-based fracture prediction model using deep learning with longitudinal data.
Methods
This study included 1,595 participants aged 50 to 75 years with at least two lumbosacral radiographs without baseline fractures from 2010 to 2015 at Seoul National University Hospital. Positive and negative cases were defined according to whether vertebral fractures developed during follow-up. The cases were divided into training (n=1,416) and test (n=179) sets. A convolutional neural network (CNN)-based prediction algorithm, DeepSurv, was trained with images and baseline clinical information (age, sex, body mass index, glucocorticoid use, and secondary osteoporosis). The concordance index (C-index) was used to compare performance between DeepSurv and the Fracture Risk Assessment Tool (FRAX) and Cox proportional hazard (CoxPH) models.
Results
Of the total participants, 1,188 (74.4%) were women, and the mean age was 60.5 years. During a mean follow-up period of 40.7 months, vertebral fractures occurred in 7.5% (120/1,595) of participants. In the test set, when DeepSurv learned with images and clinical features, it showed higher performance than FRAX and CoxPH in terms of C-index values (DeepSurv, 0.612; 95% confidence interval [CI], 0.571 to 0.653; FRAX, 0.547; CoxPH, 0.594; 95% CI, 0.552 to 0.555). Notably, the DeepSurv method without clinical features had a higher C-index (0.614; 95% CI, 0.572 to 0.656) than that of FRAX in women.
Conclusion
DeepSurv, a CNN-based prediction algorithm using baseline image and clinical information, outperformed the FRAX and CoxPH models in predicting osteoporotic fracture from spine radiographs in a longitudinal cohort.

Citations

Citations to this article as recorded by  
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  • A CT-based Deep Learning Model for Predicting Subsequent Fracture Risk in Patients with Hip Fracture
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Close layer
Review Articles
Calcium & Bone Metabolism
Review and Update of the Risk Factors and Prevention of Antiresorptive-Related Osteonecrosis of the Jaw
Ha Young Kim
Endocrinol Metab. 2021;36(5):917-927.   Published online October 21, 2021
DOI: https://doi.org/10.3803/EnM.2021.1170
  • 6,307 View
  • 307 Download
  • 12 Web of Science
  • 17 Crossref
AbstractAbstract PDFPubReader   ePub   
Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but serious adverse event of bisphosphonate or denosumab administration; it is associated with severe pain and a deteriorated quality of life. Since its first report in 2003, there have been many studies on its definition, epidemiology, pathophysiology, diagnosis, and treatment. Nevertheless, the epidemiology and mechanisms underlying this condition have not yet been fully delineated and several risk factors are known. Moreover, as there is no effective treatment currently available for osteonecrosis of the jaw, prevention is essential. Furthermore, close cooperation between prescribing physicians and dentists is important. The aim of this review was to provide up-to-date information regarding the risk factors and prevention of ARONJ from a physician’s perspective.

Citations

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    Glauco Rodrigues Carmo Silveira, Vinícius Franzão Ganzaroli, Luan Felipe Toro, Estevão Lopes-Pereira, Leandro Lemes da Costa, João Martins de Mello-Neto, Rogério Leone Buchaim, Valdir Gouveia Garcia, Leticia Helena Theodoro, José Maurício Sforcin, Priscyl
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    浩太郎 東
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  • Safety and Efficacy of Pamidronate in Neonatal Hypercalcemia Caused by Subcutaneous Fat Necrosis: A Case Report
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    Frontiers in Pediatrics.2022;[Epub]     CrossRef
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Close layer
Calcium & Bone Metabolism
Update on Preoperative Parathyroid Localization in Primary Hyperparathyroidism
Hye-Sun Park, Namki Hong, Jong Ju Jeong, Mijin Yun, Yumie Rhee
Endocrinol Metab. 2022;37(5):744-755.   Published online October 25, 2022
DOI: https://doi.org/10.3803/EnM.2022.1589
  • 6,547 View
  • 468 Download
  • 11 Web of Science
  • 15 Crossref
AbstractAbstract PDFPubReader   ePub   
Parathyroidectomy is the treatment of choice for primary hyperparathyroidism when the clinical criteria are met. Although bilateral neck exploration is traditionally the standard method for surgery, minimally invasive parathyroidectomy (MIP), or focused parathyroidectomy, has been widely accepted with comparable curative outcomes. For successful MIP, accurate preoperative localization of parathyroid lesions is essential. However, no consensus exists on the optimal approach for localization. Currently, ultrasonography and technetium-99m-sestamibi–single photon emission computed tomography/computed tomography are widely accepted in most cases. However, exact localization cannot always be achieved, especially in cases with multiglandular disease, ectopic glands, recurrent disease, and normocalcemic primary hyperparathyroidism. Therefore, new modalities for preoperative localization have been developed and evaluated. Positron emission tomography/computed tomography and parathyroid venous sampling have demonstrated improvements in sensitivity and accuracy. Both anatomical and functional information can be obtained by combining these methods. As each approach has its advantages and disadvantages, the localization study should be deliberately chosen based on each patient’s clinical profile, costs, radiation exposure, and the availability of experienced experts. In this review, we summarize various methods for the localization of hyperfunctioning parathyroid tissues in primary hyperparathyroidism.

Citations

Citations to this article as recorded by  
  • Diagnostic Ability and Correlation of Digital 11C-Methionine PET/CT in Primary Hyperparathyroidism with Inconclusive Standard Imaging
    Hee Beom Jeong, Yong-il Kim, Soyoon Yoon, Dong Yun Lee, Beom-Jun Kim, Seung Hun Lee, Jin-Sook Ryu
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    Nuclear Medicine Communications.2025; 46(1): 89.     CrossRef
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Close layer
Original Articles
Calcium & Bone Metabolism
Unveiling Genetic Variants Underlying Vitamin D Deficiency in Multiple Korean Cohorts by a Genome-Wide Association Study
Ye An Kim, Ji Won Yoon, Young Lee, Hyuk Jin Choi, Jae Won Yun, Eunsin Bae, Seung-Hyun Kwon, So Eun Ahn, Ah-Ra Do, Heejin Jin, Sungho Won, Do Joon Park, Chan Soo Shin, Je Hyun Seo
Endocrinol Metab. 2021;36(6):1189-1200.   Published online December 2, 2021
DOI: https://doi.org/10.3803/EnM.2021.1241
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Epidemiological data have shown that vitamin D deficiency is highly prevalent in Korea. Genetic factors influencing vitamin D deficiency in humans have been studied in Europe but are less known in East Asian countries, including Korea. We aimed to investigate the genetic factors related to vitamin D levels in Korean people using a genome-wide association study (GWAS).
Methods
We included 12,642 subjects from three different genetic cohorts consisting of Korean participants. The GWAS was performed on 7,590 individuals using linear or logistic regression meta- and mega-analyses. After identifying significant single nucleotide polymorphisms (SNPs), we calculated heritability and performed replication and rare variant analyses. In addition, expression quantitative trait locus (eQTL) analysis for significant SNPs was performed.
Results
rs12803256, in the actin epsilon 1, pseudogene (ACTE1P) gene, was identified as a novel polymorphism associated with vitamin D deficiency. SNPs, such as rs11723621 and rs7041, in the group-specific component gene (GC) and rs11023332 in the phosphodiesterase 3B (PDE3B) gene were significantly associated with vitamin D deficiency in both meta- and mega-analyses. The SNP heritability of the vitamin D concentration was estimated to be 7.23%. eQTL analysis for rs12803256 for the genes related to vitamin D metabolism, including glutamine-dependent NAD(+) synthetase (NADSYN1) and 7-dehydrocholesterol reductase (DHCR7), showed significantly different expression according to alleles.
Conclusion
The genetic factors underlying vitamin D deficiency in Korea included polymorphisms in the GC, PDE3B, NADSYN1, and ACTE1P genes. The biological mechanism of a non-coding SNP (rs12803256) for DHCR7/NADSYN1 on vitamin D concentrations is unclear, warranting further investigations.

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Close layer
Calcium & Bone Metabolism
Big Data Articles (National Health Insurance Service Database)
10-Year Fracture Risk in Postmenopausal Women with Osteopenia and Osteoporosis in South Korea
Yeon-Hee Baek, Sun Wook Cho, Han Eol Jeong, Ju Hwan Kim, Yunji Hwang, Jeffrey L. Lange, Ju-Young Shin
Endocrinol Metab. 2021;36(6):1178-1188.   Published online December 16, 2021
DOI: https://doi.org/10.3803/EnM.2021.1215
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  • 277 Download
  • 14 Web of Science
  • 13 Crossref
AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
In South Korea, women aged 66 years are eligible for complimentary bone mineral density (BMD) screening via the National Screening Program for Transitional Ages. We aimed to evaluate the 10-year fracture risk in women receiving BMD screening between January 2008 and December 2015.
Methods
BMD was classified as normal (T-score ≥–1.0 standard deviation [SD]), osteopenia (T-score <–1.0 SD and >–2.5 SD), and osteoporosis (T score ≤–2.5 SD) from dual-energy X-ray absorptiometry. Follow-up continued from the screening date until a diagnosis for clinical fragility fracture (including sites of the vertebrae, hip, pelvis, clavicle, humerus, forearm, wrist, lower leg, and ankle), censored at the earliest date of trauma, death, or December 2017; fracture was ascertained using diagnostic codes from the National Health Insurance Service database. A multivariable Cox proportional hazard model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the risk of fracture in women with osteopenia or osteoporosis relative to women with normal BMD.
Results
Among the 271,197 women screened, 44.0% had osteopenia and 35.2% had osteoporosis. The 10 year cumulative incidence of fragility fractures was 31.1%, 37.5%, and 44.3% in women with normal BMD, osteopenia, and osteoporosis, respectively. Fracture risk was higher in women with osteopenia (HR, 1.31; 95% CI, 1.28 to 1.34) and osteoporosis (HR, 1.68; 95% CI, 1.64 to 1.72) than in women with normal BMD.
Conclusion
Women with osteopenia and women with osteoporosis, identified by the national BMD screening program, demonstrated a substantially elevated risk of fracture.

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Review Articles
Calcium & Bone Metabolism
Applications of Machine Learning in Bone and Mineral Research
Sung Hye Kong, Chan Soo Shin
Endocrinol Metab. 2021;36(5):928-937.   Published online October 21, 2021
DOI: https://doi.org/10.3803/EnM.2021.1111
  • 6,497 View
  • 206 Download
  • 15 Web of Science
  • 13 Crossref
AbstractAbstract PDFPubReader   ePub   
In this unprecedented era of the overwhelming volume of medical data, machine learning can be a promising tool that may shed light on an individualized approach and a better understanding of the disease in the field of osteoporosis research, similar to that in other research fields. This review aimed to provide an overview of the latest studies using machine learning to address issues, mainly focusing on osteoporosis and fractures. Machine learning models for diagnosing and classifying osteoporosis and detecting fractures from images have shown promising performance. Fracture risk prediction is another promising field of research, and studies are being conducted using various data sources. However, these approaches may be biased due to the nature of the techniques or the quality of the data. Therefore, more studies based on the proposed guidelines are needed to improve the technical feasibility and generalizability of artificial intelligence algorithms.

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Calcium & bone metabolism
Acromegaly and Bone: An Update
Andrea Giustina
Endocrinol Metab. 2023;38(6):655-666.   Published online December 22, 2023
DOI: https://doi.org/10.3803/EnM.2023.601
  • 4,599 View
  • 248 Download
  • 13 Web of Science
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AbstractAbstract PDFPubReader   ePub   
Since our discovery in 2006 that acromegaly is associated with an increased risk of vertebral fractures, many authors have confirmed this finding in both cross-sectional and prospective studies. Due to the high epidemiological and clinical impact of this newly discovered comorbidity of acromegaly, this topic has progressively become more important and prominent over the years, and the pertinent literature has been enriched by new findings on the pathophysiology and treatment. The aim of this narrative review was to discuss these novel findings, integrating them with the seminal observations, in order to give the reader an updated view of how the field of acromegaly and bone is developing, from strong clinical observations to a mechanistic understanding and possible prevention and treatment.

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Calcium & Bone Metabolism
Discontinuing Denosumab: Can It Be Done Safely? A Review of the Literature
Wei Lin Tay, Donovan Tay
Endocrinol Metab. 2022;37(2):183-194.   Published online April 14, 2022
DOI: https://doi.org/10.3803/EnM.2021.1369
  • 21,962 View
  • 1,102 Download
  • 11 Web of Science
  • 12 Crossref
AbstractAbstract PDFPubReader   ePub   
Denosumab, which has been approved for the treatment of osteoporosis since 2010, is a fully humanised monoclonal antibody against a cytokine, receptor activator of nuclear factor kappa B ligand (RANKL), involved in bone resorption. Continued use of denosumab results in a potent and sustained decrease in bone turnover, an increase in bone mineral density (BMD), and a reduction in vertebral and hip fractures. The anti-resorptive effects of denosumab are reversible upon cessation, and this reversal is accompanied by a transient marked increase in bone turnover that is associated with bone loss, and of concern, an increased risk of multiple vertebral fractures. In this review, we outline the effects of denosumab withdrawal on bone turnover markers, BMD, histomorphometry, and fracture risk. We provide an update on recent clinical trials that sought to answer how clinicians can transition away from denosumab safely with follow-on therapy to mitigate bone loss and summarise the recommendations of various international guidelines.

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    Jeongmin Lee, Youn-Ju Lee, Jeonghoon Ha
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    Hans Peter Dimai, Christian Muschitz, Karin Amrein, Rosemarie Bauer, Daniel Cejka, Rudolf Wolfgang Gasser, Reinhard Gruber, Judith Haschka, Timothy Hasenöhrl, Franz Kainberger, Katharina Kerschan-Schindl, Roland Kocijan, Jürgen König, Norbert Kroißenbrunn
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  • Denosumab stimulates spermatogenesis in infertile men with preserved Sertoli cell capacity
    Christine H. Andreassen, Rune Holt, Li Juel Mortensen, Nadia Krarup Knudsen, John E. Nielsen, Nadia Nicholine Poulsen, Sam K. Yahyavi, Ida M. Boisen, Zhihui Cui, Luisina Ongaro, Jasmin P. Hjerresen, Birgitte G. Toft, Thomas Hasselager, Niklas R. Jørgensen
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  • Loss of lower extremity bone mineral density 1 year after denosumab is discontinued in persons with subacute spinal cord injury
    Christopher M. Cirnigliaro, Michael F. La Fountaine, J. Scott Parrott, Steven C. Kirshblum, Susan J. Sauer, Sue A. Shapses, Isa A. McClure, William A. Bauman
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  • Persistence with Denosumab in Male Osteoporosis Patients: A Real-World, Non-Interventional Multicenter Study
    Chaiho Jeong, Jeongmin Lee, Jinyoung Kim, Jeonghoon Ha, Kwanhoon Jo, Yejee Lim, Mee Kyoung Kim, Hyuk-Sang Kwon, Tae-Seo Sohn, Ki-Ho Song, Moo Il Kang, Ki-Hyun Baek
    Endocrinology and Metabolism.2023; 38(2): 260.     CrossRef
Close layer
Calcium & bone metabolism
Nuclear Factor-Kappa B Regulation of Osteoclastogenesis and Osteoblastogenesis
Brendan F. Boyce, Jinbo Li, Zhenqiang Yao, Lianping Xing
Endocrinol Metab. 2023;38(5):504-521.   Published online September 26, 2023
DOI: https://doi.org/10.3803/EnM.2023.501
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AbstractAbstract PDFPubReader   ePub   
Maintenance of skeletal integrity requires the coordinated activity of multinucleated bone-resorbing osteoclasts and bone-forming osteoblasts. Osteoclasts form resorption lacunae on bone surfaces in response to cytokines by fusion of precursor cells. Osteoblasts are derived from mesenchymal precursors and lay down new bone in resorption lacunae during bone remodeling. Nuclear factorkappa B (NF-κB) signaling regulates osteoclast and osteoblast formation and is activated in osteoclast precursors in response to the essential osteoclastogenic cytokine, receptor activator of NF-κB ligand (RANKL), which can also control osteoblast formation through RANK-RANKL reverse signaling in osteoblast precursors. RANKL and some pro-inflammatory cytokines, including tumor necrosis factor (TNF), activate NF-κB signaling to positively regulate osteoclast formation and functions. However, these cytokines also limit osteoclast and osteoblast formation through NF-κB signaling molecules, including TNF receptor-associated factors (TRAFs). TRAF6 mediates RANKL-induced osteoclast formation through canonical NF-κB signaling. In contrast, TRAF3 limits RANKL- and TNF-induced osteoclast formation, and it restricts transforming growth factor β (TGFβ)-induced inhibition of osteoblast formation in young and adult mice. During aging, neutrophils expressing TGFβ and C-C chemokine receptor type 5 (CCR5) increase in bone marrow of mice in response to increased NF-κB-induced CC motif chemokine ligand 5 (CCL5) expression by mesenchymal progenitor cells and injection of these neutrophils into young mice decreased bone mass. TGFβ causes degradation of TRAF3, resulting in decreased glycogen synthase kinase-3β/β-catenin-mediated osteoblast formation and age-related osteoporosis in mice. The CCR5 inhibitor, maraviroc, prevented accumulation of TGFβ+/CCR5+ neutrophils in bone marrow and increased bone mass by inhibiting bone resorption and increasing bone formation in aged mice. This paper updates current understanding of how NF-κB signaling is involved in the positive and negative regulation of cytokine-mediated osteoclast and osteoblast formation and activation with a focus on the role of TRAF3 signaling, which can be targeted therapeutically to enhance bone mass.

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    Piotr Wojdasiewicz, Paweł Turczyn, Anna Lach-Gruba, Łukasz A. Poniatowski, Daryush Purrahman, Mohammad-Reza Mahmoudian-Sani, Dariusz Szukiewicz
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Close layer
Original Articles
Calcium & Bone Metabolism
Decreased Serum Level of Sclerostin in Older Adults with Sarcopenia
Seong Hee Ahn, Hee-Won Jung, Eunju Lee, Ji Yeon Baek, Il-Young Jang, So Jeong Park, Jin Young Lee, Eunah Choi, Yun Sun Lee, Seongbin Hong, Beom-Jun Kim
Endocrinol Metab. 2022;37(3):487-496.   Published online May 27, 2022
DOI: https://doi.org/10.3803/EnM.2022.1428
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AbstractAbstract PDFPubReader   ePub   
Background
Although muscles and bones interact with each other through various secretory factors, the role of sclerostin, an osteocyte-secreted factor, on muscle metabolism has not been well studied. We investigated the levels of serum sclerostin in Korean older adults with sarcopenia.
Methods
Blood samples were collected from 129 participants who underwent evaluation of muscle mass and function in an outpatient geriatric clinic of a teaching hospital. Sarcopenia and related parameters were determined using cutoff values for the Asian population. Serum sclerostin levels were measured using an enzyme-linked immunosorbent assay.
Results
The mean age of the participants was 69.6 years, and 20 participants (15.5%) were classified as having sarcopenia. After adjusting for age, sex, and body mass index, serum sclerostin levels were significantly lower in participants with sarcopenia, low muscle mass, or weak muscle strength (P=0.003 to 0.045). Serum sclerostin levels were positively associated with skeletal muscle index and grip strength after adjusting for confounders (P=0.001 and P=0.003), whereas sarcopenic phenotype score showed a negative association (P=0.006). These increases in muscle mass and strength were also dose dependent as serum sclerostin levels increased (P for trends=0.003 and P for trends=0.015). Higher serum sclerostin levels were associated with lower odds ratio (ORs) for sarcopenia, low muscle mass, and weak muscle strength after adjusting for confounders (OR, 0.27 to 0.50; P<0.001 to 0.025).
Conclusion
Higher serum sclerostin levels were associated with a lower risk of sarcopenia, low muscle mass, and weak muscle strength in Korean older adults.

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  • Mechanism and physical activities in bone-skeletal muscle crosstalk
    Zhonghan Zhao, Kai Yan, Qiao Guan, Qiang Guo, Can Zhao
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    Jingwen Tian, Minchul Song, Kyu Jeong Cho, Ho Yeop Lee, Sang Hyeon Ju, Jung Ryul Lim, Ha Thi Nga, Thi Linh Nguyen, Ji Sun Moon, Hyo Ju Jang, Jung-Mo Hwang, Hyon-Seung Yi
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    Anika Shimonty, Lynda F. Bonewald, Fabrizio Pin
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    Hyon-Seung Yi
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    Giulia Minniti, Letícia Maria Pescinini-Salzedas, Guilherme Almeida dos Santos Minniti, Lucas Fornari Laurindo, Sandra Maria Barbalho, Renata Vargas Sinatora, Lance Alan Sloan, Rafael Santos de Argollo Haber, Adriano Cressoni Araújo, Karina Quesada, Jesse
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Close layer
Calcium & Bone Metabolism
Association between Elevated Plasma Homocysteine and Low Skeletal Muscle Mass in Asymptomatic Adults
Jae-Hyeong Choi, Jin-Woo Seo, Mi-Yeon Lee, Yong-Taek Lee, Kyung Jae Yoon, Chul-Hyun Park
Endocrinol Metab. 2022;37(2):333-343.   Published online February 8, 2022
DOI: https://doi.org/10.3803/EnM.2021.1202
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AbstractAbstract PDFSupplementary MaterialPubReader   ePub   
Background
Homocysteine has been drawing attention with a closed linkage with skeletal muscle. However, the association of hyperhomocysteinemia with decreased skeletal muscle mass remains unclear. We aimed to investigate the association of hyperhomocysteinemia with low skeletal muscle mass (LMM) in asymptomatic adults.
Methods
This was a cross-sectional study of 114,583 community-dwelling adults without cancer, stroke, or cardiovascular diseases who underwent measurements of plasma homocysteine and body composition analysis from 2012 to 2018. Hyperhomocysteinemia was defined as >15 μmol/L. Skeletal muscle mass index (SMI) was calculated based on appendicular muscle mass (kg)/height (m)2. Participants were classified into three groups based on SMI: “normal,” “mildly low,” and “severely low.”
Results
The prevalence of hyperhomocysteinemia was the highest in subjects with severely LMM (12.9%), followed by those with mildly LMM (9.8%), and those with normal muscle mass (8.5%) (P for trend <0.001). In a multivariable logistic regression model, hyperhomocysteinemia was significantly associated with having a mildly LMM (odds ratio [OR], 1.305; 95% confidence interval [CI], 1.224 to 1.392) and severely LMM (OR, 1.958; 95% CI, 1.667 to 2.286), respectively. One unit increment of log-transformed homocysteine was associated with 1.360 and 2.169 times higher risk of having mildly LMM and severely LMM, respectively.
Conclusion
We demonstrated that elevated homocysteine has an independent association with LMM in asymptomatic adults, supporting that hyperhomocysteinemia itself can be a risk for decline in skeletal musculature.

Citations

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    Cátia Pinheiro, Flávia Silva, Inês Rocha, Carina Martins, Liliana Giesteira, Bruna Dias, Ana Lucas, Ana Margarida Alexandre, Catarina Ferreira, Bruna Viegas, Isabella Bracchi, Juliana Guimarães, Joana Amaro, Teresa F. Amaral, Cláudia Camila Dias, Andreia
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Close layer
Calcium & Bone Metabolism
Real-World Safety and Effectiveness of Denosumab in Patients with Osteoporosis: A Prospective, Observational Study in South Korea
Yumie Rhee, Dong-Gune Chang, Jeonghoon Ha, Sooa Kim, Yusun Lee, Euna Jo, Jung-Min Koh
Endocrinol Metab. 2022;37(3):497-505.   Published online June 3, 2022
DOI: https://doi.org/10.3803/EnM.2022.1427
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AbstractAbstract PDFPubReader   ePub   
Background
The efficacy and safety of denosumab have been established in a phase 3, randomized, placebo-controlled trial in Korean postmenopausal women with osteoporosis. This postmarketing surveillance study was aimed to investigate the safety and effectiveness of denosumab in Korean real-world clinical practice.
Methods
Patients with osteoporosis who had received denosumab per the Korean approved indications in the postmarketing setting between September 2014 and September 2019 were enrolled. The primary endpoint was the incidence of adverse events (AEs) and adverse drug reactions (ADRs). The secondary endpoint was the percent change from baseline in bone mineral density (BMD) of the lumbar spine, total hip, and femoral neck.
Results
Of the 3,221 patients enrolled, 3,185 were included in the safety analysis set; 2,973 (93.3%) were female, and the mean± standard deviation (SD) age was 68.9±9.9 years. The mean±SD study period was 350.0±71.4 days. AEs, fatal AEs, and ADRs occurred in 19.3%, 0.8%, and 1.6%, respectively. The most frequent AEs, occurring in >0.5% of patients, were dizziness (0.7%), arthralgia (0.7%), back pain (0.6%), and myalgia (0.6%). Hypocalcemia occurred in 0.3% of patients. There were no cases of osteonecrosis of the jaw and atypical femoral fracture. Mean±SD percent change from baseline in BMD of the lumbar spine, total hip, and femoral neck was 7.3%±23.6%, 3.6%±31.4%, and 3.2%±10.7%, respectively.
Conclusion
The safety and effectiveness of denosumab in Korean patients with osteoporosis in this study were comparable with those in the Korean randomized controlled trial, with no new safety findings.

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    Chaiho Jeong, Jeongmin Lee, Jinyoung Kim, Jeonghoon Ha, Kwanhoon Jo, Yejee Lim, Mee Kyoung Kim, Hyuk-Sang Kwon, Tae-Seo Sohn, Ki-Ho Song, Moo Il Kang, Ki-Hyun Baek
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  • Denosumab

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    Sung Hye Kong
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Close layer
Review Articles
Calcium & Bone Metabolism
Interplay of Vitamin D and CYP3A4 Polymorphisms in Endocrine Disorders and Cancer
Siva Swapna Kasarla, Vannuruswamy Garikapati, Yashwant Kumar, Sujatha Dodoala
Endocrinol Metab. 2022;37(3):392-407.   Published online June 3, 2022
DOI: https://doi.org/10.3803/EnM.2021.1349
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AbstractAbstract PDFPubReader   ePub   
Vitamin D has received considerable optimistic attention as a potentially important factor in many pathological states over the past few decades. However, the proportion of the active form of vitamin D metabolites responsible for biological activity is highly questionable in disease states due to flexible alterations in the enzymes responsible for their metabolism. For instance, CYP3A4 plays a crucial role in the biotransformation of vitamin D and other drug substances. Food-drug and/or drug-drug interactions, the disease state, genetic polymorphism, age, sex, diet, and environmental factors all influence CYP3A4 activity. Genetic polymorphisms in CYP450-encoding genes have received considerable attention in the past few decades due to their extensive impact on the pharmacokinetic and dynamic properties of drugs and endogenous substances. In this review, we focused on CYP3A4 polymorphisms and their interplay with vitamin D metabolism and summarized the role of vitamin D in calcium homeostasis, bone diseases, diabetes, cancer, other diseases, and drug substances. We also reviewed clinical observations pertaining to CYP3A4 polymorphisms among the aforementioned disease conditions. In addition, we highlighted the future perspectives of studying the pharmacogenetics of CYP3A4, which may have potential clinical significance for developing novel diagnostic genetic markers that will ascertain disease risk and progression.

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    Mohamed I. Elsalahaty, Samar Sami Alkafaas, Aya O. Bashir, Khaled A. El-Tarabily, Mohamed T. El-Saadony, Eman H. Yousef
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Calcium & bone metabolism
New Insights into Calorie Restriction Induced Bone Loss
Linyi Liu, Clifford J. Rosen
Endocrinol Metab. 2023;38(2):203-213.   Published online April 27, 2023
DOI: https://doi.org/10.3803/EnM.2023.1673
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AbstractAbstract PDFPubReader   ePub   
Caloric restriction (CR) is now a popular lifestyle choice due to its ability in experimental animals to improve lifespan, reduce body weight, and lessen oxidative stress. However, more and more emerging evidence suggests this treatment requires careful consideration because of its detrimental effects on the skeletal system. Experimental and clinical studies show that CR can suppress bone growth and raise the risk of fracture, but the specific mechanisms are poorly understood. Reduced mechanical loading has long been thought to be the primary cause of weight loss-induced bone loss from calorie restriction. Despite fat loss in peripheral depots with calorie restriction, bone marrow adipose tissue (BMAT) increases, and this may play a significant role in this pathological process. Here, we update recent advances in our understanding of the effects of CR on the skeleton, the possible pathogenic role of BMAT in CR-induced bone loss, and some strategies to mitigate any potential side effects on the skeletal system.

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