Journal of Bone and Mineral Research

Six years after FDA approval of the first bone growth factor, a bone morphogenetic protein, researchers and clinicians still seek a better understanding of these powerful substances, their uses and limitations.

Of all the bone growth factors studied, bone morphogenetic proteins (BMP) expressed during bone healing have been found most effective for initiating bone growth in clinical situations such as spine fusion and fracture healing.

“I think growth-factor-based strategies are important for bone formation, especially in difficult situations,” Scott D. Boden, MD, said.

During a presentation he made to attendees at the American Academy of Orthopaedic Surgeons and Orthopaedic Research Society annual meetings, Boden discussed key issues that still require work before further clinical optimization of BMPs occurs. He said, “The issues are dose and carrier optimization, controlling local side effects and deciding when we need things of this potency.”

BMP vs. bone graft

Results of clinical trials and pilot studies continue to support use of BMPs. In some cases, they and other bone-forming growth factors have proven superior to iliac crest bone graft (ICBG).

“ICBG is continuing to become the old gold standard,” according to Boden.

An advantage that both recombinant and naturally occurring BMP has over ICBG is osteoinductivity. ICBG is mineralized and therefore not osteoinductive, “but it has osteogenic properties,” noted Boden, spine section editor for Orthopedics Today.

BMP also avoids the morbidity associated with autogenous bone that reportedly has “up to 25% of patients at 2 years still reporting chronic donor-site pain,” he said.

Osteoinductive material

BMPs work by binding to specific receptors on a cell’s surface and phosphorylizing special proteins that send signals among cells. These proteins interact with each other and pass into the cell nucleus where they control osteoblast differentiation genes.

“BMPs really are the only known osteoinductive factors,” Boden said. They are the most potent growth factors studied and have accrued the greatest evidence of efficacy. But only some BMPs form ectopic bone.

The most osteoinductive factors are BMP-2, -6 and -9. The intermediate ones are BMP-4 and -7 which have more limited inductivity properties with mesenchymal stem cells, Boden explained. The BMPs that are FDA approved for very specific indications are recombinant human BMP-2 (INFUSE Bone Graft; Medtronic) and BMP-7 (OP-1 Implant; Stryker Biotech), although OP-1 has a more limited humanitarian device exemption approval.

Side effects

Boden noted BMPs now in clinical use and those nearing approval have varying strengths and concentrations, which affect how consistently they form bone and any side effects that may occur. Side effects of chief concern are seroma or edema, bone forming where it should not be and transient cancellous bone resorption.

“Physicians should be cautious about physician-directed, off-label, use which can be associated with a higher incidence of local side effects,” Boden said.

Osteopromotive biologic substances aid in forming bone once the process has begun, but alone “are not sufficient in a non-bone location to drive bone formation,” Boden explained. Examples of osteopromotive factors are vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and peptide signaling molecules.

Animal studies and work in humans have shown some of these factors produce consistently better bone healing than either ICBG, a passive scaffold alone, or using an osteoconductive material.

Boden believes research is still needed to identify appropriate doses, carriers and release kinetics for them.

Other growth factors

Currently phase 3 clinical trials are underway for FGF, a growth factor that showed great potential in non-human primate healing studies.

VEGF, which induces angiogenesis, is expressed during normal bone formation.

According to Boden, use of PDGF has demonstrated it attracts progenitor cells. “It may be helpful in diabetic fracture healing where it is an impaired biologic model,” or in soft tissue healing, and may work by replacing factors naturally absent, he said. “Its benefit in spine has been difficult to substantiate in clinical trials,” he added.

Like PDGF, peptide signaling molecules stimulate osteoblast or osteoprogenitor cell activity and may enhance osteogenesis, however independently they cannot induce bone formation from undifferentiated cells.

The action of prostaglandin agonists of PGE₂ is being increasingly researched, Boden said. When administered locally or systemically some agonists have produced increased amounts of bone in canine defects or helped accelerate healing in rodent spine fusions, but they are not truly osteoinductive in the classic sense of producing ectopic bone.

For more information:

• Scott D. Boden, MD, is director of Emory University Spine Center. He can be reached at 59 Executive Park South, Suite 3000, Atlanta, GA 30329; 404-778-7143; e-mail: scott.boden@emoryhealthcare.org. He is a consultant to Medtronic, receives royalties from Medtronic and Osteotech, and his center receives various funding from Medtronic, Synthes, National Institutes of Health, Linvatec, Johnson & Johnson, DePuy, a Johnson & Johnson company, and Wright Medical Technology.

Reference:

• Boden SD. Growth factor-based technologies. Presented during AAOS/ORS1 Symposium: Biologic strategies to grow bone in difficult clinical situations. Presented at the American Academy of Orthopaedic Surgeons 75th Annual Meeting. March 5-9, 2008. San Francisco.

4. From thebonejournal.com , BONE, Official Journal Of The International Bone And Mineral Society, Bone, Volume 19, Issue 1, Supplement 1 , Pages S1-S12, July 1996, Link HERE

Growth factors for bone growth and repair: IGF, TGFβ and BMP

• Thomas A. Linkhart
• Subburaman Mohan
• David J. Baylink

Abstract 

Current research is reviewed regarding the actions of three growth factor systems on bone formation: insulin-like growth factors (IGFs), transforming growth factor-βs (TGFβs), and bone morphogenetic proteins (BMPs). Each growth factor family consists of multiple related growth factor genes. TGFβs and BMPs 2–7 are subfamilies of a larger TGFβ superfamily. IGFs, TGFβs and BMPs are produced by osteoblasts and other bone cells and affect osteoblast proliferation and differentiation. They are also incorporated into mineralized bone matrix and retain activity when extracted from bone. Various hormones, growth factors, and mechanical stress influence bone cell production of IGFs, TGF βs, and BMPs. Thus these growth factors may function in local regulation of bone formation. Currently there is much interest in the function of IGF binding proteins, which are also produced by bone cells, in regulating IGF activities in bone. Recently, mechanisms for activation of the TGFβ serine/threonine kinase receptors have been investigated, and receptors for BMPs have been identified which are structurally related to TGFβ receptors. In vivo studies are discussed which demonstrate the applicability of IGFs, TGFβs and BMPs to increasing bone formation systemically, promoting fracture healing and inducing bone growth around implants.

Conclusion: This is one of those article posts I write that actually shows a slight breakthrough in figuring out what direction height increase research should be moving forward towards. If we were to study the biochemistry of the human body and what types of hormones, signals, or proteins causes the bones to not just grow in terms of density, but also by volume, thus creating longitudinal growth, which bone growth factors should we be focusing on? 

From the 4 articles above, it is very clear which groups we should be focusing on.

1. Bone morphogenetic proteins (BMPs) – these are the best options we have right now to look into. I quote below…

“BMPs really are the only known osteoinductive factors,” Boden said. They are the most potent growth factors studied and have accrued the greatest evidence of efficacy. But only some BMPs form ectopic bone.

The most osteoinductive factors are BMP-2, -6 and -9. The intermediate ones are BMP-4 and -7 which have more limited inductivity properties with mesenchymal stem cells, Boden explained. The BMPs that are FDA approved for very specific indications are recombinant human BMP-2 (INFUSE Bone Graft; Medtronic) and BMP-7 (OP-1 Implant; Stryker Biotech)”

2. insulin-like growth factors –

3.  transforming growth factor-βs (TGFβs) –

4. fibroblast growth factor (FGF)

5. platelet-derived growth factor

6. VEGF, which induces angiogenesis, is expressed during normal bone formation.

7. PDGF has demonstrated it attracts progenitor cells

8. peptide signaling molecules – independently they cannot induce bone formation from undifferentiated cells.

What is clear is that one main very clear route has just been shown and it is the path of the bone morphogenetic proteins (BMPs). There must be far more research on this group of signals.