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Nishida R, Fukui T, Niikura T, Kumabe Y, Yoshikawa R, Takase K, Yamamoto Y, Kuroda R, Oe K. Preventive effects of transcutaneous CO 2 application on disuse osteoporosis and muscle atrophy in a rat hindlimb suspension model. Bone 2024; 189:117262. [PMID: 39303931 DOI: 10.1016/j.bone.2024.117262] [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: 07/26/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 09/22/2024]
Abstract
We previously demonstrated that transcutaneous CO2 application promotes muscle fiber-type switching, fracture healing, and osteogenesis by increasing blood flow and angiogenesis. Here, we aimed to investigate the preventive effects of transcutaneous CO2 application on disuse osteoporosis and muscle atrophy in a rat hindlimb suspension model. Eleven-week-old male Sprague-Dawley rats were divided into hindlimb suspension (HS), HS with transcutaneous CO2 application (HSCO2), and control groups. HSCO2 rats were administered transcutaneous 100 % CO2 gas in their bilateral hindlimbs, five times a week for 20 min. After 3 weeks, we harvested the gastrocnemius, femur, and tibia for assessment. Histological analysis revealed a significant decrease in the gastrocnemius myofiber cross-sectional area in HS rats compared to the control rats, whereas HSCO2 rats exhibited a significant increase compared to HS rats. Micro-computed tomography showed significant bone atrophy in the trabecular and cortical bones of the femur in HS rats compared to those of the control rats, whereas significant improvement was noted in HSCO2 rats. Histological analysis of the proximal tibia revealed more marrow adipose tissue in the HS rats than in the control rats. However, in the HSCO2 rats, fewer marrow adipose tissue and osteoclasts were observed. Moreover, HSCO2 rats had more osteoblasts and higher expression of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and vascular endothelial growth factor (VEGF) than the HS rats. The gastrocnemius and distal femur of HSCO2 rats also exhibited elevated PGC-1α and VEGF expression and upregulation of the myogenesis markers and osteogenesis markers compared to those of HS rats. This treatment effectively prevented disuse osteoporosis and muscle atrophy by promoting local angiogenesis and blood flow. PGC-1α is crucial for promoting this angiogenic pathway. Transcutaneous CO2 application may be a novel preventive procedure for disuse osteoporosis and muscle atrophy, complementing medication and rehabilitation.
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Affiliation(s)
- Ryota Nishida
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Tomoaki Fukui
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Hyogo Prefectural Nishinomiya Hospital, Japan
| | - Yohei Kumabe
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Ryo Yoshikawa
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Kyohei Takase
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Yuya Yamamoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan
| | - Keisuke Oe
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, Japan.
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Chandran M, Akesson KE, Javaid MK, Harvey N, Blank RD, Brandi ML, Chevalley T, Cinelli P, Cooper C, Lems W, Lyritis GP, Makras P, Paccou J, Pierroz DD, Sosa M, Thomas T, Silverman S. Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review. Osteoporos Int 2024; 35:1337-1358. [PMID: 38587674 PMCID: PMC11282157 DOI: 10.1007/s00198-024-07059-8] [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: 10/10/2023] [Accepted: 03/06/2024] [Indexed: 04/09/2024]
Abstract
Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing. BACKGROUND Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing. METHODS Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT). RESULTS Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans. CONCLUSION Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.
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Affiliation(s)
- M Chandran
- Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, DUKE NUS Medical School, Singapore, Singapore.
| | - K E Akesson
- Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Department of Orthopedics, Skåne University Hospital, Malmö, Sweden
| | - M K Javaid
- NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK
| | - N Harvey
- MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK
| | - R D Blank
- Garvan Institute of Medical Research, Medical College of Wisconsin, Darlinghurst, NSW, Australia
- Medical College of Wisconsin, Milwaukee, WI, USA
| | - M L Brandi
- Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Largo Palagi 1, Florence, Italy
| | - T Chevalley
- Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland
| | - P Cinelli
- Department of Trauma Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland
| | - C Cooper
- MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospitals Southampton NHS Foundation Trust, Southampton, UK
- NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK
| | - W Lems
- Department of Rheumatology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands
| | - G P Lyritis
- Hellenic Osteoporosis Foundation, Athens, Greece
| | - P Makras
- Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece
| | - J Paccou
- Department of Rheumatology, MABlab ULR 4490, CHU Lille, Univ. Lille, 59000, Lille, France
| | - D D Pierroz
- International Osteoporosis Foundation, Nyon, Switzerland
| | - M Sosa
- University of Las Palmas de Gran Canaria, Investigation Group on Osteoporosis and Mineral Metabolism, Canary Islands, Spain
| | - T Thomas
- Department of Rheumatology, North Hospital, CHU Saint-Etienne and INSERM U1059, University of Lyon-University Jean Monnet, Saint‑Etienne, France
| | - S Silverman
- Cedars-Sinai Medical Center and Geffen School of Medicine UCLA, Los Angeles, CA, USA
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Makino A, Hasegawa T, Yamamoto T, Takagi H, Takahashi Y, Miyakoshi N, Amizuka N. Abaloparatide promotes bone repair of vertebral defects in ovariectomized rats by increasing bone formation. Bone 2024; 182:117056. [PMID: 38402920 DOI: 10.1016/j.bone.2024.117056] [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: 11/29/2023] [Revised: 02/07/2024] [Accepted: 02/19/2024] [Indexed: 02/27/2024]
Abstract
Osteoporotic vertebral fracture (OVF) is the most common type of osteoporotic fracture and is associated with immobility and mortality. Bone anabolic agents, such as abaloparatide (ABL), are usually administered to patients with OVF to prevent subsequent fractures. Although several studies have shown that bone anabolic agents promote healing of long bone fractures, there is little evidence of their healing effect on vertebral bone fractures. In the present study, we investigated the effect of ABL on vertebral bone defects using ovariectomized (OVX) rats with vertebral body drill-hole defects, an animal model of OVF. Eight-week-old female Sprague-Dawley rats were subjected to OVX, followed by the 32-36 days of bone depletion period, once-daily subcutaneous ABL was administered to OVX rats at a dose of 30 μg/kg for a maximum of 6 weeks from the day of the vertebral defect surgery. We found that ABL significantly increased bone mineral content and improved trabecular structural parameters at the vertebral defect site. Moreover, ABL significantly increased bone strength of the defected vertebrae. Bone histochemical analysis revealed formation of thick trabecular bone networks at the defect site after ABL administration, consistent with an improvement in trabecular structural parameters by ABL. ABL increased ALPase- and PHOSPHO1-positive osteoblastic cells and ALPase/PCNA double-positive cells, indicating enhanced preosteoblast proliferation as well as bone formation at the defect site. On the other hand, ABL did not affect the number of cathepsin K-positive osteoclasts per bone surface, suggesting that ABL did not promote excessive bone resorption. Our findings suggest that ABL is useful not only for preventing secondary vertebral fractures but also for promoting bone healing in OVF.
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Affiliation(s)
- Akito Makino
- Pharmacology Research Department, Teijin Pharma Limited, Tokyo, Japan.
| | - Tomoka Hasegawa
- Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tomomaya Yamamoto
- Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Hideko Takagi
- Pharmacology Research Department, Teijin Pharma Limited, Tokyo, Japan
| | | | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Norio Amizuka
- Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
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Igarashi S, Kasukawa Y, Nozaka K, Tsuchie H, Abe K, Saito H, Shoji R, Kasama F, Harata S, Okamoto K, Oya K, Miyakoshi N. Teriparatide and etelcalcetide improve bone, fibrosis, and fat parameters in chronic kidney disease model rats. Osteoporos Sarcopenia 2023; 9:121-130. [PMID: 38374820 PMCID: PMC10874735 DOI: 10.1016/j.afos.2023.11.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Revised: 11/22/2023] [Accepted: 11/27/2023] [Indexed: 02/21/2024] Open
Abstract
Objectives Chronic kidney disease (CKD) complicated by secondary hyperparathyroidism (SHPT) is associated with an increased risk of fragility fractures. Etelcalcetide (EC) is a treatment for SHPT that reduces serum parathyroid hormone (PTH) levels. However, the effects of combined treatment with osteoporosis drugs such as teriparatide (TPTD) remain unclear. This study investigates the combined effects of EC and TPTD on bone in CKD model rats. Methods The CKD model was established in 8-week-old male Wistar rats by feeding them a 0.75% adenine diet for 4 weeks. At 20 weeks of age, the rats were divided into 4 groups (N = 9-10 in each group): CKD group (vehicle administration), TPTD group (30 μg/kg, 3 times/week), EC group (0.6 mg/kg, daily), and Comb group (TPTD and EC combined). EC was injected for 12 weeks starting at 20 weeks of age, and TPTD was injected for 8 weeks starting at 24 weeks of age. After treatment, the followings were evaluated: bone mineral density, bone strength, biochemical tests, bone and fat histomorphometry, and micro-computed tomography. Results In CKD model rats, the combination of EC and TPTD was more effective in increasing cortical bone thickness and bone strength and inhibiting porosity. In addition, the combined treatment decreased bone marrow adiposity and fibrosis, and it increased bone mass and improved bone microstructure in trabecular bone. Conclusions With the observed benefits such as improved bone mass, bone strength, structural properties, and bone marrow adiposity, combination therapy may be a potential way to improve bone fragility in CKD.
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Affiliation(s)
- Shun Igarashi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Yuji Kasukawa
- Department of Rehabilitation Medicine, Akita University Hospital, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Koji Nozaka
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Hiroyuki Tsuchie
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Kazunobu Abe
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Hikaru Saito
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Ryo Shoji
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Fumihito Kasama
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Shuntaro Harata
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Kento Okamoto
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Keita Oya
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1, Hondo, Akita, 010-8543, Japan
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Nozaka K, Miyakoshi N, Mita M, Shimada Y. The successful treatment of a Gustilo-Anderson type IIIc distal leg injury with a large bone defect in elderly patient with severe osteoporosis: a case report. J Med Case Rep 2023; 17:452. [PMID: 37828610 PMCID: PMC10571402 DOI: 10.1186/s13256-023-04193-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 01/06/2023] [Indexed: 10/14/2023] Open
Abstract
BACKGROUND Gustilo-Anderson type IIIc tibial open fracture with large bone defects in elderly patients with severe osteoporosis is a rare injury that may be a challenging clinical scenario. CASE PRESENTATION This study presents the case of a 68-year-old Japanese man who sustained a Gustilo-Anderson type IIIc open tibial fracture with a large bone defect. The patient had severe osteoporosis and the bone was contaminated; therefore, we determined that the bone could not be returned to the tibia. The patient underwent acute limb shortening and gradual lengthening with an Ilizarov external fixator combined with low-intensity pulsed ultrasound and teriparatide administration for limb reconstruction, which allowed immediate full weight-bearing capacity. The fixator was removed at 12 months postoperatively, and by this time, the fracture had completely healed. At the most recent 5-year follow-up after the injury, the patient reported full weight-bearing capacity without walking aids and had full knee and ankle range of motion. CONCLUSIONS To the best of our knowledge, this is the first study to report the use of combined Ilizarov technique, low-intensity pulsed ultrasound, and teriparatide for limb reconstruction of Gustilo-Anderson type IIIc open tibial fractures with large bone defects in elderly patients with severe osteoporosis.
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Affiliation(s)
- Koji Nozaka
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Motoki Mita
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yoichi Shimada
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
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Gao H, Huang J, Wei Q, He C. Advances in Animal Models for Studying Bone Fracture Healing. Bioengineering (Basel) 2023; 10:bioengineering10020201. [PMID: 36829695 PMCID: PMC9952559 DOI: 10.3390/bioengineering10020201] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2022] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Fracture is a common traumatic injury that is mostly caused by traffic accidents, falls, and falls from height. Fracture healing is a long-term and complex process, and the mode of repair and rate of healing are influenced by a variety of factors. The prevention, treatment, and rehabilitation of fractures are issues that urgently need to be addressed. The preparation of the right animal model can accurately simulate the occurrence of fractures, identify and observe normal and abnormal healing processes, study disease mechanisms, and optimize and develop specific treatment methods. We summarize the current status of fracture healing research, the characteristics of different animal models and the modeling methods for different fracture types, analyze their advantages and disadvantages, and provide a reference basis for basic experimental fracture modeling.
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Affiliation(s)
- Hui Gao
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Jinming Huang
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Quan Wei
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu 610041, China
- Correspondence: (Q.W.); (C.H.)
| | - Chengqi He
- Rehabilitation Medicine Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu 610041, China
- Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu 610041, China
- Correspondence: (Q.W.); (C.H.)
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Gao J, Liu X, Wu X, Li X, Liu J, Li M. A brief review and clinical evidences of teriparatide therapy for atypical femoral fractures associated with long-term bisphosphonate treatment. Front Surg 2023; 9:1063170. [PMID: 36684309 PMCID: PMC9852062 DOI: 10.3389/fsurg.2022.1063170] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 11/07/2022] [Indexed: 01/07/2023] Open
Abstract
The risk of bisphosphonate (BP)-associated atypical femur fracture (AFF) has markedly increased over recent decades due to suppression of bone turnover, accumulation of structural micro-damage and reduction of bone remodeling consequent to long-term BP treatment. These medications further delay bone union and result in challenging clinical management. Teriparatide (TPTD), a synthetic human parathyroid hormone, exhibits unique anabolic effects and can increase bone remodeling and improve bone microarchitecture, further promoting fracture healing and reducing the rate of bone non-union. In this study, we briefly define AFF as well as the effects of BPs on AFFs, detailed the role of TPTD in AFF management and the latest clinical therapeutic findings. We have confirmed that TPTD positively promotes the healing of AFFs by reducing the time to bone union and likelihood of non-union. Thus, teriparatide therapy could be considered as an alternative treatment for AFFs, however, further research is required for the establishment of effective clinical guidelines of TPTD use in the management of AFF.
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Affiliation(s)
- Jianpeng Gao
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China,National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Xiao Liu
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China,National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China
| | - Xiaoyong Wu
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Xiaoya Li
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China
| | - Jianheng Liu
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China,National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China,Correspondence: Ming Li Jianheng Liu
| | - Ming Li
- Department of Orthopaedics, Chinese PLA General Hospital, Beijing, China,National Clinical Research Center for Orthopedics, Sports Medicine & Rehabilitation, Beijing, China,Correspondence: Ming Li Jianheng Liu
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Png MA, Koh JSB, Mohan PC, Howe CY, Howe TS. Factors affecting healing and progression of conservatively treated incomplete atypical femoral fractures: retrospective observational study. J Bone Miner Metab 2023; 41:61-73. [PMID: 36371726 DOI: 10.1007/s00774-022-01378-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 10/09/2022] [Indexed: 11/14/2022]
Abstract
INTRODUCTION Incomplete atypical femoral fractures (iAFF) may occur with prolonged bisphosphonate usage. Factors influencing iAFF healing and progression are not well understood. This study of conservatively managed iAFF assessed factors influencing iAFF healing and progression including the effects of bisphosphonates and teriparatide use. MATERIALS AND METHODS Single-center retrospective observational study of 69 consecutive patients with 78 radiographically confirmed iAFF from 2002 to 2017. Serial radiographs assessed for focal cortical thickening, dreaded black line (DBL) and complete fracture. Chief outcome measures were DBL healing and complete fracture. RESULTS DBL had a significant association (p < 0.05) with fracture progression by multivariable logistic regression (55.8% versus 25.7%, odds ratio [OR] 26.57 (95% CI 1.40-504.78)) and shorter fracture-free survival (mean 3.21 versus 6.27 years). Presence of symptoms was associated with shorter fracture-free survival (mean 2.68 versus 5.98 years). Discontinuing bisphosphonates had significant associations (p < 0.001) by multivariable logistic regression with decreased fracture rate (11.6% versus 92.0%; OR 0.00, 95% CI 0.00-0.08) and longer fracture-free survival (mean 7.52 versus 1.99 years). DBL healing occurred in 36.4%, only when bisphosphonates were discontinued. Age, sex, race, fracture site, glucocorticoid use, teriparatide supplementation and duration of bisphosphonate use showed no statistically significant effect although teriparatide use appeared to improve DBL healing (50% versus 17.9%, p = 0.188). CONCLUSIONS In conservatively managed iAFF, DBL healing occurred in 36.4% if bisphosphonates were discontinued. Bisphosphonates and DBL were significantly associated with fracture progression and together with symptoms with fracture survival.
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Affiliation(s)
- Meng Ai Png
- Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore, 169608, Republic of Singapore.
| | - Joyce Suang Bee Koh
- Department of Orthopedic Surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Republic of Singapore
| | - P Chandra Mohan
- Department of Diagnostic Radiology, Singapore General Hospital, Outram Road, Singapore, 169608, Republic of Singapore
| | - Choong Yin Howe
- , 36 Jalan Sejarah, Singapore, 299077, Republic of Singapore
| | - Tet Sen Howe
- Department of Orthopedic Surgery, Singapore General Hospital, Outram Road, Singapore, 169608, Republic of Singapore
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Jolic M, Sharma S, Palmquist A, Shah FA. The impact of medication on osseointegration and implant anchorage in bone determined using removal torque-A review. Heliyon 2022; 8:e10844. [PMID: 36276721 PMCID: PMC9582727 DOI: 10.1016/j.heliyon.2022.e10844] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2022] [Revised: 08/16/2022] [Accepted: 09/26/2022] [Indexed: 11/06/2022] Open
Abstract
Permanently anchored metal implants are frequently used in dental, craniomaxillofacial, and orthopaedic rehabilitation. The success of such therapies is owed to the phenomenon of osseointegration-the direct connection between the living bone and the implant. The extent of biomechanical anchorage (i.e., physical interlocking between the implant and bone) can be assessed with removal torque (RTQ) measurement. Implant anchorage is strongly influenced by underlying bone quality, involving physicochemical and biological properties such as composition and structural organisation of extracellular matrix, extent of micro-damage, and bone turnover. In this review, we evaluated the impact of various pharmacological agents on osseointegration, from animal experiments conducting RTQ measurements. In addition to substances whose antiresorptive and/or anti-catabolic effects on bone are well-documented (e.g., alendronate, zoledronate, ibandronate, raloxifene, human parathyroid hormone, odanacatib, and the sclerostin monoclonal antibody), positive effects on RTQ have been reported for substances that do not primarily target bone (e.g., aminoguanidine, insulin, losartan, simvastatin, bone morphogenetic protein, alpha-tocopherol, and the combination of silk fibroin powder and platelet-rich fibrin). On the contrary, several substances (e.g., prednisolone, cyclosporin A, cisplatin, and enamel matrix derivative) tend to adversely impact RTQ. While morphometric parameters such as bone-implant contact appear to influence the biomechanical anchorage, increased or decreased RTQ is not always accompanied by corresponding fluctuations in bone-implant contact. This further confirms that factors such as bone quality underpin biomechanical anchorage of metal implants. Several fundamental questions on drug metabolism and bioavailability, drug dosage, animal-to-human translation, and the consequences of treatment interruption remain yet unanswered.
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Affiliation(s)
- Martina Jolic
- Department of Biomaterials, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE-405 30, Sweden
| | - Sonali Sharma
- Department of Biomaterials, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE-405 30, Sweden
| | - Anders Palmquist
- Department of Biomaterials, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE-405 30, Sweden
| | - Furqan A. Shah
- Department of Biomaterials, Sahlgrenska Academy, University of Gothenburg, Gothenburg, SE-405 30, Sweden
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The effect of osteoporosis and its treatment on fracture healing a systematic review of animal and clinical studies. Bone Rep 2021; 15:101117. [PMID: 34458509 PMCID: PMC8379440 DOI: 10.1016/j.bonr.2021.101117] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/25/2021] [Accepted: 08/10/2021] [Indexed: 01/08/2023] Open
Abstract
Introduction Osteoporosis is characterised by low bone mass and micro-architectural deterioration of bone structure. Its treatment is directed at the processes of bone formation or resorption, that are of utmost importance in fracture healing. We provide a comprehensive review of the literature aiming to summarize and clarify the effects of osteoporosis and its treatment on fracture healing. Material and methods A literature search was conducted in PubMed and Embase (OVID version). In vivo animal and human studies on long bone fractures were included. A total of 93 articles were included for this review; 23 studies on the effect of osteoporosis (18 animal and 5 clinical studies) and 70 studies on the effect of osteoporosis treatment (41 animal, 26 clinical studies and 3 meta-analyses) on fracture healing. Results In animal fracture models osteoporosis was associated with decreased callus formation and bone growth, bone mineral density, biomechanical strength and delayed cellular and differentiation processes during fracture healing. Two large databases identified osteoporosis as a risk factor for non-union whereas three other studies did not. One of those three studies however found a prolonged healing time in patients with osteoporosis. Anti-osteoporosis medication showed inconsistent effects on fracture healing in both non-osteoporotic and osteoporotic animal models. Only the parathyroid hormone and anti-resorption medication were related to improved fracture healing and delayed remodelling respectively. Clinical studies performed in predominantly hip and distal radius fracture patients showed no effect of bisphosphonates on fracture healing. Parathyroid hormone reduced time to union in several clinical trials performed in mainly hip fracture patients, but this did not result in decreased delayed or non-union rates. Conclusion Evidence that substantiates the negative influence of osteoporosis on fracture healing is predominantly from animal studies and to a lesser extent from clinical studies, since convincing clinical evidence lacks. Bisphosphonates and parathyroid hormone may be used during fracture healing, since no clear negative effect has been shown. Parathyroid hormone might even decrease time to fracture union, without decreasing union rate.
Osteoporosis negatively influences fracture healing in animal models. There is no convincing evidence for a similar effect in humans. In animals, bisphosphonates delay bone remodelling In animals, parathyroid hormone improves fracture healing In humans, anti-osteoporotic drugs do not interfere with fracture healing.
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Sato C, Miyakoshi N, Kasukawa Y, Nozaka K, Tsuchie H, Nagahata I, Yuasa Y, Abe K, Saito H, Shoji R, Shimada Y. Teriparatide and exercise improve bone, skeletal muscle, and fat parameters in ovariectomized and tail-suspended rats. J Bone Miner Metab 2021; 39:385-395. [PMID: 33392725 DOI: 10.1007/s00774-020-01184-0] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2020] [Accepted: 11/17/2020] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Although teriparatide (TPTD) and exercise may improve osteoporosis, muscle atrophy, and fat metabolism during ageing, the effects of treatment with a combination of TPTD and exercise on these factors remain unclear. Therefore, this study examined the effects of TPTD and exercise on bone, skeletal muscle, and fat in ovariectomized and tail-suspended rats. MATERIALS AND METHODS Seven-month-old female Wistar rats were ovariectomized and subjected to tail suspension. The rats were then randomized into one of the following four groups (n = 20/group) after 4 weeks: control group, treated with TPTD vehicle and no exercise; TPTD group (30 µg/kg TPTD, 3 days/week); Exercise group (treadmill at 12 m/min, 60 min/day, 5 days/week); and Combined group treated with TPTD and treadmill exercise. After 1 and 8 weeks of treatment, bone, skeletal muscle, and fat tissue parameters were evaluated. RESULTS TPTD improved bone mineral density (BMD), bone structure, bone strength at the femoral metaphysis, and the percentage of skeletal muscle mass, and decreased the percentage of fat mass and the adipose volume in the bone marrow. Treadmill exercise increased BMD, bone strength of cancellous bone, and the percentage of skeletal muscle mass, and decreased the percentage of fat mass as seen on dual-energy X-ray absorptiometry. Furthermore, combined treatment significantly affected BMD, bone structure, and bone strength of cortical bone at the femoral diaphysis. CONCLUSION TPTD or treadmill exercise improved bone, skeletal muscle, and fat mass. Combination therapy with TPTD and exercise had synergistic effects on BMD, structure, and bone strength in ovariectomized, tail-suspended rats.
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Affiliation(s)
- Chiaki Sato
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
| | - Yuji Kasukawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Koji Nozaka
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hiroyuki Tsuchie
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Itsuki Nagahata
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yusuke Yuasa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Kazunobu Abe
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hikaru Saito
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Ryo Shoji
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yoichi Shimada
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
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Etani Y, Ebina K, Hirao M, Kitaguchi K, Kashii M, Ishimoto T, Nakano T, Okamura G, Miyama A, Takami K, Goshima A, Kanamoto T, Nakata K, Yoshikawa H. Combined effect of teriparatide and an anti-RANKL monoclonal antibody on bone defect regeneration in mice with glucocorticoid-induced osteoporosis. Bone 2020; 139:115525. [PMID: 32645445 DOI: 10.1016/j.bone.2020.115525] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 06/21/2020] [Accepted: 07/02/2020] [Indexed: 01/23/2023]
Abstract
OBJECTIVE The purpose of this study was to examine the effect of single or combination therapy of teriparatide (TPTD) and a monoclonal antibody against the murine receptor activator of nuclear factor κB ligand (anti-RANKL Ab) on cancellous and cortical bone regeneration in a mouse model of glucocorticoid-induced osteoporosis (GIOP). METHODS C57BL/6 J mice (24 weeks of age) were divided into five groups: (1) the SHAM group: sham operation + saline; (2) the prednisolone (PSL) group: PSL + saline; (3) the TPTD group: PSL + TPTD; (4) the Ab group: PSL + anti-RANKL Ab; and (5) the COMB group: PSL + TPTD + anti-RANKL Ab (n = 8 per group). With the exception of the SHAM group, 7.5 mg of PSL was inserted subcutaneously into mice, to generate a mouse model of GIOP. Four weeks after insertion, bone defects with a diameter of 0.9 mm were created to assess bone regeneration on both femoral metaphysis (cancellous bone) and diaphysis (cortical bone). After surgery, therapeutic intervention was continued for 4 weeks. Saline (200 μl) or TPTD (40 μg/kg) was injected subcutaneously five times per week, whereas the anti-RANKL Ab (5 mg/kg) was injected subcutaneously once on the day after surgery. Subsequently, the following analyses were performed: microstructural assessment of bone regeneration and bone mineral density (BMD) measurement via micro-computed tomography, and histological, histomorphometrical, and biomechanical analyses with nanoindentation. RESULTS The COMB group showed the highest lumbar spine BMD increase (vs. the PSL, TPTD, and Ab groups). The volume of regenerated cancellous bone at the bone defect site was higher in the COMB group compared with the PSL, TPTD, and Ab group. The volume of the regenerated cortical bone was significantly higher in the COMB group compared with the PSL group, and its hardness was significantly higher in the COMB group compared with the PSL and TPTD groups. CONCLUSION In a mouse model of glucocorticoid-induced osteoporosis, the combination therapy of TPTD plus the anti-RANKL Ab increased bone mineral density in the lumbar spine and regenerated cancellous bone volume compared with single administration of each agent, and also increased regenerated cortical bone strength compared with single administration of TPTD.
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Affiliation(s)
- Yuki Etani
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Kosuke Ebina
- Department of Musculoskeletal Regenerative Medicine, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
| | - Makoto Hirao
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Kazuma Kitaguchi
- Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka 560-8565, Japan
| | - Masafumi Kashii
- Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka 560-8565, Japan
| | - Takuya Ishimoto
- Division of Materials and Manufacturing Science, Osaka University Graduate School of Engineering, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Osaka University Graduate School of Engineering, 2-1 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Gensuke Okamura
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Akira Miyama
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Kenji Takami
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Atsushi Goshima
- Department of Orthopaedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Takashi Kanamoto
- Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Ken Nakata
- Department of Health and Sport Sciences, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan
| | - Hideki Yoshikawa
- Department of Orthopaedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharacho, Toyonaka, Osaka 560-8565, Japan
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Yuasa Y, Miyakoshi N, Kasukawa Y, Nagahata I, Akagawa M, Ono Y, Sato C, Tsuchie H, Nozaka K, Nagasawa H, Hongo M, Shimada Y. Effects of bazedoxifene and low-intensity aerobic exercise on bone and fat parameters in ovariectomized rats. J Bone Miner Metab 2020; 38:179-187. [PMID: 31587108 DOI: 10.1007/s00774-019-01045-5] [Citation(s) in RCA: 5] [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: 05/13/2019] [Accepted: 08/29/2019] [Indexed: 12/14/2022]
Abstract
INTRODUCTION Postmenopausal osteoporosis and dyslipidemia are well-known skeletal and metabolic changes in middle-aged women. We investigated the effects of combined treatments with a selective estrogen receptor modulator (SERM) and exercise on bone and fat parameters in ovariectomized (OVX) rats. MATERIALS AND METHODS Sixteen-week-old female Sprague-Dawley rats underwent bilateral ovariectomy, and rats were randomized to BZA (bazedoxifene at 0.3 mg/kg/day), Exe (treadmill exercise at 12-15 m/min, 60 min/day, 5 days/week), Comb (BZA and Exe), and Cont (control treated with vehicle and no exercise) groups 8 weeks after ovariectomy. After 4 or 8 weeks of treatment, bone mineral density (BMD) of the total femur and lumbar spine and whole-body percentage fat mass were determined by dual-energy X-ray absorptiometry, and mechanical testing of the femoral shaft, and bone and fat histomorphometric analyses of the proximal tibia were performed. RESULTS Treadmill exercise had decreased bone marrow adipocytes from 4 weeks of treatment and whole-body percentage fat mass at 8 weeks. BZA increased BMD at the lumbar spine and decreased the whole-body percentage fat mass from 4 weeks and bone marrow adipocytes at 8 weeks. Combination therapy increased BMD for the lumbar spine and decreased bone marrow adipocytes and whole-body percentage fat mass from 4 weeks. CONCLUSION Combination therapy with BZA and exercise appears effective to improve bone and fat parameters in OVX rats.
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Affiliation(s)
- Yusuke Yuasa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan.
| | - Yuji Kasukawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Itsuki Nagahata
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Manabu Akagawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yuichi Ono
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Chiaki Sato
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hiroyuki Tsuchie
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Koji Nozaka
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Hiroyuki Nagasawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Michio Hongo
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yoichi Shimada
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
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Combined antisclerostin antibody and parathyroid hormone (1–34) synergistically enhance the healing of bone defects in ovariectomized rats. Z Gerontol Geriatr 2020; 53:163-170. [DOI: 10.1007/s00391-019-01685-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2018] [Accepted: 07/04/2019] [Indexed: 01/24/2023]
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Ikeda S, Nakamura E, Narusawa K, Fukuda F, Matsumoto H, Nakai K, Sakata T, Yoshioka T, Fujino Y, Sakai A. Comparison of once-weekly teriparatide and alendronate against new osteoporotic vertebral fractures at week 12. J Bone Miner Metab 2020; 38:44-53. [PMID: 31297652 DOI: 10.1007/s00774-019-01023-x] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/09/2019] [Accepted: 06/25/2019] [Indexed: 10/26/2022]
Abstract
The objective of the present multicenter randomized study was to compare weekly teriparatide with alendronate in their inhibition of vertebral collapse, effects on delayed union, pain relief, and improvement of quality of life (QOL) in women with new osteoporotic vertebral fractures within 1 week after onset of the fracture. Patients were randomly allocated to the teriparatide and alendronate groups. Vertebral collapse, low back pain assessed by a visual analog scale, and QOL assessed by EuroQol 5 dimension at weeks 1, 2, 4, 8, and 12 after the start of the treatment were compared between the groups. Lumbar bone mineral density (BMD) at baseline and week 12 and the rate of delayed union at week 12 were also compared. Each group consisted of 48 subjects. Vertebral collapse progressed over time in both groups, with no significant difference between the groups. Pain on rising up from lying position, turning over in bed, and resting in the lying position improved over time in both groups, with no significant difference between the groups. There were no significant differences in increase in BMD and delayed union. QOL in the teriparatide group showed significant improvement in comparison with that in the alendronate group at week 12. The weekly formulation of teriparatide showed comparable inhibition of vertebral collapse, increase in BMD, promotion of bone union, and improvement of pain and significant improvement of QOL at week 12 in comparison with alendronate in patients with a new osteoporotic vertebral fracture within 1 week after onset of the fracture. The weekly formulation of teriparatide may have improved components of QOL other than pain at week 12.
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Affiliation(s)
- Satoshi Ikeda
- Department of Orthopaedic Surgery, Ken-Ai Memorial Hospital, Onga, Japan.
| | - Eiichiro Nakamura
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
| | - Kenichiro Narusawa
- Department of Orthopaedic Surgery, Nakashibetsu Town Hospital, Nakashibetsu, Japan
| | - Fumio Fukuda
- Department of Orthopaedic Surgery, Kitakyushu General Hospital, Kitakyushu, Japan
| | | | - Kenichiro Nakai
- Department of Orthopaedic Surgery, Moriguchi Ikuno Memorial Hospital, Moriguchi, Japan
| | - Takeshi Sakata
- Department of Orthopaedic Surgery, Kitade Hospital, Gobo, Japan
| | - Toru Yoshioka
- Department of Orthopaedic Surgery, Shimura Hospital, Hiroshima, Japan
| | - Yoshihisa Fujino
- Department of Environmental Epidemiology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Kitakyusyu, Japan
| | - Akinori Sakai
- Department of Orthopaedic Surgery, University of Occupational and Environmental Health, Kitakyushu, Japan
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Kitaguchi K, Kashii M, Ebina K, Kaito T, Okada R, Makino T, Etani Y, Ishimoto T, Nakano T, Yoshikawa H. The combined effects of teriparatide and anti-RANKL monoclonal antibody on bone defect regeneration in ovariectomized mice. Bone 2020; 130:115077. [PMID: 31622773 DOI: 10.1016/j.bone.2019.115077] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2019] [Revised: 09/23/2019] [Accepted: 09/23/2019] [Indexed: 01/01/2023]
Abstract
OBJECTIVE The purpose of this study was to investigate the combined effects of teriparatide (TPTD) and anti-murine receptor activator of nuclear factor-κB ligand monoclonal antibody (anti-RANKL Ab) on both cancellous and cortical bone healing in ovariectomized mice. METHODS Thirteen-week-old mice were divided into the sham-operated group (n=11) or the ovariectomized group (n=44). At 1 month post-operation, all mice underwent bone defect surgery on the left femoral metaphysis (cancellous bone healing model) and right femoral mid-diaphysis (cortical bone healing model). After creating the bone defects, all ovariectomized mice were assigned to one of four groups to receive 1) saline (5 times a week; CNT group), 2) TPTD (40μg/kg 5 times a week; TPTD group), 3) anti-RANKL Ab (5mg/kg once; Ab group), or 4) a combination of TPTD and anti-RANKL Ab (COMB group). The following analyses were performed: Time-course microstructural analysis of healing in both cancellous and cortical bone in the bone defect, measuring the volumetric bone mineral density and the cortical bone thickness of the tibia as a representative of whole body bone with the use of micro-computed tomography, and histological analysis. RESULTS Regeneration of cancellous bone volume in the COMB group was the highest among the four groups, and combined treatment accelerated the formation of medullary callus during the early phase of bone regeneration. On the other hand, there were no significant differences in the regeneration of cortical bone volume during the early phase of bone regeneration among the four groups. Furthermore, lamellar bone was not well identified in the all four groups. Volumetric bone mineral density in the tibia in the COMB group was significantly higher compared with that in the CNT and TPTD groups and tended to be higher compared with that in the Ab group. The mean values of cortical bone thickness in the TPTD and COMB groups were significantly higher than that in the CNT group. CONCLUSION In a mouse model of postmenopausal osteoporosis, combination therapy of TPTD and anti-RANKL Ab accelerates regeneration of cancellous bone more effectively than either agent alone during the early phase of bone regeneration.
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Affiliation(s)
- Kazuma Kitaguchi
- Department of Orthopedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharamachi, Toyonaka, 560-8565, Japan; Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Masafumi Kashii
- Department of Orthopedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharamachi, Toyonaka, 560-8565, Japan; Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Kosuke Ebina
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takashi Kaito
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Rintaro Okada
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takahiro Makino
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Yuki Etani
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takuya Ishimoto
- Division of Materials and Manufacturing Science, Graduate School Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Graduate School Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871, Japan.
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Toyonaka Municipal Hospital, 4-14-1 Shibaharamachi, Toyonaka, 560-8565, Japan; Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.
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Yamashita J, McCauley LK. Effects of Intermittent Administration of Parathyroid Hormone and Parathyroid Hormone-Related Protein on Fracture Healing: A Narrative Review of Animal and Human Studies. JBMR Plus 2019; 3:e10250. [PMID: 31844831 PMCID: PMC6894727 DOI: 10.1002/jbm4.10250] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/01/2019] [Revised: 10/08/2019] [Accepted: 10/30/2019] [Indexed: 12/17/2022] Open
Abstract
Intermittent administration of parathyroid hormone (PTH) stimulates skeletal remodeling and is a potent anabolic agent in bone. PTH‐related protein (PTHrP) is anabolic acting on the same PTH1 receptor and is in therapeutic use for osteoporosis. The body of literature for PTH actions in fracture healing is emerging with promising yet not entirely consistent results. The objective of this review was to perform a literature analysis to extract up‐to‐date knowledge on the effects of intermittent PTH and PTHrP therapy in bone fracture healing. A literature search of the PubMed database was performed. Clinical case studies and articles related to “regeneration,” “implant,” and “distraction osteogenesis” were excluded. A narrative review was performed to deliberate the therapeutic potential of intermittent PTH administration on fracture healing. A smaller number of studies centered on the use of PTHrP or a PTHrP analog were also reviewed. Animal studies clearly show that intermittent PTH therapy promotes fracture healing and revealed the strong therapeutic potential of PTH. Human subject studies were fewer and not as consistent as the animal studies yet provide insight into the potential of intermittent PTH administration on fracture healing. Differences in outcomes for animal and human studies appear to be attributed partly to variable doses, fracture sites, age, remodeling patterns, and bone architectures, although other factors are involved. Future studies to examine the dose, timing, and duration of PTH administration will be necessary to further delineate the therapeutic potential of PTH for fracture healing in humans. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Affiliation(s)
- Junro Yamashita
- Center for Regenerative Medicine, Fukuoka Dental College Fukuoka Japan
| | - Laurie K McCauley
- Department of Periodontics and Oral Medicine, School of Dentistry University of Michigan Ann Arbor MI USA.,Department of Pathology, Medical School University of Michigan Ann Arbor MI USA
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Current and Future Concepts for the Treatment of Impaired Fracture Healing. Int J Mol Sci 2019; 20:ijms20225805. [PMID: 31752267 PMCID: PMC6888215 DOI: 10.3390/ijms20225805] [Citation(s) in RCA: 53] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 11/15/2019] [Accepted: 11/15/2019] [Indexed: 02/06/2023] Open
Abstract
Bone regeneration represents a complex process, of which basic biologic principles have been evolutionarily conserved over a broad range of different species. Bone represents one of few tissues that can heal without forming a fibrous scar and, as such, resembles a unique form of tissue regeneration. Despite a tremendous improvement in surgical techniques in the past decades, impaired bone regeneration including non-unions still affect a significant number of patients with fractures. As impaired bone regeneration is associated with high socio-economic implications, it is an essential clinical need to gain a full understanding of the pathophysiology and identify novel treatment approaches. This review focuses on the clinical implications of impaired bone regeneration, including currently available treatment options. Moreover, recent advances in the understanding of fracture healing are discussed, which have resulted in the identification and development of novel therapeutic approaches for affected patients.
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Locally administrated single-dose teriparatide affects critical-size rabbit calvarial defects: A histological, histomorphometric and micro-CT study. ACTA ORTHOPAEDICA ET TRAUMATOLOGICA TURCICA 2019; 53:478-484. [PMID: 31530436 PMCID: PMC6938999 DOI: 10.1016/j.aott.2019.08.007] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/04/2019] [Revised: 04/08/2019] [Accepted: 08/22/2019] [Indexed: 12/11/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the effect of teriparatide (PTH 1-34, rhPTH) on a rabbit defect model with local xenogen grafts histomorphometrically and radiologically. METHODS For this purpose, two 10 mm diameter critical-size defects were created in the calvaria of 16 rabbits. In the control group, the defect area was filled with a xenogen graft, while in the teriparatide group (PTH 1-34), a xenogen graft combination with 20 mcg teriparatide was used. For both 4 - week and 8 - week study groups, new bone, residual graft, and soft tissue areas were evaluated as well as bone volume histomorphometrically and radiologically. RESULTS Histomorphometrically, there was a significant difference in new bone area values at the 8th week (p < 0.05), but there was no significant difference between the 4 - week values (p > 0.05). There was no statistically significant difference between the groups at both 4 and 8 weeks (p > 0.05). In the radiologically measured total bone volume values, PTH1-34 group values were found to be significantly higher for both 4 - and 8 - weeks values compared to the control groups (p < 0.05). CONCLUSION In this study, rhPTH, which is used locally in defect areas to be repaired with bone grafts, increases both new bone volume and total bone volume.
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Min HK, Ahn JH, Ha KY, Kim YH, Kim SI, Park HY, Rhyu KW, Kim YY, Oh IS, Seo JY, Chang DG, Cho JH. Effects of anti-osteoporosis medications on radiological and clinical results after acute osteoporotic spinal fractures: a retrospective analysis of prospectively designed study. Osteoporos Int 2019; 30:2249-2256. [PMID: 31420700 DOI: 10.1007/s00198-019-05125-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2019] [Accepted: 08/06/2019] [Indexed: 12/28/2022]
Abstract
UNLABELLED Effects of anti-osteoporosis medications such as anti-resorptive and anabolic agents on healing of osteoporotic spinal fracture were retrospectively investigated. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented good pain relief. These findings suggest that proper selection of medication could improve initial management of acute osteoporotic spinal fractures (OSFs). INTRODUCTION Although anti-osteoporosis medications have beneficial effects on prevention of osteoporotic spinal fractures (OSFs), few studies have compared effects of medications on fracture healing following OSFs. Therefore, the purpose of this study was to elucidate the effects of different anti-osteoporosis medications on radiological and clinical outcomes after acute OSFs. METHODS A total of 132 patients diagnosed with acute OSFs were enrolled and allocated into three groups [group I (n = 39, no anti-osteoporosis medication), group II (n = 66, bisphosphonate), and group III (n = 27, parathyroid hormone (PTH)]. Radiological parameters including magnetic resonance (MR) classification, occurrence of intravertebral cleft (IVC), and clinical outcomes such as numerical rating scale (NRS) and Oswestry disability index were assessed. Risk analyses for IVC and progressive collapse were done along the related factors and medication type. RESULTS IVC sign was observed in 30 patients. The rate of IVC sign was lower in group III (7.4%) than that in group I (20.5%) or group II (30.3%), although the difference was not statistically significant. Moreover, the degree of NRS improvement was better in group III than that in group I or group II (5.7 vs. 3.1 vs. 3.5, p < 0.001). On multiple regression analysis, mid-portion type fracture in MR classification was a significant risk factor for progressive OSFs. The use of PTH showed significant lower incidences of occurrence of IVC (odds ratio (OR) = 0.160) and increase in height loss (OR = 0.325). CONCLUSIONS Different anti-osteoporosis medications presented different clinical and radiological results after acute OSFs. The use of anabolic agent significantly enhanced fracture healing, reduced progressive collapse, and presented better clinical outcomes. Proper selection of medication might improve initial management of acute OSFs.
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Affiliation(s)
- H-K Min
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137-701, South Korea
| | - J-H Ahn
- Department of Orthopedic Surgery, Mediplex Sejong Hospital, Incheon, South Korea
| | - K-Y Ha
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137-701, South Korea
| | - Y-H Kim
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137-701, South Korea.
| | - S-I Kim
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137-701, South Korea
| | - H-Y Park
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137-701, South Korea
| | - K-W Rhyu
- Department of Orthopedic Surgery, St. Vincent Hospital, College of Medicine, The Catholic University of Korea, Suwon, South Korea
| | - Y-Y Kim
- Department of Orthopedic Surgery, Daejeon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Daejeon, South Korea
| | - I-S Oh
- Department of Orthopedic Surgery, Incheon St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Incheon, South Korea
| | - J-Y Seo
- Department of Orthopedic Surgery, Jeju National University Hospital, School of Medicine, Jeju National University, Jeju, South Korea
| | - D-G Chang
- Department of Orthopedic Surgery, Sanggye Paik Hospital, College of Medicine, The Inje University, Seoul, South Korea
| | - J-H Cho
- Department of Orthopedic Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, 222 Banpo-Daero, Seocho-Gu, Seoul, 137-701, South Korea
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Carbonel AAF, Vieira MC, Simões RS, Lima PDA, Fuchs LFP, Girão ERC, Cicivizzo GP, Sasso GRS, de Moraes LOC, Soares Junior JM, Baracat EC, Simões MJ, Girão MJBC. Isoflavones improve collagen I and glycosaminoglycans and prevent bone loss in type 1 diabetic rats. Climacteric 2019; 23:75-83. [DOI: 10.1080/13697137.2019.1627314] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Affiliation(s)
- A. A. F. Carbonel
- Department of Morphology and Genetics, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - M. C. Vieira
- Department of Gynecology, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - R. S. Simões
- Department of Obstetrics and Gynecology, Medicine Faculty of University of São Paulo – FMUSP, São Paulo, Brazil
| | - P. D. A. Lima
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Canada
| | - L. F. P. Fuchs
- Department of Gynecology, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - E. R. C. Girão
- Department of Gynecology, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - G. P. Cicivizzo
- Department of Morphology and Genetics, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - G. R. S. Sasso
- Department of Gynecology, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - L. O. Carvalho de Moraes
- Department of Morphology and Genetics, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - J. M. Soares Junior
- Department of Obstetrics and Gynecology, Medicine Faculty of University of São Paulo – FMUSP, São Paulo, Brazil
| | - E. C. Baracat
- Department of Obstetrics and Gynecology, Medicine Faculty of University of São Paulo – FMUSP, São Paulo, Brazil
| | - M. J. Simões
- Department of Morphology and Genetics, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
| | - M. J. B. C. Girão
- Department of Gynecology, Paulista School of Medicine/Federal University of São Paulo – EPM/UNIFESP, São Paulo, Brazil
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Ota M, Takahata M, Shimizu T, Momma D, Hamano H, Hiratsuka S, Amizuka N, Hasegawa T, Iwasaki N. Optimal administration frequency and dose of teriparatide for acceleration of biomechanical healing of long-bone fracture in a mouse model. J Bone Miner Metab 2019; 37:256-263. [PMID: 29721806 DOI: 10.1007/s00774-018-0930-3] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2017] [Accepted: 04/23/2018] [Indexed: 01/05/2023]
Abstract
Despite preclinical studies demonstrating the effectiveness of teriparatide for skeletal repair in small animals, inconclusive data from clinical trials have raised questions regarding the optimal teriparatide dosing regimen for bone repair. To address this, we assessed the effect of teriparatide frequency and dose on long-bone healing using a mouse femur osteotomy/fracture model. Eight-week-old male ICR mice were subjected to open femur osteotomies, then randomized into following five groups (n = 8 per group): vehicle; low dose/high frequency: 3 μg/kg/dose, 3 times/day; low dose/low frequency: 9 μg/kg/dose, 1 time/day; high dose/high frequency: 9 μg/kg/dose, 3 times/day; high dose/low frequency: 27 μg/kg/dose, 1 time/day. Skeletal repair was assessed by microcomputed tomography, mechanical testing, and histology 4 weeks after surgery. High-dose and/or high-frequency teriparatide treatment increased callus bone volume but failed to have a significant impact on the biomechanical recovery of fractured femurs, possibly because of impaired cortical shell formation in fracture calluses. Meanwhile, low-dose/low-frequency teriparatide therapy enhanced callus bone formation without interfering with cortical shell formation despite a lesser increase in callus bone volume, leading to significant two and fourfold increases in ultimate load and stiffness, respectively. Our findings demonstrate that administering teriparatide at higher doses and/or higher frequencies raises fracture callus volume but does not always accelerate the biomechanical recovery of fractured bone, which points to the importance of finding the optimal teriparatide dosing regimen for accelerating skeletal repair.
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Affiliation(s)
- Masahiro Ota
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
| | - Masahiko Takahata
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan.
| | - Tomohiro Shimizu
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
| | - Daisuke Momma
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
| | - Hiroki Hamano
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
| | - Shigeto Hiratsuka
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
| | - Norio Amizuka
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Tomoka Hasegawa
- Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
| | - Norimasa Iwasaki
- Department of Orthopaedic Surgery, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15 Nishi-7, Kita-ku, Sapporo, 060-8638, Japan
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Tao ZS, Zhou WS, Wu XJ, Wang L, Yang M, Xie JB, Xu ZJ, Ding GZ. Single-dose local administration of parathyroid hormone (1-34, PTH) with β-tricalcium phosphate/collagen (β-TCP/COL) enhances bone defect healing in ovariectomized rats. J Bone Miner Metab 2019; 37:28-35. [PMID: 29392472 DOI: 10.1007/s00774-018-0906-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2017] [Accepted: 01/15/2018] [Indexed: 12/26/2022]
Abstract
Parathyroid hormone (1-34, PTH) combined β-tricalcium phosphate (β-TCP) achieves stable bone regeneration without cell transplantation in previous studies. Recently, with the development of tissue engineering slow release technology, PTH used locally to promote bone defect healing become possible. This study by virtue of collagen with a combination of drugs and has a slow release properties, and investigated bone regeneration by β-TCP/collagen (β-TCP/COL) with the single local administration of PTH. After the creation of a rodent critical-sized femoral metaphyseal bone defect, β-TCP/COL was prepared by mixing sieved granules of β-TCP and atelocollagen for medical use, then β-TCP/COL with dripped PTH solution (1.0 µg) was implanted into the defect of OVX rats until death at 4 and 8 weeks. The defected area in distal femurs of rats was harvested for evaluation by histology, micro-CT, and biomechanics. The results of our study show that single-dose local administration of PTH combined local usage of β-TCP/COL can increase the healing of defects in OVX rats. Furthermore, treatments with single-dose local administration of PTH and β-TCP/COL showed a stronger effect on accelerating the local bone formation than β-TCP/COL used alone. The results from our study demonstrate that combination of single-dose local administration of PTH and β-TCP/COL had an additive effect on local bone formation in osteoporosis rats.
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Affiliation(s)
- Zhou-Shan Tao
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China.
| | - Wan-Shu Zhou
- Department of Geriatrics, The Second Affiliated Hospital of Wannan Medical College, No.123, Kangfu Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Xin-Jing Wu
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Lin Wang
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Min Yang
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Jia-Bing Xie
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Zhu-Jun Xu
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
| | - Guo-Zheng Ding
- Department of Trauma Orthopedics, The First Affiliated Hospital of Wannan Medical College, Yijishan Hospital, No. 2, Zhe shan Xi Road, Wuhu, 241001, Anhui, People's Republic of China
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Reddi S, Mada SB, Kumar N, Kumar R, Ahmad N, Karvande A, Kapila S, Kapila R, Trivedi R. Antiosteopenic Effect of Buffalo Milk Casein-Derived Peptide (NAVPITPTL) in Ovariectomized Rats. Int J Pept Res Ther 2018. [DOI: 10.1007/s10989-018-9763-0] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
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25
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Komrakova M, Fiebig J, Hoffmann DB, Krischek C, Lehmann W, Stuermer KM, Sehmisch S. The Advantages of Bilateral Osteotomy Over Unilateral Osteotomy for Osteoporotic Bone Healing. Calcif Tissue Int 2018; 103:80-94. [PMID: 29352329 DOI: 10.1007/s00223-018-0392-6] [Citation(s) in RCA: 7] [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: 08/01/2017] [Accepted: 01/11/2018] [Indexed: 11/28/2022]
Abstract
Most models of osteoporotic bone fractures are performed unilaterally (UL). We investigated healing of tibia osteotomy performed either UL or bilaterally (BL) in ovariectomized rats. Behavior of animals and muscle structure were assessed. Three-month-old female Sprague-Dawley rats were ovariectomized (n = 32). After 10 weeks, half the rats underwent UL osteotomy of tibia metaphysis (right limb) with plate osteosynthesis. The other rats were osteotomized BL. Half of the rats in each group received either standard pain treatment with carprofen (5 mg/kg body weight (BW), 1x/day for 2 days) or carprofen and buprenorphine (5 mg/kg BW, 1x/day and 0.03 mg/kg BW, 2x/day for 5 days) after osteotomy. The UL rats started to load the injured limb from day 27 ± 9; BL rats did this from day 4 ± 4 onward. The UL rats more frequently loaded only one hind limb; BL rats more often loaded both hind limbs. Osteotomy was not bridged in 20% of UL rats and in 4% of BL rats. Callus volume and bone volume fraction were lower in UL group. Weight and fiber size of UL-intact limb muscles were enhanced, compared to the osteotomized limb and those in BL group. Most of the other parameters which assess physiology, activity, body posture, head, or coat were not different. The effect of two pain therapies was not significant on any variable studied. Welfare of the animals was acceptable in all rats. In UL rats, bone healing was delayed. The more advanced healing in BL rats suggested a positive effect of earlier loading. In studies on bone healing, it is advisable to perform BL osteotomy.
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Affiliation(s)
- M Komrakova
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center, Robert-Koch 40, 37075, Goettingen, Germany.
| | - J Fiebig
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center, Robert-Koch 40, 37075, Goettingen, Germany
| | - D B Hoffmann
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center, Robert-Koch 40, 37075, Goettingen, Germany
| | - C Krischek
- Department of Animal Sciences, University of Goettingen, Albrecht-Thaer-Weg 3, 37075, Goettingen, Germany
- Institute of Food Quality and Safety, Foundation University of Veterinary Medicine, Bischofsholer Damm 15, 30173, Hanover, Germany
| | - W Lehmann
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center, Robert-Koch 40, 37075, Goettingen, Germany
| | - K M Stuermer
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center, Robert-Koch 40, 37075, Goettingen, Germany
| | - S Sehmisch
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center, Robert-Koch 40, 37075, Goettingen, Germany
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Jiang L, Zhang W, Wei L, Zhou Q, Yang G, Qian N, Tang Y, Gao Y, Jiang X. Early effects of parathyroid hormone on vascularized bone regeneration and implant osseointegration in aged rats. Biomaterials 2018; 179:15-28. [PMID: 29960821 DOI: 10.1016/j.biomaterials.2018.06.035] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 06/19/2018] [Accepted: 06/22/2018] [Indexed: 01/02/2023]
Abstract
The decreased bone mass and impaired osteogenesis capacities that occur with aging may influence the outcome of dental implants. Parathyroid hormone (PTH) (1-34) is an anabolic agent for the treatment of osteoporosis. However, little is known about its effects and mechanisms on vascularized bone regeneration and implant osseointegration in aging. In current study, we adopted both in vivo and in vitro approaches to explore the mechanisms of early actions of PTH (1-34) on the angiogenic and osteogenic microenvironment to enhance implant osseointegration in aged rats. Daily subcutaneous injections of 30 μg/kg PTH (1-34) were given to female rats aged 20 months beginning on next day of implantation and lasting for 5 weeks. Radiological and histological analysis confirmed that PTH (1-34) improved new bone formation, angiogenesis and implant osseointegration in aged rats in the early stage. The osteogenic potential of aged bone mesenchymal stem cells (BMSCs) was enhanced, while their adipogenesis capacity was attenuated. Furthermore, PTH (1-34) was shown to promote angiogenesis directly via endothelial cell migration and blood vessel formation in vitro. Meanwhile, PTH (1-34) stimulated more osteoclasts participation in bone remodeling by secreting angiogenic and osteogenic growth factors to induce early vascularization and stimulate the migration or differentiation of BMSCs indirectly. Together, these results demonstrate mechanistic insight into how PTH (1-34) regulates the angiogenic and osteogenic microenvironment to result in more active bone remodeling and new bone formation, making it an excellent potential therapeutic agent for rapid vascularized bone regeneration and implant osseointegration in the aged population.
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Affiliation(s)
- Liting Jiang
- Department of Prosthodontics, Ninth People's Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, 200011 Shanghai, China; Department of Stomatology, Ruijin Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, 200025 Shanghai, China
| | - Wenjie Zhang
- Department of Prosthodontics, Ninth People's Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, 200011 Shanghai, China
| | - Li Wei
- Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, 200025 Shanghai, China
| | - Qi Zhou
- Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, 200025 Shanghai, China
| | - Guangzheng Yang
- Department of Prosthodontics, Ninth People's Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, 200011 Shanghai, China
| | - Niandong Qian
- Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, 200025 Shanghai, China
| | - Yun Tang
- Shanghai Institute of Traumatology and Orthopaedics, Ruijin Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, 200025 Shanghai, China
| | - Yiming Gao
- Department of Stomatology, Ruijin Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, 200025 Shanghai, China.
| | - Xinquan Jiang
- Department of Prosthodontics, Ninth People's Hospital affiliated to Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, 200011 Shanghai, China.
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Abstract
PURPOSE OF REVIEW The development of therapeutics that target anabolic pathways involved in skeletogenesis is of great importance with regard to disease resulting in bone loss, or in cases of impaired bone repair. This review aims to summarize recent developments in this area. RECENT FINDINGS A greater understanding of how drugs that modulate signaling pathways involved in skeletogenesis exert their efficacy, and the molecular mechanisms resulting in bone formation has led to novel pharmacological bone repair strategies. Furthermore, crosstalk between pathways and molecules has suggested signaling synergies that may be exploited for enhanced tissue formation. The sequential pharmacological stimulation of the molecular cascades resulting in tissue repair is a promising strategy for the treatment of bone fractures. It is proposed that a therapeutic strategy which mimics the natural cascade of events observed during fracture repair may be achieved through temporal targeting of tissue repair pathways.
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Affiliation(s)
- Scott J Roberts
- Bone Therapeutic Area, UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK.
| | - Hua Zhu Ke
- Bone Therapeutic Area, UCB Pharma, 208 Bath Road, Slough, Berkshire, SL1 3WE, UK
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Zhang W, Zhu J, Ma T, Liu C, Hai B, Du G, Wang H, Li N, Leng H, Xu Y, Song C. Comparison of the effects of once-weekly and once-daily rhPTH (1-34) injections on promoting fracture healing in rodents. J Orthop Res 2018; 36:1145-1152. [PMID: 28960481 DOI: 10.1002/jor.23750] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 09/22/2017] [Indexed: 02/04/2023]
Abstract
To compare the efficacy of once-weekly and once-daily subcutaneous injections of teriparatide (recombinant human parathyroid hormone 1-34) on fracture healing, 50 adult male Sprague-Dawley rats were subjected to a unilateral tibia fracture and received internal fixation with a Kirschner needle. Based on the injection dose and frequency, the rats were randomly divided into five groups (n = 10 each): subcutaneous injections of saline or 10 µg/kg/w, 20 µg/kg/w, 10 µg/kg/d, and 20 µg/kg/d teriparatide. Four weeks later, the rats were euthanatized, and the fractured tibiae were assessed using X-rays, dual-energy X-ray absorptiometry, micro-computed tomography, the three-point bending biomechanics test, and histology. Compared to the saline control group, either daily or weekly subcutaneous injections of teriparatide significantly increased bone mass, improved the bone microarchitecture, and promoted fracture healing (p < 0.05). There were no significant differences in bone mineral density (BMD), bone microstructure or bone strength between the 20 µg/kg/w and 10 µg/kg/d groups (p > 0.05). Teriparatide 20 µg weekly injections promoted bone fracture healing to the same extent as teriparatide 10 µg daily injections, which can dramatically decrease the cumulative dosage of teriparatide injections. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1145-1152, 2018.
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Affiliation(s)
- Wen Zhang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Junxiong Zhu
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Teng Ma
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Can Liu
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Bao Hai
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Guohong Du
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China
| | - Hong Wang
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Nan Li
- Research Center of Clinical Epidemiology, Peking University Third Hospital, Beijing, China
| | - Huijie Leng
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
| | - Yingsheng Xu
- Department of Neurology, Peking University Third Hospital, Beijing, China
| | - Chunli Song
- Department of Orthopaedics, Peking University Third Hospital, Beijing, China.,Beijing Key Laboratory of Spinal Diseases, 49 North Garden Rd Haidian District, Beijing, China
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Prevention of ovariectomy-induced osteoporosis in rats : Comparative study of zoledronic acid, parathyroid hormone (1-34) and strontium ranelate. Z Gerontol Geriatr 2018; 52:139-147. [PMID: 29476205 DOI: 10.1007/s00391-018-1376-x] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2017] [Revised: 12/14/2017] [Accepted: 01/31/2018] [Indexed: 02/08/2023]
Abstract
Recently, the use of the pharmacological agents strontium ranelate (SR), parathyroid hormone (1-34, PTH) and zoledronic acid (ZA) has come to prominence for the treatment of osteoporosis due to their ability to prevent bone loss in osteoporotic patients. Although much emphasis has been placed on using pharmacological agents for the prevention of disease, much less attention has been placed on which one is more effective. There is still no direct comparative study on these three drugs. The aim of the present study was to investigate the effect of SR, PTH, ZA on preventing ovariectomy-induced osteoporosis in rats. After bilateral ovariectomy the rats randomly received vehicle, SR (500 mg/kg body weight/day, orally), PTH (20 μg/kg/day, subcutaneously) or a single injection of ZA (0.1 mg/kg, i.v.) until death at 12 weeks. The distal femurs were harvested for evaluation of bone metabolism. The rats treated with ZA demonstrated the highest levels of new bone formation as assessed by microcomputed tomography (CT), biomechanical strength, histological analysis and bone metabolism. Furthermore, PTH and SR showed a stronger effect on improving trabecular bone mass at 12 weeks. The results from the present study demonstrate that systemic administration of PTH, SR and ZA could prevent bone loss, while a single dose of ZA has a better effect on preventing ovariectomy-induced osteoporosis than either PTH or SR.
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Kitaguchi K, Kashii M, Ebina K, Kaito T, Okada R, Makino T, Noguchi T, Ishimoto T, Nakano T, Yoshikawa H. Effects of single or combination therapy of teriparatide and anti-RANKL monoclonal antibody on bone defect regeneration in mice. Bone 2018; 106:1-10. [PMID: 28978416 DOI: 10.1016/j.bone.2017.09.021] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Revised: 09/15/2017] [Accepted: 09/30/2017] [Indexed: 01/24/2023]
Abstract
OBJECTIVE The purpose of this study is to investigate the effects of a single or combination therapy of teriparatide (TPTD) and anti-RANKL Ab (anti-murine receptor activator of nuclear factor κB ligand monoclonal antibody) on the regeneration of both cancellous and cortical bone. METHODS Nine-week-old mice underwent bone defect surgery on the left femoral metaphysis (cancellous-bone healing model) and right femoral mid-diaphysis (cortical-bone healing model). After surgery, the mice were assigned to 1 of 4 groups to receive 1) saline (5 times a week; CNT group), 2) TPTD (40μg/kg 5 times a week; TPTD group), 3) anti-RANKL Ab (5mg/kg once; Ab group), or 4) a combination of TPTD and anti-RANKL Ab (COMB group). The following analyses were performed: Time-course microstructural analysis of healing in both cancellous and cortical bone in the bone defect, the volumetric bone mineral density of the tibia with micro-computed tomography, histological, histomorphometrical, and biomechanical analysis of regenerated bone. RESULTS Regeneration of cancellous bone volume in the COMB group was the highest among the 4 groups, and this combined administration prompted medullary callus formation in the early phase of bone regeneration. On the other hand, regeneration of cortical bone volume in the COMB group was significantly higher than in the Ab group and was almost same as in the TPTD group. Histological analysis showed remaining woven bones, cartilage matrix, and immature lamellar bone in the COMB and Ab groups. However, biomechanical analysis showed that hardness and Young's modulus of regenerated cortical bone in the COMB group was not lower than in both the CNT and TPTD groups. Volumetric bone mineral density in the tibia was significantly increased in the COMB group compared with the other 3 groups. CONCLUSION In the early phase of bone regeneration, the combination of TPTD and anti-RANKL Ab accelerates regeneration of cancellous bone in bone defects and increases cancellous bone mass in the tibia more effectively than either agent does individually, but these additive effects are not observed in the regeneration of cortical bone.
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Affiliation(s)
- Kazuma Kitaguchi
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Masafumi Kashii
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Kosuke Ebina
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takashi Kaito
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Rintaro Okada
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takahiro Makino
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takaaki Noguchi
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takuya Ishimoto
- Division of Materials and Manufacturing Science, Graduate School Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takayoshi Nakano
- Division of Materials and Manufacturing Science, Graduate School Engineering, Osaka University, 2-1 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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Kumabe Y, Lee SY, Waki T, Iwakura T, Takahara S, Arakura M, Kuroiwa Y, Fukui T, Matsumoto T, Matsushita T, Nishida K, Kuroda R, Niikura T. Triweekly administration of parathyroid hormone (1-34) accelerates bone healing in a rat refractory fracture model. BMC Musculoskelet Disord 2017; 18:545. [PMID: 29268728 PMCID: PMC5740882 DOI: 10.1186/s12891-017-1917-2] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2017] [Accepted: 12/14/2017] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Some reports have shown that intermittent parathyroid hormone (PTH) (1-34) treatment for patients with delayed union or nonunion have led to successful healing. In this study, we investigated whether systemic intermittent administration of PTH (1-34) has a beneficial effect on bone healing in a rat refractory fracture model. METHODS We created a refractory femoral fracture model in 32 rats with periosteal cauterization that leads to atrophic nonunion at 8 weeks after surgery. Half the rats received subcutaneous intermittent human PTH (1-34) injections at a dosage of 100 μg/kg, thrice a week for 8 weeks. The other half received the vehicle only. At 8 weeks after fracture, radiographic, histological and mechanical assessments were performed. RESULTS Radiographic assessments showed that the union rate was significantly higher in the PTH group than in the control group (P < 0.05). The degree of fracture repair as scored using the Allen grading system in histological assessment was significantly greater in the PTH group than in the control group (P < 0.05). The ultimate stress and stiffness measurements were significantly greater in the PTH group than in the control group (p < 0.05). CONCLUSIONS We demonstrated that triweekly administration of PTH (1-34) increased union rate and accelerated bone healing in a rat refractory fracture model, suggesting that systemic administration of PTH (1-34) could become a novel and useful therapy for accelerating fracture healing in patients at high risk of delayed union or nonunion.
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Affiliation(s)
- Yohei Kumabe
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Sang Yang Lee
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.,Department of Orthopaedic Surgery, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo, 142-8666, Japan
| | - Takahiro Waki
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takashi Iwakura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Shunsuke Takahara
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Michio Arakura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Yu Kuroiwa
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoaki Fukui
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Tomoyuki Matsumoto
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takehiko Matsushita
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Kotaro Nishida
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Ryosuke Kuroda
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan
| | - Takahiro Niikura
- Department of Orthopaedic Surgery, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan.
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Kawano T, Miyakoshi N, Kasukawa Y, Hongo M, Tsuchie H, Sato C, Fujii M, Suzuki M, Akagawa M, Ono Y, Yuasa Y, Nagahata I, Shimada Y. Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of glucocorticoid-induced osteopenia rats. Osteoporos Sarcopenia 2017; 3:185-191. [PMID: 30775528 PMCID: PMC6372826 DOI: 10.1016/j.afos.2017.11.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2017] [Revised: 10/15/2017] [Accepted: 11/05/2017] [Indexed: 01/30/2023] Open
Abstract
OBJECTIVES Glucocorticoid (GC) treatment inhibits activation of runt-related transcription factor 2 (Runx2), which is essential for osteoblast differentiation from stem cells. As a result, GC treatment results in bone loss, GC-induced osteoporosis (GIO), elevated fracture risk, and delayed bone healing. Bisphosphonates such as alendronate (ALN) are recommended for treating or preventing GIO, and low-intensity pulsed ultrasound (LIPUS) facilitates fracture healing and maturation of regenerated bone. Combined therapy with ALN and LIPUS may stimulate cancellous bone healing in GIO rats. Here, we examined the effect of ALN and LIPUS on cancellous bone osteotomy repair in the proximal tibia of GIO rats. METHODS Prednisolone (10 mg/kg body weight/day) was administered for 4 weeks to induce GIO in 6-month-old female Sprague-Dawley rats. Tibial osteotomy was then performed and daily subcutaneous injection of ALN (1-μg/kg body weight) was subsequently administered alone or in combination with LIPUS (20 min/day) for 2 or 4 weeks. RESULTS ALN significantly increased bone mineral density (BMD) at 2 and 4 weeks, and ALN + LIPUS significantly increased BMD at 4 weeks. Bone union rates were significantly increased after 2 and 4 weeks ALN and ALN + LIPUS treatment. Lastly, ALN and ALN + LIPUS significantly increased the proportion of Runx2 positive cells at 4 weeks. CONCLUSIONS ALN monotherapy and combined ALN and LUPUS treatment augmented BMD and stimulated cancellous bone repair with increased Runx2 expression at the osteotomy site in GIO rats. However, the combined treatment had no additional effect on cancellous bone healing compared to ALN monotherapy.
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Affiliation(s)
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan
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Kasukawa Y, Miyakoshi N, Ebina T, Hongo M, Ishikawa Y, Kudo D, Nozaka K, Shimada Y. Enhanced bone healing and decreased pain in sacral insufficiency fractures after teriparatide treatment: retrospective clinical-based observational study. ACTA ACUST UNITED AC 2017; 14:140-145. [PMID: 29263722 DOI: 10.11138/ccmbm/2017.14.1.140] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The purpose of this retrospective clinical-based observational study was to evaluate the effects of teriparatide (TPTD) on clinical outcomes and radiologic findings of sacral insufficiency fractures (SIFs). Seven elderly women with SIFs received TPTD for at least 6 months. We evaluated the symptoms, pain, and radiological findings. At their initial clinic visit, 86% patients could not walk or sit. Computed tomography (CT) images revealed sacral wing fracture in 6 patients, and bone scintigram showed H-shaped uptake over the bilateral sacral wings in 1 patient. After the treatment, 5 patients could walk. Mean visual analog scale score was significantly lower after (12.9 mm) than before (87.4 mm) TPTD treatment (p < 0.0001). CT images revealed bone union (four patients) and sclerotic changes (three patients) at the fracture sites. Seven elderly women with SIFs had significant improvement in pain and demonstrated bone union or sclerotic changes at fracture sites by TPTD.
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Affiliation(s)
- Yuji Kasukawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
| | - Toshihito Ebina
- Department of Orthopedic Surgery, Kakunodate General Hospital, Senboku, Japan
| | - Michio Hongo
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
| | - Yoshinori Ishikawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
| | - Daisuke Kudo
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
| | - Koji Nozaka
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
| | - Yoichi Shimada
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, Akita, Japan.,Akita Bone and Osteoporosis Network (A-BONE)
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35
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Komrakova M, Hoffmann DB, Nuehnen V, Stueber H, Wassmann M, Wicke M, Tezval M, Stuermer KM, Sehmisch S. The Effect of Vibration Treatments Combined with Teriparatide or Strontium Ranelate on Bone Healing and Muscle in Ovariectomized Rats. Calcif Tissue Int 2016; 99:408-22. [PMID: 27272029 DOI: 10.1007/s00223-016-0156-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2015] [Accepted: 05/23/2016] [Indexed: 01/14/2023]
Abstract
The aim of the present study was to study the effect of combined therapy of teriparatide (PTH) or strontium ranelate (SR) with whole-body vibration (WBV) on bone healing and muscle properties in an osteopenic rat model. Seventy-two rats (3 months old) were bilaterally ovariectomized (Ovx), and 12 rats were left intact (Non-Ovx). After 8 weeks, bilateral transverse osteotomy was performed at the tibia metaphysis in all rats. Thereafter, Ovx rats were divided into six groups (n = 12): (1) Ovx-no treatment, (2) Ovx + vibration (Vib), (3) SR, (4) SR + Vib, (5) PTH, and (6) PTH + Vib. PTH (40 μg/kg BW sc. 5×/week) and SR (613 mg/kg BW in food daily) were applied on the day of ovariectomy, vibration treatments 5 days later (vertical, 70 Hz, 0.5 mm, 2×/day for 15 min) for up to 6 weeks. In the WBV + SR group, the callus density, trabecular number, and Alp and Oc gene expression were decreased compared to SR alone. In the WBV + PTH group, the cortical and callus widths, biomechanical properties, Opg gene expression, and Opg/Rankl ratio were increased; the cortical and callus densities were decreased compared to PTH alone. A case of non-bridging was found in both vibrated groups. Vibration alone did not change the bone parameters; PTH possessed a stronger effect than SR therapy. In muscles, combined therapies improved the fiber size of Ovx rats. WBV could be applied alone or in combination with anti-osteoporosis drug therapy to improve muscle tissue. However, in patients with fractures, anti-osteoporosis treatments and the application of vibration could have an adverse effect on bone healing.
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Affiliation(s)
- M Komrakova
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany.
| | - D B Hoffmann
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany
| | - V Nuehnen
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany
| | - H Stueber
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany
| | - M Wassmann
- Department of Medical Microbiology, Subdivision of General Hygiene and Environmental Health, University of Goettingen, Humboldallee 34a, 37073, Göttingen, Germany
| | - M Wicke
- Department of Animal Sciences, University of Goettingen, Albrecht-Thaer-Weg 3, 37075, Göttingen, Germany
| | - M Tezval
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany
| | - K M Stuermer
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany
| | - S Sehmisch
- Department of Trauma Surgery and Reconstructive Surgery, University Medicine of Goettingen, Robert-Koch Str. 40, 37075, Göttingen, Germany
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Kim JT, Jeong HJ, Lee SJ, Kim HJ, Yoo JJ. Adjuvant Teriparatide Therapy for Surgical Treatment of Femoral Fractures; Does It Work? Hip Pelvis 2016; 28:148-156. [PMID: 27777917 PMCID: PMC5067391 DOI: 10.5371/hp.2016.28.3.148] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Revised: 07/26/2016] [Accepted: 08/03/2016] [Indexed: 01/17/2023] Open
Abstract
PURPOSE Atypical femoral fracture (AFF), periprosthetic femoral fracture (PPFF) and femoral nonunion (FNU) are recalcitrant challenges for orthopedic surgeons. Teriparatide (TPTD) had been demonstrated to have anabolic effects on bone in various studies. We postulated that adjuvant TPTD after operation would enhance biologic stimulation for bone formation. We investigated (1) whether the adjuvant TPTD could achieve satisfactory union rate of surgically challenging cases such as displaced AFF, PPFF and FNU; (2) whether the adjuvant TPTD could promote development of abundant callus after surgical fixation; (3) whether the adjuvant TPTD had medically serious adverse effects. MATERIALS AND METHODS Thirteen patients who agreed to off label use of TPTD in combination of operation were included in this retrospective case series. Median patients' age was 68.7 years, and there were three male and ten female patients. Their diagnoses were nonunion in six patients and acute fracture in seven. Medical records and radiographic images were reviewed. RESULTS Twelve of thirteen fractures were united both clinically and radiologically within a year after adjuvant TPTD. Union completed radiologically median 5.4 months and clinically 5.7 months after the medication, respectively. Callus appeared abundantly showing median 1.4 of fracture healing response postoperatively. There was no serious adverse reaction of medication other than itching, muscle cramp, or nausea. CONCLUSION Even appropriate surgical treatment is a mainstay of treatment for AFF, PPFF, and FNU, the current report suggested that adjuvant TPTD combined with stable fixation results in satisfactory outcome for the challenging fractures of femur.
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Affiliation(s)
- Jung Taek Kim
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hyung Jun Jeong
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Soong Joon Lee
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea
| | - Hee Joong Kim
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea.; Seoul National University Medical Research Center, Seoul, Korea
| | - Jeong Joon Yoo
- Department of Orthopaedic Surgery, Seoul National University College of Medicine, Seoul, Korea
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Chen B, Lin T, Yang X, Li Y, Xie D, Cui H. Intermittent parathyroid hormone (1-34) application regulates cAMP-response element binding protein activity to promote the proliferation and osteogenic differentiation of bone mesenchymal stromal cells, via the cAMP/PKA signaling pathway. Exp Ther Med 2016; 11:2399-2406. [PMID: 27284327 DOI: 10.3892/etm.2016.3177] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Accepted: 03/01/2016] [Indexed: 12/14/2022] Open
Abstract
The potential effects of intermittent parathyroid hormone (1-34) [PTH (1-34)] administration on bone formation have previously been investigated. A number of studies have suggested that the cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) pathway is associated with PTH-induced osteogenic differentiation. However, the precise signaling pathways and molecular mechanism by which PTH (1-34) induces the osteogenic differentiation of bone mesenchymal stromal cells (BMSCs) remain elusive. The purpose of the present study was to investigate the mechanism underlying the effect of intermittent PTH (1-34) application on the proliferation and osteogenic differentiation of BMSCs. BMSCs were randomly divided into four groups, as follows: Osteogenic medium (control group); osteogenic medium and intermittent PTH (1-34); osteogenic medium and intermittent PTH (1-34) plus the adenylyl cyclase activator forskolin; and osteogenic medium and intermittent PTH (1-34) plus the PKA inhibitor H-89. A cell proliferation assay revealed that PTH (1-34) stimulates BMSC proliferation via the cAMP/PKA pathway. Furthermore, reverse transcription-quantitative polymerase chain reaction, alkaline phosphatase activity testing and cell examination using Alizarin Red S staining demonstrated that PTH (1-34) administration promotes osteogenic differentiation and mineralization, mediated by the cAMP/PKA pathway. Crucially, the results of western blot analyses suggested that PTH (1-34) treatment and, to a greater degree, PTH (1-34) plus forskolin treatment caused an increase in phosphorylated cAMP response element binding protein (p-CREB) expression, but the effect of PTH on p-CREB expression was blocked by H-89. In conclusion, the current study demonstrated that intermittent PTH (1-34) administration regulates downstream proteins, particularly p-CREB, in the cAMP/PKA signaling pathway, to enhance the proliferation, osteogenic differentiation and mineralization of BMSCs.
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Affiliation(s)
- Bailing Chen
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Tao Lin
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
| | - Xiaoxi Yang
- Department of Spine Surgery, Chinese PLA General Hospital (301 Hospital), Beijing 100853, P.R. China
| | - Yiqiang Li
- Department of Orthopedics, Guangzhou Women and Children's Medical Center, Guangzhou, Guangdong 510623, P.R. China
| | - Denghui Xie
- Department of Spine Surgery, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong 510630, P.R. China
| | - Haowen Cui
- Department of Spine Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, P.R. China
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Mansjur KQ, Kuroda S, Izawa T, Maeda Y, Sato M, Watanabe K, Horiuchi S, Tanaka E. The Effectiveness of Human Parathyroid Hormone and Low-Intensity Pulsed Ultrasound on the Fracture Healing in Osteoporotic Bones. Ann Biomed Eng 2016; 44:2480-2488. [PMID: 26795976 DOI: 10.1007/s10439-015-1533-y] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2015] [Accepted: 12/04/2015] [Indexed: 12/12/2022]
Abstract
Osteoporotic fracture has become a major public health problem, and until today, the treatments available are not satisfactory. While there is growing evidence to support the individual treatment of parathyroid hormone (PTH) administration and low-intensity pulsed ultrasound (LIPUS) exposure as respectively systemic and local therapies during osteoporotic fracture healing, their effects have not yet been investigated when introduced concurrently. This study aimed to evaluate the effects of combined treatment with PTH (1-34) and LIPUS on fracture healing in ovariectomized (OVX) rats. Thirty-two, 12-week-old female Sprague-Dawley rats were OVX to induce osteoporosis. After 12 weeks, the rats underwent surgery to create bilateral mid-diaphyseal fractures of proximal tibiae. All animals were randomly divided into 4 groups (n = 8 for each): control group as placebo, PTH group, LIPUS group, and combined group. PTH group had PTH administration at a dose of 30 μg/kg/day for 3 days/week for 6 weeks. LIPUS group received ultrasound 5 days/week for 20 min/day for 6 weeks and combined group had both PTH administration and LIPUS exposure for 6 weeks. Fracture healing was observed weekly by anteroposterior radiography and micro-CT. Five weeks after the fracture, the tibia were harvested to permit histological assessments and at week 6, for mechanical property of the fracture callus. Micro-CT showed that the PTH and combined groups exhibited significantly higher BMD and trabecular bone integrity than control group at weeks 4-6. Radiography, fracture healing score and mean callus area indicated that the combined group revealed better healing processes than the individual groups. Mechanically, bending moment to failure was significantly higher in LIPUS, PTH and combined groups than in control group. These data suggest that the combined treatment of PTH and LIPUS have been shown to accelerate fracture bone healing and enhance bone properties rather than single agent therapy, and may be considered as a treatment remedy for fracture healing in postmenopausal osteoporosis.
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Affiliation(s)
- Karima Q Mansjur
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Shingo Kuroda
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Takashi Izawa
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Yuichi Maeda
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Minami Sato
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Keiichiro Watanabe
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Shinya Horiuchi
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan
| | - Eiji Tanaka
- Department of Orthodontics and Dentofacial Orthopedics, Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramoto-cho, Tokushima, 770-8504, Japan.
- Department of Orthodontics, Faculty of Dentistry, King Abdulaziz University, Jeddah, Saudi Arabia.
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Tsuchie H, Miyakoshi N, Kasukawa Y, Nishi T, Abe H, Segawa T, Shimada Y. The effect of teriparatide to alleviate pain and to prevent vertebral collapse after fresh osteoporotic vertebral fracture. J Bone Miner Metab 2016; 34:86-91. [PMID: 25773046 DOI: 10.1007/s00774-014-0646-y] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2014] [Accepted: 12/11/2014] [Indexed: 10/23/2022]
Abstract
Vertebral fracture is often seen in osteoporotic patients. Teriparatide is expected to promote bone union. Therefore, we evaluated the action of vertebral collapse prevention by administering teriparatide to vertebral fracture patients. Thirty-four patients with fresh vertebral fracture (48 vertebrae) participated in this study. They were administered either teriparatide (daily 20 µg/day or weekly 56.5 µg/week) or risedronate (17.5 mg/week): ten patients (20 vertebrae) received teriparatide daily (Daily group), 11 patients (15 vertebrae) received teriparatide weekly (Weekly group), and 13 patients (14 vertebrae) received risedronate (RIS group). We compared some laboratory examination items, visual analogue scale (VAS) of low back pain, vertebral collapse rate and local kyphotic angle, and the cleft frequency. In addition, we evaluated 22 vertebral fracture patients (24 vertebrae) who did not take any osteoporotic medicines (Control group). There was no significant difference in any of the scores at the start of treatment. At 8 and 12 weeks after the initial visit, VAS scores in the Daily and Weekly groups were significantly lower than in the RIS group (p < 0.05). At 8 and 12 weeks, the vertebral collapse rate and local kyphotic angle in the Daily group were significantly lower than in the RIS and Control groups (p < 0.01 and p < 0.05, respectively), and those in the Weekly group were significantly lower than in the Control group (p < 0.05). The cleft frequency in the Daily group was significantly lower than in the RIS group (p < 0.05). Teriparatide is promising for the prevention of vertebral collapse progression after vertebral fracture.
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Affiliation(s)
- Hiroyuki Tsuchie
- Division of Orthopedic Surgery, Nakadori General Hospital, 3-15, Misono-cho, Minami-dori, Akita, 010-8577, Japan.
| | - Naohisa Miyakoshi
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Yuji Kasukawa
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
| | - Tomio Nishi
- Ugo Municipal Hospital, 44-5 Otomichi, Nishimonai, Ugo, 012-1131, Japan
| | - Hidekazu Abe
- Ugo Municipal Hospital, 44-5 Otomichi, Nishimonai, Ugo, 012-1131, Japan
| | - Toyohito Segawa
- Ugo Municipal Hospital, 44-5 Otomichi, Nishimonai, Ugo, 012-1131, Japan
| | - Yoichi Shimada
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan
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Kim JW, Tatad JCI, Landayan MEA, Kim SJ, Kim MR. Animal model for medication-related osteonecrosis of the jaw with precedent metabolic bone disease. Bone 2015; 81:442-448. [PMID: 26297440 DOI: 10.1016/j.bone.2015.08.012] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2015] [Accepted: 08/14/2015] [Indexed: 10/23/2022]
Abstract
Despite the fact that the medications used to treat abnormal bone conditions often induce osteonecrosis of the jaw (ONJ), previous attempts to establish an animal model for ONJ have shown insufficient consideration for this important prerequisite for the development of the disease. The purpose of this study was to establish an animal model with the most common metabolic bone disease, osteoporosis. Ninty-six rats were randomly divided into ovariectomy (Ov) group (n=48) and sham-operated group (n=48). Six weeks after Ov or sham surgery, rats in each group were subdivided into bisphosphonate group (n=36 each) and control group (n=12 each) and injected with zoledronic acid and normal saline, respectively, once a week. After additional 6weeks, surgical intervention was performed, and the injections were continued for 8 more weeks. The animals were then sacrificed for further macroscopic, histological, histomorphometric, radiological, and bone biomarker investigations. As histologically determined, the Ov group (77.8%) showed higher ONJ prevalence compared to the sham group (47.2%; P<0.05). Micro-structural and histomorphometric assessments revealed that rats with ONJ (ONJ group) presented with deteriorated bone architectures with higher necrotic bone fraction and lower number of osteoclasts (P<0.05). Compared to the sham-operated ONJ group, the Ov ONJ group showed significantly lower values of Tb.N, Tb.Sp, Conn.D, N.Oc/T.Ar, and TRACP 5b and CTX/TRACP (P<0.05). The ovariectomized rat model in this study successfully mimicked human ONJ lesions with an underlying bone disease and showed different bone characteristics than that of the previous ONJ model. Based on the differences, further researches for investigating pathophysiology of ONJ, including various pharmacological responses for deteriorated bone environment, are required.
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Affiliation(s)
- Jin-Woo Kim
- Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, Republic of Korea; Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Jacquiline Czar I Tatad
- Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, Republic of Korea; Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Maria Erika A Landayan
- Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, Republic of Korea; Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
| | - Sun-Jong Kim
- Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, Republic of Korea; Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Medicine, Ewha Womans University, Seoul, Republic of Korea.
| | - Myung-Rae Kim
- Graduate School of Clinical Implant Dentistry, Ewha Womans University, Seoul, Republic of Korea; Research Institute for Intractable Osteonecrosis of the Jaw, School of Medicine, Ewha Womans University, Seoul, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Medicine, Ewha Womans University, Seoul, Republic of Korea
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Matsumoto T, Sato D, Hashimoto Y. Individual and combined effects of noise-like whole-body vibration and parathyroid hormone treatment on bone defect repair in ovariectomized mice. Proc Inst Mech Eng H 2015; 230:30-8. [DOI: 10.1177/0954411915616987] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2015] [Accepted: 10/20/2015] [Indexed: 11/15/2022]
Abstract
The effectiveness of intermittent administration of parathyroid hormone and exposure to whole-body vibration on osteoporotic fracture healing has been previously investigated, but data on their concurrent use are lacking. Thus, we evaluated the effects of intermittent administration of parathyroid hormone, whole-body vibration, and their combination on bone repair in osteoporotic mice. Noise-like whole-body vibration with a broad frequency range was used instead of conventional sine-wave whole-body vibration at a specific frequency. Mice were ovariectomized at 9 weeks of age and subjected to drill-hole surgery in the right tibial diaphysis at 11 weeks. The animals were divided into four groups (n = 12 each): a control group, and groups treated with intermittent administration of parathyroid hormone, noise-like whole-body vibration, and both. From postoperative day 2, the groups treated with intermittent administration of parathyroid hormone and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were subcutaneously administered parathyroid hormone at a dose of 30 µg/kg/day. The groups treated with noise-like whole-body vibration and groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration were exposed to noise-like whole-body vibration at a root mean squared acceleration of 0.3g and frequency components of 45–100 Hz for 20 min/day. Following 18 days of interventions, the right tibiae were harvested, and the regenerated bone was analyzed by micro-computed tomography and nanoindentation testing. Compared with the control group, callus volume fraction was 40% higher in groups treated with intermittent administration of parathyroid hormone and 73% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration, and callus thickness was 35% wider in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration. Indentation modulus was 46% higher in groups treated with noise-like whole-body vibration and 43% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration, and hardness was 31% higher in groups treated with both intermittent administration of parathyroid hormone and noise-like whole-body vibration compared with the control group. There was no interaction between the two treatments for both structure and mechanical indexes. The main effects of intermittent administration of parathyroid hormone and noise-like whole-body vibration on bone repair included increased bone formation and enhanced mechanical function of regenerated bone, respectively. The combined treatment resulted in further regeneration of bone with high indentation modulus and hardness, suggesting the therapeutic potential of the combined use of noise-like whole-body vibration and intermittent administration of parathyroid hormone for enhancing osteoporotic bone healing.
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Affiliation(s)
- Takeshi Matsumoto
- Department of Mechanical Engineering, Graduate School of Advanced Technology and Science, Tokushima University, Tokushima, Japan
- Department of Mechanical Science and Bioengineering, Graduate School of Engineering Science, Osaka University, Toyonaka, Japan
| | - Daisuke Sato
- Department of Systems Science, School of Engineering Science, Osaka University, Toyonaka, Japan
| | - Yoshihiro Hashimoto
- Department of Mechanical Science and Bioengineering, Graduate School of Engineering Science, Osaka University, Toyonaka, Japan
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Babu S, Sandiford NA, Vrahas M. Use of Teriparatide to improve fracture healing: What is the evidence? World J Orthop 2015; 6:457-461. [PMID: 26191492 PMCID: PMC4501931 DOI: 10.5312/wjo.v6.i6.457] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 05/02/2015] [Accepted: 06/02/2015] [Indexed: 02/06/2023] Open
Abstract
Teriparatide is a recombinant form of the biologically active component of Parathyroid hormone. It has been shown to increase bone mass and prevent fractures in osteoporotic bone. It is licensed by the Food and Drug Administration for the treatment of Osteoporosis. Over the last decade, a growing body of evidence has accumulated suggesting a role for Teriparatide in the management of fractures. Studies in both normal and delayed healing models have shown improvement in callus volume and mineralisation, bone mineral content, rate of successful union and strength at fracture sites. However most of these results have been derived from animal studies. The majority of this research on humans has comprised low level evidence, with few randomised controlled trials, many case reports and case series. Nevertheless, the results from these studies seem to support research from animal models. This has led to a growing number of clinicians using Teriparatide “off license” to treat fractures and non-unions in their patients. This review presents a critical appraisal of the current evidence supporting the use of Teriparatide for fracture healing, delayed unions and non unions and in the setting of osteoporotic fractures, the studies producing this evidence and their transferability to human beings.
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Aras MH, Bozdag Z, Demir T, Oksayan R, Yanık S, Sökücü O. Effects of low-level laser therapy on changes in inflammation and in the activity of osteoblasts in the expanded premaxillary suture in an ovariectomized rat model. Photomed Laser Surg 2015; 33:136-44. [PMID: 25719203 DOI: 10.1089/pho.2014.3820] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND AND OBJECTIVE Osteoporosis is a progressive systemic skeletal disease characterized by reduced bone mass/density and microarchitectural deterioration of bone tissue. Bone formation initially exceeds bone resorption, but by the third decade, such formation is reversed, resulting in a net loss of bone mass. This resorption, in turn, increases bone fragility and susceptibility to fracture. This study aimed to evaluate the effects of low-level laser therapy (LLLT) on bone regeneration in the expanded premaxillary suture in an ovariectomized rat model. METHODS Thirty-two 12-week-old female Wistar albino rats were used in the experiment. All of the animals underwent ovariectomy 3 months before the experiment. Expansion appliances were affixed to the maxillary incisors for the expansion of premaxillary sutures. The premaxillary sutures of the laser group were exposed to 5 J/cm(2) laser energy, and no treatment was performed for the controls. All the rats in both groups were euthanized on either the 7th day (n=8) [end of expansion period; Laser Group 1(LG1) and Control Group 1 (CG1)] or the 17th day (n=8) [end of retention period; Laser Group 2 (LG2) and Control Group 2 (CG2)], respectively, for histological assessment. RESULTS Histological findings indicated that the LG1 group showed a significantly higher number of osteoblasts than did the CG1 group (p=0.028). The CG1 and CG2 groups showed a significantly higher number of osteoclasts than did the LG1 and LG2 groups, respectively (p=0.005), (p=0.032). The LG2 group exhibited a capillary increase similar to that of the other groups, without statistically significant differences. CONCLUSIONS On the basis of our methodology and results, we conclude that low-level laser associated with rapid maxillary expansion influences bone regeneration in sutures, thereby accelerating healing, even in ovariectomized rats. We found that LLLT decreased osteoclastic activity in the ovariectomized rats. Therefore, preventing osteoporosis necessitates further investigations to clarify the effect of LLLT on postmenopausal patients.
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Affiliation(s)
- Mutan Hamdi Aras
- 1 Department of Oral and Maxillofacial Surgery, Gaziantep University , Gaziantep, Turkey
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Abstract
Many orthobiologic adjuvants are available and widely utilized for general skeletal restoration. Their use for the specific task of osteoporotic fracture augmentation is less well recognized. Common conductive materials are reviewed for their value in this patient population including the large group of allograft adjuvants categorically known as the demineralized bone matrices (DBMs). Another large group of alloplastic materials is also examined-the calcium phosphate and sulfate ceramics. Both of these materials, when used for the proper indications, demonstrate efficacy for these patients. The inductive properties of bone morphogenic proteins (BMPs) and platelet concentrates show no clear advantages for this group of patients. Systemic agents including bisphosphonates, receptor activator of nuclear factor κβ ligand (RANKL) inhibitors, and parathyroid hormone augmentation all demonstrate positive effects with this fracture cohort. Newer modalities, such as trace ion bioceramic augmentation, are also reviewed for their positive effects on osteoporotic fracture healing.
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Affiliation(s)
- J Tracy Watson
- Orthopaedic Trauma Service, Department of Orthopaedic Surgery, Saint Louis University School of Medicine, 3635 Vista Ave., 7th Floor Desloge Towers, St. Louis, MO, 63110, USA,
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Tsunori K. Effects of parathyroid hormone dosage and schedule on bone regeneration. J Oral Sci 2015; 57:131-6. [DOI: 10.2334/josnusd.57.131] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Affiliation(s)
- Katsuyoshi Tsunori
- Division of Applied Oral Sciences, Nihon University Graduate School of Dentistry
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Santos MA, Florencio-Silva R, Medeiros VP, Nader HB, Nonaka KO, Sasso GRS, Simões MJ, Reginato RD. Effects of different doses of soy isoflavones on bone tissue of ovariectomized rats. Climacteric 2014; 17:393-401. [PMID: 23931625 DOI: 10.3109/13697137.2013.830606] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
AIM Studies report that hormone replacement prevents osteoporosis, but there are doubts whether isoflavones are really efficient in this process. The aim of this study was to evaluate the effects of different doses of soy isoflavones on bone tissue of ovariectomized rats. METHODS Forty female rats at the age of 6 months were ovariectomized and, after 3 months, the animals were divided into four groups: GI - Control (treated with drug vehicle); GII - treated with isoflavones (80 mg/kg per day); GIII - treated with isoflavones (200 mg/kg per day) and GIV - treated with isoflavones (350 mg/kg per day). Soy isoflavones were administered by gavage for 90 consecutive days. After treatment, the rats were euthanized and their distal femurs were removed for histological routine, histochemistry and biochemical study. Histological sections were stained with hematoxylin-eosin or subjected to picrosirius red and alcian blue methods. Shafts of femurs were submitted to biochemical assay and tibias were subjected to biophysical and biomechanical tests. RESULTS In distal femurs, the trabecular bone volume was higher in the groups treated with isoflavones, being higher in GIV, while the cortical bone width and the presence of mature type I collagen fibers were higher in GII. At the trabecular bone region, the percentage of total glycosaminoglycans (GAGs) was higher in GII and the percentage of only sulfated GAGs was higher in GIII, while the higher content of chondroitin sulfate in shafts of femurs was seen in GIV. Biophysical and biomechanical tests in tibias did not differ among the groups. CONCLUSION Our data indicate that soy isoflavones improve bone quality in femurs of rats by increasing histomorphometric parameters, the content of GAGs and mature type I collagen fibers. These positive effects are dose-dependent and it was different in cortical and trabecular bone.
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Affiliation(s)
- M A Santos
- * Federal University of São Paulo, Morphology and Genetics , São Paulo
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Combined effect of teriparatide and low-intensity pulsed ultrasound for nonunion: a case report. BMC Res Notes 2014; 7:317. [PMID: 24886079 PMCID: PMC4059730 DOI: 10.1186/1756-0500-7-317] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 05/21/2014] [Indexed: 12/31/2022] Open
Abstract
Background Low-intensity pulsed ultrasound is a pain-free therapy performed daily at home by the patient and has been shown to promote fracture healing. Teriparatide is a parathyroid hormone preparation that activates osteoblastic bone formation and is also reported to be effective in promoting bony union. Case presentation We report the case of a 56-year-old Japanese male with a femoral shaft fracture who underwent intramedullary osteosynthesis nailing initially. He had no radiologic or clinical sign of healing 3 months later and low-intensity pulsed ultrasound was initiated at that time. He was reassessed in another 3 months, with evidence of mild bone consolidation but the fracture gap persisted. Subsequent treatment with human parathyroid hormone was initiated in combination with low-intensity pulsed ultrasound. Full fracture healing was present 6 months after beginning the combination low-intensity pulsed ultrasound and teriparatide. It is hypothesized that the potential additive effects of low-intensity pulsed ultrasound and teriparatide therapy ultimately triggered sufficient bone formation to support osseous union. Conclusion The case reported herein is a femoral shaft atrophic nonunion in which traditional interventions failed. Successful fracture healing was finally achieved with low-intensity pulsed ultrasound and teriparatide therapy. This is the first reported case of diaphyseal nonunion with deterioration of bone quality in long bones resolved with teriparatide and low-intensity pulsed ultrasound.
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Aonuma H, Miyakoshi N, Kasukawa Y, Kamo K, Sasaki H, Tsuchie H, Segawa T, Shimada Y. Effects of combined therapy of alendronate and low-intensity pulsed ultrasound on metaphyseal bone repair after osteotomy in the proximal tibia of aged rats. J Bone Miner Metab 2014; 32:232-9. [PMID: 23921832 DOI: 10.1007/s00774-013-0492-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2012] [Accepted: 06/17/2013] [Indexed: 12/28/2022]
Abstract
Bisphosphonates and low-intensity pulsed ultrasound (LIPUS) are both known to maintain or promote callus formation during diaphyseal fracture healing. However, the effect of these treatments on the repair of metaphyseal fractures has not been elucidated. To evaluate the effects of bisphosphonates and/or LIPUS on cancellous bone healing, an osteotomy was performed on the proximal tibial metaphysis of 9-month-old Sprague-Dawley rats (n = 64). Treatment with alendronate (1 μg/kg/day), LIPUS (20 min/day), or a combination of both was administered for 2 or 4 weeks, after which changes in bone mineral density (BMD), bone histomorphometric parameters, and the rate of cancellous bony bonding were measured. Alendronate suppressed bone resorption parameters at 2 weeks (p = 0.019) and increased bone volume and BMD at 4 weeks (p = 0.034 and p = 0.008, respectively), without affecting bony bonding. LIPUS had no significant effect on any of the histomorphometric parameters at 2 or 4 weeks, but significantly increased in BMD at 4 weeks (p = 0.026) as well as the percentage of bony bonding at both 2 and 4 weeks (p < 0.01). The combined therapy also showed significantly increased BMD compared with the control group at 4 weeks (p = 0.010) and showed a trend toward increased bony bonding. In conclusion, alendronate and LIPUS cause an additive increase in BMD at the affected metaphysis: alendronate increases the bone volume at the osteotomy site without interrupting metaphyseal repair, whereas LIPUS promotes metaphyseal bone repair, without affecting bone histomorphometric parameters.
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Affiliation(s)
- Hiroshi Aonuma
- Department of Orthopedic Surgery, Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita, 010-8543, Japan,
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Yukata K, Xie C, Li TF, Takahata M, Hoak D, Kondabolu S, Zhang X, Awad HA, Schwarz EM, Beck CA, Jonason JH, O'Keefe RJ. Aging periosteal progenitor cells have reduced regenerative responsiveness to bone injury and to the anabolic actions of PTH 1-34 treatment. Bone 2014; 62:79-89. [PMID: 24530870 PMCID: PMC4085793 DOI: 10.1016/j.bone.2014.02.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2013] [Revised: 01/17/2014] [Accepted: 02/04/2014] [Indexed: 12/20/2022]
Abstract
A stabilized tibia fracture model was used in young (8-week old) and aged (1-year old) mice to define the relative bone regenerative potential and the relative responsiveness of the periosteal progenitor population with aging and PTH 1-34 (PTH) systemic therapy. Bone regeneration was assessed through gene expressions, radiographic imaging, histology/histomorphometry, and biomechanical testing. Radiographs and microCT showed increased calcified callus tissue and enhanced bone healing in young compared to aged mice. A key mechanism involved reduced proliferation, expansion, and differentiation of periosteal progenitor cell populations in aged mice. The experiments showed that PTH increased calcified callus tissue and torsional strength with a greater response in young mice. Histology and quantitative histomorphometry confirmed that PTH increased callus tissue area due primarily to an increase in bone formation, since minimal changes in cartilage and mesenchyme tissue area occurred. Periosteum examined at 3, 5, and 7 days showed that PTH increased cyclin D1 expression, the total number of cells in the periosteum, and width of the periosteal regenerative tissue. Gene expression showed that aging delayed differentiation of both bone and cartilage tissues during fracture healing. PTH resulted in sustained Col10a1 expression consistent with delayed chondrocyte maturation, but otherwise minimally altered cartilage gene expression. In contrast, PTH 1-34 stimulated expression of Runx2 and Osterix, but resulted in reduced Osteocalcin. β-Catenin staining was present in mesenchymal chondroprogenitors and chondrocytes in early fracture healing, but was most intense in osteoblastic cells at later times. PTH increased active β-catenin staining in the osteoblast populations of both young and aged mice, but had a lesser effect in cartilage. Altogether the findings show that reduced fracture healing in aging involves decreased proliferation and differentiation of stem cells lining the bone surface. While PTH 1-34 enhances the proliferation and expansion of the periosteal stem cell population and accelerates bone formation and fracture healing, the effects are proportionately reduced in aged mice compared to young mice. β-Catenin is induced by PTH in early and late fracture healing and is a potential target of PTH 1-34 effects.
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Affiliation(s)
- Kiminori Yukata
- Department of Orthopedics, Tokushima University Hospital, Kuramoto, Tokushima, Japan.
| | - Chao Xie
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Tian-Fang Li
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Masahiko Takahata
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Donna Hoak
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA
| | - Sirish Kondabolu
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Xinping Zhang
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Hani A Awad
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Edward M Schwarz
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Christopher A Beck
- Department of Biostatistics and Computational Biology, University of Rochester, USA.
| | - Jennifer H Jonason
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
| | - Regis J O'Keefe
- The Center for Musculoskeletal Research, University of Rochester, Rochester, NY, USA.
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Florencio-Silva R, Santos MA, de Medeiros VP, Nader HB, Nonaka KO, Simões MJ, Reginato RD. Effects of soy isoflavones and mechanical vibration on rat bone tissue. Climacteric 2013; 16:709-17. [PMID: 23347380 DOI: 10.3109/13697137.2013.769096] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
OBJECTIVE To investigate the effects of soy isoflavones (Iso) and mechanical vibration treatments alone or combined on bone extracellular matrix constituents of ovariectomized rats. METHODS Forty female Wistar rats at the age of 6 months were ovariectomized (Ovx) and ten were sham-operated (sham). After 3 months, the animals were divided into five groups: GI (sham); GII (Ovx); GIII, ovariectomized and orally treated with isoflavones (200 mg/kg) for 90 consecutive days; GIV, ovariectomized and submitted to vibration for 90 days (5 days/week); GV, ovariectomized and treated with isoflavones plus vibration. After treatments, the rats were euthanized, and their femurs were removed for histological routine and biochemical study. Histological sections were stained with hematoxylin-eosin, picrosirius red and alcian blue. Shaft of femurs were submitted to biochemical assay and tibias were subjected to biophysical and biomechanical tests. RESULTS Treatments did not have significant effects on the trabecular bone volume, but the combined treatments showed trophic effects on the cortical bone width and area. Bone density and the content of organic material of the tibias were higher in the GIV and GV groups. The GV group showed the highest presence of mature collagen fibers and content of total glycosaminoglycans, while the highest contents of chondroitin sulfate and other sulfated glycosaminoglycans were seen in the GIV group. CONCLUSION The mechanical vibration treatment is more efficient than soy isoflavones in improving bone quality by increasing the bone density, the content of sulfated glycosaminoglycans and the presence of mature collagen fibers. In addition, the combined interventions have partial trophic and synergistic effects that are bone site-specific in ovariectomized rats.
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Affiliation(s)
- R Florencio-Silva
- Department of Morphology and Genetics, Division of Histology and Structural Biology, Federal University of São Paulo , São Paulo
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