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Raad M, Kim AH, Durand WM, Kebaish KM. Low bone mineral density: a primer for the spine surgeon. Spine Deform 2024; 12:1511-1520. [PMID: 39060777 DOI: 10.1007/s43390-024-00913-z] [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: 04/04/2024] [Accepted: 06/01/2024] [Indexed: 07/28/2024]
Abstract
Within spinal surgery, low bone mineral density is associated with several postoperative complications, such as proximal junctional kyphosis, pseudoarthrosis, and screw loosening. Although modalities such as CT and MRI can be utilized to assess bone quality, DEXA scans, the "Gold Standard" for diagnosing osteoporosis, is not routinely included in preoperative workup. With an increasing prevalence of osteoporosis in an aging population, it is critical for spine surgeons to understand the importance of evaluating bone mineral density preoperatively to optimize postoperative outcomes. The purpose of this state-of-the-art review is to provide surgeons a summary of the evaluation, treatment, and implications of low bone mineral density in patients who are candidates for spine surgery.
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Affiliation(s)
- Micheal Raad
- Department of Orthopaedic Surgery, The Johns Hopkins University, 601 N Caroline St. 5th Floor, Baltimore, MD, 21205, USA
| | - Andrew H Kim
- Department of Orthopaedic Surgery, The Johns Hopkins University, 601 N Caroline St. 5th Floor, Baltimore, MD, 21205, USA
| | - Wesley M Durand
- Department of Orthopaedic Surgery, The Johns Hopkins University, 601 N Caroline St. 5th Floor, Baltimore, MD, 21205, USA
| | - Khaled M Kebaish
- Department of Orthopaedic Surgery, The Johns Hopkins University, 601 N Caroline St. 5th Floor, Baltimore, MD, 21205, USA.
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He XY, Chen HX, Zhao ZR. Efficacy and safety of different anti-osteoporotic drugs for the spinal fusion surgery: A network meta-analysis. World J Clin Cases 2023; 11:7350-7362. [PMID: 37969460 PMCID: PMC10643061 DOI: 10.12998/wjcc.v11.i30.7350] [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: 08/17/2023] [Revised: 09/10/2023] [Accepted: 09/28/2023] [Indexed: 10/25/2023] Open
Abstract
BACKGROUND Administering anti-osteoporotic agents to patients perioperatively is a widely accepted approach for improving bone fusion rates and reducing the risk of complications. The best anti-osteoporotic agents for spinal fusion surgery remain unclear. AIM To investigate the efficacy and safety of different anti-osteoporotic agents in spinal fusion surgery via network meta-analysis. METHODS Searches were conducted in four electronic databases (PubMed, EMBASE, Web of Science, the Cochrane Library and China National Knowledge Infrastructure (CNKI) from inception to November 2022. Any studies that compared anti-osteoporotic agents vs placebo for spinal fusion surgery were included in this network meta-analysis. Outcomes included fusion rate, Oswestry disability index (ODI), and adverse events. Network meta-analysis was performed by R software with the gemtc package. RESULTS In total, 13 randomized controlled trials were included in this network meta-analysis. Only teriparatide (OR 3.2, 95%CI: 1.4 to 7.8) was more effective than placebo in increasing the fusion rate. The surface under the cumulative ranking curve (SUCRA) of teriparatide combined with denosumab was the highest (SUCRA, 90.9%), followed by teriparatide (SUCRA, 74.0%), zoledronic acid (SUCRA, 43.7%), alendronate (SUCRA, 41.1%) and risedronate (SUCRA, 35.0%). Teriparatide (MD -15, 95%CI: -28 to -2.7) and teriparatide combined with denosumab (MD -20, 95%CI: -40 to -0.43) were more effective than placebo in decreasing the ODI. The SUCRA of teriparatide combined with denosumab was highest (SUCRA, 90.8%), followed by teriparatide (SUCRA, 74.5%), alendronate (SURCA, 52.7), risedronate (SURCA, 52.1%), zoledronic acid (SURCA, 24.2%) and placebo (SURCA, 5.6%) for ODI. The adverse events were not different between groups. CONCLUSION This network meta-analysis suggests that teriparatide combined with denosumab and teriparatide alone significantly increase the fusion rate and decrease the ODI without increasing adverse events. Based on current evidence, teriparatide combined with denosumab or teriparatide alone is recommended to increase the fusion rate and to reduce ODI in spinal fusion patients.
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Affiliation(s)
- Xiao-Yuan He
- Spinal Surgery, Hainan Province Clinical Medical Center, Haikou 570100, Hainan Province, China
| | - Huan-Xiong Chen
- Spinal Surgery, Hainan Province Clinical Medical Center, Haikou 570100, Hainan Province, China
| | - Zhi-Rong Zhao
- Spinal Surgery, Hainan Province Clinical Medical Center, Haikou 570100, Hainan Province, China
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Morse KW, Moore H, Kumagai H, Hahn W, Koo A, Meyers KN, Bouxsein ML, Brooks DJ, Lanske B, Iyer S, Cunningham M. Abaloparatide Enhances Fusion and Bone Formation in a Rabbit Spinal Arthrodesis Model. Spine (Phila Pa 1976) 2022; 47:1607-1612. [PMID: 35943233 PMCID: PMC10024932 DOI: 10.1097/brs.0000000000004452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 07/21/2022] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Prospective randomized placebo controlled animal trial. OBJECTIVE Determine the effect of daily subcutaneous abaloparatide injection on the intervertebral fusion rate in rabbits undergoing posterolateral fusion. STUDY OF BACKGROUND DATA Despite the wide utilization of spine fusion, pseudarthrosis remains prevalent, and results in increased morbidity. Abaloparatide is a novel analog of parathyroid hormone-related peptide (1-34) and has shown efficacy in a rat posterolateral spine fusion model to increase fusion rates. The effect of abaloparatide on the fusion rate in a larger animal model remains unknown. MATERIALS AND METHODS A total of 24 skeletally mature New Zealand White male rabbits underwent bilateral posterolateral spine fusion. Following surgery, the rabbits were randomized to receive either saline as control or abaloparatide subcutaneous injection daily. Specimens underwent manual assessment of fusion, radiographic analysis with both x-ray and high-resolution peripheral quantitative computed tomography, and biomechanical assessment. RESULTS Rabbits that received abaloparatide had a 100% (10/10) fusion rate compared with 45% (5/11) for controls ( P <0.02) as assessed by manual palpation. Radiographic analysis determined an overall mean fusion score of 4.17±1.03 in the abaloparatide group versus 3.39±1.21 for controls ( P <0.001). The abaloparatide group also had a greater volume of bone formed with a bone volume of 1209±543 mm 3 compared with 551±152 mm 3 ( P <0.001) for controls. The abaloparatide group had significantly greater trabecular bone volume fraction and trabecular thickness and lower specific bone surface and connectivity density in the adjacent levels when compared with controls. Abaloparatide treatment did not impact trabecular number or separation. There were no differences in biomechanical testing in flexion, extension, or lateral bending ( P >0.05) between groups. CONCLUSIONS Abaloparatide significantly increased the fusion rate in a rabbit posterolateral fusion model as assessed by manual palpation. In addition, there were marked increases in the radiographic evaluation of fusion.
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Affiliation(s)
- Kyle W. Morse
- Department of Spine Surgery, Hospital for Special Surgery, New York, NY, USA
| | - Harold Moore
- Weill Cornell Medical College, New York, NY, USA
| | - Hiroshi Kumagai
- Department of Orthopaedic Surgery, Tsukuba Memorial Hospital, Tsukuba, Japan
| | - William Hahn
- Department of Spine Surgery, Hospital for Special Surgery, New York, NY, USA
| | | | - Kathleen N. Meyers
- Department of Spine Surgery, Hospital for Special Surgery, New York, NY, USA
| | - Mary L. Bouxsein
- Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
- Department of Orthopedic Surgery, Harvard Medical School, Boston, MA, USA
| | - Daniel J. Brooks
- Center for Advanced Orthopaedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center, Boston, MA, USA
| | | | - Sravisht Iyer
- Department of Spine Surgery, Hospital for Special Surgery, New York, NY, USA
| | - Matthew Cunningham
- Department of Spine Surgery, Hospital for Special Surgery, New York, NY, USA
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Drakopoulos P, Flevas DA, Galanopoulos IP, Lepetsos P, Zafeiris C. Off-Label Use of Teriparatide in Spine. Cureus 2021; 13:e16522. [PMID: 34430132 PMCID: PMC8376240 DOI: 10.7759/cureus.16522] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/20/2021] [Indexed: 11/12/2022] Open
Abstract
Teriparatide belongs to osteo-anabolic compounds and has been used in recent years to treat patients with osteoporosis, with the benefits of increased bone density. Its osteo-anabolic action has led to the investigation of the use of teriparatide for the improvement of bone quality. Apart from the enhancement of fracture union, teriparatide has been extensively studied in the promotion of fusion rate after spinal fusion. This study summarizes the preclinical and clinical results of the off-label use of teriparatide in the spine, and specifically its intermittent administration after instrumented spinal arthrodesis along with its impact on the spinal bone quality and spinal bone mineral density.
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Affiliation(s)
- Panagiotis Drakopoulos
- Laboratory for the Research of the Musculoskeletal System, University of Athens, KAT Hospital, Athens, GRC.,Orthopaedics, Thriasio General Hospital, Athens, GRC
| | - Dimitrios A Flevas
- Arthroscopy and Orthopaedic Surgery, Metropolitan General Hospital, Athens, GRC
| | | | | | - Christos Zafeiris
- Orthopaedics and Spine Surgery, Metropolitan General Hospital, Athens, GRC
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Moussalem C, Ftouni L, Abou Mrad Z, Bsat S, Houshiemy M, Alomari S, Omeis I. Negative pharmacological effect on spine fusion: A narrative review of the literature of evidence-based treatment. Clin Neurol Neurosurg 2021; 207:106799. [PMID: 34304068 DOI: 10.1016/j.clineuro.2021.106799] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Revised: 06/27/2021] [Accepted: 07/05/2021] [Indexed: 10/20/2022]
Abstract
Spine fusion surgery is commonly performed for diverse indications, the most frequent one being degenerative spine diseases. Despite the growing importance of this surgery, there is limited evidence concerning the effects of drugs on the process of spine fusion and healing. While asymptomatic sometimes, nonunion of the spine can have tremendous repercussions on the patients' quality of life and the healthcare system rendering it an "expensive complication". This literature review identifies the role of some perioperative drugs in spine fusion and reveals their potential role in pseudarthrosis of the spine. This review also benefits spine surgeons looking for current evidence-based practices. We reviewed the data related to nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, vancomycin, bisphosphonates, proton pump inhibitors (PPIs), pregabalin, and opioids. From the available experimental and clinical studies, we conclude that bisphosphonates might positively influence the process of spine fusion, while steroids and vancomycin have shown variable effects, and the remaining medications likely disturb healing and union of the spine. We recommend spine surgeons be cautious about the drugs they resort to in the critical perioperative period until further clinical studies prove which drugs are safe to be used.
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Affiliation(s)
- Charbel Moussalem
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut 1107 2020, Lebanon.
| | - Louna Ftouni
- Faculty of Medicine, Beirut Arab University, P.O. Box 11-5020, Riad El Solh 1107 2809, Lebanon.
| | - Zaki Abou Mrad
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut 1107 2020, Lebanon.
| | - Shadi Bsat
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut 1107 2020, Lebanon.
| | - Mohamad Houshiemy
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut 1107 2020, Lebanon.
| | - Safwan Alomari
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut 1107 2020, Lebanon.
| | - Ibrahim Omeis
- Division of Neurosurgery, Department of Surgery, American University of Beirut Medical Center, P.O. Box 11-0236, Riad El-Solh, Beirut 1107 2020, Lebanon.
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Govindarajan V, Diaz A, Perez-Roman RJ, Burks SS, Wang MY, Levi AD. Osteoporosis treatment in patients undergoing spinal fusion: a systematic review and meta-analysis. Neurosurg Focus 2021; 50:E9. [PMID: 34062507 DOI: 10.3171/2021.3.focus2175] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Accepted: 03/19/2021] [Indexed: 11/06/2022]
Abstract
OBJECTIVE Bisphosphonates and teriparatide are the most common therapies used in the treatment of osteoporosis. Their impact on fusion rates in osteoporotic patients following spinal fusion has yet to be concretely defined, with previous systematic reviews focusing heavily on bisphosphonates and lacking clinical insight on the utility of teriparatide. Herein the authors present an updated meta-analysis of the utility of both bisphosphonates and teriparatide in improving spinal fusion outcomes in osteoporotic patients. METHODS After a comprehensive search of the English-language literature in the PubMed and Embase databases, 11 clinical studies were included in the final qualitative and quantitative analyses. Of these studies, 9 investigated bisphosphonates, 7 investigated teriparatide, and 1 investigated a combination of teriparatide and denosumab. Odds ratios and 95% confidence intervals were calculated where appropriate. RESULTS A meta-analysis of the postoperative use of bisphosphonate demonstrated better odds of successful fusion as compared to that in controls during short-term monitoring (OR 3.33, 95% CI 1.72-6.42, p = 0.0003) but not long-term monitoring (p > 0.05). Bisphosphonate use was also shown to significantly reduce the likelihood of postoperative vertebral compression fracture (VCF; OR 0.07, 95% CI 0.01-0.59, p = 0.01) and significantly reduce Oswestry Disability Index scores (mean difference [MD] = -2.19, 95% CI -2.94 to -1.44, p < 0.00001) and visual analog scale pain scores (MD = -0.58, 95% CI -0.79 to -0.38, p < 0.00001). Teriparatide was found to significantly increase fusion rates at long-term postoperative periods as compared to rates after bisphosphonate therapy, with patients who received postoperative teriparatide therapy 2.05 times more likely to experience successful fusion (OR 2.05, 95% CI 1.17-3.59, p = 0.01). CONCLUSIONS The authors demonstrate the benefits of bisphosphonate and teriparatide therapy independently in accelerating fusion during the first 6 months after spinal fusion surgery in osteoporotic patients. In addition, they show that teriparatide may have superior benefits in spinal fusion during long-term monitoring as compared to those with bisphosphonates. Bisphosphonates may be better suited in preventing VCFs postoperatively in addition to minimizing postoperative disability and pain.
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Tsai SHL, Chien RS, Lichter K, Alharthy R, Alvi MA, Goyal A, Bydon M, Fu TS, Lin TY. Teriparatide and bisphosphonate use in osteoporotic spinal fusion patients: a systematic review and meta-analysis. Arch Osteoporos 2020; 15:158. [PMID: 33030619 DOI: 10.1007/s11657-020-00738-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2020] [Accepted: 04/13/2020] [Indexed: 02/03/2023]
Abstract
PURPOSE Osteoporosis is one of the most common conditions among adults worldwide. It also presents a challenge among patients undergoing spinal surgery. Use of Teriparatide and bisphosphonates in such patients has been shown to improve outcomes after fusion surgery, including successful fusion, decreased risk of instrumentation failure, and patient-reported outcomes. Herein, we performed a systematic review and indirect meta-analysis of available literature on outcomes of fusion surgery after use of bisphosphonates or Teriparatide. METHODS We conducted a comprehensive search of all databases (Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Ovid Embase, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, and Scopus) to identify studies assessing outcomes of spinal fusion among osteoporotic patients after use of Teriparatide or bisphosphonate. Four authors independently screened electronic search results, and all four authors independently performed study selection. Two authors performed independent data extraction and assessed the studies' risk of bias assessment using standardized forms of Revised Cochrane risk-of-bias tool for randomized trials (RoB 2) and Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I). RESULTS Nineteen studies were included in the final analysis. A total of 13 studies evaluated the difference in fusion rate between bisphosphonates and Teriparatide or control group. Fusion rate was higher for bisphosphonates (effect size (ES) 83%, 95% CI 77-89%) compared with Teriparatide (ES 71%, 95% CI 57-85%), with the p value for heterogeneity between groups without statistical significance (p = 0.123). Five studies assessed the impact of using bisphosphonate or Teriparatide on screw loosening. The rate of screw loosening was higher for bisphosphonates (ES 19%, 95% CI 13-25%) compared with Teriparatide (ES 13%, 95% CI 9-16%) without statistical significance (p = 0.52). CONCLUSION Our results indicate that while both agents may be associated with positive outcomes, bisphosphonates may be associated with a higher fusion rate, while Teriparatide may be associated with lower screw loosening. The decision to treat with either agent should be tailored individually for each patient keeping in consideration the adverse effect and pharmacokinetic profiles.
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Affiliation(s)
- Sung Huang Laurent Tsai
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.,Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung branch, Keelung 204 and School of medicine, Chang Gung University, Taoyuan 333, Taiwan., F7, No 222 Mai-King Road, Keelung, Taiwan
| | - Ruei-Shyuan Chien
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung branch, Keelung 204 and School of medicine, Chang Gung University, Taoyuan 333, Taiwan., F7, No 222 Mai-King Road, Keelung, Taiwan
| | - Katie Lichter
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Raghad Alharthy
- Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA
| | - Mohammed Ali Alvi
- Mayo Clinic Neuro-Informatics Laboratory, Mayo Clinic, Rochester, MN, USA
| | - Anshit Goyal
- Mayo Clinic Neuro-Informatics Laboratory, Mayo Clinic, Rochester, MN, USA
| | - Mohamad Bydon
- Mayo Clinic Neuro-Informatics Laboratory, Mayo Clinic, Rochester, MN, USA.,Department of Neurosurgery, Mayo Clinic, Rochester, MN, USA
| | - Tsai-Sheng Fu
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung branch, Keelung 204 and School of medicine, Chang Gung University, Taoyuan 333, Taiwan., F7, No 222 Mai-King Road, Keelung, Taiwan
| | - Tung-Yi Lin
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital, Keelung branch, Keelung 204 and School of medicine, Chang Gung University, Taoyuan 333, Taiwan., F7, No 222 Mai-King Road, Keelung, Taiwan.
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Weekly Teriparatide Versus Bisphosphonate for Bone Union During 6 Months After Multi-Level Lumbar Interbody Fusion for Osteoporotic Patients: A Multicenter, Prospective, Randomized Study. Spine (Phila Pa 1976) 2020; 45:863-871. [PMID: 32049937 DOI: 10.1097/brs.0000000000003426] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Multicenter, prospective randomized study. OBJECTIVE Evaluate the impact of weekly teriparatide (WT) and bone contact (BC) status of grafted bone in patients recovering from multilevel lumbar interbody fusion (M-LIF). SUMMARY OF BACKGROUND DATA WT has been reported to significantly improve bone fusion following posterior or transforaminal interbody fusion in osteoporosis patients. METHODS Patients older than 50 years and osteoporotic were recruited. We defined the fusion of two or more consecutive intervertebral levels as M-LIF. All patients were instrumented with pedicle, iliac, or S-2 alar iliac screws after transplanting cages and autogenous bone between vertebral bodies. After surgical indication for M-LIF, the subjects were randomly allocated to receive either subcutaneous WT from 1 week to 6 months postoperatively (WT arm, N = 50) or a bisphosphonate (BP; BP arm, N = 54). Blinded radiological evaluations were performed using computed tomography (CT). Evaluation of bone fusion was performed at the intervertebral disc located at the bottom of the fixed range. The degree of bone fusion was calculated as a score from 2 to 6 points, with 2 defined as complete fusion. Bone fusion rate was also compared at 6 months postoperatively based on BC status of the grafted bone on CT immediately after surgery. RESULTS Mean bone fusion score at 6 months postoperatively was 3.9 points in the WT group and 4.2 points in the BP group. The bone fusion rate at 6 months postoperatively tended to be higher in the WT group (46.8% vs. 32.7% in the BP group). The 6-month postoperative fusion rate of immediately postoperative of BC+ patients was significantly higher than that of BC- patients (47.4% vs. 9.5%). CONCLUSION In M-LIF, there were no significant differences in bone fusion score between WT- and BP-treated patients. In contrast, BC status immediately postoperatively had a major impact on 6-month bone fusion. LEVEL OF EVIDENCE 1.
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Intermittent Administration of Parathyroid Hormone Enhances Odonto/Osteogenic Differentiation of Stem Cells from the Apical Papilla via JNK and P38 MAPK Pathways. Stem Cells Int 2020; 2020:5128128. [PMID: 32148520 PMCID: PMC7042551 DOI: 10.1155/2020/5128128] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2019] [Revised: 12/12/2019] [Accepted: 01/23/2020] [Indexed: 02/06/2023] Open
Abstract
Objective Parathyroid hormone (PTH) is considered to be essential during the tooth development. Stem cells from the apical papilla (SCAPs) are responsible for dentine formation. However, the interaction between PTH and SCAPs remains unclear. This study was aimed at investigating the effects of PTH on odonto/osteogenic differentiation capacity of SCAPs and elucidating the underlying molecular mechanisms. Materials and Methods. Here, SCAPs were isolated and identified in vitro. Effects of PTH on the proliferation of SCAPs were determined by Cell Counting Kit-8 (CCK-8), flow cytometry (FCM), and EdU. Alkaline phosphatase (ALP) activity, alizarin red staining, Western blot, and RT-PCR were carried out to detect the odonto/osteogenic differentiation of PTH-treated SCAPs as well as the participation of the MAPK signaling pathway. Results An ALP activity assay determined that 10-8 mol/L PTH was the optimal concentration for the induction of SCAPs with no significant influence on the proliferation of SCAPs as indicated by CCK-8, FCM, and EdU. The expression of odonto/osteogenic markers was significantly upregulated in mRNA levels and protein levels. Moreover, intermittent treatment of PTH also increased phosphorylation of JNK and P38, and the differentiation was suppressed following the inhibition of JNK and P38 MAPK pathways. Conclusion PTH can regulate the odonto/osteogenic differentiation of SCAPs via JNK and P38 MAPK pathways.
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Abstract
Since FDA approval in 2002, teriparatide has gained popularity as an anabolic therapy for the treatment of osteoporosis. Animal studies have suggested a role for teriparatide in spine surgery. Several recent studies have demonstrated adjunctive use of teriparatide in osteoporotic patients undergoing spine fusions improves fusion rates, decreases time to union, and decreases osteoporosis-related complications such as proximal junctional kyphosis. On the basis of the available literature, we outline an algorithm for the use of teriparatide in spine surgery.
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Urinary N-Telopeptide Can Predict Pseudarthrosis After Anterior Cervical Decompression and Fusion: A Prospective Study. Spine (Phila Pa 1976) 2019; 44:770-776. [PMID: 30475338 DOI: 10.1097/brs.0000000000002935] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN Prospective cohort study. OBJECTIVE To examine preoperative urinary cross-linked n-telopeptide (uNTx) and assess for association with fusion rates in patients undergoing single and multi-level anterior cervical decompression and fusion (ACDF). SUMMARY OF BACKGROUND DATA Although high rates of fusion have been reported for ACDF, the risk of pseudarthrosis remains substantial. An established marker of bone turnover, uNTx may prove useful as a predictor of fusion. METHODS Patients undergoing primary ACDF with allograft/plating technique from 2015 to 2017 by a single surgeon were consecutively enrolled and preoperative uNTx was collected. Patients undergoing revision, with creatinine >1.2, and with improperly-collected uNTx were excluded. Demographics, laboratory values, and fusion status were assessed at 6 months, 1 year, and 2 years postoperatively. RESULTS Of the 97 patients enrolled, 69 met inclusion criteria. Of included cases, 41%, 33%, 18%, and 8% underwent 1-, 2-, 3-, and 4-level ACDF, respectively. Overall, fusion rates were 37.3%, 70.9%, and 95.3% at 6 months, 1 year, and 2 years, respectively. uNTx was higher in the fusion group (31.1 vs. 22.2, P = 0.001) at 6 months and 1 year (30.0 vs. 21.0, P = 0.006), with no difference at 2 years. No differences were identified in the proportion of smokers, immunomodulatory agents, corpectomies, or fusion levels between groups. Multivariate regression analysis demonstrated that uNTx is an independent predictor of fusion (odds ratio, OR, 1.124, P = 0.003). Both groups experienced improvements in NDI and VAS neck pain at 6 months with no significant differences noted between groups. Of 16 patients with pseudarthrosis at 1 year, 2 underwent posterior cervical fusion for symptoms. CONCLUSION Preoperative uNTx was greater in patients with successful ACDF fusion compared with patients with pseudarthrosis at 6 months and 1 year. A negative correlation was found between preoperative uNTx and motion on dynamic imaging. These results suggest that uNTx could serve to identify patients at risk for pseudarthrosis after ACDF. LEVEL OF EVIDENCE 3.
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12
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Yoshitake S, Mashiba T, Saito M, Fujihara R, Iwata K, Takao-Kawabata R, Yamamoto T. Once-Weekly Teriparatide Treatment Prevents Microdamage Accumulation in the Lumbar Vertebral Trabecular Bone of Ovariectomized Cynomolgus Monkeys. Calcif Tissue Int 2019; 104:402-410. [PMID: 30564860 DOI: 10.1007/s00223-018-0500-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 11/26/2018] [Indexed: 01/22/2023]
Abstract
The effect of teriparatide treatment on microdamage accumulation has yet to be examined in animal studies. The purpose of this study was to investigate the effect of once-weekly teriparatide treatment on bone microdamage accumulation and the relationship between microdamage parameters and bone mass, architecture, turnover, and collagen cross-linking in the lumbar vertebral trabecular bone of ovariectomized (OVX) cynomolgus monkeys. Female monkeys were divided into four groups (n = 18-20 per group): (1) SHAM group, (2) OVX group, (3) OVX with 1.2 µg/kg once-weekly teriparatide group (LOW group), (4) OVX with 6.0 µg/kg once-weekly teriparatide group (HIGH group). After 18 months, all animals were double-labeled with calcein for histomorphometry. L3 and L7 lumbar vertebrae were harvested and analyzed for differences in histomorphometry, microdamage, and collagen cross-linking. The iliac crest was also analyzed for differences in bone turnover. In the OVX group, cancellous bone mass was reduced and microdamage accumulation was increased as compared with the SHAM control. Once-weekly teriparatide at both doses prevented the decrease in bone mass and increase in microdamage accumulation, and improved the distribution of collagen cross-linkage types. Regression analyses indicated that decreased microdamage accumulation was associated with reduced non-enzymatic cross-link pentosidine rather than increased cancellous bone mass or enzymatic cross-links. These findings suggest that once-weekly teriparatide treatment decreases microdamage accumulation by recovering the balance in collagen cross-links.
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Affiliation(s)
- Shingo Yoshitake
- Department of Orthopedic Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Tasuku Mashiba
- Department of Orthopedic Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan.
| | - Mitsuru Saito
- Department of Orthopaedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Shinbashi, Minato-ku, Tokyo, 105-8461, Japan
| | - Ryuji Fujihara
- Department of Orthopedic Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Ken Iwata
- Department of Orthopedic Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
| | - Ryoko Takao-Kawabata
- Pharmaceuticals Research Center, Asahi Kasei Pharma Corporation, 632-1 Mifuku, Izunokuni, Shizuoka, 410-2321, Japan
| | - Tetsuji Yamamoto
- Department of Orthopedic Surgery, Faculty of Medicine, Kagawa University, 1750-1 Ikenobe, Miki-cho, Kita-gun, Kagawa, 761-0793, Japan
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Lin S, Cui L, Chen G, Huang J, Yang Y, Zou K, Lai Y, Wang X, Zou L, Wu T, Cheng JCY, Li G, Wei B, Lee WYW. PLGA/β-TCP composite scaffold incorporating salvianolic acid B promotes bone fusion by angiogenesis and osteogenesis in a rat spinal fusion model. Biomaterials 2019; 196:109-121. [PMID: 29655516 DOI: 10.1016/j.biomaterials.2018.04.004] [Citation(s) in RCA: 59] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/26/2018] [Accepted: 04/02/2018] [Indexed: 12/19/2022]
Abstract
Spinal disorders often require surgical treatment called spinal fusion to restore a stabilized spine where bone grafts are implanted for the fusion of adjacent vertebras. In this study, we developed a bioactive composite scaffold incorporated with salvianolic acid B (SB), an active component extracted from Danshen. This study aimed to evaluate the effects of SB-incorporated porous scaffold on spinal fusion models. The composite scaffolds composed of poly (lactic-co-glycolic acid) and tricalcium phosphate (PLGA/β-TCP) were fabricated with low-temperature rapid prototyping technique, which incorporated SB at low (SB-L), middle (SB-M), high (SB-H) doses, and pure PLGA/β-TCP as blank control (Con). The release profile of SB from the scaffolds was determined by high performance liquid chromatography. Osteoconductive and osteoinductive properties of the scaffolds were reflected by the osteogenic differentiation ability of rat primary mesenchymal stem cells. The angiogenesis was determined by the forming of tube-like structures resembling capillaries using endothelial cell line (EA hy9.26). A well-established spinal fusion model was used to evaluate the in vivo bony fusion. Animals were transplanted with scaffolds, or autografts from iliac crest as positive controls. Micro-computed tomography (CT) analysis, CT-based angiography, manual palpation test, histomorphometry, and histology were performed after 8 weeks of transplantation. Results revealed that incorporated SB was steadily released from the scaffolds. The aliquot of released SB promoted osteogenesis and angiogenesis in vitro in a dose-dependent manner. In animal study, a dose-dependent effect of SB on new bone formation, mineral apposition rate, and vessel density within the scaffold were demonstrated. Manual palpation test showed little numerical improvement in fusion rate when compared with the blank controls. In summary, our results suggested that SB-incorporated PLGA/β-TCP composite scaffold could enhance bony fusion through the promotion of osteogenesis and angiogenesis.
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Affiliation(s)
- Sien Lin
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang 524002, China; School of Pharmacy and Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China; Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Liao Cui
- School of Pharmacy and Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China
| | - Guanghua Chen
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang 524002, China
| | - Jianping Huang
- School of Pharmacy and Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China
| | - Yanhua Yang
- Department of Key Laboratory, No.7 People's Hospital of Changzhou, Changzhou 213011, China
| | - Kaijie Zou
- Department of Key Laboratory, No.7 People's Hospital of Changzhou, Changzhou 213011, China
| | - Yuxiao Lai
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Xinluan Wang
- Translational Medicine R&D Center, Institute of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China
| | - Liyi Zou
- School of Pharmacy and Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China
| | - Tie Wu
- School of Pharmacy and Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang 524023, China
| | - Jack Chun Yiu Cheng
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
| | - Gang Li
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China; The CUHK-ACC Space Medicine Centre on Health Maintenance of Musculoskeletal System, The Chinese University of Hong Kong Shenzhen Research Institute, Shenzhen 518057, China.
| | - Bo Wei
- Orthopaedic Center, Affiliated Hospital of Guangdong Medical University, Guangdong Medical University, Zhanjiang 524002, China.
| | - Wayne Yuk Wai Lee
- Department of Orthopaedics & Traumatology, Faculty of Medicine, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China; Stem Cells and Regenerative Medicine Laboratory, Lui Che Woo Institute of Innovative Medicine, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong, China.
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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: 17] [Impact Index Per Article: 2.8] [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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Zandi M, Dehghan A, Gheysari F, Rezaeian L, Mohammad Gholi Mezerji N. Evaluation of teriparatide effect on healing of autografted mandibular defects in rats. J Craniomaxillofac Surg 2019; 47:120-126. [DOI: 10.1016/j.jcms.2018.11.015] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Revised: 10/23/2018] [Accepted: 11/16/2018] [Indexed: 10/27/2022] Open
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Yolcu Y, Alvi M, Wanderman N, Carlson B, Sebastian A, Bydon M, Freedman B. Effect of teriparatide use on bone mineral density and spinal fusion: a narrative review of animal models. Int J Neurosci 2018; 129:814-820. [PMID: 30587048 DOI: 10.1080/00207454.2018.1564051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
Purpose of the study: Teriparatide (Human recombinant Parathyroid Hormone 1-34) is an anabolic agent that is frequently used in patients with osteoporosis and has been extensively investigated with animal model and clinical studies in current literature. The purpose of the study was to evaluate the impact of teriparatide on bone mineral density and fusion. Materials and methods: The findings from preclinical studies that have investigated the role of teriparatide in animal models are summarized in presented review. Results: Overall, the studies show an improvement in bone mineral density and increased fusion rates for osteoporotic animals undergoing spine fusion with teriparatide use. Conclusion: Further studies should be conducted for unanswered questions, such as teriparatide use before surgery, the effect on cervical fusion and surgery related complications.
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Affiliation(s)
- Yagiz Yolcu
- a Mayo Clinic Neuro-Informatics Laboratory , Mayo Clinic , Rochester , MN , USA.,b Department of Neurologic Surgery , Mayo Clinic , Rochester , MN , USA
| | - Mohammed Alvi
- a Mayo Clinic Neuro-Informatics Laboratory , Mayo Clinic , Rochester , MN , USA.,b Department of Neurologic Surgery , Mayo Clinic , Rochester , MN , USA
| | - Nathan Wanderman
- c Department of Orthopaedic Surgery , Mayo Clinic , Rochester , MN , USA
| | - Bayard Carlson
- c Department of Orthopaedic Surgery , Mayo Clinic , Rochester , MN , USA
| | - Arjun Sebastian
- c Department of Orthopaedic Surgery , Mayo Clinic , Rochester , MN , USA
| | - Mohamad Bydon
- a Mayo Clinic Neuro-Informatics Laboratory , Mayo Clinic , Rochester , MN , USA.,b Department of Neurologic Surgery , Mayo Clinic , Rochester , MN , USA
| | - Brett Freedman
- c Department of Orthopaedic Surgery , Mayo Clinic , Rochester , MN , USA
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Ide M, Yamada K, Kaneko K, Sekiya T, Kanai K, Higashi T, Saito T. Combined teriparatide and denosumab therapy accelerates spinal fusion following posterior lumbar interbody fusion. Orthop Traumatol Surg Res 2018; 104:1043-1048. [PMID: 30179720 DOI: 10.1016/j.otsr.2018.07.015] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 07/09/2018] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Previous studies reported that teriparatide (recombinant human parathyroid hormone) accelerated spinal fusion following posterior lumbar inter-body fusion surgery, and combination therapy using teriparatide and denosumab increased bone marrow density more than teriparatide alone. The purpose of this study is to evaluate the influence of combination therapy with teriparaide and denosumab on spinal fusion after posterior lumbar interbody fusion. MATERIALS AND METHODS Sixteen osteoporotic patients with lumbar canal stenosis were randomly divided into two treatment groups, a teriparatide group (n=8; 20μg of teriparatide daily alone, administered from a month before surgery to 12 months after surgery) and a combination group (n=8; 20μg of teriparatide administered daily from a month before surgery to 12 months after surgery with 60mg denosumab every 6 months, administered at 2 and 8 months following surgery). All patients underwent posterior lumbar interbody fusion with local bone grafts. At 3, 6, 9, and 12 months following surgery, bone mineral density at the femoral neck was measured, and biochemical markers were obtained for bone turnover for all cases. Clinical findings were quantified using the Japanese Orthopedic Association scores before surgery, and at 6 and 12 months following surgery. Fusion rates were measured using computed tomography images before surgery, and 6 and 12 months following surgery. RESULTS Alkaline phosphatase in the teriparatide group increased more than in the combination group at 3 months following surgery (p<0.05). Femoral neck BMD increased more in the combination group than in the teriparatide group at 12 months following surgery. The combination group achieved higher fusion rates than the teriparatide group at 6 months following surgery. CONCLUSIONS Combination therapy with teriparatide and denosumab increased bone mineral density more than teriparatide alone, and accelerated spinal fusion following posterior lumbar interbody fusion.
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Affiliation(s)
- Manabu Ide
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan.
| | - Katsutaka Yamada
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan
| | - Kanichirou Kaneko
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan
| | - Tatsuhiro Sekiya
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan
| | - Kenzo Kanai
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan
| | - Takayuki Higashi
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan
| | - Tomoyuki Saito
- Department of Orthopedic Surgery, Yokohama City University, Fukuura 3-9, Kanazawa-ku, Yokohama-shi, 236-0004 Kanagawa, Japan
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Holmes CA, Ishida W, Elder BD, Lo SFL, Chen YA, Kim E, Locke J, Taylor M, Witham TF. The Effects of High-Dose Parathyroid Hormone Treatment on Fusion Outcomes in a Rabbit Model of Posterolateral Lumbar Spinal Fusion Alone and in Combination with Bone Morphogenetic Protein 2 Treatment. World Neurosurg 2018; 115:e366-e374. [DOI: 10.1016/j.wneu.2018.04.058] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 04/07/2018] [Accepted: 04/09/2018] [Indexed: 01/21/2023]
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Liu Y, Levack AE, Marty E, Or O, Samuels BP, Redko M, Lane JM. Anabolic agents: what is beyond osteoporosis? Osteoporos Int 2018; 29:1009-1022. [PMID: 29627891 PMCID: PMC5949085 DOI: 10.1007/s00198-018-4507-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2018] [Accepted: 03/23/2018] [Indexed: 02/06/2023]
Abstract
Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have been shown to improve bone mass and decrease fracture risk in osteoporosis patients by directly stimulating osteoblasts to produce new bone. Currently, two anabolic agents are available in the USA: recombinantly produced teriparatide (TPTD), which is the fully active (1-34) amino active sequence of human parathyroid hormone (PTH), and abaloparatide (APTD), a synthetic analog of parathyroid hormone-related peptide (PTHrP). At present, both agents are approved only for treatment of patients with osteoporosis at high risk of fracture. Nonetheless, their anabolic properties have led to off-label application in additional settings which include spine fusion, osteonecrosis of the jaw, arthroplasty, and fracture healing. In this article, we summarize available scientific literature regarding the efficacy, effectiveness, and safety of TPTD in these off-label settings.
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Affiliation(s)
- Y Liu
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA
| | - A E Levack
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA
| | - E Marty
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA
| | - O Or
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA
- Department of Orthopedic Surgery, Hadassah Medical Center, 91120, Jerusalem, Israel
| | - B P Samuels
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA
| | - M Redko
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA
| | - J M Lane
- Department of Orthopedic Surgery, Hospital for Special Surgery, Weill Cornell Medical College, 535 East 70th Street, New York, NY, 10021, USA.
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Yishake M, Yasen M, Jiang L, Liu W, Xing R, Chen Q, Lin H, Dong J. Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia. J Orthop Res 2018; 36:937-944. [PMID: 28796280 DOI: 10.1002/jor.23682] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/04/2017] [Accepted: 07/29/2017] [Indexed: 02/04/2023]
Abstract
There has been no study regarding the effect of a combination of teriparatide (TPTD) and zoledronic acid (ZA) on vertebral fusion. In this study, we investigate the effect of single and combined TPTD and ZA treatment on lumbar vertebral fusion in aged ovariectomized (OVX) rats. Sixty two-month-old female Sprague-Dawley rats were ovariectomized and underwent bilateral L4-L5 posterolateral intertransverse fusion after 10 months. The OVX rats received vehicle (control) treatment, or ZA (100 µg/kg, once), or TPTD (60 µg/kg/2 d for 42 d), or ZA + TPTD until they were euthanized at 6 weeks following lumbar vertebral fusion. The lumbar spine was harvested. Bone mineral density (BMD), bone fusion, bone volume (BV), and bone formation rate (BFR)were analyzed by dual-energy X-ray absorptiometry (DXA), radiography, micro-computed tomography, and histomorphometry. Compared with vehicle (control) treatment, ZA and TPTD monotherapy increased bone volume (BV) at fusion site, and ZA + TPTD combined therapy had an additive effect. Treatment with TPTD and ZA + TPTD increased the bone fusion rate when compared with the control group. ZA monotherapy did not alter the rate of bone fusion. The TPTD and ZA + TPTD treatment groups had increased mineral apposition rate (MAR), mineralizing surfaces/bone surface ((MS/BS), and BFR/BS compared with the OVX group. Our experiment confirm that the monotherapy with TPTD and combination therapy with ZA + TPTD in an OVX rat model of osteopenia following lumbar vertebral fusion surgery increased bone fusion mass and bone fusion rate, and ZA + TPTD combined therapy had an additive effect on bone fusion mass. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:937-944, 2018.
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Affiliation(s)
- Mumingjiang Yishake
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Miersalijiang Yasen
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Libo Jiang
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Wangmi Liu
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Rong Xing
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Qian Chen
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Hong Lin
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
| | - Jian Dong
- Department of Orthopedic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, China
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Chaudhary N, Lee JS, Wu JY, Tharin S. Evidence for Use of Teriparatide in Spinal Fusion Surgery in Osteoporotic Patients. World Neurosurg 2017; 100:551-556. [DOI: 10.1016/j.wneu.2016.11.135] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2016] [Revised: 11/23/2016] [Accepted: 11/24/2016] [Indexed: 11/26/2022]
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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: 100] [Impact Index Per Article: 12.5] [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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Ishida W, Elder BD, Holmes C, Lo SFL, Witham TF. Variables Affecting Fusion Rates in the Rat Posterolateral Spinal Fusion Model with Autogenic/Allogenic Bone Grafts: A Meta-analysis. Ann Biomed Eng 2016; 44:3186-3201. [PMID: 27473706 DOI: 10.1007/s10439-016-1701-8] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2016] [Accepted: 07/21/2016] [Indexed: 01/14/2023]
Abstract
The rat posterolateral spinal fusion model with autogenic/allogenic bone graft (rat PFABG) has been increasingly utilized as an experimental model to assess the efficacy of novel fusion treatments. The objective of this study was to investigate the reliability of the rat PFABG model and examine the effects of different variables on spinal fusion. A web-based literature search from January, 1970 to September, 2015, yielded 26 studies, which included 40 rat PFABG control groups and 449 rats. Data regarding age, weight, sex, and strain of rats, graft volume, graft type, decorticated levels, surgical approach, institution, the number of control rats, fusion rate, methods of fusion assessment, and timing of fusion assessment were collected and analyzed. The primary outcome variable of interest was fusion rate, as evaluated by manual palpation. Fusion rates varied widely, from 0 to 96%. The calculated overall fusion rate was 46.1% with an I 2 value of 62.4, which indicated moderate heterogeneity. Weight >300 g, age >14 weeks, male rat, Sprague-Dawley strain, and autogenic coccyx grafts increased fusion rates with statistical significance. Additionally, an assessment time-point ≥8 weeks had a trend towards statistical significance (p = 0.070). Multi-regression analysis demonstrated that timing of assessment and age as continuous variables, as well as sex as a categorical variable, can predict the fusion rate with R 2 = 0.82. In an inter-institution reliability analysis, the pooled overall fusion rate was 50.0% [44.8, 55.3%], with statistically significant differences among fusion outcomes at different institutions (p < 0.001 and I 2 of 72.2). Due to the heterogeneity of fusion outcomes, the reliability of the rat PFABG model was relatively limited. However, selection of adequate variables can optimize its use as a control group in studies evaluating the efficacy of novel fusion therapies.
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Affiliation(s)
- Wataru Ishida
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Benjamin D Elder
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA.
| | - Christina Holmes
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Sheng-Fu L Lo
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
| | - Timothy F Witham
- Department of Neurosurgery, The Johns Hopkins University School of Medicine, 1800 Orleans St., Room 6007, Baltimore, MD, 21287, USA
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Zhou Z, Tian FM, Gou Y, Wang P, Zhang H, Song HP, Shen Y, Zhang YZ, Zhang L. Enhancement of Lumbar Fusion and Alleviation of Adjacent Segment Disc Degeneration by Intermittent PTH(1-34) in Ovariectomized Rats. J Bone Miner Res 2016; 31:828-38. [PMID: 26542457 DOI: 10.1002/jbmr.2736] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2015] [Revised: 10/27/2015] [Accepted: 11/03/2015] [Indexed: 01/07/2023]
Abstract
Osteoporosis, which is prevalent in postmenopausal or aged populations, is thought to be a contributing factor to adjacent segment disc degeneration (ASDD), and the incidence and extent of ASDD may be augmented by osteopenia. Parathyroid hormone (PTH) (1-34) has already been shown to be beneficial in osteoporosis, lumbar fusion and matrix homeostasis of intervertebral discs. However, whether PTH(1-34) has a reversing or retarding effect on ASDD in osteopenia has not been confirmed. In the present study, we evaluated the effects of intermittent PTH(1-34) on ASDD in an ovariectomized (OVX) rat model. One hundred 3-month-old female Sprague-Dawley rats underwent L4 -L5 posterolateral lumbar fusion (PLF) with spinous-process wire fixation 4 weeks after OVX surgery. Control groups were established accordingly. PTH(1-34) was intermittently administered immediately after PLF surgery and lasted for 8 weeks using the following groups (n = 20) (V = vehicle): Sham+V, OVX+V, Sham+PLF+V, OVX+PLF+V, OVX+PLF+PTH. The fused segments showed clear evidence of eliminated motion on the fusion-segment based on manual palpation. Greater new bone formation in histology was observed in PTH-treated animals compared to the control group. The extent of ASDD was significantly increased by ovariotomy. Intermittent PTH(1-34) significantly alleviated ASDD by preserving disc height, microvessel density, relative area of vascular buds, endplate thickness and the relative area of endplate calcification. Moreover, protein expression results showed that PTH(1-34) not only inhibited matrix degradation by decreasing MMP-13, ADAMTS-4 and Col-I, but also promote matrix synthesis by increasing Col-II and Aggrecan. In conclusion, PTH(1-34), which effectively improves lumbar fusion and alleviates ASDD in ovariectomized rats, may be a potential candidate to ameliorate the prognosis of lumbar fusion in osteopenia.
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Affiliation(s)
- Zhuang Zhou
- Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Fa-Ming Tian
- Medical Research Center, North China University of Science and Technology, Tangshan, China
| | - Yu Gou
- Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Peng Wang
- Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Heng Zhang
- Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Hui-Ping Song
- Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
| | - Yong Shen
- Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Ying-Ze Zhang
- Department of Orthopedic Surgery, The Third Hospital of Hebei Medical University, Shijiazhuang, China
| | - Liu Zhang
- Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China
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An effect comparison of teriparatide and bisphosphonate on posterior lumbar interbody fusion in patients with osteoporosis: a prospective cohort study and preliminary data. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2015; 26:691-697. [PMID: 26661639 DOI: 10.1007/s00586-015-4342-y] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 11/25/2015] [Accepted: 11/25/2015] [Indexed: 02/01/2023]
Abstract
PURPOSE Our purpose was to evaluate the efficacy of teriparatide for posterior lumbar interbody fusion (PLIF) in osteoporotic women. METHODS Forty-seven osteoporotic patients underwent PLIF with pedicle screw fixation for degenerative lumbar stenosis and instability. Patients were divided into two groups. The teriparatide group (n = 23) was injected subcutaneously with teriparatide (20 μg daily) for 3-month cycles alternating with 3-month periods of oral sodium alendronate for 12 months. The bisphosphonate group (n = 24) was administered oral sodium alendronate (91.37 mg/week) for ≥1 year. Serial plain radiography, computed tomography, and bone mineral densitometry (BMD) evaluations were performed. Fusion rate, bony fusion duration, and T score changes were evaluated. Clinical data [pain scores, Prolo's functional scale, and Oswestry disability index (ODI)] were also serially evaluated. RESULTS The teriparatide group showed earlier fusion than the bisphosphonate group. The average period of bone fusion was 6.0 ± 4.8 months in the teriparatide group but 10.4 ± 7.2 months in the bisphosphonate group. The bone fusion rate in the teriparatide group was higher than that in the bisphosphonate group at 6 months; however, there was no difference 12 and 24 months after surgery. Pain scores and ODI were not significantly different between groups. BMD scores in the teriparatide group were significantly improved compared with the bisphosphonate group 2 years after surgery. CONCLUSIONS There was no significant improvement in overall fusion rate and clinical outcome in our patients after injection of teriparatide, but the teriparatide group showed faster bony union and highly improved BMD scores.
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Bi F, Shi Z, Zhou C, Liu A, Shen Y, Yan S. Intermittent Administration of Parathyroid Hormone [1-34] Prevents Particle-Induced Periprosthetic Osteolysis in a Rat Model. PLoS One 2015; 10:e0139793. [PMID: 26441073 PMCID: PMC4595472 DOI: 10.1371/journal.pone.0139793] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 09/17/2015] [Indexed: 11/19/2022] Open
Abstract
We examined whether intermittent administration of parathyroid hormone [1-34] (PTH[1-34]; 60 μg/kg/day) can prevent the negative effects of titanium (Ti) particles on implant fixation and periprosthetic osteolysis in a rat model. Eighteen adult male rats (12 weeks old, bones still growing) received intramedullary Ti implants in their bilateral femurs; 6 rats from the blank group received vehicle injections, and 12 rats from the control group and PTH treatment group received Ti particle injections at the time of operation and intra-articular injections 2 and 4 weeks postoperatively. Six of the rats that received Ti particles from the PTH group also received PTH[1-34] treatment. Six weeks postoperatively, all specimens were collected for assessment by X-ray, micro-CT, biomechanical, scanning electron microscopy (SEM), and dynamic histomorphometry. A lower BMD, BV/TV, Tb.N, maximal fixation strength, and mineral apposition rate were observed in the control group compared to the blank group, demonstrating that a periprosthetic osteolysis model had been successfully established. Administration of PTH[1-34] significantly increased the bone mineral density of the distal femur, BV/TV, Tb.N, Tb.Th, Tb.Sp, Con.D, SMI, and maximal fixation strength in the PTH group compared to that in the control group. SEM revealed higher bone-implant contact, thicker lamellar bone, and larger trabecular bone area in the PTH group than in the control group. A higher mineral apposition rate was observed in the PTH group compared to both the blank and control groups. These findings imply that intermittent administration of PTH[1-34] prevents periprosthetic osteolysis by promoting bone formation. The effects of PTH[1-34] were evaluated at a suprapharmacological dosage to the human equivalent in rats; therefore, additional studies are required to demonstrate its therapeutic potential in periprosthetic osteolysis.
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Affiliation(s)
- Fanggang Bi
- Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Zhongli Shi
- Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Chenhe Zhou
- Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - An Liu
- Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Yue Shen
- Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Shigui Yan
- Department of Orthopedic Surgery, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- * E-mail:
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Kömürcü E, Özyalvaçlı G, Kaymaz B, Gölge UH, Göksel F, Cevizci S, Adam G, Ozden R. Effects of Local Administration of Boric Acid on Posterolateral Spinal Fusion with Autogenous Bone Grafting in a Rodent Model. Biol Trace Elem Res 2015; 167:77-83. [PMID: 25728510 DOI: 10.1007/s12011-015-0274-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2015] [Accepted: 02/13/2015] [Indexed: 11/29/2022]
Abstract
Spinal fusion is among the most frequently applied spinal surgical procedures. The goal of the present study was to evaluate whether the local administration of boric acid (BA) improves spinal fusion in an experimental spinal fusion model in rats. Currently, there is no published data that evaluates the possible positive effects if the local administration of BA on posterolateral spinal fusion. Thirty-two rats were randomly divided into four independent groups: no material was added at the fusion area for group 1; an autogenous morselized corticocancellous bone graft was used for group 2; an autogenous morselized corticocancellous bone graft with boric acid (8.7 mg/kg) for group 3; and only boric acid was placed into the fusion area for group 4. The L4-L6 spinal segments were collected at week 6, and the assessments included radiography, manual palpation, and histomorphometry. A statistically significant difference was determined between the groups with regard to the mean histopathological scores (p = 0.002), and a paired comparison was made with the Mann-Whitney U test to detect the group/groups from which the difference originated. It was determined that only the graft + BA practice increased the histopathological score significantly with regard to the control group (p = 0.002). Whereas, there was no statistically significant difference between the groups in terms of the manual assessment of fusion and radiographic analysis (respectively p = 0.328 and p = 0.196). This preliminary study suggests that BA may clearly be useful as a therapeutic agent in spinal fusion. However, further research is required to show the most effective dosage of BA on spinal fusion, and should indicate whether BA effects spinal fusion in the human body.
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Affiliation(s)
- Erkam Kömürcü
- Faculty of Medicine, Department of Orthopaedics and Traumatology, Çanakkale Onsekiz Mart University, Çanakkale, Turkey,
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Engraftment and bone mass are enhanced by PTHrP 1-34 in ectopically transplanted vertebrae (vossicle model) and can be non-invasively monitored with bioluminescence and fluorescence imaging. Transgenic Res 2015; 24:955-69. [PMID: 26271486 DOI: 10.1007/s11248-015-9901-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2015] [Accepted: 08/04/2015] [Indexed: 10/23/2022]
Abstract
Evidence exists that parathyroid hormone-related protein (PTHrP) 1-34 may be more anabolic in bone than parathyroid hormone 1-34. While optical imaging is growing in popularity, scant information exists on the relationships between traditional bone imaging and histology and bioluminescence (BLI) and fluorescence (FLI) imaging. We aimed to evaluate the effects of PTHrP 1-34 on bone mass and determine if relationships existed between radiographic and histologic findings in bone and BLI and FLI indices. Vertebrae (vossicles) from mice coexpressing luciferase and green fluorescent protein were implanted subcutaneously into allogenic nude mice. Transplant recipients were treated daily with saline or PTHrP 1-34 for 4 weeks. BLI, FLI, radiography, histology, and µCT of the vossicles were performed over time. PTHrP 1-34 increased bioluminescence the most after 2 weeks, fluorescence at all time points, and decreased the time to peak bioluminescence at 4 weeks (P ≤ 0.027), the latter of which suggesting enhanced engraftment. PTHrP 1-34 maximized vertebral body volume at 4 weeks (P < 0.0001). The total amount of bone observed histologically increased in both groups at 2 and 4 weeks (P ≤ 0.002); however, PTHrP 1-34 exceeded time-matched controls (P ≤ 0.044). A positive linear relationship existed between the percentage of trabecular bone and (1) total bioluminescence (r = 0.595; P = 0.019); (2) total fluorescence (r = 0.474; P = 0.074); and (3) max fluorescence (r = 0.587; P = 0.021). In conclusion, PTHrP 1-34 enhances engraftment and bone mass, which can be monitored non-invasively by BLI and FLI.
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Dong Y, Li Y, Huang C, Gao K, Weng X. Systemic application of teriparatide for steroid induced osteonecrosis in a rat model. BMC Musculoskelet Disord 2015; 16:163. [PMID: 26163144 PMCID: PMC4499203 DOI: 10.1186/s12891-015-0589-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Accepted: 05/18/2015] [Indexed: 12/15/2022] Open
Abstract
Background Steroid associated osteonecrosis is difficult to treat. Teriparatide, as the only one bone anabolic drug, has achieved very promising effect in osteoporosis and other bone skeletal diseases. We carried out this animal study to evaluate the effect of subcutaneous injection of teriparatide for the steroid induced femoral head necrosis in a rat model. Methods 24 Sprague–Dawley male adult rats were included in the study. All the rats were randomized into 4 groups: 18 rats from LPS/MPS group, LPS/MPS + PTH group and LPS/MPS + NS group were given lipopolysaccharide (20 μg/kg) and methylprednisolone (40 mg/kg) to establish the steroid induced osteonecrosis model. 6 rats from NS group only received normal saline. 4 weeks later, All the rats in LPS/MPS group and NS group were sacrificed and the femoral heads were harvested. After that, the 6 rats in the LPS/MPS + PTH group received subcutaneous injection of 20 μg/kg teriparatide and LPS/MPS + NS group only received equal amount of normal saline. After 4 weeks, the serum bone marker was tested and the femoral head were harvested. Micro-CT and histological examination were performed to compare the incidence of osteonecrosis and trabeculae parameters for the femoral head. Results At 4 weeks, rats in LPS/MPS group showed significant osteonecrosis by histological examination (83.3 %) which suggested successful steroid induced osteronecrosis animal models were established. After the treatment of 4 weeks, the LPS/MPS + PTH group showed significant lower incidence rate of osteonecrosis compared with the LPS/MPS + NS group (16.7 % vs.75 %, P < 0.05). The micro CT examination showed higher bone volume/total volume, trabecula thickness and bone mineral density in the LPS/MPS + PTH group compared with the LPS/MPS + NS group. The serum osteocalcin was a little higher in the LPS/MPS + PTH group (4.54 ± 1.61vs.3.58 ± 1.81, P = 0.358), but it didn’t reach a statistical significance. Conclusions Systemic application of teriparatide for steroid induced osteonecrosis in rats showed a beneficial effect. This may be one promising therapy for early stage osteonecrosis.
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Affiliation(s)
- Yulei Dong
- Deparment of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 100730, Beijing, China.
| | - Yulong Li
- Deparment of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 100730, Beijing, China.
| | - Cheng Huang
- Deparment of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 100730, Beijing, China.
| | - Kai Gao
- Institute of laboratory animal sciences, Chinese Academy of Medical Science and Peking Union Medical College, 100021, Beijing, China.
| | - Xisheng Weng
- Deparment of Orthopaedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 100730, Beijing, China.
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Morimoto T, Kaito T, Matsuo Y, Sugiura T, Kashii M, Makino T, Iwasaki M, Yoshikawa H. The bone morphogenetic protein-2/7 heterodimer is a stronger inducer of bone regeneration than the individual homodimers in a rat spinal fusion model. Spine J 2015; 15:1379-90. [PMID: 25733023 DOI: 10.1016/j.spinee.2015.02.034] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Revised: 12/26/2014] [Accepted: 02/18/2015] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT Bone morphogenetic proteins (BMPs) are a group of dimeric growth factors that belong to the transforming growth factor super family and are capable of eliciting new bone formation. Previous studies have suggested that the coexpression of two different BMP genes in a cell can result in the production of BMP heterodimers that are more potent than homodimers. However, because of the difficulty in optimizing the level of BMP gene expression, the coexpression of two different BMP genes also produces BMP homodimers as a by-product. These homodimers could, in theory, interact with the heterodimers. PURPOSE To elucidate the effects of a BMP-2/7 heterodimer, which were investigated in depth using purified BMP-2/7 heterodimers, BMP-2 homodimers, and BMP-7 homodimers in a rat spinal fusion model. METHODS Bilateral posterolateral fusion at L4-L5 was performed in four different groups: control group animals were implanted with collagen carriers alone; BMP-7 group animals with collagen carriers+1 μg of BMP-7 homodimer; BMP-2 group animals with collagen carriers+1 μg of BMP-2 homodimer; and BMP-2/7 group animals with collagen carriers+1 μg of the BMP-2/7 heterodimer. The following assessments were performed: bone microstructural analysis of the fusion mass and tissue volume (TV) with microcomputed tomography (micro-CT); fusion assessment with manual palpation testing and three-dimensional CT images; and bone histomorphometrical analysis of the fusion mass. RESULTS The fusion scores, as determined by radiography, and the TV of the newly formed bone, as determined by micro-CT, were significantly higher in the BMP-2/7 heterodimer group than the other groups (p<.0001). The microstructural indices of the newly formed bone did not differ between the groups. Moreover, histologic analysis of the fused spines revealed that the formation of the trabecular bone bridging the transverse process was the highest in this group. CONCLUSIONS This study demonstrated that BMP-2/7 heterodimer is a stronger inducer of bone regeneration than BMP-2 or -7 homodimers. The use of a purified BMP-2/7 heterodimer may represent an efficient alternative to the current clinical use of BMP-2 or -7 homodimers. Further studies as to the side effects of BMP-2/7 heterodimer are required.
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Affiliation(s)
- Tokimitsu Morimoto
- Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takashi Kaito
- Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
| | - Yohei Matsuo
- Department of Orthopedic Biomaterial Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaok, Suita, Osaka 565-0871, Japan
| | - Tsuyoshi Sugiura
- Department of Orthopedic Biomaterial Science, Graduate School of Medicine, Osaka University, 2-2 Yamadaok, Suita, Osaka 565-0871, Japan
| | - Masafumi Kashii
- Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takahiro Makino
- Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Motoki Iwasaki
- Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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Sugiura T, Kashii M, Matsuo Y, Morimoto T, Honda H, Kaito T, Iwasaki M, Yoshikawa H. Intermittent administration of teriparatide enhances graft bone healing and accelerates spinal fusion in rats with glucocorticoid-induced osteoporosis. Spine J 2015; 15:298-306. [PMID: 25110274 DOI: 10.1016/j.spinee.2014.08.001] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2014] [Revised: 07/07/2014] [Accepted: 08/02/2014] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT There has been no study regarding the effect of intermittent administration of teriparatide (TPTD [recombinant human parathyroid hormone (1-34)]) on spinal fusion in patients with glucocorticoid-induced osteoporosis (GIOP). PURPOSE To elucidate the effect of intermittent administration of TPTD on spinal fusion in rats with GIOP. STUDY DESIGN An experimental animal study of rats under continuous glucocorticoid (GC) exposure undergoing spinal fusion surgery and administration of TPTD or saline. METHODS Male 8-week-old rats (n=18) were administered 5 mg/kg methylprednisolone (MP) for 12 weeks. After 6 weeks of MP administration, the rats underwent posterolateral spinal fusion (L4-L5) with iliac crest autograft. Then, five times a week, they were given either saline or 40 μg/kg TPTD for 6 weeks. The following assessments were performed: time-course bone microstructural analysis of the fusion mass and adjacent vertebrae (L6), with in vivo microcomputed tomography (μCT); fusion assessment, with manual palpation testing and three-dimensional CT images; and bone histomorphometrical analysis of the fusion mass. RESULTS In the TPTD group, values for bone volume and other bone microstructural parameters at the fusion mass increased and peaked 4 weeks after surgery, and these values were significantly greater than those for the control (CNT) group at 4 and 6 weeks after surgery. Fusion assessment showed that fusion rate was higher in the TPTD group than in the CNT group (CNT group: 56%, TPTD group: 89%). Bone histomorphometry revealed that values for bone formation parameters were significantly higher in the TPTD group than in the CNT group. CONCLUSIONS Under continuous GC exposure in a rat model of spinal fusion, intermittent TPTD administration accelerated bone modeling and remodeling predominantly by stimulating bone formation at the fusion mass and increasing the fusion rate. Intermittent TPTD administration also improved bone microarchitecture of adjacent vertebrae.
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Affiliation(s)
- Tsuyoshi Sugiura
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Masafumi Kashii
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
| | - Yohei Matsuo
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Tokimitsu Morimoto
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hirotsugu Honda
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Takashi Kaito
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Motoki Iwasaki
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
| | - Hideki Yoshikawa
- Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan
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Oberdorfer E, Polly D, Larson-Ode K, Smith-Wright D, Guidera K, Neglia JP, Polgreen LE. Successful Spinal Fixation Surgery Following Teriparatide Treatment in an Adolescent Boy with Severe Osteoporosis and Progressive Kyphoscoliosis: A Case Report. JBJS Case Connect 2014; 4:e89. [PMID: 29252757 DOI: 10.2106/jbjs.cc.m.00296] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Affiliation(s)
- Ewa Oberdorfer
- Department of Pediatrics (J.P.N.), Division of Endocrinology (E.O. and L.E.P.), University of Minnesota, East Building, Room MB671, 2450 Riverside Avenue, Minneapolis, MN 55454.
| | - David Polly
- Orthopaedic Clinic, University of Minnesota, 2512 South 7th Street, Minneapolis, MN 55454
| | - Katie Larson-Ode
- Department of Pediatric Endocrinology, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242
| | - Deb Smith-Wright
- Shriners Hospitals for Children - Twin Cities, 2025 East River Parkway, Minneapolis, MN 55414
| | - Kenneth Guidera
- Shriners Hospitals for Children - Twin Cities, 2025 East River Parkway, Minneapolis, MN 55414
| | - Joseph P Neglia
- Department of Pediatrics (J.P.N.), Division of Endocrinology (E.O. and L.E.P.), University of Minnesota, East Building, Room MB671, 2450 Riverside Avenue, Minneapolis, MN 55454.
| | - Lynda E Polgreen
- Department of Pediatrics (J.P.N.), Division of Endocrinology (E.O. and L.E.P.), University of Minnesota, East Building, Room MB671, 2450 Riverside Avenue, Minneapolis, MN 55454.
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Proximal junctional kyphosis following adult spinal deformity surgery. EUROPEAN SPINE JOURNAL : OFFICIAL PUBLICATION OF THE EUROPEAN SPINE SOCIETY, THE EUROPEAN SPINAL DEFORMITY SOCIETY, AND THE EUROPEAN SECTION OF THE CERVICAL SPINE RESEARCH SOCIETY 2014; 23:2726-36. [PMID: 25186826 DOI: 10.1007/s00586-014-3531-4] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/06/2014] [Revised: 08/19/2014] [Accepted: 08/20/2014] [Indexed: 10/24/2022]
Abstract
PURPOSE Proximal junctional kyphosis (PJK) is a common radiographic finding following long spinal fusions. Whether PJK leads to negative clinical outcome is currently debatable. A systematic review was performed to assess the prevalence, risk factors, and treatments of PJK. METHODS Literature search was conducted on PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials using the terms 'proximal junctional kyphosis' and 'proximal junctional failure'. Excluding reviews, commentaries, and case reports, we analyzed 33 studies that reported the prevalence rate, risk factors, and discussions on PJK following spinal deformity surgery. RESULTS The prevalence rates varied widely from 6 to 61.7%. Numerous studies reported that clinical outcomes for patients with PJK were not significantly different from those without, except in one recent study in which adult patients with PJK experienced more pain. Risk factors for PJK included age at operation, low bone mineral density, shorter fusion constructs, upper instrumented vertebrae below L2, and inadequate restoration of global sagittal balance. CONCLUSIONS Prevalence of PJK following long spinal fusion for adult spinal deformity was high but not clinically significant. Careful and detailed preoperative planning and surgical execution may reduce PJK in adult spinal deformity patients.
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Morimoto T, Kaito T, Kashii M, Matsuo Y, Sugiura T, Iwasaki M, Yoshikawa H. Effect of Intermittent Administration of Teriparatide (Parathyroid Hormone 1-34) on Bone Morphogenetic Protein-Induced Bone Formation in a Rat Model of Spinal Fusion. J Bone Joint Surg Am 2014; 96:e107. [PMID: 24990981 DOI: 10.2106/jbjs.m.01097] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
BACKGROUND Although clinical bone morphogenetic protein (BMP) therapy is effective at enhancing bone formation in patients managed with spinal arthrodesis, the required doses are very high. Teriparatide (parathyroid hormone 1-34) is approved by the U.S. Food and Drug Administration to treat osteoporosis and is a potent anabolic agent. In this study, intermittent administration of parathyroid hormone 1-34 combined with transplantation of BMP was performed to elucidate the effect of parathyroid hormone 1-34 on the fusion rate and quality of newly formed bone in a rat model. METHODS A total of forty-eight male Sprague-Dawley rats underwent posterolateral lumbar spinal arthrodesis with one of three different treatments with recombinant human (rh) BMP-2: (1) 0 μg (control), (2) 2 μg (low dose), or (3) 50 μg (high dose). Each of the rhBMP-2 treatments was studied in combination with intermittent injections of either parathyroid hormone 1-34 (180 μg/kg/wk) or saline solution starting two weeks before the operation and continuing until six weeks after the operation. Osseous fusion was assessed with use of radiographs and a manual palpation test. Microstructural indices of the newly formed bone were evaluated with use of micro-computed tomography. The serum markers of bone metabolism were also quantified. RESULTS The fusion rate in the group treated with 2 μg of rhBMP-2 significantly increased (from 57% to 100%) with the administration of parathyroid hormone 1-34 (p < 0.05). The fusion rates in the other groups did not change significantly with the administration of parathyroid hormone 1-34. The bone volume density of the newly formed bone significantly increased in both the 2-μg and 50-μg rhBMP-2 treatment groups with the administration of parathyroid hormone 1-34 (p < 0.01). Micro-computed tomography scans of the newly formed bone clearly demonstrated an abundance of trabecular bone formation in the group treated with parathyroid hormone 1-34. In addition, serum levels of osteocalcin were significantly increased in the parathyroid hormone 1-34 treatment group. CONCLUSIONS Intermittent administration of parathyroid hormone 1-34 significantly increased fusion rates in the group treated with low-dose rhBMP-2, and it improved the quality of the newly formed bone in both the high and low-dose groups in a rat model of rhBMP-2-induced spinal fusion. CLINICAL RELEVANCE Our results suggest that the combined administration of rhBMP-2 and parathyroid hormone 1-34 may lead to efficient bone regeneration.
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Affiliation(s)
- Tokimitsu Morimoto
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
| | - Takashi Kaito
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
| | - Masafumi Kashii
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
| | - Yohei Matsuo
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
| | - Tsuyoshi Sugiura
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
| | - Motoki Iwasaki
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
| | - Hideki Yoshikawa
- Departments of Orthopedic Surgery (T.M., T.K., M.K., M.I., and H.Y.) and Orthopedic Biomaterial Science (Y.M. and T.S.), Graduate School of Medicine, Osaka University, 2-1 Yamadaoka, Suita, Osaka, 565-0871 Japan. E-mail address for T. Kaito:
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Quantitative study of parathyroid hormone (1-34) and bone morphogenetic protein-2 on spinal fusion outcomes in a rabbit model of lumbar dorsolateral intertransverse process arthrodesis. Spine (Phila Pa 1976) 2014; 39:347-55. [PMID: 24365898 DOI: 10.1097/brs.0000000000000169] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
STUDY DESIGN A posterolateral rabbit spinal fusion model was used to evaluate the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and teriparatide (PTH [1-34]) used individually and in combination on spinal fusion outcomes. OBJECTIVE To test the efficacy of parathyroid hormone on improving spinal fusion outcomes when used with BMP-2. SUMMARY OF BACKGROUND DATA Of the more than 250,000 spinal fusion surgical procedures performed each year, 5% to 35% of these will result in pseudarthrosis. Growing controversy on the efficacy and cost of rhBMP-2 for improving spinal fusion outcomes has presented a challenge for clinicians. Research into PTH as an adjunct therapy to rhBMP-2 for spinal fusion has not yet been investigated. METHODS Forty-eight male New Zealand white rabbits underwent bilateral posterolateral intertransverse process arthrodesis surgery at the L5-L6 level. Animals were divided into 6 groups. Two groups were treated with autograft alone or autograft and PTH (1-34), whereas the other 4 groups were treated with low-dose rhBMP-2 alone, high-dose rhBMP-2 alone, or either dose combined with PTH (1-34). All animals were euthanized 6 weeks after surgery. The L4-L7 spinal segment was removed and assessed using manual palpation, computed tomography (CT), and biomechanical testing. RESULTS CT assessments revealed fusion in 50% of autograft controls, 75% of autograft PTH (1-34) animals, 87.5% in the 2 groups treated with low-dose rhBMP-2, and 100% in the 2 groups treated with high-dose rhBMP-2. CT volumetric analysis demonstrated that all groups treated with biologics had fusion masses that were on average significantly larger than those observed in the control group (P < 0.0001). Biomechanical data demonstrated no statistical difference between controls, PTH (1-34), and low-dose rhBMP-2 in any testing orientation. PTH (1-34) did not increase bending stiffness when used adjunctively with either low-dose or high-dose rhBMP-2. CONCLUSION Although intermittent teriparatide administration results in increased fusion mass volume, it does not improve biomechnical stiffness over use of autograft alone. When delivered concurrently with high- and low-dose rhBMP-2, teriparatide provided no statistically significant improvement in biomechanical stiffness. LEVEL OF EVIDENCE N/A.
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Koerner JD, Yalamanchili P, Munoz W, Uko L, Chaudhary SB, Lin SS, Vives MJ. The effects of local insulin application to lumbar spinal fusions in a rat model. Spine J 2013; 13:22-31. [PMID: 23295034 DOI: 10.1016/j.spinee.2012.11.030] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2012] [Revised: 09/25/2012] [Accepted: 11/08/2012] [Indexed: 02/03/2023]
Abstract
BACKGROUND CONTEXT The rates of pseudoarthrosis after a single-level spinal fusion have been reported up to 35%, and the agents that increase the rate of fusion have an important role in decreasing pseudoarthrosis after spinal fusion. Previous studies have analyzed the effects of local insulin application to an autograft in a rat segmental defect model. Defects treated with a time-released insulin implant had significantly more new bone formation and greater quality of bone compared with controls based on histology and histomorphometry. A time-released insulin implant may have similar effects when applied in a lumbar spinal fusion model. PURPOSE This study analyzes the effects of a local time-released insulin implant applied to the fusion bed in a rat posterolateral lumbar spinal fusion model. Our hypothesis was twofold: first, a time-released insulin implant applied to the autograft bed in a rat posterolateral lumbar fusion will increase the rate of successful fusion and second, will alter the local environment of the fusion site by increasing the levels of local growth factors. STUDY DESIGN Animal model (Institutional Animal Care and Use Committee approved) using 40 adult male Sprague-Dawley rats. METHODS Forty skeletally mature Sprague-Dawley rats weighing approximately 500 g each underwent posterolateral intertransverse lumbar fusions with iliac crest autograft from L4 to L5 using a Wiltse-type approach. After exposure of the transverse processes and high-speed burr decortication, a Linplant (Linshin Canada, Inc., ON, Canada) consisting of 95% microrecrystalized palmitic acid and 5% bovine insulin (experimental group) or a sham implant consisting of only palmitic acid (control group) was implanted on the fusion bed with iliac crest autograft. As per the manufacturer, the Linplant has a release rate of 2 U/day for a minimum of 40 days. The transverse processes and autograft beds of 10 animals from the experimental and 10 from the control group were harvested at Day 4 and analyzed for growth factors. The remaining 20 spines were harvested at 8 weeks and underwent a radiographic examination, manual palpation, and microcomputed tomographic (micro-CT) examination. RESULTS One of the 8-week control animals died on postoperative Day 1, likely due to anesthesia. In the groups sacrificed at Day 4, there was a significant increase in insulinlike growth factor-I (IGF-I) in the insulin treatment group compared with the controls (0.185 vs. 0.129; p=.001). No significant differences were demonstrated in the levels of transforming growth factor beta-1, platelet-derived growth factor-AB, and vascular endothelial growth factor between the groups (p=.461, .452, and .767 respectively). Based on the radiographs, 1 of 9 controls had a solid bilateral fusion mass, 2 of 9 had unilateral fusion mass, 3 of 9 had small fusion mass bilaterally, and 3 of 9 had graft resorption. The treatment group had solid bilateral fusion mass in 6 of 10 and unilateral fusion mass in 4 of 10, whereas a small bilateral fusion mass and graft resorption were not observed. The difference between the groups was significant (p=.0067). Based on manual palpation, only 1 of 9 controls was considered fused, 4 of 9 were partially fused, and 4 of 9 were not fused. In the treatment group, there were 6 of 10 fusions, 3 of 10 partial fusions, and 1 of 10 were not fused. The difference between the groups was significant (p=.0084). Based on the micro-CT, the mean bone volume of the control group was 126.7 mm(3) and 203.8 mm(3) in the insulin treatment group. The difference between the groups was significant (p=.0007). CONCLUSIONS This study demonstrates the potential role of a time-released insulin implant as a bone graft enhancer using a rat posterolateral intertransverse lumbar fusion model. The insulin-treatment group had significantly higher fusion rates based on the radiographs and manual palpation and had significantly higher levels of IGF-I and significantly more bone volume on micro-CT.
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Affiliation(s)
- John D Koerner
- Department of Orthopaedics, UMDNJ-New Jersey Medical School, 90 Bergen St, DOC 7300, Newark, NJ 07101, USA.
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