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Improving the Management of Patients with Osteoporosis Undergoing Spinal Fusion: The Need for a Bone Mineral Density-Matched Interbody Cage

Abstract With an increasingly aging population globally, a confluence has emerged between the rising prevalence of degenerative spinal disease and osteoporosis. Fusion of the anterior spinal column remains the mainstay surgical intervention for many spinal degenerative disorders. However, decreased vertebral bone mineral density (BMD), quantitatively measured by dual x-ray absorptiometry (DXA), complicates treatment with surgical interbody fusion as weak underlying bone stock increases the risk of post-operative implant-related adverse events, including cage subsidence. There is a necessity for developing cages with advanced structural designs that incorporate bioengineering and architectural principles to tailor the interbody fusion device directly to the patient’s BMD status. Specifically, lattice-designed cages that mimic the web-like structure of native cancellous bone have demonstrated excellent resistance to post-operative subsidence. This article provides an introductory profile of a spinal interbody implant designed intentionally to simulate the lattice structure of human cancellous bone, with a similar modulus of elasticity, and specialized to match a patient’s bone status across the BMD continuum. The implant incorporates an open pore design where the degree of pore compactness directly corresponds to the patient’s DXA-defined BMD status, including patients with osteoporosis.


Introduction
Orthograde human posture, with the adaptation of a curved and flexible spine, places high axial compressive loads across the spinal joint complex resulting in nearly universal evidence of arthritic deterioration among older adults. 1-5 When age-related spondylosis leads to neural compression and chronic pain, instrumented fusion of the anterior spinal column remains one of the preferred surgical interventions. [6][7][8][9] Following discectomy, an interbody fusion device or cage is typically employed to re-establish intervertebral disc space, providing immediate stability and neural decompression with symptom relief. 8 The cage also serves as a carrier for bone graft, stimulating osseointegration to facilitate endplate-to-endplate arthrodesis. 10 Set against the backdrop of an increasingly aging population, this paper elucidates the confluence between the rising prevalence of both degenerative disc disease and osteoporosis. Specifically, we highlight the necessity of developing cages with advanced structural designs that incorporate bioengineering and architectural principles to tailor the interbody fusion device directly to the patient's bone mineral density (BMD) status as commonly diagnosed by dual x-ray absorptiometry (DXA, or colloquially "DEXA").

The Aging of the Population
The "greying" of the US population is a well-established demographic phenomenon that has generated significant interest in developing medical programs and health care policy initiatives specifically targeted to advance knowledge of and plan investments for the elderly. At the root of this phenomenon are the combined effects of plunging birth rates and increased longevity. 11 In fact, in the US, the expansion of the older population will continue unabated for many decades to come, primarily fueled by the aging of the baby boom cohort. With the 65 and over age cohort projected to encompass 95 million or 23% of the population by 2060, North America remains the second oldest region globally.
With the exception of the African continent where high fertility rates persist, the demographics of the remainder of the world mirror the rapid expansion of the older population experienced in the US. 12 Worldwide in 2015, approximately 9% of the population was ≥ 65 years old. This global estimate is projected to swell to 12% by 2030, with almost 1 in 6 individuals (17%) being 65 years or older by 2050.

Epidemiology of Degenerative Disc Disease and Surgical Treatment with Interbody Fusion
Degeneration of the intervertebral disc represents the initial pathoanatomical stage of degenerative spinal changes, 13 which gradually progresses to involve deterioration of associated osteo-ligamentous structures, such as the facet joints, and stenosis of the central and foraminal canals. 14 Starting as early as the fourth decade of life, degeneration of the intervertebral disc occurs commonly. Undertaking a systematic review of 20 studies, Battie et al 15 were the first to estimate the prevalence of disc degeneration based on magnetic resonance imaging (MRI) evaluations of asymptomatic individuals. Prevalence rates for disc abnormalities at any vertebral level ranged from 3% to 56% for disc narrowing, 6% to 56% for disc tears, 10% to 81% for disc bulges, 3% to 63% for disc protrusions, and 20% to 83% for MRI signal intensity reduction. 16 Using MRI that encompassed the entire spinal column, Teraguchi et al 17 reported the occurrence of disc degeneration in 71% of men and 77% of women ≤ age 50 years, and > 90% in both men and women > age 50 years. Employing longitudinal computed tomography (CT) imaging data from 1196 participants in the Framingham study, Jarraya et al 18 found that more than one-third of women (ages 40-59) demonstrated moderate-to-severe disc height narrowing, and this prevalence increased 2-to 4-fold with increasing age. Lastly, Ravindra et al 19 calculated the global incidence of patients with degenerative disc disease coupled with clinical low back pain using the Global Burden of Disease Database (Institute for Health Metrics and Evaluation). Almost 4% of individuals worldwide, or 266 million individuals, are estimated to have clinically significant symptoms of low back pain resulting from disc disease annually.
Interbody spinal fusion represents a common surgical treatment for patients with chronically-severe back pain, impaired function and reduced quality of life. The Agency for Healthcare Research and Quality (AHRQ) estimated that approximately 488,000 spinal fusion procedures were performed in 2011, accounting for over 3% of all operating room procedures. 20 More recently, a 2020 estimate (iData Research) determined that approximately 1.62 million instrumented spinal fusion procedures were performed annually including 352,000 interbody procedures involving cages.
To address this enormous patient population, dozens of commercial entities worldwide have developed interbody cage devices of various sizes, styles, shapes, and materials including titanium, polyether ether ketone (PEEK), ceramic, carbon fiber as well as cortical allograft dowels and spacers. 21 Commercially-available devices include both static and lowprofile expandable cages. Following surgical disc removal, intervertebral cages are inserted from an anterior approach in the cervical spine, and anterior, posterior, oblique, and lateral approaches in the lumbar spine. The common purpose of all cages is to provide intervertebral distraction and neural decompression until solid fusion occurs. Supplementary fixation with pedicle screws and posterior instrumentation is often required to provide a stable construct for fusion to take place.

Prevalence of Osteoporosis
Osteoporosis is the most common bone disorder, affecting over 200 million people globally and representing a public health epidemic. 22 As an age-related medical condition, low BMD, commonly referred to as osteopenia, and https://doi.org/10.2147/ORR.S339222

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Orthopedic Research and Reviews 2021:13 282 osteoporosis, the most severe manifestation of low BMD, are being more frequently diagnosed by non-invasive imaging technologies such as DXA among the ever-expanding elderly population. While significantly increasing the risk of vertebral compression fractures, this condition occurs pari passu with the development of arthritic degenerative changes described previously. The confluence of these syndromes creates a more challenging and complex interventional strategy for the spine surgeon contemplating interbody fusion. 23 A patient with osteoporosis is characterized as having a BMD T-score of ≤ −2.5 standard deviations below the comparative reference value for a young gender-matched population at peak bone mass. 24,25 Osteopenia is the range of bone loss between normal BMD and osteoporosis (ie, T-score; < −1.0 -> −2.5). Measurement of BMD is accomplished most commonly using DXA and, less frequently, with quantitative computed tomography (qCT). 24 It has been estimated that approximately 45-50% of US adults have low BMD with 10-15% suffering from definitive osteoporosis as per current definitional standards. [26][27][28] Based on 2010 worldwide statistics, almost 160 million individuals had increased fracture risk due to low BMD and this prevalence is expected to balloon to 300 million at risk individuals by 2040. 29

Interbody Fusion in the Presence of Osteoporosis
Underlying low BMD has been associated with serious postoperative, device-related adverse events such as implant subsidence, [30][31][32][33][34][35][36] pedicle screw loosening, 37,38 subsequent adjacent-level fractures, 39,40 and the need for revision surgery. 41 Clinically-significant implant subsidence occurs in about 10% of cases, 42 precipitating spinal instability and recurrence of neuro-compressive symptoms, 34,35 particularly among older individuals with spinal osteoporosis. 43,44 Historically, a diagnosis of definitive osteoporosis has often been considered a contraindication to spinal fusion due to weak vertebral bone stock. 45,46 It is therefore impossible to exclude all at-risk patients from spinal surgery. Estimates of the proportion of patients undergoing spinal fusion procedures with undiagnosed osteoporosis have ranged from 17% to 31%. 47,48 These figures underscore the need to develop specialized techniques, procedures and implants to address this growing patient population so they may experience symptom relief and clinical benefit from surgery.

Evolution of Bioactive Interbody Fusion Devices
Spinal interbody devices have traditionally been used in a supportive role for static anatomical correction by reestablishing disc space height to provide indirect decompression, and restoring sagittal alignment by inducing lordosis. 6,49-51 Newer model devices have also introduced bone windows to act as carriers of osteopromotive bone graft. 52 Despite hundreds of cage types being cleared for commercial use in the US, 53 only recently has there emerged an appreciation of the possible contribution interbody implants may play in the fusion consolidation process. Figure 1 illustrates the evolution of interbody cage designs and materials.
Bioactive or biokinetic implants are currently being designed that maximize and optimize cage topology and microstructure to reduce the risks, such as subsidence, associated with implantation in a low BMD or osteoporotic environment. [54][55][56][57][58][59] Specifically, lattice-designed cages that mimic the web-like structure of native cancellous bone have demonstrated excellent resistance to postoperative subsidence. 60

Development of a BMD-Specific Interbody Cage Device
This article provides an introductory profile of a spinal interbody implant designed intentionally to simulate the lattice structure of human cancellous bone, with a similar modulus of elasticity, and specialized to match a patient's bone status across the BMD continuum (DEXA TiBone™, Aurora Spine, Carlsbad, Ca USA). Indeed, native vertebral bone trabeculae orient spatially in response to the direction of axial compressive forces, 63 forming a web-like structure of cancellous bone with exceptionally high load-bearing capacity. 64 The implant has an open, porous structure that supports osseointegration and vascularization (Figure 2).
The implant is optimized for size to allow maximal contact with the apophyseal ring, and also incorporates a textured surface modification. There is a large body of evidence to demonstrate that introducing a roughened surface topography elicits a bone stimulatory effect with increased bony ongrowth. [65][66][67][68][69][70] New bone matrix interdigitates within the crevices and asperities on the roughened surface to form a secure bond at the bone-implant interface. 69 By modulating the density and compactness of the pore structure, this device can be configured to match a patient's BMD T-score, with cages available to support patients across the BMD spectrum, including those with osteoporosis ( Figure 3). Three designs are available reflecting low, mid and high-density BMD T-scores as classified by DXA.
This spinal interbody device has undergone a series of bench-top biomechanical testing procedures in accordance with standardized methods and protocols (ASTM F2077, Test Methods for Intervertebral Body Fusion Devices). Testing included measurements of static axial compression, static torsion/torque, static compression-shear, dynamic compression, and dynamic torsion/torque in six implants. In addition to the DEXA TiBone™ implant, all tests were conducted with six predicate spinal interbody implants composed of polyetheretherketone (PEEK) (DISCOVERY™, Aurora Spine, Carlsbad, CA USA). Mean values between groups were compared using the two-sample t-test (2-tailed).

Conclusions
Current projections indicate a continued upward trajectory in the prevalence of patients afflicted with spinal degenerative disorders with concomitant osteoporosis that require interbody fusion procedures. Traditionally, cage devices for spinal fusion procedures have been "one size fits all" without any architectural or topological modifications to account for variations in the underlying vertebral BMD, including osteoporotic bone. Spinal fusion patients present with a range of vertebral BMD, but most commercially-available implants have a significantly higher density and are more rigid than the supporting bony structures. We introduce a new spinal interbody fusion device with a unique biomechanical profile that is bone densityspecific and may be used in patients with osteoporotic

Data Sharing Statement
Requests for data sharing can be made by contacting the corresponding author. Individual participant data that underlie the results reported in this article will be made available (after deidentification) from 9 to 36 months after article publication. Data sharing will be limited to investigators whose proposed use of the data has been approved by an independent review committee identified for this purpose.

Acknowledgments
Financial support for this work was provided by Aurora Spine (Carlsbad, Ca, USA).

Author Contributions
All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure
SMF reports personal fees for research, equity, and/or investment from Aurora, CornerLoc, PainTeq, SPR Therapeutics, Vertiflex, Abbott, Medtronic, Saluda, Vertos, SurgenTec, Mainstay, Relievant, Thermaquil, and SpineThera. He also reports ownership of Celery and Neural Integrative Solutions, outside the submitted work. SFK reports a preliminary patent pending to Spine Corpectomy Cage. TN, LG, and JL are employees of Aurora Spine. LG reports a patent (10,779,954) issued to Aurora Spine, Inc. JEB is an independent advisor to Aurora Spine and was remunerated for assistance in manuscript development. The authors report no other conflicts of interest in this work.

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