Cited by 155Inflammatory mediators and NSAID effectsBone Metabolism and DiseasesBone fractures and treatments

The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.

The Mechanisms of the Inhibitory Effects of Nonsteroidal Anti‐Inflammatory Drugs on Bone Healing: A Concise Review

Harder, Adam T., An, Yuehuei H.·2003·The Journal of Clinical Pharmacology

Open this paper in CoChat — free account

Abstract

Nonsteroidal anti-inflammatory drug (NSAID) use continues to expand at a remarkable rate due both to the broad spectrum of clinical applications for these medications and to the relatively recent introduction of the popular COX-2-selective inhibitors. The use of NSAIDs is particularly prevalent in patients with a variety of musculoskeletal conditions and injuries. Reports of impaired bone healing associated with NSAID use, therefore, are a particular cause for concern. Animal and in vitro studies have demonstrated impaired bone healing in the presence of traditional NSAIDs, as measured by a variety of different parameters. More recently, initial studies investigating the effects of COX-2-selective inhibitors on bone healing have yielded similar results. With mounting evidence that NSAIDs do in fact interfere with proper bone healing in various animal models, questions have arisen regarding the potential mechanism through which NSAIDs produce this outcome and whether these results can be translated to clinical settings. A likely pathway for these observed effects results from an understanding of the steps involved in bone healing itself. These steps include an inflammatory response, bone resorption, and new bone formation. Investigations over the past several decades have elucidated a role for prostaglandins (PGs) in each of these areas. Specifically, PGs have been shown to elicit and participate in inflammatory responses, increase osteoclast activity and subsequent bone resorption, and increase osteoblast activity and new bone formation. This apparent integral role for PGs in the process of bone healing, coupled with the knowledge that NSAIDs act by inhibiting the production of PGs, results in an understanding of the likely mechanism through which NSAIDs impart their deleterious effects on bone healing. By inhibiting the COX enzymes and the subsequent production of PGs, NSAIDs not only achieve their desired anti-inflammatory effects but also inhibit the increased production of PGs that is necessary for bone healing to occur. Despite this understanding of the potential mechanism through which NSAIDs inhibit bone healing in a laboratory setting, few studies exist that show whether these inhibitory effects are also evident clinically. Thus, further studies will need to decipher whether similar inhibitory effects occur in a clinical setting.

Integrity signals

Registry

Crossref · 10.1177/0091270003256061

Cites

60 of 60 references verified0 citation errors · 0 not checkable

Statistics

Recomputing p-values needs the paper’s full text.

Claims the paper makes

This paper’s full text isn’t openly available, so its claims and self-check weren’t run. The registry and citation checks still apply.

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

1 retracted

Postoperative Analgesic Effects of Celecoxib or Rofecoxib After Spinal Fusion Surgery
Reuben, S. S., & Connelly, N. R. (2000) · Anesthesia & Analgesia · doi:10.1097/00000539-200011000-00032 · Cited by 270
Retracted
Basic and Clinical Pharmacology
Katzung, B. G. (1982) · Andalas University Repository (Andalas University) · Cited by 1,914
Risk of Cardiovascular Events Associated with Selective COX-2 Inhibitors
Mukherjee, D. (2001) · JAMA · doi:10.1001/jama.286.8.954 · Cited by 1,741
The Value of ???Multimodal??? or ???Balanced Analgesia??? in Postoperative Pain Treatment
Kehlet, H., & Dahl, J. R. B. (1993) · Anesthesia & Analgesia · doi:10.1213/00000539-199311000-00030 · Cited by 1,477
Aspirin as an Antiplatelet Drug
Wood, A. J. J., & Patrono, C. (1994) · New England Journal of Medicine · doi:10.1056/nejm199405053301808 · Cited by 955
Advances in Prostaglandin and Thromboxane Research
Samuelsson, B. O., Paoletti, R., & Ramwell, P. W. (1976) · Medical Entomology and Zoology · Cited by 835
Nonsteroidal Antiinflammatory Drugs — Differences and Similarities
Oates, J. A., Wood, A. J. J., Brooks, P., & Day, R. O. (1991) · New England Journal of Medicine · doi:10.1056/nejm199106133242407 · Cited by 777
Advances in prostaglandin and thromboxane research: Edited by B. Samuelsson and R. Paoletti Raven Press; New York, 1976 2 volumes: xvi + 506 pages, $ 45.00 and xvi + 522 pages, $ 47.00; set price $ 90.00
Hoult, J. R. S. (1976) · FEBS Letters · doi:10.1016/0014-5793(76)80784-3 · Cited by 697
Nonsteroidal anti-inflammatory drugs and gastroenteropathy: The second hundred years
Jl, W. (1997) · Gastroenterology · doi:10.1053/gast.1997.v112.pm9041264 · Cited by 568
Swedish Aspirin Low-dose Trial (SALT) of 75 mg aspirin as secondary prophylaxis after cerebrovascular ischaemic events
The Salt Collaborative Group (1991) · The Lancet · doi:10.1016/0140-6736(91)92233-r · Cited by 553

Show all 59 references

Research works printed but not linked: 5

Katzung BG, 1998, Pharmacology
1981, National Disease and Therapeutic Index
Kumar V, 1997, Basic Pathology
High W, 1989, Effects of prostaglandin E2 on fracture healing in adult dogs, J Bone Miner Res, 4, 404S
Schelling SH, 1980, Role of the osteoclast in prostaglandin E2‐stimulated bone resorption, Lab Invest, 42, 290

Items 101–154 of 154

Aspirin Thromboprophylaxis Confers No Increased Risk for Aseptic Loosening Following Cementless Primary Hip Arthroplasty
Goswami, K., Tan, T. L., Rondon, A. J., Shohat, N., Yayac, M. F., Schlitt, P. K., & Courtney, P. M. (2019) · The Journal of Arthroplasty · doi:10.1016/j.arth.2019.07.013 · Cited by 4
Treatment of Pain in Rats, Mice, and Prairie Dogs
Oates, R. S., & Tarbert, D. K. (2022) · Veterinary Clinics of North America Exotic Animal Practice · doi:10.1016/j.cvex.2022.07.005 · Cited by 4
Pharmacotherapy of acute orofacial pain
Sharav, Y., & Benoliel, R. (2008) · Elsevier eBooks · doi:10.1016/b978-0-7234-3412-2.10015-x · Cited by 4
Erratum zu: Perioperative systemische Schmerztherapie bei Kindern. Österreichische interdisziplinäre Handlungsempfehlungen zum perioperativen Schmerzmanagement bei Kindern
Messerer, B., Grögl, G., Stromer, W., & Jaksch, W. (2014) · Der Schmerz · doi:10.1007/s00482-014-1419-1 · Cited by 4
Efficacy and Safety of Anti-nerve Growth Factor Monoclonal Antibodies in Managing Chronic Musculoskeletal Pain: A Systematic Review with Network Meta-analysis
Abouelella, A., Najah, Q., Day, R. O., Arendt‐Nielsen, L., Lopez-Olivo, M. A., Bagg, M. K., Seah, M. K. T., Alhasan, M., Hamoudah, A., Abuzied, O., et al. (2026) · Drugs · doi:10.1007/s40265-026-02304-2 · Cited by 3
The underlying metabolism of hypoalbuminemia and its clinical effects
Soeters, P. B., & de Leeuw, P. W. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820205-0.00010-4 · Cited by 3
Single-dose intravenous ibuprofen for acute postoperative pain in adults
Ferguson, M. C., Schumann, R., Gallagher, S., & McNicol, E. D. (2019) · Cochrane Database of Systematic Reviews · doi:10.1002/14651858.cd013264 · Cited by 3
Clinical Pain Management Peri-Operative Scenarios
Meyr, A. J., & Steinberg, J. S. (2008) · Clinics in Podiatric Medicine and Surgery · doi:10.1016/j.cpm.2008.02.010 · Cited by 3
Anesthesia for Orthopedic Surgery
Zuckerberg, A. L., & Yaster, M. (2011) · Elsevier eBooks · doi:10.1016/b978-0-323-06612-9.00026-2 · Cited by 3
Enhanced Osteogenesis and Antibacterial Properties of Ketoprofen-Loaded MgCu-MOF74-Coated Titanium Alloy for Bone Implant
Duan, Z., Yao, Y., Liu, J., Tan, Y., Wang, Q., Fang, M., Kanwal, A., Cheng, S., Huang, J., & Wu, H. P. (2025) · Journal of Functional Biomaterials · doi:10.3390/jfb16060222 · Cited by 3
A randomised clinical trial comparing the analgesic and anxiolytic efficacy and tolerability of Stilpane® and Tramacet® after third molar extraction
Outhoff, K., Dippenaar, J. M., Nell, M. J., Royds, M. T., & Greeff, O. B. W. (2015) · Southern African Journal of Anaesthesia and Analgesia · doi:10.1080/22201181.2015.1028229 · Cited by 2
Bone Injury and Repair
Nitz, A. J. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-28683-1.00004-7 · Cited by 2
Etofenamate and anastomoses of the colon in rats
İnan, A., SÜRGİT, Ö., ŞEN, M., AKPINAR, A., & BOZER, M. (2009) · TURKISH JOURNAL OF MEDICAL SCIENCES · doi:10.3906/sag-0901-32 · Cited by 2
Bone Repair and Fracture Healing
Hofstetter, W., & Egli, R. J. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-801238-3.00223-3 · Cited by 2
Nonopioid Analgesics in Pain Management
Berger, J. M., & Zaghi, S. (2010) · Springer eBooks · doi:10.1007/978-0-387-87579-8_9 · Cited by 3
Mandibular Implant Prostheses
(2018) · Springer eBooks · doi:10.1007/978-3-319-71181-2 · Cited by 3
The Effect of Diclofenac Sodium on Callus Formation in White Male Rat (Rattus norvegicus) Cruris Fracture Healing
Wibowo, H., & Widiyanti, P. (2022) · Folia Medica Indonesiana · doi:10.20473/fmi.v58i2.25212 · Cited by 2
Mechanistic and Clinical Studies of Platelet Rich Plasma: A Simple Clinical Method for Enhancing Bone and Soft Tissue Healing
Rutkowski, J. L. (2008) · Cited by 2
Evidence-Based Orthopaedic Post-Operative Opioid Prescribing Recommendations Following Spine Surgery
Fried, T. B., Adams, A. J., Ramtin, S., & Schroeder, G. D. (2023) · SurgiColl · doi:10.58616/001c.77650 · Cited by 1
Postoperative Schmerztherapie
Finke, W. (2015) · Springer eBooks · doi:10.1007/978-3-662-45057-4_19 · Cited by 1
Anesthesia for Pediatric Orthopedic Surgery
Zuckerberg, A. L., & Yaster, M. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-34125-7.00033-4 · Cited by 1
Review on diclofenac toxicities in different organs
Elnashar, A., Ibrahim, H., Ayman, M., Gamal, T., Hamid, L., Faisal, S., Khodier, S. A., mohamed, A., Kamel, M., El‐Shahawy, A. A. G., et al. (2023) · Ain Shams Journal of Forensic Medicine and Clinical Toxicology · doi:10.21608/ajfm.2023.233170.1109 · Cited by 1
Non-Thermal Atmospheric Pressure Plasma-Assisted Bone Morphogenetic Protein-2 Immobilisation on Titanium Nanotube Surface Promotes Osteogenesis Differentiation by Influencing Macrophage Polarisation
Ying, Y., Chen, L., Yu, C., Chen, S., Cao, Y., Zhong, G., Hong, Y., Liu, Q., & Sui, W. (2025) · Journal of Hard Tissue Biology · doi:10.2485/jhtb.34.129 · Cited by 1
Is Paracetamol Better than Diclofenac Sodium in Management of Postoperative Pain and Edema Following Major Maxillofacial Surgeries?
Girotra, C. S., Padhye, M., Mahajan, P., Savla, S., Nair, A., Pardeshi, P., Tomar, G., & Kini, Y. (2022) · Journal of Maxillofacial and Oral Surgery · doi:10.1007/s12663-022-01806-2 · Cited by 1
Acute Postoperative Pain Management in Elderly Patients
Berger, J. M. (2011) · Springer eBooks · doi:10.1007/978-1-4419-6999-6_26 · Cited by 1
The Role of Cyclooxygenase-2 Inhibition in Foot and Ankle Arthrodesis
Hill, K., Berlet, G. C., Philbin, T. M., & Lee, T. H.-Y. (2005) · Foot and Ankle Clinics · doi:10.1016/j.fcl.2005.06.001 · Cited by 1
Biological evaluation of biomaterials for bone tissue regeneration
Ps, G. (2011) · Portuguese National Funding Agency for Science, Research and Technology (RCAAP Project by FCT) · doi:10.34626/mf5d-dc29 · Cited by 1
Nonsteroidal Anti-inflammatory Drugs
Dumitrescu, A. L. (2010) · Springer eBooks · doi:10.1007/978-3-642-13211-7_6 · Cited by 1
Mechanical loading and Δ12prostaglandin J2 induce bone morphogenetic protein-2, peroxisome proliferator-activated receptor γ-1, and bone nodule formation in an osteoblastic cell line
Siddhivarn, C., Banes, A. J., Champagne, C. M., Riché, E. L., Weerapradist, W., & Offenbacher, S. (2007) · Journal of Periodontal Research · doi:10.1111/j.1600-0765.2007.00965.x · Cited by 1
Orthopaedics
Bird, J. H. (2004) · Journal of the Royal Army Medical Corps · doi:10.1136/jramc-150-03-07 · Cited by 1
The Foot in Sport
Allen, J. A. (2010) · doi:10.1002/9781118685150.ch23
Estudos dos efeitos de um anti-inflamatório não esteroidal seletivo para COX-2 na osteogênese e na expressão das proteínas COX-2 e RUNX-2 durante o reparo ósseo alveolar em ratos
Viscelli, B. A. (2012) · doi:10.11606/d.25.2012.tde-01112012-180557
Avaliação histométrica do reparo ósseo alveolar de ratos tratados com anti-inflamatórios não-esteroidais
Fracon, R. N. (2009) · Digital Library of Theses and Dissertations (Universidade de São Paulo) · doi:10.11606/d.58.2009.tde-30082010-103722
Treatment of the late complications of hip and femur fractures
Sousa, T. D. (2014)
12a Addendum: myositis ossificans
van Nugteren, K. (2011) · Bohn Stafleu van Loghum eBooks · doi:10.1007/978-90-313-8849-3_17
O comportamento do osso alveolar diante da doença periodontal
da Silva, P. C. (2012)
Comparative study between the effect of stem cells and Metacam® on induced arthritis in dogs
Luaibi, O. K. (2015) · Kufa Journal For Veterinary Medical Sciences · doi:10.36326/kjvs/2015/v6i14014
What is the Patient's Experience of Pain after a Fragility Fracture
Gheorghita, A. (2016) · TSpace (University of Toronto)
Perioperative systemische Schmerztherapie bei Kindern Österreichische interdisziplinäre Handlungsempfehlungen zum perioperativen Schmerzmanagement bei Kindern
Graz, L.-U., & Wien, R. (2014)
Pharmacology in Orthopedic Physical Therapy
Ciccone, C. D. (2017) · Elsevier eBooks · doi:10.1016/b978-0-323-28683-1.00016-3
Management of Acute Postoperative Pain in the Geriatric Patient
Spalding, W., & Berger, J. M. (2018) · Springer eBooks · doi:10.1007/978-3-319-20317-1_22-1
The osteoimmune effect of bone morphogenetic protein-2 in bone regeneration and biomaterial modification
Wei, F. (2020) · Queensland University of Technology · doi:10.5204/thesis.eprints.198148 · Cited by 1
Orthopedic and Spine Surgery
Wilton, N. C. T., & Anderson, B. J. (2009) · Elsevier eBooks · doi:10.1016/b978-141603134-5.50034-2
The harm afflicted by NSAIDs, statins, and oral antidiabetics by blocking adaptive inflammatory metabolism
Soeters, P. B., & de Leeuw, P. W. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-820205-0.00011-6
Postoperative Pain, Non Steroidal Anti-Inflammatory Drugs
Power, I., & Colvin, L. (2006) · Springer eBooks · doi:10.1007/978-3-540-29805-2_3449
To the Editor:
Hill, R. G. (2012) · Pain · doi:10.1016/j.pain.2012.02.034
Bone Repair and Fracture Healing
Hofstetter, W., & Egli, R. J. (2014) · Elsevier eBooks · doi:10.1016/b978-0-12-814081-9.00223-5
Management of Acute Postoperative Pain in the Geriatric Patient
Spalding, W., & Berger, J. M. (2020) · Springer eBooks · doi:10.1007/978-3-319-47771-8_22
Myositis ossificans
van Nugteren, K. (2020) · Orthopedische casuïstiek · doi:10.1007/978-90-368-2507-8_4
Preclinical Studies Design and Place of Rabbits
Sandgren, R. (2023) · Springer eBooks · doi:10.1007/978-3-031-37234-6_3
Patterns of Use of Nonsteroidal Anti-Inflammatory Analgesic Drugs in Emergency Room Pharmacy Services at Regional Hospitals. Dr. Pirngadi Medan
Suryaningsih, F., Syamsul, D., & Zubaidi, P. A. (2023) · Jurnal Indah Sains dan Klinis · doi:10.52622/jisk.v4i3.03
Mitigation of hepatic and gastric impairments induced by flunixin meglumine through co-administration with alpha lipoic acid in male rats
ElMaddawy, Z., Mashalla, A.-W., Alnasser, S. M., ElSawy, A., Abdo, W., Kamel, M. A. E.-N., Alotaibi, M., Khormi, M. A., Aborasain, A. M., Abd‐Elhafeez, H. H., et al. (2025) · BMC Veterinary Research · doi:10.1186/s12917-025-04751-7
Modulation de l'inflammation à des fins de régénération parodontale
Morand, D.-N. (2016) · theses.fr (ABES) · doi:10.70675/3afc62f7z8c92z42d6z95caz4f0bf97d0438
A Review on Anti-inflammatory Agents in Promoting Osteogenesis
Kourabbaslou, F. D., Sojoudi, S., Dehghan, M., Karkhaneh, M., & Mesgarzadeh, A. H. (2026) · Recent Advances in Inflammation & Allergy Drug Discovery · doi:10.2174/0127722708438632251121022511

Authors: Harder, A. T., & An, Y. H.
Affiliations: Medical University of South Carolina (US)
Corresponding author: An, Yuehuei H.
Venue: The Journal of Clinical Pharmacology
Publisher: Wiley
Published: 2003-08
Volume: 43
Issue: 8
Pages: 807-815
ISSN: 0021-9754 (ISSN-L)
0091-2700
1552-4604
DOI: 10.1177/0091270003256061
OpenAlex: W1966052052
Cited by: 155
References: 59
Citations by year: 2026: 2 · 2025: 4 · 2024: 2 · 2023: 6 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 7 · 2017: 10 · 2016: 9 · 2015: 5 · 2014: 10 · 2013: 4 · 2012: 6
FWCI: 0.87
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor, 3507 d)
Locations: The Journal of Clinical Pharmacology (publishedVersion)
PubMed (publishedVersion)
Topics: Health Sciences › Medicine › Pharmacology (medical) › Inflammatory mediators and NSAID effects
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Health Sciences › Medicine › Orthopedics and Sports Medicine › Bone fractures and treatments
Keywords: nonsteroidal anti-inflammatory drugs, bone regeneration, COX-2 inhibitors, prostaglandins, bone resorption, osteoclasts, osteoblasts, inflammation, fracture healing
MeSH terms: Animals, Anti-Inflammatory Agents, Non-Steroidal, Bone and Bones, Humans, Wound Healing, Cyclooxygenase Inhibitors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review

Data sources

Bibliographic data: Semantic Scholar, OpenAlex, Crossref.

Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.

The Mechanisms of the Inhibitory Effects of Nonsteroidal Anti‐Inflammatory Drugs on Bone Healing: A Concise Review

Abstract

Overview

Integrity signals

Verification

Claims the paper makes

Claims other papers make about this one

Citations

Cites

Cited by

Related

Metadata

Record

About these checks

Data sources