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According to Dr. Yoon, enthusiasm has outpaced evidence for some of these products. Sometimes the only substantial proof of efficacy is in small animals such as rats and rabbits. “It’s easy to make things heal in rats,” Dr. Yoon said. “If something works in a rabbit, that means nothing in humans except that it has potential.” Results achieved in primates are more telling but not yet available.

AAOS Now

Published 4/1/2013
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Terry Stanton

“Orthobiologics” Have Promise Across Surgery Categories

The use of biologic agents such as platelet-rich plasma (PRP) and recombinant human bone morphogenetic protein (rhBMP) continues to draw heightened interest. Research is expanding the understanding of both their potential and their limitations. In addition, results of clinical experience are helping to guide physicians in applying these products in their practices.

During the session “PRP, BMP, and Stem Cells: What Surgeons Need to Know,” a panel of surgeons reviewed the current state of knowledge for these “orthobiologics” and offered guidance on their indications in treatment settings such as the spine, rotator cuff and tendons, trauma, and osteoporosis and fracture.

Biologics in spine surgery
S. Tim Yoon, MD, PhD,
of Emory University, addressed the use of biologics in spine surgery. Although iliac crest bone graft (ICBG) is the standard for bone replacement in the lumbar spine due to its “ideal” properties and high success rate, it is not without drawbacks, including blood loss, pain, increased surgery time, and a nonunion rate of 5 percent to 40 percent. Thus, a $1 billion market has arisen for alternatives and adjuncts to autograft, such as ceramics, demineralized bone matrix (DBM), cell-based therapies including stem cells, and BMP.


S. Tim Yoon, MD, PhD

The challenge of conducting trials with human patients accounts for the scarcity of high-quality evidence for many biologics. For example, a fusion-rate comparison for a single-level spine procedure requires 300 patients for a non-inferiority trial and 750 patients for a superiority trial. Many claims made for fusion rates achieved do not hold up to scrutiny, and more rigorous studies demonstrate lower fusion rates.

Stem cells from bone marrow aspirate are among the agents used in the spine. The obtainable concentration is only about 1 mesenchymal stem cell (MSC) per 10,000 bone marrow cells, yet animal studies that demonstrate some positive effects use large numbers of MSCs—around 100 million—pointing to the difficulty of providing a therapeutic dose. Dr. Yoon said that high variability in the cells exists among patients. “It’s difficult to know how much of an effect this therapy has,” he said.

PRP has a high profile, but much remains to be known about its mechanism of action. “PRP contains growth factors, and that sounds great,” said Dr. Yoon. “But each growth factor has unique properties. Platelet-derived growth factor does not have osteoinductive growth factor. Transforming growth factor is really a chondrocyte-specific agent.”

Common ceramic products include hydroxyapatite (HA) and beta-tricalcium phosphate (TCP). “In the world of tissue engineering, the holy triad consists of cells, factors, and matrix,” Dr. Yoon said, “and these agents can serve as matrix. Bone graft products are generally classified as substitutes, enhancers, or extenders.”

A substitute involves no graft. An enhancer “is something you use with the usual amount of bone graft or less, but it makes it better in fusion than autograft alone.” An extender adds to volume. In one study, HA appeared to have some benefit as an extender, but it should not be used alone, advised Dr. Yoon.

DBMs have a long history of use. The BMPs in them are naturally occurring molecules that become active when acid-treated, yielding bone formation. Thus they can serve as either extenders or enhancers. In clinical use, however, the BMP content in DBMs is highly variable. “This inconsistency makes it difficult to evaluate,” said Dr. Yoon.

To date, the U.S. Food and Drug Administration has approved use of BMP only for anterior lumbar interbody fusion, “but there is a lot of physician-directed (off-label) use,” Dr. Yoon said.

Biologics and osteoporosis
Joseph M. Lane, MD,
of the Hospital for Special Surgery, provided an update on therapies used for osteoporosis and related fractures. Although bone repair biology is not compromised in patients with osteoporosis, the compromised tissue impairs instrumentation and causes malaligned healing.

At the forefront of treatment for bone resorption are diphosphonates, which work by providing a loading of bone surface that inhibits osteoclast penetration. During fracture healing, Dr. Lane explained, diphosphonates delay fracture maturation; the large periosteal callus overcomes the delayed maturation and leads to a mechanical strength comparable to that of controls. Conversely, if the fracture heals by membranous bone, the diphosphonates will delay healing.

Another agent used to enhance bone is parathyroid hormone (PTH). It is an anabolic agent, in contrast to denosumab and diphosphonates. It induces the production of the active vitamin D metabolite, increases renal resorption of calcium, and, when continuously administered, increases osteoclastic resorption; when administered intermittently, it only stimulates osteoblastic bone formation.

Patients with osteoporosis should have a metabolic workup to measure complete blood count, calcium, phosphorus, alkaline, phosphatase (bone), PTH, and vitamin D. Dr. Lane noted that 70 percent of patients with acute fractures have low levels of calcium and vitamin D.

“If the fracture is metaphyseal and the union reliable, diphosphonate use can be delayed until early healing is established,” he suggested. Patients who are taking diphosphonates and sustain a fracture should cease taking the diphosphonate and switch to PTH.

“In fractures that occur in untreated osteoporotic patients, consider PTH if the fracture occurs in weight-bearing diaphysis or metaphyseal bone with poor purchase by the implant,” Dr. Lane said. He added that the subgroup of patients at risk for fracture due to prolonged exposure to diphosphonates is relatively small and that diphosphonates “protect from fracture but not for life.”

He also implored physicians to use the World Health Organization Fracture Risk Assessment Tool (FRAX®), a short instrument that assesses the 10-year risk of fracture.

Biologics and rotator cuff
Evan L. Flatow, MD,
addressed the issue of biologic therapies in the context of rotator cuff injury and tendon repair. He noted that most rotator cuff tears are degenerative and that data derived from study of repairs of healthy tendons “have no bearing on healing a damaged tendon.”

Overall, he said, biologic and structural augmentation have the potential to address poor healing. Xenografts, such as those from pigs, are of unclear value. Acellular dermal allografts appear promising. Synthetic materials may offer “designer mechanics,” particularly for deficient and poor tissue (as in a revision setting). The application of growth factors, perhaps in combination with stem cells, may be promising.

Although PRPs have demonstrated some success in treating conditions of tendinopathy such as Achilles tendon injury and lateral epicondylitis, no published evidence demonstrates any improvement in healing when they are used in rotator cuff repair.

Biologics and trauma
Trauma surgeon L. Tracy Watson, MD,
of St. Louis University, discussed the use of low-intensity pulsed ultrasound (LIPUS) for the treatment of fresh fractures. Basic science trials and some clinical trials have shown that it may be useful for such injuries, shortening the time required for remodeling and enhancing the mineralization of callus. Randomized controlled trials are needed to establish its efficacy.

However, Dr. Watson noted, “Orthobiologics and advanced technology won’t compensate for poor surgical technique.”

Disclosure information: Dr. Yoon—Meditech; Stryker; Biomed; Phygen; Medysse; SpineNet; The Spine Journal. Dr. Lane—Amgen; Eli Lilly; Weber Chilcott; CollPlant; Bone Therapeutics; DFINE; Graftys; Zimmer; BioMimetics. Dr. Flatow—Innomed; Zimmer; Wolters Kluwer Health–Lippincott Williams & Wilkins. Dr. Watson—Biomet; DePuy, a Johnson & Johnson company; Smith & Nephew; Medtronic; Stryker; Bioventus; Accelalox; Ellipse.

Terry Stanton is senior science writer for AAOS Now. He can be reached at tstanton@aaos.org