In reviewing the available data, the panel found the complex range of grafting materials difficult to compare due to the wide differences in regulatory pathways, mechanisms of action, and clinical evidence used to support them.

In brief, their review concluded:

• Non-structural allografts remain a viable and an inexpensive option,
• While 398 demineralized bone grafts (DBMs) and synthetic bone substitute products have been 510(k) cleared there is little supporting clinical evidence,
• Cellular-based allografts do not have compelling clinical evidence to support broad use, and
• Class III drug-device combinations, while supported by compelling science still lack supportive clinical evidence.

Non-Structural Allografts

With respect to non-structural allografts the reviewers note that such bone grafting materials have been used since the late 19th century. Non-structural allografts are regulated as human cell or tissue products, and as such, preclinical or clinical data is not required prior to marketing for commercial use.

Nevertheless, non-structural allografts have broad supporting clinical evidence for sinus augmentation, tibial fractures and spinal fusion, with one study showing 92.7% fusion success after two years for pediatric scoliosis. Similar rates of success were found in lumbar fusion with comparable pain reduction as autografts at 1, 2 and 3 years after the procedure. The panel concluded that the lack of donor site morbidity, outcomes success rates, and reduced surgical times make non-structural allografts a low-risk alternative to autologous bone grafts.

Demineralized Bone Grafts

Derived from cadaver bone with minerals removed leaving 90% to 95% collagen, the National Organ and Tissue Donor has been screening DBMs since 1997 and in 2006 the FDA reclassified DBM with growth factors to be Class II products requiring 510(k) clearance, while DBMS without growth factors are considered HCT/Ps and are not regulated as devices.

Used alone or as augmentation for autogenous bone grafts, DBMs have a successful track record for cyst repair, fractures, nonunions and spinal fusions. Clinical studies comparing Grafton-Gel implanted patients with instrumented fusions with autografts showed statistically comparable fusion rates. The reviewers concluded that fusion rates for commercial DBM as an autograft extender in posterolateral spinal is statistically similar to that of autologous iliac crest bone graft (ICBG).

Cellular-based Allografts

Combining osteoconductive carriers and cryogenically preserved mesenchymal stem cells from cadaver bone and adipose, CBMs are used to provide inert scaffolding for the delivery of the stem cells for bone repairs.

While manufacturers indicate their products are osteoconductive, osteoinductive and osteogenic properties, there is limited published clinical evidence to establish CBMs as osteoinductive. Owing to classification as HCT/P, validation for growth factor production is not required.

The limited clinical evidence includes a study of 57 patients treated with CBMs who were compared to a retrospective paired cohort that showed an 87.7% fusion rate at 12 months compared to 94.7% for the allograft controls, which was not statistically different. In a larger non-controlled study of 182 patients CBMs showed 92% fusion rate at 2 years and improvements in neck disability index scores (NDI). Another non-controlled study also showed similar improvements in NDI and fusion rates at 12 months. Similar studies with similar results suggest that CBMs as a bone graft extender might be considered equal to or better than ICBG.

The reviewers concluded that CBMs represent a promising bone grafting technology but that the biological mechanism has not been well established, and post implant benchmarks for cell viability, differentiation, immunogenicity and growth factor production have not been demonstrated in clinical trials.

Synthetic Bone Grafts

The FDA currently allows via 510(k) clearance synthetic grafts using tricalcium phosphate (TCP, hydroxyapatite, or combinations of the two for use in extremities, pelvis and spine, based on different animal models for each application.

While there are numerous pre-clinical studies of laboratory-derived b-TCP, they are difficult to interpret for clinical relevance and there is scant preclinical evidence of the commercially available b-TCP. In one report of 32 patients treated with posterolateral spine fusion who were available for follow up, 100% demonstrated good consolidation of graft material. A similar report on 7 patients with three to six months follow up also showed 100 percent solid fusion.

Autologous Cellular Grafts

While both platelet-derived growth factors or bone marrow derived mesenchymal stem cells (MSCs) are attractive from cost and immunoreactive standpoints, autologous cellular grafts are not without significant challenges.

The bioactive factors released by platelet activation are complex and poorly understood. Results of autologous cellular grafts with platelet-growth factors have been limited and controversial showing conflicting results in the few trials published. There is inadequate evidence to definitively conclude that platelet-rich plasma provides a benefit for patients treated with spinal fusion.

Similarly, commercial systems to concentrate MSCs from bone marrow aspirate have produced varied and conflicting results, and such critical factors as formulation, dosage, and timing remain unknown.

Class III drug-device combinations

Bone Morphogenetic Protein (BMP)

Since combining demineralized bone (DBM) with bone morphogenetic protein (BMP) was first proposed in 1970 there have been 15 BMPs identified and studied. Of those only two, BMP-2 and BMP-7 have been shown to have bone forming potential.

In an two-year clinical trial comparing BMP-2 combined with a lumbar tapered cylinder cage (InFUSE LT-Cage®) to LT-cage with ICBG showed that 143 patients treated with the InFUSE LT-Cage experienced slightly shorter operative times (1.6 hours vs. 2 hours) and at 24 months a 6% higher infusion rate than the 136 patients in the ICBG group (94.5% vs. 88.7%). Based on those results FDA granted approval of InFUSE LT-Cage for degenerative disc disease in the lumbar spine.

For the posterolateral spine fusion application, a small trial of 25 patients with less than grade 1 spondylolisthesis were treated with autograft and pedicle screws, rhBMP-2 with pedicle screws or rhBMP-2 alone. Radiographic follow up showed a fusion rate of 40% for the autograft and pedicle screw group and 100% for both BMP-2 groups.

In a trial of 421 patients with tibial fractures were treated with two different concentrations of InFUSE and intramedullary nail compared to a third group treated with standard treatment with nail and soft tissue management showed that both InFUSE groups had higher union rates with significantly fewer secondary interventions and higher healing rates with fewer hardware failures, infections than the control group.

Peptide-Based Grafts

Peptide-based bone grafts are a new category developed in the 1990s based on using MSCs to initiate new bone formation. To date approximately 50 peptides have been evaluated for potential to bind and stimulate MSCs. A specific peptide from the master control region of type I collagen has been found to be 4500 times more potent than any others for cell-binding properties.

A synthesized version of that peptide P-15 studied for two decades finally resulted in FDA premarket approval (PMA) for P-15 for dental bone grafting was granted to Portuguese device maker Ceramed. It has subsequently been used in approximately a half million patients.

A year later a second version of P-15 was issued a PMA to Colorado-based Cerapedics for its i-FACTOR™ for use in orthopedics and spine surgery indications.

To date there are 2 drug-device combination products have received FDA PMA approval for spinal use based on level I clinical trials showing them to be safe and effective as autograft replacements. These two spine products are InFuse (rhBMP-2), and i-FACTOR (P-15 peptide.)

The reviewers conclude that alternatives to autologous bone grafting are evolving with a number of promising options lack substantial clinical evidence to support broad adoption.

Source: Abjornson C., Lorio M. et al. “ISASS Recommendations and coverage critera for bone graft substitutes used in spinal surgery”