1. J Oral Maxillofac Surg
70:765-767, 2012
Adverse Events Reported After the Use of
Recombinant Human Bone
Morphogenetic 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 an
alternative to autogenous bone graft for sinus augmentations and for localized alveolar ridge
augmentations for defects associated with extraction sockets. The objective of this analysis was to
characterize 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 Facility
Device Experience database contains reports of adverse events involving medical devices. The publicly
available 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 contained
83 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 or
alveolar 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 required
additional surgery to address the reported adverse event.
Conclusions: Serious adverse events, some of which may require a second operation, can occur after
the use of rhBMP-2 in oral and maxillofacial procedures. In this analysis graft, failure and pseudarthrosis
were 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 behalf
of 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- tions for defects associated with extraction sockets.1
tion (FDA) approved recombinant human bone mor- Infuse Bone Graft is contraindicated in patients with a
phogenetic protein 2 (rhBMP-2) (Infuse Bone Graft; known hypersensitivity to rhBMP-2, bovine type I
Medtronic Sofamor Danek, Minneapolis, MN) as an collagen, or other components of the formulation; in
alternative to autogenous bone graft for sinus aug- patients with any active malignancy or patients un-
mentations and for localized alveolar ridge augmenta- dergoing treatment for a malignancy; in skeletally
immature patients; in pregnant women; or in patients
with an active infection at the operative site.2 It
*Medical Officer, US Food and Drug Administration, Rockvi-
should not be used in the vicinity of a resected or
lle, MD.
extant tumor.2 The manufacturer’s package insert
There was no external funding source. The author does not have
any commercial association with the pharmaceutical industry. The
also includes warnings about potential adverse effects
views expressed in this article are the author’s own and do not
during pregnancy and lactation; warnings about bone
reflect the official policy or position of the US Food and Drug resorption, fluid formation, and edema; precautions
Administration. regarding the potential for ectopic, heterotopic, or
Address correspondence and reprint requests to Dr Woo: US exuberant bone formation; and a statement that the
Food and Drug Administration, HFM-222, 1401 Rockville Pike, product has not been studied in extraction sites asso-
Rockville, MD 20852; e-mail: jane.woo@fda.hhs.gov ciated with molars or in the mandible.2
This is a US government work. There are no restrictions on its use. Postmarketing surveillance may reveal important
Published by Elsevier Inc on behalf of the American Association of Oral and information about adverse events that were not ob-
Maxillofacial Surgeons served in clinical trials. The objective of this analysis
0278-2391/12/7004-0$36.00/0 was to characterize adverse events reported to the
doi:10.1016/j.joms.2011.09.008 FDA after oral and maxillofacial procedures in which
765

2. 766 ADVERSE EVENTS WITH RECOMBINANT HUMAN BMP-2
Table 1. OPERATIONS IN WHICH rhBMP-2 Results
WAS USED
Through April 30, 2011, MAUDE has received 929
Operation n (%) reports of adverse events involving rhBMP-2, of which
83 (8.9%) described oral and maxillofacial operations.
Approved indications 28 (33.7) Of these, 28 (33.7%) described procedures in which
Sinus augmentation 20 (24.1)
Alveolar ridge augmentation 8 (9.6)
rhBMP-2 was used in accordance with the approved
Off-label uses 44 (53.0) indication (Table 1). Off-label uses included recon-
Mandibular reconstruction 25 (30.1) struction of the mandible after fracture or cancer (25
Alveolar cleft repair 19 (22.9) reports) and alveolar cleft repair (19 reports). Table 2
Other or unspecified oral and maxillofacial summarizes the adverse events reported after use of
surgery 11 (13.3)
rhBMP-2 in oral and maxillofacial surgery. Three clin-
Woo. Adverse Events with Recombinant Human BMP-2. J Oral ical categories together accounted for 76% of re-
Maxillofac Surg 2012. ported adverse events: local reactions, surgical site
infections and other wound complications, and graft
failure. Of all the reports, 25 (30.1%) stated that the
rhBMP-2 was used, as well as the types of operations patient required additional surgery to address the re-
during which the product was applied. ported adverse event. Seven reports described the use
of rhBMP-2 at the site of a resected tumor. There were
Materials and Methods no reports of rhBMP-2 use in pregnant/lactating
women or in persons with known hypersensitivity to
The FDA’s Manufacturer and User Facility Device any of the device components. No deaths after oral
Experience (MAUDE) database contains reports of and maxillofacial surgery involving rhBMP-2 were
adverse events involving medical devices.3 Reports do reported.
not necessarily reflect a conclusion by the party sub-
mitting the report or by the FDA that the device
caused or contributed to the adverse event.3 The
Discussion
publicly available version of the MAUDE database was
searched for reports for the brand name Infuse Bone Encompassing 4 years of postmarketing experi-
Graft. Adverse events were reviewed and summa- ence, this article summarizes all adverse reports re-
rized. The public dataset does not include demo- ported to MAUDE after oral and maxillofacial proce-
graphic information (age, gender, and so on), medical dures involving rhBMP-2. Fifty-three percent of
history, clinical and radiologic records related to the reports explicitly described off-label uses; an addi-
reported adverse event, or follow-up information re- tional 11 reports did not state whether the operation
garding complications and long-term outcomes. involved an approved use, so the percentage of off-
For this analysis, the guidelines of the Helsinki label uses may have been even higher. Although the
Declaration do not apply, and institutional review manufacturer’s package insert states that Infuse Bone
board approval was not required. The analysis took Graft has not been studied in the mandible,2 many
place after surgery and exposure to rhBMP-2. Further- reports described its use in operations to address
more, the public dataset does not contain any patient mandibular reconstruction. Similarly, the prescribing
identifiers, so there is no risk to confidentiality. information specifies that the use of Infuse Bone Graft
Table 2. ADVERSE EVENTS REPORTED AFTER USE OF rhBMP-2
Approved Off-Label Type of Use Could Total
Principal Adverse Event Use [n (%)] Use [n (%)] Not Be Determined [n (%)] [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.

3. WOO 767
is contraindicated at the site of a resected or extant denominator, but it would not be appropriate to com-
tumor,2 yet MAUDE received numerous reports stat- bine MAUDE results and claims data to calculate inci-
ing that rhBMP-2 had been used in such a manner. dence rates of adverse events. Conclusions about the
The package insert further states that rhBMP-2 is in- risk of adverse events after approved and off-label
dicated for skeletally mature patients,2 but some of uses cannot be drawn. Nevertheless, results from pas-
the procedures in this analysis, such as alveolar cleft sive surveillance data are useful for detecting new and
repair, are generally performed in children and ado- unexpected safety concerns. Serious adverse events,
lescents. Local reactions, infections and other wound some of which may require a second operation, can
complications, and graft failure were among the most occur after the use of rhBMP-2 in oral and maxillofa-
commonly reported adverse events. Because the pub- cial procedures. In this analysis, graft failure and pseu-
lic version of the MAUDE database does not include darthrosis were more commonly reported after off-
follow-up information, it was not possible to evaluate label uses of rhBMP-2 than approved uses.
risk factors and alternative etiologies of the reported
complications. References
The findings reported in this article do not neces- 1. PMA P050053, original application. Available from: URL: http://
www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMA/pma.cfm.
sarily reflect the true range or proportions of adverse Accessed September 1, 2011.
events that can occur after oral and maxillofacial op- 2. Available from: URL: https://www.infusebonegraft.com/omf_
erations involving rhBMP-2. The number of patients package_insert.pdf. Accessed September 1, 2011.
3. Available from: URL: http://www.fda.gov/medicaldevices/
who have been exposed to rhBMP-2 is not known. deviceregulationandguidance/postmarketrequirements/reporting
Insurance claims data could be used to estimate the adverseevents/ucm127891.htm. Accessed September 1, 2011.