The Effect of NSAID Use in the Acute Phase of Skeletally Immature Bone Healing: A Prospective Study

• Sponsor: University of Missouri-Columbia (Other)
• Overall Status: Completed
• CT.gov ID: NCT02076321
• Collaborator: (none)
• Enrollment: 102
• Location: 1
• Arms: 2
• Actual Duration (Months): 34
• Patients Per Site Per Month: 3

Study Details

Study Description

Brief Summary

Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, are excellent medications for providing pain control in children with fractures or those who have surgery to correct bony deformity requiring the bone to be cut (osteotomy) and realigned. There is some data to suggest that these types of medications can adversely affect bone healing in adult patients with broken bones or those having spine fusion surgery. There is little data with regard to how these medications effect bone healing in children. With this project, the investigators' goal is to determine if NSAIDs delay or otherwise adversely effect bone healing and to demonstrate that these medications adequately control pain in children with broken bones or those who have had an osteotomy.

Condition or Disease	Intervention/Treatment	Phase
Fractures	Drug: Acetaminophen; Drug: Ibuprofen	Phase 4

Detailed Description

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective in controlling both post-operative pain and pain associated with orthopaedic injuries, particularly in the pediatric population. Additionally, use of NSAIDs for pain control in this setting avoids the use of narcotic pain medications, the adverse effects of which are well known.

Recent research has suggested a possible association between use of NSAIDs and impaired fracture healing in the skeletally mature, or adult, population. Several adult mammal studies have demonstrated inhibition of bony repair with administration of NSAIDs. Yet, other adult animal studies have failed to find the same effect. Clinical data in the adult population is similarly conflicted, with some studies showing an inhibition of bone healing after posterior spinal fusion, while a larger study found no correlation. The data investigating the effects of NSAID use in adults after fracture or osteotomy is even less clear with some studies demonstrating higher rates of non-union with NSAID administration and others finding no significant effect on bone healing.

The research investigating these outcomes in the skeletally immature population is limited; one study compared administration of ketorolac versus normal saline for 7, 14 and 21 days in a juvenile rat model with a stabilized tibia fracture. They found no significant difference in strength, stiffness or histological characteristics of fracture callus between the two groups. Clinical retrospective studies of the pediatric population with regard to use of NSAIDs after posterior spinal fusion have failed to reproduce findings of inhibitory effects on bone healing. Similarly, two retrospective studies found no cases of delayed union or non-union in pediatric patients who received perioperative ketorolac around the time of operative fixation of fractures, or osteotomy. Given these results, the way in which and the degree to which NSAIDs perturb the inflammatory mileu during the acute phase of healing is potentially distinct from the effects on bone healing in the skeletally mature.

There have been no clinical prospective, randomized studies to evaluate the effect, if any, that NSAIDs have on bone healing in the skeletally immature patient population. The investigators hypothesize that NSAID administration in the acute phase of bone healing, whether it be a fracture or osteotomy, will not result in delayed union or non-union as compared to patients who take acetaminophen for pain control during this same time period.

Study Design

• Study Type: Interventional
• Actual Enrollment: 102 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: The Effect of NSAID Use in the Acute Phase of Skeletally Immature Bone Healing: A Prospective Study
• Actual Study Start Date: Jan 1, 2014
• Actual Primary Completion Date: Nov 1, 2016
• Actual Study Completion Date: Nov 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Other: Acetaminophen control group	Drug: Acetaminophen; acetaminophen for pain control with dose and frequency of 10-15mg/kg/dose, Maximum dose 1000mg. Maximum amount per day: 75mg/kg (not to exceed 4g/day).; Other Names: Tylenol
Other: NSAID (Ibuprofen) Study group	Drug: Ibuprofen; ibuprofen for pain control with dose and frequency 4-10mg/kg/dose. Maximum of 40mg/kg/day, not to exceed 3,200mg/day. Maximum one-time dose of 800mg.; Other Names: Advil Motrin

Outcome Measures

Primary Outcome Measures

1. Compare the Time to Union of Fractures and Osteotomies in Skeletally Immature Patients Administered NSAIDs for Pain Control, Versus Those Administered Acetaminophen for Pain Control. [The subject will be enrolled/assessed up to 6 months post-injury/osteotomy.]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 16 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• • Male aged 16 years or less or female aged 14 years or less

• Open physis on radiographs

• Fracture undergoing closed treatment or operative treatment or patient undergoing elective osteotomy

Exclusion Criteria:

• • Regular use of NSAIDs

• Allergy to NSAIDs

• Inability to take breakthrough medications due side effects or allergy

• Systemic illness

• Renal impairment

• Liver disease

• Polytrauma

• Uncontrolled diabetes

• Regular use of corticosteroids

• History of any skeletal dysplasia

• History of neuromuscular disorder

• History of bleeding disorder

• History of liver disorder

• Pathologic fracture

• Closed physes

• Male greater than 16 years old

• Female greater than 14 years old

• Pregnant or possibly pregnant females based on report and last menstrual period

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Missouri Health System	Columbia	Missouri	United States	65212

Sponsors and Collaborators

• University of Missouri-Columbia

Investigators

• Principal Investigator: Daniel G Hoernschemeyer, MD, University of Missouri-Columbia

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Daniel Hoernschemeyer, Orthopaedic Surgeon, University of Missouri-Columbia
• ClinicalTrials.gov Identifier: NCT02076321
• Other Study ID Numbers: 1207111
• First Posted: Mar 3, 2014
• Last Update Posted: Mar 5, 2019
• Last Verified: Jan 1, 2019

• Additional relevant MeSH terms: Acetaminophen; Ibuprofen

Study Results

Participant Flow

Arm/Group Title	Acetaminophen	NSAID (Ibuprofen)
Arm/Group Description	control group Acetaminophen: acetaminophen for pain control with dose and frequency of 10-15mg/kg/dose, Maximum dose 1000mg. Maximum amount per day: 75mg/kg (not to exceed 4g/day).	Study group Ibuprofen: ibuprofen for pain control with dose and frequency 4-10mg/kg/dose. Maximum of 40mg/kg/day, not to exceed 3,200mg/day. Maximum one-time dose of 800mg.
Period Title: Overall Study
STARTED	51	51
COMPLETED	46	49
NOT COMPLETED	5	2

Baseline Characteristics

Arm/Group Title	Acetaminophen	NSAID (Ibuprofen)	Total
Arm/Group Description	control group Acetaminophen: acetaminophen for pain control with dose and frequency of 10-15mg/kg/dose, Maximum dose 1000mg. Maximum amount per day: 75mg/kg (not to exceed 4g/day).	Study group Ibuprofen: ibuprofen for pain control with dose and frequency 4-10mg/kg/dose. Maximum of 40mg/kg/day, not to exceed 3,200mg/day. Maximum one-time dose of 800mg.	Total of all reporting groups
Overall Participants	46	49	95
Age (Count of Participants)
<=18 years	46 100%	49 100%	95 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	7.44	7.67	7.56
Sex: Female, Male (Count of Participants)
Female	16 34.8%	21 42.9%	37 38.9%
Male	30 65.2%	28 57.1%	58 61.1%

Outcome Measures

1. Primary Outcome

Title	Compare the Time to Union of Fractures and Osteotomies in Skeletally Immature Patients Administered NSAIDs for Pain Control, Versus Those Administered Acetaminophen for Pain Control.
Time Frame	The subject will be enrolled/assessed up to 6 months post-injury/osteotomy.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Acetaminophen	NSAID (Ibuprofen)
Arm/Group Description	control group Acetaminophen: acetaminophen for pain control with dose and frequency of 10-15mg/kg/dose, Maximum dose 1000mg. Maximum amount per day: 75mg/kg (not to exceed 4g/day).	Study group Ibuprofen: ibuprofen for pain control with dose and frequency 4-10mg/kg/dose. Maximum of 40mg/kg/day, not to exceed 3,200mg/day. Maximum one-time dose of 800mg.
Measure Participants	51	51
Mean (Full Range) [Days]	41.2	40.5

Adverse Events

Arm/Group Title	Acetaminophen		NSAID (Ibuprofen)
Arm/Group Description	control group Acetaminophen: acetaminophen for pain control with dose and frequency of 10-15mg/kg/dose, Maximum dose 1000mg. Maximum amount per day: 75mg/kg (not to exceed 4g/day).		Study group Ibuprofen: ibuprofen for pain control with dose and frequency 4-10mg/kg/dose. Maximum of 40mg/kg/day, not to exceed 3,200mg/day. Maximum one-time dose of 800mg.
All Cause Mortality
	Acetaminophen		NSAID (Ibuprofen)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Acetaminophen		NSAID (Ibuprofen)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/51 (0%)		0/51 (0%)
Other (Not Including Serious) Adverse Events
	Acetaminophen		NSAID (Ibuprofen)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/51 (0%)		0/51 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.