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Jain S. Prevention and Management of Denosumab Discontinuation Rebound Fractures. Endocrinol Metab Clin North Am 2024; 53:559-583. [PMID: 39448137 DOI: 10.1016/j.ecl.2024.08.002] [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] [Indexed: 10/26/2024]
Abstract
Denosumab rebound-associated fractures occur in approximately 1 out of 14 patients who discontinue denosumab therapy without sequential antiresorptive therapy. They occur due to excessive bone resorption after missed or delayed denosumab doses. The fractures are multiple and quality of life altering. This phenomenon occurs in all patient populations that use prolonged denosumab therapy. Average delay in denosumab dosing beyond 7 months or discontinuation of denosumab without sequential therapy is associated with increased mortality in retrospective studies. Multiple medication regimens used after the end of denosumab therapy have been shown to substantially reduce the risk of rebound vertebral fractures.
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Affiliation(s)
- Sumeet Jain
- Division of Endocrinology, Department of Medicine, Rush University Medical Center, 1725 West Harrison Street Suite 250, Chicago, IL 60612, USA.
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Qin X, Wei Q, An R, Yang Y, Cai M, Han X, Mao H, Gao X. Regulation of bone and fat balance by Fructus Ligustri Lucidi in ovariectomized mice. PHARMACEUTICAL BIOLOGY 2023; 61:391-403. [PMID: 36740874 PMCID: PMC9904306 DOI: 10.1080/13880209.2023.2168019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2022] [Revised: 12/03/2022] [Accepted: 01/09/2023] [Indexed: 06/18/2023]
Abstract
CONTEXT Fructus Ligustri Lucidi (FLL), a commonly used herb of traditional Chinese medicine (TCM), is the fruit of Ligustrum lucidum Ait. (Oleaceae). The ethanol extract of FLL is a potential candidate for preventing and treating postmenopausal osteoporosis (PMOP) by nourishing the liver and kidneys. OBJECTIVE This study determines whether an ethanol extract of FLL has anti-osteoporotic effects in ovariectomized (OVX) mice and explores the underlying mechanism. MATERIALS AND METHODS The OVX model of eight-week-old C57BL/6J female mice was taken, and ovariectomy was used as PMOP. Mice were divided into five groups: sham-operated group (n = 10), OVX group (n = 10), OVX + E2 group (n = 10; 0.039 mg/kg), OVX + FLL group (n = 10; 2 g/kg) and OVX + FLL group (n = 10; 4 g/kg). Mice were treated by gavage with FLL or CMCNa once daily for 8 weeks. We harvested uteri, femur, and tibias from mice; bone mineral density (BMD) and bone microstructure were obtained by X-ray absorptiometry and micro-CT. Furthermore, the effect of FLL on the balance of osteoblast and adipocyte differentiation was investigated using bone marrow mesenchymal stem cells (BMMSCs). RESULTS The results indicated that FLL did not affect OVX-induced estradiol reduction. Compared with OVX mice, FLL significantly increased BMD (63.54 vs. 61.96), Conn. D (86.46 vs. 57.00), and left tibial strength (13.91 vs. 11.27), decreased Tb. Sp (0.38 vs. 0.44) and body fat content (4.19% vs. 11.24%). FLL decreased osteoclast activity and enhanced RUNX2 expression; inhibited perilipin peroxisome proliferator-activated receptor gamma (PPARγ) expression and adipocyte differentiation from BMMSCs. CONCLUSIONS FLL prevented additional bone loss and improved bone microstructure in OVX mice by modulating bone and fat balance, suggesting that FLL might be a therapeutic agent for PMOP.
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Affiliation(s)
- Xiaoyan Qin
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Qiu Wei
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ran An
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Yun Yang
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Mingqi Cai
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoling Han
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Haoping Mao
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiumei Gao
- Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
- Tianjin State Key Laboratory of Modern Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Bell A, Kendler DL, Khan AA, Shapiro C M M, Morisset A, Leung JP, Reiner M, Colgan SM, Slatkovska L, Packalen M. A retrospective observational study of osteoporosis management after a fragility fracture in primary care. Arch Osteoporos 2022; 17:75. [PMID: 35513573 PMCID: PMC9072526 DOI: 10.1007/s11657-022-01110-z] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Accepted: 04/18/2022] [Indexed: 02/03/2023]
Abstract
In many countries, osteoporosis is predominantly managed by primary care physicians; however, management after a fragility fracture has not been widely investigated. We describe osteoporosis care gaps in a real-world patient cohort. Our findings help inform initiatives to identify and overcome obstacles to effective management of patients after fragility fracture. PURPOSE A fragility fracture is a major risk factor for subsequent fracture in adults aged ≥ 50 years. This retrospective observational study aimed to characterize post-fracture management in Canadian primary care. METHODS A total of 778 patients with an index fragility fracture (low-trauma, excluding small bones) occurring between 2014 and 2016 were identified from medical records at 76 primary care centers in Canada, with follow-up until January 2018. RESULTS Of 778 patients (80.5% female, median age [IQR] 73 [64-80]), 215 were on osteoporosis treatment and 269 had osteoporosis diagnosis recorded prior to their index fracture. The median follow-up was 363 (IQR 91-808) days. Of patients not on osteoporosis treatment at their index fracture, 60.2% (n = 339/563) remained untreated after their index fracture and 62.2% (n = 23/37) continued untreated after their subsequent fracture. After their index fracture, fracture risk assessment (FRAX or CAROC) was not performed in 83.2% (n = 647/778) of patients, and 59.9% (n = 466/778) of patients did not receive bone mineral density testing. Of patients without osteoporosis diagnosis recorded prior to their index date, 61.3% (n = 300/489) remained undiagnosed after their index fracture. At least one subsequent fracture occurred in 11.5% (n = 86/778) of patients. CONCLUSION In the primary care setting, fragility fracture infrequently resulted in osteoporosis treatment or fracture risk assessment, even after multiple fragility fractures. These results suggest a fragility fracture is not recognized as a major risk factor for subsequent fracture and its occurrence does not prompt primary care physicians to intervene. These data urge initiatives to identify and overcome obstacles to primary care physicians' effective management of patients after fragility fractures.
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Affiliation(s)
- Alan Bell
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
| | - David L Kendler
- Department of Medicine, Division of Endocrinology, University of British Columbia, Vancouver, BC, Canada
| | - Aliya A Khan
- Department of Medicine, Divisions of Endocrinology and Metabolism and Geriatrics, McMaster University, Hamilton, ON, Canada
| | - Marla Shapiro C M
- Department of Family and Community Medicine, University of Toronto, Toronto, ON, Canada
| | - Anne Morisset
- Department of Medicine, Division of Internal Medicine, Sherbrooke University, Sherbrooke, QC, Canada
| | - Jean-Pierre Leung
- Department of Family Medicine, University of Calgary, Calgary, AB, Canada
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Tay WL, Tay D. Discontinuing Denosumab: Can It Be Done Safely? A Review of the Literature. Endocrinol Metab (Seoul) 2022; 37:183-194. [PMID: 35417954 PMCID: PMC9081316 DOI: 10.3803/enm.2021.1369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/17/2022] [Accepted: 02/22/2022] [Indexed: 11/30/2022] Open
Abstract
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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Affiliation(s)
- Wei Lin Tay
- Department of General Medicine, Sengkang General Hospital, Singhealth, Singapore
- Duke NUS Medical School, Singapore
| | - Donovan Tay
- Department of General Medicine, Sengkang General Hospital, Singhealth, Singapore
- Duke NUS Medical School, Singapore
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Yeh KL, Wu SH, Liaw CK, Hou SM, Wu SS. Outcomes of different minimally invasive surgical treatments for vertebral compression fractures: An observational study. World J Clin Cases 2021; 9:9509-9519. [PMID: 34877285 PMCID: PMC8610862 DOI: 10.12998/wjcc.v9.i31.9509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/12/2021] [Revised: 08/31/2021] [Accepted: 09/08/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Osteoporosis with vertebral compression fractures is increasingly common in the elderly population. Cement augmentation is one of the effective surgical treatments for these patients. Currently, there are several different types of cement augmentation treatments. No studies have compared the safety and efficacy of different cement augmentation types for the treatment of such fractures; thus, we retrospectively compared vertebroplasty, balloon kyphoplasty, and kyphoplasty with SpineJack or an intravertebral expandable pillar.
AIM To compare the postoperative safety and efficacy of each surgical intervention in treating vertebral compression fractures.
METHODS We retrospectively analyzed 354 patients with acute vertebral compression fractures, defined as signal changes in the T1 weighted magnetic resonance imaging, and randomly divided the patients into five groups. Their visual analog scale scores for pain, kyphotic angle, average body height, rate of cement leakage, and occurrence of adjacent vertebral compression fractures were followed for 1 year. One-way analysis of variance, the post hoc Bonferroni test, and Fisher exact probability test were used for statistical analyses.
RESULTS All pain scores significantly improved 12 mo postoperatively; however, there was no significant difference between the groups (P = 0.325). Kyphoplasty with SpineJack significantly reduced the kyphotic angle (P = 0.028) and restored the height of the vertebral body (P = 0.02). The rate of adjacent compression fractures was the highest in the vertebroplasty group, with a statistically significant difference according to the Fisher exact probability test (P = 0.02). The treatment with the lowest cement leakage rate cannot be identified because of the small sample size; however, kyphoplasty with SpineJack, an IVEP, and vesselplasty resulted in lower rates of cement leakage than balloon kyphoplasty and vertebroplasty.
CONCLUSION Kyphoplasty with SpineJack has good outcomes in kyphotic angle reduction and body height restoration. Vertebroplasty has the highest cement leakage rate and adjacent compression fracture occurrence.
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Affiliation(s)
- Kuei-Lin Yeh
- Department of Orthopedics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan
| | - Szu-Hsien Wu
- Department of Physical Medicine and Rehabilitation, Taipei Veterans General Hospital, Taipei 11217, Taiwan
| | - Chen-Kun Liaw
- Department of Orthopedics, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Department of Orthopedics, Shuang Ho Hospital, Taipei Medical University, New Taipei 23561, Taiwan
- Graduate Institute of Biomedical Optomechatronics, College of Biomedical Engineering, Research Center of Biomedical Device, Taipei Medical University, Taipei 11301, Taiwan
| | - Sheng-Mou Hou
- Department of Orthopedics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan
| | - Shing-Sheng Wu
- Department of Orthopedics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei 11101, Taiwan
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Tanphiriyakun T, Rojanasthien S, Khumrin P. Bone mineral density response prediction following osteoporosis treatment using machine learning to aid personalized therapy. Sci Rep 2021; 11:13811. [PMID: 34226589 PMCID: PMC8257695 DOI: 10.1038/s41598-021-93152-5] [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] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Accepted: 06/22/2021] [Indexed: 11/09/2022] Open
Abstract
Osteoporosis is a global health problem for ageing populations. The goals of osteoporosis treatment are to improve bone mineral density (BMD) and prevent fractures. One major obstacle that remains a great challenge to achieve the goals is how to select the best treatment regimen for individual patients. We developed a computational model from 8981 clinical variables, including demographic data, diagnoses, laboratory results, medications, and initial BMD results, taken from 10-year period of electronic medical records to predict BMD response after treatment. We trained 7 machine learning models with 13,562 osteoporosis treatment instances [comprising 5080 (37.46%) inadequate treatment responses and 8482 (62.54%) adequate responses] and selected the best model (Random Forests with area under the receiver operating curve of 0.70, accuracy of 0.69, precision of 0.70, and recall of 0.89) to individually predict treatment responses of 11 therapeutic regimens, then selected the best predicted regimen to compare with the actual regimen. The results showed that the average treatment response of the recommended regimens was 9.54% higher than the actual regimens. In summary, our novel approach using a machine learning-based decision support system is capable of predicting BMD response after osteoporosis treatment and personalising the most appropriate treatment regimen for an individual patient.
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Affiliation(s)
- Thiraphat Tanphiriyakun
- Department of Orthopaedics, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
- Biomedical Informatics Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Sattaya Rojanasthien
- Department of Orthopaedics, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Piyapong Khumrin
- Department of Family Medicine, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Biomedical Informatics Center, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Shieh A, Karlamangla AS, Huang MH, Han W, Greendale GA. Faster Lumbar Spine Bone Loss in Midlife Predicts Subsequent Fracture Independent of Starting Bone Mineral Density. J Clin Endocrinol Metab 2021; 106:e2491-e2501. [PMID: 33903908 PMCID: PMC8208668 DOI: 10.1210/clinem/dgab279] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Indexed: 11/19/2022]
Abstract
CONTEXT Bone mineral density (BMD) decreases rapidly during menopause transition (MT), and continues to decline in postmenopause. OBJECTIVE This work aims to examine whether faster BMD loss during the combined MT and early postmenopause is associated with incident fracture, independent of starting BMD, before the MT. METHODS The Study of Women's Health Across the Nation, a longitudinal cohort study, included 451 women, initially premenopausal or early perimenopausal, and those transitioned to postmenopause. Main outcome measures included time to first fracture after early postmenopause. RESULTS In Cox proportional hazards regression, adjusted for age, body mass index, race/ethnicity, study site, use of vitamin D and calcium supplements, and use of bone-detrimental or -beneficial medications, each SD decrement in lumbar spine (LS) BMD before MT was associated with a 78% increment in fracture hazard (P = .007). Each 1% per year faster decline in LS BMD was related to a 56% greater fracture hazard (P = .04). Rate of LS BMD decline predicted future fracture, independent of starting BMD. Women with a starting LS BMD below the sample median, and an LS BMD decline rate faster than the sample median had a 2.7-fold greater fracture hazard (P = .03). At the femoral neck, neither starting BMD nor rate of BMD decline was associated with fracture. CONCLUSION At the LS, starting BMD before the MT and rate of decline during the combined MT and early postmenopause are independent risk factors for fracture. Women with a below-median starting LS BMD and a faster-than-median LS BMD decline have the greatest fracture risk.
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Affiliation(s)
- Albert Shieh
- Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
- Correspondence: Albert Shieh, MD, UCLA Division of Geriatrics, 10945 Le Conte Ave, Suites 2339 to 2345, Los Angeles, CA 90095-1687, USA.
| | - Arun S Karlamangla
- Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - Mei-Hua Huang
- Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - Weijuan Han
- Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
| | - Gail A Greendale
- Department of Medicine, David Geffen School of Medicine at University of California, Los Angeles, California, USA
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