Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population
Abstract
Stress fractures are common in military personnel and endurance athletes, and nonsteroidal anti-inflammatory drug (NSAID) use is widespread in these populations. NSAIDs inhibit prostaglandin synthesis, which blunts the anabolic response of bone to physical activity and could therefore increase risk of stress fracture. The objective of this study was to determine whether prescribed NSAIDs were associated with stress fracture diagnoses among US Army soldiers. We also aimed to establish whether acetaminophen, an analgesic alternative to NSAIDs, was associated with stress fracture risk. A nested case-control study was conducted using data from the Total Army Injury and Health Outcomes Database from 2002 to 2011 (n = 1,260,168). We identified soldiers with a diagnosis of stress fracture (n = 24,146) and selected 4 controls per case matched on length of military service (n = 96,584). We identified NSAID and acetaminophen prescriptions 180 to 30 days before injury (or match date). We also identified soldiers who participated in basic combat training (BCT), a 10-week period of heightened physical activity at the onset of Army service. Among these individuals, we identified 9088 cases and 36,878 matched controls. Conditional logistic regression was used to calculate incident rate ratios (RR) for stress fracture with adjustment formore »
- Authors:
-
- Army Research Institute of Environmental Medicine, Natick, MA (United States)
- Army Research Institute of Environmental Medicine, Natick, MA (United States); Harvard University, Boston, MA (United States)
- Massachusetts General Hospital, Boston, MA (United States)
- Massachusetts General Hospital, Boston, MA (United States); Beth Israel Deaconess Medical Center, Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
- Army Research Institute of Environmental Medicine, Natick, MA (United States); VA Boston Healthcare System, Boston, MA (United States); Boston University School of Public Health, Boston, MA (United States)
- Publication Date:
- Research Org.:
- Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); US Army Medical Research and Materiel Command
- OSTI Identifier:
- 1623566
- Grant/Contract Number:
- SC0014664
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Journal of Bone and Mineral Research
- Additional Journal Information:
- Journal Volume: 34; Journal Issue: 3; Journal ID: ISSN 0884-0431
- Publisher:
- Wiley
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; endocrinology and metabolism; stress fractures; nonsteroidal anti-inflammatory drugs; NSAID; ibuprofen; bone formation
Citation Formats
Hughes, Julie M., McKinnon, Craig J., Taylor, Kathryn M., Kardouni, Joseph R., Bulathsinhala, Lakmini, Guerriere, Katelyn I., Popp, Kristin L., Bouxsein, Mary L., Proctor, Susan P., and Matheny, Ronald W. Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population. United States: N. p., 2018.
Web. doi:10.1002/jbmr.3616.
Hughes, Julie M., McKinnon, Craig J., Taylor, Kathryn M., Kardouni, Joseph R., Bulathsinhala, Lakmini, Guerriere, Katelyn I., Popp, Kristin L., Bouxsein, Mary L., Proctor, Susan P., & Matheny, Ronald W. Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population. United States. https://doi.org/10.1002/jbmr.3616
Hughes, Julie M., McKinnon, Craig J., Taylor, Kathryn M., Kardouni, Joseph R., Bulathsinhala, Lakmini, Guerriere, Katelyn I., Popp, Kristin L., Bouxsein, Mary L., Proctor, Susan P., and Matheny, Ronald W. Fri .
"Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population". United States. https://doi.org/10.1002/jbmr.3616. https://www.osti.gov/servlets/purl/1623566.
@article{osti_1623566,
title = {Nonsteroidal Anti-Inflammatory Drug Prescriptions Are Associated With Increased Stress Fracture Diagnosis in the US Army Population},
author = {Hughes, Julie M. and McKinnon, Craig J. and Taylor, Kathryn M. and Kardouni, Joseph R. and Bulathsinhala, Lakmini and Guerriere, Katelyn I. and Popp, Kristin L. and Bouxsein, Mary L. and Proctor, Susan P. and Matheny, Ronald W.},
abstractNote = {Stress fractures are common in military personnel and endurance athletes, and nonsteroidal anti-inflammatory drug (NSAID) use is widespread in these populations. NSAIDs inhibit prostaglandin synthesis, which blunts the anabolic response of bone to physical activity and could therefore increase risk of stress fracture. The objective of this study was to determine whether prescribed NSAIDs were associated with stress fracture diagnoses among US Army soldiers. We also aimed to establish whether acetaminophen, an analgesic alternative to NSAIDs, was associated with stress fracture risk. A nested case-control study was conducted using data from the Total Army Injury and Health Outcomes Database from 2002 to 2011 (n = 1,260,168). We identified soldiers with a diagnosis of stress fracture (n = 24,146) and selected 4 controls per case matched on length of military service (n = 96,584). We identified NSAID and acetaminophen prescriptions 180 to 30 days before injury (or match date). We also identified soldiers who participated in basic combat training (BCT), a 10-week period of heightened physical activity at the onset of Army service. Among these individuals, we identified 9088 cases and 36,878 matched controls. Conditional logistic regression was used to calculate incident rate ratios (RR) for stress fracture with adjustment for sex. NSAID prescription was associated with a 2.9-fold increase (RR = 2.9, 95% confidence interval [CI] 2.8–2.9) and acetaminophen prescription with a 2.1-fold increase (RR = 2.1, 95% CI 2.0–2.2) in stress fracture risk within the total Army population. The risk was more than 5-fold greater in soldiers prescribed NSAIDs (RR = 5.3, 95% CI 4.9–5.7) and more than 4-fold greater in soldiers prescribed acetaminophen (RR= 4..4, 95% CI 3.9–4.9) during BCT. Our results reveal an association between NSAID and acetaminophen prescriptions and stress fracture risk, particularly during periods of heightened physical activity. Prospective observational studies and randomized controlled trials are needed to support these findings before clinical recommendations can be made.},
doi = {10.1002/jbmr.3616},
journal = {Journal of Bone and Mineral Research},
number = 3,
volume = 34,
place = {United States},
year = {Fri Nov 23 00:00:00 EST 2018},
month = {Fri Nov 23 00:00:00 EST 2018}
}
Web of Science
Works referenced in this record:
The Use of NSAIDs and Nutritional Supplements in Athletes with Osteoarthritis: Prevalence, Benefits, and Consequences
journal, January 2005
- Gorsline, Robert T.; Kaeding, Christopher C.
- Clinics in Sports Medicine, Vol. 24, Issue 1
Role of Nitric Oxide and Prostaglandins in Mechanically Induced Bone Formation
journal, June 1998
- Chow, J. W. M.; Fox, S. W.; Lean, J. M.
- Journal of Bone and Mineral Research, Vol. 13, Issue 6
Paracetamol effectively reduces prostaglandin E2 synthesis in brain macrophages by inhibiting enzymatic activity of cyclooxygenase but not phospholipase and prostaglandin E synthase
journal, February 2003
- Greco, Anita; Ajmone-Cat, Maria Antonietta; Nicolini, Alessia
- Journal of Neuroscience Research, Vol. 71, Issue 6
Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin
journal, July 2015
- Schwartz, Jules I.; Musser, Bret J.; Tanaka, Wesley K.
- Clinical Pharmacology in Drug Development, Vol. 4, Issue 5
Temporal changes in the nature of disability: U.S. Army soldiers discharged with disability, 1981−2005
journal, July 2008
- Bell, Nicole S.; Schwartz, Carolyn E.; Harford, Thomas C.
- Disability and Health Journal, Vol. 1, Issue 3
Prevention of Lower Extremity Stress Fractures in Athletes and Soldiers: A Systematic Review
journal, December 2002
- Jones, B. H.
- Epidemiologic Reviews, Vol. 24, Issue 2
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair
journal, October 2002
- Zhang, X.
- Journal of Clinical Investigation, Vol. 110, Issue 8
Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Induced Dyspepsia
journal, October 2015
- Yap, Paul; Goh, Khean-Lee
- Current Pharmaceutical Design, Vol. 21, Issue 35
Anti-inflammatory interventions and skeletal muscle injury: benefit or detriment?
journal, September 2013
- Urso, Maria L.
- Journal of Applied Physiology, Vol. 115, Issue 6
Stress Fracture Risk Factors in Basic Combat Training
journal, July 2012
- Knapik, J.; Montain, S.; McGraw, S.
- International Journal of Sports Medicine, Vol. 33, Issue 11
The cyclooxygenase-2 selective inhibitor NS-398 does not influence trabecular or cortical bone gain resulting from repeated mechanical loading in female mice
journal, February 2012
- Sugiyama, T.; Meakin, L. B.; Galea, G. L.
- Osteoporosis International, Vol. 24, Issue 1
Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity
journal, July 2016
- Ghanem, Carolina I.; Pérez, María J.; Manautou, José E.
- Pharmacological Research, Vol. 109
Enhancement by Sex Hormones of the Osteoregulatory Effects of Mechanical Loading and Prostaglandins in Explants of Rat Ulnae
journal, September 1997
- Cheng, Ming Zhao; Zaman, Gul; Rawlinson, Simon C. F.
- Journal of Bone and Mineral Research, Vol. 12, Issue 9
Differential inhibition of fracture healing by non-selective and cyclooxygenase-2 selective non-steroidal anti-inflammatory drugs
journal, July 2003
- Gerstenfeld, Louis C.; Thiede, Mark; Seibert, Karen
- Journal of Orthopaedic Research, Vol. 21, Issue 4
Nonsteroidal Anti-Inflammatory Drugs and the Heart
journal, February 2014
- Patrono, Carlo; Baigent, Colin
- Circulation, Vol. 129, Issue 8
Timing of ibuprofen use and bone mineral density adaptations to exercise training
journal, January 2010
- Kohrt, Wendy M.; Barry, Daniel W.; Pelt, Rachael E. Van
- Journal of Bone and Mineral Research, Vol. 25, Issue 6
Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population: THE USE OF ASPIRIN AND NSAIDS IN THE U.S. POPULATION
journal, May 2013
- Zhou, Yingjun; Boudreau, Denise M.; Freedman, Andrew N.
- Pharmacoepidemiology and Drug Safety, Vol. 23, Issue 1
Cyclooxygenase-2 Inhibitor Inhibits the Fracture Healing.
journal, January 2002
- Endo, Kenji; Sairyo, Koichi; Komatsubara, Shinji
- Journal of PHYSIOLOGICAL ANTHROPOLOGY and Applied Human Science, Vol. 21, Issue 5
Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo
journal, November 1996
- Forwood, M. R.
- Journal of Bone and Mineral Research, Vol. 11, Issue 11
Rates of Knee Injury in the U.S. Active Duty Army, 2000–2005
journal, July 2012
- Hill, Owen T.; Kay, Ashley B.; Wahi, Monika M.
- Military Medicine, Vol. 177, Issue 7
Nonsteroid drug selectivities for cyclo-oxygenase-1 rather than cyclo-oxygenase-2 are associated with human gastrointestinal toxicity: A full in vitro analysis
journal, June 1999
- Warner, T. D.; Giuliano, F.; Vojnovic, I.
- Proceedings of the National Academy of Sciences, Vol. 96, Issue 13
Acetaminophen (paracetamol) is a selective cyclooxygenase‐2 inhibitor in man
journal, September 2007
- Hinz, Burkhard; Cheremina, Olga; Brune, Kay
- The FASEB Journal, Vol. 22, Issue 2
Bone Adaptation to a Mechanical Loading Program Significantly Increases Skeletal Fatigue Resistance
journal, December 2004
- Warden, Stuart J.; Hurst, Julie A.; Sanders, Megan S.
- Journal of Bone and Mineral Research, Vol. 20, Issue 5
Qualitative assessment of cause-of-injury coding in U.S. military hospitals: NATO standardization agreement (STANAG) 2050
journal, January 2000
- Amoroso, P.
- American Journal of Preventive Medicine, Vol. 18, Issue 1
Association between stress fracture incidence and predicted body fat in United States Army Basic Combat Training recruits
journal, May 2018
- Knapik, Joseph J.; Sharp, Marilyn A.; Montain, Scott J.
- BMC Musculoskeletal Disorders, Vol. 19, Issue 1
Changing perceptions and practices regarding aspirin, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs among US primary care providers
journal, November 2008
- Elnachef, N.; Scheiman, J. M.; Fendrick, A. M.
- Alimentary Pharmacology & Therapeutics, Vol. 28, Issue 10
Intrinsic risk factors for exercise-related injuries among male and female army trainees
journal, September 1993
- Jones, Bruce H.; Bovee, Matthew W.; Harris, John McA.
- The American Journal of Sports Medicine, Vol. 21, Issue 5
Risk Factors for Stress Fractures
journal, January 1999
- Bennell, Kim; Matheson, Gordon; Meeuwisse, Willem
- Sports Medicine, Vol. 28, Issue 2
Comparison of the effects of ibuprofen and acetaminophen on PGE2 levels in the GCF during orthodontic tooth movement: a human study
journal, May 2013
- Shetty, Niveditha; Patil, Anand K.; Ganeshkar, Sanjay V.
- Progress in Orthodontics, Vol. 14, Issue 1
Acetaminophen-sensitive prostaglandin production in rat cerebral endothelial cells
journal, April 2005
- Kis, Bela; Snipes, James A.; Simandle, Steve A.
- American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, Vol. 288, Issue 4
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair
journal, October 2002
- Zhang, Xinping; Schwarz, Edward M.; Young, Donald A.
- Journal of Clinical Investigation, Vol. 110, Issue 8
Suppression of Prostaglandin Synthesis with NS-398 Has Different Effects on Endocortical and Periosteal Bone Formation Induced by Mechanical Loading
journal, March 2002
- Li, J.; Burr, D. B.; Turner, C. H.
- Calcified Tissue International, Vol. 70, Issue 4
Cyclooxygenase-2 regulates mesenchymal cell differentiation into the osteoblast lineage and is critically involved in bone repair
journal, June 2002
- Zhang, Xinping; Schwarz, Edward M.; Young, Donald A.
- Journal of Clinical Investigation, Vol. 109, Issue 11
Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation
journal, January 2007
- Lee, Yun-Sil; Kim, Hyungsuk; Brahim, Jaime S.
- Pain, Vol. 129, Issue 3
The role of adaptive bone formation in the etiology of stress fracture
journal, August 2016
- Hughes, Julie M.; Popp, Kristin L.; Yanovich, Ran
- Experimental Biology and Medicine, Vol. 242, Issue 9
Risk factors for training-related injuries among men and women in basic combat training
journal, January 2001
- Knapik, Joseph J.; Sharp, Marilyn A.; Canham-Chervak, Michelle
- Medicine and Science in Sports and Exercise, Vol. 33, Issue 6
Prevalence, attitudes, and behaviors related to the use of nonsteroidal anti-inflammatory drugs (NSAIDs) in student athletes1 1The body of this work was done while D.C.W. and M.S.B. were students at Depauw University and Indiana University School of Medicine, respectively.
journal, March 2002
- Warner, David C.; Schnepf, Greg; Barrett, Matthew S.
- Journal of Adolescent Health, Vol. 30, Issue 3
Strontium Ranelate Promotes Osteoblastic Differentiation and Mineralization of Murine Bone Marrow Stromal Cells: Involvement of Prostaglandins
journal, March 2007
- Choudhary, Shilpa; Halbout, Philippe; Alander, Cynthia
- Journal of Bone and Mineral Research, Vol. 22, Issue 7
Inhibition of prostacyclin and thromboxane biosynthesis in healthy volunteers by single and multiple doses of acetaminophen and indomethacin
journal, July 2015
- Schwartz, Jules I.; Musser, Bret J.; Tanaka, Wesley K.
- Clinical Pharmacology in Drug Development, Vol. 4, Issue 5
Timing of ibuprofen use and bone mineral density adaptations to exercise training
journal, January 2010
- Kohrt, Wendy M.; Barry, Daniel W.; Pelt, Rachael E. Van
- Journal of Bone and Mineral Research, Vol. 25, Issue 6
Inducible cyclo-oxygenase (COX-2) mediates the induction of bone formation by mechanical loading in vivo
journal, November 1996
- Forwood, M. R.
- Journal of Bone and Mineral Research, Vol. 11, Issue 11
Indomethacin modulation of load-related stimulation of new bone formationin vivo
journal, January 1989
- Pead, M. J.; Lanyon, L. E.
- Calcified Tissue International, Vol. 45, Issue 1
The cyclooxygenase-2 selective inhibitor NS-398 does not influence trabecular or cortical bone gain resulting from repeated mechanical loading in female mice
journal, February 2012
- Sugiyama, T.; Meakin, L. B.; Galea, G. L.
- Osteoporosis International, Vol. 24, Issue 1
The Use of NSAIDs and Nutritional Supplements in Athletes with Osteoarthritis: Prevalence, Benefits, and Consequences
journal, January 2005
- Gorsline, Robert T.; Kaeding, Christopher C.
- Clinics in Sports Medicine, Vol. 24, Issue 1
Temporal changes in the nature of disability: U.S. Army soldiers discharged with disability, 1981−2005
journal, July 2008
- Bell, Nicole S.; Schwartz, Carolyn E.; Harford, Thomas C.
- Disability and Health Journal, Vol. 1, Issue 3
Acetaminophen selectively suppresses peripheral prostaglandin E2 release and increases COX-2 gene expression in a clinical model of acute inflammation
journal, January 2007
- Lee, Yun-Sil; Kim, Hyungsuk; Brahim, Jaime S.
- Pain, Vol. 129, Issue 3
Acetaminophen from liver to brain: New insights into drug pharmacological action and toxicity
journal, July 2016
- Ghanem, Carolina I.; Pérez, María J.; Manautou, José E.
- Pharmacological Research, Vol. 109
Mechanotransduction in bone cells proceeds via activation of COX-2, but not COX-1
journal, June 2003
- Bakker, A. D.; Klein-Nulend, J.; Burger, E. H.
- Biochemical and Biophysical Research Communications, Vol. 305, Issue 3
Stress Fracture Risk Factors in Basic Combat Training
journal, July 2012
- Knapik, J.; Montain, S.; McGraw, S.
- International Journal of Sports Medicine, Vol. 33, Issue 11
Acetaminophen (paracetamol) is a selective cyclooxygenase‐2 inhibitor in man
journal, September 2007
- Hinz, Burkhard; Cheremina, Olga; Brune, Kay
- The FASEB Journal, Vol. 22, Issue 2
Risk factors for training-related injuries among men and women in basic combat training
journal, January 2001
- Knapik, Joseph J.; Sharp, Marilyn A.; Canham-Chervak, Michelle
- Medicine and Science in Sports and Exercise, Vol. 33, Issue 6
Nonsteroidal anti-inflammatory drugs’ impact on nonunion and infection rates in long-bone fractures
journal, January 2014
- Jeffcoach, David R.; Sams, Valerie G.; Lawson, Christy M.
- Journal of Trauma and Acute Care Surgery, Vol. 76, Issue 3
Changing perceptions and practices regarding aspirin, nonsteroidal anti-inflammatory drugs, and cyclooxygenase-2 selective nonsteroidal anti-inflammatory drugs among US primary care providers
journal, November 2008
- Elnachef, N.; Scheiman, J. M.; Fendrick, A. M.
- Alimentary Pharmacology & Therapeutics, Vol. 28, Issue 10
Indomethacin has distinct early and late actions on bone formation induced by mechanical stimulation
journal, August 1994
- Chow, J. W.; Chambers, T. J.
- American Journal of Physiology-Endocrinology and Metabolism, Vol. 267, Issue 2
Intrinsic risk factors for exercise-related injuries among male and female army trainees
journal, September 1993
- Jones, Bruce H.; Bovee, Matthew W.; Harris, John McA.
- The American Journal of Sports Medicine, Vol. 21, Issue 5
The role of adaptive bone formation in the etiology of stress fracture
journal, August 2016
- Hughes, Julie M.; Popp, Kristin L.; Yanovich, Ran
- Experimental Biology and Medicine, Vol. 242, Issue 9
Comparison of the effects of ibuprofen and acetaminophen on PGE2 levels in the GCF during orthodontic tooth movement: a human study
journal, May 2013
- Shetty, Niveditha; Patil, Anand K.; Ganeshkar, Sanjay V.
- Progress in Orthodontics, Vol. 14, Issue 1
Association between stress fracture incidence and predicted body fat in United States Army Basic Combat Training recruits
journal, May 2018
- Knapik, Joseph J.; Sharp, Marilyn A.; Montain, Scott J.
- BMC Musculoskeletal Disorders, Vol. 19, Issue 1
Skeletal Muscle PGF2αand PGE2in Response to Eccentric Resistance Exercise: Influence of Ibuprofen and Acetaminophen
journal, October 2001
- Trappe, T. A.; Fluckey, J. D.; White, F.
- The Journal of Clinical Endocrinology & Metabolism, Vol. 86, Issue 10
Strontium Ranelate Promotes Osteoblastic Differentiation and Mineralization of Murine Bone Marrow Stromal Cells: Involvement of Prostaglandins
journal, March 2007
- Choudhary, Shilpa; Halbout, Philippe; Alander, Cynthia
- Journal of Bone and Mineral Research, Vol. 22, Issue 7
Role of Nitric Oxide and Prostaglandins in Mechanically Induced Bone Formation
journal, June 1998
- Chow, J. W. M.; Fox, S. W.; Lean, J. M.
- Journal of Bone and Mineral Research, Vol. 13, Issue 6
Renal effects of nonselective NSAIDs and coxibs.
journal, April 2002
- Weir, M. R.
- Cleveland Clinic Journal of Medicine, Vol. 69, Issue Suppl_1
Risk Factors for Soft Tissue Knee Injuries in Active Duty U.S. Army Soldiers, 2000–2005
journal, June 2013
- Hill, Owen T.; Bulathsinhala, Lakmini; Scofield, Dennis E.
- Military Medicine, Vol. 178, Issue 6
Widespread Use of Prescription Nonsteroidal Anti-Inflammatory Drugs Among U.S. Army Active Duty Soldiers
journal, March 2017
- Walker, Leila A.; Zambraski, Edward J.; Williams, Roger F.
- Military Medicine, Vol. 182, Issue 3