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Yuthavong S, Chatiketu P, Keadto O, Srichairatanakool P, Srichairatanakool S, Chatupos V. Evaluating and comparing the effects of paracetamol and ibuprofen on wound healing, MMP-9, and TGF-β1 levels in patients following upper third molar tooth extraction. BMC Oral Health 2025; 25:484. [PMID: 40181349 PMCID: PMC11969977 DOI: 10.1186/s12903-024-04916-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 09/16/2024] [Indexed: 04/05/2025] Open
Abstract
BACKGROUND Paracetamol and ibuprofen are commonly prescribed pain relievers used in dental treatments, but their use can delay wound healing and lead to malunion and weaken the strength of newly formed bones. This randomized controlled clinical trial aimed to evaluate the wound healing (WH) and anti-inflammatory effects of paracetamol and ibuprofen on tooth extraction wounds in patients. METHODS This study involved a total of 20 patients who required removal of their fully erupted upper third molar under local anaesthesia at the Oral and Maxillofacial Surgery Clinic, Faculty of Dentistry, Chiang Mai University. The study subjects were divided into two groups of 10 patients each who were prescribed 400 mg of ibuprofen or 500 mg of paracetamol for seven days. Subsequently, WH was evaluated and the resulting proportions were compared using Landry Turnbull and Howley Index (LTHI) scores. Salivary matrix metalloproteinase 9 (MMP-9) and transforming growth factor beta1 (TGF-β1) concentrations were used as proinflammatory indicators. Accordingly, the WH values and the resulting proportions were compared using Fisher's exact test with a confidence interval (CI) of 95% (P < 0.05). The concentrations of MMP-9 and TGF-β1 were measured using ELISA and compared using the Mann‒Whitney U test at 95% CI (P < 0.05). The obtained statistical values were then analysed and interpreted accordingly. RESULTS LTHI values on days 3 and 7 after tooth extraction were not significantly different between the two treatment groups. Salivary MMP-9 levels were lower in the paracetamol-treated group than in the ibuprofen-treated group (P < 0.01) on day 3 only. The LTHI concentration was also negatively correlated (r = -0.433) with the MMP-9 concentration (P < 0.05) but was positively correlated (r = 0.369) with the salivary TGF-β1 concentration (P < 0.05). Interestingly, MMP-9 was negatively correlated with TGF-β1 in the ibuprofen treatment group (r2 = -0.351). CONCLUSION Ibuprofen can inhibit the inflammatory process and delay healing in the extraction socket. After discontinuation of medication, no differences were observed in the healing effects between the paracetamol and ibuprofen groups. TRIAL REGISTRATION The clinical trial was retrospectively registered at the Australian New Zealand Clinical Trial Registry (ANZCTR) NHMRC Clinical Trials Centre, Camperdown, Australia (Registry URL: https://www.anzctr.org.au ) (Registration number: ACTRN12624000595516 Date: 9/5/2024).
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Affiliation(s)
- Sumatee Yuthavong
- Residency Training Program in Oral and Maxillofacial Surgery, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Piyanart Chatiketu
- Department of Family and Community Dentistry, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Onsaya Keadto
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | | | - Somdet Srichairatanakool
- Department of Biochemistry, Faculty of Medicine, Chiang Mai University, Chiang Mai, 50200, Thailand
| | - Vuttinun Chatupos
- Residency Training Program in Oral and Maxillofacial Surgery, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.
- Department of Oral and Maxillofacial Surgery, Faculty of Dentistry, Chiang Mai University, Chiang Mai, 50200, Thailand.
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Helm JM, Stocks O, Crowley B, Aboulafia A, Siahaan J, Mansour AA. Incidence of Heterotopic Ossification Without Additional Long-Term NSAID Prophylaxis After Periacetabular Osteotomy and Concomitant Hip Arthroscopy. Orthop J Sports Med 2025; 13:23259671241310230. [PMID: 39949630 PMCID: PMC11822842 DOI: 10.1177/23259671241310230] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Accepted: 08/23/2024] [Indexed: 02/16/2025] Open
Abstract
Background Periacetabular osteotomy (PAO) is an established treatment for hip dysplasia and has been increasingly combined with concomitant hip arthroscopy to address additional intra-articular hip pathology. Heterotopic ossification (HO) is a complication of arthroscopic and open hip procedures. Nonsteroidal anti-inflammatory drugs (NSAIDs) have become an established form of HO prophylaxis, but their use may delay bone healing. Purpose To examine the incidence of HO without NSAID prophylaxis in patients after PAO with concomitant hip arthroscopy and to evaluate the impact of other variables on the development of HO in these patients. Study Design Case series; Level of evidence, 4. Methods Of 243 hips that underwent PAO with concomitant hip arthroscopy by a single surgeon over 11 years, 182 met the study inclusion criteria. No patients were discharged on NSAIDs for HO prophylaxis, although most took up to 6 weeks of aspirin 81 mg as part of the prophylaxis protocol for deep venous thrombosis. Radiographic images at 2 weeks, 6 weeks, and 3 months postoperatively were reviewed and graded for HO using the Brooker classification. Patient characteristics and surgical variables were recorded. The chi-square and t tests were used to determine HO incidence rates, compare groups, and identify variables associated with the presence of HO. Results The incidence of radiographic HO was 6.6% (12/182 hips). Nine hips were Brooker grade 1, 2 were grade 2, and 1 was grade 3. Four patients experienced clinical symptoms of HO- including pain and restricted motion. Only 1 patient required a return trip to the operating room for surgical excision. Male patients were significantly more likely to develop HO than female patients (P = .01). No other demographic or surgical factor influenced the development of HO. There were no cases of nonunion. Conclusion There was a low incidence of HO and symptomatic HO in patients who underwent PAO with concomitant hip arthroscopy without using NSAIDs for HO prophylaxis. HO was significantly more likely to develop in male patients. Given the potential risk of NSAID use on bony union, the low incidence found in this study may obviate the need for postoperative HO prophylaxis.
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Affiliation(s)
- J. Matthew Helm
- Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Omar Stocks
- Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Brian Crowley
- Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Alexis Aboulafia
- Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Jacob Siahaan
- Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
| | - Alfred A. Mansour
- Department of Orthopaedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, Texas, USA
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Çelik M, Karaduman ZO, Turhan Y, Arıcan M, Gamsızkan M, Saglam S, Uludag V. The Effects of Phenyramidol and Diclofenac Treatment on Fracture Healing in Rats. Clin Orthop Surg 2024; 16:836-844. [PMID: 39364103 PMCID: PMC11444952 DOI: 10.4055/cios24056] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Revised: 04/30/2024] [Accepted: 05/23/2024] [Indexed: 10/05/2024] Open
Abstract
Background Fracture healing or nonunion refers to a process in which many factors interact. In this study, we aimed to evaluate the radiological, histological, and biomechanical effects of phenyramidol and diclofenac, which are frequently used to treat post-fracture ture pain worldwide, on fracture healing and nonunion in a rat femur fracture model. Methods In this study, 72 male Wistar-Albino rats aged 2-3 months and weighing 250 ± 30 g were divided into 4 main groups. The rats were divided into 12 subgroups according to the early, middle, and late periods. A fracture model was created in rat femurs, and surgical fixation was performed. Postoperative analgesic treatment protocols included phenyramidol, diclofenac, phenyramidol + diclofenac, and the control group. The rats were sacrificed on the fifteenth, thirtieth, and forty-fifth days and were evaluated radiologically, histopathologically, and biomechanically. Results Scoring was conducted independently by 2 orthopedists not involved in the study. When the results were analyzed statistically, no statistically significant difference was observed between the fifteenth and thirtieth day radiology score values of the control, diclofenac, phenyramidol, and Phenyramidol + diclofenac groups (p > 0.05), but there was a statistically significant difference (p < 0.05) between the forty-fifth day radiology score values of the control, diclofenac, phenyramidol, and phenyramidol + diclofenac groups. Conclusions Our study shows that the use of diclofenac or phenyramidol alone negatively affects postoperative fracture healing. However, this effect was less pronounced in the combined treatment group. Histologic examination revealed that neither treatment had a significant effect on healing. There were statistical differences in biomechanical and radiologic properties between the phenyramidol and diclofenac groups; in particular, the diclofenac group had lower biomechanical properties.
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Affiliation(s)
- Mücahit Çelik
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Duzce University, Düzce, Türkiye
| | - Zekeriya Okan Karaduman
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Duzce University, Düzce, Türkiye
| | - Yalcın Turhan
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Duzce University, Düzce, Türkiye
| | - Mehmet Arıcan
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Duzce University, Düzce, Türkiye
| | - Mehmet Gamsızkan
- Department of Pathology, Faculty of Medicine, Duzce University, Düzce, Türkiye
| | - Sönmez Saglam
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Duzce University, Düzce, Türkiye
| | - Veysel Uludag
- Department of Orthopaedics and Traumatology, Faculty of Medicine, Duzce University, Düzce, Türkiye
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Gorgy A, Dalfen J, Barone N, Efanov JI. Non-steroidal anti-inflammatory drugs in postoperative hand fracture management: Do they positively or negatively impact recovery? World J Clin Cases 2024; 12:4856-4858. [PMID: 39070820 PMCID: PMC11235475 DOI: 10.12998/wjcc.v12.i21.4856] [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: 03/03/2024] [Revised: 05/31/2024] [Accepted: 06/14/2024] [Indexed: 06/30/2024] Open
Abstract
This editorial explores the impact of non-steroidal anti-inflammatory drugs (NSAIDs) on postoperative recovery in hand fracture patients, amidst shifting pain management strategies away from opioids due to their adverse effects. With hand fractures being significantly common and postoperative pain management crucial for recovery, the potential of NSAIDs offers a non-addictive pain control alternative. However, the controversy over NSAIDs' effects on bone healing-stemming from their Cyclooxygenase-2 inhibition and associated risks of fracture non-union or delayed union-necessitates further investigation. Despite a comprehensive literature search, the study finds a lack of specific research on NSAIDs in postoperative hand fracture management, highlighting an urgent need for future studies to balance their benefits against possible risks.
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Affiliation(s)
- Andrew Gorgy
- Department of Plastic, Reconstructive, and Aesthetic Surgery, McGill University, Montreal H4A 3J1, QC, Canada
| | - Jacqueline Dalfen
- Faculty of Medicine and Health Sciences, McGill University, Montreal H4A 3J1, QC, Canada
| | - Natasha Barone
- Department of Plastic and Reconstructive Surgery, University of Toronto, Toronto M5S 1A1, ON, Canada
| | - Johnny Ionut Efanov
- Department of Plastic and Reconstructive Surgery, Centre Hospitalier de l’Université de Montréal, Montreal H2X 3E4, QC, Canada
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Fisher A, Fisher L, Srikusalanukul W. Prediction of Osteoporotic Hip Fracture Outcome: Comparative Accuracy of 27 Immune-Inflammatory-Metabolic Markers and Related Conceptual Issues. J Clin Med 2024; 13:3969. [PMID: 38999533 PMCID: PMC11242639 DOI: 10.3390/jcm13133969] [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: 06/11/2024] [Revised: 06/26/2024] [Accepted: 07/03/2024] [Indexed: 07/14/2024] Open
Abstract
Objectives: This study, based on the concept of immuno-inflammatory-metabolic (IIM) dysregulation, investigated and compared the prognostic impact of 27 indices at admission for prediction of postoperative myocardial injury (PMI) and/or hospital death in hip fracture (HF) patients. Methods: In consecutive HF patient (n = 1273, mean age 82.9 ± 8.7 years, 73.5% females) demographics, medical history, laboratory parameters, and outcomes were recorded prospectively. Multiple logistic regression and receiver-operating characteristic analyses (the area under the curve, AUC) were used to establish the predictive role for each biomarker. Results: Among 27 IIM biomarkers, 10 indices were significantly associated with development of PMI and 16 were indicative of a fatal outcome; in the subset of patients aged >80 years with ischaemic heart disease (IHD, the highest risk group: 90.2% of all deaths), the corresponding figures were 26 and 20. In the latter group, the five strongest preoperative predictors for PMI were anaemia (AUC 0.7879), monocyte/eosinophil ratio > 13.0 (AUC 0.7814), neutrophil/lymphocyte ratio > 7.5 (AUC 0.7784), eosinophil count < 1.1 × 109/L (AUC 0.7780), and neutrophil/albumin × 10 > 2.4 (AUC 0.7732); additionally, sensitivity was 83.1-75.4% and specificity was 82.1-75.0%. The highest predictors of in-hospital death were platelet/lymphocyte ratio > 280.0 (AUC 0.8390), lymphocyte/monocyte ratio < 1.1 (AUC 0.8375), albumin < 33 g/L (AUC 0.7889), red cell distribution width > 14.5% (AUC 0.7739), and anaemia (AUC 0.7604), sensitivity 88.2% and above, and specificity 85.1-79.3%. Internal validation confirmed the predictive value of the models. Conclusions: Comparison of 27 IIM indices in HF patients identified several simple, widely available, and inexpensive parameters highly predictive for PMI and/or in-hospital death. The applicability of IIM biomarkers to diagnose and predict risks for chronic diseases, including OP/OF, in the preclinical stages is discussed.
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Affiliation(s)
- Alexander Fisher
- Department of Geriatric Medicine, The Canberra Hospital, ACT Health, Canberra 2605, Australia
- Department of Orthopaedic Surgery, The Canberra Hospital, ACT Health, Canberra 2605, Australia
- Medical School, Australian National University, Canberra 2601, Australia
| | - Leon Fisher
- Frankston Hospital, Peninsula Health, Melbourne 3199, Australia
| | - Wichat Srikusalanukul
- Department of Geriatric Medicine, The Canberra Hospital, ACT Health, Canberra 2605, Australia
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Soliman L, Sobti N, Rao V, Klinge P, Woo AS. Spontaneous Reossification Following Craniectomy in a Pediatric Patient. Cleft Palate Craniofac J 2024; 61:166-171. [PMID: 35918810 DOI: 10.1177/10556656221118426] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Spontaneous reossification following a cranial defect is described by only a few case reports. A 6-month-old male with epidural hematoma underwent decompressive craniotomy, subsequently complicated by scalp abscess requiring removal of the bone flap. On serial outpatient follow-up, the patient demonstrated near-complete resolution of cranial defect over the course of 18 months, thus deferring the need for future cranioplasty. Prior articles have identified this occurrence in children and young adults; however, the present case is the first to report of this phenomenon in an infant less than 1 year of age. A brief review of the literature is provided with the proposed physiologic underpinning for the spontaneous reossification observed. While prior studies propose that recranialization is mediated by contact with the dura mater and pericranium, new investigations suggest that calvarial bone repair is also mediated by stem cells from the suture mesenchyme.
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Affiliation(s)
- Luke Soliman
- Division of Plastic and Reconstructive Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Nikhil Sobti
- Division of Plastic and Reconstructive Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Vinay Rao
- Division of Plastic and Reconstructive Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Petra Klinge
- Division of Neurosurgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
| | - Albert S Woo
- Division of Plastic and Reconstructive Surgery, The Warren Alpert Medical School of Brown University, Providence, RI, USA
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Iyer P, Hwang M, Ridley L, Weisman MM. Biomechanics in the onset and severity of spondyloarthritis: a force to be reckoned with. RMD Open 2023; 9:e003372. [PMID: 37949613 PMCID: PMC10649803 DOI: 10.1136/rmdopen-2023-003372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 10/23/2023] [Indexed: 11/12/2023] Open
Abstract
Increasing evidence suggests that there is a pivotal role for physical force (mechanotransduction) in the initiation and/or the perpetuation of spondyloarthritis; the review contained herein examines that evidence. Furthermore, we know that damage and inflammation can limit spinal mobility, but is there a cycle created by altered spinal mobility leading to additional damage and inflammation?Over the past several years, mechanotransduction, the mechanism by which mechanical perturbation influences gene expression and cellular behaviour, has recently gained popularity because of emerging data from both animal models and human studies of the pathogenesis of ankylosing spondylitis (AS). In this review, we provide evidence towards an appreciation of the unsolved paradigm of how biomechanical forces may play a role in the initiation and propagation of AS.
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Affiliation(s)
- Priyanka Iyer
- Division of Rheumatology, Department of Medicine, UC Irvine Healthcare, Orange, California, USA
| | - Mark Hwang
- Rheumatology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, USA
| | - Lauren Ridley
- Rheumatology, The University of Texas Health Science Center at Houston John P and Katherine G McGovern Medical School, Houston, Texas, USA
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Hanga-Farcaș A, Miere (Groza) F, Filip GA, Clichici S, Fritea L, Vicaș LG, Marian E, Pallag A, Jurca T, Filip SM, Muresan ME. Phytochemical Compounds Involved in the Bone Regeneration Process and Their Innovative Administration: A Systematic Review. PLANTS (BASEL, SWITZERLAND) 2023; 12:2055. [PMID: 37653972 PMCID: PMC10222459 DOI: 10.3390/plants12102055] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2023] [Revised: 05/19/2023] [Accepted: 05/20/2023] [Indexed: 09/02/2023]
Abstract
Bone metabolism is a complex process which is influenced by the activity of bone cells (e.g., osteocytes, osteoblasts, osteoclasts); the effect of some specific biomarkers (e.g., parathyroid hormone, vitamin D, alkaline phosphatase, osteocalcin, osteopontin, osteoprotegerin, osterix, RANKL, Runx2); and the characteristic signaling pathways (e.g., RANKL/RANK, Wnt/β, Notch, BMP, SMAD). Some phytochemical compounds-such as flavonoids, tannins, polyphenols, anthocyanins, terpenoids, polysaccharides, alkaloids and others-presented a beneficial and stimulating effect in the bone regeneration process due to the pro-estrogenic activity, the antioxidant and the anti-inflammatory effect and modulation of bone signaling pathways. Lately, nanomedicine has emerged as an innovative concept for new treatments in bone-related pathologies envisaged through the incorporation of medicinal substances in nanometric systems for oral or local administration, as well as in nanostructured scaffolds with huge potential in bone tissue engineering.
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Affiliation(s)
- Alina Hanga-Farcaș
- Doctoral School of Biomedical Science, University of Oradea, 410087 Oradea, Romania;
| | - Florina Miere (Groza)
- Department of Preclinical Discipline, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (F.M.); (L.F.); (M.E.M.)
| | - Gabriela Adriana Filip
- Department of Physiology, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babeș Street, 400347 Cluj-Napoca, Romania; (G.A.F.); (S.C.)
| | - Simona Clichici
- Department of Physiology, Iuliu Hațieganu University of Medicine and Pharmacy, 8 Victor Babeș Street, 400347 Cluj-Napoca, Romania; (G.A.F.); (S.C.)
| | - Luminita Fritea
- Department of Preclinical Discipline, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (F.M.); (L.F.); (M.E.M.)
| | - Laura Grațiela Vicaș
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (E.M.); (A.P.); (T.J.)
| | - Eleonora Marian
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (E.M.); (A.P.); (T.J.)
| | - Annamaria Pallag
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (E.M.); (A.P.); (T.J.)
| | - Tunde Jurca
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (E.M.); (A.P.); (T.J.)
| | - Sanda Monica Filip
- Department of Physics, Faculty of Informatics and Sciences, University of Oradea, 1 University Street, 410087 Oradea, Romania;
| | - Mariana Eugenia Muresan
- Department of Preclinical Discipline, Faculty of Medicine and Pharmacy, University of Oradea, 10, 1 December Square, 410073 Oradea, Romania; (F.M.); (L.F.); (M.E.M.)
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Gil D, Hugard S, Borodinov N, Ovchinnikova OS, Muratoglu OK, Bedair H, Oral E. Dual-analgesic loaded UHMWPE exhibits synergistic antibacterial effects against Staphylococci. J Biomed Mater Res B Appl Biomater 2023; 111:912-922. [PMID: 36462210 DOI: 10.1002/jbm.b.35201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 09/15/2022] [Accepted: 11/06/2022] [Indexed: 12/07/2022]
Abstract
Total joint arthroplasty is one of the most common surgeries in the United States, with almost a million procedures performed annually. Periprosthetic joint infections (PJI) remain the most devastating complications associated with total joint replacement. Effective antibacterial prophylaxis after primary arthroplasty could substantially reduce incidence rate of PJI. In the present study we propose to provide post-arthroplasty prophylaxis via dual-analgesic loaded ultra-high molecular weight polyethylene (UHMWPE). Our approach is based on previous studies that showed pronounced antibacterial activity of analgesic- and NSAID-loaded UHMWPE against Staphylococci. Here, we prepared bupivacaine/tolfenamic acid-loaded UHMWPE and assessed its antibacterial activity against Staphylococcus aureus and Staphylococcus epidermidis. Dual-drug loaded UHMWPE yielded an additional 1-2 log reduction of bacteria, when compared with single-drug loaded UHMWPE. Analysis of the drug elution kinetics suggested that the observed increase in antibacterial activity is due to the increased tolfenamic acid elution from dual-drug loaded UHMWPE. We showed that the increased fractal dimension of the drug domains in UHMWPE could be associated with increased drug elution, leading to higher antibacterial activity. Dual-analgesic loaded UHMWPE proposed here can be used as part of multi-modal antibacterial prophylaxis and promises substantial reduction in post-arthroplasty mortality and morbidity.
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Affiliation(s)
- Dmitry Gil
- Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Orthopaedic Surgery, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
| | - Shannon Hugard
- Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA
| | - Nikolay Borodinov
- Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA
| | - Olga S Ovchinnikova
- Center for Nanophase Materials Sciences, Oak Ridge National Laboratory, Oak Ridge, Tennessee, USA
| | - Orhun K Muratoglu
- Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Orthopaedic Surgery, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
| | - Hany Bedair
- Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Orthopaedic Surgery, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
| | - Ebru Oral
- Harris Orthopaedic Laboratory, Massachusetts General Hospital, Boston, Massachusetts, USA.,Department of Orthopaedic Surgery, Harvard Medical School, Harvard University, Boston, Massachusetts, USA
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Stroud S, Katyal T, Gornitzky AL, Swarup I. Effect of non-steroidal anti-inflammatory drugs on fracture healing in children: A systematic review. World J Orthop 2022; 13:494-502. [PMID: 35633742 PMCID: PMC9125002 DOI: 10.5312/wjo.v13.i5.494] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 09/14/2021] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most commonly prescribed medications in the United States. Although they are safe and effective means of analgesia for children with broken bones, there is considerable variation in their clinical use due to persistent concerns about their potentially adverse effect on fracture healing.
AIM To assess whether NSAID exposure is a risk factor for fracture nonunion in children.
METHODS We systematically reviewed the literature reporting the effect of NSAIDs on bone healing. We included all clinical studies that reported on adverse bone healing complications in children with respect to NSAID exposure. The outcomes of interest were delayed union or nonunion. Study quality was assessed using the Newcastle-Ottawa scale for non-randomized studies. A final table was constructed summarizing the available evidence.
RESULTS A total of 120 articles were identified and screened, of which 6 articles were included for final review. Nonunion in children is extremely rare; among the studies included, there were 2011 nonunions among 238822 fractures (0.84%). None of the included studies documented an increased risk of nonunion or delayed bone healing in those children who are treated with NSAIDs in the immediate post-injury or peri-operative time period. Additionally, children are likely to take these medications for only a few days after injury or surgery, further decreasing their risk of adverse side-effects.
CONCLUSION This systematic review suggests that NSAIDS can be safely prescribed to pediatric orthopaedic patients absent other contraindications without concern for increased risk of fracture non-union or delayed bone healing. Additional prospective studies are needed focusing on higher risk fractures and elective orthopaedic procedures such as osteotomies and spinal fusion.
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Affiliation(s)
- Sarah Stroud
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, United States
| | - Toshali Katyal
- Department of Orthopaedic Surgery, University of California, San Francisco Benioff Children’s Hospital, San Francisco, CA 94143, United States
| | - Alex L Gornitzky
- Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA 94143, United States
| | - Ishaan Swarup
- Department of Orthopaedic Surgery, University of California, San Francisco Benioff Children’s Hospital Oakland, Oakland, CA 94609, United States
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How Do Drugs Affect the Skeleton? Implications for Forensic Anthropology. BIOLOGY 2022; 11:biology11040524. [PMID: 35453723 PMCID: PMC9030599 DOI: 10.3390/biology11040524] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 02/21/2022] [Accepted: 03/18/2022] [Indexed: 01/10/2023]
Abstract
Simple Summary Forensic anthropologists analyze human remains to assist in the identification of the deceased, predominantly by assessing age-at-death, sex, stature, ancestry and any unique identifying features. Whilst methods have been established to create this biological profile of the skeleton, these may be influenced by a number of factors. This paper, for the first time, provides an overview from a reading of the clinical and pharmacological literature to explore whether the intake of drugs can affect the skeleton and whether these may have implications for forensic anthropology casework. In effect, drugs such as tobacco, heroin, and prescription medications can alter bone mineral density, can increase the risk of fractures, destroy bone and changes to the dentition. By considering how drugs can affect the skeleton, forensic anthropologists can be aware of this when attempting to identify the deceased. Abstract Forensic anthropologists rely on a number of parameters when analyzing human skeletal remains to assist in the identification of the deceased, predominantly age-at-death, sex, stature, ancestry or population affinity, and any unique identifying features. During the examination of human remains, it is important to be aware that the skeletal features considered when applying anthropological methods may be influenced and modified by a number of factors, and particular to this article, prescription drugs (including medical and non-medical use) and other commonly used drugs. In view of this, this paper aims to review the medical, clinical and pharmacological literature to enable an assessment of those drug groups that as side effects have the potential to have an adverse effect on the skeleton, and explore whether or not they can influence the estimation of age-at-death, sex and other indicators of the biological profile. Moreover, it may be that the observation of certain alterations or inconsistencies in the skeleton may relate to the use of drugs or medication, and this in turn may help narrow down the list of missing persons to which a set of human remains could belong. The information gathered from the clinical and medical literature has been extracted with a forensic anthropological perspective and provides an awareness on how several drugs, such as opioids, cocaine, corticosteroids, non-steroidal anti-inflammatory drugs, alcohol, tobacco and others have notable effects on bone. Through different mechanisms, drugs can alter bone mineral density, causing osteopenia, osteoporosis, increase the risk of fractures, osteonecrosis, and oral changes. Not much has been written on the influence of drugs on the skeleton from the forensic anthropological practitioner perspective; and this review, in spite of its limitations and the requirement of further research, aims to investigate the current knowledge of the possible effects of both prescription and recreational drugs on bones, contributing to providing a better awareness in forensic anthropological practice and assisting in the identification process of the deceased.
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Flunixin Meglumine Enhanced Bone Fracture Healing in Rabbits Associated with Activation of Early Collagen Deposition and Enhancement of Vascular Endothelial Growth Factor Expression. Animals (Basel) 2021; 11:ani11102834. [PMID: 34679855 PMCID: PMC8532723 DOI: 10.3390/ani11102834] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2021] [Revised: 09/18/2021] [Accepted: 09/22/2021] [Indexed: 01/15/2023] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most commonly used postoperative analgesics, antipyretics, and anti-inflammatories, and they help prevent blood clotting. However, most NSAIDs delay bone healing. This study was aimed to investigate bone healing in a rabbit animal model by assessing the ability of flunixin meglumine (FM) and ketoprofen to induce fracture healing by examining histology, radiological changes, and vascular endothelial growth factor (VEGF) immunostaining during bone healing. For this purpose, 24 New Zealand rabbits were assigned to three groups: the control group, the FM group, and the ketoprofen group. Our results revealed that there were no intraoperative complications, and all surviving rabbits achieved full-weight bearing. Significant periosteal reaction and callus formation were confirmed at 2 postoperative weeks. Interestingly, FM enhanced callus formation, bone union, and remodeling in the FM group compared to the control and ketoprofen groups. FM enhanced bone healing through early collagen deposition and marked angiogenesis process activation by increasing the expression of VEGF. Our findings demonstrated, for the first time, the potential imperative action of FM in the bone healing process rather than other NSAIDs in animals.
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Al-Waeli H, Reboucas AP, Mansour A, Morris M, Tamimi F, Nicolau B. Non-steroidal anti-inflammatory drugs and bone healing in animal models-a systematic review and meta-analysis. Syst Rev 2021; 10:201. [PMID: 34238360 PMCID: PMC8268344 DOI: 10.1186/s13643-021-01690-w] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2020] [Accepted: 04/26/2021] [Indexed: 12/09/2022] Open
Abstract
BACKGROUND Non-steroidal anti-inflammatory drugs (NSAID) have excellent anti-inflammatory and analgesic properties and are extensively used to treat post-traumatic or surgical musculoskeletal pain. Although an extensive literature exists on the administration of NSAID on animal bone healing, no systematic review and meta-analysis of animal studies that investigate the effect of NSAID administration on bone fracture healing. Objective of this study is to conduct a systematic review and meta-analysis to estimate the effect of NSAIDs administration on bone healing biomechanical and histomorphometric measurements in different animal models after bone fracture surgery. METHODS We performed a systematic review and meta-analysis of animal studies to estimate the effect of NSAID administration after bone fracture on healing outcomes. We searched eight databases without limiting the search to starting date up to 1 February 2021 for articles on fractured bone healing in animal models in which NSAID were administered. RESULTS Out of 6732 articles screened, 47 were included and 3 common bone healing outcomes were analysed: biomechanical properties (maximum force to break, stiffness, and work-to-failure), micro-computed tomography (μ-CT), and histomorphometric measurements. The studies were generally of low-quality scores because crucial information, especially concerning randomization, blinding, and allocation concealment, was poorly reported. Our results show that the negative effects of NSAID after bone fracture on certain biomechanical properties of the healing bones was not statistically significant in mice compared with other animals, in females compared with males, and in younger compared with older animals. CONCLUSION The findings demonstrated that NSAIDs administration decreased the biomechanical properties of healing bones after fracture surgery in comparison to the control group. Moreover, different effect on certain outcomes was detected among different sites, sex of the animals, and the time of assessment. TRIAL REGISTRATION Protocol published and registered in SYstematic Review Center for Laboratory animal Experimentation (SYRCLE) in 2017, https://www.radboudumc.nl/getmedia/757ec408-7a9e-4635-8233-ae951effea54/Non-Steroidal-Anti-inflammatory-Drugs-and-bone-healing-in-animal-Models-Systematic-Review-and-Meta-Analysis.aspx.
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Affiliation(s)
- Haider Al-Waeli
- Faculty of Dentistry, Dalhousie University, 5981 University Ave, Halifax, Nova Scotia, B3H 4R2, Canada.
| | - Ana Paula Reboucas
- Faculty of Dentistry, Federal University of Minas Gerais, Minas Gerais, Brazil
- College of Dental Medicine, Qatar University, University Street, Doha, Qatar
| | - Alaa Mansour
- School of Dental Medicine, University at Buffalo, Buffalo, NY, 14214, USA
| | - Martin Morris
- Schulich Library, McGill University, 2001 Avenue McGill College Suite 500, Montréal, QC, H3A 1G1, Canada
| | - Faleh Tamimi
- College of Dental Medicine, Qatar University, University Street, Doha, Qatar
| | - Belinda Nicolau
- Faculty of Dentistry, McGill University, 2001 Avenue McGill College Suite 500, Montréal, QC, H3A 1G1, Canada
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Hadjicharalambous C, Alpantaki K, Chatzinikolaidou M. Effects of NSAIDs on pre-osteoblast viability and osteogenic differentiation. Exp Ther Med 2021; 22:740. [PMID: 34046094 DOI: 10.3892/etm.2021.10172] [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: 07/11/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022] Open
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used in the treatment of a variety of musculoskeletal conditions, injuries and after surgery for postoperative pain management. Their use has been associated with impaired bone healing, possibly due to a multifactorial function, which may include inhibition of osteoblast recruitment and differentiation. However, up to date, there is no consensus regarding the impact of NSAIDs on bone-healing. The aim of the current study was to investigate the effects of five NSAIDs on the cellular functions of mouse MC3T3-E1 pre-osteoblasts. Cells were treated with the non-selective COX inhibitors lornoxicam and diclofenac, the COX-2 selective inhibitors parecoxib, meloxicam and paracetamol, as well as steroidal prednisolone at different doses and exposure times. The PrestoBlue™ technique was used to measure cell viability, an enzymatic assay was employed for alkaline phosphatase (ALP) activity and alizarin red S mineral staining was used to determine osteogenic differentiation. All drugs had a negative impact on pre-osteoblast cell growth, with the exception of paracetamol. Lornoxicam, diclofenac and meloxicam reduced ALP activity, while the other NSAIDs had no effect and prednisolone strongly increased ALP activity. In contrast, calcium deposits were either unaffected or increased by NSAID treatments but were significantly decreased by prednisolone. These results provide evidence that NSAIDs may adversely affect the viability of mouse pre-osteoblast cells but their actions on the osteogenic differentiation are drug-specific. The direct comparison of the effects of different NSAIDs and prednisolone on pre-osteoblasts may serve to place some NSAIDs in a preferential position for analgesic and anti-inflammatory therapy during bone repair.
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Affiliation(s)
- Chrystalleni Hadjicharalambous
- Department of Materials Science and Technology, University of Crete, Heraklion 70013, Greece.,Department of Chemistry, University of Crete, Heraklion 70013, Greece
| | - Kalliopi Alpantaki
- Department of Orthopedics and Trauma, Venizeleion General Hospital of Heraklion, Heraklion 71409, Greece
| | - Maria Chatzinikolaidou
- Department of Materials Science and Technology, University of Crete, Heraklion 70013, Greece.,Institute of Electronic Structure and Laser (IESL), Foundation for Research and Technology Hellas (FORTH), Heraklion 70013, Greece
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15
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Lajolo C, Gioco G, Rupe C, Patini R, Rizzo I, Romeo U, Contaldo M, Cordaro M. Patient perception after oral biopsies: an observational outpatient study. Clin Oral Investig 2021; 25:5687-5697. [PMID: 33704571 DOI: 10.1007/s00784-021-03870-3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 03/01/2021] [Indexed: 11/27/2022]
Abstract
OBJECTIVE The aim of this study was to evaluate the postoperative course in patients undergoing oral mucosal biopsies, considering clinical and patient's perception variables potentially correlated to poor healing. SUBJECTS AND METHODS Eighty patients underwent oral biopsies. All the variables connected with the surgery were recorded, and the harvested volume was calculated through image software (ImageJ, NIH, Betesda, USA). To evaluate the postoperative discomfort, the OHIP-14 and the numeric rating scale of pain (NRS) were administered at 6 h, 7 days and 21 days after biopsy. RESULTS Six hours after the biopsy, 22 (OHIP-14 ≥ 20) and 24 (NRS ≥ 4) patients experienced a troublesome or painful healing, respectively. A significant statistical correlation between poor healing and high scores of NRS and OHIP was detected (Pearson's correlation test p < 0.05). Higher values of OHIP-14 were correlated to the type of lesion (OR = 1.165; p < 0.05), whereas high values of NRS were correlated to the use of systemic drugs (p < 0.05). No surgical variable had a significant statistical correlation with any of the outcomes. CONCLUSIONS The clinical evaluation was correlated with the patient's perception of pain and discomfort. This finding could be suggestive of the fact that wound healing can be reliably monitored with the help of these tools. CLINICAL RELEVANCE Patient perception can be a predictor of the healing of biopsied tissues.
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Affiliation(s)
- C Lajolo
- Head and Neck Department, "Fondazione Policlinico Universitario A. Gemelli - IRCCS," School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy
| | - G Gioco
- Head and Neck Department, "Fondazione Policlinico Universitario A. Gemelli - IRCCS," School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy
| | - C Rupe
- Head and Neck Department, "Fondazione Policlinico Universitario A. Gemelli - IRCCS," School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy.
| | - R Patini
- Head and Neck Department, "Fondazione Policlinico Universitario A. Gemelli - IRCCS," School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy
| | - I Rizzo
- Head and Neck Department, "Fondazione Policlinico Universitario A. Gemelli - IRCCS," School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy
| | - U Romeo
- Department of Oral and Maxillofacial Sciences, Sapienza University of Rome, Rome, Italy
| | - M Contaldo
- Multidisciplinary Department of Medical-Surgical and Dental Specialties, University of Campania Luigi Vanvitelli, Via Luigi de Crecchio, 6, 80138, Naples, Italy
| | - M Cordaro
- Head and Neck Department, "Fondazione Policlinico Universitario A. Gemelli - IRCCS," School of Dentistry, Università Cattolica del Sacro Cuore, Largo A. Gemelli, 8, 00168, Rome, Italy
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Reich KM, Viitanen P, Apu EH, Tangl S, Ashammakhi N. The Effect of Diclofenac Sodium-Loaded PLGA Rods on Bone Healing and Inflammation: A Histological and Histomorphometric Study in the Femur of Rats. MICROMACHINES 2020; 11:mi11121098. [PMID: 33322731 PMCID: PMC7764049 DOI: 10.3390/mi11121098] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/07/2020] [Accepted: 12/10/2020] [Indexed: 12/03/2022]
Abstract
Implants made of poly(lactide-co-glycolide) (PLGA) are biodegradable and frequently provoke foreign body reactions (FBR) in the host tissue. In order to modulate the inflammatory response of the host tissue, PLGA implants can be loaded with anti-inflammatory drugs. The aim of this study was to analyze the impact of PLGA 80/20 rods loaded with the diclofenac sodium (DS) on local tissue reactions in the femur of rats. Special emphasis was put on bone regeneration and the presence of multinucleated giant cells (MGCs) associated with FBR. PLGA 80/20 alone and PLGA 80/20 combined with DS was extruded into rods. PLGA rods loaded with DS (PLGA+DS) were implanted into the femora of 18 rats. Eighteen control rats received unloaded PLGA rods. The follow-up period was of 3, 6 and 12 weeks. Each group comprised of six rats. Peri-implant tissue reactions were histologically and histomorphometrically evaluated. The implantation of PLGA and PLGA+DS8 rods induced the formation of a layer of newly formed bone islands parallel to the contour of the implants. PLGA+DS rods tended to reduce the presence of multi-nucleated giant cells (MGCs) at the implant surface. Although it is known that the systemic administration of DS is associated with compromised bone healing, the local release of DS via PLGA rods did not have negative effects on bone regeneration in the femora of rats throughout 12 weeks.
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Affiliation(s)
- Karoline M. Reich
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, Division of Oral Surgery, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria;
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
| | - Petrus Viitanen
- Institute of Biomaterials, Tampere University of Technology, 33101 Tampere, Finland;
| | - Ehsanul Hoque Apu
- Laboratory of Developmental Biology, Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90220 Oulu, Finland;
- Institute for Quantitative Health Science and Engineering, Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Stefan Tangl
- Karl Donath Laboratory for Hard Tissue and Biomaterial Research, Division of Oral Surgery, University Clinic of Dentistry, Medical University of Vienna, 1090 Vienna, Austria;
- Austrian Cluster for Tissue Regeneration, 1200 Vienna, Austria
- Correspondence: (S.T.); (N.A.)
| | - Nureddin Ashammakhi
- Division of Plastic Surgery, Department of Surgery, Oulu University Hospital, 90220 Oulu, Finland
- Center for Minimally Invasive Therapeutics (C-MIT), University of California, Los Angeles, CA 90095, USA
- Department of Bioengineering, University of California, Los Angeles, CA 90095, USA
- Department of Biomedical Engineering, Michigan State University, East Lansing, MI 48824, USA
- Correspondence: (S.T.); (N.A.)
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17
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Tian R, Zheng F, Zhao W, Zhang Y, Yuan J, Zhang B, Li L. Prevalence and influencing factors of nonunion in patients with tibial fracture: systematic review and meta-analysis. J Orthop Surg Res 2020; 15:377. [PMID: 32883313 PMCID: PMC7469357 DOI: 10.1186/s13018-020-01904-2] [Citation(s) in RCA: 100] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2019] [Accepted: 08/20/2020] [Indexed: 02/06/2023] Open
Abstract
OBJECTIVE The aim of this study is to assess the prevalence of nonunion in patients with tibia fracture and the association between influencing factors and tibia fracture nonunion. METHOD A database searches of PubMed, the Cochrane Library, EMBASE, China National Knowledge Infrastructure (CNKI), Weipu database, and Wanfang database from inception until June 2019 was conducted. The pooled prevalence, odds ratio (OR), and 95% confidence intervals (CI) were calculated with Stata software. RESULTS In this study, 111 studies involving 41,429 subjects were included. In the study of the relationship between influencing factors and tibia fracture nonunion, 15 factors significantly influenced the fracture union, including > 60 years old, male, tobacco smoker, body mass index > 40, diabetes, nonsteroidal anti-inflammatory drugs (NSAIDs) user, opioids user, fracture of middle and distal tibia, high-energy fracture, open fracture, Gustilo-Anderson grade IIIB or IIIC, Müller AO Classification of Fractures C, open reduction, fixation model, and infection. CONCLUSION The prevalence of nonunion in patients with tibia fracture was 0.068 and 15 potential factors were associated with the prevalence. Closed reduction and minimally invasive percutaneous plate osteosynthesis (MIPPO) have the low risks of nonunion for the treatment of tibial fractures.
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Affiliation(s)
- Ruifeng Tian
- Department of Orthopaedics, No.1 Hospital of China Medical University, Shenyang, China
| | - Fang Zheng
- Department of Orthopaedics, No.1 Hospital of China Medical University, Shenyang, China
- Department of Orthopaedics, Shenyang Orthopaedic Hospital, Shenyang, China
| | - Wei Zhao
- Department of Orthopaedics, No.1 Hospital of China Medical University, Shenyang, China
- Department of Orthopaedics, No.4 Hospital of China Medical University, Guangzhou, China
| | - Yuhui Zhang
- Department of Dermatology, No.1 Hospital of China Medical University, Guangzhou, China
| | - Jinping Yuan
- Department of Dermatology, No.1 Hospital of China Medical University, Guangzhou, China
| | - Bowen Zhang
- Department of Orthopaedics, No.1 Hospital of China Medical University, Shenyang, China
| | - Liangman Li
- Department of Orthopaedics, No.1 Hospital of China Medical University, Shenyang, China.
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18
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Hassan MK, Karlock LG. The effect of post-operative NSAID administration on bone healing after elective foot and ankle surgery. Foot Ankle Surg 2020; 26:457-463. [PMID: 31196697 DOI: 10.1016/j.fas.2019.05.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2018] [Revised: 05/22/2019] [Accepted: 05/23/2019] [Indexed: 02/04/2023]
Abstract
BACKGROUND Post-operative pain is a common concern following elective foot and ankle surgery. NSAIDs used for pain relief have led to bone-healing complications in animal models and in vitro studies. This retrospective study examined the rate of bone-healing complications in post-surgical patients using NSAIDs. METHODS Participants underwent elective foot surgeries between January 2016 and May 2018. Radiographs were used to identify bony nonunion at osteotomy sites 12 weeks post-surgery. RESULTS Two-hundred thirty-two patients were evaluated; 59 (25.43%) were prescribed ibuprofen, 62 (27%) ketorolac, 15 (6.47%) acetaminophen, and 92 (40%) hydrocodone-acetaminophen. Two-hundred and twelve (91.38%) patients exhibited radiographic evidence of osseous union at 12 weeks and 20 (8.62%) had radiographic evidence of non-union of the osteotomy sites. There was no significant relationship between NSAID use and osseous non-union (p<0.05). CONCLUSIONS Short-term use of oral ibuprofen and ketorolac in the post-operative period was not associated with bony non-union.
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Affiliation(s)
- Mohammed K Hassan
- East Liverpool City Hospital, 425 W 5th St., East Liverpool, 43920, OH United States.
| | - Lawrence G Karlock
- Austintown Podiatry Associates, 1300 S Canfield-Niles Rd #1, Austintown, 44515, OH, United States; The Orthopedic Surgery Center, 6505 Market St #101, Boardman, 44512, OH, United States
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19
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Karmacharya P, Duarte-Garcia A, Dubreuil M, Murad MH, Shahukhal R, Shrestha P, Myasoedova E, Crowson CS, Wright K, Davis JM. Effect of Therapy on Radiographic Progression in Axial Spondyloarthritis: A Systematic Review and Meta-Analysis. Arthritis Rheumatol 2020; 72:733-749. [PMID: 31960614 PMCID: PMC7218689 DOI: 10.1002/art.41206] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Accepted: 01/09/2020] [Indexed: 12/20/2022]
Abstract
OBJECTIVE To investigate the effect of therapies on radiographic progression in patients with axial spondyloarthritis (SpA). METHODS A comprehensive database search for studies assessing radiographic progression in axial SpA (particular treatment versus no treatment of interest) was performed. Study-specific standardized mean differences in treatment outcomes at 2 and ≥4 years were estimated and combined using random-effects models. RESULTS Twenty-four studies in patients with axial SpA were identified, of which 18 involved tumor necrosis factor inhibitors (TNFi), 8 involved nonsteroidal antiinflammatory drugs (NSAIDs), and 1 involved secukinumab. Spinal radiographic progression, as measured by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS), was not significantly different between TNFi-treated and biologics-naive patients at 2 years (mSASSS difference -0.73 [95% confidence interval (95% CI) -1.52, 0.12], I2 = 28%) and ≥4 years (mSASSS difference -2.03 [95% CI -4.63, 0.72], I2 = 63%). Sensitivity analyses restricted to studies with a low risk of bias showed a significant difference in spinal radiographic progression between TNFi-treated and biologics-naive patients at ≥4 years (mSASSS difference -2.17 [95% CI -4.19, -0.15]). No significant difference in spinal radiographic progression was observed between NSAID-treated and control patients (mSASSS difference -0.30 [95% CI -2.62, 1.31], I2 = 71%) or between secukinumab-treated and biologics-naive patients (mSASSS difference -0.34 [95% CI -0.85, 0.17]). With regard to treatment differences in patients with nonradiographic axial SpA or in patients with radiographic progression measured using the sacroiliac joint score, an insufficient number of studies were available for analysis. CONCLUSION Although no significant protective effect of TNFi treatment on spinal radiographic progression was seen over the course of 2 years or ≥4 years in patients with axial SpA, our analysis restricted to studies with a low risk of bias showed a protective effect of TNFi after ≥4 years. Therefore, long-term TNFi exposure might confer beneficial effects on spinal radiographic progression in axial SpA. No difference in radiographic progression at 2 years was seen in either the NSAID or secukinumab treatment groups compared to their controls. Future studies should explore the effects of biologic treatment on radiographic progression, as well as the effects of long-term biologics exposure, in patients with early axial SpA or those with nonradiographic axial SpA.
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Affiliation(s)
- Paras Karmacharya
- Division of Rheumatology, Department of Medicine, Mayo Clinic. Rochester, MN, USA
| | - Ali Duarte-Garcia
- Division of Rheumatology, Department of Medicine, Mayo Clinic. Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN. USA
| | | | - M. Hassan Murad
- Evidence-based Practice Center, Mayo Clinic, Rochester, MN, USA
| | | | - Pragya Shrestha
- Asthma Epidemiology Research Unit, Mayo Clinic, Rochester, MN, USA
| | - Elena Myasoedova
- Division of Rheumatology, Department of Medicine, Mayo Clinic. Rochester, MN, USA
| | - Cynthia S. Crowson
- Division of Rheumatology, Department of Medicine, Mayo Clinic. Rochester, MN, USA
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Kerry Wright
- Division of Rheumatology, Department of Medicine, Mayo Clinic. Rochester, MN, USA
| | - John M. Davis
- Division of Rheumatology, Department of Medicine, Mayo Clinic. Rochester, MN, USA
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Aliuskevicius M, Østgaard SE, Hauge EM, Vestergaard P, Rasmussen S. Influence of Ibuprofen on Bone Healing After Colles' Fracture: A Randomized Controlled Clinical Trial. J Orthop Res 2020; 38:545-554. [PMID: 31646668 DOI: 10.1002/jor.24498] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/03/2019] [Accepted: 10/04/2019] [Indexed: 02/04/2023]
Abstract
Non-steroidal anti-inflammatory drugs (NSAIDs) may delay bone healing. [Therefore, it is important to establish whether NSAID preparations delay bone healing and what correlations, if any, exist between different bone studies-DEXA-scanning, bone markers, roentgenology controls, and histological examination of newly formed bone]. The purpose of this prospective controlled study was to investigate whether ibuprofen affects bone mineral density, turnover biomarkers, and histomorphometric characteristics of the callus after a Colles' fracture. This study was a single-center, triple-blinded, randomized clinical trial. Ninety-five patients (80 females) with displaced Colles' fracture, median age 65 (range 40-85) years were included in the study and operated on by external fixation from June 2012 through to June 2015. Eighty-nine patients received interventional medicine and 83 completed the 1-year follow-up. The 7-day ibuprofen group received 600 mg of ibuprofen three times a day (N = 29), the 3-day ibuprofen group received ibuprofen for 3 days (N = 30) and a placebo for the following 4 days, and finally, the placebo group received a placebo for 7 days (N = 30). The primary outcome was the difference in bone mineral density between the ultra-distal region of the injured and non-injured radius at 3 months after surgery. The histomorphometric outcomes included the assessment of callus tissue volume and surface fractions at 6 weeks postoperatively. The biomarkers Osteocalcin and CrossLaps were measured at baseline, 1 week, 2 weeks, 6 weeks, 3 months, and 1 year. We included the results of the dropped-out patients in the intention to treat analysis. There was no difference between treatment groups in bone mineral density, histomorphometric estimations, and changes in bone biomarkers. These findings may offer an indication of ibuprofen as a bone-safe analgesic treatment in an acute fracture-phase. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:545-554, 2020.
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Affiliation(s)
- Marius Aliuskevicius
- Department of Orthopedic Surgery, Clinic Orto-Head, Aalborg University Hospital, 18-22 Hobrovej, DK-9000, Aalborg, Denmark
| | - Svend Erik Østgaard
- Department of Orthopedic Surgery, Clinic Orto-Head, Aalborg University Hospital, 18-22 Hobrovej, DK-9000, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, 15 Sdr. Skovvej, DK-9000, Aalborg, Denmark
| | - Ellen Margrethe Hauge
- Department of Rheumatology, Aarhus University Hospital, 99 Palle Juul-Jensens Boulevard, DK-8200, Aarhus N, Denmark.,Department of Clinical Medicine, Aarhus University, Incuba/Skejby, Building 2, Palle Juul-Jensens Boulevard 82, DK-8200, Aarhus N, Denmark
| | - Peter Vestergaard
- Department of Clinical Medicine, Aalborg University, 15 Sdr. Skovvej, DK-9000, Aalborg, Denmark.,Department of Endocrinology, Clinic of Internal Medicine, Aalborg University Hospital, 18-22 Hobrovej, DK-9000, Aalborg, Denmark.,Steno Diabetes Center North Jutland, Aalborg University Hospital, Dk-9000, Aalborg, Denmark
| | - Sten Rasmussen
- Department of Orthopedic Surgery, Clinic Orto-Head, Aalborg University Hospital, 18-22 Hobrovej, DK-9000, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University, 15 Sdr. Skovvej, DK-9000, Aalborg, Denmark
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Rothe R, Schulze S, Neuber C, Hauser S, Rammelt S, Pietzsch J. Adjuvant drug-assisted bone healing: Part I – Modulation of inflammation. Clin Hemorheol Microcirc 2020; 73:381-408. [PMID: 31177205 DOI: 10.3233/ch-199102] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Affiliation(s)
- Rebecca Rothe
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Dresden, Germany
| | - Sabine Schulze
- University Center of Orthopaedics & Traumatology (OUC), University Hospital Carl Gustav Carus, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
| | - Christin Neuber
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Dresden, Germany
| | - Sandra Hauser
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Dresden, Germany
| | - Stefan Rammelt
- University Center of Orthopaedics & Traumatology (OUC), University Hospital Carl Gustav Carus, Dresden, Germany
- Center for Translational Bone, Joint and Soft Tissue Research, University Hospital Carl Gustav Carus and Faculty of Medicine, Technische Universität Dresden, Dresden, Germany
- Center for Regenerative Therapies Dresden (CRTD), Dresden, Germany
| | - Jens Pietzsch
- Helmholtz-Zentrum Dresden-Rossendorf (HZDR), Institute of Radiopharmaceutical Cancer Research, Department of Radiopharmaceutical and Chemical Biology, Dresden, Germany
- Technische Universität Dresden, School of Science, Faculty of Chemistry and Food Chemistry, Dresden, Germany
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22
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Heterotopic ossification: radiological and pathological review. Radiol Oncol 2019; 53:275-284. [PMID: 31553710 PMCID: PMC6765162 DOI: 10.2478/raon-2019-0039] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2019] [Accepted: 07/11/2019] [Indexed: 02/07/2023] Open
Abstract
Background Heterotopic Ossification (HO) is a common condition referring to ectopic bone formation in soft tissues. It has two major etiologies, acquired (more common) and genetic. The acquired form is closely related to tissue trauma. The exact pathogenesis of this disease remains unclear; however, there is ongoing research in prophylactic and therapeutic treatments that is promising. Conclusions Due to HO potential to cause disability, it is so important to differentiate it from other causes in order to establish the best possible management.
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Gallaher HM, Butler JR, Wills RW, Priddy LB, Elder SH, Heller SM, Brinkman E, Baumgartner W. Effects of short- and long-term administration of nonsteroidal anti-inflammatory drugs on osteotomy healing in dogs. Vet Surg 2019; 48:1318-1329. [PMID: 31291009 DOI: 10.1111/vsu.13282] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Revised: 04/17/2019] [Accepted: 06/18/2019] [Indexed: 12/17/2022]
Abstract
OBJECTIVE To determine the influence of short-term administration of carprofen on bone healing in dogs. STUDY DESIGN Randomized controlled experimental study. ANIMALS Eighteen purpose-bred sexually mature hound dogs. METHODS Tibial osteotomies were performed, and dogs were divided into three groups: no carprofen (n = 6), 2-week administration of carprofen at 2.2 mg/kg twice daily (n = 6), and 8-week administration of carprofen at 2.2 mg/kg twice daily (n = 5). Bone healing was evaluated radiographically at 4 and 8 weeks postoperatively. Postmortem, fracture healing was assessed via biomechanical testing (three-point bending), histological cartilage:callus ratio, and bone mineral density (BMD) with quantitative computed tomography. RESULTS No biomechanical difference was detected between dogs that received no carprofen and those that received 2 weeks of carprofen or between those that received 2 weeks vs 8 weeks of carprofen. Stiffness (P = .035) and maximum stress (P = .042) were higher in dogs that received no carprofen than in those that received 8 weeks of carprofen. Radiographic healing did not differ between dogs without carprofen and those with 2-week administration of carprofen (P = .9923). However, tibias of dogs without carprofen and those with 2-week administration of carprofen were more healed compared with those in the 8-week-carprofen group at 4 and 8 weeks after surgery (P = .0011). No treatment effect was detected by cartilage:callus ratio or BMD. CONCLUSION Long-term administration of carprofen had a negative effect on bone healing compared with short-term or no administration of carprofen. CLINICAL SIGNIFICANCE Nonsteroidal anti-inflammatory drugs should be used cautiously in dogs at risk for delayed bone healing, and administration should be discontinued beyond the perioperative period in dogs with fractures or osteotomies.
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Affiliation(s)
- Hayley M Gallaher
- Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
| | - James R Butler
- Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
| | - Robert W Wills
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
| | - Lauren B Priddy
- Department of Agricultural and Biological Engineering, Bagley College of Engineering, Mississippi State University, Mississippi State, Mississippi
| | - Steven H Elder
- Department of Agricultural and Biological Engineering, Bagley College of Engineering, Mississippi State University, Mississippi State, Mississippi
| | - Sarah M Heller
- Department of Agricultural and Biological Engineering, Bagley College of Engineering, Mississippi State University, Mississippi State, Mississippi
| | - Erin Brinkman
- Department of Clinical Sciences, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
| | - Wes Baumgartner
- Department of Pathobiology and Population Medicine, College of Veterinary Medicine, Mississippi State University, Mississippi State, Mississippi
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Feuerherm AJ, Dennis EA, Johansen B. Cytosolic group IVA phospholipase A2 inhibitors, AVX001 and AVX002, ameliorate collagen-induced arthritis. Arthritis Res Ther 2019; 21:29. [PMID: 30665457 PMCID: PMC6341602 DOI: 10.1186/s13075-018-1794-6] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 12/11/2018] [Indexed: 02/08/2023] Open
Abstract
Background Cytosolic phospholipase A2 group IVA (cPLA2α)-deficient mice are resistant to collagen-induced arthritis, suggesting that cPLA2α is an important therapeutic target. Here, the anti-inflammatory effects of the AVX001 and AVX002 cPLA2α inhibitors were investigated. Methods In vitro enzyme activity was assessed by a modified Dole assay. Effects on inhibiting IL-1β-induced release of arachidonic acid (AA) and prostaglandin E2 (PGE2) were measured using SW982 synoviocyte cells. In vivo effects were studied in prophylactic and therapetic murine collagen-induced arthritis models and compared to methotrexate (MTX) and Enbrel, commonly used anti-rheumatic drugs. The in vivo response to treatment was evaluated in terms of the arthritis index (AI), histopathology scores and by plasma levels of PGE2 following 14 and 21 days of treatment. Results Both cPLA2α inhibitors are potent inhibitors of cPLA2α in vitro. In synoviocytes, AVX001 and AVX002 reduce, but do not block, release of AA or PGE2 synthesis. In both CIA models, the AI and progression of arthritis were significantly lower in the mice treated with AVX001, AVX002, Enbrel and MTX than in non- treated mice. Several histopathology parameters of joint damage were found to be significantly reduced by AVX001 and AVX002 in both prophylactic and therapeutic study modes; namely articular cavity and peripheral tissue inflammatory cell infiltration; capillary and synovial hyperplasia; articular cartilage surface damage; and periostal and endochondral ossification. In comparison, MTX did not significantly improve any histopathology parameters and Enbrel only improved ossification. Finally, as a biomarker of inflammation and as an indication that AVX001 and AVX002 blocked the cPLA2α target, we determined that plasma levels of PGE2 were significantly reduced in response to the AVX inhibitors and MTX, but not Enbrel. Conclusions AVX001 and AVX002 display potent anti-inflammatory activity and disease-modifying properties in cellular and in vivo models. The in vivo effects of AVX001 and AVX002 were comparable to, or superior, to those of MTX and Enbrel. Taken together, this study suggests that cPLA2α inhibitors AVX001 and AVX002 are promising small molecule disease-modifying anti-rheumatic therapies.
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Affiliation(s)
- A J Feuerherm
- Department of Biology, Norwegian University of Science and Technology, N-7491, Trondheim, Norway
| | - E A Dennis
- Department of Chemistry and Biochemistry, University of California-San Diego, La Jolla, California, 92093-0601, USA.,Department of Pharmacology, School of Medicine, University of California-San Diego, La Jolla, California, 92093-0601, USA
| | - B Johansen
- Department of Biology, Norwegian University of Science and Technology, N-7491, Trondheim, Norway.
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25
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Saul D, Weber M, Zimmermann MH, Kosinsky RL, Hoffmann DB, Menger B, Taudien S, Lehmann W, Komrakova M, Sehmisch S. Effect of the lipoxygenase inhibitor baicalein on bone tissue and bone healing in ovariectomized rats. Nutr Metab (Lond) 2019; 16:4. [PMID: 30651746 PMCID: PMC6329162 DOI: 10.1186/s12986-018-0327-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 12/10/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Osteoporosis is one of the world's major medical burdens in the twenty-first century. Pharmaceutical intervention currently focusses on decelerating bone loss, but phytochemicals such as baicalein, which is a lipoxygenase inhibitor, may rescue bone loss. Studies evaluating the effect of baicalein in vivo are rare. METHODS We administered baicalein to sixty-one three-month-old female Sprague-Dawley rats. They were divided into five groups, four of which were ovariectomized (OVX) and one non-ovariectomized (NON-OVX). Eight weeks after ovariectomy, bilateral tibial osteotomy with plate osteosynthesis was performed and bone formation quantified. Baicalein was administered subcutaneously using three doses (C1: 1 mg/kg BW; C2: 10 mg/kg BW; and C3: 100 mg/kg BW) eight weeks after ovariectomy for four weeks. Finally, femora and tibiae were collected. Biomechanical tests, micro-CT, ashing, histological and gene expression analyses were performed. RESULTS Biomechanical properties were unchanged in tibiae and reduced in femora. In tibiae, C1 treatment enhanced callus density and cortical width and decreased callus area. In the C3 group, callus formation was reduced during the first 3 weeks after osteotomy, correlating to a higher mRNA expression of Osteocalcin, Tartrate-resistant acid phosphatase and Rankl. In femora, baicalein treatments did not alter bone parameters. CONCLUSIONS Baicalein enhanced callus density and cortical width but impaired early callus formation in tibiae. In femora, it diminished the biomechanical properties and calcium-to-phosphate ratio. Thus, it is not advisable to apply baicalein to treat early bone fractures. To determine the exact effects on bone healing, further studies in which baicalein treatments are started at different stages of healing are needed.
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Affiliation(s)
- Dominik Saul
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Marie Weber
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Marc Hendrik Zimmermann
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Robyn Laura Kosinsky
- Department of General, Visceral and Pediatric Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Daniel Bernd Hoffmann
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Björn Menger
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Stefan Taudien
- Division of Infection Control and Infectious Diseases, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Wolfgang Lehmann
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Marina Komrakova
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
| | - Stephan Sehmisch
- Department of Trauma Surgery, Orthopaedics and Plastic Surgery, University Medical Center Goettingen, 37075 Goettingen, Germany
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Moilanen E, Vuolteenaho K. Nonsteroidal Anti-inflammatory Drugs. NIJKAMP AND PARNHAM'S PRINCIPLES OF IMMUNOPHARMACOLOGY 2019:689-707. [DOI: 10.1007/978-3-030-10811-3_33] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
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Melguizo-Rodríguez L, Costela-Ruiz VJ, Manzano-Moreno FJ, Illescas-Montes R, Ramos-Torrecillas J, García-Martínez O, Ruiz C. Repercussion of nonsteroidal anti-inflammatory drugs on the gene expression of human osteoblasts. PeerJ 2018; 6:e5415. [PMID: 30128197 PMCID: PMC6097469 DOI: 10.7717/peerj.5415] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2018] [Accepted: 07/20/2018] [Indexed: 01/31/2023] Open
Abstract
Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used in clinical practice, which can have adverse effects on the osteoblast. The objective of this study was to determine the effect of NSAIDs on the osteoblast by analyzing the gene expression of different markers related to osteoblast maturation and function when treated in vitro with different NSAIDs. Methods Three human osteoblast lines from bone samples of three healthy volunteers were treated with 10 µM acetaminophen, indomethacin, ketoprofen, diclofenac, ibuprofen, ketorolac, naproxen, and piroxicam. The gene expression of different markers (run related transcription factor 2 [RUNX-2], type 1 collagen [COL-I], osterix [OSX], osteocalcin [OSC], bone morphogenetic protein 2 [BMP-2] and 7 [BMP-7], transforming growth factor β1 [TGF-β1], and TGFβ receptors [TGFβR1, TGFβR2; TGFBR3]) were analyzed by real-time PCR at 24 h of treatment. Results Expression of RUNX-2, COL-I, OSX, was reduced by treatment with all studied NSAIDs, OSC expression was reduced by all NSAIDs except for ketoprofen, naproxen, or piroxicam. Expression of BMP-7 was reduced by all NSAIDs; BMP-2 was reduced by all except for naproxen. In general, NSAID treatment increased the expression of TGF-β1, but not of its receptors (TGFβ-R1, TGFβ-R2, andTFGβ-R3), which was either unchanged or reduced by the treatment. Conclusion These data confirm that NSAIDs can affect osteoblast physiology, suggesting their possible impact on bone.
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Affiliation(s)
- Lucia Melguizo-Rodríguez
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Instituto Investigación Biosanitaria, ibs.Granada, University of Granada, Granada, Spain
| | - Víctor J Costela-Ruiz
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain
| | - Francisco J Manzano-Moreno
- Instituto Investigación Biosanitaria, ibs.Granada, University of Granada, Granada, Spain.,Biomedical Group (BIO277), Department of Stomatology, School of Dentistry, University of Granada, Granada, Spain
| | - Rebeca Illescas-Montes
- Instituto Investigación Biosanitaria, ibs.Granada, University of Granada, Granada, Spain.,Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Melilla, Spain
| | - Javier Ramos-Torrecillas
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Instituto Investigación Biosanitaria, ibs.Granada, University of Granada, Granada, Spain
| | - Olga García-Martínez
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Instituto Investigación Biosanitaria, ibs.Granada, University of Granada, Granada, Spain
| | - Concepción Ruiz
- Biomedical Group (BIO277), Department of Nursing, Faculty of Health Sciences, University of Granada, Granada, Spain.,Instituto Investigación Biosanitaria, ibs.Granada, University of Granada, Granada, Spain.,Institute of Neuroscience, University of Granada, Granada, Spain
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Lisowska B, Kosson D, Domaracka K. Positives and negatives of nonsteroidal anti-inflammatory drugs in bone healing: the effects of these drugs on bone repair. DRUG DESIGN DEVELOPMENT AND THERAPY 2018; 12:1809-1814. [PMID: 29950815 PMCID: PMC6016595 DOI: 10.2147/dddt.s164565] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Tissue damage following injury triggers the processes of coagulation, inflammation and healing. In tissues surrounding the bone, the result of the healing process is a scar, while bone tissue has a unique ability to achieve shape, strength and pre-injury function. Bone healing is a process of regeneration rather than classic recovery. The result of this process is the formation of new, healthy bone tissue instead of a scar. Many factors can inhibit or impair the bone healing process, and their influence is critical during the stages of inflammation and angiogenesis and finally on the clinical outcome. Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential role associated with their analgesic potency and anti-inflammatory effects. NSAIDs are also the most often used drugs in patients who require pain control and inflammation reduction due to musculoskeletal diseases or injures. Although their analgesic effect is well documented, NSAIDs also interfere with bone healing; therefore, the relative benefits and disadvantages connected with their administration should be taken into consideration. Despite the negative effect, NSAIDs have beneficial properties, but their clinical benefits in relation to dose and time of use are still unclear. Therefore, in this review, we focus on bone healing with relation to the impact of NSAIDs.
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Affiliation(s)
- Barbara Lisowska
- Department of Anesthesiology and Intensive Care, John Paul II Western Hospital, Grodzisk Mazowiecki, Poland
| | - Dariusz Kosson
- Department of Anaesthesiology and Intensive Care, Medical University of Warsaw, Division of Teaching Warsaw, Warsaw, Poland
| | - Karolina Domaracka
- Department of Anaesthesiology and Intensive Care, Medical University of Warsaw, Warsaw, Poland
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Gunaydin C, Bilge SS. Effects of Nonsteroidal Anti-Inflammatory Drugs at the Molecular Level. Eurasian J Med 2018; 50:116-121. [PMID: 30002579 DOI: 10.5152/eurasianjmed.2018.0010] [Citation(s) in RCA: 121] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2017] [Accepted: 04/19/2018] [Indexed: 01/07/2023] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used for their anti-inflammatory, analgesic, and antipyretic effects. NSAIDs generally work by blocking the production of prostaglandins (PGs) through the inhibition of two cyclooxygenase enzymes. PGs are key factors in many cellular processes, such as gastrointestinal cytoprotection, hemostasis and thrombosis, inflammation, renal hemodynamics, turnover of cartilage, and angiogenesis. Interest has grown in the various effects of NSAIDs during the last decade. Epidemiological studies have revealed the reduced risk of several cancer types and neurodegenerative diseases by prolonged use of NSAIDs. Recent advances in the understanding of the cellular and molecular mechanisms of NSAIDs will accelerate the processes of discovery and clinical implementation. This review summarizes the molecular mechanisms of NSAIDs on the body systems.
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Affiliation(s)
- Caner Gunaydin
- Department of Pharmacology, Ondokuz Mayıs University School of Medicine, Samsun, Turkey
| | - S Sirri Bilge
- Department of Pharmacology, Ondokuz Mayıs University School of Medicine, Samsun, Turkey
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Kuchálik J, Magnuson A, Lundin A, Gupta A. Local infiltration analgesia: a 2-year follow-up of patients undergoing total hip arthroplasty. J Anesth 2017; 31:837-845. [PMID: 28856511 PMCID: PMC5680378 DOI: 10.1007/s00540-017-2403-6] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Accepted: 08/11/2017] [Indexed: 11/29/2022]
Abstract
Purpose Local infiltration analgesia (LIA) is commonly used for postoperative pain management following total hip arthroplasty (THA). However, the long-term effects of the component drugs are unclear. The aim of our study was to investigate functional outcome, quality of life, chronic post-surgical pain, and adverse events in patients within 2 years of undergoing THA. Methods The study was a secondary analysis of data from a previous larger study. Eighty patients were randomized to receive either intrathecal morphine (Group ITM) or local infiltration analgesia (Group LIA) for pain management in a double-blind study. The parameters measured were patient-assessed functional outcome [using the Hip dysfunction and Osteo-arthritis Outcome Score (HOOS) questionnaire], health-related quality of life [using the European Quality of Life–5 dimensions (EQ-5D) questionnaire and the 36-Item Short Form Health Survey (SF-36) score], and pain using the numeric rating score (NRS), with persistent post-surgical pain having a NRS of > 3 or a HOOS pain sub-score of > 30. All complications and adverse events were investigated during the first 2 years after primary surgery. Results Pain intensity and rescue analgesic consumption were similar between the groups after hospital discharge. No differences were found in HOOS or SF-36 score between the groups up to 6 months after surgery. A significant group × time interaction was seen in the EQ 5D form in favor of the LIA group. No between-group difference in persistent post-surgical pain was found at 3 or 6 months, or in adverse events up to 2 years after surgery. Conclusion Analysis of functional outcome, quality of life, and post-discharge surgical pain did not reveal significant differences between patients receiving LIA and those receiving ITM. LIA was found to be a safe technique for THA during the long-term follow-up. However, it should be noted that these conclusions are based on a limited number of patients.
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Affiliation(s)
- Ján Kuchálik
- Department of Anaesthesiology and Intensive Care, Institution for Medicine and Health, Örebro University Hospital, Örebro, Sweden
| | - Anders Magnuson
- Clinical Epidemiology and Biostatistics Unit, Örebro University Hospital, Örebro, Sweden
| | - Anders Lundin
- Department of Orthopaedic Surgery, Institution for Medicine and Health, Örebro University Hospital, Örebro, Sweden
| | - Anil Gupta
- Department of Anaesthesiology and Intensive Care, Institution for Medicine and Health, Örebro University Hospital, Örebro, Sweden. .,Department of Anaesthesiology and Intensive Care, Karolinska University Hospital Solna-Karolinska Institutet, Stockholm, 17176, Sweden.
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31
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Sivaganesan A, Chotai S, White-Dzuro G, McGirt MJ, Devin CJ. The effect of NSAIDs on spinal fusion: a cross-disciplinary review of biochemical, animal, and human studies. 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 2017; 26:2719-2728. [PMID: 28283838 DOI: 10.1007/s00586-017-5021-y] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 02/19/2017] [Accepted: 02/25/2017] [Indexed: 12/21/2022]
Abstract
PURPOSE Non-steroidal anti-inflammatory drugs (NSAIDs) play an important role in postoperative pain management. However, their use in the setting of spine fusion surgery setting has long been a topic of controversy. In this review we examined relevant research, including in vivo, animal, and clinical human studies, with the aim of understanding the effect of NSAIDs on spinal fusion. STUDY DESIGN/SETTING Systematic review of study designs of all types from randomized controlled trials and meta-analyses to single-institution retrospective reviews. METHODS A search of PubMed and Embase was conducted using the keywords: "spine," "spinal fracture," NSAIDs, anti-inflammatory non-steroidal agents, bone, bone healing, fracture, fracture healing, yielding a total of 110 studies. Other 28 studies were identified by cross-referencing, resulting in total 138 studies. RESULTS There is no level I evidence from human studies regarding the use of NSAIDs on spinal fusion rates. The overall tone of the spine literature in the early 2000s was that NSAIDs increased the rate of non-union; however, nearly all human studies published after 2005 suggest that short-term (<2 weeks) postoperative use have no such effect. The dose dependency that is seen with a 2-week postoperative course is not present when NSAIDs are only used for 48 h after surgery. CONCLUSIONS NSAID appear to have dose-dependent and duration-dependent effects on fusion rates. The short-term use of low-dose NSAIDs around the time of spinal fusion surgery is reasonable. Spine surgeons can consider the incorporation of NSAIDs into pain control regimens for spinal fusion patients with the goal of improving pain control and reducing the costs and complications associated with opioids.
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Affiliation(s)
- Ahilan Sivaganesan
- Department of Neurological Surgery, Vanderbilt University Medical Center, 1161 21st Ave. So., T4224 Medical Center North, Nashville, TN, 37232-2380, USA.
| | - Silky Chotai
- Department of Neurological Surgery, Vanderbilt University Medical Center, 1161 21st Ave. So., T4224 Medical Center North, Nashville, TN, 37232-2380, USA.,Department of Orthopedic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | | | - Matthew J McGirt
- Department of Neurological Surgery, Carolina Neurosurgery and Spine Associates, Charlotte, NC, USA
| | - Clinton J Devin
- Department of Neurological Surgery, Vanderbilt University Medical Center, 1161 21st Ave. So., T4224 Medical Center North, Nashville, TN, 37232-2380, USA.,Department of Orthopedic Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
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Chronic Osteoporotic Pain in Mice: Cutaneous and Deep Musculoskeletal Pain Are Partially Independent of Bone Resorption and Differentially Sensitive to Pharmacological Interventions. J Osteoporos 2017; 2017:7582716. [PMID: 28299231 PMCID: PMC5337358 DOI: 10.1155/2017/7582716] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2016] [Accepted: 01/26/2017] [Indexed: 01/06/2023] Open
Abstract
Although the pathological changes in osteoporotic bones are well established, the characterization of the osteoporotic pain and its appropriate treatment are not fully elucidated. We investigated the behavioral signs of cutaneous and deep musculoskeletal pain and physical function; time-dependent changes in bone mineral density (BMD) and the emergence of the behavioral phenotype; and the effects of pharmacological interventions having different mechanisms of action (chronic intraperitoneal administration of pamidronate [0.25 mg/kg, 5x/week for 5 weeks] versus acute treatment with intraperitoneal morphine [10 mg/kg] and pregabalin [100 mg/kg]) in a mouse model of ovariectomized or sham-operated mice 6 months following surgery. We observed reduced BMD associated with weight gain, referred cutaneous hypersensitivity, and deep musculoskeletal pain that persisted for 6 months. Chronic bisphosphonate treatment, 6 months after ovariectomy, reversed bone loss and hypersensitivity to cold, but other behavioral indices of osteoporotic pain were unchanged. While the efficacy of acute morphine on cutaneous pain was weak, pregabalin was highly effective; deep musculoskeletal pain was intractable. In conclusion, the reversal of bone loss alone is insufficient to manage pain in chronic osteoporosis. Additional treatments, both pharmacological and nonpharmacological, should be implemented to improve quality of life for osteoporosis patients.
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Park JW, Kwon HM, Park JK, Choi JY, Lee EB, Song YW, Lee EY. Impact of Dose Tapering of Tumor Necrosis Factor Inhibitor on Radiographic Progression in Ankylosing Spondylitis. PLoS One 2016; 11:e0168958. [PMID: 28033420 PMCID: PMC5199008 DOI: 10.1371/journal.pone.0168958] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2016] [Accepted: 12/08/2016] [Indexed: 12/17/2022] Open
Abstract
Objective To investigate the impact of dose reduction of tumor necrosis factor inhibitor (TNFi) on radiographic progression in ankylosing spondylitis (AS). Methods One hundred and sixty-five patients treated with etanercept or adalimumab were selected from a consecutive single-center observational cohort based on the availability of radiographs at baseline and after two- and/or four-years of follow up. Radiographs were assessed by two blinded readers using the modified Stokes AS Spinal Score (mSASSS). Radiographic progression in patients treated with standard-dose TNFi (standard-dose group, n = 49) was compared with patients whose dosage was tapered during the treatment (tapering group, n = 116) using linear mixed models. Results Baseline characteristics between two groups were comparable except for higher BASDAI (7.1 vs. 6.3, p = 0.003) in the standard-dose group. At two years after the treatment, mean dose quotient (S.D.) of the tapering group was 0.59 (0.17). During follow up, rate of radiographic progression in overall patients was 0.90 mSASSS units/year. Radiographic progression over time between the two groups was similar at the entire group level. However, in the subgroup of patients with baseline syndesmophytes, progression occurred significantly faster in the tapering group after the adjustment for baseline status (1.23 vs. 1.72 mSASSS units/year, p = 0.023). Results were consistent when radiographic progression was assessed by the number of newly developed syndesmophytes (0.52 vs. 0.73/year, p = 0.047). Sensitivity analysis after multiple imputation of missing radiographs also showed similar results. Conclusion A dose tapering strategy of TNFi is associated with more rapid radiographic progression in AS patients who have syndesmophytes at baseline.
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Affiliation(s)
- Jun Won Park
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Hyun Mi Kwon
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jin Kyun Park
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Ja-Young Choi
- Department of Radiology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Eun Bong Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Yeong Wook Song
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Eun Young Lee
- Division of Rheumatology, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- * E-mail:
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Winkler S, Springorum HR, Vaitl T, Handel M, Barta S, Kehl V, Craiovan B, Grifka J. Comparative clinical study of the prophylaxis of heterotopic ossifications after total hip arthroplasty using etoricoxib or diclofenac. INTERNATIONAL ORTHOPAEDICS 2016; 40:673-80. [PMID: 26728611 DOI: 10.1007/s00264-015-3077-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/23/2015] [Accepted: 10/29/2015] [Indexed: 11/25/2022]
Abstract
PURPOSE This study investigated whether etoricoxib (COX-II blocker) has a superior efficacy of preventing heterotopic ossification (HO) after total hip arthroplasty (THA) compared to diclofenac (non-selective NSAID). METHODS One hundred patients were included (50 in each group) in this single centre, prospective, double-blinded, randomized, controlled trial. Etoricoxib (90 mg) was administered once and diclofenac (75 mg) twice per day for a perioperative period of nine days. The incidence of HO was evaluated on radiographs of the pelvis six months after surgery. RESULTS Eighty nine of 100 (89 %) patients could be analysed. The overall HO incidence was 37.8 %. There was no significant difference between both study groups. Twelve patients (27.3 %) of the DIC group and 13 patients (28.9 %) of the ETO group showed Brooker grade I ossifications. Five patients (11.4 %) of the DIC and four patients of the ETO (8.9 %) group showed grade II HO formations. No class III or IV HO formations occured in both groups. Ad hoc analysis detected a negative correlation between HO incidence and limited abduction and internal rotation of the hip. CONCLUSIONS Etoricoxib and diclofenac are equally effective for oral HO prophylaxis after primary cementless THA when given for nine peri-operative days to ensure a full recovery and high patient satisfaction.
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Affiliation(s)
- Sebastian Winkler
- Department of Orthopaedic Surgery, Regensburg University Medical Centre, Kaiser-Karl-V-Allee 3, 93077, Bad Abbach, Germany.
| | - Hans-Robert Springorum
- Department of Orthopaedic Surgery, Regensburg University Medical Centre, Kaiser-Karl-V-Allee 3, 93077, Bad Abbach, Germany
| | - Tobias Vaitl
- Department of Orthopaedic Surgery, Regensburg University Medical Centre, Kaiser-Karl-V-Allee 3, 93077, Bad Abbach, Germany
| | - Martin Handel
- Department of Orthopaedic Surgery, Regensburg University Medical Centre, Kaiser-Karl-V-Allee 3, 93077, Bad Abbach, Germany
| | - Sabine Barta
- Münchner Studienzentrum, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
| | - Victoria Kehl
- Institute for Medical Statistics and Epidemiology, Technische Universität, Munich, Germany
| | - Benjamin Craiovan
- Department of Orthopaedic Surgery, Regensburg University Medical Centre, Kaiser-Karl-V-Allee 3, 93077, Bad Abbach, Germany
| | - Joachim Grifka
- Department of Orthopaedic Surgery, Regensburg University Medical Centre, Kaiser-Karl-V-Allee 3, 93077, Bad Abbach, Germany
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Abstract
OBJECTIVE To examine the use of medication of top-level male players during the 2014 FIFA World Cup Brazil. DESIGN Retrospective survey. PARTICIPANTS/INFORMATION 736 top level players. SETTING The teams' physicians disclosed a list of the medications used by each player within 72 h before each match of the 2014 FIFA World Cup Brazil. OUTCOME MEASURES Average number of medications used per player per match or during the tournament; average number and percentage of players using at least one medication per match or during the tournament. RESULTS 67.0% of all players took various types of medication during the tournament. The most used medications during the tournament were non-steroidal anti-inflammatory drugs (NSAIDs), by 54.2% of all players, followed by analgaesics (12.6%); β-2 agonists were only used by 0.5%. On average, 0.8 medications per player were used before each match. More players were reported taking medications during the knockout round than during the qualification round (0.36±0.48 vs 0.49±0.50, p<0.001). Players from the South American and Asian Confederations took twice as many medications per match as players from the African Confederation (1.17±1.55 and 1.01±1.26 vs 0.48±0.69, both p<0.001). CONCLUSIONS There was high use of NSAIDs during the 2014 FIFA World Cup. Although the intake of NSAIDs per match (0.35±0.46 vs 0.31±0.48, p<0.01) in the 2014 FIFA World Cup decreased compared to the 2010 FIFA World Cup, the average use was still higher than in the 2006 FIFA World Cup, and the average number of all used medications per player remained the same level as 4 years prior, with all its implications for the player's health. More efforts need to be undertaken worldwide in order to reduce the administration of medications in sports, through continuous education for players, starting from a young age, as well as for doctors and paramedics.
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Affiliation(s)
- Martin Vaso
- Fédération Internationale de Football Association, Zurich, Switzerland
- Department of Sports Medicine, Schulthess Clinic, Zurich, Switzerland
| | - Alexis Weber
- Fédération Internationale de Football Association, Zurich, Switzerland
| | - Philippe M Tscholl
- FIFA—Medical Assessment and Research Center (F-MARC), Schulthess Clinic, Zurich, Switzerland
- Division of Orthopedics and Trauma Surgery, Geneva University Hospital, Geneva, Switzerland
| | - Astrid Junge
- FIFA—Medical Assessment and Research Center (F-MARC), Schulthess Clinic, Zurich, Switzerland
- MSH Medical School Hamburg, Hamburg, Germany
| | - Jiri Dvorak
- Fédération Internationale de Football Association, Zurich, Switzerland
- FIFA—Medical Assessment and Research Center (F-MARC), Schulthess Clinic, Zurich, Switzerland
- Department of Neurology, Schulthess Clinic, Zurich, Switzerland
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Ranganathan K, Loder S, Agarwal S, Wong VW, Forsberg J, Davis TA, Wang S, James AW, Levi B, Levi B. Heterotopic Ossification: Basic-Science Principles and Clinical Correlates. J Bone Joint Surg Am 2015; 97:1101-11. [PMID: 26135077 PMCID: PMC6948799 DOI: 10.2106/jbjs.n.01056] [Citation(s) in RCA: 266] [Impact Index Per Article: 26.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
➤ Heterotopic ossification occurs most commonly after joint arthroplasty, spinal cord injury, traumatic brain injury, blast trauma, elbow and acetabular fractures, and thermal injury.➤ The conversion of progenitor cells to osteogenic precursor cells as a result of cell-mediated interactions with the local tissue environment is affected by oxygen tension, pH, availability of micronutrients, and mechanical stimuli, and leads to heterotopic ossification.➤ Radiation and certain nonsteroidal anti-inflammatory medications are important methods of prophylaxis against heterotopic ossification.➤ Well-planned surgical excision can improve patient outcomes regardless of the joint involved or the initial cause of injury.➤ Future therapeutic strategies are focused on targeted inhibition of local factors and signaling pathways that catalyze ectopic bone formation.
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Affiliation(s)
- Kavitha Ranganathan
- Department of Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Taubman Center, XPC 5340, Ann Arbor, MI 48109-0219. E-mail address for B. Levi:
| | - Shawn Loder
- Department of Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Taubman Center, XPC 5340, Ann Arbor, MI 48109-0219. E-mail address for B. Levi:
| | - Shailesh Agarwal
- Department of Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Taubman Center, XPC 5340, Ann Arbor, MI 48109-0219. E-mail address for B. Levi:
| | - Victor W. Wong
- Department of Surgery, Johns Hopkins School of Medicine, 4924 Campbell Boulevard, Baltimore, MD 21236
| | - Jonathan Forsberg
- Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, MD 20910
| | - Thomas A. Davis
- Department of Regenerative Medicine, Naval Medical Research Center, Silver Spring, MD 20910
| | - Stewart Wang
- Department of Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Taubman Center, XPC 5340, Ann Arbor, MI 48109-0219. E-mail address for B. Levi:
| | - Aaron W. James
- Department of Pathology & Laboratory Medicine, University of California at Los Angeles, DGSOM, 200 Medical Plaza, Los Angeles, CA 90095
| | - Benjamin Levi
- Department of Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Taubman Center, XPC 5340, Ann Arbor, MI 48109-0219. E-mail address for B. Levi:
| | - Benjamin Levi
- Department of Surgery, University of Michigan Health Systems, 1500 East Medical Center Drive, Taubman Center, XPC 5340, Ann Arbor, MI 48109-0219. E-mail address for B. Levi:
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Baschera D, Rad H, Collopy D, Zellweger R. Incidence and clinical relevance of heterotopic ossification after internal fixation of acetabular fractures: retrospective cohort and case control study. J Orthop Surg Res 2015; 10:60. [PMID: 25956896 PMCID: PMC4429472 DOI: 10.1186/s13018-015-0202-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2015] [Accepted: 04/27/2015] [Indexed: 12/13/2022] Open
Abstract
Objective The aim of the study was to evaluate predictors and clinical relevance of heterotopic ossification (HO) in patients treated for acetabular fractures in a tertiary referral centre. Patients and methods The study is a retrospective cohort study with a nested case–control study. All patients treated with internal fixation of acetabular fractures from January 2004 to October 2013. Ninety patients had postoperative imaging available at 6 and 12 months postoperatively and received no prophylaxis. Plain radiographs were used to grade HO. The Hip disability and Osteoarthritis Outcome Score (HOOS) was used to compare outcomes between patients suffering from HO with patients who did not. Results Sixteen patients (17.7%) suffered from HO. According to the Brooker classification, 5 had class I, 4 class II, 3 class III and 4 class IV HO. Traumatic brain injury (TBI) was the only significant risk factor for developing HO (odds ratio (OR) 8.6, 95% confidence interval (CI) (1.693–43.753), p = 0.014). The HO rate in patients with an anterior (ilioinguinal) or posterior (Kocher-Langenbeck) surgical approach was 20% and 21% respectively, and the HO rate in patients with a combined approach was much lower at 11%. Neither fracture type nor gender nor age increased the risk of HO significantly. The outcome measured by HOOS was not significantly different between patients with HO and patients in the control group. Patients with HO Brooker class II–IV had slightly lower (effect estimate +4.25, 95% CI (−10.2 to +12.10), p = 0.220) HOOS compared to the majority of the control group. Conclusion A very low rate of HO was found compared to the HO rates described in other studies with similar patient cohorts who received prophylaxis. Based on our findings and the current literature, we do not recommend giving prophylaxis against HO to patients after internal fixation of acetabular fractures.
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Affiliation(s)
- Dominik Baschera
- Department of Orthopaedics and Trauma Surgery, Royal Perth Hospital, Perth, WA, 6000, Australia.
| | - Hooman Rad
- Department of Orthopaedics and Trauma Surgery, Royal Perth Hospital, Perth, WA, 6000, Australia.
| | - Dermot Collopy
- Department of Orthopaedics and Trauma Surgery, Royal Perth Hospital, Perth, WA, 6000, Australia.
| | - René Zellweger
- Department of Orthopaedics and Trauma Surgery, Royal Perth Hospital, Perth, WA, 6000, Australia. .,University of Western Australia, Crawley, WA, 6009, Australia.
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Salem O, Wang HT, Alaseem AM, Ciobanu O, Hadjab I, Gawri R, Antoniou J, Mwale F. Naproxen affects osteogenesis of human mesenchymal stem cells via regulation of Indian hedgehog signaling molecules. Arthritis Res Ther 2014; 16:R152. [PMID: 25034046 PMCID: PMC4223691 DOI: 10.1186/ar4614] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2014] [Accepted: 07/04/2014] [Indexed: 12/12/2022] Open
Abstract
INTRODUCTION We previously showed that type X collagen, a marker of late stage chondrocyte hypertrophy (associated with endochondral ossification), is constitutively expressed by mesenchymal stem cells (MSCs) from osteoarthritis patients and this may be related to Naproxen (Npx), a nonsteroidal anti-inflammatory drug used for therapy. Hedgehog (HH) signaling plays an important role during the development of bone. We tested the hypothesis that Npx affected osteogenic differentiation of human MSCs through the expression of Indian hedgehog (IHH), Patched-1 (PTC1) and GLI family members GLI1, GLI2, GLI3 in vitro. METHODS MSCs were cultured in osteogenic differentiation medium without (control) or with 0.5 μM Npx. The expression of collagen type X, alpha 1 (COL10A1), alkaline phosphatase (ALP), osteopontin (OPN), osteocalcin (OC), collagen type I, alpha 1 (COL1A1) was analyzed with real-time reverse transcription (RT) PCR, and the ALP activity was measured. The osteogenesis of MSCs was monitored by mineral staining and quantification with alizarin red S. To examine whether Npx affects osteogenic differentiation through HH signaling, the effect of Npx on the expression of IHH, GLI1, GLI2, GLI3 and PTC1 was analyzed with real-time RT PCR. The effect of cyclopamine (Cpn), a HH signaling inhibitor, on the expression of COL10A1, ALP, OC and COL1A1 was also determined. RESULTS When MSCs were cultured in osteogenic differentiation medium, Npx supplementation led to a significant decrease in ALP gene expression as well as its activity, and had a tendency to decrease mineral deposition. It also decreased the expression of COL1A1 significantly. In contrast, the gene expression of COL10A1 and OPN were upregulated significantly by Npx. No significant effect was found on OC expression. The expression of IHH, PTC1, GLI1, and GLI2 was increased by Npx, while no significant difference was observed on GLI3 expression. Cpn reversed the effect of Npx on the expression of COL10A1, ALP, OPN and COL1A1. CONCLUSIONS These results indicate that Npx can affect gene expression during osteogenic differentiation of MSCs, and downregulate mineral deposition in the extracellular matrix through IHH signaling. Therefore, Npx could affect MSC-mediated repair of subchondral bone in OA patients.
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Sommerfelt RM, Feuerherm AJ, Jones K, Johansen B. Cytosolic phospholipase A2 regulates TNF-induced production of joint destructive effectors in synoviocytes. PLoS One 2013; 8:e83555. [PMID: 24349530 PMCID: PMC3861525 DOI: 10.1371/journal.pone.0083555] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2013] [Accepted: 11/06/2013] [Indexed: 11/18/2022] Open
Abstract
INTRODUCTION Rheumatoid arthritis (RA) is an inflammatory disease of the joint characterized by chronic synovitis causing pain, swelling and loss of function due to destruction of cartilage and bone. The complex series of pathological events occurring in RA is largely regulated via excessive production of pro-inflammatory cytokines, the most prominent being tumor necrosis factor (TNF). The objective of this work was to elucidate possible involvement of group IVA cytosolic phospholipase A2 (cPLA2α) in TNF-induced regulation of synovitis and joint destructive effectors in RA, to evaluate the potential of cPLA2α as a future therapeutic target. METHODS The involvement of cPLA2α in tumor necrosis factor (TNF)-induced intracellular signaling cascades in synoviocytes (synovial fibroblast-like cells) was analyzed by arachidonic acid (AA) release assay, synoviocyte enzyme activity assay, gene expression analysis by real-time PCR and ELISA immunoassay for the detection of prostaglandin E2 (PGE2), interleukin 8 (IL8) and stromelysin-1 (MMP3), respectively. RESULTS Inhibitors of cPLA2α enzyme activity (AVX002, ATK) significantly reduced TNF-induced cellular release of AA, PGE2, IL8 and MMP3. This reduction was evident both at transcriptional, protein or metabolite levels. Interestingly, cPLA2α inhibition affected several key points of the arachidonyl cascade; AA-release, cyclooxygenase-2 (COX2) expression and PGE2 production. Furthermore, the results suggest that cPLA2α is subject to transcriptional auto-regulation as inhibition of cPLA2α resulted in reduced PLA2G4A gene expression in TNF-stimulated synoviocytes. CONCLUSIONS cPLA2α appears to be an important regulator of central effectors of inflammation and joint destruction, namely MMP3, IL8, COX2, and PGE2. Decreased transcription of the PLA2G4A and COX2 genes in response to cPLA2α enzyme inhibition further suggest a self-reinforcing effect of cPLA2α inhibition in response to TNF. Collectively, these results support that cPLA2α is an attractive therapeutic target candidate as its inhibition reduces the production of multiple key pro-inflammatory factors involved in RA pathogenesis.
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Affiliation(s)
- Randi M. Sommerfelt
- Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway
| | - Astrid J. Feuerherm
- Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway
| | - Kymry Jones
- Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway
| | - Berit Johansen
- Department of Biology, Norwegian University of Science and Technology, Trondheim, Norway
- * E-mail:
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De Luna-Bertos E, Ramos-Torrecillas J, García-Martínez O, Guildford A, Santin M, Ruiz C. Therapeutic doses of nonsteroidal anti-inflammatory drugs inhibit osteosarcoma MG-63 osteoblast-like cells maturation, viability, and biomineralization potential. ScientificWorldJournal 2013; 2013:809891. [PMID: 24170983 PMCID: PMC3793504 DOI: 10.1155/2013/809891] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2013] [Accepted: 08/14/2013] [Indexed: 01/22/2023] Open
Abstract
Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used to reduce pain and inflammation. However, their effect on bone metabolisms is not well known, and results in the literature are contradictory. The present study focusses on the effect of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid, at therapeutic doses, on different biochemical and phenotypic pathways in human osteoblast-like cells. Osteoblasts (MG-63 cell line) were incubated in culture medium with 1-10 μM of dexketoprofen, ketorolac, metamizole, and acetylsalicylic acid. Flow cytometry was used to study antigenic profile and phagocytic activity. The osteoblastic differentiation was evaluated by mineralization and synthesis of collagen fibers by microscopy and alkaline phosphatase activity (ALP) by spectrophotometric assay. Short-term treatment with therapeutic doses of NSAIDs modulated differentiation, antigenic profile, and phagocyte activity of osteoblast-like cells. The treatment reduced ALP synthesis and matrix mineralization. However, nonsignificant differences were observed on collagen syntheses after treatments. The percentage of CD54 expression was increased with all treatments. CD80, CD86, and HLA-DR showed a decreased expression, which depended on NSAID and the dose applied. The treatments also decreased phagocyte activity in this cellular population. The results of this paper provide evidences that NSAIDs inhibit the osteoblast differentiation process thus reducing their ability to produce new bone mineralized extracellular matrix.
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Affiliation(s)
- E. De Luna-Bertos
- Department of Nursing, Faculty of Health Sciences, University of Granada, Avenida Madrid s/n, 18071 Granada, Spain
| | - J. Ramos-Torrecillas
- Department of Nursing, Faculty of Health Sciences, University of Granada, Avenida Madrid s/n, 18071 Granada, Spain
| | - O. García-Martínez
- Department of Nursing, Faculty of Health Sciences, University of Granada, Avenida Madrid s/n, 18071 Granada, Spain
| | - A. Guildford
- School of Pharmacy & Biomolecular Science, University of Brighton, Huxlye Building, Moulsecoomb, Brighton BN2 4G1, UK
| | - M. Santin
- School of Pharmacy & Biomolecular Science, University of Brighton, Huxlye Building, Moulsecoomb, Brighton BN2 4G1, UK
| | - C. Ruiz
- Department of Nursing, Faculty of Health Sciences, University of Granada, Avenida Madrid s/n, 18071 Granada, Spain
- Institute of Neurosciences, Faculty of Medicine, University of Granada, Granada Health-Science Technology Park, 18100 Armilla, Granada, Spain
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Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) are effective at controlling pain in children, especially in the treatment of fractures. Adult animal and adult clinical studies demonstrate conflicting evidence for the inhibitory relationship between NSAIDs and fracture healing. Published pediatric orthopaedic clinical studies do not demonstrate an inhibitory effect of ketorolac on bone healing. Little is known about the effects of any NSAID on bone formation in juvenile animals. This study investigates the effects of the NSAID ketorolac on fracture healing in a juvenile rat model. METHODS Unilateral surgically induced and stabilized tibial shaft fractures were created in 45 juvenile (3 to 4 wk old) male Sprague-Dawley rats. Either ketorolac (5 mg/kg; n=24) or saline (0.9% normal saline; n=21) was then administered to the rats 6 d/wk by intraperitoneal injections. Animals were then randomly assigned into time groups and euthanized at 7 days (n=8 ketorolac, n=7 saline), 14 days (n=8 ketorolac, n=7 saline), or 21 days (n=8 ketorolac, n=7 saline) postfracture. Biomechanical analysis was performed using a custom-designed 4-point bending loading apparatus. Statistics for tibial stiffness and strength data were performed using software package Systat 11. Specimens were also evaluated histologically using hematoxylin and eosin staining. RESULTS Strength and stiffness of all fractured tibiae increased over time from day 7 to day 21 regardless of treatment type. No statistical difference was found between the fractured tibiae strength or stiffness in the ketorolac or control-treated specimens at the same time point. In addition, the quality of the fracture callus was similar in both groups at each of the time points. CONCLUSIONS In this study of a juvenile rat model with a stabilized tibia fracture, fracture callus strength, stiffness, and histologic characteristics were not affected by the administration of ketorolac during the first 21 days of fracture healing. CLINICAL RELEVANCE The absence of inhibitory effects of ketorolac on early juvenile rat fracture healing supports the clinical practice of utilizing NSAIDs for analgesia in children with long bone fractures.
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Konya V, Marsche G, Schuligoi R, Heinemann A. E-type prostanoid receptor 4 (EP4) in disease and therapy. Pharmacol Ther 2013; 138:485-502. [PMID: 23523686 PMCID: PMC3661976 DOI: 10.1016/j.pharmthera.2013.03.006] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2013] [Accepted: 03/07/2013] [Indexed: 01/06/2023]
Abstract
The large variety of biological functions governed by prostaglandin (PG) E2 is mediated by signaling through four distinct E-type prostanoid (EP) receptors. The availability of mouse strains with genetic ablation of each EP receptor subtype and the development of selective EP agonists and antagonists have tremendously advanced our understanding of PGE2 as a physiologically and clinically relevant mediator. Moreover, studies using disease models revealed numerous conditions in which distinct EP receptors might be exploited therapeutically. In this context, the EP4 receptor is currently emerging as most versatile and promising among PGE2 receptors. Anti-inflammatory, anti-thrombotic and vasoprotective effects have been proposed for the EP4 receptor, along with its recently described unfavorable tumor-promoting and pro-angiogenic roles. A possible explanation for the diverse biological functions of EP4 might be the multiple signaling pathways switched on upon EP4 activation. The present review attempts to summarize the EP4 receptor-triggered signaling modules and the possible therapeutic applications of EP4-selective agonists and antagonists.
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Key Words
- ampk, amp-activated protein kinase
- camp, cyclic adenylyl monophosphate
- cftr, cystic fibrosis transmembrane conductance regulator
- clc, chloride channel
- cox, cyclooxygenase
- creb, camp-response element-binding protein
- dp, d-type prostanoid receptor
- dss, dextran sodium sulfate
- egfr, epidermal growth factor receptor
- enos, endothelial nitric oxide synthase
- ep, e-type prostanoid receptor
- epac, exchange protein activated by camp
- eprap, ep4 receptor-associated protein
- erk, extracellular signal-regulated kinase
- fem1a, feminization 1 homolog a
- fp, f-type prostanoid receptor
- grk, g protein-coupled receptor kinase
- 5-hete, 5-hydroxyeicosatetraenoic acid
- icer, inducible camp early repressor
- icam-1, intercellular adhesion molecule-1
- ig, immunoglobulin
- il, interleukin
- ifn, interferon
- ip, i-type prostanoid receptor
- lps, lipopolysaccharide
- map, mitogen-activated protein kinase
- mcp, monocyte chemoattractant protein
- mek, map kinase kinase
- nf-κb, nuclear factor kappa-light-chain-enhancer of activated b cells
- nsaid, non-steroidal anti-inflammatory drug
- pg, prostaglandin
- pi3k, phosphatidyl insositol 3-kinase
- pk, protein kinase
- tp, t-type prostanoid receptor
- tx, thromboxane receptor
- prostaglandins
- inflammation
- vascular disease
- cancerogenesis
- renal function
- osteoporosis
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Affiliation(s)
| | | | | | - Akos Heinemann
- Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Austria
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Poddubnyy D, Rudwaleit M, Haibel H, Listing J, Märker-Hermann E, Zeidler H, Braun J, Sieper J. Effect of non-steroidal anti-inflammatory drugs on radiographic spinal progression in patients with axial spondyloarthritis: results from the German Spondyloarthritis Inception Cohort. Ann Rheum Dis 2012; 71:1616-22. [PMID: 22459541 DOI: 10.1136/annrheumdis-2011-201252] [Citation(s) in RCA: 227] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To investigate the influence of non-steroidal anti-inflammatory drugs (NSAIDs) intake on radiographic spinal progression over 2 years in patients with ankylosing spondylitis (AS) and non-radiographic axial spondyloarthritis (SpA). METHODS 164 patients with axial SpA (88 with AS and 76 with non-radiographic axial SpA) were selected for this analysis based on availability of spinal radiographs at baseline and after 2 years of follow-up and the data on NSAIDs intake. Spinal radiographs were scored by two trained readers in a concealed randomly selected order according to the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) system. An index of the NSAID intake counting both dose and duration of drug intake was calculated. RESULTS High NSAIDs intake (NSAID index≥50) in AS was associated with lower likelihood of significant radiographic progression defined as an mSASSS worsening by ≥2 units: OR=0.15, 95% CI 0.02 to 0.96, p=0.045 (adjusted for baseline structural damage, elevated C reactive protein (CRP) and smoking status) in comparison with patients with low NSAIDs intake (NSAID index<50). This effect was most pronounced in patients with baseline syndesmophytes plus elevated CRP: mean mSASSS progression was 4.36±4.53 in patients with low NSAIDs intake versus 0.14±1.80 with high intake, p=0.02. In non-radiographic axial SpA, no significant differences regarding radiographic progression between patients with high and low NSAIDs intake were found. CONCLUSION A high NSAIDs intake over 2 years is associated with retarded radiographic spinal progression in AS. In non-radiographic axial SpA this effect is less evident, probably due to a low grade of new bone formation in the spine at this stage.
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Affiliation(s)
- Denis Poddubnyy
- Med. Department I, Rheumatology, Charité - Campus Benjamin Franklin, Hindenburgdamm 30, 12203 Berlin, Germany
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Gurkan UA, Golden R, Kishore V, Riley CP, Adamec J, Akkus O. Immune and inflammatory pathways are involved in inherent bone marrow ossification. Clin Orthop Relat Res 2012; 470:2528-40. [PMID: 22798134 PMCID: PMC3830098 DOI: 10.1007/s11999-012-2459-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Bone marrow plays a key role in bone formation and healing. Although a subset of marrow explants ossifies in vitro without excipient osteoinductive factors, some explants do not undergo ossification. The disparity of outcome suggests a significant heterogeneity in marrow tissue in terms of its capacity to undergo osteogenesis. QUESTIONS/PURPOSES We sought to identify: (1) proteins and signaling pathways associated with osteogenesis by contrasting the proteomes of ossified and poorly ossified marrow explants; and (2) temporal changes in proteome and signaling pathways of marrow ossification in the early and late phases of bone formation. METHODS Explants of marrow were cultured. Media conditioned by ossified (n = 4) and poorly ossified (n = 4) subsets were collected and proteins unique to each group were identified by proteomic analysis. Proteomic data were processed to assess proteins specific to the early phase (Days 1-14) and late phase (Days 15-28) of the culture period. Pathways involved in bone marrow ossification were identified through bioinformatics. RESULTS Twenty-eight proteins were unique to ossified samples and eight were unique to poorly ossified ones. Twelve proteins were expressed during the early phase and 15 proteins were specific to the late phase. Several identified pathways corroborated those reported for bone formation in the literature. Immune and inflammatory pathways were specific to ossified samples. CONCLUSIONS The marrow explant model indicates the inflammatory and immune pathways to be an integral part of the osteogenesis process.
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Affiliation(s)
- Umut Atakan Gurkan
- />Harvard-MIT Division of Health Sciences and Technology, Brigham and Women’s Hospital, Harvard Medical School, 65 Landsdowne Street, PRB 252, Cambridge, MA 02139 USA
| | - Ryan Golden
- />Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN USA
| | - Vipuil Kishore
- />Department of Mechanical and Aerospace Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 USA
| | - Catherine P. Riley
- />Department of Research and Development Pathology Associates, Medical Laboratories, Spokane, WA 99204 USA
| | - Jiri Adamec
- />Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE USA
| | - Ozan Akkus
- />Department of Mechanical and Aerospace Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 USA
- />Department of Biomedical Engineering, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106 USA
- />Department of Orthopaedics, University Hospitals of Cleveland, Cleveland, OH USA
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Díaz-Rodríguez L, García-Martínez O, De Luna-Bertos E, Ramos-Torrecillas J, Ruiz C. Effect of ibuprofen on proliferation, differentiation, antigenic expression, and phagocytic capacity of osteoblasts. J Bone Miner Metab 2012; 30:554-60. [PMID: 22543821 DOI: 10.1007/s00774-012-0356-2] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2011] [Accepted: 03/18/2012] [Indexed: 10/28/2022]
Abstract
Ibuprofen is a nonselective nonsteroidal antiinflammatory drug commonly prescribed for acute postsurgical and posttraumatic pain. However, little known is about the effect of this drug on osteoblasts. In this study, we aimed to investigate the effect of ibuprofen on cell proliferation, differentiation, antigenic profile, and phagocytic activity, in a human MG-63 osteosarcoma cell line, as a model of osteoblasts. Flow cytometry was used to study proliferation, antigenic profile, and phagocytic activity, and radioimmunoassay was used to determine osteocalcin synthesis as a cell differentiation marker. Our results showed that therapeutic doses of ibuprofen (5 and 25 μM) did not modify cell proliferation and osteocalcin synthesis in the MG-63 cellular line. However, treatment with a higher dose (25 μM) increased the expression of antigens CD21, CD44, CD80, CD86, and HLA-DR and decreased phagocytic activity. The results indicate that a therapeutic dose of ibuprofen has no adverse effects on growth of the osteoblast-like cells. Treatment with ibuprofen alone may produce some cell activation, which would explain the increase in expression of membrane markers and decrease in phagocytic capacity.
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Affiliation(s)
- Lourdes Díaz-Rodríguez
- Faculty of Health Sciences, University of Granada, Avda. de Madrid s/n, 18071, Granada, Spain.
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Low SA, Kopeček J. Targeting polymer therapeutics to bone. Adv Drug Deliv Rev 2012; 64:1189-204. [PMID: 22316530 DOI: 10.1016/j.addr.2012.01.012] [Citation(s) in RCA: 123] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2011] [Revised: 01/16/2012] [Accepted: 01/18/2012] [Indexed: 12/13/2022]
Abstract
An aging population in the developing world has led to an increase in musculoskeletal diseases such as osteoporosis and bone metastases. Left untreated many bone diseases cause debilitating pain and in the case of cancer, death. Many potential drugs are effective in treating diseases but result in side effects preventing their efficacy in the clinic. Bone, however, provides a unique environment of inorganic solids, which can be exploited in order to effectively target drugs to diseased tissue. By integration of bone targeting moieties to drug-carrying water-soluble polymers, the payload to diseased area can be increased while side effects decreased. The realization of clinically relevant bone targeted polymer therapeutics depends on (1) understanding bone targeting moiety interactions, (2) development of controlled drug delivery systems, as well as (3) understanding drug interactions. The latter makes it possible to develop bone targeted synergistic drug delivery systems.
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Affiliation(s)
- Stewart A Low
- Department of Bioengineering, University of Utah, Salt Lake City, UT 84112, USA
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Quaile A. Comment on Peerbooms et al.: No positive bone healing after using platelet rich plasma in a skeletal defect. An observational prospective cohort study. INTERNATIONAL ORTHOPAEDICS 2012; 36:1973. [PMID: 22814520 DOI: 10.1007/s00264-012-1617-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/21/2012] [Accepted: 06/26/2012] [Indexed: 11/26/2022]
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A soluble factor from Trypanosoma cruzi inhibits transforming growth factor-ß-induced MAP kinase activation and gene expression in dermal fibroblasts. PLoS One 2011; 6:e23482. [PMID: 21931601 PMCID: PMC3169535 DOI: 10.1371/journal.pone.0023482] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 07/18/2011] [Indexed: 02/04/2023] Open
Abstract
The protozoan parasite Trypanosoma cruzi, which causes human Chagas' disease, exerts a variety of effects on host extracellular matrix (ECM) including proteolytic degradation of collagens and dampening of ECM gene expression. Exposure of primary human dermal fibroblasts to live infective T. cruzi trypomastigotes or their shed/secreted products results in a rapid down-regulation of the fibrogenic genes collagenIα1, fibronectin and connective tissue growth factor (CTGF/CCN2). Here we demonstrate the ability of a secreted/released T. cruzi factor to antagonize ctgf/ccn2 expression in dermal fibroblasts in response to TGF-ß, lysophosphatidic acid or serum, where agonist-induced phosphorylation of the mitogen-activated protein (MAP) kinases Erk1/2, p38 and JNK was also inhibited. Global analysis of gene expression in dermal fibroblasts identified a discrete subset of TGF-ß-inducible genes involved in cell proliferation, wound repair, and immune regulation that are inhibited by T. cruzi secreted/released factors, where the genes exhibiting the highest sensitivity to T. cruzi are known to be regulated by MAP kinase-activated transcription factors. Consistent with this observation, the Ets-family transcription factor binding site in the proximal promoter region of the ctgf/ccn2 gene (−91 bp to −84 bp) was shown to be required for T. cruzi-mediated down-regulation of ctgf/ccn2 reporter expression. The cumulative data suggest a model in which T. cruzi-derived molecules secreted/released early in the infective process dampen MAP kinase signaling and the activation of transcription factors that regulate expression of fibroblast genes involved in wound repair and tissue remodelling, including ctgf/ccn2. These findings have broader implications for local modulation of ECM synthesis/remodelling by T. cruzi during the early establishment of infection in the mammalian host and highlight the potential for pathogen-derived molecules to be exploited as tools to modulate the fibrogenic response.
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Thomas MV, Puleo DA. Infection, inflammation, and bone regeneration: a paradoxical relationship. J Dent Res 2011; 90:1052-61. [PMID: 21248364 PMCID: PMC3169879 DOI: 10.1177/0022034510393967] [Citation(s) in RCA: 224] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2010] [Revised: 11/17/2010] [Accepted: 11/18/2010] [Indexed: 02/06/2023] Open
Abstract
Various strategies have been developed to promote bone regeneration in the craniofacial region. Most of these interventions utilize implantable materials or devices. Infections resulting from colonization of these implants may result in local tissue destruction in a manner analogous to periodontitis. This destruction is mediated via the expression of various inflammatory mediators and tissue-destructive enzymes. Given the well-documented association among microbial biofilms, inflammatory mediators, and tissue destruction, it seems reasonable to assume that inflammation may interfere with bone healing and regeneration. Paradoxically, recent evidence also suggests that the presence of certain pro-inflammatory mediators is actually required for bone healing. Bone injury (e.g., subsequent to a fracture or surgical intervention) is followed by a choreographed cascade of events, some of which are dependent upon the presence of pro-inflammatory mediators. If inflammation resolves promptly, then proper bone healing may occur. However, if inflammation persists (which might occur in the presence of an infected implant or graft material), then the continued inflammatory response may result in suboptimal bone formation. Thus, the effect of a given mediator is dependent upon the temporal context in which it is expressed. Better understanding of this temporal sequence may be used to optimize regenerative outcomes.
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Affiliation(s)
- M V Thomas
- Department of Oral Health Practice, University of Kentucky College of Dentistry, 800 Rose Street, Room D-124, Lexington, KY 40536-0297, USA.
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Ren W, Markel DC. Emerging ideas: can erythromycin reduce the risk of aseptic loosening? Clin Orthop Relat Res 2011; 469:2399-403. [PMID: 21584820 PMCID: PMC3126949 DOI: 10.1007/s11999-011-1918-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Accepted: 05/04/2011] [Indexed: 01/31/2023]
Abstract
BACKGROUND Persistent inflammatory reaction to wear debris causes periprosthetic osteolysis and loosening. Some authors have advocated pharmaceutical approaches to reduce the inflammatory reaction. Erythromycin has antiinflammatory effects independent of its antimicrobial properties. Although oral erythromycin reportedly inhibits periprosthetic tissue inflammation in patients with aseptic loosening, long-term systematic erythromycin treatment is not recommended owing to its side effects. Therefore, it would be advantageous to restrict erythromycin delivery to the inflammatory periprosthetic tissue without causing side effects. QUESTIONS/HYPOTHESES Erythromycin eluted from hydroxyapatite-coated titanium (Ti) pins inhibits periprosthetic tissue inflammation and osteolysis. METHOD OF STUDY We propose restricting erythromycin delivery to the inflammatory periprosthetic site. A previously described rat model of ultrahigh molecular weight polyethylene (UHMWPE) particle-induced periprosthetic tissue inflammation and osteolysis will be used to test the effect of local delivery of erythromycin via Peri-Apatite(TM)-coated Ti implants. The outcome measures will include bone ingrowth (μCT), implant stability (pullout test), and histologic analysis of periprosthetic tissues. SIGNIFICANCE Pharmacologic intervention aimed at slowing, preventing, or reversing the aseptic loosening process would represent an advance in the management of joint replacement. Erythromycin may be appropriate for prophylactically treating patients who have repeated revision surgery and/or show early signs of progressive osteolysis after arthroplasty.
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Affiliation(s)
- Weiping Ren
- Department of Biomedical Engineering, Wayne State University, 818 West Hancock, Detroit, MI 48201, USA.
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