Clinical Evaluation of BMPs and Bone Marrow Stromal Cells in Orthopedic Surgery - Engineered Bone: Tissue Engineering Intelligence Unit - page 198

precludes the BMPs from being used routinely in acute fractures is that the panel of available
treatments would be then significantly reduced in case of failure. Only one injection of BMP is
recommended by the manufacturers in order to avoid allergic and immunological responses.
Spinal Disorders
Autologous bone grafting is routinely indicated in many spinal disorders in order to reduce
pain and stabilize the spine (lumbar stenosis, degenerative disc disease, scoliosis, fractures…).
It is estimated that half of the 200,000 spine fusion procedures performed every year in the US
will fail to achieve fusion. 27 Based on the results of pre-clinical models, 11,28 Burkus et al 29 have
recently reported the results of a multi-center prospective clinical trial on the use of rh-BMP2
delivered on an absorbable collagen sponge (InFUSE Bone Graft ® , Wyeth-Ayerst Research)
inserted in a hollow threaded titanium cage (LT device ® , Medtronic Sofamor Danek) for
lumbar spine anterior fusion. This study enrolled 279 degenerative disc disease patients that
randomly received either the InFUSE Bone Graft or autologous iliac crest bone grafting. Blood
loss was significantly lower in the rh-BMP2 treated patients (109,8cc vs 153,8cc). At 2 years
follow-up, 32% of the autograft bone patients still experienced pain at the donor site. Fusion
rates were similar in both groups, with a fusion rate as high as 94.5% in the BMP treated
group. This high rate of fusion was consistent with a significant improvement of function and
reduction of pain as assessed by a standardized low back pain questionnaire completed by the
patients. The InFUSE-LT ® device has received approval from the US FDA for anterior lum-
bar spine fusion.
The efficacy of BMPs has also been tested in posterolateral fusion. 30 In a prospective trial,
25 patients suffering from single-level disc degeneration were randomized to receive either
autologous bone grafting and the Texas Scottish Rite Hospital (TSRH) pedicle screw instru-
mentation, or 20 mg of rh-BMP2 per side delivered on a calcium phosphate carrier (60%
hydroxyapatite-40% tricalcium phosphate) with or without the TSRH instrumentation. At an
average follow-up of 17 months (range 12-27 months), posterolateral fusion was achieved in
100% of the rh-BMP2 treated patients (20/20), as compared to the bone autograft group
(40%). These two preliminary studies on anterior and posterolateral spine fusion demonstrated
that rh-BMP2 was as efficient as autologous bone grafting to stimulate bone growth along
spinal vertebrae. Although very encouraging, these results need to be validated on a larger
number of patients and care should be taken to confirm the safety of BMPs implanted for
spinal purposes before widespread use. Heterotopic ossification may lead to dramatic restenosis
of the lumbar canal, with potential ossification of an exposed dura, and adjacent level steno-
sis. 31
Although there has been some overwhelming evidence of the clinical efficacy of the BMPs
in numerous indications, several issues persist and are of concern. One issue is the dose of BMP
implanted in each trial and the optimal delivery system that remains to be found. The dose of
BMP implanted is excessively high (3.5 to 40 mg 30 ) when compared to the quantity present in
bone, which could set off unpredictable local or systemic reactions: the BMPs are expressed in
many tissues (kidney, peripheral and central nervous system, heart, lung…), and have potent
effects on morphogenesis and growth in tissues other than bone. 32 Recent studies have concen-
trated on delivery systems in order to achieve a slow release of BMPs and thus reduce the dose
of BMP implanted. Several investigators have focused on the use of bovine type1 collagen
gel, 33 but this material carries the risk for disease transmission. One attractive alternative is the
use of biodegradable polymer foams that are bioresorbable and biocompatible, and which po-
rosity can be controlled accurately during processing. The development of a suitable drug
delivery system would retain the BMP for a longer period of time, and limit the risk of bone
overgrowth, immunogenicity, and potential effects on distal organs. With regards to potential
systemic effects, one issue that needs to be addressed is how to secure the BMP-carrier implant
at the target site. To date, the BMPs are delivered on collagen gel carriers that are not viscous
enough and it is hard to ensure they will remain at the bone fracture site when the tourniquet