J Oral Maxillofac Surg70:765-767, 2012

Adverse Events Reported After the Use ofRecombinant Human BoneMorphogenetic Protein 2

Emily Jane Woo, MD, MPH*

Purpose: The US Food and Drug Administration has approved recombinant human bone morpho-genetic protein 2 (rhBMP-2) (Infuse Bone Graft; Medtronic Sofamor Danek, Minneapolis, MN) as analternative to autogenous bone graft for sinus augmentations and for localized alveolar ridgeaugmentations for defects associated with extraction sockets. The objective of this analysis was tocharacterize adverse events reported after the use of rhBMP-2 in oral and maxillofacial procedures.

Materials and Methods: The US Food and Drug Administration’s Manufacturer and User FacilityDevice Experience database contains reports of adverse events involving medical devices. The publiclyavailable version of the database was searched for reports for the brand name Infuse Bone Graft.Descriptive statistics were used to summarize the procedures and adverse events.

Results: As of April 30, 2011, the Manufacturer and User Facility Device Experience database contained83 reports of adverse events after oral and maxillofacial operations involving rhBMP-2. Of these reports,55 (66.3%) described off-label uses, such as reconstruction of the mandible after fracture or cancer oralveolar cleft repair. The most commonly reported adverse events included local reactions, graft failure,infections, and other wound complications. Of the reports, 25 (30.1%) stated that the patient requiredadditional surgery to address the reported adverse event.

Conclusions: Serious adverse events, some of which may require a second operation, can occur afterthe use of rhBMP-2 in oral and maxillofacial procedures. In this analysis graft, failure and pseudarthrosiswere more commonly reported after off-label uses of rhBMP-2 than approved uses.This is a US government work. There are no restrictions on its use. Published by Elsevier Inc on behalfof the American Association of Oral and Maxillofacial Surgeons.J Oral Maxillofac Surg 70:765-767, 2012

On March 9, 2007, the US Food and Drug Administra-tion (FDA) approved recombinant human bone mor-phogenetic protein 2 (rhBMP-2) (Infuse Bone Graft;Medtronic Sofamor Danek, Minneapolis, MN) as analternative to autogenous bone graft for sinus aug-mentations and for localized alveolar ridge augmenta-

tions for defects associated with extraction sockets.1

Infuse Bone Graft is contraindicated in patients with aknown hypersensitivity to rhBMP-2, bovine type Icollagen, or other components of the formulation; inpatients with any active malignancy or patients un-dergoing treatment for a malignancy; in skeletallyimmature patients; in pregnant women; or in patientswith an active infection at the operative site.2 Itshould not be used in the vicinity of a resected orextant tumor.2 The manufacturer’s package insertalso includes warnings about potential adverse effectsduring pregnancy and lactation; warnings about boneresorption, fluid formation, and edema; precautionsregarding the potential for ectopic, heterotopic, orexuberant bone formation; and a statement that theproduct has not been studied in extraction sites asso-ciated with molars or in the mandible.2

Postmarketing surveillance may reveal importantinformation about adverse events that were not ob-served in clinical trials. The objective of this analysiswas to characterize adverse events reported to theFDA after oral and maxillofacial procedures in which

*Medical Officer, US Food and Drug Administration, Rockvi-

lle, MD.

There was no external funding source. The author does not have

any commercial association with the pharmaceutical industry. The

views expressed in this article are the author’s own and do not

reflect the official policy or position of the US Food and Drug

Administration.

Address correspondence and reprint requests to Dr Woo: US

Food and Drug Administration, HFM-222, 1401 Rockville Pike,

Rockville, MD 20852; e-mail: jane.woo@fda.hhs.gov

This is a US government work. There are no restrictions on its use.

Published by Elsevier Inc on behalf of the American Association of Oral and

Maxillofacial Surgeons

0278-2391/12/7004-0$36.00/0

doi:10.1016/j.joms.2011.09.008

765

rhBMP-2 was used, as well as the types of operationsduring which the product was applied.

Materials and MethodsThe FDA’s Manufacturer and User Facility Device

Experience (MAUDE) database contains reports ofadverse events involving medical devices.3 Reports donot necessarily reflect a conclusion by the party sub-mitting the report or by the FDA that the devicecaused or contributed to the adverse event.3 Thepublicly available version of the MAUDE database wassearched for reports for the brand name Infuse BoneGraft. Adverse events were reviewed and summa-rized. The public dataset does not include demo-graphic information (age, gender, and so on), medicalhistory, clinical and radiologic records related to thereported adverse event, or follow-up information re-garding complications and long-term outcomes.

For this analysis, the guidelines of the HelsinkiDeclaration do not apply, and institutional reviewboard approval was not required. The analysis tookplace after surgery and exposure to rhBMP-2. Further-more, the public dataset does not contain any patientidentifiers, so there is no risk to confidentiality.

ResultsThrough April 30, 2011, MAUDE has received 929

reports of adverse events involving rhBMP-2, of which83 (8.9%) described oral and maxillofacial operations.Of these, 28 (33.7%) described procedures in whichrhBMP-2 was used in accordance with the approvedindication (Table 1). Off-label uses included recon-struction of the mandible after fracture or cancer (25reports) and alveolar cleft repair (19 reports). Table 2summarizes the adverse events reported after use ofrhBMP-2 in oral and maxillofacial surgery. Three clin-ical categories together accounted for 76% of re-ported adverse events: local reactions, surgical siteinfections and other wound complications, and graftfailure. Of all the reports, 25 (30.1%) stated that thepatient required additional surgery to address the re-ported adverse event. Seven reports described the useof rhBMP-2 at the site of a resected tumor. There wereno reports of rhBMP-2 use in pregnant/lactatingwomen or in persons with known hypersensitivity toany of the device components. No deaths after oraland maxillofacial surgery involving rhBMP-2 werereported.

DiscussionEncompassing 4 years of postmarketing experi-

ence, this article summarizes all adverse reports re-ported to MAUDE after oral and maxillofacial proce-dures involving rhBMP-2. Fifty-three percent ofreports explicitly described off-label uses; an addi-tional 11 reports did not state whether the operationinvolved an approved use, so the percentage of off-label uses may have been even higher. Although themanufacturer’s package insert states that Infuse BoneGraft has not been studied in the mandible,2 manyreports described its use in operations to addressmandibular reconstruction. Similarly, the prescribinginformation specifies that the use of Infuse Bone Graft

Table 1. OPERATIONS IN WHICH rhBMP-2WAS USED

Operation n (%)

Approved indications 28 (33.7)Sinus augmentation 20 (24.1)Alveolar ridge augmentation 8 (9.6)

Off-label uses 44 (53.0)Mandibular reconstruction 25 (30.1)Alveolar cleft repair 19 (22.9)

Other or unspecified oral and maxillofacialsurgery 11 (13.3)

Woo. Adverse Events with Recombinant Human BMP-2. J OralMaxillofac Surg 2012.

Table 2. ADVERSE EVENTS REPORTED AFTER USE OF rhBMP-2

Principal Adverse EventApproved

Use [n (%)]Off-Label

Use [n (%)]Type of Use Could

Not Be Determined [n (%)]Total

[n (%)]

Local edema/erythema/pain 15 (53.6) 13 (46.4) 0 28 (100)Surgical site infections/wound

complications 8 (44.4) 6 (33.3) 4 (22.2) 18 (100)Graft failure 3 (17.6) 12 (70.6) 2 (11.8) 17 (100)Pseudarthrosis 0 5 (100%) 0 5 (100)Other* 2 (13.3) 8 (53.3) 5 (33.3) 15 (100)

*Other reported events included hardware complications (3 reports), constitutional symptoms (2), no adverse event reported(2), gastrointestinal distress (1), giant cell granuloma (1), hypertrophic scar (1), lipoma (1), medication error (1), paresthesia(1), respiratory distress (1), and unintentional injury (1).

Woo. Adverse Events with Recombinant Human BMP-2. J Oral Maxillofac Surg 2012.

766 ADVERSE EVENTS WITH RECOMBINANT HUMAN BMP-2

is contraindicated at the site of a resected or extanttumor,2 yet MAUDE received numerous reports stat-ing that rhBMP-2 had been used in such a manner.The package insert further states that rhBMP-2 is in-dicated for skeletally mature patients,2 but some ofthe procedures in this analysis, such as alveolar cleftrepair, are generally performed in children and ado-lescents. Local reactions, infections and other woundcomplications, and graft failure were among the mostcommonly reported adverse events. Because the pub-lic version of the MAUDE database does not includefollow-up information, it was not possible to evaluaterisk factors and alternative etiologies of the reportedcomplications.

The findings reported in this article do not neces-sarily reflect the true range or proportions of adverseevents that can occur after oral and maxillofacial op-erations involving rhBMP-2. The number of patientswho have been exposed to rhBMP-2 is not known.Insurance claims data could be used to estimate the

denominator, but it would not be appropriate to com-bine MAUDE results and claims data to calculate inci-dence rates of adverse events. Conclusions about therisk of adverse events after approved and off-labeluses cannot be drawn. Nevertheless, results from pas-sive surveillance data are useful for detecting new andunexpected safety concerns. Serious adverse events,some of which may require a second operation, canoccur after the use of rhBMP-2 in oral and maxillofa-cial procedures. In this analysis, graft failure and pseu-darthrosis were more commonly reported after off-label uses of rhBMP-2 than approved uses.

References1. PMA P050053, original application. Available from: URL: http://

www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm.Accessed September 1, 2011.

2. Available from: URL: https://www.infusebonegraft.com/omf_package_insert.pdf. Accessed September 1, 2011.

3. Available from: URL: http://www.fda.gov/medicaldevices/deviceregulationandguidance/postmarketrequirements/reportingadverseevents/ucm127891.htm. Accessed September 1, 2011.

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