April 01, 2004
6 min read
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Many synthetic bone graft substitutes available: different indications

Some can carry compressive loads: More work needed before they can be a structural component of repairs.

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This defect has been filled with Opteform demineralized bone matrix and Collagraft, an osteoconductive matrix of bovine collagen and hydroxyapatite/tricalcium phosphate beads.

COURTESY OF CHARLES CORNELL

Over the last decade, a great deal of the discussion regarding bone graft substitutes has focused on bone morphogenetic proteins. But while two of these biologics have been approved for use in humans, their indications are still rather limited.

Synthetic bone graft substitutes, however, have been available for decades and have a great deal of data to support their use. In 1892, H. Dressmann first described the use of Gypsum (plaster of Paris) to fill bony defects, and in 1961 L.F. Peltier published a study on its use and recommended it as an inexpensive bone graft substitute.

Over the years, other synthetics have emerged, including coralline ceramics in the 1970s and 1980s, calcium phosphates in the 1970s and collagen-based substitutes in the 1990s. But even though these synthetic substitutes are used in many of the estimated 500,000 bone grafting procedures performed annually in the United States, they are far from being a perfect substitute for autogenous bone.

“Nobody’s hit a home run with these products, but they’re working on it,” said Richard F. Kyle, MD, chair of the department of orthopedics at the Hennepin County Medical Center in Minneapolis.

“The problem with all of these substances right now is that they are very weak when it comes to resisting torsion and bending. Some of them can carry compressive load, but even then they aren’t fantastic; but definitely for torsion and bending, they’re very weak. I think we have a way to go before we can truly make them a structural component of our repairs,” said Kyle, who is also medical director of Hennepin’s biomechanics lab.

Shortcomings, but still beneficial

Despite shortcomings, synthetic bone graft substitutes can still benefit both surgeons and patients, said Charles N. Cornell, MD, of the Hospital for Special Surgery and a professor of clinical orthopedic surgery at the Weill Medical College of Cornell University.

“The synthetics are available in infinite supply. They avoid the risks of injury to the donor site, so you avoid all the problems and complications and increased pain associated with an iliac crest bone harvest. They are relatively inexpensive compared to demineralized bone and recombinant proteins, and they are completely sterile,” Cornell said.

The ideal synthetic bone graft substitute would have a number of qualities, said David Jacofsky, MD, of the Mayo Clinic, Rochester, Minn. It would:

  • Resorb with a predictable degradation time.
  • Be cost effective.
  • Have handling characteristics familiar to the surgeon.
  • Have no immunogenicity.
  • Have results as good as or better than autograft for achieving union.
  • Not interfere with modern imaging modalities.
  • Act locally and have no systemic effects.
  • Be osteoconductive and osteoinductive and would also supply or attract progenitor cells.
  • Harden via a nonexothermic reaction to prevent heat damage to antibiotics and growth factors.

“Currently autograft is the gold standard, but certainly the goal is to have a synthetic agent that is cost effective and is actually better than autograft, but we don’t have that yet. That’s kind of the Holy Grail.”

Calcium sulfate well-established

Jacofsky said medical grade calcium sulfate-based products such as OsteoSet (Wright Medical Technology Inc.), BonePlast (Interpore Cross International) and Jax Bone Void Filler (Smith & Nephew) have a “well-established” track record for use in benign bone tumors and for filling nonstructural voids. Their mechanism of action, however, remains somewhat unclear.

One advantage of calcium sulfate-based products is that they have the quickest resorption time of all synthetics. OsteoSet, for example, comes in a pellet form that typically resorbs in four to eight weeks, depending on the location, and is replaced with normal bone matrix. BonePlast resorbs in six to eight weeks.

Research on calcium phosphate-based bone graft substitutes began appearing in the 1970s. Today, they come in a number of forms, including blocks and morsels (Vitoss, Orthovita; and OsSatura, Isotis OrthoBiologics) or injectable bioactive cements (Norian SRS, Synthes-Stratec; BoneSource BVF, Stryker Orthopaedics; and Alpha-BSM, ETEX Corp.).

“I think calcium phosphate can be constructed to have some better flow characteristics for delivery than calcium sulfates and they can be delivered into the fracture site a little bit more easily,” Kyle said. He believes that the newer tricalcium phosphates, which are similar to hydroxyapatite, will eventually supplant earlier calcium phosphates and calcium sulfates.

“Their morphology looks more like real bone and I think that the closer we make their lattice work to real bone, the body will accept and integrate them faster and more easily. … I think the engineering of the tricalcium phosphates is going to be significant over the next few years.”

Collagen-based products

Collagraft, an osteoconductive bone graft matrix developed by Zimmer/NeuColl, was approved by the Food and Drug Administration in 1991 for use with acute bone fractures. It is a mixture of collagen and hydroxyapatite/tricalcium phosphate ceramic beads.

Cornell was the lead investigator for the study that led to Collagraft’s FDA approval. It was the first prospective trial to compare a bone graft substitute to autogenous bone in extremity fractures and it demonstrated equivalency between the two, he said. Another product is Healos from Orquest, a collagen sponge mineralized with hydroxyapatite. Kyle said that while such collagen-based products allow surgeons to fill a void, they have “poor” mechanical characteristics.

Coralline ceramics like ProOsteon from Interpore Cross International were some of the first bone substitutes available. ProOsteon is made from marine coral exoskeletons that are hydrothermally converted to hydroxyapatite and have architecture similar to cancellous bone. Kyle said coralline ceramics can be carved to fit a void and are as good as autogenous bone when it comes to mechanics.

Cornell believes the downside of coralline ceramics is that they are completely insoluble and do not resorb. “Most people are thinking that we should be using materials that are completely remodeled back into host bone. That’s why things like Alpha-BSM and Norian, both of which remodel — but slowly — are more attractive.”

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This patient underwent autograft harvesting for a spinal fusion (left and middle). The patient was referred to the Mayo Clinic after developing a stress fracture and nonunion through the iliac wing. The result was symphyseal degeneration with significant symptoms. The picture on the far right is a postoperative radiograph of the patient after a front-back ORIF to restore pelvic stability. This case demonstrates a major reason to use substitutes for bone graft, according to David Jacofsky.

COURTESY OF DAVID JACOFSKY

Surgeon education needed

There are many synthetic bone grafts on the market, so surgeons need to educate themselves to determine which one is appropriate for a particular injury, Jacofsky said. “Surgeons need to understand the advantages and disadvantages and the indications for each product. They all behave differently, their resorption times are unique and site dependent, and their mechanical characteristics are variable, so the indications that they should be used for are different.”

If a surgeon needs to buttress a joint surface, then an injectable, resorbable cement would have advantages in some settings over beads, which have less structural stability and compression, he added. Cornell said injectable cements like Norian and Alpha-BSM have been shown to provide good support to depressed articular fractures, for instance, in the tibial plateau.

If surgeons intend to use bone graft substitutes in conjunction with antibiotics, that must be taken into account as well. Jacofsky said calcium sulfates have become the main choice of the orthopedic community for use as delivery systems for antibiotics because they resorb rapidly. Calcium phosphate and collagen-based bone substitutes are not as effective for this application, he added.

Cornell said there have been several studies using synthetics in animal models of osteomyelitis in which they worked “very, very well.” He added that there are various formulations being developed in which ceramic materials are manufactured with the antibiotics in them.

“As they resorb, it’s almost like peeling away the layers of an onion. The antibiotics are released as the material resorbs, so you can get fairly prolonged local delivery of the material. They are very good carriers for that.”

Bone cocktails

Kyle said he has mixed antibiotics with synthetics to treat open fractures, infected fractures and infected revision total joint implants. He believes that several years down the line, surgeons will be able to use them to deliver a “cocktail” of antibiotics and growth factors.

Those kinds of cocktails are not available today, but many surgeons are producing their own. “A bone graft substitute doesn’t have to be used by itself; that’s an important point. You can always mix it with other materials,” Cornell said.

“Oftentimes the best application of these materials might be to mix them with local autogenous bone to expand the volume of the bone graft or to change the properties. You might want to add some ceramics to give it a little bit more support function. You might want to add some demineralized bone matrix to enhance the osteoinductive potential of the material. You might want to add some aspirated bone marrow to any of these materials to add cells.”

“There is obviously more work to be done in this area. There are multiple offerings at this time and the surgeon must be familiar with the properties and advocated use of each product,” Kyle said.