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Ont Health Technol Assess Ser. 2005; 5(6): 1–57.
Published online 2005 April 1.
PMCID: PMC3382627

Osteogenic Protein-1 for Long Bone Nonunion

An Evidence-Based Analysis
Health Quality Ontario

Executive Summary

Objective

To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion.

Clinical Need

Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life.

Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, or vitamin C, and side effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, and radiation. It has been shown that smoking interferes with bone repair in several ways.

Incidence of Nonunion and Delayed Union Cases

An estimated 5% to 10% of fractures do not heal properly and go on to delayed union or nonunion. If this overall estimate of incidence were applied to the Ontario population1, the estimated number of delayed union or nonunion in the province would be between 3,863 and 7,725.

Treatment of Nonunion Cases

The treatment of nonunion cases is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site.

Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells (osteogenesis), a stimulator of mesenchymal cells (osteoinduction), or a scaffold-like structure (osteoconduction).

The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone. This process has been defined as osteogenesis. Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue, and capillaries into these structures.

Bone Grafts and Bone Graft Substitutes

Bone graft and bone graft substitutes have one or more of the following components:

  • Undifferentiated stem cells
  • Growth factors
  • Structural lattice

Undifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue.

Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen.

Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. Of the many bone growth factors studied, bone morphogenetics (BMPs) have generated the greatest attention because of their osteoinductive potential. The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). Human osteogenic protein-1 (OP-1) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction.

The structural lattice is osteoconductive; it supports the ingrowth of developing capillaries and perivascular tissues. Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate. These materials can be used to replace a lost segment of bone.

Grafts Used for Nonunion

Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, the matrix, and bone morphogenetic proteins. The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves, and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research.

Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. Demineralized bone matrix (DBM) is human cortical and cancellous allograft. These products are prepared by acid extraction of allograft bone, resulting in the loss of most of the mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. Figures 1 to to55 demonstrate the osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow.

Figure 1.
Autologous Bone Graft
Figure 5.
Autologous Bone Marrow Graft
Figure 2.
Osteogenic Protein-1
Figure 3.
Allograft bone and Demineralized Bone Matrix
Figure 4.
Bone Graft Substitutes

New Technology Being Reviewed: Osteogenic Protein-1

Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA).

The United States Food and Drug Administration (FDA) issued a humanitarian device exemption for the application of the OP-1 implant as an “alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed.” Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions.

According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated in the patient has a hypersensitivity to the active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis.

Review Strategy

Objective

  • To summarize the safety profile and effectiveness of OP-1 in the treatment of cases of long bone nonunion and bone defects
  • To compare the effectiveness and cost effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft.

Literature Search

International Network of Agencies for Health Technology Assessments (INAHTA), the Cochrane Database of Systematic Reviews and the CCTR (formerly Cochrane Controlled Trials Register) were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference.

Summary of Findings

Friedlaender et al. conducted a prospective, randomized, partially blinded clinical trial on the treatment tibial nonunions with OP-1. Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Table 1 summarizes the clinical outcomes of this study.

Table 1:
Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone Grafting

The results of this study demonstrated that recombinant OP-1 is associated with substantial clinical and radiographic success for the treatment of tibial nonunions when used with intramedullary rod fixation. No adverse event related to sensitization was reported. Five per cent of the patients in the OP-1 group had circulating antibodies against type 1 collagen. Only 10% of the patients had a low level of anti-OP-1 antibodies, and all effects were transient. Furthermore, the success rate with the OP-1 implant was comparable with those achieved with autograft at 9 and 24 months follow-up. Eighty-two per cent of patients were successful at 24 months follow-up in both groups.

Statistically significant increased blood loss in the group treated with the autograft was observed (P = .049). Patients treated with autograft had longer operation and hospitalization times. All patients in the autograft group had pain at the donor site after surgery, and more than 80% judged their postoperative pain as moderate or severe. At their 6-month visit, 20% of the patients in the autograft group had persistent pain, mild or moderate in nature, at the donor site. This number fell to 13% at 12 months.

All patients in each of the groups had at least 1 adverse event that wasn’t serious, such as fever, nausea and vomiting, leg edema, discomfort, and bruising at the operative site. The incidence of these events was similar in both groups. Serious adverse events were observed in 44% of both groups, none of which were considered related to the OP-1 implant or autograft.

On the basis of this data, the FDA issued a humanitarian device exemption for the application of OP-1 implant as an alternative to autograft in recalcitrant long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.

Study on Fibular Defects

Geesink et al. investigated the osteogenic activity of OP-1 by assessing its value in bridging fibular defects made at the time of tibial osteotomy for varus or valgus deformity of the knee. This study had 2 phases and included 12 patients in each phase. Each phase included 12 patients (6 in each group). Patients in the first phase received either DBM or were left untreated. Patients in the second phase received either OP-1 on collagen type-1 or collagen type-1 alone.

Radiological and Dual Energy X-ray Absorptiometry (DEXA) evaluation showed that in patients in whom the defect was left untreated, no formation of bone occurred. At 12 months follow-up, new bone formation with bridging occurred in 4 of the 6 patients in DMB group, and 5 of the 6 patients in OP-1 group. One patient in OP-1 group did not show any evidence of new bone formation at any point during the study.

Ontario Pilot Study

A prospective pilot study was conducted in Ontario, Canada to investigate the safety and efficacy of OP-1 for the treatment of recalcitrant long bone nonunions. The study looked at 15 patients with complex, recalcitrant, long bone nonunions whose previous treatment had failed. The investigators concluded that this bone graft substitute appears to be safe and effective in providing sufficient biological stimulation in difficult to treat nonunions. Results of a more complete study on 70 patients are ready for publication. According to the principal investigator, OP-1 was 90% effective in inducing bone formation and bone healing in this sample.

Alternative Technologies

The Medical Advisory Secretariat conducted a literature search from January 1, 2000 to February 28, 2005 to identify studies on nonunions/bone defects that had been treated with alternative technologies. A review of these studies showed that, in addition to the gold standard autologous bone marrow grafting, bone allografts, demineralized bone matrices, bone graft substitutes, and autologous bone marrow have been used for treatment of nonunions and bone defects. These studies were categorized according to the osteoinductive, osteoconductive, and osteogenesis properties of the technologies studied.

A review of these studies showed that bone allografts have been used mostly in various reconstruction procedures to restore the defect after excavating a bone lesion. Two studies investigated the effectiveness of DBM in healing fracture nonunions. Calcium phosphate and calcium sulphate have been used mostly for repair of bone defects.

Several investigators have looked at the use of autologous bone marrow for treatment of long bone nonunions. The results of these studies show that method of percutaneous bone marrow grafting is highly effective in the treatment of long bone nonunions. In a total of 301 fractures across all studies, 268 (89%) healed with a mean healing time of 2.5 to 8 months. This healing time as derived from these case series is less than the timing of the primary end point in Friedlaender’s study (9 months). Table 2 summarizes the results of these studies. Table 2 summarizes the results of these studies.

Table 2:
Studies that used Percutaneous Bone Marrow Grafting for Treatment of Nonunions

Economic Analysis

Based on annual estimated incidence of long-bone nonunion of 3,863 - 7,725, the annual hospitalization costs associated with this condition is between $21.2 and $42.3 million based on a unit cost of $5,477 per hospital separation. When utilized, the device, a single vial of OP-1, is approximately $5,000 and if adopted universally in Ontario, the total device costs would be in the range of $19.3 - $38.6 million annually. The physician fee for harvest, insertion of bone, or OP-1 is $193 and is $193 for autologous bone marrow transplantation. Total annual physician costs are expected to be in the range of from $0.7 million to $1.3 million per year. Expenditures associated with long-bone nonunion are unlikely to increase since incidence of long-bone nonunion is unlikely to change in the future. However, the rate of uptake of OP-1 could have a significant impact on costs if the uptake were large.

The use of OP-1 and autologous bone marrow transplantation may offset pain medication costs compared with those associated with autologous bone harvest given that the former procedures do not involve the pain associated with the bone harvest site. However, given that this pain is normally not permanent, the overall offset is likely to be small. There are likely to be smaller OHIP costs associated with OP-1 than bone-harvest procedures given that only 1, rather than 2, incisions are needed when comparing the former with the latter procedure. This offset could amount to between $0.3 million to $0.7 million annually.

No data on the cost-effectiveness of OP-1 is available.

Appraisal

OP-1

OP-1 is a Class IV device and is indicated for use as an alternative treatment when other options have failed or are not feasible. However, Friedlaender’s study shows that the incidence of adverse events were similar when treating patients with OP-1 and autologous bone graft; therefore, using OP-1 does not impose additional risk to patients.

Alternative Technologies

Following reports by Connolly et al. and Healey et al. that showed percutaneous injection of autologous bone marrow successfully treated between 78% and 95% of long bone nonunions, a number of investigators were encouraged to study the use of autologous bone marrow grafting in their patients. All these investigators have reported that percutaneous injection of bone marrow is a simple, safe, and useful technique that can become the procedure of choice in many patients with delayed union or nonunion. In addition, they have indicated that this is a useful procedure for patients at high risk for anesthesia and surgery, and also those who are waiting for any definitive surgical procedures.

Autologous cancellous bone grafting is considered the gold standard in the treatment of long bone nonunions. Unfortunately, this procedure is associated with complications at the donor and recipient sites including infection, pain, bruising, scaring, wound problems, nerve injury, and fracture. Harvesting the graft requires an additional surgical procedure. This increases the risk of perioperative blood loss and infection, leading to a prolonged hospital stay and additional cost. The need to open the nonunion site also adds to the risk of devascularization at the fracture site where healing is already impaired. An alternative technology must be equally successful in achieving union, as well as providing some increased benefit to justify its use. OP-1 and autologous bone marrow grafting both eliminate the risk of donor site morbidity. Autologous bone marrow grafting has the additional advantage of decreased cost and no hospital stay because the procedure is performed in an outpatient setting.

Three technologies that demonstrated positive clinical outcomes in the treatment of fracture nonunions were ranked according to 10 criteria. For each criterion, a score from 1 to 3 (1=the best outcome) was assigned to each technology. According to this schema, autologous bone marrow grafting has the lowest total score and the best ranking. (See the full report, page 48.)

Since the studies on autologous bone marrow grafting are case series in which the patients serve as their own control, it cannot be concluded whether this procedure is as effective as autologous bone grafting. A randomized comparative study is needed to clarify this issue.

Conclusions

Based on level 1 evidence (1 randomized controlled trial), OP-1 is a reasonable alternative to autologous bone grafting in the treatment of long bone nonunions.

Based on level 4 evidence (10 studies, a total of 301 patients), percutaneous autologous bone marrow grafting is effective in the treatment of long bone nonunions in patients with no active infection at the fracture site.

Based on the above evidence and the fact that both procedures (percutaneous autologous bone marrow grafting and OP-1) eliminate the risk of donor site morbidity and reduce the risk of infection at the recipient site, the following questions should be considered in making decisions regarding these competing technologies:

  • Should the effectiveness of percutaneous bone marrow grafting as a treatment modality for non-infected long bone nonunions be explored further?
  • Should access to OP-1 be provided to the patients with long bone nonunions (according to the definitions set by FDA) when other methods of treatment have failed?

Objective

To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion.

Background

Clinical Need: Target Population and Condition

Although most fractures show normal bone healing, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. (1) Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life. (2)

It has been over a decade since the first bone morphogenetic protein (BMP) gene was reported. A large variety of animal models have evaluated the therapeutic potential of these proteins, particularly BMP-2 and BMP-7. Of the many growth factors studied, BMPs have generated the most attention because of their osteoinductive potential. Osteoinduction is a process that supports the proliferation of undifferentiated mesenchymal cells and the formation of cells with the capacity to form bone. (2) More recently, the efficacy of BMPs in bone repair has been demonstrated in humans. BMPs have proven to be an important new area of developmental biology and have become an important tool in the field of tissue engineering.

The potential clinical application of OP-1 includes treatment of nonunion and segmental bone defects. The human OP-1 combined with a bioresorbable carrier matrix, when introduced at the fracture site, initiates the proliferation and differentiation of mesenchymal cells, leading to new bone formation.

Incidence of Nonunion and Delayed Union

An estimated 5% to 10% of fractures do not heal properly and go on to be delayed union or nonunion fractures. (1) If this overall estimate of incidence were applied to the Ontario population2, the estimated number of delayed union or nonunions in the province would be between 3,863 and 7,725.

Bone Formation Process and Bone Healing

Bone fracture initiates an orchestrated series of events involving serial participation of different cells and factors. After a fracture, or an interruption of the blood supply, dead bone must be resorbed, and new bone reformed. Resorption of bone is carried out mainly by multinucleated cells called osteoclasts and formation of new bone is carried out by cells from mesenchymal origin called osteoblasts. Osteoblasts line the outer surface of the bones and are also present inside most of the bone cavities. These cells secrete a very strong protein matrix, made up mainly of collagen fibres, which gives the bone its toughness. The matrix is then mineralized, and osteoblasts become surrounded by the matrix and become osteocytes.

The bone marrow contains mesenchymal (stromal) stem cells that have the capacity to transform into other cell types to repair the damaged tissue. In fractures in which the apposition of fragments is poor and motion exists at the fracture site, the progenitor stromal cells differentiate into cells with different functional capacities; therefore, varying amount of fibrous tissue and cartilage are formed. On the other hand, when there is good apposition with bone fixation and little motion at the fracture site, new bone forms without scar tissues.

Re-establishment of vascularity and formation of new vessels are early events in fracture healing. Blood vessels carrying the mineral elements are key contributors to the process of osteogenesis. (3) Inadequate or inappropriate bone vascularity is associated with decreased bone formation and bone mass. The importance of arterial integrity in tibial fracture healing, for example, has been demonstrated in a study of 114 patients who were treated for an open fracture of the tibia. In this study, the group of patients who had arterial occlusion had a significantly higher incidence of delayed unions or nonunions and notably more cases of osteomyelitis. (4) Fracture of bone may disrupt its circulation leading to acute necrosis and hypoxia of adjacent bone and marrow.

Nonunion Fractures

Some fractures take a long time to heal or fail to unite, most commonly with fibrous bridging of the fragments or persistence of the fracture gap. Occasionally a pseudoarthrosis with a fluid-filled cavity and fibrocartilaginous capping of the ends develops. (5) Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, vitamin C, and the adverse effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, (5) and radiation. It has been shown that smoking interferes with bone repair in several ways. (6) It is associated with a decrease in bone density in the axial skeleton (7), a decrease in parathyroid hormone, resistance to calcitonin, and it also interferes with osteoblastic function. (6) Furthermore, nicotine stimulates sympathetic vasoconstriction and results in reduced cellular metabolic processes. (6)

The tibia is one of the most commonly fractured long bones (8) Tibial fractures are also associated with a high incidence of delayed union and nonunion fractures (35% to 65% of all nonunion fractures). (4)

Segmental Bone Defects

In a variety of clinical circumstances such as trauma, infection, primary and metastatic tumours, or failed arthroplasty, a segment of the bone is lost or excised. (9) Large amounts of bone graft materials are used to aid healing of bone defects. The usefulness of autologous bone grafting to treat segmental bone defects is often limited by the amount that is available. The limited supply, additional surgical time required, and morbidity associated with autograft bone harvesting, has resulted in the use of various types of allograft bone. Patients with large segmental defects and bone loss require additional bone graft alternatives to augment bone regeneration. Allograft bone is attractive because it supports bone formation and its supply is less limited. (9) However, allograft bone has little osteoinductive capacity, (10) and in cases in which allograft bone is expected to sustain mechanical load, failure may occur if it is subjected to repetitive weight bearing. (9)

Treatment of Nonunion

The treatment of nonunion is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site. Several biological and biophysical approaches have been introduced to treat delayed union and nonunions.

Biophysical Approach

Electrical and Ultrasound Stimulation

A number of physical modalities have been approved for the management of nonunion and delayed union fractures. Pulsed electromagnetic fields (PEMF) and capacitive coupling induce fields through the soft tissue, resulting in low-magnitude voltage and currents at the fracture site. Electrical signals can be delivered with an implantable direct current stimulator, or noninvasively with inductive or capacitive coupling to induce currents in the tissues. (11) The effectiveness of PEMF in promoting healing of delayed nonunions has been the subject of a comprehensive review. (12) Twenty-eight studies of nonunion tibial fractures treated with PEMF were compared with 14 studies of similar fractures treated with bone graft with or without internal fixation. The overall success rate for the surgical treatment of 569 ununited tibial fractures was 82% (range, 70% – 100%) and the overall success rate of PEMF treatment of 1,718 ununited tibial fractures was 81% (range, 13% – 100%). Ito et al. (13) have shown that PEMF therapy is an effective treatment for ununited tibial fractures with good blood supply to the bone ends. Treatment failures occurred only among lesions with a poor blood supply, where there was radiological evidence of necrotic or defective bone. (13) Capacitive coupling appears to be effective both in extremity nonunions and lumbar fusions. (14)

Low-intensity pulsed ultrasound (frequency 1.5 MHz) transmitted transcutaneously was shown to accelerate fresh fracture healing both clinically and experimentally (15; 16) A systematic review and meta-analysis of randomized controlled trials of low-intensity pulsed ultrasound therapy for healing of fractures showed that ultrasound therapy may be beneficial to fracture healing. (17) The conclusion of this review was that treatment with a low-intensity pulsed ultrasound signal may reduce healing time, and could yield substantial cost-savings and decreases in disability associated with delayed union and nonunion of fractures.

Biological Approach

Fracture stabilization and immobilization are frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells, a stimulator of mesenchymal cells, or a scaffold-like structure. The biological processes involved in bone formation are osteogenesis, osteoinduction, and osteoconduction. The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone (osteogenesis). Activation of the stem cells to initiate an osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue and capillaries into these structures.

Bone Grafts and Bone Graft Substitutes

Bone graft and bone graft substitutes have one or more of the following components: (18)

  • Undifferentiated stem cells
  • Growth factors
  • A structural lattice

Undifferentiated Stem Cells

Undifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Stem cells have been derived from a variety of tissues including umbilical cord and placenta. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue.

Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. (18) Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the nonunion site. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. Approximately 1 of every 100,000 nucleated cells aspirated from bone marrow is a stem cell. (18) It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen. (19) Centrifugation of aspirated bone marrow can separate the marrow cells from plasma and decrease the volume of the material injected while preserving the osteogenic potential of the cells. (18)

Growth Factors

In 1965, Urist (20) discovered that the extracellular matrix of bone contains a substance that has the capacity to induce new bone formation when implanted into extraskeletal sites (osteoinduction). It was later shown that it was the protein contained within the matrix that was responsible for ectopic bone formation. (21) These proteins were named bone morphogenetic proteins and were shown to exist across all species and highly conserved in mammals. (22) Observation by Urist and later by Sampath and Reddi (23) provided a basis for the development of an assay for the purification of these proteins. In the 1980s, the inductive preparations were purified from bovine bone to provide amino acid sequence data. This further resulted in the identification and characterization of deoxyribonucleic acid (DNA) sequence encoding of these proteins. (23)

All of the BMPs are members of the transforming growth factor-β (TGF-β) superfamily of genes. (24) Members of the BMP subfamily play a critical role in regulating the growth, differentiation, and apoptosis of various cell types, including osteoblasts, chondroblasts, neural cells, and epithelial cells.

Structural Lattice

The structural lattice is osteoconductive and can be used to replace a lost segment of bone. Osteoconduction is a process that supports the ingrowth of developing capillaries and perivascular tissues. (25) Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate.

Collagen is used as a bone graft substitute. In its most commonly used form, purified fibrillar collagen obtained from bovine dermis is mixed with hydroxyapatite, and tricalcium phosphate to form a paste or a sheet. The manufacturer recommends mixing of the collagen and hydroxyapatite with autologous bone marrow. (18)

The advantage of the calcium sulphate is that it can be absorbed by the osteoclasts, so that the osteoblasts can attach to it and deposit osteoid on its surface. (26)

The most common forms of calcium phosphate are coralline hydroxyapatite and tricalcium phosphate. Coralline hydroxyapatite is the exoskeleton of 2 marine corals, Porites and Goniopora. The dense material obtained from Porites has a pore diameter of 200μm and is used primarily for dental applications. (27) The less dense material obtained from Goniopora has a pore diameter of about 500μm and is used primarily for orthopedic applications. The potential advantages of tricalcium phosphate over the other calcium phosphates is its low crystallinity and smaller grain size. This makes it more absorbable by osteoclasts. (18) However, tricalcium is applied in a liquid state, and then hardens in situ. It acts as a cement to add mechanical stability to the construct, but it also may leak into the surrounding tissues.

Autologous Bone Graft

Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, (18) (osteogenic component), the matrix (osteoconductive property), and bone morphogenetic proteins (osteoinductive property). (18;25;28) The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. More graft can be obtained from the iliac crest than from the other sites, and evidence shows that bone of membranous origin (ilium) is more osteoinductive than bone of endochondral origin (tibia and femur). (29)

However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research.

Vascularized Bone Transfer

In vascularized bone transfer, the transferred bone is living. Theoretically, living bone is more resistant to infection and will heal more quickly to the native bone (18). In reality, healing of transferred vascularized bone segment to native bone is not reliable and frequently supplemental autogenous bone grafting is required. (18) The bone most frequently transferred is from the fibula, followed by that from the iliac crest. (18) A defect of 6cm is the minimum indication for vascularized bone transfer, and a prolonged immobilization and no weight bearing is a necessary part of the treatment. (18)

Allograft

Allograft is graft of tissue between individuals who are of the same species but are of disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. (30) Allograft bone is used in small, morselized fragments or as a structural component for reconstruction of bony defect after tumour resection, trauma, and total arthroplasty. Active infection is an absolute contraindication for allograft implant. Infection and fracture may occur in allograft implant and complicate the results. Allografts have been used successfully in a variety of clinical circumstances, but there are concerns regarding immunological reactions and the potential transmission of infectious diseases.

Demineralized bone matrix (DBM) is human cortical and cancellous allograft are prepared by acid extraction of allograft bone, resulting in the loss of most of mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. (28) DBMs do not contain osteoprogenitor cells, but the osteoconductivity of their carrier complex may be an important factor in promoting the migration of osteoprogenitor cells to the bone defect site. (28) A growing number of bone alternatives are commercially available for orthopedic applications including segmental bone defects. Many bone banks supply various forms and preparations of DBMs. The content and activity of osteoinductive property of these products can range widely depending on the type of bone and tissue processing. In the United States, DBM is considered a transplantable tissue and is regulated primarily by the American Association of Tissue Banks. (31)

Gene Therapy

In gene therapy, the transfer of genetic information to a cell that either resides in the host or is derived from the host is another way to deliver proteins to a specific anatomic site. Different methods of gene transfer are being investigated for the purpose of bone repair; in the future, gene therapy may be one of the tools available to orthopedic surgeons to treat difficult bone loss cases. (32)

Figures 1 to to55 demonstrate osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow.

New Technology Being Reviewed: Osteogenic Protein-1

The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). (25) Human OP-1 has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction. Preclinical and clinical research has demonstrated that OP-1 combined with a collagen carrier induces bone formation and healing of bone defects and accelerates fracture repair when it is surgically implanted. (33) The osteoinductive properties of recombinant human BMP (rhBMP) have been established in many animal models. (34)

OP-1 is typically applied in a carrier or matrix material. A carrier has several functions, including to providing a format for delivery of the osteoinductive protein, maintaining the material at the site of application long enough for the bone-inductive process to occur, and providing an environment in which bone formation can take place. (35) Currently, the available carrier and delivery system for OP-1 is type-1 collagen.

Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. (36) These include members of the fibroblast growth factor (FGF), transforming growth factor (TGF), insulin-like growth factor (IGF), and platelet-derived growth factor (PDGF) families (36), as well as vascular endothelial growth factor (VGEF). (37) These factors are produced by many cell types present at the fracture site. (37) BMPs are members of the TGF-β superfamily of growth factors. (38) composed of at least 14 proteins. (See Table 3.) Of the many bone growth factors studied, BMPs have generated the greatest attention because of their osteoinductive potential.

Table 3:
Bone Morphogenetic Protein Family

According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated if the patient has a hypersensitivity to active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis.

Regulatory Status

Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA).

The United States Food and Drug Administration (FDA) has issued a humanitarian device exemption for the application of the OP-1 implant as an “alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed.” Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions.

Literature Review on Effectiveness

Objective

  • To summarize the safety profile and effectiveness of OP-1 in the treatment of long bone nonunions and bone defects
  • To compare the effectiveness and cost-effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft.

Questions Asked

  • Is there any risk associated with the use of OP-1 for treatment of long bone nonunion and bone defects?
  • How do outcomes of treatment with OP-1 in long bone nonunions and bone defects compare with those with alternative approaches, particularly autologous bone grafting.

Methods

Inclusion Criteria

  • Studies reporting on the safety and effectiveness of OP-1 for the treatment of long bone nonunions and bone defects
  • Studies comparing the clinical outcomes of treatment with OP-1 in long bone nonunions and bone defects with alternative approaches

Exclusion Criteria

  • Studies investigating the clinical usefulness of OP-1 for the treatment of other conditions
  • Studies focusing on technical aspects of OP-1

Literature Search

INAHTA, Cochrane Database of Systematic Reviews and the Cochrane Controlled Trials Register were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies.

Results of Literature Search

No health technology assessments were identified. A Technote report3 (2002) provided by the Alberta Heritage Foundation for Medical Research was identified. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference). Levels of evidence were assigned according to the scale based on the hierarchy by Goodman (1985) and modified by the Medical Advisory Secretariat. An additional designation “g” was added for preliminary reports of studies that have been presented at international scientific meetings (Table 4).

Table 4:
Quality of Evidence of Included Studies

The results of 1 RCT on fresh tibial fractures was reviewed and added to this document as additional information.

Summary of Medical Advisory Secretariat Review

Study on Tibial Nonunion

Friedlaender et al. (40) conducted a prospective, randomized, partially blinded clinical trial on the treatment of tibial nonunions with rhBMP-7 (OP-1). Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Exclusion criteria included patients to whom the following applied:

  • Were unable or unwilling to fulfil the follow-up requirements
  • Were skeletally immature
  • Had severely compromised soft tissue coverage at the nonunion site
  • Had nonunion as a result of pathological fractures (neoplasia, metabolic bone disease)
  • Were receiving radiation, chemotherapy, immunosuppression, or chronic steroids
  • Were or could become pregnant during the study or were breastfeeding
  • Had infection either systemically or at the site of nonunion
  • Were under other investigational treatment
  • Had congenital or synovial pseudoarthrosis of the tibia
  • Had complete neuropathy that would interfere with walking or appreciation of pain
  • Had nonunions of multiple bones (other than the tibia)
  • Had a known autoimmune disease
  • Were sensitive to collagen

A summary of the patient characteristics is shown in Table 5.

Table 5:
Patient Characteristics in a Randomized Clinical Trial on Tibial Nonunions and Recombinant Human Osteogenic Protein (40)

Clinical assessment included checking the presence of pain at the fracture site (none, mild, moderate, and severe), and the ability to bear weight (none, partial, or full) at the involved extremity. Clinical success was defined as full weight bearing, less than severe pain at the fracture site on weight bearing, and no further surgical intervention required to enhance fracture repair. Outcomes are shown in Table 6.

Table 6:
Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone Grafting

The results of this study demonstrated that recombinant OP-1 is associated with substantial clinical and radiographic success for the treatment of tibial nonunions when used with intramedullary rod fixation. No adverse event related to sensitization was reported. Five per cent of the patients in the OP-1 group had circulating antibodies against type 1 collagen. Only 10% of the patients had a low level of anti-OP-1 antibodies, and all effects were transient. At 9 months following surgery, 81% of the OP-1 treated group and 85% of the autograft-treated group had successful outcomes. This difference was not statistically significant. Furthermore, the success rate with the OP-1 implant was similar with those achieved with autograft at 24 months follow-up. Furthermore, the success rate with the OP-1 implant was comparable with those achieved with autograft at 9 and 24 months follow-up. Eighty-two per cent of patients were successful at 24 months follow-up in both groups.

Statistically significant increased blood loss in the group treated with the autograft was observed (P = .049). Patients treated with autograft had longer operation and hospitalization times. All patients in the autograft group had pain at the donor site after surgery, and more than 80% judged their postoperative pain as moderate or severe. At their 6-month visit, 20% of the patients in the autograft group had persistent pain, mild or moderate in nature, at the donor site. This number fell to 13% at 12 months.

All patients in each of the groups had at least 1 adverse event that wasn’t serious, such as fever, nausea and vomiting, leg edema, discomfort, and bruising at the operative site. The incidence of these events was similar in both groups. Serious adverse events was observed in 44% of both groups, none of which were considered related to the OP-1 implant or to the autograft.

Clinical success and radiographic outcomes in a subset of patients who had received autografts prior to the study (43% of the OP-1 group, and 31% of the autograft group) were not significantly different between the 2 groups.

This study was only partially blinded, because it is difficult to maintain blinding of the radiologists on the nature of autograft, which is mineralized, when compared with the OP-1, which has a radiolucent nature. However, without the benefit of history and period since surgery for each set of radiographs, it was impossible to distinguish the pre-existing mineral of bone graft from induced new bone.

On the basis of these data, the FDA issued a humanitarian device exemption for the application of OP-1 implant as an alternative to autograft in recalcitrant long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.

Study on Fibular Defects

Geesink et al. (34) investigated the osteogenic activity of OP-1 by assessing its value in bridging fibular defects made at the time of tibial osteotomy for varus or valgus deformity of the knee. A summary of the patient characteristics is shown in Table 7.

Table 7:
Patient Characteristics in a Randomized Clinical Trial with Recombinant Human Osteogenic Protein in the Treatment of Fibular Defects (34)
Table 8:
Severity of Pain on Fibular Osteotomy at Each Follow-up Period in a Randomized Clinical Trial of Fibular Defects and Recombinant Human Osteogenic Protein (34)

Three patients were not satisfied with the results of surgery at 10 weeks and at 12 months follow-up (1 in untreated group, 1 in OP-1 group, and 1 in DMB group).

One patient in the OP-1 group had bruising on the lower leg at 1 week, which resolved spontaneously. One patient in the collagen group had an oozing fibular wound for 1 week, but required no intervention.

Radiological and DEXA (Dual Energy X-ray Absorptiometry) evaluation showed that in patients in whom the defect was left untreated, no formation of bone occurred. At 12 months follow-up, new bone formation with bridging occurred in 4 of the 6 patients in DMB group, and 5 of the 6 patients in OP-1 group. One patient in OP-1 group did not show any evidence of new bone formation at any point during the study. This observation shows that the size of the gap in fibular defect was such that it would require the use of an osteogenic agent. The results of the radiological evaluation are shown in Table 9.

Table 9:
Radiological Evidence: Formation of New Bone and Bridging of the Fibular Defect in a Randomized Clinical Trial with Recombinant Human Osteogenic Protein (34)

During follow-up, the mean bone mineral density for the DBM and OP-1 groups increased by more than 80%. The difference between the untreated and DMB groups was significant (P = .001). The difference between the OP-1 and collagen groups was also significant (P = .038). There was no difference between the OP-1 and DMB groups at any time. Similarly, no significant differences between the mean bone mineral density of the untreated and the collagen groups were observed.

Low levels of anti-OP-1 antibodies developed in 10% of those treated with OP-1, but all titres were low and transient. No allergic reaction was reported. Circulating antibodies against type 1 collagen was observed in 5% of those who received this matrix, but no adverse events were reported.

One patient treated with OP-1 developed pain at the implantation site. A local resection was performed and histological examination confirmed the presence of active bone remodelling. It was presumed that the localized discomfort reflected an increased bulk of bone at the gap site, which caused mechanical irritation in adjacent soft tissues. The symptoms were relieved by excision of the bony response. The authors concluded that the dose of human OP-1 could have been too high. They suggested that concentrations of OP-1 needed in vivo might be lower than in vitro especially when dealing with normal bone. The authors suggested that the dose - response profiles, the effects of different carriers, and the biological and mechanical characteristics of new bone should be investigated in future trials.

Ontario-Based Pilot Study

A prospective pilot study (41) was conducted in Ontario, Canada to investigate the safety and efficacy of OP-1 in the treatment of recalcitrant long bone nonunions. Fifteen patients with complex, recalcitrant, long bone nonunions whose previous treatment had failed were identified and included. A summary of the patient characteristics and outcomes are shown in Table 10.

Table 10:
Patient Characteristics and Clinical Outcomes of Study on Complex, Recalcitrant, Long Bone Nonunions (41)

The investigators concluded that this bone graft substitute appears to be safe and effective in providing sufficient biological stimulation in difficult-to-treat nonunions. Results of a more complete study on 70 patients are ready for publication. According to the principal investigator, OP-1 was effective in inducing bone formation and bone healing in this sample and had a success rate of about 90%.

Study on Fresh Tibial Fractures

Recent laboratory experiments have suggested that BMPs may be injected to enhance the treatment of fractures that do not require operative treatment. Maniscalco et al. (42) did a clinical study to verify the potential of OP-1 in fresh tibial closed fractures. The aims of the study were to standardize the surgical technique; to evaluate tolerance and toxicity; to study the advantages and disadvantages of OP-1 in terms of bone healing and functional therapy; and to identify the types of fractures that could benefit from this therapeutic protocol.

Fourteen patients with closed fractures of the tibial shaft were randomly assigned to 2 groups. Each had 7 patients. Patients with open fractures, pathologic fractures, and vascular and/or nerve lesions were excluded. In the control group, only external fixation was applied. In the OP-1 group, after external fixation, a 1-cm incision was made above the fracture site, and the protein was inserted by a custom-designed system. A hole was created in the fracture site with a drill, and the liquid fluid protein was applied a pusher. In the immediate postoperative period, the leg was placed in a non weight-bearing position, and ankle movement was permitted immediately. All patients had prophylactic antithrombosis therapy with heparin. The same standardized rehabilitation program was applied to both groups. A summary of the patient characteristics is shown in Table 11.

Table 11:
Randomized Clinical Trial with Recombinant Human Osteogenic Protein in the Treatment of Fresh Tibial Fractures: Maniscalco et al. (42)

Fracture union was confirmed by the presence of the callus bridging at the fracture site on the anteroposterior and lateral radiographs. Radiological evaluation was done postoperatively, and at 1 month, 2 months, 4 months, and 5 months to check for the presence of the callus bridging the fracture site. In addition, in the OP-1 group, an ultrasound was done immediately after surgery and at 1 month, 2 months, and 4 months after to evaluate the progressive formation of bone callus.

In the OP-1 group, all of the patients had blood and urine tests at baseline and 1 month, 2 months, and 3 months. This was to measure calcium, phosphate, alkaline phosphatase, serum nitrogen, and creatinine. Table 12 shows the result of this study.

Table 12:
Clinical, Radiological, and Laboratory Results of Treatment of Fresh Tibial Fracture with OP-1: Maniscalco et al. (42)

The consistency of OP-1 used for this study was different from that in the other 2 RCTs, and the injection of OP-1 necessitated excessive fluidity of the solution. The investigators concluded that OP-1 is not indicated for fresh shaft fractures of tibia. However, the study was not sufficiently powered to justify this conclusion.

Summary of Findings: OP-1

  • OP-1 is an osteoinductive bone graft material. It contains human osteogenic protein and bovine bone derived collagen (3.5 mg OP-1 and 1 g collagen).
  • So far, evidence for safety and effectiveness of OP-1 is based on 1 large RCT, 1 small RCT, and 1 pilot case series.
  • There is level 1 evidence that OP-1 is as effective as autologous bone graft in the treatment of tibial nonunion. The rate of clinical success in tibial nonunions was similar to that for the autologous bone graft when used with intramedullary rod fixation.
  • None of the studies using OP-1 documented any adverse systemic effects.
  • The major advantages of using OP-1 rather than harvesting bone for autograft is the avoidance of pain and infection at the donor site associated with autograft procedures.
  • Reconstruction of a bone defect with a large gap between the 2 ends requires the use of an osteogenic agent. Based on level 2 evidence, OP-1 may be used in the treatment of segmental bone defect, but this evidence is based on a small-sized trial; therefore, OP-1 can be considered still investigational in this area.
  • There is level 2 evidence that OP-1 is not indicated for fresh shaft fractures of tibia.
  • The dose - response profile and biological and biomechanical characteristics of new bone needs further evaluation.
  • The FDA has limited the use of OP-1 to long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.
  • According to the FDA, OP-1 should not be used in the presence of the following conditions:
    • Hypersensitivity to the active substance or to collagen
    • Pregnancy
    • Skeletal immaturity (e.g., in patients < 18 years of age)
    • At the site of a resected tumour that is at or near the defect or fracture

Alternative Technologies

The Medical Advisory Secretariat searched the literature from January 1, 2000 to February 28, 2005 to identify studies on nonunions and bone defects that used alternative technologies. A review of these studies showed that in addition to the gold standard autologous bone marrow grafting, bone allografts, demineralized bone matrices, bone graft substitutes, and autologous bone marrow have been used for treatment of nonunion and bone defects. These studies were categorized according to their osteoinductive, osteoconductive and osteogenesis properties.

Materials with Osteoconductive and Limited Osteoinductive Properties

Bone Allografts

Bone allografts have been used mostly in various reconstruction procedures to restore the defective bone after excavating a bone lesion. Table 13 shows a summary of these studies.

Table 13:
Studies on the use of Allografts in Nonunions and Bone Defects (2000 – 2005)

Two studies investigated the effectiveness of DBM in healing fracture nonunions. However, in these studies, autologous bone marrow grafting has also been used to stimulate healing. A summary of the patient characteristics, procedures, and results of these studies is shown in Table 14.

Table 14.
Studies on the use of Demineralized Bone Matrix in Nonunions and Bone Defects (2000 – 2005)

No definite conclusion can be made from the studies on DBMs. The objective of Ring’s study was to investigate the usefulness of a fixation technique for treatment of osteoporotic nonunions. In the study by Wilkins et al., (56) some patients had also received bone marrow aspirate or strut allograft. These investigators were contacted for additional information and updates. According to the investigators, about one third of the patients in their current database have also received either bone marrow aspirate or allograft.

Materials with Osteoconductive Property

Calcium phosphate and calcium sulphate are osteoconductive materials that have been used mostly for repair of bone defects (See Table 15).

Table 15.
Studies on the use of Calcium Phosphate and Calcium Sulphate in Nonunion/Bone Defects (2000 – 2005)

Material with Osteogenic Property

Bone Marrow Grafting

Several investigators have investigated the use of autologous bone marrow for treatment of long bone nonunions. A summary of the patient characteristics, procedures, and results of these studies is shown in Tables 16A to 16D.

Table 16A.
Studies that used Percutaneous Injection of Bone Marrow for Treatment of Nonunions and Bone Defects
Table 16B:
Studies That used Percutaneous Injection of Bone Marrow for Treatment of Nonunions and Bone Defects
Table 16C.
Studies that used Percutaneous Injection of Bone Marrow for Treatment of Nonunions/Bone Defects
Table 16D.
Studies that used Percutaneous Injection of Bone Marrow for Treatment of Nonunions/Bone Defects

These case series show that percutaneous bone marrow grafting is highly effective in the treatment of long bone nonunions. In a total of 301 fractures across all studies, 268 (89%) healed with a mean healing time of 2.5 to 8 months. This healing time as derived from these case series is less than the timing of the primary end point in Friedlaender’s study (9 months). Table 2 summarizes the results of these studies.

Reports show that cases with atrophic nonunions were successfully treated with percutaneous bone marrow grafting. (56;69;74). Jean et al. (71) and Matsuda et al. (73) reported that cases with initial infection failed the treatment. These investigators have indicated that active infection is a contraindication for this technique.

Summary of Findings: Bone Marrow Grafting

  • Bone marrow grafting is a minimally invasive, simple, and inexpensive technique that has successfully treated long bone nonunions.
  • None of the studies of autologous bone marrow grafting documented any adverse systemic effects.
  • So far, evidence for effectiveness of bone marrow grafting is based on 10 case series in which clinical outcomes were compared with the patients’ baseline conditions. No RCT has been conducted to compare the effectiveness of this technique with the gold standard, autologous bone grafting.

Economic Analysis

Results of Literature Review on Economics

One published poster on the economic aspects of OP-1 for long bone nonunion was identified (78). This study compared the efficacy of OP-1 with autogenous bone graft in the management of tibial nonunions. Forty-one patients with nonunions amenable to intramedullary nailing were prospectively randomized into the OP-1 group or the autograft group. All patients underwent open intramedullary nailing and placement of either OP-1 or autograft. All patients were followed clinically and radiographically for a minimum of 1 year. Both groups were similar in respect to the duration of the nonunion, number of prior surgeries, and smoking history. Nineteen of 20 nonunions in the OP-1 group and 17 of 21 nonunion in the autograft group were consolidated. The cost of treatment with OP-1 was compared with the cost of treatment with autograft in 1 hospital (18 patients, 9 in each group). Table 17 shows the cost of treatment with OP-1 and autograft in these patients.

Table 17:
The Cost Comparison Between Osteogenic Protein-1 and Autograft for the Treatment of Tibial Nonunion

Ontario-Based Economic Analysis

Disclaimer: This economic analysis represents an estimate only, based on assumptions and costing methodologies that have been explicitly stated. These estimates will change if different assumptions and costing methodologies are applied for the purpose of developing implementation plans for the technology.

Hospitalization Costs

In 2003, an estimated total of 6,150 hospital separations were identified from the discharge abstracts database (DAD) that could have been associated with long bone nonunion. (A combination of ICD-10 diagnosis codes and CCI procedure codes were used.) An estimated total of 6,630 hospital separations were identified in 2002. Both figures are within the range of the incidence figures for long bone nonunion used in this report, i.e., 3,863 - 7,725 per year. Therefore, these discharge data are considered to be a valid depiction of the situation in Ontario. To determine the cost per case, the prospectively adjusted for complexity resource intensity weights (PAC-10 weights) were used based on a weight of 1.0 having a dollar value of $3,809 during 2003 (Personal Communication: Finance and Information Management Branch, MOHLTC). The mean PAC-10 weight in 2003 was 1.4, and since the 2002 average weight was within 0.1 of this figure, this was considered to be the overall average with an associated cost of $5,477 per hospital separation. Based on the range of annual incidence, the current annual hospitalization cost is between $21.2 million and $42.3 million.

Device Costs

A single vial of OP-1 is normally used per case of long bone nonunion. Given that the cost of a single vial is approximately $5,000 (Cdn) (according to figures provided by an Ontario hospital), the annual total cost of OP-1, if it were used universally for the treatment of long bone nonunion, would be in the range of $19.3 million to $38.6 million. There are no device costs associated with autologous bone marrow transplantation.

Professional (OHIP) Costs4

OP-1

The course of treatment for OP-1 is similar to that of autologous bone harvest except that a separate incision for harvesting bone from the iliac crest is not necessary when using OP-1. Therefore, it is assumed that similar FSC codes would be used for both procedures.

The physician fees for harvest, insertion of bone, or OP-1 is $193 (FSC E551 and E552 or Z279—we assume the latter is more common).

Autologous Bone Marrow Transplantation

The course of treatment for autologous bone marrow transplantation normally involves 2 procedures 6 weeks apart. The total physician costs are therefore doubled to reflect this normal course of treatment.

The cost for autologous bone marrow transplantation is $193 (FSC Z403 and Z426).

Based on annual incidence figures, total annual physician billings regardless of procedure—autologous bone harvest, OP-1, or autologous bone marrow transplantation—would be in the range of $0.7 million to $1.3 million per year.

Diffusion Pressure

Given that long bone nonunion is a definitive diagnosis that is unlikely to increase over time, the long-term prospects for diffusion beyond existing incidence figures is unlikely. However, the uptake is difficult to assess since annual sales data in the United States for the OP-1 product were not made available by the manufacturers.

Downstream Cost Savings

There may be pain medication cost offsets by using OP-1 and autologous bone marrow transplantation instead of autologous bone harvest, given that the former procedures do not involve the pain associated with the bone harvest site. However, given that this pain is normally not permanent, the overall offset is likely to be small. There are likely to be smaller OHIP costs associated with OP-1 than bone-harvest procedures given that only 1, rather than 2, incisions are needed in the former procedure. This offset could amount to between $0.3 million to $0.7 million annually.

Cost-Effectiveness

Given the recent development of OP-1, no cost-effectiveness data is available regarding this product. Though autologous bone-marrow transplantation has been used in jurisdictions outside Canada for some time, no cost-effectiveness data regarding the treatment of long bone nonunion were found regarding this technology.

Appraisal/Policy Development

OP-1 is a Class IV device and is indicated for use as an alternative treatment when other options have failed or are not feasible. However, Friedlaender’s (40) study shows that the incidence of adverse events were similar when treating patients with OP-1 and autologous bone graft; therefore, using OP-1 does not impose additional risk to patients.

Patient Outcomes — Medical, Clinical

In patients with nonunion fractures in which harvesting autograft is deemed unfeasible, OP-1 can be considered as a reasonable alternative. These cases may include the following patient conditions:

  • Insufficient bone tissue
  • Infection at the donor site
  • Discomfort or pain at the donor site
  • Lesion/pathology at the donor site
  • Poor quality of bone at the donor site
  • Osteoporosis
  • Comorbid conditions that increase the risk of harvesting autograft
  • Extreme obesity
  • Elderly

The cost of a vial of OP-1 is $5,000 to $5,500 (Cdn). Typically, 1 vial of OP-1 is used per treatment. Medical resources are among the other cost components and include surgical time, hospitalization, drugs, laboratory tests, and diagnostic imaging tests. However, in an analysis from a patient or social perspective, loss of productivity due to postoperative pain and infection following autograft may influence the analysis.

Diffusion — International, National, Provincial

Over the past few years, 15 to 20 hospitals in Ontario have used OP-1 for long bone nonunions. The manufacturer, Stryker Biotech, provides on-site training to the orthopedic surgeons. A package of inactive samples identical to OP-1 is used for training purposes. The manufacturer also supplies surgical techniques and videos demonstrating how the product is to be used.

FDA issued a humanitarian device exemption to authorize the marketing of OP-1. This exemption is applied when a device is intended to benefit patients in the treatment and diagnosis of diseases or conditions that affect or is manifested in fewer than 4,000 individuals in the United States per year. These devices bypass the premarket approval application process. However, humanitarian device exemption application must include sufficient data to show the probable benefits outweigh the risks.

Policy Considerations

Following reports by Connolly et al. (77) and Healey et al. (79) that showed percutaneous injection of autologous bone marrow successfully treated between 78% and 95% of long bone nonunions, a number of investigators were encouraged to study the use of autologous bone marrow grafting in their patients. All these investigators have reported that percutaneous injection of bone marrow is a simple, safe, and useful technique that can become the procedure of choice in many patients with delayed union or nonunion. In addition, they have indicated that this is a useful procedure for patients at high risk for anesthesia and surgery and also for those who are waiting for any definitive surgical procedures.

Autologous cancellous bone grafting is considered the gold standard in the treatment of long bone nonunions. Unfortunately, this procedure is associated with complications at the donor and recipient sites including infection, pain, bruising, scaring, wound problems, nerve injury, and fracture. Harvesting the graft requires an additional surgical procedure. This increases the risk of perioperative blood loss and infection, leading to a prolonged hospital stay and additional cost. The need to open the nonunion site also adds to the risk of devascularization at the fracture site where healing is already impaired. An alternative technology must be equally successful in achieving union, as well as providing some increased benefit to justify its use. OP-1 and autologous bone marrow grafting both eliminate the risk of donor site morbidity. Autologous bone marrow grafting has the additional advantage of decreased cost and no hospital stay because the procedure is performed in an outpatient setting.

Other advantages of autologous bone marrow graft include the following:

  1. The use of autologous cells is facilitated by less stringent ethical and regulatory issues and does not require the patient to be immunologically suppressed. (80)
  2. The procedure does not jeopardize any future procedure that may have to be done because bone marrow is a restorable source.

Three technologies that demonstrated positive clinical outcomes in the treatment of fracture nonunions were ranked according to 10 criteria. For each criterion, a score from 1 to 3 (1=the best score) were assigned to each technology. Ranking scores are shown in Table 18. According to this schema, a low total score would be associated with a better ranking.

Table 18:
Ranking Scores for Technologies used for Long Bone Nonunions

The method of percutaneous aspiration and injection of autologous bone marrow offers the advantages of treating long bone nonunions without exposing the patients to the risk of surgery and the complications of graft harvesting. The bone marrow is harvested by needle aspiration from the patient’s pelvic bone and is then injected percutaneously into the fracture site under fluoroscopic control.

Autologous bone marrow grafting can heal a fracture because it has the key element in the process of bone generation (osteogenesis). Bone marrow contains stem cells, which are unspecialized cells that can produce mature osteoblasts and regenerate bone. Clinical use of stem cell transplants for hematopoietic conditions, such as various blood cell cancers, has been established over a decade ago.

Since the studies on autologous bone marrow grafting are case series in which patients serve as their own control, it cannot be concluded whether this procedure is as effective as autologous bone grafting. A randomized comparative study is needed to clarify this issue.

Conclusions

Based on level 1 evidence, (1 RCT, 124 patients) OP-1 is a reasonable alternative to autologous bone grafting in the treatment of long bone nonunions.

Based on level 4 evidence, (10 studies, a total of 301 patients), percutaneous autologous bone marrow grafting is effective in the treatment of long bone nonunions in patients with no active infection at the fracture site.

Based on the above evidence and the fact that both procedures (percutaneous autologous bone marrow grafting and OP-1) eliminate the risk of donor site morbidity and reduce the risk of infection at the recipient site, the following would form some of the important considerations in making decisions regarding these competing technologies:

  • Should the effectiveness of percutaneous bone marrow grafting as a treatment modality for non-infected long bone nonunions be explored further?
  • Should access to OP-1 be provided to the patients with long bone nonunions (according to the definitions set by FDA) where other methods of treatment have failed?

Glossary

Allograft
A graft of tissue between individuals of the same species but of disparate genotype
Apoptosis
Programmed cell death - a mechanism for cell destruction
Autogenous
Autologous
Autologous
Related to self
Cancellous bone
Spongy bone
Chondroblast
A cell that forms cartilage
Comminuted fracture
Broken or crushed into small pieces
DNA
Deoxyribonucleic acid
Osteoblast
Cell that produces bone
Osteoclast
A large multinucleated cell responsible for bone resorption
Osteoconduction
A process that supports ingrowth of developing capillaries and perivascular tissue
Osteoinduction
The process of stimulating osteogenesis
Osteoprogenitor cells
Precursor cells

Notes

Suggested Citation

This report should be cited as follows:

Medical Advisory Secretariat. Osteogenic protein-1 for long bone nonunion: an evidence-based analysis. Ontario Health Technology Assessment Series 2005; 5(6)

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Conflict of Interest Statement

All analyses in the Ontario Health Technology Assessment Series are impartial and subject to a systematic evidence-based assessment process. There are no competing interests or conflicts of interest to declare.

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Contact Information

The Medical Advisory Secretariat

Ministry of Health and Long-Term Care

20 Dundas Street West, 10th floor

Toronto, Ontario

CANADA

M5G 2N6

Email: MASinfo/at/moh.gov.on.ca

Telephone: 416-314-1092

ISSN 1915-7398 (Online)

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About the Medical Advisory Secretariat

The Medical Advisory Secretariat is part of the Ontario Ministry of Health and Long-Term Care. The mandate of the Medical Advisory Secretariat is to provide evidence-based policy advice on the coordinated uptake of health services and new health technologies in Ontario to the Ministry of Health and Long-Term Care and to the healthcare system. The aim is to ensure that residents of Ontario have access to the best available new health technologies that will improve patient outcomes.

The Medical Advisory Secretariat also provides a secretariat function and evidence-based health technology policy analysis for review by the Ontario Health Technology Advisory Committee (OHTAC).

The Medical Advisory Secretariat conducts systematic reviews of scientific evidence and consultations with experts in the health care services community to produce the Ontario Health Technology Assessment Series.

About the Ontario Health Technology Assessment Series

To conduct its comprehensive analyses, the Medical Advisory Secretariat systematically reviews available scientific literature, collaborates with partners across relevant government branches, and consults with clinical and other external experts and manufacturers, and solicits any necessary advice to gather information. The Medical Advisory Secretariat makes every effort to ensure that all relevant research, nationally and internationally, is included in the systematic literature reviews conducted.

The information gathered is the foundation of the evidence to determine if a technology is effective and safe for use in a particular clinical population or setting. Information is collected to understand how a new technology fits within current practice and treatment alternatives. Details of the technology’s diffusion into current practice and information from practicing medical experts and industry, adds important information to the review of the provision and delivery of the health technology in Ontario. Information concerning the health benefits; economic and human resources; and ethical, regulatory, social and legal issues relating to the technology assist policy makers to make timely and relevant decisions to maximize patient outcomes.

If you are aware of any current additional evidence to inform an existing Evidence-Based Analysis, please contact the Medical Advisory Secretariat: MASInfo/at/moh.gov.on.ca. The public consultation process is also available to individuals wishing to comment on an analysis prior to publication. For more information, please visit http://www.health.gov.on.ca/english/providers/program/ohtac/public engage overview.html

Disclaimer

This evidence-based analysis was prepared by the Medical Advisory Secretariat, Ontario Ministry of Health and Long-Term Care, for the Ontario Health Technology Advisory Committee and developed from analysis, interpretation and comparison of scientific research and/or technology assessments conducted by other organizations. It also incorporates, when available, Ontario data, and information provided by experts and applicants to the Medical Advisory Secretariat to inform the analysis. While every effort has been made to do so, this document may not fully reflect all scientific research available. Additionally, other relevant scientific findings may have been reported since completion of the review. This evidence-based analysis is current to the date of publication. This analysis may be superceded by an updated publication on the same topic. Please check the Medical Advisory Secretariat Website for a list of all evidence-based analyses: http://www.health.gov.on.ca/ohtas

Footnotes

1Based on the number of fee-for-service claims - fiscal year 2003/2004

2Based on the number of fee-for-service claims - fiscal year 2003/2004

3The Alberta Heritage Foundation for Medical Research has defined “Technotes” as brief reports, prepared on an urgent basis, which draw on limited reviews and analysis of relevant literature and on expert opinion and regulatory status where appropriate. They are not subject to an external review process.

4All physician billings are adjusted upward by 2% to reflect the 2005 OMA agreement.

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