Vertebroplasty☆

7.12 Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty☆ JJ Verlaan, University Medical Center Utrecht, Utrecht, The Netherlands MA Lopez-Heredia, University Medical Center Nijmegen, Nijmegen, The Netherlands J Alblas and FC Oner, University Medical Center Utrecht, Utrecht, The Netherlands JA Jansen, University Medical Center Nijmegen, Nijmegen, The Netherlands WJA Dhert, University Medical Center Utrecht, Utrecht, The Netherlands r 2017 Elsevier Ltd. All rights reserved.

7.12.1 7.12.2 7.12.2.1 7.12.2.2 7.12.3 7.12.3.1 7.12.3.2 7.12.3.3 7.12.3.4 7.12.4 7.12.4.1 7.12.4.2 7.12.4.3 7.12.5 7.12.6 References

Introduction History of Spinal Column Augmentation With Injectable Bone Cements and Currently Accepted Indications History Currently Accepted Indications Overview of Frequently Used Injectable Bone Cements for Spinal Augmentation Acrylate Cements Calcium Phosphate Cements Composite Cements (Hybrid Acrylic/Calcium Phosphate Cements) Miscellaneous Cements Clinical Results of Spinal Column Augmentation With Injectable Bone Cements Osteoporotic Vertebral Compression Fractures Metastatic/Malignant Vertebral Body Lesions Traumatic Fractures Complications in Spinal Column Augmentation Future Directions and Conclusions

Abbreviations CaP Calcium phosphate Cas Calcium sulfate CPC Calcium phosphate cement DmpT N,N-dimethyl-p-toluidine KP Kyphoplasty

Glossary Balloon kyphoplasty Minimal invasive technique using bone tamp(s) to inflate a balloon(s) in the vertebral body prior to injection of cement.

7.12.1

199 200 200 201 202 202 203 205 206 207 207 208 208 209 211 212

PMMA Polymethyl methacrylate SF-36 PCS Short form 36 physical component summary VAS Visual analog scale VP Vertebroplasty Zn GPC Zinc-based glass polyalkenoate cement

Vertebroplasty Minimal invasive technique using large bore needles to inject cement in a vertebral body.

Introduction

In contemporary surgical practice, injectable bone cements are increasingly being used to treat a variety of pathological conditions of the spine including osteoporotic vertebral compression fractures, metastatic vertebral body lesions and traumatic fractures. The principal goal of applying these injectable bone cements is to augment impaired bony structures in order to maintain or improve strength and stability of the spinal column. The first type of cement used in the spine, polymethyl methacrylate (PMMA), was originally developed for completely different purposes in humans and used, for example, as the material for dental implants, ☆ Change History: November 2016. J.J. Verlaan, J. Alblas, F.C. Oner, W.J.A. Dhert, M.A. Lopez-Heredia, and J.A. Jansen have updated the text and added new references.

This is an update of J.J. Verlaan, M.A. Lopez-Heredia, J. Alblas, F.C. Oner, J.A. Jansen and W.J.A. Dhert, 6.611 – Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty. In Comprehensive Biomaterials, edited by Paul Ducheyne, Elsevier, Oxford, 2011, pp. 147–160.

Comprehensive Biomaterials II, Volume 7

doi:10.1016/B978-0-12-803581-8.10230-9

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ocular prosthetics and later for implant fixation in artificial joints prosthetics. Currently, new injectable bone cements are designed specifically for application in the vertebral body. The clinical results obtained in the last decades by using PMMA bone cement in vertebroplasty and balloon kyphoplasty procedures have clearly established a demand for biomaterials better adapted to their function as vertebral body bone void filler. Many biomaterial research centers now focus on incorporating into new bone cements the features notably absent in PMMA, such as the properties for osseointegration, capability of remodeling and mechanical characteristics better approximating that of cancellous bone. This chapter aims to provide the reader with a brief introduction on the history of injectable bone cements for spinal column augmentation and will discuss its currently accepted indications. Furthermore, an overview of frequently used injectable bone cements and their respective technical characteristics will be described in detail followed by a summary of the clinical results obtained by this procedure. The clinical implications of cement leakage will be discussed together with guidelines for bone cement handling to prevent this complication. A quick glance at possible future directions in the field of injectable bone cements for spinal column augmentation will conclude this chapter.

7.12.2 7.12.2.1

History of Spinal Column Augmentation With Injectable Bone Cements and Currently Accepted Indications History

The first published case of vertebroplasty, a technique referring to the injection of bone cement into a vertebral body, dates back to 1987 when Frenchmen Galibert and Deramond treated a painful hemangioma, refractory to conservative medical treatment, by filling the intravertebral lesion with an injectable bone cement (PMMA) resulting in immediate and long lasting relief of symptoms (Galibert et al., 1987). This paper is regarded as the index work on injectable bone cements for spinal column augmentation. However, the material used in this case had already been developed in 1928 and the process of polymerizing methyl-methacrylate was invented as early as 1877 by Fittig and Paul. PMMA became commercially available in the year 1936 and is widely known to the public as an alternative to glass under the name plexiglas or perspex. The first clinical application of this material was in odontology where it was used to build dental implants. Following the observation by ophthalmologist Ridley during the second World War that splinters of perspex from shattered aircraft cockpit canopies did not trigger an inflammation reaction in the eyes of wounded pilots, he made the material suitable for implantation in the form of artificial lenses, an operation he first conducted in 1949. Sir Charnley was among the first pioneers to use PMMA in orthopedic surgery to establish a bond between bone and implants in hip replacement surgery; a highly successful practice still in use today (Boss et al., 1993). Although the landmark paper by Galibert and Deramond, currently cited over 1500 times, was followed by several other publications in French journals on this subject, vertebroplasty as a new treatment for painful osteoporotic vertebral body fractures, did not gain momentum until the late 1990s when the first article in English was published by Jensen et al. (1997). Jacques Dion, a French Canadian and senior author of the article, became the pivotal link importing the French knowledge into North American medical practice. The year 1999 saw a large number of papers published on various topics related to vertebroplasty including the expansion of indications to metastatic lesions; the first prospective trials; the first descriptions of serious complications including infection, pulmonary embolism and neurological deficits after extravasation of cement (Cortet et al., 1999; Martin et al., 1999; Padovani et al., 1999; Perrin et al., 1999). Around this time the first critical notes on the (lack of) scientific evidence of the efficacy of injecting polymethyl methacrylate in the spinal column were also expressed (Jarvik and Deyo, 2000). Trout and Kallmes raised the question whether vertebroplasty caused incident vertebral fractures but failed to reach strong conclusions due to insufficient quality of data available from the literature (Trout and Kallmes, 2006). It can be estimated that over two million procedures have been performed worldwide (Buchbinder et al., 2009; Kallmes et al., 2009; Lee et al., 2009). Meanwhile, in 2001 an alternative to vertebroplasty, balloon kyphoplasty, was described by Lieberman et al. (2001). In this technique, balloons were inserted in the vertebral body and inflated prior to injection of the cement. The potential benefits of this procedure consisted of improved restoration of vertebral body anatomy and a reduction in cement extravasation due to the creation of a cavity lined by higher density bone facilitating lower pressures needed to inject bone cement. Subsequent clinical studies have shown results comparable to vertebroplasty with often lower rates of cement extravasation (Taylor et al., 2006). Virtually all studies described above dealt with the treatment of painful osteoporotic vertebral compression fractures treated by injection of PMMA cement in the affected vertebral level. Notable exceptions published in the same timeframe were the studies by, amongst others, Nakano, Hillmeier, Matsuyama and Grafe in which painful osteoporotic vertebral compression fractures were treated by vertebroplasty or balloon kyphoplasty using calcium phosphate cement instead of PMMA cement (Grafe et al., 2008; Hillmeier et al., 2004; Matsuyama et al., 2004; Nakano et al., 2002). The rationale behind the use of calcium phosphate cement was the assumed superior biocompatibility, potentially leading to a more intimate bone–cement interface and subsequent remodeling of the biomaterial into bone by creeping substitution (Verlaan et al., 2004b). In an attempt to combine the favorable characteristics of both PMMA (immediate stability) and calcium phosphate cement (superior osteointegration), some manufacturers have designed hybrid cements containing both materials (Dalby et al., 2001). To our best knowledge no clinical data on the performance of these hybrid cements is available from the literature and the application of these biomaterials must currently be regarded to be mostly in the experimental phase (Heini and Berlemann, 2001).

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Augmentation of the spinal column using either PMMA or calcium phosphate cement has, in combination with pedicle screw instrumentation, recently also become an adjunct to the surgical treatment of traumatic burst fractures of the spine. Proponents of this new indication for vertebroplasty/balloon kyphoplasty suggested this technique to be able to (partially) restore the anatomy of the intervertebral disk space thereby decreasing the chance for secondary deformity due to disk intrusion into the fractured vertebral body (Verlaan et al., 2002).

7.12.2.2

Currently Accepted Indications

As can be concluded from the considerable media coverage and editorials that rapidly emerged following the publication of the first attempt at randomized controlled trials on vertebroplasty and balloon kyphoplasty in 2009, showing no significant effect over sham procedures, the efficacy of augmenting the spinal column with injectable biomaterials for any of the indications stated above was intensely debated (Aebi, 2009; Kallmes and Jarvik, 2009; Weinstein, 2009). In 2010, an open-label randomized trial of vertebroplasty versus conservative treatment for acute vertebral compression fractures was published showing that vertebroplasty was effective and safe (Klazen et al., 2010). Pain relief after vertebroplasty was immediate, was sustained for at least a year and was greater than that achieved with conservative measures. In 2016 a multi-center, randomized, double-blind, placebo-controlled trial assessing the safety and efficacy of vertebroplasty for acute painful osteoporotic fractures was published showing vertebroplasty to be superior to placebo intervention for pain reduction in patients with acute osteoporotic spinal fractures (Clark et al., 2016). Notwithstanding the conflicting results gained from the studies conducted in the past two decades, augmentation of the spinal column with injectable biomaterials can presently be divided into the following main categories of indications for treatment: 1. painful osteoporotic vertebral compression fractures; 2. painful metastatic/malignant vertebral body lesions; 3. traumatic fractures. Ad 1. (painful osteoporotic vertebral compression fractures): Most of the spinal augmentations with injectable bone cement are being performed due to painful osteoporotic vertebral compression fractures refractory to conservative medical treatment which mainly consists of bed rest and analgesics (Evans et al., 2003). The natural history of this type of fractures is frequently benign with progressive resolution of symptoms 6–12 months after the onset of pain regardless of index treatment. It is the immediate and dramatic reduction of pain, typically within 24 h, giving vertebroplasty or balloon kyphoplasty the edge over nonoperative treatment strategies in the first 3 months of treatment (Voormolen et al., 2007). Currently, the principal hypothesis explaining the beneficial effect of injecting bone cement into osteoporotic vertebral compression fractures holds that cement injected in the vertebral body stabilizes the fracture and the subsequent decrease in residual motion leads to a reduction of perceived pain (Heini et al., 2001). Supporting this hypothesis, it has been demonstrated by many studies that painful vertebral bodies showing edema on magnetic resonance images, indicating unhealed vertebral body fractures, respond better to vertebroplasty or balloon kyphoplasty (Koh et al., 2007). To prevent cement extravasation, the amount of bone cement injected has steadily decreased in the last decade without affecting the high success rates. It can be argued whether ever-decreasing volumes of bone cement injected can still adequately stabilize a vertebral body fracture in which case the “stabilizing hypothesis” may ultimately prove to be incorrect. Alternative hypotheses claim the exothermic and polymerizing effects of curing PMMA to result in thermal and chemical destruction of nociceptors, respectively. These two hypotheses have been refuted by in vivo animal experiments showing little or no tissue necrosis or inflammatory response, after injection of PMMA cement (Aebli et al., 2006; Togawa et al., 2003; Verlaan et al., 2003, 2004b). Furthermore, by using calcium phosphate cement as bone void filler for osteoporotic vertebral compression fractures, Nakano et al. (2002) demonstrated this isothermic, non-polymerizing biomaterial to lead to identical results compared to PMMA cement when injected in the spinal column. Ad 2. (painful metastatic/malignant vertebral body lesions): The first lesion to be treated by vertebroplasty was a painful hemangioma. Many other pathologic lesions including metastatic spinal tumors and multiple myeloma have subsequently been shown to respond favorably to the injection of bone cements provided the pedicles and laminae were not affected and compression of the spinal cord was not present (Chi and Gokaslan, 2008). Spinal pain due to metastatic or hematological disease may be caused by a variety of factors and have been suggested to include (imminent) pathological fractures, chemical mediators, increased pressure within bone, microfractures, overstretched periosteum and compression of neural structures such as the spinal cord and roots (Bouza et al., 2009; Fourney et al., 2003). Similar to the group of osteoporotic vertebral compression fractures, the exact mechanism by which augmentation of the spine with injectable bone cements achieves its beneficial effect in metastatic/ malignant spinal disease has not been elucidated. It is possible that stabilization of the vertebral body after vertebroplasty or balloon kyphoplasty also underlies the relief of pain for this indication (Chi and Gokaslan, 2008). Deducting from the observation that tumor recurrence was rare in vertebral bodies treated with cement injection, some authors have suggested PMMA to have some antitumor properties. These properties could include cytotoxicity, hyperthermia and local induction of ischemia. In a recently published review, Chi and Gokaslan (2008) recommend vertebroplasty or balloon kyphoplasty in properly selected patients with painful pathologic fractures to be performed as early as possible. Furthermore, they speculate that newer more elastic biomaterials than currently used may lower the risk for adjacent level collapse and reduce complication rates. Ad 3. (traumatic fractures): Oner et al. (1999a) suggested that recurrent kyphosis after surgical treatment of traumatic thoracolumbar fractures resulted from improperly reduced endplate fractures. It was shown that intervertebral disks adjacent to the fractured segment could intrude through fractured endplates into the burst vertebral body thereby causing spinal deformity

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(Oner et al., 1999b). Hypothesizing that proper reduction of the endplates and subsequent augmentation of the vertebral body with bone cement could largely prevent this deformity, a technique was developed and subsequently tested to reduce fractured endplates in traumatic thoracolumbar burst fractures by pedicle screw fixation and balloon assisted endplate reduction (Verlaan et al., 2002). After optimal endplate reduction was achieved, the balloons were removed and the intravertebral void was filled with calcium phosphate cement. The choice for this filler material was based on the expected average age of patients with traumatic spine fractures, which is significantly lower (mean age approximately 35–40 years) compared to patients with osteoporotic vertebral compression fractures (Knop et al., 1999).

7.12.3

Overview of Frequently Used Injectable Bone Cements for Spinal Augmentation

The biomaterials used for spinal column augmententation by vertebroplasty or balloon kyphoplasty require several characteristics including injectability, biocompatibility and mechanical stability (Heini and Berlemann, 2001). In selecting the biomaterial, a treating physician considers many parameters: patient condition; patient age; fracture configuration; selection of surgical technique; characteristics of the biomaterial and environment of implantation site. In the next sections, the characteristics of the cements frequently used in, or with potential use for, vertebroplasty and balloon kyphoplasty will be discussed.

7.12.3.1

Acrylate Cements

Virtually all cements commercially available for augmentation of the spinal column are based on PMMA, the synthetic polymer of methyl-methacrylate. The monomer methyl-methacrylate is an organic compound with the formula CH2 ¼ C(CH3)CO2CH3 (Fig. 1(a–b)) which can be produced by several manufacturing routes. In 1877 two German physicists, Fittig and Paul, were the first to invent the polymerization reaction leading to polymethyl methacrylate (PMMA; C5O2H8)n (Fig. 2). PMMA is a transparent material with a density of 1180 g/L and has good resistance against mechanical impact (Heini and Berlemann, 2001). The melting and boiling temperature are 1301C (403 K) and 2001C (473 K) respectively while the material autoignites at 4601C (733 K). The polymerization reaction of methyl-methacrylate to form polymethyl methacrylate is initiated by benzoyl peroxide, while N,N-dimethyl-p-toluidine (DmpT) is used as a radical forming activator. Before the bone cement can be injected in the spinal column, its ingredients, a powder (containing polymethyl powder; benzoyl peroxide and often an opaque material such as barium sulfate to improve radiological visibility) and a liquid (methyl-methacrylate and DmpT) must be mixed. In the ensuing process, benzoyl peroxide and DmpT react to produce benzoyl radicals which are highly reactive and readily bind to the C¼C bond of methyl-methacrylate. The radical-enhanced methyl-methacrylate molecule subsequently starts the polymerization process by reacting with nearby non-radical methyl-methacrylate molecules. The resulting (methyl-methacrylate)n molecule retains its radical characteristics and continuous addition of new methyl methacrylate molecules leads to the formation of increasingly large chains of PMMA. The addition of each methyl-methacrylate molecule to the developing chain is an exothermic process and can lead to temperatures of up to 1001C in the core of the polymerizing cement when the maximum number of reactions per time unit is reached (Jefferiss et al., 1975). As methyl-methacrylate molecules eventually become rare in the increasingly viscous cement and radicals start to

Fig. 1 (a) Molecular structure of methyl-methacrylate. (b) Three-dimensional representation of methyl-methacrylate.

Fig. 2 Molecular structure of polymethyl-methacrylate.

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react with each other, self-extinguishing their reactivity, the chain-forming process decelerates and the chemical reaction peters out. The process from mixing the components to finalization of the polymerization reaction can be described in four functional phases: 1. 2. 3. 4.

mixing phase; initial propagation phase; injection phase; curing phase.

Ad 1. (mixing phase): In this phase the components of the bone cement are combined and mixed into a low viscosity fluid; radicals form to start the polymerization process. Ad 2. (initial propagation phase): During initial propagation, the number and length of (methyl-methacrylate)n chains increase rapidly. The viscosity of the cement, although increasing, is still too low for safe injection. Ad 3. (injection phase): Many polymer chains have now been formed resulting in a substantial increase in cohesion and simultaneously decreased adhesion within the bone cement. To assess whether the bone cement has entered the injection phase, many physicians probe or test the material qualitatively in what is sometimes, frivolously, called the “toothpaste test” or “spaghetti test” as the viscosity of these familiar products accurately resemble the ideal constitution for injection of bone cement into the spinal column. Ad 4. (curing phase): The cement is not injectable anymore and now starts to radiate the heat generated by the exothermic polymerization reaction. Although the cement may appear fully hardened, the polymerization process is not complete for another 24 h. The duration of each phase is highly variable and depends mainly on the temperature of the premixed bone cement components and ambient temperature of the operating theater or radiological suite (Baroud et al., 2004a; Debrunner and Wettstein, 1975; Lewis and Mishra, 2007). This variability in duration of the various phases of the polymerizing cement poses a problem for physicians since it directly affects the time window available for safe injection (Krebs et al., 2005). It has been noted by many authors that a change of only a few degrees in ambient or cement component temperature may lead to substantial deviations in the duration of the injection phase (Hansen and Jensen, 1990). Several in vitro studies have verified these observations and currently devices are being deployed to intraoperatively probe cement viscosity in real-time (Boger et al., 2009). Concerns have been expressed regarding the increased risk for adjacent level fractures after spinal augmentation with PMMA cement in osteoporotic vertebral compression fractures (Baroud et al., 2006). Although no study has proven that the occurrence of adjacent level fractures is directly related to a change of the mechanical and elastic characteristics of the spinal column after augmentation (as opposed to the natural history of an already weakened spine where the presence of one vertebral compression fracture is highly predictive for subsequent fractures) many clinical studies have, nonetheless, reported the phenomenon to occur frequently (Lin et al., 2004). Moreover, in vitro studies assessing the stiffness (Young’s modulus) of human cadaveric vertebral specimens after vertebroplasty or balloon kyphoplasty using PMMA cement have demonstrated significant increases in stiffness after treatment compared to untreated control specimens (Berlemann et al., 2002). The stiffness of PMMA cement has been shown in earlier biomechanical experiments to range somewhere between cortical and cancellous bone (Berlemann et al., 2002). As a consequence, it has been hypothesized that the increase in stiffness resulting from cement augmentation may attribute to failure of adjacent levels. Presently, some institutions are in the process of designing and testing PMMA cements with altered biomechanical properties to better approximate the compliancy of cancellous bone found in osteoporotic vertebral bodies, with the aim of reducing the adjacent level fracture rate (Boger et al., 2008b). Boger and co-authors added N-methyl-pyrrolidone to regular PMMA cement and found a significant decrease in Young’s modulus, yield strength and polymerization temperature while the handling time of the cement (ie, injection phase) was increased by 200% (Boger et al., 2008c). It was suggested that this type of cement was promising, showing compliancy closer to cancellous bone, while simultaneously exhibiting favorable handling and thermal characteristics compared to unmodified PMMA cement. Other methods to reduce the stiffness of PMMA have been investigated and include increasing cement porosity by addition of ingredients such as hydrogels or oligomers (Puska et al., 2003). Alternative acrylic cement compositions, such as dimethacrylate-based cements, have been designed showing favorable biomechanical and biocompatible properties compared to regular PMMA cements (Erbe et al., 2001). Currently, most of these biomaterials continue to be studied in a meticulous way. Recent data suggest that the principles underlying their formulation, may lead to enhanced clinical performance.

7.12.3.2

Calcium Phosphate Cements

When performing spinal column augmentation with injectable bone cements, several material characteristics including injectability and moldability are required. Heini et al. compiled the requirements for materials in vertebroplasty (VP) and kyphoplasty (KP). This was later elaborated upon by Lewis (Heini and Berlemann, 2001; Lewis, 2006). These requirements can be subdivided into those intrinsically belonging to the material and the desired performance of the material and technique involved. Calcium phosphate cements satisfy some of the requirements and this category of biomaterials is being considered useful for application in the spinal column. Calcium phosphate (CaP) materials have already been used for a long time in dentistry and maxillofacial surgery, but only recently in the field of spinal surgery (Bohner, 2001). Calcium phosphate cements are obtained by mixing a solid phase with a liquid phase, producing a paste that can be injected. Depending on the interaction between the solid and liquid phase and the particle distribution of the CaP powder used, there will

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Table 1 Calcium phosphates that may be used in the solid phase of a calcium phosphate cement

Table 2

Name

Formula

Ca/P

Monocalcium phosphate monohydrated Monocalcium phosphate anhydrous Dicalcium phosphate dihydrate Dicalcium phosphate anhydrous Octacalcium phosphate Alpha-tricalcium phosphate Beta b - Tricalcium phosphate Hydroxyapatite Fluoroapatite TTCP – Tetracalcium phosphate

Ca(H2PO4)2  H2O Ca(H2PO4)2 CaHPO4  2H2O CaHPO4 Ca8H2(PO4)6  5H2O Ca3(PO4)2 Ca3(PO4)2 Ca10(PO4)6(OH)2 Ca10(PO4)6F2 Ca4(PO4)2O

0.5 0.5 1.0 1.0 1.33 1.5 1.5 1.67 1.67 2.0

Commercially available cements for spine surgery (Heini and Berlemann, 2001; Lewis, 2006)

Cement type

Product name (Company)

PMMA

Spineplex (Stryker-Howmedica); Corinplast (Corin); Simplex P (Stryker-Howmedica); Palacos LV (Zimmer/Heraeus Kulzer); Palacos R (Zimmer/Heraeus Kulzer); CMW (CMW-DePuy); Codman Cranioplastic (CMW-DePuy); KyphX (Kyphon); HV-R (Kyphon); Osteopal (Heraeus Kulzer); Symphony VR (Advanced Biomaterial Systems); Osteobond (Zimmer) BSM/Biobon (ETEX/Merck/Biomet/Lorenz Surgical); Biopex R (Mitsubishi) BoneSave (Stryker); BoneSource (Orthofix/StrykerHowmedica); ChronOS Inject (Synthes), MCPC (Biomatlante); Calcibon (Merck/Biomet); Eurovbone (F-H Orthopedics); Norian SRS (Norian/Synthes); Mimix (Lorenz Surgical); Cementek (Teknimed); Fracture Grout (Norian); Collagraft (Zimmer); KyphOs (Kyphon) BonePlast (Interpore Cross Int.); MIIG X3 (Wright Medical)

Calcium phosphate

Calcium Sulfate Composites

Cortoss (Orthovita), CAP (Kuraray)

be a variability in moldability and pressure filtering effect, the latter phenomenon referring to the undesired separation of the solid and liquid components when put under pressure, thereby greatly influencing injectability of the material (Habib et al., 2009; Khairoun et al., 1998). For application in vertebroplasty or balloon kyphoplasty, calcium phosphate cement is preferentially tailored to mimic the viscous behavior of PMMA during injection, since this is considered the reference, without displaying the pressure filtering effect (Bohner and Baroud, 2005). Table 1 lists the CaP that can be found in several calcium phosphate cement compositions. Calcium phosphate cement holds distinct advantages over PMMA cement by having the potential to undergo resorption while also displaying osteoconductive properties. In recent in vitro studies the effect of calcium phosphate cements on vertebral body repair has been investigated (Lieberman et al., 2005). Two types of calcium based materials, namely calcium phosphates and calcium sulfates (CaS), are used in spinal applications (see also Table 2). Calcium sulfate cements are sometimes considered not to have osteoconductive properties and, due to their fast dissolution characteristics, achieving adequate mechanical support in the spinal column is found to be more difficult (Glazer et al., 2001). In either case, CaP and CaS cements have demonstrated a superior biocompatibility profile in vitro compared to PMMA cements (Lazary et al., 2008). Calcium phosphate cements are considered suitable scaffolds for bone substitution since they affect cellular function by virtue of their composition that is similar to the mineral phase of bone (Hartman et al., 2005; Huse et al., 2004). CaP allows adhesion and differentiation of osteoblasts while calcium phosphate cements are injectable and can be molded to the defect they have to fill. Calcium phosphate cements exhibit plasticity during their working period allowing the material to occupy the defect well in which they are injected (Anselme, 2000; Denissen et al., 1989). In addition, by using different CaP powders, the dissolution/degradation and resorption behavior of calcium phosphate cements can be tailored. Calcium phosphate cements are intended to be used as temporary scaffolds and the initial contact between cement and surrounding bone tissue is considered a key factor for the osseointegration and bone formation at the implantation site (Gosain et al., 1996). Calcium phosphate cements are required to present a resorption behavior in synchrony with the bone formation (Daculsi et al., 2003). Calcium phosphate cements can be classified into four categories depending on the role and condition of the calcium phosphate solid and liquid components (Chow, 2001; Ooms et al., 2003). Among these, hydraulic cements are the most commonly used and usually the term cement refers to this category. Depending on the end solubility product, these calcium phosphate cements can be classified into two types: brushite or apatite cements (Bohner and Baroud, 2005; Bohner et al., 2006). Brushite cements contain less favorable mechanical properties but show faster biodegradability when compared to apatite cements (Habraken et al., 2006). Apatite calcium phosphate cements have been studied since the early 1970s and by the 1990s started to make inroads into reconstructive surgery (LeGeros, 1993). When mixing CaP powder with the liquid phase, it will create a partial dissolution of the CaP, causing the creation of a paste with the liquid phase supersaturated with calcium and phosphorus

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ions, which then will reprecipitate, producing crystal growth and entanglement providing the initial mechanical properties for the calcium phosphate cement. During this phase the calcium phosphate cement will be moldable. For calcium phosphate cement, solutions of 1–4 wt% Na2HPO4 are commonly used as the liquid phase (Habraken et al., 2008b; Ooms et al., 2003). The degree of supersaturation, pH and temperature of the mixture will dictate the endproduct, which can be resorbed and remodeled in vivo. Contrary to acrylic cements, calcium phosphate cements have the advantage that the setting phase is an isothermic process reducing the risk of thermal damage to surrounding tissues (Heini and Berlemann, 2001; Lieberman et al., 2005). The phase formed after the reprecipitation of the CaP will dictate the resorption properties of the calcium phosphate cement (Schmitz et al., 1999). Each phase presents a different solubility behavior (Ishikawa et al., 1994). The injectability and mechanical properties of calcium phosphate cements can be changed by modifying the liquid-to-powder ratio, the type of liquid component or the use of a pore generator without affecting the final obtained CaP phase (Habraken et al., 2008a; Khairoun et al., 1998; Ruhe et al., 2003). Porosity is found among the requirements for cements used in vertebroplasty and balloon kyphoplasty. After injection, calcium phosphate cements present a certain degree of microporosity depending on the dissolution–reprecipitation process which is related to the liquid to powder ration used (Habraken et al., 2008b). If the calcium phosphate cement is used by itself, comprising only the microporosity, it will take years for the material to degrade since it will do it by a layer-by-layer mechanism, even if it possesses the good chemical characteristics (Bohner, 2001). To increase the degradation between the material and the surrounding tissue, an increase in microporosity and/or the incorporation of a macroporous network could be used. This can be achieved by using various techniques (del Real et al., 2002; Ruhe et al., 2006). However, it is important to remember that the mechanical properties of the calcium phosphate cement will come mainly from two sides, firstly from the dissolution–reprecipitation mechanism and further crystallization which creates the microporosity of the material and secondly from the contribution of additives or pore generators which will influence the macroporosity. Calcium phosphate cements can withstand compression forces of around 50 MPa after full crystallization which is within the ranges of human bone (Habraken et al., 2006; Motoyoshi et al., 2009). It has been reported that calcium phosphate cement loaded with particles, acting as pore generators or drug delivery systems, can reduce compression values by 80% compared to cements not loaded with particles (Habraken et al., 2006; Ruhe et al., 2003). If particles are used for pore generator or drug delivery purposes, the mechanical properties will be dependent on the size, amount and distribution of the particles in the cement, as well as their compositions (Bohner, 2001; Habraken et al., 2006). An agglomeration of these particles should be avoided to not drastically reduce the mechanical properties of the cement (Link et al., 2006). The use of drug delivery systems can be used to enhance the biological behavior and activity of calcium phosphate cement. Several studies have reported the use of growth factors and proteins in combination with this calcium phosphate cement (Bodde et al., 2008; Plachokova et al., 2007a,b). Surgical interventions of the spine are typically carried out under radiological guidance, therefore the material used must be radiopaque (Lieberman et al., 2005). In contrast to acrylic cements, calcium phosphate cements are radiopaque once injected and fully crystallized. However, this action may take one or more days depending upon the characteristics of the cement used. Improving the contrast characteristics of these cements in its early stage is important if calcium phosphate cements are aimed to be used in minimal invasive surgery. Tracking the material during the intervention is of high importance in order to avoid leakage of the material that may increase the risk of injuries or adverse effects (Kim et al., 2009). Some common contrasting agents used are barium, iodine, tantalum and tungsten (Sabokbar et al., 1997). Although this approach is relatively new for calcium phosphate cement, some groups have already explored this field (Wang et al., 2007).

7.12.3.3

Composite Cements (Hybrid Acrylic/Calcium Phosphate Cements)

The goal of adding CaP additives to acrylic cements is to establish a compromise between the desired mechanical and biological properties (Beruto et al., 2000; Dalby et al., 1999; Vallo et al., 1999). These composite cements may be able to reduce stiffness, polymerization temperature and potential monomer toxicity of PMMA while strengthening the bone–cement interface by creating a chemical bonding and changing the encapsulation of the acrylic cement to a direct contact with bone (Dalby et al., 1999; Dalby et al., 2001; Saito et al., 1994). This type of cement has been developed quite recently and the interaction between the components is currently under research (Beruto et al., 2000; Vallo et al., 1999). From the possible CaP candidates, hydroxyapatite (HA) has been most investigated due to the closest similarity of this material to the mineral phase of bone and its high stability (Castaldini and Cavallini, 1985; Harper et al., 2000). However, there are also studies directing attention to other CaPs (Beruto et al., 2000; Canul-Chuil et al., 2003). Bioactive glass has also been studied (Heikkila et al., 1996). All these studies aim to provide a better characterization and understanding of the physical, chemical, mechanical and biological behaviors of composite materials. It has been proven that the inclusion of CaP additives in the acrylic matrix does not modify the properties of the CaP. CaPs maintain their ability to promote bone ingrowth while the monomer concentration of the acrylic cements stays stable (Canul-Chuil et al., 2003). When considering composites, understanding the properties related to the interaction between the phases will be essential to better understand the composite material overall. In the case of the acrylic composites, this interaction will affect setting times, temperature and mechanical properties. Table 3 shows the factors affecting the acrylate–CaP composites. The setting time of these composites will be affected mainly by the amount of CaP added while the exact type of CaP will only have a minor effect (Beruto et al., 2000; Canul-Chuil et al., 2003). While PMMA by itself can reach temperatures up to 1001C (373 K), the addition of CaP can reduce it to room temperature (Beruto et al., 2000; Canul-Chuil et al., 2003; Saito et al., 1994). The addition of CaP will interfere with the polymerization of the acrylic cement and can therefore act as a heat absorber (Beruto et al., 2000). The mechanical behavior will be a complex interaction between the shape of the additive, its dissolution and transformation properties as well as

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Table 3

Factors affecting CaP–acrylic composite cement behavior

Molecular structure of CaP Characteristics of the CaP (eg, porous, thermally treated, doped, etc.) Amount added Particle size of the CaP Fabrication process

its distribution within the sample, amount within the sample and the anisotropy created (Dalby et al., 2002). CaP particles may act as stress concentration factors or fracture energy absorbers, hence affecting mechanical properties in several ways (Vallo et al., 1999). Some authors reported that the addition of CaP does not change significantly the mechanical properties while others report an improvement or even a decrease in these properties (Canul-Chuil et al., 2003; Dalby et al., 1999; Harper et al., 2000). These differences may be related to the type and size of the CaP and their bonding to the acrylic matrix. Standard ISO 5833 indicates that acrylic cements must present a minimum compressive, tensile and bending strength of 70, 30 and 50 MPa, respectively. Concerning porosity, acrylic cements by themselves have low porosity (Canul-Chuil et al., 2003; Lewis, 1997; Vallo et al., 1999). When the CaP is added, an important factor is the porosity and interconnectivity between CaP particles. If particles are embedded in the acrylic matrix without contact to surrounding tissue, the properties of the CaP, and the reason of including them, will not be utilized. Here the CaP particle size and amount included will play a significant role, as it happens when loading a CPC with particles for pore generator or drug delivery systems (Canul-Chuil et al., 2003; Saito et al., 1994). It has been demonstrated that including HA particles causes a void increment (Vallo et al., 1999). Therefore, CaP additives per se will have an effect also on the pore size in the cement. This effect will be related to the additive content and its wettability towards the acrylic material (Canul-Chuil et al., 2003). CaP materials are hydrophilic, so they are partially covered by the liquid monomer that later will polymerize with the powder polymer embedding the CaP into the acrylic matrix but without a strong interface (Beruto et al., 2000; Harper et al., 2000). Treated and untreated CaP additives (silanized) have proven to have a different interaction with the acrylic matrix and influence the mechanical behavior of the composites (Harper et al., 2000). However, these treatments may modify the hydrophobicity of the CaP additives, which could affect their biological properties. Thermal treatments affect the surface properties of CaP (Bohner et al., 2006). This approach could be used to increase the interaction of the CaP with the liquid monomer without affecting the biological properties of the CaP. Another approach that has been studied to modify the mechanical properties of this type of cement is the creation of a porous acrylic cement by preparing the PMMA with a biodegradable gel (Boger et al., 2008a; Bruens et al., 2003). In this last approach, if combined with the loading of CaP particles, the structure will be affected on the mechanical properties due to the porous network and type, size and amount of the particles included (Beruto et al., 2000; Boger et al., 2008c). Acrylic cements with lower modulus are attractive since they allow better stress distribution in the filled vertebral body, thus potentially reducing the risk of fractures on the vertebrae adjacent to the operated sites (Boger et al., 2007). In the case of using radiopaque agents for tracking the material during the surgical intervention, composite cements show a higher degree of complexity since the cement will be a three-phase composite system hence the interaction of each component will not be one-toone but one-to-two. Although studied to some extent by some groups the characterization of these three-phase systems is an area that needs to be researched further in order to fully validate the use of these composites (Vallo et al., 1999).

7.12.3.4

Miscellaneous Cements

Acknowledging the several drawbacks found in commonly used biomaterials for spinal augmentation (ie, PMMA and calcium phosphate cement) consisting of difficult handling characteristics, thermal issues, potential for toxic reactions, mismatched Young’s modulus and limited mechanical strength, researchers have recently started to focus on entirely different materials to be used for this application (Heini and Berlemann, 2001; Verlaan et al., 2005). Boyd et al. (2008) suggested aluminum free, zinc based glass polyalkenoate cements (Zn-GPC) to be a suitable alternative for use in vertebroplasty. In their recent work, comparing polymerization temperature, strength, Young’s modulus and biocompatibility of this cement formulation with three commercially available bone cements (two PMMA cements and one composed of resins and glass ceramic particles) it was found that, although setting times precluded clinical use in the current composition, thermal behavior of the new material was benign, its stiffness exhibited values similar to cancellous bone while biocompatibility was superior. The authors suggested Zn-GPC to be a suitable candidate material for further development as bone cement once the setting parameters were optimized. In recent studies by Perry et al. (2005) two new biomaterials, polypropylene fumarate cement and calcium sulfate cement, were tested as alternatives for PMMA cement in a model for human cadaveric osteoporotic vertebral compression fractures treated by balloon kyphoplasty. The authors concluded from their biomechanical tests, showing similar mechanical properties to PMMA, that both polypropylene fumarate and calcium sulfate were potential new candidates for this application. Zhao et al. (2004) reported on the properties of a strontium-containing hydroxyapatite cement with surface treatment using methyl methacrylate to be used for vertebroplasty and found favorable biomechanical results. Other promising cement compositions include glass-ceramic based cements (Yamamuro et al., 1998; Erbe et al., 2001). The studies described in this section cover just a small selection of several biomaterials currently under study, but it can be expected that many more new biomaterials will be designed, tested and eventually qualify for clinical

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investigation in the near future. The prospect of the availability of biomaterials better adapted to the needs of both treating physicians, in terms of superior handling profiles, and patients, in terms of improved safety, efficacy and biocompatibility, is encouraging.

7.12.4 7.12.4.1

Clinical Results of Spinal Column Augmentation With Injectable Bone Cements Osteoporotic Vertebral Compression Fractures

Gangi et al. (1994) described one of the first, small-scale, series of patients treated for various indications including osteoporotic vertebral body collapse and spinal metastasis treated with vertebroplasty using PMMA cement. They noted immediate relief of pain and absence of further vertebral body compression during follow up in all. Jensen et al. (1997) published a series of 47 spinal levels treated in 29 patients suffering from osteoporotic vertebral compression fracture and found relief of pain immediately after treatment. Identical results were reported by Martin and co-workers in their series of 68 levels treated in 40 patients with 80% of the patients experiencing substantially improved symptoms (Martin et al., 1999). According to the authors, failures were related to insufficient pretreatment clinical evaluation and excessive injection of PMMA. In 2003 a prospective controlled trial was published by Diamond et al. (2003), describing vertebroplasty as a safe technique resulting in prompt relief of pain when compared to conservative medical treatment. The same year a review was published, in which it was emphasized that this technique should be reserved for carefully selected patients who do not respond to conservative treatment (Hendrikse et al., 2003). In 2006, a review of the treatment of osteoporotic vertebral compression fractures by vertebroplasty summarized 15 studies (11 prospective, three retrospective and one controlled trial) containing a total of 1136 procedures in 793 patients (Ploeg et al., 2006). The visual analog scale for pain (VAS); a validated pain measuring tool, ranging from 0 to 10, with zero meaning no pain and ten the worst pain imaginable, improved from a mean of 7.8 to 3.1. The rate of complications ranged between 0.4 and 75.6%, was frequently related to cement extravasation and included major adverse events. It was concluded that long-term, properly controlled trials were required to address the lack of sound scientific and clinical understanding of this technique. Hochmuth et al. (2006) performed yet another review on vertebroplasty, describing the results from 30 studies and 2086 patients and, again, concluded that although spinal augmentation with PMMA cement seemed to dramatically improve symptoms in patients with osteoporotic vertebral compression fractures, randomized controlled trials were needed to confirm the efficacy of the procedure. Bouza et al. (2006) published a review of the literature on balloon kyphoplasty presenting the pooled clinical data of 26 previously published articles. It was found that, although the methodological quality of the papers on which their review was based was generally low, balloon kyphoplasty for the treatment of painful vertebral compression fractures led to significant improvements in pain intensity, vertebral height, sagittal alignment, functional capacity and quality of life. The authors concluded the review suggesting that balloon kyphoplasty was safe and effective. Hulme et al. (2006), in their review of 69 articles published in the literature on the outcome of vertebroplasty and balloon kyphoplasty, refuted this claim, stating that definite proof of safety and efficacy of both procedures could not be obtained without comparative, blinded, randomized trials. Taylor et al. (2006) found, in contrast again, Level III evidence to support balloon kyphoplasty and vertebroplasty as effective therapies in the management of patients with symptomatic osteoporotic vertebral compression fractures refractory to conventional medical therapy. Moreover, balloon kyphoplasty was suggested to offer a better profile with respect to adverse events than vertebroplasty. The first randomized controlled trial on this subject was the FREE trial published in Lancet in 2009 and describing the efficacy and safety of balloon kyphoplasty compared with non-surgical care for the treatment of osteoporotic vertebral compression fractures, metastatic spinal lesions and multiple myeloma (Wardlaw et al., 2009). In this trial a total of 300 patients were enrolled and randomly assigned to receive balloon kyphoplasty with PMMA cement or optimal non-surgical care. A total of 266 patients completed the 1-month follow up and a significant difference in SF-36 PCS was found between the two groups favoring the surgical intervention group. At 12 months, 38 out of 115 patients in the balloon kyphoplasty group and 24 out of 95 in the nonoperative group had new or worsening vertebral fractures. It was concluded that balloon kyphoplasty with PMMA cement was an effective and safe technique for patients with acute vertebral fractures. In the same year two studies were published in one issue of the New England Journal of Medicine (Buchbinder et al., 2009; Kallmes et al., 2009). These papers generally received a critical reception (Aebi, 2009; Weinstein, 2009). In the paper by Buchbinder and co-authors, a randomized, double-blind, placebocontrolled trial was performed to study the efficacy of vertebroplasty using PMMA cement for the treatment of painful osteoporotic vertebral compression fractures in 78 patients. In this study patients were randomly assigned to receive regular vertebroplasty or a sham operation in which the needle used to inject cement was not advanced in the vertebral body but rested upon the lamina but cement was not injected. During follow up, the authors found no significant difference in perceived pain between the groups at any time point while incident vertebral fractures occurred in both groups (three in the vertebroplasty group and four in the placebo group). The authors concluded that vertebroplasty had no beneficial effect when compared to the sham procedure used. The study by Kallmes included a total of 131 patients who were assigned to undergo vertebroplasty with PMMA cement (n ¼68) or infiltration of the skin and periosteum with the possibility to cross over from either group at 1-month post-treatment. After 1 month no difference was found in disability scores or pain rating. At 3 months a significantly higher rate of crossover was found in patients from the control group than in the vertebroplasty group. No incident fractures were reported for any of the groups. The authors concluded that improvements in the vertebroplasty study group were similar to improvements in the control group. Both studies have been criticized by virtue of a number of limitations: the low percentage of cases included from the total number of

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patients eligible; the improvement in pain after receiving treatment being unusually small for both the treatment and control arm, indicating that patients might have undergone inadequate or suboptimal vertebroplasty procedures; the insufficient statistical power; the potential bias in patient selection, the inclusion of patients possibly not indicated for the treatment and the sham not being a proper control (Aebi, 2009; Weinstein, 2009). Newer, high quality studies including the VERTOS II and VAPOUR trials evaluating the safety and efficacy of vertebroplasty for painful acute osteoporotic compression fractures showed positive findings and the results of ongoing trials (including VERTOS IV and VERTOS V) are currently awaited (Klazen et al., 2010; Clark et al., 2016; Firanescu et al., 2011). Studies describing the clinical results following vertebroplasty using calcium phosphate cement to treat painful osteoporotic vertebral compression fractures are relatively rare. Nakano et al. (2002, 2005) were, to our best knowledge, the first to describe the treatment of 65 osteoporotic vertebral compression fractures with vertebroplasty using calcium phosphate cement. Their results were indistinguishable from studies describing similar cohorts of patients treated with vertebroplasty based on PMMA cement. Hillmeier and co-authors reported on the treatment of 102 patients with 192 osteoporotic vertebral compression fractures treated by balloon kyphoplasty with PMMA cement in 138 cases and with calcium phosphate cement in 54 cases (Hillmeier et al., 2004). Again, the results were comparable for both groups and led to immediate, substantial and long term relief of pain in 89% of the patients. In 7% of all treated vertebral bodies cement leakage occurred, however, without clinical sequelae. Grafe et al. (2008) performed a prospective comparative trial in which 20 patients received balloon kyphoplasty with calcium phosphate cement and 20 patients with PMMA cement. After 3 years of follow up, no differences were detected at any time point between the two groups. It was concluded that calcium phosphate cement was as effective as PMMA cement to achieve pain reduction and improvement of mobility in this category of patients. Furthermore, since calcium phosphate cement has the potential of being resorbed and replaced by new bone, they concluded this type of cement to be a promising alternative for PMMA cement especially in younger patients. In 2012, Nakano and coauthors published a longer-term series of 86 patients undergoing 99 vertebroplasty procedures with calcium phosphate cement. They concluded that the procedures led to satisfactory results without delayed complications after a minimum follow-up of 2 years (Nakano et al., 2012).

7.12.4.2

Metastatic/Malignant Vertebral Body Lesions

Metastatic vertebral body lesions and pathological fractures are exclusively being treated with vertebroplasty or balloon kyphoplasty in combination with PMMA cement. Fourney et al. (2003) described the treatment of 97 vertebral levels in 56 patients with multiple myeloma (n¼ 21) or other primary malignancies (n¼ 35) by vertebroplasty or balloon kyphoplasty. At a median follow up length of 4.5 months, 84% of the patients noted marked or complete relief of pain while no patient was worse after treatment. Asymptomatic cement leakage was observed in six cases of vertebroplasty; no cement leakage was observed in the kyphoplasty group. The authors concluded that both procedures provided significant and durable pain relief in a high percentage of patients. In a recent review on cement injection for spinal metastases Heini and Pfäffli stated vertebroplasty and balloon kyphoplasty with PMMA cement to be extremely efficient procedures provided that treatment is restricted to osteolytic lesions in the presence of mechanically challenged bony structures. In a review of the literature, Bouza and co-authors reported on the pooled data of seven studies describing the clinical outcome of balloon kyphoplasty with PMMA cement for the treatment of malignant spinal fractures and concluded, despite the limited methodological quality of the original studies, that balloon kyphoplasty is a well-tolerated, relatively safe and effective technique to provide early relief of pain and improved functional outcomes in this category of patients (Bouza et al., 2009). A preference for vertebroplasty or balloon kyphoplasty with respect to clinical outcome or complications rates is currently not supported by the literature (Bae et al., 2016).

7.12.4.3

Traumatic Fractures

Traumatic fractures of the spine are mostly seen in young and active individuals and bone void fillers used for vertebral body augmentation in this group of patients are likely to remain in situ for many decades and will be subjected to many load cycles (Oner et al., 2006; Verlaan et al., 2004a). Concerns on the detrimental long term effects of acrylic cements in the spine, including short-term inflammation or thermal necrosis and long-term particle-induced osteolysis, have prompted researchers and clinicians to revert to alternative biomaterials. Verlaan et al. (2005) reported on the application of calcium phosphate cement after pedicle screw fixation and balloon assisted endplate reduction in a small series of 20 patients with traumatic thoracolumbar fractures. It was found that the procedure was relatively undemanding for patients, a significant restoration of the vertebral body anatomy was achieved and major complications were not observed except for an adjacent level fracture in one patient necessitating a secondary surgical intervention. All patients underwent elective removal of their pedicle instrumentation between 12 and 18 months posttrauma as part of the study protocol. At a minimum of 6 years follow up it was found that recurrence of kyphosis had not occurred (Verlaan et al., 2015). Similar studies were published by Korovessis et al. (2008) and Marco and Kushwaha (2009). In the series by Korovessis and co-authors, a total of 23 patients with thoracolumbar burst fractures underwent pedicle screw instrumentation followed by balloon kyphoplasty with calcium phosphate cement and concluded after a minimum of 2 years follow up that the technique provided excellent immediate reduction of posttraumatic kyphosis, significant spinal canal clearance and restored vertebral body height of the fractured level. Marco and co-authors described a series of 38 patients with unstable thoracolumbar burst fractures with and without associated neurological deficits treated with short-segment pedicle screw fixation followed by

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transpedicular balloon assisted endplate reduction and injection of calcium phosphate cement. It was concluded that the procedure led to maintained or improved neurological function in all patients with pre-existent neurological deficits and a low rate of instrumentation failure or loss of correction. Maestretti et al. (2007) reported on a series of patients with traumatic thoracolumbar fractures treated with standalone (ie, without pedicle screw fixation) balloon kyphoplasty using calcium phosphate cement. Although the clinical results were good, it was noted that calcium phosphate cement had distinctive biomechanical disadvantages compared to PMMA cement sometimes leading to loss of fracture correction and unpredictable resorption behavior. Currently, Blattert et al. (2009) recommend against standalone treatment of traumatic thoracolumbar fractures by vertebroplasty or balloon kyphoplasty. To our knowledge, the first article published on the treatment of traumatic thoracolumbar burst fractures treated by pedicle screw fixation and vertebroplasty using PMMA cement was by Cho et al. (2003). In this work, Cho et al. (2003) report on a series of 70 patients of which 20 underwent vertebroplasty additional to pedicle screw fixation and 50 underwent regular pedicle screw fixation. The authors concluded from their work that reinforcement of the anterior column with vertebroplasty using PMMA cement may achieve and maintain kyphosis correction and decrease instrument failure rate.

7.12.5

Complications in Spinal Column Augmentation

Within 2 years after the widespread use of vertebroplasty with PMMA bone cement, the first descriptions of serious complications occurred. Two independent cases of symptomatic pulmonary embolism resulted from extravasation of bone cement into the pulmonary circulation (Padovani et al., 1999; Perrin et al., 1999). Shortly after it was found that the incidence of asymptomatic pulmonary embolism could be as high as 87.9% and was predominantly related to an excessive volume of cement injected (Schmidt et al., 2005; Yeom et al., 2003). It is a currently accepted notion that during vertebroplasty or balloon kyphoplasty, leakage of cement into the surrounding soft tissue, venous circulation or pulmonary system often goes unnoticed by both the physician and the patient. Complications arising from vertebroplasty or balloon kyphoplasty can be divided into categories of minor and major severity (Lee et al., 2009). Minor complications include wound hematoma, superficial infection, rib fracture due to patient manipulation, needle malpositioning and asymptomatic cement extravasation. These minor complications are responsible for an estimated 95–98% of all adverse events. Major complications include symptomatic pulmonary embolism, cement infection, symptomatic spinal cord or root compression, myocardial infarction and death. Many studies have reported cement emboli to be present in the pulmonary circulation after augmentation of the spinal column by vertebroplasty or balloon kyphoplasty. In a recent meta-analysis of the literature, Lee et al. (2009) reported on a total of 3078 cases of cement leakage found in 4097 patients treated with vertebroplasty using PMMA leading to an unusually high leakage percentage of 75%. Symptomatic leakage of cement was, however, found in only 1.5% of cases reported. The number of asymptomatic versus symptomatic cement leakage after treatment with balloon kyphoplasty was found to be 14 and 0.06% respectively. The review by McGirt et al. (2009) confirmed these results and, moreover, reported neurological decline to occur in less than 1% of cases treated by vertebroplasty and balloon kyphoplasty. These results raise the question why cement leakage is, apparently, tolerated so well by the majority of patients. It is currently, for example, not known what factors are involved or necessary for pulmonary embolism to become symptomatic after cement leakage has occurred. Patient related factors, such as decreased pulmonary capacity or heart failure, may lead to a predilection for symptomatic pulmonary embolism but do not explain the actual occurrence since these highly prevalent conditions may be present in the asymptomatic group as well. Many reviews of the pertinent literature have, however, shown almost all complications, both of minor and major severity, to be related to leakage of bone cement. Two groups of factors have been identified to potentially influence the risk of adverse events following vertebroplasty or balloon kyphoplasty: 1. Factors increasing the risk of cement leakage: • Fracture type • Duration of symptoms • Instruments/instrument positioning/spinal anatomy • Viscosity of cement injected • Volume of cement injected 2. Factors not increasing the risk of cement leakage: • Mechanical/thrombogenic/thermal properties of cement • General patient health characteristics Ad 1. (fracture type): Osteoporotic vertebral compression fractures are associated with less cement extravasation than malignant spinal lesions, which in turn, are less prone to cement leakage than traumatic fractures (Mousavi et al., 2003). The explanation for the differences may be found in the varying degree of fracture comminution; cortical disruption and surrounding soft tissue damage for these three categories (Whyne et al., 2003). It is hypothesized that postural reduction and subsequent ligamentotaxis, may decrease the risk of cement extravasation due to minimization of fracture gaps and (partial) restoration of the vertebral anatomy thereby facilitating unimpeded cement flow (Koh et al., 2007). Ad 2. (duration of symptoms): The duration of symptoms has been suggested to influence both clinical outcome and incidence of cement extravasation in osteoporotic vertebral compression fractures. It is generally accepted that the optimal window for

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treatment ranges approximately between 6 and 12 weeks after onset of symptoms. Performing spinal augmentation at an earlier stage is, considering the generally benign nature of these lesions showing full resolution in the majority of patients, considered overtreatment while after 3 months the effect of postural reduction is diminished. The optimal timing of intervention for metastatic spinal disease or traumatic fractures by vertebroplasty or balloon kyphoplasty is unknown but, considering the natural history of the lesions in this category of patients, is rather on acute or emergency basis than elective (Marco and Kushwaha, 2009). Ad 3. (instruments/instrument positioning/spinal anatomy): In order to minimize the resistance of bone cement to flow, short, large diameter cement delivering needles are recommended, regardless of the type of biomaterial used. Assuming laminar flow of a liquid with a given viscosity through a tube, the following equation can be applied (nonalgebraic version of Poiseuille’s Law): Flow ¼ pressure  diameter 4 =diameter 4  length Assuming a limitation of the pressure that can be generated by human force using a manually operated syringe and assuming a lower threshold of viscosity needed for safe injection of the biomaterial in the vertebral body, shortening the length of the needle while increasing its diameter will increase flow. Since the increase in flow is proportional to needle diameter by the fourth power, it is clear that using large bore needles optimally facilitates injection of higher viscosity cement. The topic of cement viscosity and flow in relation to cement extravasation is described in more detail elsewhere in this Chapter. The optimal positioning of the needle(s) is considered to be close to the midline in the anterior third of the vertebral body. Deviating from this position may lead to uneven distribution of cement and increased risk for cement extravasation due to the proximity of venous structures (anterior vertebral venous plexus; intraspinal extradural venous plexus) (Prymka et al., 2003). Unipedicular, bipedicular or extrapedicular procedures are currently being performed for both vertebroplasty and balloon kyphoplasty and are showing identical results (Tohmeh et al., 1999). It can be argued that utilization of the unipedicular approach would decrease the chance of instrument malposition by 50%. However, controlled clinical trials showing this theoretical advantage to lead to better clinical results and less cement extravasation or complications have not been performed. Variations in patient anatomy, most notably small diameter or aberrant pedicles, can lead to difficulties in proper access to the vertebral body and may, in case of pedicle wall fracture, increase the risk of false routes and subsequent leakage of cement. Ad 4. (viscosity of cement injected): The viscosity of the bone cement injected in the spinal column is of utmost importance to achieve even flow and controlled distribution of the biomaterial in the vertebral cancellous bone. However, during polymerization of PMMA cement (or formation of hydroxyapatite crystals during setting in case of calcium phosphate cements), the viscosity increases slowly but exponentially with time from the moment of mixing the components until the fully cured state (Baroud et al., 2004c). The interval in which bone cement can safely be injected is often called the working time or injection phase and is dependent on:

• • • • • •

the initial ratio of ingredients (monomer-to-polymer in PMMA cement and ratio of liquid-to-calcium phosphate in calcium phosphate cement) (Baroud et al., 2004a; Hernandez et al., 2006); the presence of additives in PMMA cement or alternative solutions for calcium phosphate cement (Cheung et al., 2005; Gbureck et al., 2004); the temperature of the components before mixing (Sullivan and Topoleski, 2007); the mixing process itself (Baroud et al., 2004c); the temperature of the environment (“room temperature”) during polymerization/setting (Sullivan and Topoleski, 2007); considering the significant variations in working time under apparently identical circumstances: miscellaneous yet unidentified factors (Boger et al., 2009).

By trial and error, clinicians have found, rather unscientifically, that the optimal viscosity for safe injection resembles that of toothpaste or spaghetti; cement of lower viscosity (before the injection phase) led to frequent extravasation while cement displaying higher viscosity (after the injection phase) substantially reduced injectability (Anselmetti et al., 2008). Baroud et al. (2004b) quantified this observation using cements of different viscosity in an in vitro model of vertebroplasty. It was demonstrated that the highest viscosity cement stabilized flow and prevented extravasation but was no longer injectable using human force. An experimental study by Loeffel et al. (2008), published in 2008, assessed distribution of PMMA cement in the vertebral body as function of cement viscosity, bone porosity and injection speed. Their main conclusion was that viscosity was the key factor to reduce cement extravasation and should be adapted to each patient individually according to the degree of osteoporosis present. It was advised to use high viscosity cement combined with high injecting speed to safely augment the vertebral body. The experimental work by Krebs, Aebli et al. (2002, 2003), investigating bone marrow fat embolism in an in vivo vertebroplasty model, however, suggests that increasing cement viscosity and injection speed could lead to different, yet no less harmless, adverse events. A recent publication described a sequential cement injection technique that, in an in vitro setting, took advantage of the different polymerizing rates of the cement inside the vertebral body (at core temperature) versus the polymerizing rate within the syringe (at room temperature). With this simple adaptation of the injecting technique, cement leakage outside the vertebral body could be greatly reduced. Ad 5. (volume of cement injected): In the first decade following the invention of vertebroplasty, near-complete filling of a vertebral body with bone cement was considered necessary for good clinical outcome. However, soon it was realized that smaller amounts of cement injected led to identical good results while substantially decreasing the occurrence of adverse events related to cement extravasation. Injection of 3–4 mL bone cement in the thoracic spine and of 4–6 mL cement in the lumbar spine is presently recommended by many authors and this practice has, thus far, been shown to yield the optimal compromise between clinical outcome and adverse events related to cement leakage (Cotten et al., 1996). No data are yet available on the efficacy and safety of spinal augmentation using even less cement.

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Ad 6. (mechanical/thrombogenic/thermal properties of cement): Limited data are available whether the contribution of bone cement to the development of pulmonary embolism after extravasation is by direct mechanical blockage of pulmonary vessels or by promotion of thromboembolic processes downstream. In multiple in vitro studies conducted by Cenni et al. (2001a, 2002a,b) it was demonstrated that several acrylic cements, when tested for hemolytic activity; antithrombotic properties and the plasmatic phase of coagulation, did not seem to influence these parameters. Further work by the same group showed that, in general, products released from acrylic cements were not able to elicit a specific immune or endothelial response (Cenni et al., 2001b). The lack of thrombogenic activity in PMMA cement was confirmed by the work of Blinc et al. (2004), adding that liquid components of this type of cement inhibited platelet aggregation and plasma clotting in vitro. Concluding from these studies it seems plausible that mechanical blocking of the pulmonary circulation by cement particles, as opposed to chemical induction of thrombogenesis, is responsible for the development of pulmonary embolism when using PMMA cement. Large cement particle size (42 mm) in combination with preexistent risk factors for symptomatic pulmonary embolism can be hypothesized to constitute the key etiological factors for the occurrence of this complication (Kim et al., 2009). With respect to calcium phosphate cements and the occurrence of pulmonary embolism, two experimental in vivo studies have been conducted to test the hypothesis that extravasation of calcium phosphate cement into the venous circulation may result in uncontrolled activation of the coagulation cascade (Bernards et al., 2004; Krebs et al., 2007). In the study by Bernards et al. (2004), calcium phosphate was injected directly into the venous system of 21 pigs to investigate any cardiopulmonary insults. An overall mortality of 13 out of 21 pigs was observed following a profound increase in pulmonary artery pressure and subsequent drop in left atrial and systemic blood pressure after cement injection. On autopsy, massive thromboemboli were found in the arterial pulmonary circulation and right ventricle. The authors hypothesized that semi-liquid, curing calcium phosphate cement may have acted as a powerful scaffold for blood clot formation. Furthermore, it was suggested that the release of significant amounts of calcium in the circulation, being an important co-factor in the coagulation cascade, may have further stimulated the coagulation process. The occurrence of neurological deterioration after leakage of cement into the spinal canal or neural foramina has been suggested to result from mechanical compression of neural structures (ie, spinal cord, cauda equina or neural roots) or thermal damage. Currently, the damage by mechanical compression of neural structures, resulting from cement extravasation after vertebroplasty or balloon kyphoplasty, is undisputed and warrants immediate surgical decompression (Harrington, 2001). Patients in any of the three indication categories presenting with neurological deficits are not considered good candidates for spinal augmentation with injectable bone cements without additional surgical decompressive measures, since leakage of cement into the spinal canal may further compromise neurological function. The often suggested possibility that local heat, produced during the exothermic polymerization of PMMA, may cause neural tissue damage has received considerable attention in recent in vitro and in vivo studies (Aebli et al., 2006; Deramond et al., 1999; Verlaan et al., 2003). Several experimental investigations have demonstrated conductive and convective mechanisms by the circulation and flow of cerebrospinal fluid to effectively dispose of the excessive thermal energy generated by the curing cement. The heat effect of large quantities of polymerizing PMMA cement located in the spinal canal, however, was not studied and may still pose a considerable threat to neural tissue integrity. Calcium phosphate cements set isothermically and concerns about thermal damage therefore do not apply. Ad 7. (general patient health characteristics): Health hazards that are generally prevalent in the frail and elderly include hypertension, osteoporosis, diabetes mellitus, coronary artery disease, heart failure, coagulation disorders and chronic obstructive pulmonary disease. These are obvious patient-related factors associated with an increased complication risk for virtually any surgical treatment and may account for, at least, some of the complications occurring after spinal augmentation including both minor and major events such as rib fracture, infection, hematoma, pulmonary embolism and myocardial infarction (Lee et al., 2009).

7.12.6

Future Directions and Conclusions

The number of articles published in basic scientific and clinical journals on injectable bone cements for spinal column augmentation has expanded immensely in the last decade. Despite all this work, no generally accepted explanations have emerged why augmenting the vertebral body leads, in general, to such good clinical results; whether adjacent fractures occur more frequently after augmentation of the spine; why cement leakage sometimes, but certainly not always, leads to serious complications. Acknowledging the logistic (study enrollment, blinding procedures and obtaining adequate follow up) and ethical (sham operations) difficulties in conducting randomized controlled trials to find an effect of vertebroplasty or balloon kyphoplasty for the different indications, investigators could focus on well-controlled dose-dependent studies. In these studies the minimal amount of cement needed for adequate pain reduction could be established which could serve as a basis to support or refute the fracture stabilization theory and find the optimum balance between treatment effect and complication rate. If augmentation of the spinal column indeed leads to pain reduction, by stabilization or other means, the next step would be to identify the key-factors that determine success or failure. Considering the exceedingly large number of procedures of vertebroplasty and balloon kyphoplasty performed each year, establishing a registry (similar to the large total hip/knee replacement databases in worldwide use today) may help clinicians identify factors leading to the occurrence of adjacent level fractures and symptomatic pulmonary embolism, for example. Such analyses are generally useful for suggesting better performing biomaterial characteristics. It is a tempting concept that the biomechanical and biological properties of an ideal bone cement more closely

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match the individual patient requirements. Factors such as cement stiffness and capacity for osseointegration, may be adapted to unique individual characteristics including easily quantifiable variables such as gender, age and bone mineral density and further including more qualitative concepts such as activities of daily life, workload, risk of major intraoperative complications and lifeexpectancy. As the medical community is slowly gaining a better understanding of the specific needs for patients with spinal lesions, it is possible that, in time, more individualized vertebral bone void fillers may become available. The last two decades have brought us promising new minimal invasive techniques and biomaterials to augment the spinal column of patients who otherwise would be confined to long-term immobilization, analgesics or subjected to major surgery. By virtue of sheer need, these techniques and biomaterials were introduced, and became widely accepted. Well controlled studies addressing safety and efficacy were not routinely performed. Continued progress in this exciting field should depend on rigorous scientific and clinical studies.

References Aebi, M. Vertebroplasty: About Sense and Nonsense of Uncontrolled Controlled Randomized Prospective Trials. Eur. Spine J. 2009, 18 (9), 1247–1248. Aebli, N.; Goss, B. G.; Thorpe, P.; Williams, R.; Krebs, J. In Vivo Temperature Profile of Intervertebral Discs and Vertebral Endplates During Vertebroplasty: An Experimental Study in Sheep. Spine 2006, 31 (15), 1674–1678. Aebli, N.; Krebs, J.; Davis, G.; Walton, M.; Williams, M. J.; Theis, J. C. Fat Embolism and Acute Hypotension During Vertebroplasty: An Experimental Study in Sheep. Spine 2002, 27 (5), 460–466. Aebli, N.; Krebs, J.; Schwenke, D.; Davis, G.; Theis, J. C. Pressurization of Vertebral Bodies During Vertebroplasty Causes Cardiovascular Complications: An Experimental Study in Sheep. Spine 2003, 28 (14), 1513–1519. Anselme, K. Osteoblast Adhesion on Biomaterials. Biomaterials 2000, 21 (7), 667–681. Anselmetti, G. C.; Zoarski, G.; Manca, A.; et al. Percutaneous Vertebroplasty and Bone Cement Leakage: Clinical Experience With a New High-Viscosity Bone Cement and Delivery System for Vertebral Augmentation in Benign and Malignant Compression Fractures. Cardiovasc. Intervent. Radiol. 2008, 31 (5), 937–947. Bae, J. W.; Gwak, H. S.; Kim, S.; et al. Percutaneous Vertebroplasty for Patients With Metastatic Compression Fractures of the Thoracolumbar Spine: Clinical and Radiological Factors Affecting Functional Outcomes. Spine J. 2016, 16, 355–364. Baroud, G.; Bohner, M.; Heini, P.; Steffen, T. Injection Biomechanics of Bone Cements Used in Vertebroplasty. Biomed. Mater. Eng. 2004a, 14 (4), 487–504. Baroud, G.; Falk, R.; Crookshank, M.; Sponagel, S.; Steffen, T. Experimental and Theoretical Investigation of Directional Permeability of Human Vertebral Cancellous Bone for Cement Infiltration. J. Biomech. 2004b, 37 (2), 189–196. Baroud, G.; Matsushita, C.; Samara, M.; Beckman, L.; Steffen, T. Influence of Oscillatory Mixing on the Injectability of Three Acrylic and Two Calcium-Phosphate Bone Cements for Vertebroplasty. J. Biomed. Mater. Res. 2004c, 68B (1), 105–111. Baroud, G.; Vant, C.; Wilcox, R. Long-Term Effects of Vertebroplasty: Adjacent Vertebral Fractures. J. Long Term Eff. Med. Implants. 2006, 16 (4), 265–280. Berlemann, U.; Ferguson, S. J.; Nolte, L. P.; Heini, P. F. Adjacent Vertebral Failure After Vertebroplasty. A Biomechanical Investigation. J. Bone Jt. Surg. Br. 2002, 84 (5), 748–752. Bernards, C.M.; Chapman J.; Mirza, S. Lethality of Embolized Norian Bone Cement Varies With the Time Between Mixing and Embolization. In Proceedings of the 50th Annual Meeting of the Orthopaedic Research Society [Paper No: 0254], 2004 (Ref Type: Abstract). Beruto, D. T.; Mezzasalma, S. A.; Capurro, M.; Botter, R.; Cirillo, P. Use of Alpha-Tricalcium Phosphate (TCP) as Powders and as an Aqueous Dispersion to Modify Processing, Microstructure, and Mechanical Properties of Polymethylmethacrylate (PMMA) Bone Cements and to Produce Bone-Substitute Compounds. J. Biomed. Mater. Res. 2000, 49 (4), 498–505. Blattert, T. R.; Jestaedt, L.; Weckbach, A. Suitability of a Calcium Phosphate Cement in Osteoporotic Vertebral Body Fracture Augmentation: A Controlled, Randomized, Clinical Trial of Balloon Kyphoplasty Comparing Calcium Phosphate Versus Polymethylmethacrylate. Spine 2009, 34 (2), 108–114. Blinc, A.; Bozic, M.; Vengust, R.; Stegnar, M. Methyl-Methacrylate Bone Cement Surface Does Not Promote Platelet Aggregation or Plasma Coagulation in Vitro. Thromb. Res. 2004, 114 (3), 179–184. Bodde, E. W.; Kowalski, R. S.; Spauwen, P. H.; Jansen, J. A. No Increased Bone Formation Around Alendronate or Omeprazole Loaded Bioactive Bone Cements in a Femoral Defect. Tissue Eng. Part A 2008, 14 (1), 29–39. Boger, A.; Bisig, A.; Bohner, M.; Heini, P.; Schneider, E. Variation of the Mechanical Properties of PMMA to Suit Osteoporotic Cancellous Bone. J. Biomater. Sci. Polym. Ed. 2008a, 19 (9), 1125–1142. Boger, A.; Bohner, M.; Heini, P.; Schwieger, K.; Schneider, E. Performance of Vertebral Cancellous Bone Augmented With Compliant PMMA Under Dynamic Loads. Acta Biomater. 2008b, 4 (6), 1688–1693. Boger, A.; Bohner, M.; Heini, P.; Verrier, S.; Schneider, E. Properties of an Injectable Low Modulus PMMA Bone Cement for Osteoporotic Bone. J. Biomed. Mater. Res. B Appl. Biomater. 2008c, 86B (2), 474–482. Boger, A.; Heini, P.; Windolf, M.; Schneider, E. Adjacent Vertebral Failure After Vertebroplasty: A Biomechanical Study of Low-Modulus PMMA Cement. Eur. Spine J. 2007, 16 (12), 2118–2125. Boger, A.; Wheeler, K. D.; Schenk, B.; Heini, P. F. Clinical Investigations of Polymethylmethacrylate Cement Viscosity During Vertebroplasty and Related In Vitro Measurements. Eur. Spine J. 2009, 18 (9), 1272–1278. Bohner, M. Physical and Chemical Aspects of Calcium Phosphates Used in Spinal Surgery. Eur. Spine J. 2001, 10 (Suppl. 2), S114–S121. Bohner, M.; Baroud, G. Injectability of Calcium Phosphate Pastes. Biomaterials 2005, 26 (13), 1553–1563. Bohner, M.; Doebelin, N.; Baroud, G. Theoretical and Experimental Approach to Test the Cohesion of Calcium Phosphate Pastes. Eur. Cell Mater. 2006, 12, 26–35. Boss, J. H.; Shajrawi, I.; Dekel, S.; Mendes, D. G. The Bone–Cement Interface: Histological Observations on the Interface of Cemented Arthroplasties Within the Immediate and Late Phases. J. Biomater. Sci. Polym. Ed. 1993, 5 (3), 221–230. Bouza, C.; Lopez-Cuadrado, T.; Cediel, P.; Saz-Parkinson, Z.; Amate, J. M. Balloon Kyphoplasty in Malignant Spinal Fractures: A Systematic Review and Meta-Analysis. BMC Palliat. Care 2009, 8, 12. Bouza, C.; Lopez, T.; Magro, A.; Navalpotro, L.; Amate, J. M. Efficacy and Safety of Balloon Kyphoplasty in the Treatment of Vertebral Compression Fractures: A Systematic Review. Eur. Spine J. 2006, 15 (7), 1050–1067. Boyd, D.; Clarkin, O. M.; Wren, A. W.; Towler, M. R. Zinc-Based Glass Polyalkenoate Cements With Improved Setting Times and Mechanical Properties. Acta Biomater. 2008, 4 (2), 425–431. Bruens, M. L.; Pieterman, H.; de, W., Jr.; Vaandrager, J. M. Porous Polymethylmethacrylate as Bone Substitute in the Craniofacial Area. J. Craniofac. Surg. 2003, 14 (1), 63–68. Buchbinder, R.; Osborne, R. H.; Ebeling, P. R.; et al. A Randomized Trial of Vertebroplasty for Painful Osteoporotic Vertebral Fractures. N. Engl. J. Med. 2009, 361 (6), 557–568.

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

213

Canul-Chuil, A.; Vargas-Coronado, R.; Cauich-Rodriguez, J. V.; Martinez-Richa, A.; Fernandez, E.; Nazhat, S. N. Comparative Study of Bone Cements Prepared With Either HA or Alpha-TCP and Functionalized Methacrylates. J. Biomed. Mater. Res. B Appl. Biomater. 2003, 64 (1), 27–37. Castaldini, A.; Cavallini, A. Setting Properties of Bone Cement With Added Synthetic Hydroxyapatite. Biomaterials 1985, 6 (1), 55–60. Cenni, E.; Ciapetti, G.; Granchi, D.; et al. Evaluation of the Effect of Seven Acrylic Bone Cements on Erythrocytes and Plasmatic Phase of Coagulation. Biomaterials 2001a, 22 (11), 1321–1326. Cenni, E.; Ciapetti, G.; Granchi, D.; et al. Evaluation of Tissue-Factor Production by Human Endothelial Cells Incubated With Three Acrylic Bone Cements. J. Biomed. Mater. Res. 2001b, 55 (1), 131–136. Cenni, E.; Granchi, D.; Ciapetti, G.; Savarino, L.; Corradini, A. Effect of Four Acrylic Bone Cements on Transforming Growth Factor-Beta1 Expression by Osteoblast-Like Cells MG63. Biomaterials 2002a, 23 (1), 305–311. Cenni, E.; Granchi, D.; Pizzoferrato, A. Platelet Activation After In Vitro Contact With Seven Acrylic Bone Cements. J. Biomater. Sci. Polym. Ed. 2002b, 13 (1), 17–25. Cheung, K. M.; Lu, W. W.; Luk, K. D.; et al. Vertebroplasty by Use of a Strontium-Containing Bioactive Bone Cement. Spine 2005, 30 (17 Suppl.), S84–S91. Chi, J. H.; Gokaslan, Z. L. Vertebroplasty and Kyphoplasty for Spinal Metastases. Curr. Opin. Support. Palliat. Care 2008, 2 (1), 9–13. Cho, D. Y.; Lee, W. Y.; Sheu, P. C. Treatment of Thoracolumbar Burst Fractures With Polymethyl Methacrylate Vertebroplasty and Short-Segment Pedicle Screw Fixation. Neurosurgery 2003, 53 (6), 1354–1360. Chow, L. C. Calcium Phosphate Cements. Monogr. Oral Sci. 2001, 18, 148–163. Clark, W.; Bird, P.; Gonski, P.; et al. Safety and Efficacy of Vertebroplasty for Acute Painful Osteoporotic Fractures (VAPOUR): A Multicentre, Randomised, Double-Blind, Placebo-Controlled Trial. Lancet 2016, 388, 1408–1416. Cortet, B.; Cotten, A.; Boutry, N.; et al. Percutaneous Vertebroplasty in the Treatment of Osteoporotic Vertebral Compression Fractures: An Open Prospective Study. J. Rheumatol. 1999, 26 (10), 2222–2228. Cotten, A.; Dewatre, F.; Cortet, B.; et al. Percutaneous Vertebroplasty for Osteolytic Metastases and Myeloma: Effects of the Percentage of Lesion Filling and the Leakage of Methyl Methacrylate at Clinical Follow-Up. Radiology 1996, 200 (2), 525–530. Daculsi, G.; Laboux, O.; Malard, O.; Weiss, P. Current State of the Art of Biphasic Calcium Phosphate Bioceramics. J. Mater. Sci. Mater. Med. 2003, 14 (3), 195–200. Dalby, M. J.; Di, S. L.; Harper, E. J.; Bonfield, W. In Vitro Evaluation of a New Polymethylmethacrylate Cement Reinforced With Hydroxyapatite. J. Mater. Sci. Mater. Med. 1999, 10 (12), 793–796. Dalby, M. J.; Di, S. L.; Harper, E. J.; Bonfield, W. Initial Interaction of Osteoblasts With the Surface of a Hydroxyapatite–Poly(Methylmethacrylate) Cement. Biomaterials 2001, 22 (13), 1739–1747. Dalby, M. J.; Di, S. L.; Harper, E. J.; Bonfield, W. Increasing Hydroxyapatite Incorporation Into Poly(Methylmethacrylate) Cement Increases Osteoblast Adhesion and Response. Biomaterials 2002, 23 (2), 569–576. Debrunner, H. U.; Wettstein, A. Working Time of Bone Cements. Arch. Orthop. Unfallchir. 1975, 81 (4), 291–299. Denissen, H. W.; Kalk, W.; Veldhuis, A. A.; Van Den, H. A. Eleven-Year Study of Hydroxyapatite Implants. J. Prosthet. Dent. 1989, 61 (6), 706–712. Deramond, H.; Wright, N. T.; Belkoff, S. M. Temperature Elevation Caused by Bone Cement Polymerization During Vertebroplasty. Bone 1999, 25 (2 Suppl.), 17S–21S. Diamond, T. H.; Champion, B.; Clark, W. A. Management of Acute Osteoporotic Vertebral Fractures: A Nonrandomized Trial Comparing Percutaneous Vertebroplasty With Conservative Therapy. Am. J. Med. 2003, 114 (4), 257–265. Erbe, E. M.; Clineff, T. D.; Gualtieri, G. Comparison of a New Bisphenol-A-Glycidyl Dimethacrylate-Based Cortical Bone Void Filler With Polymethyl Methacrylate. Eur. Spine J. 2001, 10, S147–S152. Evans, A. J.; Jensen, M. E.; Kip, K. E.; et al. Vertebral Compression Fractures: Pain Reduction and Improvement in Functional Mobility After Percutaneous Polymethylmethacrylate Vertebroplasty Retrospective Report of 245 Cases. Radiology 2003, 226 (2), 366–372. Firanescu, C.; Lohle, P. N.; de Vries, J.; et al. A Randomised Sham Controlled Trial of Vertebroplasty for Painful Acute Osteoporotic Vertebral Fractures (VERTOS IV). Trials 2011, 12. 93-6215-12-93. Fourney, D. R.; Schomer, D. F.; Nader, R.; et al. Percutaneous Vertebroplasty and Kyphoplasty for Painful Vertebral Body Fractures in Cancer Patients. J. Neurosurg. 2003, 98 (1 Suppl.), 21–30. Galibert, P.; Deramond, H.; Rosat, P.; Le Gars, D. Preliminary Note on the Treatment of Vertebral Angioma by Percutaneous Acrylic Vertebroplasty. Neurochirurgie 1987, 33 (2), 166–168. Gangi, A.; Kastler, B. A.; Dietemann, J. L. Percutaneous Vertebroplasty Guided by a Combination of CT and Fluoroscopy. AJNR Am. J. Neuroradiol. 1994, 15 (1), 83–86. Gbureck, U.; Barralet, J. E.; Spatz, K.; Grover, L. M.; Thull, R. Ionic Modification of Calcium Phosphate Cement Viscosity. Part I: Hypodermic Injection and Strength Improvement of Apatite Cement. Biomaterials 2004, 25 (11), 2187–2195. Glazer, P. A.; Spencer, U. M.; Alkalay, R. N.; Schwardt, J. In Vivo Evaluation of Calcium Sulfate as a Bone Graft Substitute for Lumbar Spinal Fusion. Spine J. 2001, 1 (6), 395–401. Gosain, A. K.; McCarthy, J. G.; Staffenberg, D.; Glat, P. M.; Simmons, D. J. The Histomorphologic Changes in Vascularized Bone Transfer and Their Interrelationship With the Recipient Sites: A 1-Year Study. Plast. Reconstr. Surg. 1996, 97 (5), 1001–1013. Grafe, I. A.; Baier, M.; Noldge, G.; et al. Calcium-Phosphate and Polymethylmethacrylate Cement in Long-Term Outcome After Kyphoplasty of Painful Osteoporotic Vertebral Fractures. Spine 2008, 33 (11), 1284–1290. Habib, M.; Baroud, G.; Gitzhofer, F.; Bohner, M. Mechanisms Underlying the Limited Injectability of Hydraulic Calcium Phosphate Paste. Part Capital I, Ukrainiancapital I, Ukrainian: Particle Separation Study. Acta Biomater. 2009, 6 (1), 250–256. Habraken, W. J.; Wolke, J. G.; Mikos, A. G.; Jansen, J. A. Injectable PLGA Microsphere/Calcium Phosphate Cements: Physical Properties and Degradation Characteristics. J. Biomater. Sci. Polym. Ed. 2006, 17 (9), 1057–1074. Habraken, W. J.; de Jonge, L. T.; Wolke, J. G.; Yubao, L.; Mikos, A. G.; Jansen, J. A. Introduction of Gelatin Microspheres Into an Injectable Calcium Phosphate Cement. J. Biomed. Mater. Res. A 2008a, 87 (3), 643–655. Habraken, W. J.; Zhang, Z.; Wolke, J. G.; et al. Introduction of Enzymatically Degradable Poly(Trimethylene Carbonate) Microspheres Into an Injectable Calcium Phosphate Cement. Biomaterials 2008b, 29 (16), 2464–2476. Hansen, D.; Jensen, J. S. Prechilling and Vacuum Mixing Not Suitable for all Bone Cements. Handling Characteristics and Exotherms of Bone Cements. J. Arthroplasty 1990, 5 (4), 287–290. Harper, E. J.; Braden, M.; Bonfield, W. Mechanical Properties of Hydroxyapatite Reinforced Poly(Ethylmethacrylate) Bone Cement After Immersion in a Physiological Solution: Influence of a Silane Coupling Agent. J. Mater. Sci. Mater. Med. 2000, 11 (8), 491–497. Harrington, K. D. Major Neurological Complications Following Percutaneous Vertebroplasty With Polymethylmethacrylate: A Case Report. J. Bone Jt. Surg. Am. 2001, 83A (7), 1070–1073. Hartman, E. H.; Vehof, J. W.; Spauwen, P. H.; Jansen, J. A. Ectopic Bone Formation in Rats: The Importance of the Carrier. Biomaterials 2005, 26 (14), 1829–1835. Heikkila, J. T.; Aho, A. J.; Kangasniemi, I.; Yli-Urpo, A. Polymethylmethacrylate Composites: Disturbed Bone Formation at the Surface of Bioactive Glass and Hydroxyapatite. Biomaterials 1996, 17 (18), 1755–1760. Heini, P. F.; Berlemann, U. Bone Substitutes in Vertebroplasty. Eur. Spine J. 2001, 10 (Suppl. 2), S205–S213. Heini, P. F.; Berlemann, U.; Kaufmann, M.; Lippuner, K.; Fankhauser, C.; van Landuyt, P. Augmentation of Mechanical Properties in Osteoporotic Vertebral Bones – A Biomechanical Investigation of Vertebroplasty Efficacy With Different Bone Cements. Eur. Spine J. 2001, 10 (2), 164–171.

214

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

Hendrikse, C. A.; Kalmijn, S.; Voormolen, M. H.; Verhaar, H. J.; Mali, W. P. Percutaneous Vertebroplasty in the Treatment of Osteoporotic Vertebral Compression Fractures: Review of the Literature. Ned. Tijdschr. Geneeskd. 2003, 147 (32), 1553–1559. Hernandez, L.; Gurruchaga, M.; Goni, I. Influence of Powder Particle Size Distribution on Complex Viscosity and Other Properties of Acrylic Bone Cement for Vertebroplasty and Kyphoplasty. J. Biomed. Mater. Res. B Appl. Biomater. 2006, 77 (1), 98–103. Hillmeier, J.; Grafe, I.; Da Fonseca, K.; et al. The Evaluation of Balloonkyphoplasty for Osteoporotic Vertebral Fractures. An Interdisciplinary Concept. Orthopade 2004, 33 (8), 893–904. Hochmuth, K.; Proschek, D.; Schwarz, W.; Mack, M.; Kurth, A. A.; Vogl, T. J. Percutaneous Vertebroplasty in the Therapy of Osteoporotic Vertebral Compression Fractures: A Critical Review. Eur. Radiol. 2006, 16 (5), 998–1004. Hulme, P. A.; Krebs, J.; Ferguson, S. J.; Berlemann, U. Vertebroplasty and Kyphoplasty: A Systematic Review of 69 Clinical Studies. Spine 2006, 31 (17), 1983–2001. Huse, R. O.; Quinten, R. P.; Wolke, J. G.; Jansen, J. A. The Use of Porous Calcium Phosphate Scaffolds With Transforming Growth Factor Beta 1 as an Onlay Bone Graft Substitute. Clin. Oral Implants Res. 2004, 15 (6), 741–749. Ishikawa, K.; Takagi, S.; Chow, L. C.; Ishikawa, Y.; Eanes, E. D.; Asaoka, K. Behavior of a Calcium Phosphate Cement in Simulated Blood Plasma In Vitro. Dent. Mater. 1994, 10 (1), 26–32. Jarvik, J. G.; Deyo, R. A. Cementing the Evidence: Time for a Randomized Trial of Vertebroplasty. AJNR Am. J. Neuroradiol. 2000, 21 (8), 1373–1374. Jefferiss, C. D.; Lee, A. J.; Ling, R. S. Thermal Aspects of Self-Curing Polymethylmethacrylate. J. Bone Jt. Surg. Br. 1975, 57 (4), 511–518. Jensen, M. E.; Evans, A. J.; Mathis, J. M.; Kallmes, D. F.; Cloft, H. J.; Dion, J. E. Percutaneous Polymethylmethacrylate Vertebroplasty in the Treatment of Osteoporotic Vertebral Body Compression Fractures: Technical Aspects. AJNR Am. J. Neuroradiol. 1997, 18 (10), 1897–1904. Kallmes, D. F.; Comstock, B. A.; Heagerty, P. J.; et al. A Randomized Trial of Vertebroplasty for Osteoporotic Spinal Fractures. N. Engl. J. Med. 2009, 361 (6), 569–579. Kallmes, D. F.; Jarvik, J. G. Spinal Augmentation Research: FREE at Last? Lancet 2009, 373 (9668), 982–984. Khairoun, I.; Boltong, M. G.; Driessens, F. C.; Planell, J. A. Some Factors Controlling the Injectability of Calcium Phosphate Bone Cements. J. Mater. Sci. Mater. Med. 1998, 9 (8), 425–428. Kim, Y. J.; Lee, J. W.; Park, K. W.; et al. Pulmonary Cement Embolism After Percutaneous Vertebroplasty in Osteoporotic Vertebral Compression Fractures: Incidence, Characteristics, and Risk Factors. Radiology 2009, 251 (1), 250–259. Klazen, C. A.; Lohle, P. N.; de Vries, J.; et al. Vertebroplasty Versus Conservative Treatment in Acute Osteoporotic Vertebral Compression Fractures (Vertos II): An Open-Label Randomised Trial. Lancet 2010, 376, 1085–1092. Knop, C.; Blauth, M.; Buhren, V.; et al. Surgical Treatment of Injuries of the Thoracolumbar Transition. 1: Epidemiology. Unfallchirurg 1999, 102 (12), 924–935. Koh, Y. H.; Han, D.; Cha, J. H.; Seong, C. K.; Kim, J.; Choi, Y. H. Vertebroplasty: Magnetic Resonance Findings Related to Cement Leakage Risk. Acta Radiol. 2007, 48 (3), 315–320. Korovessis, P.; Repantis, T.; Petsinis, G.; Iliopoulos, P.; Hadjipavlou, A. Direct Reduction of Thoracolumbar Burst Fractures by Means of Balloon Kyphoplasty With Calcium Phosphate and Stabilization With Pedicle–Screw Instrumentation and Fusion. Spine 2008, 33 (4), E100–E108. Krebs, J.; Aebli, N.; Goss, B. G.; et al. Cardiovascular Changes After Pulmonary Embolism From Injecting Calcium Phosphate Cement. J. Biomed. Mater. Res. B Appl. Biomater. 2007, 82 (2), 526–532. Krebs, J.; Ferguson, S. J.; Bohner, M.; Baroud, G.; Steffen, T.; Heini, P. F. Clinical Measurements of Cement Injection Pressure During Vertebroplasty. Spine 2005, 30 (5), E118–E122. Lazary, A.; Speer, G.; Varga, P. P.; et al. Effect of Vertebroplasty Filler Materials on Viability and Gene Expression of Human Nucleus Pulposus Cells. J. Orthop. Res. 2008, 26 (5), 601–607. Lee, M. J.; Dumonski, M.; Cahill, P.; Stanley, T.; Park, D.; Singh, K. Percutaneous Treatment of Vertebral Compression Fractures: A Meta-Analysis of Complications. Spine 2009, 34 (11), 1228–1232. LeGeros, R. Z. Biodegradation and Bioresorption of Calcium Phosphate Ceramics. Clin. Mater. 1993, 14 (1), 65–88. Lewis, G. Properties of Acrylic Bone Cement: State of the Art Review. J. Biomed. Mater. Res. 1997, 38 (2), 155–182. Lewis, G. Injectable Bone Cements for Use in Vertebroplasty and Kyphoplasty: State-of-the-Art Review. J. Biomed. Mater. Res. B Appl. Biomater. 2006, 76 (2), 456–468. Lewis, G.; Mishra, S. R. Influence of Changes in the Composition of an Acrylic Bone Cement on Its Polymerization Kinetics. J. Biomed. Mater. Res. B Appl. Biomater. 2007, 81 (2), 524–529. Lieberman, I. H.; Dudeney, S.; Reinhardt, M. K.; Bell, G. Initial Outcome and Efficacy of “Kyphoplasty” in the Treatment of Painful Osteoporotic Vertebral Compression Fractures. Spine 2001, 26 (14), 1631–1638. Lieberman, I. H.; Togawa, D.; Kayanja, M. M. Vertebroplasty and Kyphoplasty: Filler Materials. Spine J. 2005, 5 (6 Suppl.), 305S–316S. Lin, E. P.; Ekholm, S.; Hiwatashi, A.; Westesson, P. L. Vertebroplasty: Cement Leakage Into the Disc Increases the Risk of New Fracture of Adjacent Vertebral Body. AJNR Am. J. Neuroradiol. 2004, 25 (2), 175–180. Link, D. P.; van den, D. J.; Jurgens, W. J.; Wolke, J. G.; Jansen, J. A. Mechanical Evaluation of Implanted Calcium Phosphate Cement Incorporated With PLGA Microparticles. Biomaterials 2006, 27 (28), 4941–4947. Loeffel, M.; Ferguson, S. J.; Nolte, L. P.; Kowal, J. H. Vertebroplasty: Experimental Characterization of Polymethylmethacrylate Bone Cement Spreading as a Function of Viscosity, Bone Porosity, and Flow Rate. Spine 2008, 33 (12), 1352–1359. Maestretti, G.; Cremer, C.; Otten, P.; Jakob, R. P. Prospective Study of Standalone Balloon Kyphoplasty With Calcium Phosphate Cement Augmentation in Traumatic Fractures. Eur. Spine J. 2007, 16 (5), 601–610. Marco, R. A.; Kushwaha, V. P. Thoracolumbar Burst Fractures Treated With Posterior Decompression and Pedicle Screw Instrumentation Supplemented With Balloon-Assisted Vertebroplasty and Calcium Phosphate Reconstruction. J. Bone Jt. Surg. Am. 2009, 91 (1), 20–28. Martin, J. B.; Jean, B.; Sugiu, K.; et al. Vertebroplasty: Clinical Experience and Follow-Up Results. Bone 1999, 25 (2 Suppl.), 11S–15S. Matsuyama, Y.; Goto, M.; Yoshihara, H.; et al. Vertebral Reconstruction With Biodegradable Calcium Phosphate Cement in the Treatment of Osteoporotic Vertebral Compression Fracture Using Instrumentation. J. Spinal Disord. Tech. 2004, 17 (4), 291–296. McGirt, M. J.; Parker, S. L.; Wolinsky, J. P.; Witham, T. F.; Bydon, A.; Gokaslan, Z. L. Vertebroplasty and Kyphoplasty for the Treatment of Vertebral Compression Fractures: An Evidenced-Based Review of the Literature. Spine J. 2009, 9 (6), 501–508. Motoyoshi, M.; Ueno, S.; Okazaki, K.; Shimizu, N. Bone Stress for a Mini-Implant Close to the Roots of Adjacent Teeth – 3D Finite Element Analysis. Int. J. Oral Maxillofac. Surg. 2009, 38 (4), 363–368. Mousavi, P.; Roth, S.; Finkelstein, J.; Cheung, G.; Whyne, C. Volumetric Quantification of Cement Leakage Following Percutaneous Vertebroplasty in Metastatic and Osteoporotic Vertebrae. J. Neurosurg. 2003, 99 (1 Suppl.), 56–59. Nakano, M.; Hirano, N.; Ishihara, H.; Kawaguchi, Y.; Matsuura, K. Calcium Phosphate Cement Leakage after Percutaneous Vertebroplasty for Osteoporotic Vertebral Fractures: Risk Factor Analysis for Cement Leakage. J. Neurosurg. Spine 2005, 2 (1), 27–33. Nakano, M.; Hirano, N.; Matsuura, K.; et al. Percutaneous Transpedicular Vertebroplasty With Calcium Phosphate Cement in the Treatment of Osteoporotic Vertebral Compression and Burst Fractures. J. Neurosurg. 2002, 97 (3 Suppl.), 287–293. Nakano, M.; Hirano, N.; Zukawa, M.; et al. Vertebroplasty Using Calcium Phosphate Cement for Osteoporotic Vertebral Fractures: Study of Outcomes at a Minimum Follow-up of Two Years. Asian Spine J. 2012, 6, 34–42. Oner, F. C.; van Gils, A. P.; Dhert, W. J.; Verbout, A. J. MRI Findings of Thoracolumbar Spine Fractures: A Categorisation Based on MRI Examinations of 100 Fractures. Skeletal Radiol. 1999a, 28 (8), 433–443.

Injectable Bone Cements for Spinal Column Augmentation: Materials for Kyphoplasty/Vertebroplasty

215

Oner, F. C.; vd Rijt, R. H.; Ramos, L. M.; Groen, G. J.; Dhert, W. J.; Verbout, A. J. Correlation of MR Images of Disc Injuries With Anatomic Sections in Experimental Thoracolumbar Spine Fractures. Eur. Spine J. 1999b, 8 (3), 194–198. Oner, F. C.; Verlaan, J. J.; Verbout, A. J.; Dhert, W. J. Cement Augmentation Techniques in Traumatic Thoracolumbar Spine Fractures. Spine 2006, 31 (11 Suppl.), S89–S95. Ooms, E. M.; Wolke, J. G.; van de Heuvel, M. T.; Jeschke, B.; Jansen, J. A. Histological Evaluation of the Bone Response to Calcium Phosphate Cement Implanted in Cortical Bone. Biomaterials 2003, 24 (6), 989–1000. Padovani, B.; Kasriel, O.; Brunner, P.; Peretti-Viton, P. Pulmonary Embolism Caused by Acrylic Cement: A Rare Complication of Percutaneous Vertebroplasty. AJNR Am. J. Neuroradiol. 1999, 20 (3), 375–377. Perrin, C.; Jullien, V.; Padovani, B.; Blaive, B. Percutaneous Vertebroplasty Complicated by Pulmonary Embolus of Acrylic Cement. Rev. Mal Respir. 1999, 16 (2), 215–217. Perry, A.; Mahar, A.; Massie, J.; Arrieta, N.; Garfin, S.; Kim, C. Biomechanical Evaluation of Kyphoplasty With Calcium Sulfate Cement in a Cadaveric Osteoporotic Vertebral Compression Fracture Model. Spine J. 2005, 5 (5), 489–493. Plachokova, A.; Link, D.; van den, D. J.; van den, B. J.; Jansen, J. Bone Regenerative Properties of Injectable PGLA-CaP Composite With TGF-Beta1 in a Rat Augmentation Model. J. Tissue Eng. Regen. Med. 2007a, 1 (6), 457–464. Plachokova, A. S.; van den, D. J.; Stoelinga, P. J.; Jansen, J. A. Early Effect of Platelet-Rich Plasma on Bone Healing in Combination With an Osteoconductive Material in Rat Cranial Defects. Clin. Oral Implants Res. 2007b, 18 (2), 244–251. Ploeg, W. T.; Veldhuizen, A. G.; The, B.; Sietsma, M. S. Percutaneous Vertebroplasty as a Treatment for Osteoporotic Vertebral Compression Fractures: A Systematic Review. Eur. Spine J. 2006, 15 (12), 1749–1758. Prymka, M.; Puhler, T.; Hirt, S.; Ulrich, H. W. Extravertebral Cement Drainage With Occlusion of the Extradural Venous Plexus Into the Vena Cava After Vertebrobplasty. Case Report and Review of the Literature. Unfallchirurg 2003, 106 (10), 860–864. Puska, M. A.; Kokkari, A. K.; Narhi, T. O.; Vallittu, P. K. Mechanical Properties of Oligomer-Modified Acrylic Bone Cement. Biomaterials 2003, 24 (3), 417–425. del Real, R. P.; Wolke, J. G.; Vallet-Regi, M.; Jansen, J. A. A New Method to Produce Macropores in Calcium Phosphate Cements. Biomaterials 2002, 23 (17), 3673–3680. Ruhe, P. Q.; Hedberg-Dirk, E. L.; Padron, N. T.; Spauwen, P. H.; Jansen, J. A.; Mikos, A. G. Porous Poly(DL-Lactic-Co-Glycolic Acid)/Calcium Phosphate Cement Composite for Reconstruction of Bone Defects. Tissue Eng. 2006, 12 (4), 789–800. Ruhe, P. Q.; Hedberg, E. L.; Padron, N. T.; Spauwen, P. H.; Jansen, J. A.; Mikos, A. G. rhBMP-2 Release From Injectable Poly(DL-Lactic-Co-Glycolic Acid)/Calcium-Phosphate Cement Composites. J. Bone Jt. Surg. Am. 2003, 85A (Suppl. 3), 75–81. Sabokbar, A.; Fujikawa, Y.; Murray, D. W.; Athanasou, N. A. Radio-Opaque Agents in Bone Cement Increase Bone Resorption. J. Bone Jt. Surg. Br. 1997, 79 (1), 129–134. Saito, M.; Maruoka, A.; Mori, T.; Sugano, N.; Hino, K. Experimental Studies on a New Bioactive Bone Cement: Hydroxyapatite Composite Resin. Biomaterials 1994, 15 (2), 156–160. Schmidt, R.; Cakir, B.; Mattes, T.; Wegener, M.; Puhl, W.; Richter, M. Cement Leakage During Vertebroplasty: An Underestimated Problem? Eur. Spine J. 2005, 14, 466–473. Schmitz, J. P.; Hollinger, J. O.; Milam, S. B. Reconstruction of Bone Using Calcium Phosphate Bone Cements: A Critical Review. J. Oral Maxillofac. Surg. 1999, 57 (9), 1122–1126. Sullivan, S. J.; Topoleski, L. D. Influence of Initial Component Temperature on the Apparent Viscosity and Handling Characteristics of Acrylic (PMMA) Bone Cement. J. Biomed. Mater. Res. B Appl. Biomater. 2007, 81 (1), 224–230. Taylor, R. S.; Taylor, R. J.; Fritzell, P. Balloon Kyphoplasty and Vertebroplasty for Vertebral Compression Fractures: A Comparative Systematic Review of Efficacy and Safety. Spine 2006, 31 (23), 2747–2755. Togawa, D.; Bauer, T. W.; Lieberman, I. H.; Takikawa, S. Histologic Evaluation of Human Vertebral Bodies After Vertebral Augmentation With Polymethyl Methacrylate. Spine 2003, 28 (14), 1521–1527. Tohmeh, A. G.; Mathis, J. M.; Fenton, D. C.; Levine, A. M.; Belkoff, S. M. Biomechanical Efficacy of Unipedicular Versus Bipedicular Vertebroplasty for the Management of Osteoporotic Compression Fractures. Spine 1999, 24 (17), 1772–1776. Trout, A. T.; Kallmes, D. F. Does Vertebroplasty Cause Incident Vertebral Fractures? A Review of Available Data. AJNR Am. J. Neuroradiol. 2006, 27 (7), 1397–1403. Vallo, C. I.; Montemartini, P. E.; Fanovich, M. A.; Porto Lopez, J. M.; Cuadrado, T. R. Polymethylmethacrylate-Based Bone Cement Modified With Hydroxyapatite. J. Biomed. Mater. Res. 1999, 48 (2), 150–158. Verlaan, J. J.; Cumhur, O. F.; Dhert, W. J. Anterior Spinal Column Augmentation With Injectable Bone Cements. Biomaterials 2005a, 27 (3), 290–301. Verlaan, J. J.; Dhert, W. J.; Verbout, A. J.; Oner, F. C. Balloon Vertebroplasty in Combination With Pedicle Screw Instrumentation: A Novel Technique to Treat Thoracic and Lumbar Burst Fractures. Spine 2005b, 30 (3), E73–E79. Verlaan, J. J.; Diekerhof, C. H.; Buskens, E.; et al. Surgical Treatment of Traumatic Fractures of the Thoracic and Lumbar Spine: A Systematic Review of the Literature on Techniques, Complications, and Outcome. Spine 2004a, 29 (7), 803–814. Verlaan, J. J.; van Helden, W. H.; Oner, F. C.; Verbout, A. J.; Dhert, W. J. Balloon Vertebroplasty With Calcium Phosphate Cement Augmentation for Direct Restoration of Traumatic Thoracolumbar Vertebral Fractures. Spine 2002, 27 (5), 543–548. Verlaan, J. J.; Oner, F. C.; Slootweg, P. J.; Verbout, A. J.; Dhert, W. J. Histologic Changes After Vertebroplasty. J. Bone Jt. Surg. Am. 2004b, 86A (6), 1230–1238. Verlaan, J. J.; Oner, F. C.; Verbout, A. J.; Dhert, W. J. Temperature Elevation After Vertebroplasty With Polymethyl-Methacrylate in the Goat Spine. J. Biomed. Mater. Res. 2003, 67B (1), 581–585. Verlaan, J. J.; Somers, I.; Dhert, W. J.; Oner, F. C. Clinical and Radiological Results 6 Years after Treatment of Traumatic Thoracolumbar Burst Fractures With Pedicle Screw Instrumentation and Balloon Assisted Endplate Reduction. Spine J. 2015, 15, 1172–1178. Voormolen, M. H.; Mali, W. P.; Lohle, P. N.; et al. Percutaneous Vertebroplasty Compared With Optimal Pain Medication Treatment: Short-Term Clinical Outcome of Patients With Subacute or Chronic Painful Osteoporotic Vertebral Compression Fractures. The Vertos Study. AJNR Am. J. Neuroradiol. 2007, 28 (3), 555–560. Wang, X.; Ye, J.; Wang, Y. Influence of a Novel Radiopacifier on the Properties of an Injectable Calcium Phosphate Cement. Acta Biomater. 2007, 3 (5), 757–763. Wardlaw, D.; Cummings, S. R.; Van, M. J.; et al. Efficacy and Safety of Balloon Kyphoplasty Compared With Non-Surgical Care for Vertebral Compression Fracture (FREE): A Randomised Controlled Trial. Lancet 2009, 373 (9668), 1016–1024. Weinstein, J. N. Balancing Science and Informed Choice in Decisions About Vertebroplasty. N. Engl. J. Med. 2009, 361 (6), 619–621. Whyne, C. M.; Hu, S. S.; Lotz, J. C. Burst Fracture in the Metastatically Involved Spine: Development, Validation, and Parametric Analysis of a Three-Dimensional Poroelastic Finite-Element Model. Spine 2003, 28 (7), 652–660. Yamamuro, T.; Nakamura, T.; Iida, H.; et al. Development of Bioactive Bone Cement and Its Clinical Applications. Biomaterials 1998, 19, 1479–1482. Yeom, J. S.; Kim, W. J.; Choy, W. S.; Lee, C. K.; Chang, B. S.; Kang, J. W. Leakage of Cement in Percutaneous Transpedicular Vertebroplasty for Painful Osteoporotic Compression Fractures. J. Bone Jt. Surg. Br. 2003, 85 (1), 83–89. Zhao, F.; Lu, W. W.; Luk, K. D. K.; et al. Surface Treatment of Injectable Strontium-Containing Bioactive Bone Cement for Vertebroplasty. J. Biomed. Mater. Res. B 2004, 69B, 79–86.