The Role for Biologics in the Aging Spine

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58 The Role for Biologics in the Aging Spine

David A. Essig, Christopher P. Miller, Jonathan N. Grauer

KEY POINTS

• Define the current biologic options for treatment of degenerative conditions of the spine.
• Define the role for bone morphogenetic proteins (BMPs) in degenerative conditions of the spine.
• Identify bone graft substitutes and their properties.
• Discuss other potential application of biologics in the aging spine.

Introduction

Currently, there are over 36 million people over the age of 65 years in the United States. This number is projected to increase to 71 million (nearly 20%) by 2030.1 As the population ages there will be a similar increase in age-related diseases, such as degenerative disorders of the spine. The elderly are also living a more active lifestyle than at any other time, and thus the demand for addressing issues in this population will only increase over time. However, treating degenerative conditions of the aging spine poses particularly challenging situations to surgeons. Not only must the spinal surgeon address the spinal pathology, but these patients often have serious comorbidities that may affect the treatment options.2,3 Therefore, patients, families, and physicians will have to weigh the additional risks of operative treatment against the benefits of reducing disabling pain and improving quality of life.

Spinal fusion is commonly considered in this population to address degeneration, deformity, and/or stabilize a decompressed segment. Although instrumentation is frequently used for initial stability, fusion is a biological event in which solid bridging bone forms between adjacent vertebrae.

Currently, iliac crest autologous bone (autograft) remains the gold standard bone graft material for achieving spinal fusion in all ages. It is an excellent choice because it is the only bone graft option that provides all of the components necessary for arthrodesis: osteoconductive matrix, osteoinductive proteins, and osteogenic cells. However, there are significant problems with using autograft including the limited supply of available bone and subjecting the patient to a secondary invasive procedure to harvest the autologous bone which is, in itself, associated with potential morbidity, such as infection, fracture, and intractable pain.4,5 This consideration is particularly relevant for the elderly population who, because of their medical comorbidities, often have longer recovery times and more complications following surgeries of any kind. As a result, there has been significant work to develop materials to supplement or even replace iliac crest bone graft in the hope of minimizing surgical morbidities while ensuring that the treatment objectives are still achieved.

There have been few studies examining the use of biologics specifically in older patients. What has been done has focused primarily on complications as opposed to health outcomes and fusion success. Despite the limited information, older patients would intuitively seem to be an ideal target population for bone graft alternatives because of their poorer quality iliac crest bone and their higher risk for graft-associated complications. Although the roles of such biologics are still being defined, they provide an exciting adjunct or alternative treatment for spinal conditions in the aging patient population. This chapter will discuss some of these biologics designed to stimulate a successful spinal arthrodesis and their use in the elderly population.

Bone Morphogenetic Proteins

Bone morphogenetic proteins (BMPs), members of the transforming growth factor-beta superfamily, have gradually become better understood since their initial identification by Marshall Urist6 in the 1960s.7 They function by binding to the cell membrane of undifferentiated mesenchymal type of cells to promote the induction of bone formation. Although more than 12 BMPs have been identified, only a few have been explored for potential clinical use.

Two BMP molecules have been approved for use in humans. Recombinant human bone morphogenetic protein-2 (rhBMP-2) is currently approved, in conjunction with a collagen sponge and threaded intervertebral cage, for the treatment of degenerative lumbar spine disease. Recombinant human bone morphogenetic protein-7 (rhBMP-7), also referred to as osteogenic protein-1 (OP-1), currently has a humanitarian device exemption (HDE) status for posterolateral lumbar fusions in challenging fusion environments.

In a prospective, randomized trial comparing anterior lumbar interbody fusion with either rhBMP-2 implanted on a collagen sponge in a tapered fusion cage or autogenous iliac crest bone graft, there was a 94.5% fusion rate in the BMP group versus an 88.7% fusion rate in the control group, as determined radiographically.8 Moreover, 5.9% of the subjects in the autograft control group experienced adverse events related to their bone grafting procedures, and 32% reported persistent pain at the donor site at the time of final follow-up. Back, leg, and neurologic pain scores improved in both groups to a similar extent. Nonetheless, this procedure is less commonly considered than posterior procedures in the aged population because of the increase in complication rate and recovery time associated with anterior approaches.

Posterior lumbar fusion with BMP has significant challenges including limited surface area for healing, distractive forces, and the large gap between transverse processes needing to be bridged. Furthermore, studies have demonstrated the need for a bulking agent in posterior procedures. One recent retrospective study comparing instrumented posterolateral fusion with rhBMP-2 versus iliac crest autograft demonstrated equivalent fusion masses between the two groups at 2-year follow-up.9 Nonunion rate was 6.6% in the BMP group compared to 11.1% in the control group. No significant differences in the bulking agent used (local bone, allograft bone, demineralized bone matrix, and ceramic) were noted. Demonstrated outcomes when rhBMP-7 (OP-1) is used are comparable to those of autograft when used in uninstrumented posterolateral fusion for the treatment of degenerative spondylolisthesis.10

Recently Glassman and colleagues11 reported on the utility of rhBMP-2 with an absorbable collagen sponge (ACS) compared to autograft in an elderly population (older than 60 years of age). They assessed the clinical, radiographic, and economic outcomes at 2-year follow-up for 102 patients treated by posterolateral lumbar fusion with iliac crest autograft versus rhBMP-2/ACS. They found no increased rates of complications due to the rhBMP-2 (8 of the 50 patients) in this population. In fact, there were increased perioperative complications in the autograft group (23 of the 52 patients). These complications included donor site infections, cardiac issues, pain, urinary tract infections, and neurologic deficit. Additionally, they found that the rhBMP-2 group had significantly better fusion grades on radiographic imaging and equivalent improvements in health-related quality of life outcomes for both groups.

Though BMPs provide substantial benefits in spinal arthrodesis, their use is not always without complication.12 Potential complications include the formation of ectopic bone, hematoma and seroma formation, bone resorption and graft subsidence, antibody formation, and possible carcinogenicity. While some of the effects may be dose or carrier related, many of the applications currently considered for their use are off-label and their use has to be considered carefully. Further, the cost-to-benefit considerations remain to be elucidated.

Other Bone Graft Alternatives

Many other potential bone graft materials have also been considered for use alone or in combination with local bone to limit morbidity associated with iliac crest autograft. Some of these alternatives include allograft, demineralized bone matrix (DBM), and synthetic materials such as ceramics. While none of these bone graft alternatives possess all three factors necessary to promote osteogenesis, their utility in specific clinical situations is being studied. No matter what substance is chosen, the local and systemic environment must be hospitable to the formation of new bone, and there must be adequate blood supply, mechanical stability, and a lack of growth-inhibiting factors (e.g., nicotine, infection).

Allograft

Allograft bone provides an osteoconductive scaffold for new bone formation. Various allograft bone types are available. Successful use of allograft bone in spinal surgery is largely dependent on its placement. When structural allograft is implanted in the anterior column, it is associated with relatively high fusion rates, both in the cervical and the thoracolumbar regions of the spine.13,14 However, when nonstructural allograft bone is placed under tension, as in the posterior spine, it incorporates at a slower rate than autograft and leads to lower rates of arthrodesis when used alone.15,16

A recent study by Anderson and associates17 evaluated the use of morcelized femoral head allograft with and without instrumentation in the elderly. The study did not harvest autograft from any of the patients. The demonstrated successful fusion, determined by radiographs, is 68% with allograft alone and 81% with allograft plus instrumentation. Additionally, there were 15 of the 94 patients treated who required revision surgeries, a revision rate that is similar to what is seen when using autograft alone. This study demonstrated superior outcomes with allograft plus instrumentation for posterolateral fusion surgeries. However, more importantly for this review, it is one of the few studies to specifically evaluate allograft in an elderly population.

Demineralized Bone Matrix

Demineralized bone matrix is allograft bone that has been decalcified to produce a product of collagen and noncollagenous proteins. Multiple products are available, but there are relatively limited data available regarding their efficacy, as limited regulatory requirements have been established for these minimally manipulated tissue products. Further, studies have questioned the osteoinductive nature of one product versus another, as well as lot-to-lot variability.18,19

There are few randomized controlled clinical trials evaluating the use of DBMs in humans. In one series, 77 patients underwent one, two, or three level noninstrumented anterior cervical discectomy and fusion procedures, using freeze-dried structural allografts filled with a DBM or autogenous iliac crest bone graft alone.20 At a minimum of 1-year follow-up, fusion rates were 54% and 74% for the allograft/DBM and autograft groups, respectively. Despite this relatively easy fusion environment, inferior fusion rates were observed in the experimental study arm.

In contrast, another study, involving 50 subjects who received lumbar interbody fusions, reported a 96% success rate after implanting titanium mesh cages packed with a DBM and a coralline hydroxyapatite carrier.21 The authors performed circumferential fusions with posterior instrumentation and autograft but they did not have a control group to compare against. However, they only used the DBM anteriorly. Again, this study only used the DMB in the anterior spinal column where fusion is generally more easily achieved. This is an excellent example of how DBM could be used as a bone graft extender by eliminating the need for iliac crest bone graft (ICBG) in the anterior fusion construct.

Unfortunately, there are no studies specifically evaluating the use of DBM in the elderly. However, given the highly variable composition and ability to induce fusion between different DBM products, it is doubtful that a definitive study could be adequately performed in an elderly population that could be generalized across multiple DBM products or even across different production lots of the same product.

Synthetic Materials (Ceramics)

Synthetic materials are being considered with increased frequency as bone graft materials. These provide an osteoconductive scaffolding and are generally used as bone graft extenders or supplements to local or iliac crest bone graft. Again, because the regulatory pathways for approval of such products are not as stringent as for other products, such as the BMPs, the studies are generally less controlled and rigorous, making the efficacy of such products more challenging to interpret.

One of the inherent disadvantages of ceramics is that they are relatively weak and brittle. When ceramics are introduced into the anterior spinal column they must be protected from the significant compressive forces by internal fixation until the graft is incorporated into the new bone growth.13 Like allograft, ceramics are also inferior to autogenous bone when placed under tension.22 Other biologically active materials, such as local autograft, demineralized bone matrices (DBMs), or osteoinductive growth factors, may be combined with ceramic osteoconductive matrices to form a composite graft that can then lead to increased amounts of bone formation.23,24

Bone Marrow Aspirates

Autologous bone marrow represents another source of osteogenic cells and osteoinductive proteins for spinal fusion. The most significant advantage of this technique is that aspiration of bone marrow has much less morbidity than the procurement of iliac crest autograft. However, it must be used in combination with an osteoconductive matrix, bone marrow aspirate to form a composite graft. The major limitation to this technique is that unfractionated bone marrow has only moderate osteogenic potential. Even in healthy adults, it is estimated that only 1 out of every 50,000 nucleated bone marrow cells is capable of undergoing differentiation into an osteoblast.25 Additionally, it has been shown that the number of viable bone marrow cells decreases significantly with age, which may limit utility in an elderly population.26

One recent study demonstrated comparable fusion rates to autograft in an instrumented posterolateral fusion study.27 Both allograft and DBM can be combined with the osteogenic elements of bone marrow aspirate to help promote fusion. By adding bone marrow aspirate, osteogenic elements may be added to help promote fusion. Studies have shown improved fusion rates with the use of bone marrow aspirate from iliac crest when used in conjunction with autologous autograft in a bone paucity model.28 Recently, aspirates from the vertebral bodies accessed during pedicle screw instrumentation have been shown to be an excellent source of osteogenic cells with only modest depletion with serial aspirations.29 However, there was a reduction in the cellularity of the specimens in older individuals.

Other Potential Application of Biologics in the Aging Spine

Vertebral Body Augmentation in Vertebral Body Compression Fractures

Unique to elderly patients, vertebral compression fractures are the most common type of osteoporotic fragility fracture that can occur from low energy trauma, such as a fall from standing height or less. Although many are asymptomatic, the possible consequences of such injuries can be serious, resulting in limited ambulation, chronic pain, depression, and loss of independence. The primary goals for treatment include pain control and treatment, surgical or nonsurgical, aimed at returning the patient to full activity as quickly as possible to avoid long-term sequelae of deconditioning and muscle weakness.

Surgical options for vertebral body compression fractures include vertebroplasty and kyphoplasty to inject bone cement into the collapsed vertebrae with or without the use of an inflatable balloon to elevate the endplates prior to injecting the cement. Both procedures provide short-term improvement in pain and correction of the deformity, and long-term benefits for functional capacity and prevention of recurrent pain.30

A recent meta-analysis30 comparing kyphoplasty and vertebroplasty found that both treatments resulted in significant improvements in pain and functionality compared to baseline. Compared to medical treatment there was improvement in function, but not pain. Comparing the two surgical treatments, this meta-analysis concluded that balloon kyphoplasty provided better correction of the kyphotic angle and vertebral height while also having less complications from cement extravasation and pulmonary embolism. This study concluded that balloon kyphoplasty is likely superior to traditional vertebroplasty for compression fractures refractory to conventional medical therapy; however they based their assessments on level III data because no randomized control trials were available to appropriately evaluate these treatments.30

Newer alternatives to the traditional polymethylmethacrylate (PMMA) bone cement used for these procedures are also being evaluated. The current cement material has a number of shortcomings including a strong exothermic polymerization reaction, which could damage surrounding tissues, lack of bioavailability and osteoconductivity, toxicity of the cement, and extremely limited resorption over time.31,32 Thus newer cements are being developed to address some of these issues. A recent study evaluating the use of two novel variants (aluminum-free and zinc-based glass polyalkenoate cement) in an in vitro model of osteoporotic compression fractures found them to have similar material properties (injectability, radiopacity, uniaxial compression strength, and biaxial flexural modulus) to traditional cement and performed well over serial compression tests in the lab.33

Clinical trials for some of these new cement alternatives have begun with differing results. One study of calcium phosphate cement in balloon kyphoplasty demonstrated improvement in pain and disability outcomes, but poor resistance to flexural, tractive, and shear forces, which resulted in radiographic loss of correction.34 The authors ultimately recommended against the routine use of this cement alternative to traditional PMMA.

The hope for future advances in cement technology is to develop materials that will accomplish the pain relief and structural correction in the short term while allowing gradual bony healing and replacement of the cement with new bone in the long run. Future research must be done for developing both the basic material science and clinical efficacy before cement alternatives are widely accepted.

Nonfusion Applications: Addressing Disc Degeneration Directly

Much of low back pain in the aging spine is believed to be a result of disc pathology. Various studies have attempted to identify changes in disc anatomy that may play a role in the generation of back discomfort. Recent studies have demonstrated that there is an overall decrease in cellular density within the disc as well as a reduction in the production of cartilage-specific extracellular matrix components.35 As a result, there is an overall loss of water-binding capacity and thus an alteration in the biomechanics of the disc. Despite the paucity of cells within the disc, it plays an integral role in the maintenance of matrix proteins. The reduction in cells during aging is believed to be attributable to both apoptotic and necrotic processes. A focus of recent scientific work has been to induce or augment these cells.36 Cellular transplantation offers potential promise in the treatment of degenerative disc disease; other therapies that have been proposed are the injection of biomaterials into the disc to augment the nucleus pulposus.

However, as noted previously, these technologies are very early in their development from a clinical standpoint. Most of these technologies are only being evaluated for use early in the degenerative cascade. By the time that degeneration is more advanced, such as in the elderly population being considered here, this technology may not be applicable.

Conclusion

Performing spinal surgeries in the elderly presents significant challenges to the surgeon with regard to advanced pathology and preexisting illness, which may complicate the treatment options. Iliac crest autograft has long been the gold standard treatment option for patients of all age groups because it is the only graft option that contains osteogenic cells, osteoinductive growth factors, and an osteoconductive matrix. Unfortunately, harvesting autograft also forces the patient to undergo an additional invasive procedure, which can result in significant postoperative morbidity, particularly in the elderly. The evolution of bone graft alternatives and supplements provides exciting, less morbid alternatives to the use of iliac crest autograft for spinal fusion that may be considered for use alone or in combination with local bone graft material.

The use of biologics in the elderly offers the potential to reduce complications associated with harvesting ICBG while maintaining successful fusion. A number of different types of biologics are currently available, including various recombinant growth factor signaling proteins (rhBMPs), demineralized bone matrix, and synthetic ceramics. The future of these technologies likely lies in composite grafts that use these and other biologic materials in combination to attempt to recreate and stimulate the native bone formation system. There are similar advances being made in nonfusion alternatives to surgery, such as in the treatment of vertebral compression fractures in the elderly, an increasingly common condition as the population ages and osteoporotic, fragility fractures become more prevalent. New cements used for these treatments are being developed as alternative to PMMA bone cement and will likely play an increasingly important role in the future treatment of vertebral compression fractures. Additionally, there may be a role for biologics to assist in the restoration of disc health. This may be accomplished through possible chondrocyte transplantation or through the use of BMP. This may offer the possibility of avoiding the cascade of degenerative spine disease.

As these graft alternatives continue to advance, it will be important to carefully evaluate their use in the elderly, who are the most likely to require surgery for degenerative, age-related conditions of the spine. However, regardless of how these new technologies are employed, the success of these complex surgeries will remain dependent upon the basic principles essential to achieving a solid arthodesis: proper patient selection, optimization of the biological environment and selection of the best bone graft material, preparation of the fusion bed, and maintenance of adequate biomechanical stability during bone formation.

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