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Guo SH, Li C, Gao YJ, Zhang Z, Lu K. Teriparatide as a non-surgical salvage therapy for prolonged humerus fracture nonunion: A case report and literature review. World J Orthop 2025; 16:101656. [PMID: 39850036 PMCID: PMC11752478 DOI: 10.5312/wjo.v16.i1.101656] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2024] [Revised: 12/12/2024] [Accepted: 01/02/2025] [Indexed: 01/13/2025] Open
Abstract
BACKGROUND Fracture nonunion represents a challenging complication during fracture repair, often necessitating surgical intervention. Teriparatide, a recombinant human parathyroid hormone, has demonstrated promise in enhancing fracture healing, although its efficacy in treating established nonunion remains under investigation. CASE SUMMARY We report a case of a 27-year-old male who presented with a right humerus fracture following a traffic accident. Despite undergoing open reduction and internal fixation, the fracture resulted in a delayed union and subsequent nonunion. After 4 years of conservative management, teriparatide treatment was initiated due to persistent nonunion. Teriparatide injections were administered daily for 6 months, resulting in complete fracture healing and resolution of pain. CONCLUSION Our case demonstrates the successful use of teriparatide in treating a prolonged nonunion of a humerus fracture. Teriparatide may provide a valuable therapeutic option for established bone nonunion, even in cases that have not responded to conservative treatments.
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Affiliation(s)
- Shao-Han Guo
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
| | - Chong Li
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
| | - Yi-Jun Gao
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
| | - Zhen Zhang
- Department of Radiology, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
| | - Ke Lu
- Department of Orthopedics, Affiliated Kunshan Hospital of Jiangsu University, Suzhou 215300, Jiangsu Province, China
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Grossi JRA, Deliberador TM, Giovanini AF, Zielak JC, Sebstiani AM, Gonzaga CC, Coelho PG, Zétola AL, Weiss FP, Benalcázar Jalkh EB, Storrer CLM, Witek L. Effects of local single dose administration of parathormone on the early stages of osseointegration: A pre-clinical study. J Biomed Mater Res B Appl Biomater 2022; 110:1806-1813. [PMID: 35218605 DOI: 10.1002/jbm.b.35038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2021] [Revised: 12/27/2021] [Accepted: 02/09/2022] [Indexed: 11/06/2022]
Abstract
The present study aimed to evaluate the effect of parathormone (PTH) administered directly to the implant's surface prior to insertion, using a large translational animal model. Sixty titanium implants were divided into four groups: (i) Collagen, control group, where implants were coated with Type-I Bovine-collagen, and three experimental groups, where implants received varying doses of PTH: (ii) 12.5, (iii) 25, and (iv) 50 μg, prior to placement. Fifteen female sheep (~2 years old, weighing ~65 kg) received four implants in an interpolated fashion in C3, C4 or C5 vertebral bodies. After 3-, 6- and 12-weeks, samples were harvested, histologically processed, qualitatively and quantitatively assessed for bone-to-implant contact (BIC) and bone area fraction occupancy (BAFO). BIC yielded lower values at 6-weeks for 50 μg relative to the control group, with no significant differences, when compared to the 12.5- and 25-μg. No significant differences were detected at 6-weeks between collagen, 12.5- and 25-μg groups. At 3- and 12-weeks, no differences were detected for BIC among PTH groups. With respect to BAFO, no significant differences were observed between the control and experimental groups independent of PTH concentration and time in vivo. Qualitative observations at 3-weeks indicated the presence of a more mature bone near the implant's surface with the application of PTH, however, no significant differences in new bone formation or healing patterns were observed at 6- and 12-weeks. Single local application of different concentrations of PTH on titanium implant's surface did not influence the osseointegration at any time-point evaluation in low-density bone.
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Affiliation(s)
| | | | | | - João César Zielak
- School of Health Sciences, Graduate Program in Dentistry, Universidade Positivo, Curitiba, Paraná, Brazil
| | | | - Carla Castiglia Gonzaga
- School of Health Sciences, Graduate Program in Dentistry, Universidade Positivo, Curitiba, Paraná, Brazil
| | - Paulo G Coelho
- Department of Biomaterials, New York University College of Dentistry, New York, New York, USA.,Hansjörg Wyss Department of Plastic Surgery, New York University Langone Medical Center, New York, New York, USA.,Department of Mechanical and Aerospace Engineering, New York University Tandon School of Engineering, Brooklyn, New York, USA
| | - André Luis Zétola
- Department of Oral and Maxillofacial Surgery, Universidade Positivo, Curitiba, Paraná, Brazil
| | - Fernando P Weiss
- Department of Biomaterials, New York University College of Dentistry, New York, New York, USA
| | - Ernesto B Benalcázar Jalkh
- Department of Biomaterials, New York University College of Dentistry, New York, New York, USA.,Department of Prosthodontics and Periodontology, University of São Paulo - Bauru School of Dentistry, Bauru, São Paulo, Brazil
| | | | - Lukasz Witek
- Department of Biomaterials, New York University College of Dentistry, New York, New York, USA.,Department of Biomedical Engineering, New York University Tandon School of Engineering, Brooklyn, New York, USA
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Does Systemic Administration of Parathyroid Hormone After Noninstrumented Spinal Fusion Surgery Improve Fusion Rates and Fusion Mass in Elderly Patients Compared to Placebo in Patients With Degenerative Lumbar Spondylolisthesis? Spine (Phila Pa 1976) 2019; 44:157-162. [PMID: 30005049 DOI: 10.1097/brs.0000000000002791] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Prospective, randomized, double-blinded, placebo-controlled clinical trial. OBJECTIVE To evaluate whether 90-day subcutaneous injections with 20 μg teriparatide increases the volume and quality of the fusion mass compared to placebo based on 12-month postop fine cut computed tomography scans. The secondary objective is to evaluate whether parathyroid hormone (PTH) increases fusion rates compared to placebo. SUMMARY OF BACKGROUND DATA Few studies have investigated the effects of PTH on fusion in patients undergoing spinal arthrodesis. Early studies showed a more robust fusion mass with PTH after spinal fusion surgery. But the efficiency of PTH on noninstrumented spinal fusion surgery remains unclear. METHODS Patients with degenerative spondylolisthesis scheduled for noninstrumented posterolateral fusion were randomized to receive 90-day subcutaneous injections with 20 μg teriparatide (N = 41) or placebo (N = 46) in a 1:1 fashion. Fusion volume and quality was evaluated using 12-month postoperative fine cut computed tomography scans. RESULTS The two groups were comparable in terms of age, sex, and numbers of levels operated. PTH treatment was well tolerated but provided no additional benefit versus placebo. Fusion rates, the mean volume, and robustness of the fusion mass were similar between the PTH and placebo groups. CONCLUSION Ninety-day subcutaneous administration of 20 μg teriparatide did not increase fusion volume or improve the quality of the fusion mass in elderly patients compared to placebo after noninstrumented spinal fusion surgery for degenerative spondylolisthesis. LEVEL OF EVIDENCE 1.
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Komatsu J, Nagura N, Iwase H, Igarashi M, Ohbayashi O, Nagaoka I, Kaneko K. Effect of intermittent administration of teriparatide on the mechanical and histological changes in bone grafted with β-tricalcium phosphate using a rabbit bone defect model. Exp Ther Med 2018; 15:19-30. [PMID: 29387179 PMCID: PMC5768114 DOI: 10.3892/etm.2017.5424] [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: 02/02/2016] [Accepted: 02/10/2017] [Indexed: 11/10/2022] Open
Abstract
Grafting β-tricalcium phosphate (TCP) is a well-established method for restoring bone defects; however, there is concern that the mechanical stability of the grafted β-TCP is not maintained during bone translation. Teriparatide has an anabolic effect, stimulating bone formation and increasing bone mineral density for the treatment of osteoporosis. The aim of the present study was to evaluate the effect of intermittent teriparatide treatment on changes in bone grafted with β-TCP using a rabbit bone defect model. Bone defects (5×15 mm) were created in the distal femoral condyle of Japanese white rabbits, and β-TCP granules of two different total porosities were manually grafted. Teriparatide (40 µg/kg) or 0.2% rabbit serum albumin solution as a vehicle control was subcutaneously injected three times per week following the surgery. At 4 or 8 weeks post-surgery, serum samples were obtained and the levels of γ-carboxylated osteocalcin (Gla-OC) were quantified using ELISA. Histomorphometry was also performed using sections of graft sites following staining for tartrate resistant acid phosphatase. Activity and mechanical strength (maximum shear strength, maximum shear stiffness and total energy absorption) were evaluated using an axial push-out load to failure test. Teriparatide treatment significantly increased (P<0.05) the serum levels of Gla-OC, a specific marker for bone formation, suggesting that teriparatide enhances bone formation in β-TCP-grafted rabbits. Furthermore teriparatide increased the degradation of β-TCP by bone remodeling (P<0.05) and promoted the formation of new bone following application of the graft compared with the control group (P<0.01). Furthermore, teriparatide suppressed the reduction in mechanical strength (P<0.05) during bone translation in bone defects grafted with β-TCP. The results of the present study demonstrate that teriparatide is effective in maintaining the mechanical stability of grafted β-TCP, possibly by promoting new bone formation.
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Affiliation(s)
- Jun Komatsu
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Nana Nagura
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Hideaki Iwase
- Department of Bio-Engineering, Juntendo University Institute of Casualty Center, Izunokuni, Shizuoka 410-2295, Japan
| | - Mamoru Igarashi
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Osamu Ohbayashi
- Department of Orthopaedic Surgery, Juntendo University Shizuoka Hospital, Izunokuni, Shizuoka 410-2295, Japan
| | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
| | - Kazuo Kaneko
- Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113-8421, Japan
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Shao Y, Hernandez-Buquer S, Childress P, Stayrook KR, Alvarez MB, Davis H, Plotkin LI, He Y, Condon KW, Burr DB, Warden SJ, Robling AG, Yang FC, Wek RC, Allen MR, Bidwell JP. Improving Combination Osteoporosis Therapy in a Preclinical Model of Heightened Osteoanabolism. Endocrinology 2017; 158:2722-2740. [PMID: 28637206 PMCID: PMC5659666 DOI: 10.1210/en.2017-00355] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2017] [Accepted: 06/15/2017] [Indexed: 11/19/2022]
Abstract
Combining anticatabolic agents with parathyroid hormone (PTH) to enhance bone mass has yielded mixed results in osteoporosis patients. Toward the goal of enhancing the efficacy of these regimens, we tested their utility in combination with loss of the transcription factor Nmp4 because disabling this gene amplifies PTH-induced increases in trabecular bone in mice by boosting osteoblast secretory activity. We addressed whether combining a sustained anabolic response with an anticatabolic results in superior bone acquisition compared with PTH monotherapy. Additionally, we inquired whether Nmp4 interferes with anticatabolic efficacy. Wild-type and Nmp4-/- mice were ovariectomized at 12 weeks of age, followed by therapy regimens, administered from 16 to 24 weeks, and included individually or combined PTH, alendronate (ALN), zoledronate (ZOL), and raloxifene (RAL). Anabolic therapeutic efficacy generally corresponded with PTH + RAL = PTH + ZOL > PTH + ALN = PTH > vehicle control. Loss of Nmp4 enhanced femoral trabecular bone increases under PTH + RAL and PTH + ZOL. RAL and ZOL promoted bone restoration, but unexpectedly, loss of Nmp4 boosted RAL-induced increases in femoral trabecular bone. The combination of PTH, RAL, and loss of Nmp4 significantly increased bone marrow osteoprogenitor number, but did not affect adipogenesis or osteoclastogenesis. RAL, but not ZOL, increased osteoprogenitors in both genotypes. Nmp4 status did not influence bone serum marker responses to treatments, but Nmp4-/- mice as a group showed elevated levels of the bone formation marker osteocalcin. We conclude that the heightened osteoanabolism of the Nmp4-/- skeleton enhances the effectiveness of diverse osteoporosis treatments, in part by increasing hyperanabolic osteoprogenitors. Nmp4 provides a promising target pathway for identifying barriers to pharmacologically induced bone formation.
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Affiliation(s)
- Yu Shao
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Selene Hernandez-Buquer
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Paul Childress
- Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Keith R. Stayrook
- Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Marta B. Alvarez
- Department of Orthopedic Surgery, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Hannah Davis
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Lilian I. Plotkin
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Yongzheng He
- Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202
- Herman B. Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Keith W. Condon
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - David B. Burr
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Stuart J. Warden
- Center for Translational Musculoskeletal Research, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana 46202
- Department of Physical Therapy, School of Health and Rehabilitation Sciences, Indiana University, Indianapolis, Indiana 46202
| | - Alexander G. Robling
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Feng-Chun Yang
- Department of Biochemistry and Molecular Biology, Miller School of Medicine, University of Miami, Miami, Florida 33136
| | - Ronald C. Wek
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
| | - Matthew R. Allen
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
- Richard A. Roudebush Veterans Administration Medical Center, Indianapolis, Indiana 46202
| | - Joseph P. Bidwell
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana 46202
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana 46202
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Liu J, Liang C, Guo B, Wu X, Li D, Zhang Z, Zheng K, Dang L, He X, Lu C, Peng S, Pan X, Zhang BT, Lu A, Zhang G. Increased PLEKHO1 within osteoblasts suppresses Smad-dependent BMP signaling to inhibit bone formation during aging. Aging Cell 2017; 16:360-376. [PMID: 28083909 PMCID: PMC5334543 DOI: 10.1111/acel.12566] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/28/2016] [Indexed: 12/13/2022] Open
Abstract
Emerging evidence indicates that the dysregulation of protein ubiquitination plays a crucial role in aging‐associated diseases. Smad‐dependent canonical BMP signaling pathway is indispensable for osteoblastic bone formation, which could be disrupted by the ubiquitination and subsequent proteasomal degradation of Smad1/5, the key molecules for BMP signaling transduction. However, whether the dysregulation of Smad1/5 ubiquitination and disrupted BMP signaling pathway is responsible for the age‐related bone formation reduction is still underexplored. Pleckstrin homology domain‐containing family O member 1 (PLEKHO1) is a previously identified ubiquitination‐related molecule that could specifically target the linker region between the WW domains of Smurf1 to promote the ubiquitination of Smad1/5. Here, we found an age‐related increase in the expression of PLEKHO1 in bone specimens from either fractured patients or aging rodents, which was associated with the age‐related reduction in Smad‐dependent BMP signaling and bone formation. By genetic approach, we demonstrated that loss of Plekho1 in osteoblasts could promote the Smad‐dependent BMP signaling and alleviated the age‐related bone formation reduction. In addition, osteoblast‐specific Smad1 overexpression had beneficial effect on bone formation during aging, which could be counteracted after overexpressing Plekho1 within osteoblasts. By pharmacological approach, we showed that osteoblast‐targeted Plekho1 siRNA treatment could enhance Smad‐dependent BMP signaling and promote bone formation in aging rodents. Taken together, it suggests that the increased PLEKHO1 could suppress Smad‐dependent BMP signaling to inhibit bone formation during aging, indicating the translational potential of targeting PLEKHO1 in osteoblast as a novel bone anabolic strategy for reversing established osteoporosis during aging.
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Affiliation(s)
- Jin Liu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Chao Liang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Baosheng Guo
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Xiaohao Wu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Defang Li
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Zongkang Zhang
- School of Chinese Medicine; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong SAR China
| | - Kang Zheng
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Basic Research in Clinical Medicine; China Academy of Chinese Medical Sciences; Beijing China
| | - Lei Dang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Xiaojuan He
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Basic Research in Clinical Medicine; China Academy of Chinese Medical Sciences; Beijing China
| | - Changwei Lu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Department of Orthopaedics; Xi'an Third Hospital; Xi'an, Chinajing China
| | - Songlin Peng
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Department of Spine Surgery; Shenzhen People's Hospital; Ji Nan University Second College of Medicine; Shenzhen China
| | - Xiaohua Pan
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Department of Orthopaedics and Traumatology; Bao'an Hospital Affiliated to Southern Medical University & Shenzhen 8th People Hospital; Shenzhen China
| | - Bao-Ting Zhang
- School of Chinese Medicine; Faculty of Medicine; The Chinese University of Hong Kong; Hong Kong SAR China
| | - Aiping Lu
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
| | - Ge Zhang
- Institute for Advancing Translational Medicine in Bone & Joint Diseases; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Integrated Bioinfomedicine and Translational Science; School of Chinese Medicine; Hong Kong Baptist University; Hong Kong SAR China
- Institute of Precision Medicine and Innovative Drug Discovery; Hong Kong Baptist University; Hong Kong SAR China
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Ebata S, Takahashi J, Hasegawa T, Mukaiyama K, Isogai Y, Ohba T, Shibata Y, Ojima T, Yamagata Z, Matsuyama Y, Haro H. Role of Weekly Teriparatide Administration in Osseous Union Enhancement within Six Months After Posterior or Transforaminal Lumbar Interbody Fusion for Osteoporosis-Associated Lumbar Degenerative Disorders: A Multicenter, Prospective Randomized Study. J Bone Joint Surg Am 2017; 99:365-372. [PMID: 28244906 DOI: 10.2106/jbjs.16.00230] [Citation(s) in RCA: 97] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND For elderly patients, posterior lumbar interbody fusion (PLIF) or transforaminal lumbar interbody fusion (TLIF) is usually performed to treat lumbar degenerative diseases. However, some patients exhibit pseudarthrosis following such procedures. The anabolic agent teriparatide is an approved treatment for promoting bone formation in osteoporotic patients. Our multicenter, prospective randomized study assessed the role of once-weekly teriparatide administration on patient outcomes following interbody fusion. METHODS Patients were females who were ≥50 years of age, had a bone mineral density (BMD) of <80% of the sex-matched young adult mean and/or previous spinal compression or femoral fractures, and had lumbar degenerative disease. Patients were randomly allocated to receive either weekly teriparatide, administered subcutaneously starting at week 1, for 6 months postoperatively (the teriparatide arm), or no teriparatide (the control arm). Blinded radiographic evaluations were performed using dynamic radiography and computed tomography (CT) and assessed by modified intention-to-treat analysis and per-protocol analysis. Clinical and neurological symptoms were evaluated using the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOA-BPEQ) and the Oswestry Disability Index (ODI). RESULTS Seventy-five patients were randomized to treatment, and 66 patients completed treatment. At 4 months postoperatively, bone fusion in the 2 center CT slices was significantly higher in the teriparatide arm compared with the control arm in the age-adjusted modified intention-to-treat analysis and was significantly higher at 6 months in the per-protocol analysis. Radiographic examinations showed no disc-space narrowing and no intervertebral disc instability. JOA-BPEQ and ODI results were improved postoperatively in both treatment arms. CONCLUSIONS Weekly administration of teriparatide promoted bone formation at the surgical fusion site and decreased bone resorption, as indicated by bone metabolic marker results, within the early postoperative period. Our findings suggest that combining lumbar interbody fusion and teriparatide treatment may be an effective option for managing lumbar degenerative disease in elderly patients. LEVEL OF EVIDENCE Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
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Affiliation(s)
- Shigeto Ebata
- 1Departments of Orthopaedic Surgery (S.E., T.O., and H.H.) and Health Science for Clinical Medicine (Z.Y.), Graduate School of Medicine, University of Yamanashi, Chuo, Yamanashi, Japan 2Department of Orthopaedic Surgery, Shinshu University School of Medicine, Matsumoto, Nagano, Japan 3Departments of Orthopaedic Surgery (T.H. and Y.M.) and Community Health and Preventive Medicine (Y.S. and T.O.), Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan 4Medical Affairs Department, Pharmaceutical Business Administration Division, Asahi Kasei Pharma Corporation, Tokyo, Japan
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Martin TJ. Parathyroid Hormone-Related Protein, Its Regulation of Cartilage and Bone Development, and Role in Treating Bone Diseases. Physiol Rev 2016; 96:831-71. [DOI: 10.1152/physrev.00031.2015] [Citation(s) in RCA: 99] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Although parathyroid hormone-related protein (PTHrP) was discovered as a cancer-derived hormone, it has been revealed as an important paracrine/autocrine regulator in many tissues, where its effects are context dependent. Thus its location and action in the vasculature explained decades-long observations that injection of PTH into animals rapidly lowered blood pressure by producing vasodilatation. Its roles have been specified in development and maturity in cartilage and bone as a crucial regulator of endochondral bone formation and bone remodeling, respectively. Although it shares actions with parathyroid hormone (PTH) through the use of their common receptor, PTHR1, PTHrP has other actions mediated by regions within the molecule beyond the amino-terminal sequence that resembles PTH, including the ability to promote placental transfer of calcium from mother to fetus. A striking feature of the physiology of PTHrP is that it possesses structural features that equip it to be transported in and out of the nucleus, and makes use of a specific nuclear import mechanism to do so. Evidence from mouse genetic experiments shows that PTHrP generated locally in bone is essential for normal bone remodeling. Whereas the main physiological function of PTH is the hormonal regulation of calcium metabolism, locally generated PTHrP is the important physiological mediator of bone remodeling postnatally. Thus the use of intermittent injection of PTH as an anabolic therapy for bone appears to be a pharmacological application of the physiological function of PTHrP. There is much current interest in the possibility of developing PTHrP analogs that might enhance the therapeutic anabolic effects.
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Affiliation(s)
- T. John Martin
- St Vincent's Institute of Medical Research, Department of Medicine, University of Melbourne, St Vincent's Hospital, Melbourne, Australia
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Isogai Y, Takao-Kawabata R, Takakura A, Sugimoto E, Nakazono O, Ikegaki I, Kuriyama H, Ishizuya T. Early Effects of Single and Low-Frequency Repeated Administration of Teriparatide, hPTH(1-34), on Bone Formation and Resorption in Ovariectomized Rats. Calcif Tissue Int 2015; 97:412-20. [PMID: 26141479 PMCID: PMC4564449 DOI: 10.1007/s00223-015-0026-1] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2015] [Accepted: 06/15/2015] [Indexed: 01/01/2023]
Abstract
Intermittent repeated administration of teriparatide (TPTD) has potent anabolic effects on bones in vivo. However, TPTD has both anabolic and catabolic effects on osteoblasts in vitro, and the mechanisms underlying its promotion of bone formation are unclear. This study aimed to elucidate the time-dependent changes in bone formation and resorption by examining changes in bone turnover markers and bone tissue over time after TPTD administration with low frequency in ovariectomized rats. The amount of serum osteocalcin, a bone formation marker, was transiently reduced after single TPTD administration, but increased thereafter, remaining increased for several days. In contrast, the amount of excreted urinary C-telopeptide, a bone resorption marker, increased transiently after single TPTD administration, and subsequently returned to control levels on the day after administration. Tissue histomorphometric analyses conducted 8 h after administration showed no changes in bone formation or bone resorption parameters. However, at 48 h, the bone formation parameters OS/BS and Ob.S/BS were increased, while the bone resorption parameter ES/BS was decreased. After repeated TPTD administration for 4 weeks, OS/BS, Ob.S/BS, and MS/BS increased, while Oc.S/BS decreased. Serum osteocalcin at 4 weeks after repeated administration was significantly correlated with OS/BS and Ob.S/BS. These present findings indicate that TPTD has dual, time-dependent effects on bone resorption and bone formation. Immediately after single administration, there was transient promotion of bone resorption and suppression of bone formation. However, sustained stimulation of bone formation occurred thereafter. Furthermore, these data suggest that this sustained bone formation led to anabolic effects with repeated TPTD administration.
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Affiliation(s)
- Yukihiro Isogai
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan.
| | - Ryoko Takao-Kawabata
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
| | - Aya Takakura
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
| | - Emika Sugimoto
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
| | - Osamu Nakazono
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
| | - Ichiro Ikegaki
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
| | - Hiroshi Kuriyama
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
| | - Toshinori Ishizuya
- Laboratory for Pharmacology, Pharmaceutical Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni-shi, Shizuoka, 410-2321, Japan
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Gajic-Veljanoski O, Tomlinson G, Srighanthan J, Adachi JD, Josse R, Brown JP, Cheung AM. Effect of odanacatib on BMD and fractures: estimates from Bayesian univariate and bivariate meta-analyses. J Clin Endocrinol Metab 2014; 99:3070-9. [PMID: 24823462 DOI: 10.1210/jc.2014-1162] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
CONTEXT Odanacatib (ODN), a selective cathepsin-K inhibitor, was found to increase bone mineral density (BMD); the effect on fractures is based on adverse event reports. OBJECTIVE To estimate current effects and predict future effects of ODN on BMD and fractures. DATA SOURCES Electronic databases (Medline, EMBASE, Cochrane Library), conference proceedings, and bibliographies. STUDY SELECTION Trials that compared ODN 50 mg/wk to placebo for at least 1 year and reported changes in BMD or fractures. Meta-analysis: Two bone outcomes were pooled as independent and as joint outcomes in Bayesian univariate and bivariate random-effects models. DATA SYNTHESIS Of 32 potentially eligible articles, six citations describing four trials (993 patients) were included. ODN for 3 years increased mean BMD at the lumbar spine by 5.0% (95% credible interval [CrI], 2.7, 7.5), total hip by 3.6% (95% CrI, 1.6, 5.9), and femoral neck (FN) by 3.6% (95% CrI, 1.6, 5.7). In a future trial of 3-year duration, the predicted mean increase in BMD, adjusted for the effect on fractures, was 4.9% for lumbar spine (95% CrI, 2.5, 7.4), 3.4% for total hip (95% CrI, 1.7, 5.2), and 3.5% for FN (95% CrI, 1.8, 5.3). After accounting for the effect on FN BMD, ODN for 3 years was associated with a population odds ratio of 0.38 (95% CrI, 0.1, 0.8). In a future trial, the odds ratio was 0.41 (95% CrI, 0.1, 1.1). The probability of benefit on fractures was 96-99%. The estimates remained robust in sensitivity analyses. CONCLUSIONS Our analyses suggest that ODN will increase BMD and decrease all fractures in the fracture outcome trial; however, direct demonstration of this antifracture efficacy is needed.
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Affiliation(s)
- Olga Gajic-Veljanoski
- Osteoporosis Program (O.G.-V., J.S., A.M.C.), University Health Network/Mt Sinai Hospital, Toronto, ON M5G 2C4, Canada; Institute of Health Policy, Management and Evaluation (G.T., A.M.C.), and Department of Medicine (G.T., R.J., A.M.C.), University of Toronto, Toronto, ON M5T 3M6, Canada; St Joseph's Healthcare and McMaster University (J.D.A.), Hamilton, ON L8N 1Y2, Canada; St Michael's Hospital (R.J.), Toronto, ON M5C 2T2, Canada; and Centre Hospitalier Universitaire de Québec Research Centre and Laval University (J.P.B.), Quebec, QC G1V 4G2, Canada
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