Bone cements for percutaneous vertebroplasty and balloon kyphoplasty: Current status and future developments.

Introduction

Ageing has become a global issue as a result of improved living conditions and health care [1] . Due to inadequate calcium and vitamin D intake, as well as reduced daily activities, there is a high incidence of osteoporosis in the elderly. As a result, osteoporosis with subsequent vertebral compression fractures (VCFs) has evolved into a common social and economic burden globally. The annual incidence of osteoporotic fractures exceeds 1.5 million in the US, of which more than 50% are VCFs, and this is twice the incidence of hip fractures [2] . About 20% of individuals over 50 years old and 45% of women over 50 experience OVCFs. If left untreated, OVCFs may lead to dramatic physical, functional, and psychological consequences that impair the quality of life of the patient [3] . VCF patients usually suffer from severe back pain. Moreover, restrictive lung diseases may develop when there are multiple thoracic fractures [4] . In the worst cases, female VCF patients have a 23% higher mortality rate compared to those without VCFs [5] . Until recently, conservative treatments have been the only options [6] .

In order to reduce the morbidity of patients with acute OVCFs and improve their life quality, vertebroplasty (VP), a minimally invasive surgery (MIS), was developed in the 1980s by Galibert et al [7] ( Fig. 1 A,B). By using a needle to deliver bone cement to fractured vertebra through the pedicle of the vertebral arch, the VP technique successfully relieved the pain of 75–85% of patients [8] . Compared to conservative treatments, VP is safe, the pain relief after surgery is immediate, and the effect can last for at least 1 year [6] . However, VP does not restore the height of the compressed vertebral body (VB), which may reoccur in the later stage of treatment such that the patients still suffer from kyphosis and chronic low back pain. A variation of VP, kyphoplasty (KP), attempts to restore the height and angle of kyphosis of a fractured VB and to stabilize it using injected bone cement. BKP, developed in the 1990s by Dr Mark Reiley, is the most commonly used KP technique. BKP involves the use of a balloon to create a cavity within the cancellous bone, followed with bone cement delivery to the cavity to reinforce the VB ( Fig. 1 A,C). Using this technique, BKP not only relieves the back pain of the patient, but also corrects deformities such as kyphosis. BKP also provides controlled cement filling to make the cement more uniformly distributed within the VB. While the extent of pain relief is similar, BKP results in markedly fewer complications and has a lower risk of mortality than VP [9] , [10] . However, the survival rates for VCF patients following VP or BKP were all markedly higher than nonoperated patients [10] . Figure 1 (A) A schematic illustration of VP and BKP procedures. (B) VP for a patient with severe vertebral compression: (a–c) lateral, anteroposterior X-ray radiographs and sagittal MR image showing severe H-shaped VCF at the T9 VB; (d) postoperational lateral radiograph showing the VB filling with cement. (C) BKP for a patient with L1 vertebral compression: (a–b) X-ray radiograph and MR image showing a compression fracture at the L1 VB; (c) fluoroscopy image showing the filling of bone cement in a cavity created by a balloon; (d,e) anteroposterior and sagittal fluoroscopy images showing complete filling of bone cement and restoration of vertebral height after BKP BKP = balloon kyphoplasty; MR = magnetic resonance; VB = vertebral body; VCF = vertebral compression fracture; VP = vertebroplasty. Note . Figure 1 B is from “Unilateral versus bilateral vertebroplasty for severe osteoporotic vertebral compression fractures,” by C. Chen et al, 2014, J Spinal Disord Tech 2014;27:E301–E304 [73] . Reproduced with permission.

Apparently, the filling material, i.e., the bone cement, plays a critical role in the effectiveness of VP or BKP treatments. Bone cements for VP or BKP are self-curing compounds that are applied in a flowable state and become fully cured in the body to provide adequate support to the fractured VB. They must have considerable mechanical strength and toughness in order to achieve long-term sustainability. They should have adequate viscosity and be injectable for facilitating VP or BKP surgeries. In addition, they should have appropriate working and setting times to match the general progress of surgeries. They should also be radiopaque and present clear contrast under fluoroscopy. These fundamental requirements make VP and BKP bone cements a special category, which largely differs from the cements for other purposes such as total hip arthroplasty (THA) or total knee arthroplasty (TKA).

To date, the most popular bone cement is poly(methyl methacrylate) (PMMA)-based acrylic bone cement (ABC). However, several drawbacks of PMMA, including nonbiodegradability, monomer toxicity, heat generation during exothermic polymerization, and leakage of monomer, limit its applications. To overcome these disadvantages, biodegradable calcium phosphate cements (CPCs) and other types of cements that generate no or little heat upon curing have been developed and their applications in VP and BKP have been recently explored. In this article, we summarize the bone cements that are currently available in the market and have been clinically used. We also provide our perspectives on the future development of bone cements for VP and BKP.

ABCs

In 1958, Dr John Charnley [11] first started to use self-curing PMMA cement in total hip replacement (THR) and succeeded in anchoring femoral head prostheses in the femur. Since this major breakthrough, use of PMMA-based bone cements has prevailed in various orthopaedic applications. In 1987, Galibert et al [7] first used PMMA bone cement to treat cervical vertebral haemangioma in patients. Since then, this technique has been successfully applied to many spine disorders including OVCFs, vertebral metastasis of malignant tumours, multiple myeloma, and even traumatic VCFs. In 2004, the Food and Drug Administration (FDA) formally approved PMMA bone cements for treating vertebral fractures resulting from osteoporosis and tumours. Advantages such as bio-inertness, ease of handling, considerable mechanical strength, and cost-effectiveness make PMMA an ideal choice for bone cement. To date, ABCs represent the vast majority of bone cements for VP and BKP.

Compositions of ABCs

The main components of ABCs are acrylic compounds that are capable of self-curing. All of them are composed of solid and liquid phases. When the solid and liquid phases of an ABC are mixed, curing occurs rapidly at room or body temperatures. The compositions of ABCs only vary slightly. A large number of cement brands have been developed and are commercially available ( Table 1 ). Table 1 Commercially available acrylic bone cements (ABCs). Brand Prepolymer Monomer Radiopacifier Initiator and additives Working time (min) Setting time (min) Viscosity Bending modulus (MPa) Bending strength (MPa) Compressive strength (MPa) Supplier CMW1 PMMA: 88.85% MMA: 99.18% BaSO 4 : 9.1% BPO: 2.05% DMPT: 0.82% HQ: 0.0025% 6.5 11 High 2634 67.81 94.4 Depuy CMW2 PMMA: 86.7% MMA: 99.18% BaSO 4 : 11.3% BPO: 2.0% DMPT: 0.82% HQ: 0.0025% 3 6 High 3008 74.3 97.8 Depuy CMW3 PMMA: 88.0% MMA: 97.5% BaSO 4 : 10% BPO: 2.0% DMPT: 2.50% HQ: 0.0025% 5.5 11 Medium 2764 70.3 96.3 Depuy Smartset HV PMMA-co-PMA: 84% MMA: 97.5% ZiO 2 : 15% BPO: 1% DMPT: 2.5% HQ: 0.0075% 8.0 12.5 High 3010 64.32 86.54 Depuy Endurance PMMA: 67.5% PMMA-co-PS: 21.1% MMA: 98.0% BaSO 4 : 10% BPO: 1.85% DMPT: 2.0% HQ: 0.0011% 8.0 14 Low 2896 76.1 94 Depuy Smartset MV PMMA-co-PS: 15–30% PMMA: >50.0% MMA: >50.0% BaSO 4 : 5–10% BPO: 1–3% DMPT: ≤2.0% 8.0 14 Medium 3010 64.32 70 Depuy Simplex P PMMA-co-PS: 73.5% PMMA:15% MMA: 97.45% BaSO 4 : 10% BPO: 1.5% DMPT: 2.55% HQ: 0.008% 7 14.3 Medium 2681 71 90.32 Stryker Spineplex PMMA: 8.51% PMMA-co-PS: 58.3% MMA: 97.5% BaSO 4 : 30% BPO: 1.5% DMPT: 2.5% HQ: 0.0079% 10–12 8.7 Low 55.1 80.91 Stryker Palacos ® R PMA: 83.9% MMA: 97.98% ZiO 2 : 15.3% BPO: 0.8% DMPT: 2.0% 5.0 12.5 High 2628 72.2 79.6 Heraeus Osteopal V PMMA-co-PMA: 54.6% MMA: 97.87% ZiO 2 : 45% BPO: 0.38% DMPT: 2.13% HQ 8 14 Low 3504 ± 235 46 ± 8 82 ± 3 Heraeus Cobalt HV PMMA-co-PMA: 83.55–84.65% MMA: 98% ZiO 2 : 14.9% BPO: 0.5–1.6% DMPT: 4.27% 5 10 High 67.84 96.04 Biomet Osteobond PMMA-co-PS: 88.75% MMA: 99.26% BaSO 4 : 10% BPO:1.25% DMPT: 0.745% HQ: 0.008% 5 14.5 Low 2828 73.7 104.6 Zimmer KyphX HV-R PMMA-co-PS: 68% MMA: 99.11% BaSO 4 : 30% BPO: 2% DMPT: 0.888% HQ: 0.0075% 8 20 High 111 Kyphon ABC PMMA-co-PS: 99.55% MMA: 99% BPO: 4.5% DMPT: 1% HQ: 0.006% 4.5–6.5 12 Medium 3300 68 93 Tianjin Institute of Synthetic Materials Industry BaSO 4 = barium sulphate; BPO = benzoyl peroxide; DMPT = N – N -dimethyl- p -toluidine; HQ = hydroquinone; HV = high viscosity; MMA = methyl methacrylate; MPa = megapascals; MV = medium viscosity; PMA = poly(methyl acrylate); PMMA-co-PMA = methyl methacrylate-methylacrylate copolymer; PMMA-co-PS = methyl methacrylate-styrene copolymer; ZiO 2 = zirconium dioxide.

The solid phase of an ABC mainly comprises PMMA prepolymer and/or copolymers of acrylic acid (AA), ethyl acrylate (EA), methyl acrylate (MA), MMA, and styrene. The average molecular weight of the prepolymers ranges from 44,000 to 1,980,000, and the bead size ranges from 30 μm to 150 μm. The prepolymer powder accounts for approximately 80 wt% of bone cement. The solid phase also contains benzoyl peroxide (BPO) as the initiator, at a concentration of 0.75–2.5 wt%. In addition, radiopacifiers, such as barium sulfate, zirconium dioxide, tantalum, and tungsten powders, are included in the powder to make the cement radiographically visible. Their concentration is generally 10–30 wt% of powder, and their particle size is around 5 μm [12] , [13] . In order to prevent infection, some commercial products also supplement antibiotics, including gentamicin, keflin, erythromycin, and colistin, to the powder. Occasionally, dyes or pigments such as chlorophyll may also be supplemented to provide additional features to cements.

The main composition of the liquid phase is MMA monomer, usually at a concentration of 95 wt%. In order to initiate polymerization, an activator N - N -dimethyl- p -toluidine (DMPT) is usually supplied (0.89–2.7 wt%). In addition, the liquid phase contains an inhibitor, usually hydroquinone (HQ), which functions to inhibit premature polymerization during storage [12] , [13] .

Current development of ABCs

Although the ABC industry is mature and a broad range of products have appeared in the market, some drawbacks of ABCs cannot be ignored, including nondegradability and significant mechanical mismatch with the VB. As such, many efforts have been made to improve the products in terms of mechanical characteristics, porosity, biodegradability, and to provide additional merits such as osteoconductivity and drug delivery capability [14] , [15] , [16] . Such improvements are mainly achieved by fabricating composite materials using ABCs and filling materials of desired properties.

Cortoss Bone Augmentation Material represents a typical composite ABC. It is a polymer–inorganics composite consisting of crosslinking resins and reinforcing glass ceramic particles. It consists of a terpolymer resin containing Bisphenol-A-glycidyl dimethacrylate (Bis-GMA), Bisphenol-A-ethoxy dimethacrylate (Bis-EMA), and triethyleneglycol dimethacrylate (TEGDMA). It is supplemented with bioactive combeite glass–ceramic particles for stimulating bone apposition at the interface, barium boroaluminosilicate glass for providing radiopacity and strength, and silica particles for achieving adequate viscosity [17] . It functions to strengthen weakened bone and achieves a compressive strength equal to approximately 75% of human cortical bone (210 megapascals, MPa) within 15 minutes of application [18] .

The porosity of ABC significantly affects its mechanical and biological performance. Ideally, the cured cement as an implant material within the VB should contain pores of varying size and distribution to mimic the trabecular-like structure of the VB. However, such a porous structure inevitably weakens the mechanical properties of the cement. Therefore, it is desired to have a composite cement in which biodegradable fillers are embedded throughout the cement to provide enough initial mechanical strength. When they degrade, new bone ingrowth happens so that the voids are filled with new bone tissue to continuously provide adequate mechanical support to the VB [19] .

A radiopacifier is an essential component in VP and BKP cements. However, addition of traditional radiopacifiers significantly lowers the mechanical strength of ABCs. In order to provide the ABC with adequate radiopacity yet minimize mechanical property loss, new radiopacifiers have been developed. For example, owing to the high radiopacity of organobismuth, ABCs containing bismuth salicylate showed higher radiopacity and better injection properties compared to current commercial bone cements while retaining good mechanical properties [15] . Surface functionalization of existing radiopacifiers also appeared to effectively improve the mechanical properties of cements [20] , [21] .

CPCs

A category of biodegradable bone cements, CPCs, were first invented by Brown and Chow in the early 1980s [22] . Compared to ABCs, CPCs hold a unique combination of osteoconductivity, injectability, mouldability, biodegradability, nonexothermic setting, and negligible shrinkage. CPCs upon mixing form a viscous paste that can be easily manipulated and moulded. Importantly, they can be injected into the defect area and harden in vivo without generating heat [23] . Therefore, CPCs are potentially an ideal filling material for VP and BKP applications.

In general, all CPCs consist of a powder phase containing one or more calcium phosphate (CaP) compounds ( Table 2 ) and a liquid phase, which can be water or a calcium- or phosphate-containing aqueous solution. Despite the large number of CaP combinations in different CPC systems ( Table 3 ), the setting chemistry is similar—dissolution and reprecipitation [22] . Based on the nature of the end hydration product, which depends on the pH of the cement paste, CPCs can be divided into two categories: apatite (hydroxyapatite, HA; or calcium-deficient hydroxyapatite, CDHA) (formed at pH > 4.2) and brushite (dicalcium phosphate dehydrate, DCPD) (formed at pH < 4.2) [24] . At a physiological pH, brushite is one to two orders of magnitude more soluble than apatite and degrades faster [25] . Due to the short setting time, low mechanical strength, and inferior injectability, brushite cements only have limited clinical applications [26] . Table 2 Calcium orthophosphates commonly used in bone cements [64] , [74] . Compound name Abbreviation Chemical formula Ca/P ratio Amorphous calcium phosphate ACP Ca 3 (PO 4 ) 2 ·nH 2 O 1.2–2.2 Calcium-deficient hydroxyapatite CDHA Ca 10−x (HPO 4 ) x (PO 4 ) 6–x (OH) 2–x (0 < × < 1) 1.5–1.67 Dicalcium phosphate anhydrous DCPA CaHPO 4 1.00 Dicalcium phosphate dihydrate DCPD CaHPO 4 ·2H 2 O 1.00 Hydroxyapatite HA Ca 10 (PO 4 ) 6 (OH) 2 1.67 Monocalcium phosphate anhydrous MCPA Ca(H 2 PO 4 ) 2 0.50 Monocalcium phosphate monohydrate MCPM Ca(H 2 PO 4 ) 2 ·H 2 O 0.50 Octacalcium phosphate OCP Ca 8 H 2 (PO 4 ) 6 1.33 Tetracalcium phosphate TTCP Ca 4 (PO 4 ) 2 O 2.00 α-Tricalcium phosphate α-TCP α-Ca 3 (PO 4 ) 2 1.50 β-Tricalcium phosphate β-TCP β-Ca 3 (PO 4 ) 2 1.50 Table 3 Commercially available calcium phosphate cements (CPCs). Brand Powder composition Initial setting time Full hardening time End product Porosity Pore size (μm) Degradability Injectability Compressive strength (MPa) Supplier BoneSource 72.3% TTCP, 27.7% DCPA 7 min 4 h Apatite 5–10% 33.4 ± 6.2 Minimal No 26 Stryker Norian SRS α-TCP, CaCO 3 , MCPM 10–15 min 12 h Carbonated apatite 50% 47.2 ± 21.9 Yes Yes 50 Synthes α-BSM ACP, DCPD 15–20 min 1 h Apatite 80% <1 Yes Yes 4 ETEX Biopex 75% α-TCP, 18% TTCP, 5% DCPD, 2% HA 7–10 min 24 h Apatite 40–50% Yes Yes 80 Mitsubishi Calcibon α-TCP, DCPA, CaCO 3 , HA 10 min 6 h Carbonated apatite 30–40% 41.6 ± 22.0 Yes Yes 60 Biomet-Merck Cementek α-TCP, TTCP, Ca(OH) 2 3–15 min 24–48 h Apatite 50% 26 Yes Yes 13 Teknimed Graftys HBS HA, TCP 15 min 72 h Apatite 65–70% 100–300 Yes Yes 12 Graftys Graftys Quickset HA, TCP 8 min 24 h Apatite 70% 10–100 Yes Yes 24 Graftys Ostim HA 20 min Apatite 53% 70 Yes Yes 0.24 Hereaus chronOS Inject β-TCP, DCPD 6–12 min 24 h Brushite 60–75% 70–170 Yes Yes 3 Synthes Embarc ACP, DCPD Apatite Yes Lorenz Surgical Fracture Grout α-TCP, CaCO 3 Apatite Yes Norian Eurobone TCP, DCPD 3–15 min Apatite 2% 162.2 ± 107.1 Yes 17 FH Orthopedics KyphOs FS 5 min 24 h Apatite Yes 61 Kyphon ACP = amorphous calcium phosphate; DCPD = dicalcium phosphate dihydrate; HA = hydroxyapatite; MCPM = monocalcium phosphate monohydrate; TCP = tricalcium phosphate; TTCP = tetracalcium phosphate.

Biocompatibility and degradability of CPCs

Since CPCs consist of a network of CaP crystals that resemble the HA in native bone tissue, they are considered biocompatible and osteoconductive. In vivo , CPCs may undergo passive and/or active absorption. The passive absorption relies mainly on solubility and dispersion of the materials. The active resorption is related to the activity of osteoclasts. Bone formation is initiated as soon as the active and/or passive resorption of CPCs starts. Woven bone usually forms after approximately 2 weeks. Depending on the specific characteristics of CPCs, the implanted site may be almost completely converted to bone within a few months to a couple of years [27] . In addition, CPCs may have bone-like elastic modulus, which helps prevent stress shielding and maintain adequate toughness to prevent fatigue fracture under cyclic loading [28] .

Intrinsically, CPCs have nano/micron-sized pores. Their porosity is approximately 30–50% [29] . While porosity can be a limitation for them to be used in high load-bearing sites, such a porous structure enables fluid exchange and inclusion of growth factors, matrix proteins, and cells [30] . The micropores also significantly contribute to the resorption of CPCs and replacement of them by newly formed bone. Owing to their inherent porosity, CPCs have been widely used as carriers for controlled drug delivery [29] , [31] . Being able to function as both a supporting material and a delivery system to release bioactive substances, CPCs have been considered a promising cement material for bone defect repair and vertebral augmentation.

Reinforcement of CPCs

From a clinical point of view, the mechanical strength of a cement material should be similar to or greater than cancellous bone. Although CPCs are highly promising for bone regeneration, the usually poor mechanical properties constitute a major challenge toward their applications. To date, CPCs are mainly used at non- or moderate load-bearing sites [22] . Therefore, mechanical reinforcement has been a major challenge in CPC development. In addition to chemical composition ( Table 3 ), the mechanical properties of CPCs are markedly affected by granularity, crystal type, powder/liquid ratio, and porosity.

Since CPCs are porous, decreasing the porosity by compacting the cement paste prior to hydration has an immediate boosting effect on their mechanical properties, while increasing pore density and size causes mechanical strength loss [32] . However, when CPC is compacted enough and its porosity reaches a critical level (< 30%), its strength becomes constant [33] . It should be noted that while pressurization improves the mechanical strength of CPCs, it also deteriorates their injectability, making it difficult for them to be used in MIS procedures [22] .

Supplementation of certain compounds, including small organic molecules, biodegradable polymers, proteins, polysaccharides, inorganic molecules, bioceramics, and bioglass, has proven effective in improving the mechanical properties of CPCs. For example, adding citric acid into an apatite cement paste increased both the injectability and strength of the cement. This is likely because the citrate ions facilitated the sliding and dispersion of apatite crystals, inducing their growth and entanglement to form a stronger matrix [34] . When CPC was blended with a silanised-hydroxypropyl methylcellulose (Si-HPMC) hydrogel, the mechanical and handling properties were improved, yet the rheological property was not affected [35] . Recently, we found that supplementing silk fibroin (SF) to CPCs helped improve their mechanical strength and washout resistance [36] . Further, when a mineralized complex, HA–SF, was supplemented to the CPC/SF composite, the compressive strength of the composite increased in a HA–SF content-dependent fashion, likely due to the improved interfacial integrity and the presence of nucleation seeds, which induced oriented growth of HA crystals [37] .

Inclusion of fibres, either nondegradable or biodegradable, into CPCs can also improve their mechanical strength, probably through a crack-arresting mechanism [22] , [38] . Depending on the strength, length, volume fraction, and orientation of fibres, and fibre–matrix interfacial adhesion, the mechanical properties of fibre-reinforced CPCs (frCPCs) may be up to two orders of magnitude higher than CPCs, which permits their potential in load-bearing applications [24] , [38] . Commonly used nondegradable fibres include polyamides, carbon fibres, and glass fibres. Biodegradable fibres include natural biomolecules such as proteins (e.g., collagen) and polysaccharides (e.g., chitosan) or synthetic polymers such as poly(glycolic acid) (PGA), polylactide (PLA), poly(lactic-co-glycolic acid) (PLGA), and polycaprolactone (PCL). In addition to the relatively long fibres, whiskers made of HA, calcium carbonate, silicon nitride, silicon carbide, or bioglass have also been used for improving the mechanical strength of CPCs [39] , [40] .

CPCs for VP and BKP

While no commercially available CPC products have been approved specifically for VP and BKP purposes, there have indeed been many off-label uses of CPCs ( Table 3 ) for vertebral augmentation and spinal fusion. According to biomechanical tests of vertebra filled with CPCs or PMMA by VP/KP procedures, CPCs could restore the strength but not stiffness of vertebra [41] . In the treatment of fractured vertebra, both PMMA and CPCs restored strength and stiffness and resulted in similar anterior vertebral height restoration [42] .

Using a canine VP model, Turner et al [43] compared the histological responses and mechanical characteristics of VBs injected with CPC (BoneSource, Stryker) or PMMA. Histologically, both cement materials were well integrated to VB bone tissue. Unlike PMMA, CPC underwent resorption and remodelling with vascular invasion and bone ingrowth, indicating its excellent biocompatibility and osteoconductivity. There was no significant difference in VB height and compressive strength between PMMA- and CPC-treated VBs. Interestingly, the compressive strength of CPC-treated VBs continuously increased, whereas PMMA-treated VBs presented decreased compressive strength, indicating that CPC injection might have both intermediate and short-term effects in treating vertebral defects.

The inconsistency of degradability of CPCs, possibly due to the complexity in their composition, setting chemistry, and environment, may present a major limitation toward their clinical usage. For example, it has been reported that no resorption of BoneSource was observed after several years of implantation [44] . However, Turner et al [43] found that BoneSource indeed degraded in a canine VP model. Another study reported that approximately 30% of BoneSource was resorbed and replaced with bone after only 12 weeks, and 90% degraded after 40 weeks [45] .

Strontium-substituted CPCs

Strontium belongs to the same family as calcium in the Periodic Table of Elements. Systematic administration of strontium ranelate has been used to prevent bone loss and stimulate bone regeneration [46] . Taking advantage of the dual functions of strontium, strontium-modified CPC systems (Sr-CPCs) have recently been explored in order to develop novel bioactive bone cements [47] , [48] , [49] , [50] , [51] . Different ways to introduce strontium into the CPC paste, however, may result in very different end products. When amorphous Sr-substituted CaP and DCPD were mixed half and half, strontium could be doped into the lattice of the HA, which increased the lattice dimension and volume. However, when a mixture of amorphous CaP and amorphous strontium phosphate (SrP) were blended with DCPD, the HA and Sr-hydroxyapatite (Sr-HA) precipitated separately in the hydrated cement [52] . Therefore, in the majority of studies, Sr-containing CaP was first synthesized and then supplemented to the CPCs.

The supplementation of strontium to CPCs causes the release of biologically effective doses of Sr 2+ , which stimulates bone formation in and around the implant and enhances osseointegration. In a critical-size metaphyseal defect in the femur of ovariectomised rats filled with Sr-CPC and CPC, a significant increase in bone formation was achieved in the Sr-CPC group compared to the CPC group [48] . However, the release of strontium from the Sr-CPC implants did not lead to a serum Sr 2+ level that was sufficiently high to induce systemic bone mass increase [49] .

In addition to promoting bone formation, Sr-CPCs also show improved mechanical properties. Compared to nonsubstituted CPCs, the compressive strength of Sr-CPCs can achieve a high of 74.9 MPa [50] , [53] and may be further improved upon surface treatment of the Sr compounds. When the Sr-HA powder was surface-treated using acrylolpamidronate, the compression strength and stiffness of the Sr-HA cement were improved by 22% and 14%, respectively [54] .

Furthermore, Sr-CPCs are radiopaque cements. The radiopacity of brushite cements containing 10 wt% strontium halides was similar to or higher than that of commercial radiopaque cements, which usually contain 20 wt% or more radiopacifiers [55] . With moderate mechanical strength yet without the need for the addition of another radiopacifier, Sr-CPCs may be good candidates for repairing nonloading sites or reinforcing osteoporotic vertebrae through MISs [51] .

Other types of bone cements

Besides ABCs and CPCs, there are also some other types of bone cements. Taking advantage of the controllable degradation, rapid solidification, excellent biocompatibility, and osteoconductivity of calcium sulfate (CaS), calcium sulfate cements (CSCs) have been developed [28] . Compared to CPCs, CSCs have relatively higher mechanical strength. However, CSCs not only cure very fast, but also degrade fast. They may be fully absorbed within 6 weeks upon implantation in vivo . Such fast degradation of the filling material does not match the bone formation process. Therefore, the development and clinical applications of CSCs are relatively limited compared to CPCs [56] .

Magnesium phosphate cement (MPC) is another type of biodegradable bone cement. Because the released magnesium ions can enhance the activity of osteoblasts, MPC may function as a bioactive bone cement. However, the setting time of MPCs is as short as 3 minutes, which largely limits their applications. Similar to CSCs, MPCs are often used in combination with other cement systems such as CaPs and CaSs. Yang et al [57] mixed CaS powder with magnesium phosphate (MgP) to form a CaP/MgP bone cement. The setting time could be controlled up to 6 minutes by adjusting the content of MgP in the composite cement. The compressive strength was up to 70 MPa.

Future development of VP/BKP cements

Ideally, the next generation of cements for VP and BKP should have (a) adequate injectability, setting property, cohesion, and radiopacity for best handling property; (b) sufficient mechanical strength for immediate reinforcement; (c) adequate porosity to allow body fluid circulation, cell migration, and new bone ingrowth; (d) excellent osteoconductivity and osteoinductivity for promoting new bone formation; (e) moderate biodegradability so that the resorption of cement material matches new bone formation; and (f) high efficiency of drug delivery [28] . In addition, future development of VB/BKP cements should also take into consideration the following issues.

Mechanical characteristics

Bone cement is subjected to high stress and a challenging body environment. As such, improving mechanical properties has been one of the main topics of bone cement development. It should be noted, however, that higher compressive strength of bone cements does not necessarily mean a better choice. When a complex 3D load is applied in vivo , the shear and tensile stresses, in addition to compressive stress, indeed play a prominent role [58] . The choice of cement for augmentation of a fractured VB should be based on comprehensive biomechanical considerations including fracture configuration, rotational/flexional fracture stability, load-bearing capacity, and the bone mineral density of the VB [59] .

The stiffness of VP/BKP cements should also be seriously evaluated. Vertebrae augmentation using rigid ABCs (stiffness being as high as 11 times that of osteoporotic vertebral cancellous bone) may cause massive vertebrae stiffness change [60] . Osteoporotic cancellous bone augmented by rigid bone cement can be at least 12 times stiffer and 35 times stronger than untreated bone [61] . The rigid cement augmentation leads to load increase in the structures adjacent to the augmented VB, which may inhibit the normal endplate to bulge into the augmented VB and thus pressurizes adjacent discs, leading to increased loading of untreated vertebra and even VB fracture. In addition, finite element analyses showed that the compressive stiffness of the spinal unit increased over 10% after VP using ABCs, yet the hydrostatic pressure within the nucleus pulposus increased by about 15% [62] . The stiffening effect of regular cement, however, can be largely avoided by using low-modulus cements, which cause less stiffness alteration of vertebrae and therefore better preservation of vertebrae strength [60] .

Incorporation of bioactive additives and cells

Bone cements usually lack sufficient osteoinductivity. Therefore, various bioactive, osteogenic agents are supplemented in order to promote osteogenic differentiation of progenitor cells and new bone formation. The incorporation of several bioactive ions, for example, strontium, magnesium, zinc, copper, and fluoride, has been shown to improve the biological performance of CPCs by promoting bone metabolism [63] .

Because of their intrinsic porosity and high surface area, CPCs are an ideal carrier system for growth factor (GF) and drug delivery. GFs such as bone morphogenetic proteins (BMPs), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) have been incorporated into CPCs, which improved their osteogenic and angiogenic capabilities [64] . The GFs may be mixed with CPC components alone, or be encapsulated within microspheres of chitosan, gelatin, or hyaluronic acid before incorporation into the CPC for best preservation of their bioactivity [65] . Plasmids or small interfering RNAs (siRNAs) may also be incorporated into CPCs to achieve gene delivery to cells at the injection area [64] , [66] . Recently, platelet-rich plasma (PRP) and autologous bone marrow concentrate (BMC) have been used together with CPCs as autologous bone substitutes [67] .

In general, the bone metabolism of VP/BKP patients is impaired due to the significantly reduced number and functionality of osteogenic stem/progenitor cells. Delivery of mesenchymal stem cells (MSCs) along with injection of biodegradable bone cements such as CPCs, therefore, is desirable for regenerating fractured VBs [68] . Since the potential chemical or heat release during the cement setting reaction may harm the cells, appropriate short-term protection of cells is needed during cement handling. Various biodegradable carriers including chitosan, alginate, and fibrin have been used as encapsulating gels to protect the cells [69] . With such protection, the cells remained in the CPC with a high survival rate (close to 90%) and showed excellent proliferation, osteo-differentiation, and mineralization upon implantation [70] .

Radiopacifiers

The addition of traditional radiopacifiers to VP/BKP cements may affect cement setting behaviour and significantly reduce the mechanical strength of cements. It may even significantly increase bone resorption, likely as a result of enhanced macrophage/osteoclast differentiation [71] . In the development of new radiopacifiers, the surface functionalization of existing radiopacifiers appears to be an effective way to overcome such problems. Using barium sulfate or zirconia dioxide nanoparticles that were surface-treated with a difunctional agent, usually an acrylated compound which can be copolymerized with MMA, the interface between radiopacifier particles and PMMA was ameliorated, resulting in enhanced mechanical properties of ABCs [20] , [21] . Supplementing MMA-treated, Sr-HA to ABCs not only improved the handling property and compressive strength of ABCs, but also enhanced their radiopacity and bioactivity [72] .

Hybrid cements

Currently, various PMMA-based hybrid or composite cements have been developed by incorporating CaPs or polymers in order to combine the bone augmentation characteristics of ABCs and biodegradability of CPCs. Such studies may eventually lead to the development of a range of bone cements that are tailored for specific VP or BKP needs. For example, for young patients with traumatic burst fractures, excellent biocompatibility and degradability of cement are required to facilitate bone formation and remodelling. In elderly OVCF patients, however, immediate weight-bearing stability is more important. Therefore, cements that provide long-term multidirectional stability and are slowly resorbed are needed. For application in metastatic lesions or osteoid osteomata, the cement could be designed to produce local heat and resolve quickly. Developing cements with characteristics matching the needs of specific VP/BKP indications, therefore, may help solve many practical issues and lead to better treatment outcomes yet reduced complications [59] .

Concluding remarks

To date, a broad range of bone cements have been approved for clinical applications and many have been used for VP and BKP procedures. While ABCs still prevail as the VP/BKP filling material of choice, their intrinsic nondegradability constitutes a formidable obstacle toward broader applications. By contrast, given the unique combination of biodegradability, osteoconductivity, mouldability, nonexothermic setting, and negligible shrinkage, CPCs are determined to play a significant role in the development of next-generation VP/BKP cements. Being able to simultaneously promote bone formation yet suppress bone resorption, Sr-CPCs represent a promising type of bone cement for augmentation of fractured vertebra.

New technical advances in the development of VP/BKP cements rely on innovative concepts and interdisciplinary knowledge. With the advent of new biodegradable and mechanically matched bone cements, the indications of VP/BKP will likely be broadened, for example, to VCFs with no neurological symptoms in the elderly or even traumatic VCFs in young adults. These types of fractures require bone cements with adjustable mechanical properties that meet the loading requirements early and can be absorbed to avoid stress shielding in the later stage of treatment. If achieved, patients suffering from such fractures may no longer need extra vertebral fixation surgeries. Therefore, a wide spectrum of spinal lesions that were previously left untreated may potentially benefit from these ongoing advancements of bone cements.

Conflicts of interest

The authors declare no conflicts of interest.

References

1 Parry J. Network of cities tackles age-old problems Bull World Health Org 88 2010 406 407 10.2471/BLT.10.020610 PMC2878157 20539851

2 Mitchell B.D. Streeten E.A. Clinical impact of recent genetic discoveries in osteoporosis App Clin Genet 6 2013 75 85 10.2147/TACG.S52047 PMC3796859 24133373

3 Marcucci G. Brandi M.L. Kyphoplasty and vertebroplasty in the management of osteoporosis with subsequent vertebral compression fractures Clin Cases Miner Bone Metab 7 2010 51 60 22461293 PMC2898008

4 Longo U.G. Loppini M. Denaro L. Maffulli N. Denaro V. Osteoporotic vertebral fractures: current concepts of conservative care Br Med Bull 102 2012 171 189 22130906 10.1093/bmb/ldr048

5 Kado D.M. Browner W.S. Palermo L. Nevitt M.C. Genant H.K. Cummings S.R. Vertebral fractures and mortality in older women: a prospective study. Study of Osteoporotic Fractures Research Group Arch Internal Med 159 1999 1215 1220 10371229 10.1001/archinte.159.11.1215

6 Klazen C.A. Lohle P.N. de Vries J. Jansen F.H. Tielbeek A.V. Blonk M.C. Vertebroplasty versus conservative treatment in acute osteoporotic vertebral compression fractures (Vertos II): an open-label randomised trial Lancet 376 2010 1085 1092 20701962 10.1016/S0140-6736(10)60954-3

7 Galibert P. Deramond H. Rosat P. Le Gars D. Preliminary note on the treatment of vertebral angioma by percutaneous acrylic vertebroplasty Neuro-Chirurgie 33 1987 166 168 3600949

8 Lieberman I.H. Togawa D. Kayanja M.M. Vertebroplasty and kyphoplasty: filler materials Spine J 5 2005 305S 316S 16291128 10.1016/j.spinee.2005.02.020

9 Kasper D.M. Kyphoplasty Semin Intervent Radiol 27 2010 172 184 21629406 10.1055/s-0030-1253515 PMC3036523

10 Edidin A.A. Ong K.L. Lau E. Kurtz S.M. Mortality risk for operated and nonoperated vertebral fracture patients in the medicare population J Bone Miner Res 26 2011 1617 1626 21308780 10.1002/jbmr.353

11 Charnley J. Anchorage of the femoral head prosthesis to the shaft of the femur J Bone Joint Surg Br 42 1960 28 30 13855642 10.1302/0301-620X.42B1.28

12 Kühn K.-D. Bone cements: up-to-date comparison of physical and chemical properties of commercial materials 2000 Springer Berlin, Germany

13 Liu-Snyder P. Webster T.J. Developing a new generation of bone cements with nanotechnology Curr Nanosci 4 2008 111 118

14 Lopes P.P. Garcia M.P. Fernandes M.H. Acrylic formulations containing bioactive and biodegradable fillers to be used as bone cements: properties and biocompatibility assessment Mater Sci Eng C Mater Biol Appl 33 2013 1289 1299 23827574 10.1016/j.msec.2012.12.028

15 Hernandez L. Fernandez M. Collia F. Gurruchaga M. Goni I. Preparation of acrylic bone cements for vertebroplasty with bismuth salicylate as radiopaque agent Biomaterials 27 2006 100 107 16009418 10.1016/j.biomaterials.2005.05.074

16 Vallo C.I. Schroeder W.F. Properties of acrylic bone cements formulated with Bis-GMA J Biomed Mater Res B Appl Biomater 74 2005 676 685 15954119 10.1002/jbm.b.30211

17 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 10 Suppl. 2 2001 S147 S152 11716012 10.1007/s005860100288 PMC3611546

18 Yamamuro T. Nakamura T. Iida H. Kawanabe K. Matsuda Y. Ido K. Development of bioactive bone cement and its clinical applications Biomaterials 19 1998 1479 1482 9794522 10.1016/s0142-9612(98)00062-3

19 Lopez-Heredia M.A. Sa Y. Salmon P. de Wijn J.R. Wolke J.G. Jansen J.A. Bulk properties and bioactivity assessment of porous polymethylmethacrylate cement loaded with calcium phosphates under simulated physiological conditions Acta Biomater 8 2012 3120 3127 22588072 10.1016/j.actbio.2012.05.007

20 Fang C. Hou R. Zhou K. Hua F. Cong Y. Zhang J. Surface functionalized barium sulfate nanoparticles: controlled in situ synthesis and application in bone cement J Mater Chem B 2 2014 1264 1274 10.1039/c3tb21544j 32261363

21 Gillani R. Ercan B. Qiao A. Webster T.J. Nanofunctionalized zirconia and barium sulfate particles as bone cement additives Int J Nanomed 1 2010 1 11 PMC2819907 20161983

22 Zhang J. Liu W. Schnitzler V. Tancret F. Bouler J.M. Calcium phosphate cements for bone substitution: chemistry, handling and mechanical properties Acta Biomater 10 2014 1035 1049 24231047 10.1016/j.actbio.2013.11.001

23 Khairoun I. Magne D. Gauthier O. Bouler J.M. Aguado E. Daculsi G. In vitro characterization and in vivo properties of a carbonated apatite bone cement J Biomed Mater Res 60 2002 633 642 11948522 10.1002/jbm.10132

24 Kruger R. Groll J. Fiber reinforced calcium phosphate cements – on the way to degradable load bearing bone substitutes? Biomaterials 33 2012 5887 5900 22632767 10.1016/j.biomaterials.2012.04.053

25 Dorozhkin S.V. Calcium orthophosphate cements for biomedical application J Mater Sci 43 2008 3028 3057

26 Dorozhkin S.V. Biphasic, triphasic and multiphasic calcium orthophosphates Acta Biomater 8 2012 963 977 21945826 10.1016/j.actbio.2011.09.003

27 Tsai C.H. Lin R.M. Ju C.P. Chern Lin J.H. Bioresorption behavior of tetracalcium phosphate-derived calcium phosphate cement implanted in femur of rabbits Biomaterials 29 2008 984 993 18096221 10.1016/j.biomaterials.2007.10.014

28 Lewis G. Injectable bone cements for use in vertebroplasty and kyphoplasty: state-of-the-art review J Biomed Mater Res B Appl Biomater 76 2006 456 468 16196037 10.1002/jbm.b.30398

29 Espanol M. Perez R.A. Montufar E.B. Marichal C. Sacco A. Ginebra M.P. Intrinsic porosity of calcium phosphate cements and its significance for drug delivery and tissue engineering applications Acta Biomater 5 2009 2752 2762 19357005 10.1016/j.actbio.2009.03.011

30 Low K.L. Tan S.H. Zein S.H. Roether J.A. Mourino V. Boccaccini A.R. Calcium phosphate-based composites as injectable bone substitute materials J Biomed Mater Res B Appl Biomater 94 2010 273 286 20336722 10.1002/jbm.b.31619

31 Ginebra M.P. Canal C. Espanol M. Pastorino D. Montufar E.B. Calcium phosphate cements as drug delivery materials Adv Drug Deliv Rev 64 2012 1090 1110 22310160 10.1016/j.addr.2012.01.008

32 Lopez-Heredia M.A. Sariibrahimoglu K. Yang W. Bohner M. Yamashita D. Kunstar A. Influence of the pore generator on the evolution of the mechanical properties and the porosity and interconnectivity of a calcium phosphate cement Acta Biomater 8 2012 404 414 21884833 10.1016/j.actbio.2011.08.010

33 Ishikawa K. Asaoka K. Estimation of ideal mechanical strength and critical porosity of calcium phosphate cement J Biomed Mater Res 29 1995 1537 1543 8600144 10.1002/jbm.820291210

34 Sarda S. Fernandez E. Nilsson M. Balcells M. Planell J.A. Kinetic study of citric acid influence on calcium phosphate bone cements as water-reducing agent J Biomed Mater Res 61 2002 653 659 12115456 10.1002/jbm.10264

35 Liu W. Zhang J. Rethore G. Khairoun K. Pilet P. Tancret F. A novel injectable, cohesive and toughened Si-HPMC (silanized-hydroxypropyl methylcellulose) composite calcium phosphate cement for bone substitution Acta Biomater 10 2014 3335 3345 24657196 10.1016/j.actbio.2014.03.009

36 Gu Y. Chen L. Yang H.L. Luo Z.P. Tang T.S. Evaluation of an injectable silk fibroin enhanced calcium phosphate cement loaded with human recombinant bone morphogenetic protein-2 in ovine lumbar interbody fusion J Biomed Mater Res A 97 2011 177 185 21381189 10.1002/jbm.a.33018

37 Cao C. Li H. Li J. Liu C. Yang H. Li B. Mechanical reinforcement of injectable calcium phosphate cement/silk fibroin (SF) composite by mineralized SF Ceram Int 40 2014 13987 13993

38 Canal C. Ginebra M.P. Fiber-reinforced calcium phosphate cements: a review J Mechan Behav Biomed Mater 4 2011 1658 1671 10.1016/j.jmbbm.2011.06.023 22098867

39 Kon M. Hirakata L.M. Miyamoto Y. Kasahara H. Asaoka K. Strengthening of calcium phosphate cement by compounding calcium carbonate whiskers Dental Mater J 24 2005 104 110 10.4012/dmj.24.104 15881216

40 Xu H.H. Quinn J.B. Whisker-reinforced bioactive composites containing calcium phosphate cement fillers: effects of filler ratio and surface treatments on mechanical properties J Biomed Mater Res 57 2001 165 174 11484178 10.1002/1097-4636(200111)57:2<165::aid-jbm1155>3.0.co;2-w

41 Tomita S. Molloy S. Jasper L.E. Abe M. Belkoff S.M. Biomechanical comparison of kyphoplasty with different bone cements Spine 29 2004 1203 1207 15167659 10.1097/00007632-200406010-00009

42 Bai B. Jazrawi L.M. Kummer F.J. Spivak J.M. The use of an injectable, biodegradable calcium phosphate bone substitute for the prophylactic augmentation of osteoporotic vertebrae and the management of vertebral compression fractures Spine 24 1999 1521 1526 10457570 10.1097/00007632-199908010-00004

43 Turner T.M. Urban R.M. Singh K. Hall D.J. Renner S.M. Lim T.H. Vertebroplasty comparing injectable calcium phosphate cement compared with polymethylmethacrylate in a unique canine vertebral body large defect model Spine J 8 2008 482 487 18455113 10.1016/j.spinee.2006.12.007

44 Friedman C.D. Costantino P.D. Takagi S. Chow L.C. BoneSource hydroxyapatite cement: a novel biomaterial for craniofacial skeletal tissue engineering and reconstruction J Biomed Mater Res 43 1998 428 432 9855201 10.1002/(sici)1097-4636(199824)43:4<428::aid-jbm10>3.0.co;2-0

45 Rupprecht S. Merten H.A. Kessler P. Wiltfang J. Hydroxyapatite cement (BoneSource) for repair of critical sized calvarian defects—an experimental study J Cranio Maxill Surg 31 2003 149 153 10.1016/s1010-5182(03)00017-9 12818599

46 Querido W. Campos A.P. Martins Ferreira E.H. San Gil R.A. Rossi A.M. Farina M. Strontium ranelate changes the composition and crystal structure of the biological bone-like apatite produced in osteoblast cell cultures Cell Tissue Res 357 2014 793 801 24859219 10.1007/s00441-014-1901-1

47 Schumacher M. Lode A. Helth A. Gelinsky M. A novel strontium(II)-modified calcium phosphate bone cement stimulates human-bone-marrow-derived mesenchymal stem cell proliferation and osteogenic differentiation in vitro Acta Biomater 9 2013 9547 9557 23917042 10.1016/j.actbio.2013.07.027

48 Thormann U. Ray S. Sommer U. Elkhassawna T. Rehling T. Hundgeburth M. Bone formation induced by strontium modified calcium phosphate cement in critical-size metaphyseal fracture defects in ovariectomized rats Biomaterials 34 2013 8589 8598 23906515 10.1016/j.biomaterials.2013.07.036

49 Baier M. Staudt P. Klein R. Sommer U. Wenz R. Grafe I. Strontium enhances osseointegration of calcium phosphate cement: a histomorphometric pilot study in ovariectomized rats J Orthopaed Surg Res 8 2013 16 10.1186/1749-799X-8-16 PMC3680072 23758869

50 Schumacher M. Henss A. Rohnke M. Gelinsky M. A novel and easy-to-prepare strontium(II) modified calcium phosphate bone cement with enhanced mechanical properties Acta Biomater 9 2013 7536 7544 23523939 10.1016/j.actbio.2013.03.014

51 Romieu G. Garric X. Munier S. Vert M. Boudeville P. Calcium-strontium mixed phosphate as novel injectable and radio-opaque hydraulic cement Acta Biomater 6 2010 3208 3215 20144746 10.1016/j.actbio.2010.02.008

52 Wang X. Ye J. Variation of crystal structure of hydroxyapatite in calcium phosphate cement by the substitution of strontium ions J Mater Sci Mater Med 19 2008 1183 1186 17701299 10.1007/s10856-007-3209-0

53 Yu T. Ye J. Wang Y. Preparation and characterization of a novel strontium-containing calcium phosphate cement with the two-step hydration process Acta Biomater 5 2009 2717 2727 19380262 10.1016/j.actbio.2009.03.015

54 Li Z.Y. Yang C. Lu W.W. Xu B. Lam W.M. Ni G.X. Characteristics and mechanical properties of acrylolpamidronate-treated strontium containing bioactive bone cement J Biomed Mater Res B Appl Biomater 83 2007 464 471 17415774 10.1002/jbm.b.30818

55 Lopez A. Montazerolghaem M. Engqvist H. Ott M.K. Persson C. Calcium phosphate cements with strontium halides as radiopacifiers J Biomed Mater Res B Appl Biomater 102 2014 250 259 23997030 10.1002/jbm.b.33002

56 Vlad M.D. Sindilar E.V. Marinoso M.L. Poeata I. Torres R. Lopez J. Osteogenic biphasic calcium sulphate dihydrate/iron-modified alpha-tricalcium phosphate bone cement for spinal applications: in vivo study Acta Biomater 6 2010 607 616 19607944 10.1016/j.actbio.2009.07.010

57 Yang G. Liu J. Li F. Pan Z. Ni X. Shen Y. Bioactive calcium sulfate/magnesium phosphate cement for bone substitute applications Mater Sci Eng C Mater Biol Appl 35 2014 70 76 24411353 10.1016/j.msec.2013.10.016

58 Charriere E. Terrazzoni S. Pittet C. Mordasini P.H. Dutoit M. Lemaitre J. Mechanical characterization of brushite and hydroxyapatite cements Biomaterials 22 2001 2937 2945 11561900 10.1016/s0142-9612(01)00041-2

59 Verlaan J.J. Oner F.C. Dhert W.J. Anterior spinal column augmentation with injectable bone cements Biomaterials 27 2006 290 301 16102818 10.1016/j.biomaterials.2005.07.028

60 Boger A. Heini P. Windolf M. Schneider E. Adjacent vertebral failure after vertebroplasty: a biomechanical study of low-modulus PMMA cement Eur Spine J 16 2007 2118 2125 17713795 10.1007/s00586-007-0473-0 PMC2140124

61 Baroud G. Vant C. Wilcox R. Long-term effects of vertebroplasty: adjacent vertebral fractures J Long Term Eff Med Implants 16 2006 265 280 17073569 10.1615/jlongtermeffmedimplants.v16.i4.10

62 Baroud G. Nemes J. Ferguson S.J. Steffen T. Material changes in osteoporotic human cancellous bone following infiltration with acrylic bone cement for a vertebral cement augmentation Comp Methods Biomech Biomed Eng 6 2003 133 139 10.1080/1025584031000095746 12745427

63 Yang L. Perez-Amodio S. Barrere-de Groot F.Y. Everts V. van Blitterswijk C.A. Habibovic P. The effects of inorganic additives to calcium phosphate on in vitro behavior of osteoblasts and osteoclasts Biomaterials 31 2010 2976 2989 20122718 10.1016/j.biomaterials.2010.01.002

64 Bose S. Tarafder S. Calcium phosphate ceramic systems in growth factor and drug delivery for bone tissue engineering: a review Acta Biomater 8 2012 1401 1421 22127225 10.1016/j.actbio.2011.11.017 PMC3418064

65 Habraken W.J. Boerman O.C. Wolke J.G. Mikos A.G. Jansen J.A. In vitro growth factor release from injectable calcium phosphate cements containing gelatin microspheres J Biomed Mater Res Part A 91 2009 614 622 10.1002/jbm.a.32263 18985784

66 Pittella F. Miyata K. Maeda Y. Suma T. Watanabe S. Chen Q. Pancreatic cancer therapy by systemic administration of VEGF siRNA contained in calcium phosphate/charge-conversional polymer hybrid nanoparticles J Control Release 161 2012 868 874 22580114 10.1016/j.jconrel.2012.05.005

67 He F. Chen Y. Li J. Lin B. Ouyang Y. Yu B. Improving bone repair of femoral and radial defects in rabbit by incorporating PRP into PLGA/CPC composite scaffold with unidirectional pore structure J Biomed Mater Res A 2014 10.1002/jbm.a.35248 24890626

68 Weir M.D. Xu H.H. Culture human mesenchymal stem cells with calcium phosphate cement scaffolds for bone repair J Biomed Mater Res B Appl Biomater 93 2010 93 105 20091907 10.1002/jbm.b.31563 PMC2989678

69 Chen W. Zhou H. Weir M.D. Bao C. Xu H.H. Umbilical cord stem cells released from alginate-fibrin microbeads inside macroporous and biofunctionalized calcium phosphate cement for bone regeneration Acta Biomater 8 2012 2297 2306 22391411 10.1016/j.actbio.2012.02.021 PMC3360975

70 Zhou H. Weir M.D. Xu H.H. Effect of cell seeding density on proliferation and osteodifferentiation of umbilical cord stem cells on calcium phosphate cement-fiber scaffold Tissue Eng Part A 17 2011 2603 2613 21745111 10.1089/ten.tea.2011.0048 PMC3204200

71 Provenzano M.J. Murphy K.P. Riley L.H. 3rd Bone cements: review of their physiochemical and biochemical properties in percutaneous vertebroplasty AJNR Am J Neuroradiol 25 2004 1286 1290 15313726 PMC7976525

72 Hernandez L. Parra J. Vazquez B. Bravo A.L. Collia F. Goni I. Injectable acrylic bone cements for vertebroplasty based on a radiopaque hydroxyapatite. Bioactivity and biocompatibility J Biomed Mater Res B Appl Biomater 88 2009 103 114 18683227 10.1002/jbm.b.31156

73 Chen C. Bian J. Zhang W. Zhao C. Wei H. Unilateral versus bilateral vertebroplasty for severe osteoporotic vertebral compression fractures J Spinal Disord Tech 27 2014 E301 E304 24901876 10.1097/BSD.0000000000000118

74 Dorozhkin S.V. Calcium orthophosphates: occurrence, properties, biomineralization, pathological calcification and biomimetic applications Biomatter 1 2011 121 164 23507744 10.4161/biom.18790 PMC3549886

Acknowledgements

This work was supported by the National Natural Science Foundation of China (81171479, 81471790), Scientific Research Foundation for Returned Overseas Chinese Scholars, State Education Ministry (K524703513), and Jiangsu Provincial Special Program of Medical Science (BL2012004).