Treatment with rhBMP-2 of extreme radial bone atrophy secondary to fracture management in an Italian Greyhound
rhBMP-2 solution on a collagen sponge was placed along the diaphysis of an atrophicradius, which had a history of recurring fractures. Two months after rhBMP-2 treatment, new mineralized bone was present, which significantly increased the diameter of the radius and allowed the removal of the external skeletal fixator (ESF). Due to carpo-metacarpal joint compromise, a pancarpal arthrodesis was performed seven months later. At follow-up evaluation two years later the dog was only very mildly lame.
Inherent biomechanical instability (1, 2), decreased intraosseous blood supply (1, 3), and limited overlying soft tissue for the provision of an extraosseous circulation (1, 4, 5), all contribute to the higher frequency of nonunion fractures in toy breeds dogs. For these reasons, anatomical reduction with rigid internal fixation and use of a cancellous bone autograft has been recommended as the preferred treatment option for distal radial fractures in these patients (3). Implant-induced osteoporosis may occur due to early bone vascular insufficiency, the result of open fracture fixation, plate induced compression and occlusion of the medullary blood supply (6, 7). It has been suggested that stress shielding, because of excessive rigidity of the metal implants, is also a further cause of osteoporosis (6, 8). Distal radial fractures in toy breeds of dogs are common and have a high rate of complications following surgical correction (3). The development of nonunion or osteopenia are potentially serious and often require several surgical procedures and may ultimately necessitate limb amputation (9). More recently, the use of osteogenic enhancing factors have been tried in order to overcome bone healing deficiencies (10). One of the most potent of these factors is recombinant human bone morphogenetic pro-tein-2 (rhBMP-2) (10). This factor has been shown to elicit ectopic bone formation, which leads to the healing of critical size defects in both skull and long bones and non-unions in dogs (10-16). To the authors' knowledge, this is the first description of the use of rhBMP-2 in order to increase bone volume in clinical cases of osteopenia in the dog.
A 13-month-old, 3.5 kg female Italian Grey-hound was referred for a recurrence of a fracture and secondary osteopenia of the right radius and ulna. The dog had sustained a displaced transverse diaphyseal fracture of the right radius and ulna at five months of age (Fig. 1). The fracture had been treated at another veterinary practice using a 7-hole, 2 mm DCP bone plate and six screws (Fig. 2). After bone healing, the plate was removed at six months post application due to stress protection osteopenia. Refracture of the mid diaphyseal antebrachium occurred at the level of a screw hole one week later. Radial and ulnar fractures were then stabilized with external coaptation for seven weeks and until presentation at our clinic.
On orthopaedic examination, the dog had a non-weightbearing lameness of the right frontlimb. Generalized muscle wasting of the limb was noted. The fracture site was grossly unstable. On radiographs, a moderately hypertrophic non-union was present. There was diffuse diaphyseal atrophy of the radius and ulna, more severe in the distal half, and decreased radioopacity of the radius and ulna and the carpal and metacarpal bones (Fig. 3).
In order to minimize bone devascularization, a classical craniomedial approach to the right radius was performed. The bone fragments of the radius were aligned and stabilized with a bilateral-uniplanar (type II) ESF using seven 1.25 mm K-wires and two 2 mm connecting bars. The transfixation pins were implanted a distance away from the fracture site due to severe bone atrophy around the fracture site. Two K-wires were placed in the carpal and metacarpal bones. Cancellous bone was harvested from both proximal humeri and placed along the radial bone diaphysis. Routine closure of the surgical site was performed. Radiographs were obtained postoperatively and a soft padded bandage was placed around the limb and ESF device. One month after surgery, radiographs showed minimal bony callus and extra skeletal bone formation at the localization of the cancel bus bone graft (Fig. 4). The dog was reluctant to bear weight on the leg. Radiographs performed two months after surgery revealed a complete bridging of the fracture site but a further decrease in radial and ulnar diameter. A second surgery was performed at that stage in an attempt to augment the radial bone diameter. Cancellous bone was harvested from both proximal humerii and placed along the radial bone diaphysis.
Radiographs obtained five months after initial ESF surgery did not show any improvement in the diameter of the bones (Fig. 5). The dog was anaesthetized a third time. The radial diaphysis appeared very thin and flexible at surgery. rhBMP-2 reconstituted with its solvent Inductos 12 ml® (5 ml) was evenly applied to a 3.75 x 5 cm bovine Type I absorbable collagen sponge (ACS). The sponge containing 1.5 mg/ml rhBMP was carefully placed around the medial and lateral sides and the cranial aspect of the distal two-thirds of the radius. The ESF appliance was still stable at that point.
One month after rhBMP-2/ACS treatment, the radiographs revealed excessive partially mineralized bony proliferation along the cranial border of the distal two-thirds of the radius. The ESF was dynamized at this time by removing the most proximal K-wires and the K-wire in proximal row of carpal bones. The Fixator was removed following radiographic confirmation of new bone mineralization, seven months after it was put in place (two months after rhBMP-2/ACS treatment) (Fig. 6). The dog was re-examined one year after the first surgery and was ambulating. However, a mild lameness of the right forelimb was still present. Pain was elicited on manipulation of the carpometacarpal joint. Radiographs showed osteophytes in the metacarpal joint and in the elbow joint. Pancarpal arthrodesis was per-formed using an 8-hole, 2 mm DCP and eight screws applied on the dorsal aspect of the antebrachiocarpal joint and proximal matacarpal bones with an autogenous cancellous bone graft. Nine months after this last surgery, complete pancarpal arthrodesis was evident on radiographs (Fig. 7). At this time, due to discomfort, the plate and the screws were removed (Fig. 8). At 30 months (25 months after rhBMP-2/ACS) a telephone conversation with the owner indicated that the dog had excellent use of the limb with only a very mild lameness.
Traditionally, fresh autogenous bone graft is considered to be the most effective biological resource to assist repair or reconstruction of the skeletal system (14, 17). However, additional surgical approach(es) is/are required to harvest the graft, and the quantity of cancellous bone harvested is limited, especially in toy or miniature breeds (18). Devitalized periosteal vascular attachments, due to the additional tissue dissection that is required to place the graft along the diaphyseal defect, may be an important factor associated with a trend toward a higher incidence of fracture-healing complications with the use of cancellous graft (5). In the case reported herein, bone augmentation was not successful; most likely due to poor vascularization of the graft and an absence of integration within the diaphysis of the radius. The prognosis for small dogs with distal radial and ulnar fractures in which initial fracture management has failed is 'fair' (19). Unfortunately, not all cases are amenable to salvage, particularly those individuals with poor bone quality associated with advanced disuse osteoporosis (19). In some cases, limb amputation is the only alternative (19). Osteoinductive substances, including bone morphogenetic protein (BMP), are expected to be substitutes of autogenous bone graft. rhBMP-2 induces endochondral ossification by stimulating proliferation and differentiation of mesenchymal cells into chondroblasts and osteoblasts and by stimulating production and maturation of cartilage in bone matrix (18, 20). Several studies have demonstrated a beneficial effect of rhBMP-2 to restore bone defects, to induce bone fusion in dogs, and to treat fracture non-union, (12, 16, 21, 22). rhBMP-2/ACS can accelerate bone healing and can stimulate the formation of bone, which histologically, radiographically and functionally, appears to be normal (12, 22-24). For the clinical use of BMP, (which is a water-soluble protein), it needs to be impregnated into a substrate that facilitates the approximation of the protein to responsive cells and their receptors (21). A comparison of available carrier substrates suggests that bovine type I collagen carrier has good biocompatible and biodegradable properties (21). This paper describes the first successful bone volume augmentation with rhBMP-2 impregnated into a carrier to treat severe isolated long bone osteopenia in a dog. The preparation and implantation of the rhBMP-2/ACS protein complex proved to be a simple procedure and adverse reactions to the implant were not observed, which is in accordance with previous reports (12, 24). It is clear that the optimal dose of rhBMP-2 for bone healing varies from species to species, as well as individual to individual, and the type of carrier used (24). Higher doses of rhBMP-2 do not always improve bone healing to a greater degree than a lower dose (24). Higher concentrations of rhBMP-2 are needed for bone formation in clinical defects than in experimental use (25). There is still little data about the doses of rhBMP-2 used in clinical cases, making it difficult to compare results. Too high a dose of rhBMP-2 may result in hypertrophic bone. However, this excess bone is resorbed with time, most likely due to its lack of contribution to weight bearing (12, 23, 26).
The result of this case suggests that rhBMP plays a role in the management of osteoporotic fractures in toy and miniature dogs. Further studies are warranted in clinical veterinary cases in order to confirm these findings, to determine the optimal dose of rhBMP and to define its preferred carrier.
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