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Factors Affecting Aseptic Loosening Of 4750 Total Hip Arthroplasties: Multivariate Survival Analysis
Authors: Barbara Bordini, Susanna Stea, Manuela De Clerico, Sergio Strazzari, Antonio Sasdelli and Aldo Toni Istituti Ortopedici Rizzoli Via Barbiano, Bologna, Italy

The Role Of Calcium Based Bone Cements
Author: Bob Chatterjee

Mixing And Management Of Acrylic Bone Cement
Authors: Dr Nicholas Dunne BSc, PhD, CEng (School of Mechanical and Aerospace, Queen’s University of Belfast, UK), Mr Robert Lee BSc, MBBS, MRCS



Factors Affecting Aseptic Loosening Of 4750 Total Hip Arthroplasties: Multivariate Survival Analysis
Authors: Barbara Bordini, Susanna Stea, Manuela De Clerico, Sergio Strazzari, Antonio Sasdelli and Aldo Toni Istituti Ortopedici Rizzoli Via Barbiano, Bologna, Italy

Background
 From a surgical point of view, total hip arthroplasty is a well-standardized operation that has proven to be very effective. However, failure can sometimes occur in the immediate postoperative period or even some years after. According to the NICE guidelines, for a hip prosthesis to be considered safe its mean survival rate should be at least 90% at ten years1. Although the failure rate is low, it varies greatly and can be influenced by several factors, such as the type of prosthesis used and the patient’s characteristics, and whereas the patient’s characteristics are practically unchangeable, factors related to s and their choices can be modified. The literature includes numerous studies analysing factors that influence hip prosthesis failure, but they often concern small series of patients. Poon observed that weight and age influenced the outcome of total hip arthroplasty (THA) using cemented prostheses2. Kobayashi studied a consecutive series of 293 primary cemented Charnley prostheses and found that rapid wear of polyethylene and abnormal geometry of the femoral medullary canal affect prosthesis survival3. Kolundzic found that demographic factors explained only a minor part of the survival variability of 82 cementless acetabular cups4.

The largest series concerned only patients treated using cemented prostheses. Among them Berry analysed 2000 primary Charnley prostheses at 25 years’ follow-up and found that age, gender and underlying diagnosis affected long-term survivorship of both components5. Dawson compared 598 cemented prostheses and found no significant differences between the performance of the two models6. As clearly stated the weakness of all the long-term studies depends on the fact that they assess the success or failure of old technologies and designs7. Comparison among prostheses with different fixation (cementless vs cemented) is limited to few clinical trials that indicate the better performance of cementless components8-10.

Analyses performed on data from northern European registers only partially fill this gap since there is a clear-cut prevalence of cemented prostheses with metal-polyethylene couplings.

In fact, 93.1% of prostheses implanted in patients in Sweden between 1979–200411, and 80% of those used in Norway between 1987–200412 were cemented. The figure is lower in Denmark, 49.8% between 1995–200413, and in Finland 55% from 1980–200314. The data collected for the UK were only for 2004, and although they included cemented prostheses in 49% of cases, they cannot be used for an effective analysis15.

However, an analysis of the data from the Norwegian resister Furnes revealed that in over 53,000 operations some diseases (femoral neck fracture sequelae, congenital hip dysplasia, and rare diseases) represent risk factors for prosthesis survival16. When limiting the analysis to young osteoarthritic patients, Eskelinen found that age and gender influence the result17. The Danish register identified age and gender as confounding factors in the evaluation of prosthesis survival13.

None of these analyses, due to the nature of the operations analyzed, considered the influence of the type of prosthesis fixation among the possible risk factors. Only when analysing the Finish data Visuri find that low age, male gender, uncemented prostheses and first 10 year-period of surgery were risk factors for loosening of the prostheses18. Therefore, we analyzed the data of a series of patients with a minimum of six years’ follow-up taken from the RIPO register (Register of Orthopedic Prosthetic Implantology), which includes cemented and uncemented prostheses, to determine the influence of patient characteristics’s experience, and type of prosthesis used, on the outcome of the operation.

Methods
 Materials
A consecutive series of 4,750 primary total hip arthroplasties performed on 4,450 patients at Istituto Rizzoli between 1st January 1995 and 31st December 2000 was analysed. The number of operations progressively increased from 1995 (664) to 2000 (847). The patients were treated in 11 different wards. They underwent regular clinical evaluation, and if they missed their clinical examination for longer than 18 months they were contacted by phone, to establish whether the prosthesis was still in place. The survival of the prosthesis was recorded at the time of death.

The characteristics of patients are shown in Table 1 and in Table 2.

They received cemented (12.1%), cementless (51.5%), or hybrid (36.4%) total hip prostheses. Femoral and acetabular components were classified on the basis of their characteristics and economic value. Relative value was calculated respectively as a ratio to the value of all-polyethylene cup encompassing the cost of cement and to the value of a straight cemented stem. In Table 3 and 4 cups and stem are classified respectively into three and five groups where the main characteristics and relevant economic values are reported. Details of the different types of cup/stem that compose each group are also presented. These were classified on the basis of their experience, i.e. the number of operations performed as primary in the five-year period. All the surgeons implanted the hip prosthesis by lateral approach.

Statistics
 Implant survivorship was estimated with use of the Cox proportional -hazards model19. Ninety – five percent confidence intervals were calculated. The death of a patient or or the revision of any component was recorded. All cases that failed due to septic loosening were excluded. The end point for the acetabular component was revision of the metal back and/or of the liner. The end-point for the femoral component was revision of the stem and/or of the modular neck (if present). Revision of the neck due to head damage was not considered considered as modular neck failure; in those cases the neck is revised as a precautionary measure, and is not an index of stem failure. For patients that suffered a cup failure their follow-up time would not be registered at the date of this failure when analysing stem failures and viceversa. It was preliminarly verified that variables entering the model were not different among patients suffering for a single component failure or for contemporary failure of both stem and cup.

Variables included gender, age, diagnosis, Charnley score, right or left side, surgeon’s skill, type of component. Cox multivariate test enables verification of the influence of one variable on equal terms with the others.

Results
 The results are presented separately for the two main components, cup and stem. The chi-square test used to test globally the model applied was significant if, on the whole, the variables put into the model influenced significantly the outcome of prosthetic surgery (chi-square for cup = 52.49; chi-square for stem = 69.604, both significant AT p = 0.001). In the analysis of cup failure the total number of valid observations was 4,750, of which 4,616 were not removed and 134 were revised (Table 5). 46 patients out of 134 had cup and stem failure at the same time.


The outcome is not significantly affected by clinical condition, right or left side, or surgeon’s skill. In the analysis of stem failure the total number of valid observations was 4,750, of which 4,645 were not removed and 86 were revised.

Outcome is not significantly affected by Charnley score, side, or diagnosis.(Table 6) Both cup and stem survival are negatively affected by age under forty, and cemented fixation of the components. Besides this, the cup survival is also negatively affected by a preoperative congenital disease or fracture and sequelae. On the contrary, stem survival is not affected by the pathology, but is negatively affected by male gender and lower surgeon skill.


Discussion
 To determine the factors that influence component survival we followed a large number of consecutive primary total hip arthroplasties performed in the same Institute. The cohort was large enough to be analysed by age, gender, diagnosis, Charnley score, side, skill of surgeon, and type of component. Distribution of frequencies of some variables (ie age at surgery, surgeon experience) is clearly different among types of implants. Multivariate analysis applied to test the influence of single factors can limit this bias. By analysing prostheses implanted between 1995–2000, we were able to include designs that are still modern, and at the same time have a long enough follow-up to highlight any failures.

Since the register was started at Rizzoli Institute in 1990, all patients have been monitored; if patients fail to attend scheduled clinical exams, they are contacted by phone or asked to fill in a questionnaire. This was acceptable as the recorded end-point (revision) was independent of clinical examination. The chosen end-point is undoubtedly a raw parameter, which does not take into account the quality of life and restoration of function in the treated limb, but its strength lies precisely in its objectivity.

Some of the results obtained from this analysis support data reported by other authors in comparable series. In agreement with the literature, the risk of failure is increased by male gender, young age, and certain diseases17,18,20. These variables, which constitute the patient’s characteristics, are unchangeable. However, knowing the influence they can have enables a correct statistical interpretation. The interesting finding that has emerged from this study is that among the factors that influence the risk of failure are the surgeon’s skill, and the type of prosthesis-to-bone fixation used.

The surgeon’s skill is an extremely delicate aspect, which might depend on the reliability of the hospital where the operation is performed rather than the experience of the single surgeon. High-risk patients, who are often admitted to hospitals not necessarily near home, might be treated more safely in highly specialised centres. It should be remembered that the data presented in this study come from operations performed at a highly specialised hospital and includes very complex cases, which, on the other hand, have been treated by highly specialised surgeons.

Another important factor that can be modified is the prosthetic component. Uncemented components are generally much less likely to fail than cemented ones. However, our results appear to be in contrast with those of other registers11. Nevertheless, reading the data more carefully reveals that as experience using uncemented components increases, the difference in results between the two types of prostheses decreases, and the efficacy of uncemented prostheses is highlighted especially with regards to young12,17 or middle-aged patients13.

An interesting finding that emerged from our study was that the more expensive the prosthesis, the longer its survival was.

With regards to the cup, all other variables being equal, compared to the monoblock polyethylene cup the failure rate of the press-fit cup with a polyethylene liner, which costs four times more than the monoblock cup, was reduced by half, and reduced by 2/3 when using the press-fit cup with a ceramic liner, which costs five times more than the monoblock cup.

Concerning the stem, there were no significant differences in the failure rate between the straight cemented stem and the anatomical cemented stem, which costs 10% more. Conversely, compared to the cemented straight stem, the failure rate of the uncemented straight stem, which costs 90% more than the cemented one, is 60% less. The reduction in the failure rate is 60% also when using uncemented modular stems, which cost 150% more than the cemented straight stem.

Finally, coated and/or anatomical uncemented stems cost 110% more than cemented straight stems but the failure rate is reduced by 80%.

All the conclusions drawn from these data have intrinsic and unavoidable limits due to the low rate of revision (less than 3%) that affect primary Total Hip Arthroplasty. The revision rate is fortunately lower than the 10% suggested as the maximum acceptable by NICE1. For this reason a non-parametric statistical method of analysis was used, which can handle correctly this kind of data.

This analysis provides the basis for a cost-benefit assessment, which aims at determining whether a certain clinical result can be achieved while reducing the resources used. From a strictly ethical point of view the results give a clear indication of the choice, but the availability of economic resources can only be determined by healthcare policy. Undoubtedly, subsequent cost-benefit analysis should take into account that this type of operation is performed on elderly people who need a long recovery period. Therefore, there is also a need for rehabilitation centres, which are often lacking, and so elderly people often have to rely on the help of their families.

Besides social aspects, also technical difficulties should not be underestimated. Sometimes surgeons are faced with difficult operations and have to make bold choices. However, cost-benefit analysis is not within the scope of this paper, which is limited to providing data to enable correct elaboration21,22. We reiterate that the data presented come from a series of patients and include the use of cemented and uncemented components, unlike those based on large databanks of northern European registers, which show that cemented components perform better23,24 or at least as well as25 uncemented ones. Since cemented prostheses are cheaper, they are more advantageous from a cost-benefit point of view. The data we have presented, which do not include only the cost of materials26 will enable a cost-benefit analysis that is closer to reality in countries where the use of uncemented prostheses is more widespread.

Conclusion
 The only variable that affects survival and that can be modified by surgeon is the type of prosthesis: a lower cost is associated to a higher risk. Results concerning the risk associated with cemented components are partially in disagreement with studies performed in countries where cemented prostheses are used more often than uncemented ones.

Competing interests
 The author(s) declare that they have no competing interests.

Authors’ contributions
 BB and MDC performed statistical analysis, SuS drafted the manuscript, AT gave its experience as Orthopedic Surgeon, SeS and AS collected and treated data on cost.

Pre-publication history
 The pre-publication history for this paper can be accessed here: http://www.biomedcentral.com/1471-2474/8/69/prepub

Acknowledgements
 The authors would like to thank Mr Keith Smith for his help in translating the manuscript.

References
  1. Excellence NIfC: Guidance on selection of prostheses for Primary Total Hip Replacement. Technology Appraisal Guidance 2000, 2.
  2. Poon PC, Rennie J, Gray DH: Review of total hip replacement. The Middlemore Hospital experience, 1980-1991. N Z Med J 2001, 114(1133):254-256.
  3. Kobayashi S, Takaoka K, Saito N, Hisa K: Factors affecting aseptic failure of fixation after primary Charnley total hip arthroplasty. Multivariate survival analysis. J Bone Joint Surg Am 1997, 79(11):1618-1627.
  4. Kolundzic R, Sulentic M, Smerdelj M, Orlic D, Trkulja V: Stability of Endler cementless polyethylene acetabular cup: long-term follow-up. Croat Med J 2005, 46(2):261-267.
  5. Berry DJ, Harmsen WS, Cabanela ME, Morrey BF: Twenty-five-year survivorship of two thousand consecutive primary Charnley total hip replacements: factors affecting survivorship of acetabular and femoral components. J Bone Joint Surg Am 2002, 84-A(2):171-177.
  6. Dawson J, Jameson-Shortall E, Emerton M, Flynn J, Smith P, Gundle R, Murray D: Issues relating to long-term follow-up in hip arthroplasty surgery: a review of 598 cases at 7years comparing 2 prostheses using revision rates, survival analysis, and patient-based measures. J Arthroplasty 2000, 15(6):710-717.
  7. Berry DJ: Long-term follow-up studies of total hip arthroplasty. Orthopedics 2005, 28(8 Suppl):s879-880.
  8. Laupacis A, Bourne R, Rorabeck C, Feeny D, Tugwell P, Wong C: Comparison of total hip arthroplasty performed with and without cement : a randomized trial. J Bone Joint Surg Am 2002, 84-A(10):1823-1828.
  9. Kim YH, Oh SH, Kim JS, Koo KH: Contemporary total hip arthroplasty with and without cement in patients with osteonecrosis of the femoral head. J Bone Joint Surg Am 2003, 85-A(4):675-681.
  10. Clohisy JC, Harris WH: Matched-pair analysis of cemented and cementless acetabular reconstruction in primary total hip arthroplasty. J Arthroplasty 2001, 16(6):697-705.
  11. Herberts P, Karrholm J, Galleric G: Annual Report 2004. Swedish National Hip Arthoplasty Register. 2004.
  12. Furnes O: Annual Report 2005. The Norvegian Arthroplasty Register. 2005.
  13. Lucht U: Annual Report 2005. Danish Hip Arthroplasty Register. 2005.
  14. Nevelainen Jea: A study of the outcome of arthroplasty register in Finland, commissioned by the Ministry of Social Affairs and Health, 1998. 1998.
  15. Gregg Pea: The National Joint Registry 2nd Annual Report, 2005. 2005.
  16. Furnes O, Lie SA, Espehaug B, Vollset SE, Engesaeter LB, Havelin LI: Hip disease and the prognosis of total hip replacements. A review of 53,698 primary total hip replacements reported to the Norwegian Arthroplasty Register 1987-99. J Bone JointSurg Br 2001, 83(4):579-586.
  17. Eskelinen A, Remes V, Helenius I, Pulkkinen P, Nevalainen J, Paavolainen P: Uncemented total hip arthroplasty for primary osteoarthritis in young patients: a mid-to long-term follow-up study from the Finnish Arthroplasty Register. Acta Orthop 2006, 77(1):57-70.
  18. Visuri T, Turula KB, Pulkkinen P, Nevalainen J: Survivorship of hip prosthesis in primary arthrosis: influence of bilaterality and interoperative time in 45,000 hip prostheses from the Finnish endoprosthesis register. Acta Orthop Scand 2002, 73(3):287-290.
  19. Cox DR: Regression Models and Life Tables. Royal Statistical Society 1972, 34:187-220.
  20. Roder C, Parvizi J, Eggli S, Berry DJ, Muller ME, Busato A: Demographic factors affecting long-term outcome of total hip arthroplasty. Clin Orthop Relat Res 2003(417):62-73.
  21. Saleh KJ, Gafni A, Saleh L, Gross AE, Schatzker J, Tile M: Economic evaluations in the hip arthroplasty literature: lessons to be learned. J Arthroplasty 1999, 14(5):527-532.
  22. Bozic KJ, Saleh KJ, Rosenberg AG, Rubash HE: Economic evaluation in total hip arthroplasty: analysis and review of the literature. J Arthroplasty 2004, 19(2):180-189.
  23. Briggs A, Sculpher M, Britton A, Murray D, Fitzpatrick R: The costs and benefits of primary total hip replacement. How likely are new prostheses to be cost-effective? Int J Technol Assess Health Care 1998, 14(4):743-761.
  24. Fitzpatrick R, Shortall E, Sculpher M, Murray D, Morris R, Lodge M, Dawson J, Carr A, Britton A, Briggs A: Primary total hip replacement surgery: a systematic review of outcomes and modelling of cost-effectiveness associated with different prostheses. Health Technol Assess 1998, 2(20):1-64.
  25. Baxter K, Bevan G: An economic model to estimate the relative costs over 20 years of different hip prostheses. J Epidemiol Community Health 1999, 53(9):542-547.
  26. Yates P, Serjeant S, Rushforth G, Middleton R: The relative cost of cemented and uncemented total hip arthroplasties. J Arthroplasty 2006, 21(1):102-105.
© 2007 Bordini et al; licensee BioMed Central Ltd.

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The Role Of Calcium Based Bone Cements
Author: Bob Chatterjee

An Introduction to Bioactive Materials in Orthopaedics
 Metaphyseal defects are a common complication of periarticular trauma, where the cancellous bone is subject to compressive forces. In order to address this situation, a mechanical pillar of support (buttress) is required to uphold the periarticular cortical bone. Traditionally autogenous bone graft has been the material of choice when faced with the problem of metaphyseal bone defects however the associated problems with harvesting the graft and the extra surgical time required obtaining it, have opened the door for the use of artificial graft substitutes.

These substitutes can be divided into three main types.
1. Osteogenic: these materials contain living cells with the capacity to differentiate into bone e.g. autogenous bone graft and bone marrow stromal cells (both are also osteoconductive)
2. Osteoinductive: these materials provide biological stimulus for local or transplanted cells to differentiate into osteoblasts e.g. bone morphogenic proteins
3. Osteoconductive: these materials act as a scaffold to promote bone growth into the artificial graft e.g. hydroxyapatite and calcium bone cements

It should be pointed out that many graft substitutes display a combination of these properties. Demineralised bone matrix is both osteoconductive and osteoinductive and the other prime example is autogenous bone graft which is both osteogenic and osteoconductive as mentioned above.

In the application of primarily osteoconductive substances, one should bear in mind that they are not appropriate for either the treatment of non-unions or for large segmental defects by themselves. The more appropriate choice would be either to use them in conjunction with an osteogenic or osteoinductive material or to choose a substitute which displays multiple properties. In general osteoconductive substances are also contraindicated in the presence of osteomyelitis and in children with open growth plates1.

So Why Choose Calcium Phosphate Bone Cements?
 Returning to basic fracture treatment principles, management of periarticular trauma with metaphyseal compromise requires stable fixation. Stable fixation in turn allows you to commence early movement and weight bearing which is beneficial in the return of joint function. The complicating factors common to achieving stable fixation in older patients with periarticular trauma are lack of a buttress to support the cortical bone and the presence of osteoporosis.

There are several options for filling the metaphyseal defect. Autogenous bone graft is the current gold standard. But in addition to the surgical morbidity involved in its extraction it is further compromised by the lack of immediate support it provides to the periarticular cortical bone. This can lead to failure of the hardware before the bone has healed. Acrylic bone cements such as commonly used in arthroplasty e.g. (polymethylmethacrylate) have been shown to provide fracture stability in osteoporotic patients. But there are several concerns with its use relating to the exothermic reaction during its curing process, the inability for the cement to be remodelled and the difficulty with its removal in revision surgery2.

Calcium bone cements show several advantages in these respects. Firstly, they provide immediate support to the fracture site, preventing early hardware failure. Secondly, they effect hardware support by increasing screw pull out strength either directly in cancellous bone or in combination with plate fixation3. Thirdly they undergo osteoclastic reabsorption and are eventually replaced by circumferential lamellae of new bone. Fourthly, the rate of reabsorption matches that of host bone formation which prevents premature fracture collapse.

Biomechanical & Biochemical Properties Of Calcium Bone Cements
 In the early 1980s, at the National Institute of Standards and Technology in America, researchers were working on developing mineralising pastes for the treatment of dental caries based on calcium phosphate. When some of these pastes were inadvertently left for a few hours in test tubes with water, they were found to have hardened into a solid mass of hydroxyapatite. Many experiments followed in the subsequent years substituting various calcium compounds and other solvents which resulted in the first calcium phosphate cement being licensed for the repair of cranial defects in 1996. The properties of calcium cements which make them so attractive include their superb biocompatibility, self hardening and their gradual resorption by bone.

The calcium phosphate cements were prepared in a similar fashion to polymethylmethracylate (PMMA) cements involving a powder and a liquid. Tricalcium phosphate (TCP), monocalcium phosphate (MCP) and calcium carbonate in powder form were mixed with a liquid containing a solution of sodium phosphate.

Preparation of the cement involves five stages.
1. Dry Mix: grinding of the powders into a uniform consistency
2. Wet Mix: add liquid, mix and then place into the appropriate delivery system e.g. syringe
3. Working Time: it remains a injectable paste for about 5 min (at 20°C) but this is affected by the ambient temperature (lower temperature = increased working time)
4. Setting Time: sets in about 10 minutes. During this stage, pressure is not required and neither should it be subjected to any probing or movement.
5. Curing Time: after about 12 hours it cures to its final strength

The components crystallise and form a carbonated apatite (dahlite). The low crystalline order, small crystal size, lattice structure very much resembles that of bone mineral. The solubility of the cement is also similar to that of bone mineral i.e. insoluble at neutral pH and increasingly soluble as the environment acidifies (low pH). This property is relevant to the osteoclastic resorption undergone by the material during remodelling which requires an acidic environment in order to occur. The bone cement cures at normal physiologic pH and at body temperature. There is no polymerisation process, hence no exothermic reaction and therefore no local cellular destruction. After injection, the cement interdigitates with bone and after 10 minutes of setting provides about 10 Mpa of compressive strength. This strength then further improves to about 50 Mpa after 12 hours. The final tensile and shear strength attributes are low being only 2 to 3 Mpa. It is useful to compare these approximate figures with that of cortical and cancellous bone as shown in the table below.

Strength Cortical Bone Cancellous Bone Calcium Phosphate Cement
Compressive 200 Mpa 5-15 Mpa 50 Mpa
Tensile 130 Mpa variable 2-3 Mpa
Shear 60 – 70 Mpa variable 2-3 Mpa

Analysis of animal studies showed bone apposition commencing at about two weeks. Over the following months osteoclastic resorption of the cement commences, vascular penetration and bone formation similar to bone remodelling4. Human studies relating to more than one year post surgery, show bone cement at this stage appeared to be fully adhered to bone and cement resorption was present in the vicinity of osteoclasts. Vascular ingrowth was present in the cement and there was an absence of fibrous tissue. Qualitative the appearances seem very similar to bone remodelling.

However in some cases samples from unstable regions showed cement fragmentation with a prominence of macrophages thereby implying that fracture stability is an essential prerequisite for the successful use of calcium phosphate cements4,5. A rare recent study looked at the histology in 13 patients, 16 months following tibial osteotomies and confirmed previous animal studies’ conclusions that the cements show good osteoconductive properties and display excellent biocompatability6.

Literature Review Of Current Applications
 Calcium phosphate cements have been used in a variety of settings. This is a summary of the current literature concerning the applications of calcium bone cements.

1. Distal Radial Fractures
Biomechanical studies have been carried out on the stability of distal radial fractures fixed with cement versus Kirschner wiring and the cemented group had a significantly higher load to failure and were more stable7. Studies have also been conducted on fresh fractures with a treatment protocol comprising injection of the metaphyseal defect and manipulation as compared with external fixation. Again the cemented group showed a faster gain of grip strength and range of movement at eight weeks although there were no significant differences at one year post surgery. The definitive study so far is a multicentre randomized trial looking at 323 patients with distal radial fractures. They were treated with or without cement although patients in both groups had supplementary K-wires as required.

Significant clinical differences were seen at six to eight weeks postoperatively, with better grip strength, wrist range of motion, digital motion, use of the hand, and social and emotional function, and less swelling in the patients treated with cement. By three months, these differences had normalized except for digital motion, which remained significantly better. At one year, no clinical differences were detected. Radiographically, the average change in ulnar variance was greater in the patients treated with cement. No differences were seen in the total number of complications, including loss of reduction. The infection rate, however, was significantly higher in the control group and the infections were always related to metalwork. Accelerated rehabilitation therefore seems to be the major benefit8.

A newer application is in the field of corrective distal radial osteotomies in the elderly with osteoporotic bone. A series of 6 cases with using the combination above were subject to radiological and functional outcome assessment. They found 77% range of motion and 88% grip strength as compared with the unaffected side after an average 16 month follow up with all patients returning to neutral or better alignment in the sagittal plane9.

2. Tibial Plateau Fractures
The theoretical advantages of the cement were reviewed in a trial allowing free weight bearing six weeks post surgery in 41 patients fixed using cement as an adjunct to the hardware. Only one patient suffered a loss of reduction in that trial. Keating et al treated 47 patients with Schatzker II & III type fractures with cement augmented internal fixation. They reported a functional outcome score of over 90% at one year10. Another clinical trial with a total of 26 matched patients were assessed for operative time, quality of reduction, maintenance of reduction and development of post-traumatic osteoarthritis. Overall anatomic criteria were significantly better in the cemented group and none developed post traumatic arthritis at a minimum of 1 year follow up11.

3. Calcaneal Fractures
Fixation of calcaneal fractures is a controversial issue. There is usually only a limited stability of the fracture achievable and the underlying cause is often the presence of cancellous bone defects. Biomechanical studies suggested less deformation if internal fixation is augmented with cement12. In a prospective clinical trial, 36 calcaneal fractures were treated with internal fixation and cement. Progressively shorter times to full weight bearing were prescribed with the shortest being full weight bearing three weeks after surgery. None of the cases showed a loss of reduction13.

A more recent clinical trial looked at 18 patients with intraarticular calcaneal fractures fixed with cement and internal fixation. At the current three year follow up, there is no difference in functional outcome although the authors report earlier weight bearing and the lack of graft site morbidity as advantages of the cement technique14.

4. Hip Fractures
Fractured necks of femora in the elderly are associated with osteoporosis. Although fixation is a well established method of treatment for some fractures, there are still considerable complications. Most of these complications are a result of compromised blood flow but lack of stable fixation is still a recognised obstacle to successful outcome15.

One study examined the use of cement with cannulated hip screw fixation in a cadaver study. They found they were stiffer and had a higher load to failure threshold than fixation alone16. Prospective randomised control trials have also been conducted comparing fixation versus fixation augmented with cement. The cement was used to augment the bone around the screw threads to improve pull out strength and to fill the fracture void.

Results showed significantly improved stability, less distal head migration and less varus angulation in the early rehabilitative phase but the differences were not borne out at the 6 and 12 month follow up. Interestingly, the same authors, also performed a study on displaced intracapsular neck of femur fractures (Garden III & IV) which did not show any improvement in the cement augmented group17.

The other type of hip fracture pattern which lends itself to cement augmentation is the multifragmentary trochanteric fracture types. Initial biomechanical studies conducted using trochanteric fracture models with a detached lesser trochanter suggested that fixation with cement and dynamic hip screw versus hip screw alone provided better biomechanics. Improved stiffness, stability and strength with less collapse at the fracture site were seen in the cement augmented group18.

A randomised clinical trial was conducted with patients sustaining a detached posteromedial fragment with their trochanteric fractures of the hip. Treatment was again randomised to dynamic hip screw or dynamic hip screw with cement augmentation. The theoretical advantage was that an intact posteromedial surface would allow better fracture end contact, and reduce potential fracture displacement and screw cut out. Radiostereometric analysis suggested reduced overall movement, including less angulation and displacement with the augmented group19.

There are early reports of the attempted use of cement is restoring acetabular defects but no clear benefits biomechanically have yet been shown20.

5. Spine
This in some ways is the most interesting area for calcium phosphate bone cement applications. The reasons for this include the fact that osteoporotic wedge fractures are commonly left untreated with the functionally limiting complication of painful, progressive kyphosis. Initial theoretical concerns were based around the forces to which the cement in vertebrae would be subjected. As shown earlier, shear and tension strengths of calcium phosphate cements are not high and therefore it was suggested that unlike the distal radius or tibial plateau, in vertebrae subjected to these forces the cement would fail. However several studies have reported looking at calcium phosphate cements for vertebroplasty and they have been promising.

Biomechanical studies in human cadaver vertebrae and paired spinal units have suggested that calcium phosphate cements are superior to PMMA cements for vertebroplasty in terms of normalising maximal load compressive strength and also did not show evidence of inducing compressive fractures in adjacent spinal segments21. Further biomechanical studies confirmed in terms of mode of failure and compressive strength there was a superiority of vertebroplasty undertaken with cement22,23. Takemasa and Yamamoto had a series of 38 patients whom underwent kyphoplasty with calcium bone cement and all had substantial pain relief and radiographs at 3 months and did not show any vertebral collapse or radiolucent lines24.

A recent study looked at sixty patients with osteoporotic vertebral compression fractures in a case control study. The two groups were matched and underwent either conservative treatment or cement kyphoplasty. Radiographic and clinical follow up at a mean of 17 months showed statistically significant lower back pain, lower analgesia requirement and less kyphosis in the cemented group25.

6. Tendon-Bone Healing
A newer potential application of bone cements is in anterior cruciate ligament reconstruction. Currently hamstring graft usage in ACL reconstruction is popular but one of its disadvantages is the early healing and internal fixation of the graft. An animal study comparing ACL reconstruction with hamstring alone compared with hamstring augmented with calcium phosphate cement in the bony tunnel. Histologically the augmented group showed superior bone formation and ingrowth into the tendon.

Biomechanically, superior pull out strength and tensile characteristics were also shown in the augmented group26. Human studies are being conducted but are yet to report.

7. Tumour surgery
As a void filler, recently calcium cements are being used in tumour surgery. A review of 56 patients who underwent curettage of their tumour and cement implantation was conducted with radiographic and clinical follow up. One patient had a postoperative fracture, three had local recurrence and one had a superficial wound infection. With an average follow up of 18 months, all patients demonstrated good radiographic adaptation of the cement to host bone27.

The Future
 In 2004 researchers at the University of Birmingham, found that adding sodium citrate made the cement far less porous greatly improved the mechanical properties. The sodium citrate is non toxic and does not affect the biocompatibility. These cements can be drilled and even support screws. Their compressive strength exceeds that of cortical bone at around 150 Mpa and so opens up the possibility of extensive use in reconstruction surgery. It promises to be an interesting few years in the development of cement technology.

References
  1. Hak DJ. The use of osteoconductive bone graft substitutes in orthopaedic trauma. J.Am.Acad.Orthop.Surg. 2007;15:525-36.
  2. Burger EL,.Patel V. Calcium phosphates as bone graft extenders. Orthopedics 2007;30:939-42.
  3. Collinge C, Merk B, Lautenschlager EP. Mechanical evaluation of fracture fixation augmented with tricalcium phosphate bone cement in a porous osteoporotic cancellous bone model. J.Orthop.Trauma 2007;21:124-8.
  4. Frankenburg EP, Goldstein SA, Bauer TW, Harris SA, Poser RD. Biomechanical and histological evaluation of a calcium phosphate cement. J.Bone Joint Surg.Am. 1998;80:1112-24.
  5. Goodman SB, Bauer TW, Carter D, Casteleyn PP, Goldstein SA, Kyle RF et al. Norian SRS cement augmentation in hip fracture treatment. Laboratory and initial clinical results. Clin.Orthop.Relat Res. 1998;42-50.
  6. Meyer S, Floerkemeier T, Windhagen H. Histological osseointegra- tion of a calciumphosphate bone substitute material in patients. Biomed.Mater.Eng 2007;17:347-56.
  7. Yetkinler DN, Ladd AL, Poser RD, Constantz BR, Carter D. Biomechanical evaluation of fixation of intra-articular fractures of the distal part of the radius in cadavera: Kirschner wires compared with calcium-phosphate bone cement. J.Bone Joint Surg.Am. 1999;81:391-9.
  8. Cassidy C, Jupiter JB, Cohen M, Delli-Santi M, Fennell C, Leinberry C et al. Norian SRS cement compared with conventional fixation in distal radial fractures. A randomized study. J.Bone Joint Surg.Am. 2003;85-A:2127-37.
  9. Lozano-Calderon S, Moore M, Liebman M, Jupiter JB. Distal radius osteotomy in the elderly patient using angular stable implants and Norian bone cement. J.Hand Surg.[Am.] 2007;32:976-83.
  10. Keating JF, Hajducka CL, Harper J. Minimal internal fixation and calcium-phosphate cement in the treatment of fractures of the tibial plateau. A pilot study. J.Bone Joint Surg.Br. 2003;85:68-73.
  11. Simpson D,.Keating JF. Outcome of tibial plateau fractures man aged with calcium phosphate cement. Injury 2004;35:913-8.
  12. Thordarson DB, Hedman TP, Yetkinler DN, Eskander E, Lawrence TN, Poser RD. Superior compressive strength of a calcaneal fracture construct augmented with remodelable cancellous bone cement. J.Bone Joint Surg.Am. 1999;81:239-46.
  13. Schildhauer TA, Bauer TW, Josten C, Muhr G. Open reduction and augmentation of internal fixation with an injectable skeletal cement for the treatment of complex calcaneal fractures. J.Orthop.Trauma 2000;14:309-17.
  14. Elsner A, Jubel A, Prokop A, Koebke J, Rehm KE, Andermahr J. Augmentation of intraarticular calcaneal fractures with injectable calcium phosphate cement: densitometry, histology, and functional outcome of 18 patients. J.Foot Ankle Surg. 2005;44:390-5.
  15. Rehnberg L,.Olerud C. The stability of femoral neck fractures and its influence on healing. J.Bone Joint Surg.Br. 1989;71:173-7.
  16. Stankewich CJ, Swiontkowski MF, Tencer AF, Yetkinler DN, Poser RD. Augmentation of femoral neck fracture fixation with an injectable calcium-phosphate bone mineral cement. J.Orthop.Res. 1996;14:786-93.
  17. Mattsson P,.Larsson S. Calcium phosphate cement for augmentation did not improve results after internal fixation of displaced femoral neck fractures: a randomized study of 118 patients. Acta Orthop. 2006;77:251-6.
  18. Yetkinler DN, Goodman SB, Reindel ES, Carter D, Poser RD, Constantz BR. Mechanical evaluation of a carbonated apatite cement in the fixation of unstable intertrochanteric fractures. Acta Orthop.Scand. 2002;73:157-64.
  19. Mattsson P, Alberts A, Dahlberg G, Sohlman M, Hyldahl HC, Larsson S. Resorbable cement for the augmentation of internally- fixed unstable trochanteric fractures. A prospective, randomised multicentre study. J.Bone Joint Surg.Br. 2005;87:1203-9.
  20. Olson SA, Kadrmas MW, Hernandez JD, Glisson RR, West JL. Augmentation of posterior wall acetabular fracture fixation using calcium-phosphate cement: a biomechanical analysis. J.Orthop.Trauma 2007;21:608-16.
  21. Hong SJ, Park YK, Kim JH, Lee SH, Ryu KN, Park CM et al. The biomechanical evaluation of calcium phosphate cements for use in vertebroplasty. J.Neurosurg.Spine 2006;4:154-9.
  22. Ikeuchi M, Yamamoto H, Shibata T, Otani M. Mechanical augmentation of the vertebral body by calcium phosphate cement injection. J.Orthop.Sci. 2001;6:39-45.
  23. Lim TH, Brebach GT, Renner SM, Kim WJ, Kim JG, Lee RE et al. Biomechanical evaluation of an injectable calcium phosphate cement for vertebroplasty. Spine 2002;27:1297-302.
  24. Takemasa R,.Yamamoto H. [Calcium phosphate paste injection for the treatment of vertebral fracture due to osteoporosis]. Clin.Calcium 2001;11:1595-600.
  25. Nakano M, Hirano N, Ishihara H, Kawaguchi Y, Watanabe H, Matsuura K. Calcium phosphate cement-based vertebroplasty compared with conservative treatment for osteoporotic compression fractures: a matched case-control study. J.Neurosurg.Spine 2006;4:110-7.
  26. Tien YC, Chih TT, Lin JH, Ju CP, Lin SD. Augmentation of tendon- bone healing by the use of calcium-phosphate cement. J.Bone Joint Surg.Br. 2004;86:1072-6.
  27. Matsumine A, Kusuzaki K, Matsubara T, Okamura A, Okuyama N, Miyazaki S et al. Calcium phosphate cement in musculoskeletal tumor surgery. J.Surg.Oncol. 2006;93:212-20.


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Mixing And Management Of Acrylic Bone Cement
Authors: Dr Nicholas Dunne BSc, PhD, CEng (School of Mechanical and Aerospace, Queen’s University of Belfast, UK), Mr Robert Lee BSc, MBBS, MRCS

Approximately 6,200 hip and 3,300 knee revision operations (National Joint Registry, 2006) are conducted every year in the UK with the average cost of a revision in Europe being £8,000 (Rasanen et al, 2007), which represents a significant burden on the National Health Service. Due to an ageing population and a growth in primary procedures, the number of revisions is anticipated to grow significantly over the next 10 years.

Preparation of the bone cement is one of the key steps in cemented joint arthroplasty. The perioperative practitioner needs not only to be familiar with the vacuum mixing device being used, but also must ensure that attention is given to the timing of each phase of the mixing process. This article sets out to demonstrate the importance of mixing technique and the implications of incorrect timing on the longevity of the prosthesis.

What is bone cement?
 Polymethyl methacrylate (PMMA) bone cements are two-component systems, comprising a polymer powder and a liquid monomer. The polymer powder component is composed of PMMA and/or methacrylate copolymers. Furthermore, the polymer powder contains benzoyl peroxide (BPO), which acts as an initiator of the free radical polymerisation reaction. The BPO can form part of the polymer micro-beads or simply be incorporated into the powder. The powder also contains an X-ray contrast agent and possibly an antibiotic. In the liquid phase MMA is the main constituent but sometimes other methacrylates such as butyl methacrylate are also present.

In order for the MMA to be used for bone cements it must be polymerisable, therefore it must contain a carbon double bond which can be broken. As an activator of the formation of radicals the liquid contains an aromatic amine, such as N,N-dimethyl-p-toluidine (DmpT). Additionally, it contains an inhibitor (hydroquinone) to avoid premature polymerisation during storage and optionally a colouring agent such as chlorophyll.

The behaviour of the cement differs between manufacturer depending on the ratio of the polymer powder and liquid monomer components, the size, shape and weight of the molecules, the manufacturing process and the methods of sterilisation.

The function of bone cement
 PMMA bone cements are primarily used for the fixation of joint prostheses. In the fixation of joint replacement the self-curing cement fills the free space between the prosthesis and the bone, and constitutes a very important interface (Figure 1). Due to their optimum elasticity, the bone cements can evenly cushion the forces acting against the bone. The close association between the cement and the bone leads to optimal distribution of the stresses and interface strain energy.

Figure 1: Schematic diagram of prostheses and PMMA bone cement in an acetabular socket and femur.
The transfer of the force from bone-to-implant and implant-to-bone is the primary function of bone cement. The ability to do this reliably for a long time is crucial for long-term survival of the implant. Adequate cement interdigitation and reinforcement of the cancellous bone are of utmost importance. If the extremely generated stresses exceed the capability of the bone cement to transfer and absorb forces, a fatigue fracture is possible.

Antibiotic loaded bone cements are also used as drug-delivery systems. Artificial implants are more susceptible to bacterial colonisation on their surfaces because the germs can then hide from the natural protection via the body and cause periprosthetic infection. When loaded with antibiotics, bone cement functions as carrier matrix.

Choosing the right mixing technique
 When bone cement was first used in arthroplasty, it was hand mixed in a bowl in the operating room and then inserted by hand or transferred and injected into the desired location. Because PMMA comes as a powder composed of pre-polymerised particles to be mixed with the liquid monomer, monomer fumes are released into the air. Furthermore with hand mixing, a certain amount of porosity in the final material is unavoidable owing to air entrapment, even in lower viscosity cements.

During the 1980s different techniques were introduced in the hope of improving mixing and thereby bone cement properties (Burke et al., 1984, Lindén, 1991). The results, however, were not convincing. Lidgren et al., (1984) introduced vacuum mixing of bone cement. The quality of the bone cement was improved. Today, vacuum mixing is widely accepted as the method of choice for achieving homogenous cement, reducing porosity and increasing cement strength, which is why it is an integral part of modern cementing technique (Malchau and Herberts, 1996).

Vacuum mixing systems reduce the monomer exposure to the operating theatre staff by 50–70% (Schlegel et al., 2004) and eliminate contact with bone cement during delivery (Buchhorn et al., 1992, Darre et al., 1988, Bettencourt et al., 2001, Eveleigh, 2002). The working environment for the theatre staff is improved, and the risk of fume-induced headaches, respiratory irritation and allergic reactions are minimal.

Conventional mixing of bone cement produces a porosity of 5–16%. Vacuum mixing produces porosity of 0.1–1% (Lindén and Gillquist, 1989, Wang and Kjellson, 2001). Porosity has been found to be the major cause of decreased mechanical performance of bone cement. To ensure its in vivo survival, the cement must be able to withstand the varying loads it endures. Thus fatigue property, which is directly affected by porosity, is as important in determining the long-term survival of a joint replacement as static strength. Fatigue failure occurs when cement cracks are initiated from defects in the cement mantle. It is known that vacuum mixing of cement improves mechanical properties (Lidgren et al., 1984, Alkire et al., 1987, Wixson et al., 1987, Lindén and Gillquist, 1989, Dunne and Orr, 2001, Mau et al., 2004) largely as a result of minimising micro- and macropores (Wang et al., 1993, 1996). Numerous studies have confirmed that vacuum mixing enhances the fatigue life of the bone cement (Lewis, 2000, Harper and Bonfield, 2000, Wilkinson et al., 2000, Dunne et al., 2003).

Incomplete mixing of the monomer and polymer may lead to partially united and, in some cases, free unbonded cement particles. Vacuum mixing of bone cement not only decreases the number of voids, but also improves the microscopic homogeneity of bone cement (Wang et al., 1994). When cement fracture occurs, inhomogeneous cement may release PMMA and contrast media particles to the bone-cement interface. These particles may evoke a foreign body response or stimulate osteoclast activity (Wimhurst et al., 2001), resulting in osteolysis of the surrounding bone.

Extensive porosity at the cement-stem interface has been found in retrieved cement mantles and in laboratory-prepared specimens (James et al., 1993, Bishop et al., 1996). This interface porosity is caused by entrapment of air at the stem surface during stem insertion and by residual porosity in the cement. When cement is mixed under vacuum, cement porosity is significantly reduced, thus producing less porosity at the cement-prosthesis interface (Bishop et al., 1996). Various studies have shown that interface porosity weakens the resistance of the cement to torsional load (Davies et al., 1995) and decreases fatigue life of the cement-metal interface (Iesaka et al., 2003). Interface porosity has also been linked to the initiation of cement cracks (Jasty et al., 1991). The evidence is convincing that reduction of interface porosity improves the strength of the interface, thereby increasing the survival of cemented implants.

The variation of cement porosity from different mixing systems is still considerable (Dunne et al., 2004, Mau et al., 2004). Various studies indicate that macropores increase the risk of fatigue failure, and the current opinion is that efforts should be made to minimise the number and size of macropores. Orr et al. (2003) reported that when cement is mixed thermal shrinkage occurs resulting in the formation of microcracks within the cement from the time of implantation and prior to functional loading. The occurrence and frequency of these microcracks is significantly higher for cement that has been prepared under vacuum conditions. However, mixing cement under sub-optimal vacuum levels (<550 mmHg) produces a highly porous bone cement that demonstrates inferior mechanical properties (Dunne et al., 2001).

Understanding the viscosity and handling properties
 The viscosity of bone cements at the dough stage is determined mainly by the chemical composition of the polymer powder and liquid components and the powder to liquid ratio (Dunne and Orr, 1998). These characteristics should never be altered in operating theatre in an attempt to modify the viscosity of the cement. The acceptable method to adjust the viscosity of the cement without compromising its properties is the prechilling of the polymer powder and liquid components prior to mixing. The velocity of the reaction, and ultimately the viscosity, depends on the temperature. Prechilling of the polymer powder and liquid components, especially of high viscosity cements, has been used with the introduction of vacuum mixing systems to make mixing of the cement more convenient and improve the quality of the cement, especially with respect to porosity (Lidgren et al., 1987).

Bone cements can be divided into two main categories: high and low viscosity cements. High viscosity bone cements have shorter mixing phases and lose their stickiness quickly. During the working phase the viscosity remains constant and slowly increases toward the end of this phase. Generally, the working phase is long. Low viscosity bone cements have a long lasting liquid to low viscosity mixing phase. The cement remains sticky for three minutes or longer. In its working phase the viscosity quickly increases. During the working phase there is already heat formation caused by polymerisation and therefore the temperature of the cement dough increases. The waiting phase of the low viscosity cements lasts a few minutes. High viscosity cements are injectable almost directly after the mixing phase and they have a longer application phase. The high viscosity during mixing could be a disadvantage because it allows air to become entrapped.

The handling of bone cements can be described by four different phases (Figure 2) with their corresponding viscosities: mixing phase, waiting phase, application or working phase and setting or hardening phase (Dunne and Orr, 2002).

Figure 3: Four stages of polymerisation for PMMA bone cement that has been stored under different temperatures.
The mixing phase (up to one minute) is the time for thorough homogenisation of the polymer powder and the liquid components. Significant differences are observed in the mixing phase for different bone cements. Some bone cements mix more readily than others because of higher initial viscosity. Therefore, care must be taken not to introduce air bubbles into the dough at this early stage, which could lead to high porosity within the cement resulting in premature failure when subjected to mechanical loading. The homogeneity of the dough is influenced by a number of factors such as the design of the mixing vessel and the spatula, the mixing speed, number of strokes or revolutions per minute, and so on. The longer and more vigorous the cement is mixed the more porous it becomes.

The waiting phase (up to several minutes, depending of bone cement type and the handling temperature) is the period for the cement to achieve a non-sticky consistency and therefore be ready for use. The application or working phase (2–4 minutes, depending on bone cement type and handling temperature) is the period when the cement in injected into the bone prior to implantation of the prosthesis. At this stage of the polymerisation, the cement dough is of moderate viscosity. To achieve a proper interdigitation of interface at the cement mantle and cancellous bone it is important for the surgeon to know the working time in order to correctly pressurise the cement and insert the prosthesis at an optimal viscosity.

The viscosity at beginning of the application stage must not be too low, otherwise the injected dough will not withstand the bleeding pressure (13 kPa) in the bone. Blood infiltration into the bone cement will lead to laminations, ultimately reducing its mechanical strength. This is the main problem when using low viscosity cements with their short working time. High viscosity cements in this regard are more user-friendly and forgiving, therefore resulting in better long-term performance (Breusch, 2001). Late application of bone cement of too high viscosity can also result in problems such as poor interdigitation of the cement into the cancellous bone. The setting or hardening phase (1–2 minutes) is the period of the final setting process and the development of the polymerisation heat.

The temperature of the cement prior to mixing and of the surroundings has a significant influence on the progress of the bone cement through the different phases (Figures 2 and 3). The information given by the temperature vs elapsed time from start of mixing is not always comparable, because manufacturers use different measuring techniques resulting in different lengths of the working phases. This disagreement is caused primarily by the lack of a universal test method. A wide experience and knowledge by the surgeon is therefore beneficial to determine the optimal time to inject the cement and insert the prosthesis.

Figure 2: Four stages of polymerisation for PMMA bone cements can be described by four different phases as a function of ambient temperatures
For the surgeon the viscosity is the most important handling characteristic and determines the working properties of the bone cement. The timing for injection and pressurisation of the PMMA bone cement is critical to the success of the surgical procedure.

Conclusion
 PMMA bone cement for joint replacement surgery was introduced nearly 50 years ago, and has been used widely throughout the world. Our understanding of the properties and use of bone cement have increased greatly since then. The users of cemented joint replacement need to know the chemical and physical properties of bone cement, which change by even slight variations in the chemical composition. The final bone cement is produced by nurses and surgeons in the operating theatre. These users have enormous influence on the quality of the final cement. Control of handling procedures is of the utmost importance in producing a well cemented implant. The use of modern cementing techniques has demonstrated increased long term survival rate of cemented implants. Further education and training on bone cement and cementation techniques will reduce the complications of bone cement use and lead to yet longer implant survival.

References

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