In vivo BMP-7 (OP-1) enhancement of osteoporotic vertebral bodies in an ovine model.
BACKGROUND
Prevention of osteoporotic vertebral fractures could help at-risk individuals avoid the pain and morbidity associated with these fractures. Currently, patients with osteoporosis are treated with systemic medications to reduce fracture risk. Although effective, these therapies do not eliminate fractures and also tend to have a gradual time-dependent effect on fracture risk. The mechanism of action of the bone morphogenetic protein (BMP) family theoretically makes these molecules candidates for rapidly enhancing local bone structure.


METHODS
An in vivo study analyzing the effects of BMP-7 (osteogenic protein 1 [OP-1]) treatment on osteopenic ovine vertebral architecture and biomechanics.


OBJECTIVE
We tested the hypothesis that local injection of OP-1 into osteopenic ovine vertebrae will improve bone mass and trabecular distribution, thereby reducing bone fragility and fracture risk. We specifically evaluated compressive biomechanics and morphology of osteopenic ovine vertebral bodies 6 months after local OP-1 treatment.


METHODS
In vivo animal study.


METHODS
Skeletally mature sheep (n=24) underwent ovariectomy and were placed on low cation relative to anion diet. These interventions reduce bone density and induce skeletal fragility. After 6 months, sheep were randomly assigned to six treatment groups based on OP-1 dose (370 mg or 0 mg) and carrier with 4 animals/treatment group. Carriers A and B were poly-L-glycolic acid (PLGA) biospheres with different release kinetics (B allowing sustained BMP release); Carrier C was carboxymethylcellulose. After creating an 8-mm-diameter defect in the midvertebral body, sheep underwent intravertebral body implantation at two nonadjacent levels. Animals were euthanized 6 months after implantation and bone mineral density (BMD), biomechanics, and histomorphometry were assessed. Two-way analysis of variance was used to determine effects of OP-1 (alpha=0.05).


RESULTS
An 81.9%, 333.2%, and 39.9% increase in stiffness was seen for OP-1 treated vertebra with Carriers A, B, and C respectively. Although these effects did not reach statistical significance, trends toward improvement were evident. Histology showed varied degrees of bony healing in the injection sites. Histomorphometrically, OP-1 treated vertebrae showed improvements in percent bone of up to 38% and star volume of up to 55% (with Carrier B). Improvements in whole vertebral body BMD were not detected for any treatment.


CONCLUSIONS
In this study, local OP-1 treatment showed a positive trend in improving mechanical strength and histomorphometric parameters of osteopenic vertebra, despite the absence of consistent change in BMD. Controlled slow release of OP-1 using PLGA microspheres appeared to be the most effective method of protein delivery. In conclusion, we feel that the pilot data suggest that the use of OP-1 in the treatment of vertebral osteoporosis in an attempt to enhance bone strength merits further study.
Phillips
Frank M
FM
Rush University Medical Center, 1725 W. Harrison Street, Suite 1063, Chicago, IL 60612, USA. frank.phillips@rushortho.com
Turner
A Simon
AS
Seim
H B
HB
MacLeay
Jennifer
J
Toth
Carol A
CA
Pierce
Allen R
AR
Wheeler
Donna L
DL
D000138:Acidosis / Q000209:etiology / Q000378:metabolism; D000821:Animal Feed; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000008:administration & dosage*; D001861:Bone Regeneration / Q000187:drug effects* / Q000502:physiology; D019245:Compressive Strength / Q000187:drug effects / Q000502:physiology; D004032:Diet; D004195:Disease Models, Animal; D004337:Drug Carriers / Q000008:administration & dosage; D005260:Female; D015552:Injections, Intralesional; D008863:Microspheres; D010024:Osteoporosis / Q000209:etiology / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D010052:Ovariectomy; D011100:Polyglycolic Acid / Q000008:administration & dosage; D012756:Sheep; D013131:Spine / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D016212:Transforming Growth Factor beta / Q000008:administration & dosage*
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004337:Drug Carriers; D016212:Transforming Growth Factor beta; D011100:Polyglycolic Acid