Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients.
BACKGROUND
The treatment of open fractures of the tibial shaft is often complicated by delayed union and nonunion. The objective of this study was to evaluate the safety and efficacy of the use of recombinant human bone morphogenetic protein-2 (rhBMP-2; dibotermin alfa) to accelerate healing of open tibial shaft fractures and to reduce the need for secondary intervention.


METHODS
In a prospective, randomized, controlled, single-blind study, 450 patients with an open tibial fracture were randomized to receive either the standard of care (intramedullary nail fixation and routine soft-tissue management [the control group]), the standard of care and an implant containing 0.75 mg/mL of rhBMP-2 (total dose of 6 mg), or the standard of care and an implant containing 1.50 mg/mL of rhBMP-2 (total dose of 12 mg). The rhBMP-2 implant (rhBMP-2 applied to an absorbable collagen sponge) was placed over the fracture at the time of definitive wound closure. Randomization was stratified by the severity of the open wound. The primary outcome measure was the proportion of patients requiring secondary intervention because of delayed union or nonunion within twelve months postoperatively.


RESULTS
Four hundred and twenty-one (94%) of the patients were available for the twelve-month follow-up. The 1.50-mg/mL rhBMP-2 group had a 44% reduction in the risk of failure (i.e., secondary intervention because of delayed union; relative risk = 0.56; 95% confidence interval = 0.40 to 0.78; pairwise p = 0.0005), significantly fewer invasive interventions (e.g., bone-grafting and nail exchange; p = 0.0264), and significantly faster fracture-healing (p = 0.0022) than did the control patients. Significantly more patients treated with 1.50 mg/mL of rhBMP-2 had healing of the fracture at the postoperative visits from ten weeks through twelve months (p = 0.0008). Compared with the control patients, those treated with 1.50 mg/mL of rhBMP-2 also had significantly fewer hardware failures (p = 0.0174), fewer infections (in association with Gustilo-Anderson type-III injuries; p = 0.0219), and faster wound-healing (83% compared with 65% had wound-healing at six weeks; p =0.0010).


CONCLUSIONS
The rhBMP-2 implant was safe and, when 1.50 mg/mL was used, significantly superior to the standard of care in reducing the frequency of secondary interventions and the overall invasiveness of the procedures, accelerating fracture and wound-healing, and reducing the infection rate in patients with an open fracture of the tibia.
Govender
Shunmugam
S
Department of Orthopaedics, 4th Floor, University of Natal, 719 Umbilo road, Durban, South Africa.
Csimma
Cristina
C
Genant
Harry K
HK
Valentin-Opran
Alexandre
A
Amit
Yehuda
Y
Arbel
Ron
R
Aro
Hannu
H
Atar
Dan
D
Bishay
Michael
M
Börner
Martin G
MG
Chiron
Philippe
P
Choong
Peter
P
Cinats
John
J
Courtenay
Brett
B
Feibel
Robert
R
Geulette
Bernard
B
Gravel
Charles
C
Haas
Norbert
N
Raschke
M
M
Hammacher
Eric
E
van der Velde
D
D
Hardy
Philippe
P
Holt
Michael
M
Josten
Christof
C
Ketterl
Rupert Ludwig
RL
Lindeque
Bennie
B
Lob
Günter
G
Mathevon
Henry
H
McCoy
Gerald
G
Marsh
D
D
Miller
Russell
R
Munting
Everard
E
Oevre
Stein
S
Nordsletten
L
L
Patel
Amratlal
A
Pohl
Anthony
A
Rennie
William
W
Reynders
Peter
P
Rommens
Pol Maria
PM
Rondia
Jean
J
Rossouw
Willem C
WC
Daneel
P J
PJ
Ruff
Stephen
S
Rüter
Axel
A
Santavirta
Seppo
S
Schildhauer
Thomas A
TA
Gekle
C
C
Schnettler
Reinhard
R
Segal
David
D
Seiler
Hanns
H
Snowdowne
Robert B
RB
Stapert
Jouwert
J
Taglang
Gilbert
G
Verdonk
Rene
R
Vogels
Lucas
L
Weckbach
Arnulf
A
Wentzensen
Andreas
A
Wisniewski
Tadeusz
T
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000627:therapeutic use*; D005260:Female; D005597:Fractures, Open / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D011994:Recombinant Proteins; D016037:Single-Blind Method; D013978:Tibial Fractures / Q000188:drug therapy*; D016212:Transforming Growth Factor beta / Q000627:therapeutic use*
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; C499469:recombinant human bone morphogenetic protein-2