The Effects of NSAIDs on Bone Metabolism Following Exercise

The Effects of Non-steroidal Anti-inflammatory Drugs on Circulating Markers of Bone Metabolism Following Plyometric Exercise in Humans

The purpose of this study is to determine the effects of a single dose of non-steroidal anti-inflammatory drugs on post-exercise markers of bone and muscle metabolism.

Study Overview

• Status: Completed
• Conditions: Bone Resorption; Stress Fracture; Bone Injury
• Intervention / Treatment: Drug: Ibuprofen 800 mg; Drug: Celecoxib 200mg; Drug: Flurbiprofen 100 mg; Drug: Placebo

Detailed Description

This protocol intends to determine how consuming a single dose of a non-steroidal anti-inflammatory drug (NSAID) affects circulating bone metabolism biomarkers and markers of damage skeletal muscle in response to a bout of plyometric exercise. This will be accomplished using a four trial, placebo-controlled crossover design with trials examining ibuprofen, celecoxib, flurbiprofen and placebo. These particular NSAIDs were chosen because of their widespread use in military populations and differing molecular mechanisms, which could cause differing effects on bone and muscle. Two hours after of consuming a single dose of an NSAID, participants will perform 10 sets of 10 plyometric jumps to induce a mechanical loading stimulus the bone and muscle tissues. Blood, urine, and muscle biopsy samples will be collected before and up to four hours after exercise. Biomarkers representing bone and muscle metabolism will determine the magnitude of adaptive responses to plyometric exercise while using NSAIDs.

• Study Type: Interventional
• Enrollment (Actual): 12
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Natick, Massachusetts, United States, 01760
      • United States Army Research Institute of Environmental Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 40 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Must currently exercise at least 2 times per week
• Must be willing to discontinue the use of nutritional supplements, alcohol and nicotine during each study period (4 trials of 5 consecutive days each), unless approved by PI
• Must be willing to refrain from taking NSAIDs and similar medications during the course of the study (other than those given by the study team)
• Weigh at least 110 lbs and have a hemoglobin of 12.5 g/dL or higher

Exclusion Criteria:

• Known allergic reaction to any NSAID type medication
• History of gastrointestinal disorders/discomfort associated with or which may be aggravated with NSAID use
• History or known gastric ulcer
• History of endocrine disorders (e.g., diabetes, uncontrolled thyroid dysfunction, hypoparathyroidism, or hyperparathyroidism)
• History of bone-modifying disorder (e.g., osteogenesis imperfecta, osteoporosis, or rickets)
• Diagnosed bone fracture within last 6 months
• History of cardiovascular or renal diseases
• Pregnant or lactation in the last 6 months
• Currently taking or history of routine use of medications known to affect bone or calcium metabolism (e.g., thiazide diuretics, bisphosphonates, oral steroids)
• History of back or shoulder injury which may be aggravated by exercise
• Blood donation within 8 weeks of the study
• Current physical illness or injury limiting physical activity
• Known allergy to lidocaine

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Ibuprofen; Participants will consume a single dose of ibuprofen prior to a plyometric exercise bout	Drug: Ibuprofen 800 mg; Ibuprofen taken orally 2 hours prior to exercise; Other Names: Advil; Motrin
Experimental: Celecoxib; Participants will consume a single dose of celecoxib prior to a plyometric exercise bout	Drug: Celecoxib 200mg; Celebrex taken orally 2 hours prior to exercise; Other Names: Celebrex
Experimental: Flurbiprofen; Participants will consume a single dose of flurbiprofen prior to a plyometric exercise bout	Drug: Flurbiprofen 100 mg; Flurbiprofen taken orally 2 hours prior to exercise; Other Names: Ansaid
Placebo Comparator: Placebo; Participants will consume a single dose of an inert placebo prior to a plyometric exercise bout	Drug: Placebo; Inert placebo taken orally 2 hours prior to exercise

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline circulating marker of bone formation	Concentration (pg/mL) of serum N-terminal propeptide of type 1 collagen (P1NP)	Change from pre-exercise to 4 hours post-exercise

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline circulating marker of bone resorption	Concentration (pg/mL) of serum C-terminal propeptide of type I collagen (CTX)	Change from pre-exercise to 4 hours post-exercise
Markers of muscle inflammation	Interlukin-6 (IL-6), Interlukin-10 (IL-10), and tissue necrosis factor (TNF-a) messenger ribonucleic acid (mRNA) concentration in muscle biopsy tissue	Change from pre-exercise to 3 hours post-exercise

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Muscle protein synthesis	ribosomal protein S6 (p-RPS6) protein concentration in muscle biopsy tissue	Change from pre-exercise to 3 hours post-exercise

Collaborators and Investigators

• Sponsor: United States Army Research Institute of Environmental Medicine

Publications and helpful links

General Publications

• Staab JS, Kolb AL, Tomlinson RE, Pajevic PD, Matheny RW Jr, Hughes JM. Emerging evidence that adaptive bone formation inhibition by non-steroidal anti-inflammatory drugs increases stress fracture risk. Exp Biol Med (Maywood). 2021 May;246(9):1104-1111. doi: 10.1177/1535370221993098. Epub 2021 Feb 27.
• Jankowski CM, Shea K, Barry DW, Linnebur SA, Wolfe P, Kittelson J, Schwartz RS, Kohrt WM. Timing of Ibuprofen Use and Musculoskeletal Adaptations to Exercise Training in Older Adults. Bone Rep. 2015 Jan 1;1:1-8. doi: 10.1016/j.bonr.2014.10.003.
• Kohrt WM, Barry DW, Van Pelt RE, Jankowski CM, Wolfe P, Schwartz RS. Timing of ibuprofen use and bone mineral density adaptations to exercise training. J Bone Miner Res. 2010 Jun;25(6):1415-22. doi: 10.1002/jbmr.24.
• Wherry SJ, Wolfe P, Schwartz RS, Kohrt WM, Jankowski CM. Ibuprofen taken before exercise blunts the IL-6 response in older adults but does not alter bone alkaline phosphatase or c-telopeptide. Eur J Appl Physiol. 2021 Aug;121(8):2187-2192. doi: 10.1007/s00421-021-04691-8. Epub 2021 Apr 19.
• Brewer CB, Bentley JP, Day LB, Waddell DE. Resistance exercise and naproxen sodium: effects on a stable PGF2alpha metabolite and morphological adaptations of the upper body appendicular skeleton. Inflammopharmacology. 2015 Dec;23(6):319-27. doi: 10.1007/s10787-015-0248-x. Epub 2015 Aug 20.
• Park J, Fertala A, Tomlinson RE. Naproxen impairs load-induced bone formation, reduces bone toughness, and diminishes woven bone formation following stress fracture in mice. Bone. 2019 Jul;124:22-32. doi: 10.1016/j.bone.2019.04.009. Epub 2019 Apr 15.

Study record dates

Study Major Dates

• Study Start (Actual): February 15, 2022
• Primary Completion (Actual): April 1, 2023
• Study Completion (Actual): April 1, 2023

Study Registration Dates

• First Submitted: August 16, 2022
• First Submitted That Met QC Criteria: August 19, 2022
• First Posted (Actual): August 23, 2022

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Fractures, Bone; Wounds and Injuries; Musculoskeletal Diseases; Bone Diseases; Bone Resorption; Fractures, Stress; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Anti-Inflammatory Agents, Non-Steroidal; Analgesics, Non-Narcotic; Anti-Inflammatory Agents; Antirheumatic Agents; Cyclooxygenase Inhibitors; Cyclooxygenase 2 Inhibitors; Celecoxib; Ibuprofen; Flurbiprofen
• Other Study ID Numbers: 21-18H

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes