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The Use of Calcium Phosphate Bone Cement in Fracture Treatment. A Meta-Analysis of Randomized Trials
Sohail S. Bajammal, Michael Zlowodzki, Amy Lelwica, Paul Tornetta, III, Thomas A. Einhorn, Richard Buckley, Ross Leighton, Thomas A. Russell, Sune Larsson and Mohit Bhandari J Bone Joint Surg Am. 2008;90:1186-1196. doi:10.2106/JBJS.G.00241

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C OPYRIGHT 2008
BY

T HE J OURNAL

OF

B ONE

AND J OINT

S URGERY, I NCORPORATED

The Use of Calcium Phosphate Bone Cement in Fracture Treatment

A Meta-Analysis of Randomized Trials
By Sohail S. Bajammal, MBChB, MSc, FRCSC, Michael Zlowodzki, MD, Amy Lelwica, MD, Paul Tornetta III, MD, Thomas A. Einhorn, MD, Richard Buckley, MD, FRCSC, Ross Leighton, MD, FRCSC, Thomas A. Russell, MD, Sune Larsson, MD, PhD, and Mohit Bhandari, MD, MSc, FRCSC
Investigation performed at the Orthopaedic Research Division, Department of Surgery, McMaster University, Hamilton, Ontario, Canada

Background: Available options to ll fracture voids include autogenous bone, allograft bone, and synthetic bone materials. The objective of this meta-analysis was to determine whether the use of calcium phosphate bone cement improves clinical and radiographic outcomes and reduces fracture complications as compared with conventional treatment (with or without autogenous bone graft) for the treatment of fractures of the appendicular skeleton in adult patients. Methods: Multiple databases, online registers of randomized controlled trials, and the proceedings of the meetings of major national orthopaedic associations were searched. Published and unpublished randomized controlled trials were included, and data on methodological quality, population, intervention, and outcomes were abstracted in duplicate. Data were pooled across studies, and relative risks for categorical outcomes and weighted mean differences for continuous outcomes, weighted according to study sample size, were calculated. Heterogeneity across studies was determined, and sensitivity analyses were conducted. Results: We identied eleven published and three unpublished randomized controlled trials. Of the fourteen studies, six involved distal radial fractures, two involved femoral neck fractures, two involved intertrochanteric femoral fractures, two involved tibial plateau fractures, one involved calcaneal fractures, and one involved multiple types of metaphyseal fractures. All of the studies evaluated the use of calcium phosphate cement for the treatment of metaphyseal fractures occurring primarily through trabecular, cancellous bone. Autogenous bone graft was used in the control group in three studies, and no graft material was used in the remaining studies. Patients managed with calcium phosphate had a signicantly lower prevalence of loss of fracture reduction in comparison with patients managed with autograft (relative risk reduction, 68%; 95% condence interval, 29% to 86%) and had less pain at the fracture site in comparison with controls managed with no graft (relative risk reduction, 56%; 95% condence interval, 14% to 77%). We were unable to compare pain at the bone-graft donor site between the studies because of methodological reasons. Three studies independently demonstrated improved functional outcomes when the use of calcium phosphate was compared with the use of no grafting material. Conclusions: The use of calcium phosphate bone cement for the treatment of fractures in adult patients is associated with a lower prevalence of pain at the fracture site in comparison with the rate in controls (patients managed with no graft material). Loss of fracture reduction is also decreased in comparison with that in patients managed with autogenous bone graft. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.

he incidence of fractures in the United States exceeds 6 million fractures annually1. Metaphyseal fractures are among the most difcult fractures to treat. Depressed ar-

ticular fragments can crush the underlying weak subchondral cancellous bone, leaving a void when the articular segments are reduced surgically. Potential long-term problems

Disclosure: In support of their research for or preparation of this work, one or more of the authors received, in any one year, outside funding or grants in excess of $10,000 from the Osteosynthesis and Trauma Care Foundation (OTCF), formerly known as the Association Internationale pour l Ost osynth` se e e Dynamique (AIOD). In addition, one or more of the authors or a member of his or her immediate family received, in any one year, payments or other benets in excess of $10,000 or a commitment or agreement to provide such benets from a commercial entity (Norian, Callos, and ETEX). Also, a commercial entity (ETEX, Cambridge, Massachusetts) paid or directed in any one year, or agreed to pay or direct, benets of less than $10,000 to a research fund, foundation, division, center, clinical practice, or other charitable or nonprot organization with which one or more of the authors, or a member of his or her immediate family, is afliated or associated. One of the authors receives salary support in part, by a Canada Research Chair, McMaster University. A commentary is available with the electronic versions of this article, on our web site (www.jbjs.org) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM).

J Bone Joint Surg Am. 2008;90:1186-96

doi:10.2106/JBJS.G.00241

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such as pain, posttraumatic arthritis, and limitation of motion and function might occur if joint surface subsidence cannot be prevented or at least limited. Autogenous bone, typically from the iliac crest, remains the preferred source of bone for grafting. However, it is associated with donor-site morbidity, including chronic pain and wound complications2-8. Alternative graft materials for lling fracture voids include allograft bone and synthetic bone materials. While the use of allograft avoids the donor-site morbidity associated with the use of autograft, it also can lead to complications, including potential disease transmission, histoincompatibility, and possibly lower union rates9-11. Therefore, synthetic bone materials, such as different types of calcium phosphate bone cement products, appear to be an attractive alternative because they lack the disadvantage of donor-site morbidity associated with autografts and the disadvantages of potential infection and disease transmission associated with allograft. Several narrative review articles have addressed the use of bone-grafting for the treatment of fractures and traumatic injuries. Some studies have focused on the use of synthetic bone materials, including different types of calcium phosphate bone cement, and have described the biomechanical, histological, and clinical characteristics of these materials1,12-14. However, none of the reviews described the search methodology or the criteria for including studies. Thus, it is difcult to assess the comprehensiveness of the reviews and to determine whether bias in selecting studies was avoided. A comprehensive systematic review with explicit transparent reporting of the search methodology and criteria for including studies coupled with a validity assessment of included studies and statistical pooling of studies, when appropriate, allows stronger unbiased inferences to be made. The objective of the present meta-analysis was to identify and summarize the evidence from randomized controlled trials that compared the use of a type of calcium phosphate bone cement with other alternatives and its effects on functional and radiographic outcomes in adults with fractures of the appendicular skeleton. We hypothesized that the use of calcium phosphate bone cement improved outcomes in patients with metaphyseal fractures of the upper and lower extremities. Materials and Methods Eligibility Criteria e identied articles in which (1) the target population was skeletally mature patients with a fracture of a bone of the appendicular skeleton, (2) the intervention was the use of calcium phosphate bone cement for the treatment of these fractures (as compared with alternative treatment or no treatment), (3) the outcome was measured on the basis of functional criteria (pain or impairment), radiographic criteria (fracture-healing or subsidence), or the rate of infection, and (4) the study was a published or unpublished randomized controlled trial. We excluded any study that did not meet all of the aforementioned inclusion criteria.

(from 1966 to September 2006), EMBASE (from 1980 to September 2006), CINAHL (from 1982 to September 2006), and AMED (from 1985 to September 2006). We considered studies in all languages, regardless of publication status. We also searched the Cochrane Database for Systematic Reviews, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Abstracts of Reviews of Effects, the United Kingdom National Research Register (https://portal.nihr.ac.uk/Pages/NRRArchive. aspx), the ClinicalTrials.gov web site, the Current Controlled Trials metaRegister of Controlled Trials web site (http://controlled-trials. com/mrct/), and archives of abstracts of the annual meetings of the Orthopaedic Trauma Association (www.hwbf.org/ota/am/, 1996-2004), the American Academy of Orthopaedic Surgeons (www.aaos.org/wordhtml/libscip.htm, 2003-2004; accessed September 2006), and the Canadian Orthopaedic Association (www. coa-aco.org/c/meeting-archives.html, 2003-2005) to identify additional studies. Additionally, we searched the proceedings of the Eleventh Meeting of the Combined Orthopaedic Associations 2004, Sydney, Australia, by hand. One of us (S.S.B.) reviewed the bibliography of each article that met our inclusion criteria for additional relevant studies. We contacted corresponding authors, eld experts, and companies manufacturing calcium phosphate (Synthes, Paoli, Pennsylvania; Stryker, Kalamazoo, Michigan; DePuy, Warsaw, Indiana) to provide additional potentially relevant studies. We conducted our electronic search in three stages. In the rst stage, two of us (S.S.B. and A.L.) reviewed the titles and, if the title suggested any possibility that the article might meet eligibility criteria, we retrieved the abstract. In the second stage, we reviewed the abstracts and chose potentially eligible studies for retrieval of the full text. In the third stage, we checked the full-text articles for eligibility criteria. When the same data were reported in more than one article, only the article with the most complete data set was included and the duplicate publication was eliminated. Assessment of Study Quality Two of us (S.S.B. and A.L.) independently assessed the methodological quality of each included study with respect to the method of random sequence generation, allocation concealment, baseline comparability, similarity of care programs, blinding of patients and outcome assessors, statement of primary outcome, sample size calculation, statistical analysis, and the proportion of patients who had been lost to follow-up. In addition, the two of us used the Detsky scale to grade the quality of reporting of published studies15. This scale grades the reporting of studies on the basis of eligibility criteria, the adequacy of randomization, the description of therapies, the assessment of outcomes, and statistical analysis. In both cases, we resolved disagreements by means of discussion to achieve consensus. Data Extraction For each eligible study, two of us (S.S.B. and A.L.) independently extracted relevant data and checked the accuracy. Specically, we abstracted the number of participating centers, the country where the trial was centered, the type of fracture, the type of calcium phosphate cement, the inclusion and exclusion criteria, the sample sizes of the intervention and control groups, de-

Data Sources and Search Strategy We conducted, in duplicate (S.S.B. and A.L.) and independently, a computerized search of the electronic databases MEDLINE

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TABLE I Characteristics of Included Studies No. of Female Patients (Intervention Group, Control Group) 18, 18 48, 49 9, 9 9, 11 129, 143

First Author, Year Kopylov

25,40

No. of Centers, Country 1, Sweden 1, Spain 1, United Kingdom 1, Sweden 23, United States

No. of Patients* 40 (20, 20) 110 (55, 55) 18 (9, 9) 20 (9, 11) 323 (161,162)

Age (Intervention Group, Control Group) (yr) 69, 66 65, 67 71, 74 65, 67 64, 64

Population (Type of Fracture, Age Range) Distal radial, 50 to 80 years Distal radial, 50 to 85 years Distal radial, >60 years Distal radial, 50 to 80 years Distal radial, 45 years

, 1999
28

Sanchez-Sotelo , 2000 Jeyam , 2002 Kopylov , 2002 Cassidy , 2003

21 24 23

Dickson , 2002 Mattsson , 2003 Zimmermann , 2003 Mattsson , 2004 Russell , 2004# Larsson , 2004# Mattsson , 2005 Mattsson , 2006 Reed , 2005#
35 31 30 32 33 27 29 26

22

3, United States 1, Sweden 1, Austria 1, Sweden 12, United States, Canada 1, Sweden 3, Sweden 1, Sweden 1, Canada

40 fractures (21, 19) 40 (20, 20) 52 (26, 26) 26 (14, 12) 120 fractures (82, 38) 26 (13, 13)** 112 (55, 57) 118 (58, 60) 48 fractures (21, 27)**

7, 6 18, 15 26, 26 12, 10 Overall, 46 Not reported 44, 47 46, 49** 1, 1**

45, 40 78, 78 63, 57 84, 82 43, 43 50, 52 81, 82 77, 77** 36, 37**

Multiple metaphyseal types, 18 to 80 years Low-energy femoral neck, 62 to 92 years Distal radial, menopausal women Unstable trochanteric Tibial plateau, 16 to 77 years Tibial plateau, 18 to 60 years** Unstable trochanteric, >65 years Displaced femoral neck, >60 years Displaced calcaneal, >16 years

*The values are given as the total number of patients in the study, with the numbers of patients in the intervention and control groups in parentheses. The values are given as the mean. ORIF = open reduction and internal xation. SF-36 = Short Form-36; DASH = Disabilities of the Arm, Shoulder and Hand; LEM = Lower Extremity Measure. #Abstract. **Author contact. Intertrochanteric fractures in the North American literature.

mographic data (age and gender), the intervention and control protocols, the duration of the study, the rate of loss to follow-up, the study outcomes measured (including clinical outcomes [pain or impairment], radiographic outcomes [fracture-healing or subsidence], and complications [infection]), and the source of funding. The reviewers resolved disagreements by means of discussion to achieve consensus. In addition, we contacted the corresponding author of each eligible study to verify the accuracy of our data abstraction as well as to provide additional information that had not been reported in the published studies. Assessing Reviewer Agreement Kappa, a measure of chance-corrected agreement, provided most estimates of agreement among reviewers for the titles, abstracts,

and methods sections of potentially relevant articles. Donner and Klar16 and Fleiss17 provided persuasive arguments favoring the use of this statistic over other measures of agreement. For variables with more than two categories, we used weighted kappa with quadratic weights. For continuous variables, we chose quantitated agreement with use of an intraclass correlation coefcient that yields identical values to weighted kappa with quadratic weights. We chose an a priori criterion of k 0.65 for adequate agreement18. We calculated the kappa for the initial agreement, and any disagreement was resolved by means of discussion. Data Synthesis For each study, we calculated the relative risks and relative risk reductions (with 95% condence intervals) for dichotomous

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TABLE I (continued)

Fracture Treatment (Intervention Group/Control Group) Closed reduction, Norian, and cast/closed reduction and external xation Closed reduction, Norian, and cast/closed reduction and cast Closed reduction, BoneSource, and cast/closed reduction, Kirschner wires, and cast Closed reduction, Norian, and cast/retain original cast (no reduction) Closed reduction, Norian, and either cast or external xation Kirschner wires/closed reduction and either cast or external xation Kirschner wires BoneSource/autogenous iliac crest bone graft Closed reduction, two screws, and Norian/closed reduction and two screws Closed reduction, Norian, Kirschner wires, and cast/closed reduction, Kirschner wires, and cast Dynamic hip screw and Norian/dynamic hip screw ORIF and a-BSM/ORIF and autogenous iliac crest bone graft ORIF and Norian/ORIF and autogenous iliac crest bone graft Dynamic hip screw and Norian/dynamic hip screw Closed reduction, two screws, and Norian/closed reduction and two screws ORIF and a-BSM/ORIF

Major Outcome Measures Pain, range of motion, grip strength, radiographic parameters, radiostereometric analysis Pain, range of motion, grip strength, radiographic parameters, malunion Range of motion, grip strength, radiographic parameters Pain, range of motion, grip strength, radiographic parameters Pain, range of motion, grip strength, radiographic parameters, loss of reduction, SF-36 Pain, regain of function, fracture-healing, loss of reduction Radiostereometric analysis Range of motion, grip strength, radiographic parameters, fracture-healing, DASH Radiostereometric analysis Range of motion, fracture-healing, loss of reduction Pain, weight-bearing, radiostereometric analysis, Lysholm knee score Pain, activities of daily living functions, muscle strength, SF-36, radiographic parameters Pain, activities of daily living functions, muscle strength, radiographic parameters Radiographic parameters, SF-36, LEM score

Funding Industry and peer-reviewed Not reported Industry Industry and peer-reviewed Industry

Industry Industry Not reported Industry Industry Industry and peer-reviewed Industry and peer-reviewed Industry and peer-reviewed Industry

outcomes (the number of patients in the intervention and control groups with pain, impairment of function, fracture healing, loss of reduction, and infection) and mean differences (with 95% condence intervals) for continuous outcomes (the mean difference between the intervention and control groups with regard to grip strength, range of motion, and radiographic parameters). When possible, we pooled data across studies with use of relative risks, relative risk reductions, the number needed to treat for dichotomous outcomes, and the weighted mean differences for continuous outcomes. Our rationale for statistical pooling included (1) a similarity of point estimates of treatment effects with widely overlapping condence intervals across studies resulting in nonsignicant tests of heterogeneity across studies and (2) a belief that across the populations, interventions, and outcomes, we could expect, more or less, the same direction of treatment effect. Given the potential diversity of included studies, we used a conservative method of statistical pooling, the random-effects model. This model assumes that the studies included in the

meta-analysis are a random sample of a population of studies addressing the question posed. It takes into account both within-study and between-study variability19. We assessed heterogeneity among studies with use of the Cochranes x 2 value and reported the p value and the I 2 value as proposed by Higgins and Thompson20. We used Review Manager 4.2.8 (The Cochrane Collaboration) for statistical analysis and graphical output. We conducted funnel plots to test for publication bias by plotting the study sample size against the magnitude of treatment effect (relative risk or weighted mean difference). In the absence of publication bias, the plot should resemble a symmetrical inverted funnel. Evaluation of Heterogeneity We dened study heterogeneity as a signicant Cochranes x 2 test of heterogeneity (p < 0.1). We used a lower-thanconventional threshold of signicance because tests of heterogeneity are typically underpowered. We identied, a priori, hypotheses regarding potential sources of heterogeneity in the

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TABLE II Quality Assessment of Included Studies Random Sequence Generation Computer Not reported Not reported Computer Not reported Computer Not reported Not reported

First Author, Year Kopylov

25,40

Allocation Concealment Sequentially numbered sealed envelopes Not reported Not reported Sequentially numbered sealed envelopes Not reported Sealed envelopes Sealed envelopes Not reported Yes Yes Yes Yes

Baseline Comparability

, 1999
28

Sanchez-Sotelo , 2000 Jeyam , 2002 Kopylov , 2002 Cassidy , 2003 Dickson , 2002 Mattsson , 2003 Zimmermann , 2003
29 26 22 21 24 23

Gender differences Differences in age, defect size, occupation, and smoking Gender differences Age differences

Mattsson , 2004 Russell , 2004# Larsson , 2004# Mattsson , 2005 Mattsson , 2006 Reed , 2005#
35 31 30 32 33

27

Not reported Computer Computer Computer Computer Computer

Sealed envelopes Sealed envelopes Sealed envelopes Sealed envelopes Sealed envelopes Independent person pulls consecutive tab

Yes Yes Yes Yes Yes Yes

*Similarity of care program other than intervention under investigation (intervention group compared with control group). Original Detsky score transformed to percentage. Author contact. The intervention group was managed with BoneSource and a cast (no internal xation), and the control group was managed with Kirschner wire and a cast. #Abstract.

major outcomes. We hypothesized that heterogeneity might be due to differences in the type of control group (autogenous bone graft or no graft), the type of fracture (radial, tibial, femoral, or multiple), and study quality score (<70% or 70%). We hypothesized that studies involving the use of autogenous bone graft in the control group would demonstrate less signicant differences in pain, functional impairment, fracture-healing, subsidence, and infection rate between the intervention and control groups than would studies that involved the use of no graft in the control group. Similarly, we hypothesized that studies with higher quality scores would have less signicant differences than those with lower quality scores. With regard to fracture type, we hypothesized that studies involving fractures of the non-weight-bearing upper extremity (distal radial fractures) would demonstrate less signicant differences in terms of treatment effects with regard to pain, functional impairment, fracture-healing, and subsidence between the intervention and control groups than would studies involving fractures of the lower extremity (femoral and tibial fractures).

Results Study Identication ur three stages of search eliminated all but twenty-three of 526 potentially relevant citations. Of the twenty-three included citations, eleven were published randomized controlled trials21-31, four were abstracts of three unpublished randomized controlled trials that had been presented at international meetings32-35, four were abstracts of three of the included published randomized controlled trials that had been presented at international meetings36-39, one40 reported on a different outcome for a subset of patients who had been involved in an included published randomized controlled trial25, one reported the early results for a subset of patients who had been involved in an included published randomized controlled trial41, one was a report of an early experience42, and one was a Spanishlanguage version of an included English-language study43. Thus, fourteen randomized controlled trials (including eleven full-text articles21-31 and three abstracts32,33,35) proved to be eligible for inclusion in the present systematic review. Figures E1-A and E1-B in the Appendix summarize the literature search ow. The

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TABLE II (continued) Duration of Follow-up, Percentage of Patients with Complete Follow-up 12 months, 95% 12 months, 100% 6 months, 86% 6 months, 90% 12 months, 91% 12 months, 55% 6 weeks, 100% 24 months, 100%

Similarity of Care Program* Different duration of immobilization (2 weeks or 5 weeks) Different duration of immobilization (2 weeks or 6 weeks) Different xation devices Operative compared with nonoperative Different duration of immobilization (2 weeks or 6 to 8 weeks) Surgeon preference Yes Different duration of immobilization (3 weeks or 6 weeks), different duration of Kirschner wire (4 weeks or 6 weeks) Yes Yes Different duration of weight-bearing restriction (6 weeks or 12 weeks) Yes Yes Yes

Post-Randomization Exclusions No No 1 of 21 fractures No No 4 of 38 patients No No

Sample-Size Calculation Yes Not reported Not reported Yes Yes Not reported Not reported Not reported

Detsky Score 70% 60% 50% 70% 75% 55% 65% 60%

No No No No No 7 of 48 fractures had <3 months of follow-up

Yes Not reported Yes Yes Yes Yes

6 months, 81% 12 months, 81% 12 months, 100% 6 months, 83% 24 months, 36% 12 months, 31%

65% 55% 75% 75% 70% 90%

weighted kappa coefcient on the initial agreement of the included citations was 0.85. Disagreement was resolved with discussion and consensus. We obtained responses from ve authors24,26,32,33,35. All authors of the three included abstracts provided their full manuscript32,33,35. Study Characteristics The characteristics of the included studies are summarized in Table I. Of the fourteen studies, six involved fractures of the distal part of the radius21,23-25,28,29, two involved fractures of the femoral neck26,31, two involved unstable femoral trochanteric fractures (intertrochanteric fractures in the North American literature)27,30, two involved fractures of the tibial plateau32,33, one involved multiple types of metaphyseal fractures22, and one involved fractures of the calcaneus35. Only four studies were multicenter trials21,22,30,33. The total number of fractures was 1179. Ten studies were conducted in a European country23-32, and four were conducted in a North American country21,22,33,35. The type of calcium phosphate used was Norian SRS (Skeletal Repair System) (monocalcium phosphate monohydrate, calcite, alpha-tricalcium phosphate) (Synthes, Paoli, Pennsylvania) in ten studies21,24-32, BoneSource (dicalcium phosphate anhydrous, tetracalcium phosphate) (Stryker, Kalamazoo, Michigan) in two22,23, and a-BSM (dicalcium

phosphate dehydrate, alpha-tricalcium phosphate) (DePuy, Warsaw, Indiana) in two33,35. Autogenous iliac crest bone graft was used in the control group in three studies22,32,33; in the other eleven studies, no grafting was performed. The funding source was reported to be industry in seven studies21-23,26,27,33,35 and industry and peer-reviewed organizations in ve studies24,25,30-32; the funding source was not reported in two studies28,29. Study Quality The methodological quality of the included studies is summarized in Table II. All studies were randomized controlled trials. Only one study22 reported the method of random sequence generation. Additional information regarding the type of randomization was obtained for seven additional studies by contacting the authors24,25,30-33,35. While the method of allocation concealment was not reported in four studies, the method of concealment was reported to be sealed envelopes in nine other studies22,24-27,30-33. Blinding of the patients was not reported in any study. The study by Reed et al. was the only study in which the outcome assessors were partially blinded35. Calcium phosphate cement is radiodense, and therefore it is impossible to blind the outcome assessors; in the study by Reed and colleagues, the radiologists were blinded to the follow-up interval.

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TABLE III Results No. of Patients with the Outcome in Each Group (N/Intervention, N/Control)*

Outcome Clinical outcome Pain: number of patients with pain (mild to severe) at 1 year (Figs. E-2A and E-2B in Appendix) Grip strength: mean percentage of contralateral side At 6 months At 1 year Range of motion for distal part of radius: mean percentage of contralateral side Flexion at 1 year Supination at 1 year Radiographic outcome Fracture-healing: number of healed fractures at 1 year Loss of reduction: number of fractures with loss of reduction (Figs. E-3A and E-3B in Appendix) Radiographic parameters of distal radial fractures Mean loss of radial inclination at 1 year Mean loss of dorsal angulation at 1 year Radiostereometric analysis Mean maximal total point motion (mm) Complications Infection: number of patients with documented infection

No. of Studies (Sample Size)

Point Estimate (95% Condence Interval) (P Value)

Tests for Heterogeneity (P value, I2)

3 (n = 455)

15/225, 31/230

RR = 0.57 (0.33 to 0.99) (p = 0.04)

0.39, 0%

5 (n = 490) 4 (n = 494)

NA NA

WMD = 5.28 (0.7 to 9.87) (p = 0.02) WMD = 5.95 (26.39 to 18.29) (p = 0.34)

0.12, 59% <0.01, 94%

3 (n = 456) 3 (n = 456)

NA NA

WMD = 2.11 (210.9 to 15.13) (p = 0.75) WMD = 3.18 (7.8 to 14.16) (p = 0.57) Not possible to calculate RR = 0.54 (0.26 to 1.13) (p = 0.10)

<0.01, 94% <0.01, 96%

4 (n = 216) 5 (n = 599)

129/129, 87/87 64/320, 78/279

NA 0.01, 69%

3 (n = 456) 4 (n = 492)

NA NA

WMD = 4.04 (11.78 to 3.7) (p = 0.31) WMD = 22.75 (7.45 to 1.9) (p = 0.25) WMD = 21.99 (25.84 to 1.86) (p = 0.31) RR = 0.74 (0.19 to 2.87) (p = 0.66)

<0.01, 98% 0.03, 79%

4 (n = 106)

NA

0.01, 79%

7 (n = 718)

12/381, 32/337

0.03, 59%

*NA = not applicable. RR = relative risk, and WMD = weighted mean difference.

The inclusion criteria were reported in all studies, and the exclusion criteria were reported in eleven. Four studies had differences in baseline characteristics that were not adjusted for in the nal analysis, which could bias the results and limits the generalizability of the ndings21,22,26,29. Sample-size calculation and specication of the primary outcome were reported in eight studies21,24,25,27,30-32,35. Post-randomization exclusions were reported in three studies, in which the statistical analysis conducted was per-protocol22,23,35. The percentage of patients who had complete study follow-up ranged from 31% to 100%. The Detsky score of the quality of reporting was transformed to percentage for ease of reporting. We determined an arbitrary

cut-off point of study quality of 70%. Seven of fourteen studies scored 70%21,24,25,30-32,35. We conducted sensitivity analysis on the basis of the quality of the study (Detsky score) for each outcome to study the causes of potential heterogeneity between the studies. Pain The results of statistical pooling are summarized in Table III. Of the fourteen studies, eight evaluated the outcome with regard to pain21,22,24,25,28,30-32. Three of these presented the data categorically (i.e., the number of patients with no pain, mild pain, moderate pain, and severe pain)21,22,28, and ve presented

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the data as a continuous outcome (i.e., as a mean pain score based on a visual analog scale)24,25,30-32. It was not possible to transform either form into the other. We included the pain data from the three studies that used a categorical outcome (n = 455 patients)21,22,28. The data from the ve studies that used a continuous outcome were not included, because three of the ve studies did not include the standard deviation, which limits the ability of statistical pooling. The categorical presentation was dichotomous (present or absent) in two studies21,22 and ordinal (mild, moderate, or severe) in one study28. We collapsed the ordinal categories into dichotomous categories (present or absent) in order to allow pooling across the studies. Of the three studies from which we were able to pool the pain outcomes, only one involved the use of autogenous iliac crest bone graft in the control group22. Pain at the iliac crest graft harvest site is a potential confounder for pain assessment. However, Dickson et al. showed no pain at the graft harvest site in any patient at six and twelve-month follow-up visits22. Hence, we pooled all of the pain outcomes of the fracture site across the three studies21,22,28. There was a lower prevalence of pain at the fracture site in the intervention group (n = 455 patients) (relative risk, 0.57 [95% condence interval, 0.33 to 0.99]; relative risk reduction, 43% [95% condence interval, 1% to 67%]; p = 0.04; heterogeneity tests, p = 0.39, I 2 = 0%). Although tests for heterogeneity were nonsignicant, we conducted sensitivity analyses to test our hypotheses. The sensitivity analysis by the type of control group showed that the calcium phosphate group had more signicant pain control when the control group used no bone graft21,28 compared with a nonsignicant difference in pain control in the calcium phosphate group when the control group used autogenous iliac crest bone graft22 (relative risk, 0.44 [95% condence interval, 0.23 to 0.86] [p = 0.02] compared with 0.96 [95% condence interval, 0.38 to 2.46] [p = 0.94]) (see Appendix, Fig. E-2A). This translates into a relative risk reduction of 56% (95% condence interval, 14% to 77%) in the prevalence of pain when the use of calcium phosphate was compared with the use of no grafting material. Therefore, for every sixteen patients managed with calcium phosphate, one episode of postoperative pain could be averted (number needed to treat, 16). Studies of fractures of the less-weightbearing upper extremity (the distal part of the radius)21,28 demonstrated a more signicant difference in terms of pain in favor of calcium phosphate cement than did studies of fractures of the weight-bearing lower extremity22 (relative risk, 0.44 [95% condence interval, 0.23 to 0.86], p = 0.02; relative risk reduction, 56% [95% condence interval, 14% to 77%]; number needed to treat, 16) (see Appendix). There was no signicant difference in treatment effect in association with study quality (relative risk, 0.65 [95% condence interval, 0.31 to 1.33] [p = 0.24] for lowerquality studies, compared with 0.40 [95% condence interval, 0.13 to 1.26] [p = 0.12] for higher-quality studies). Functional Outcome A functional outcome measure was reported in ve of the fourteen studies. The outcome measure was categorical in one

study22 and continuous in four21,29,30,35; in the latter group, the SF-36 (Medical Outcome Study 36-Item Short Form) was used in three studies21,30,35, and the DASH (Disabilities of the Arm, Shoulder and Hand) was used in one29. One of the three studies that involved the SF-36 did not provide the actual results21 and the other two did not provide standard deviations30,35, so datapooling was not feasible for the continuous outcome. Three of those ve studies demonstrated signicantly improved functional scores in association with the use of calcium phosphate21,29,30. In contrast, Dickson et al. found a difference in functional impairment in favor of the use of iliac crest bone graft22; however, the difference was not signicant (relative risk, 5.8 [95% condence interval, 0.77 to 43.5], p = 0.09). In the three studies in which the SF-36 was used as an outcome measure, one demonstrated no signicant differences between the study and control groups in terms of any of the eight SF-36 subdomains35, whereas two demonstrated signicantly better scores for the calcium phosphate group; specically, Cassidy et al. found signicantly higher scores (representing better function) in the bodily pain, role physical, role emotional, social functioning, and mental health subdomains21, and Mattsson et al. found higher scores in the physical functioning, vitality, social functioning, mental health, and general health subdomains30. Zimmermann et al. found signicantly better DASH scores for the calcium phosphate group29. Given the few outcome measures for which we were able to pool across studies, we explored the possibility of pooling across other surrogate measures of function (e.g., range of motion and grip strength). These data were reported for distal radial fractures only. The results are summarized in Table III. Fracture-Healing Four studies (n = 216 patients) evaluated fracture-healing at one year22,29,32,33. In all studies, all fractures healed in both the calcium phosphate and control groups. Loss of Fracture Reduction Five studies (n = 599 patients) evaluated outcome with regard to the loss of reduction21,22,28,32,33. Point estimates suggested that the use of calcium phosphate reduced the prevalence of loss of fracture reduction as compared with that in controls; however, this difference was not signicant (n = 599; relative risk, 0.54 [95% condence interval, 0.26 to 1.13], p = 0.10; heterogeneity p = 0.01, I 2 = 69%). We conducted sensitivity analyses to explore causes of heterogeneity. Calcium phosphate reduced the risk of loss of reduction compared with autogenous bone graft by 68% (n = 166, relative risk, 0.32 [95% condence interval, 0.14 to 0.70], p < 0.001; relative risk reduction, 68% [95% condence interval, 30% to 86%]; number needed to treat, 6; heterogeneity, p = 0.87, I 2 = 0%) (see Appendix); in patients with tibial plateau fractures (relative risk, 0.3 [95% condence interval, 0.13 to 0.72], p = 0.007; relative risk reduction, 70% [95% condence interval, 28% to 87%]; number needed to treat, 6; heterogeneity, p = 0.64, I 2 = 0) (see Appendix); and in studies with lower-quality scores (rel-

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ative risk, 0.38 [95% condence interval, 0.23 to 0.63], p = 0.0002; relative risk reduction, 62% [95% condence interval, 37% to 87%]; heterogeneity, p = 0.74, I 2 = 0%). Inverted funnel plots did not suggest publication bias. We attempted to pool secondary radiographic outcomes (radiographic analysis of the distal part of the radius and radiostereometric analysis measurement) across four studies (n = 492 patients) (Table III)21,25,28,29. However, study heterogeneity was high (I 2 = 79% to 100%), and therefore inferences based on this analysis are limited. Infection Seven studies (n = 718 patients) provided details regarding infection following surgery21,22,29,31-33,35. All studied outcomes were dichotomous (the presence or absence of infection). There was no signicant difference in the prevalence of infection between the calcium phosphate bone cement group and the control group (relative risk, 0.74 [95% condence interval, 0.19 to 2.87], p = 0.66; heterogeneity, p = 0.03, I 2 = 59%). We conducted sensitivity analyses to explore the sources of heterogeneity. There was no signicant difference in the prevalence of infection regardless of the type of control group or the quality of the study. However, the use of calcium phosphate signicantly reduced the risk of infection in patients with distal radial fractures (relative risk, 0.15 [95% condence interval, 0.15 to 0.42], p < 0.0001; relative risk reduction, 85% [95% condence interval, 58% to 85%]). Discussion Summary of Findings ur meta-analysis conrmed that the use of calcium phosphate bone cement for the treatment of fractures is associated with the benets of (1) less pain at the fracture site compared with that in controls managed with no bone graft or no bone-graft substitutes, and (2) a reduced risk of losing fracture reduction when compared with autogenous bone graft, especially in patients with tibial plateau fractures. Since the pooling of the loss of reduction outcome across ve studies21,22,28,32,33 revealed no statistical difference between the calcium phosphate bone group cement and the control group with signicant heterogeneity (I 2 = 69%), the sensitivity analysis revealed that the heterogeneity is potentially due to the differences in the control group and the differences in the fracture type. The analysis showed that the risk of loss of reduction was signicantly lower in the calcium phosphate bone cement group than in the autogenous iliac crest bone graft group. Similarly, it showed that the risk of loss of reduction was signicantly lower in patients with tibial plateau fractures as compared with other types of fractures. Although we were not able to pool the functional outcomes across the studies, the results of individual studies suggested improved functional outcomes in association with the use of calcium phosphate cement. This nding could be explained by the fact that patients in the calcium phosphate group had less pain and less risk of loss of reduction. There was no signicant difference in the prevalence of infection between the calcium phosphate bone cement group and

the control group. Sensitivity analysis showed that, among individuals with radial fractures, the rate of infection was signicantly lower among patients who were managed with calcium phosphate bone cement than in controls who were managed with no bone graft substitute. We found no differences in the rates of fracture-healing between the two groups. Strengths and Limitations Our meta-analysis met accepted standards for the conduct of systematic reviews, including literature search, study selection, validity assessment, and data abstraction, in duplicate and independently, to ensure the reproducibility of the search methodology. We improved the generalizability of the systematic reviews by including studies published in any language. We limited the risk of publication bias by using a very comprehensive search strategy involving multiple data sources, including multiple electronic databases, registers of randomized trials, web sites of major national orthopaedic association meetings, corresponding authors, eld experts, manufacturers of calcium phosphate cement, and citation lists. Although the inclusion of unpublished trials in meta-analyses is controversial, we included unpublished studies to avoid the risk of publication bias and subjected them to the same rigorous methodological assessment as was used for the published studies44,45. As a nal safeguard to limit bias, we developed, a priori, hypotheses and their direction to explain potential sources of heterogeneity of pooled outcomes. Despite our efforts, limitations exist. We cannot exclude the presence of additional unpublished trials that showed a negative or an equivocal difference between the intervention and control groups. Because of the small number of studies assessing each outcome, we were not able to construct meaningful funnel plots. Some studies had methodological limitations, including small sample sizes and incomplete reporting of treatment allocation concealment. Differences in the care programs between the intervention and control groups in terms of the duration of immobilization and the types of supplemental xation may limit inferences. Another potential source of bias was the use of different xation devices or techniques in the intervention and control groups. Finally, although we pooled results from studies that involved the use of different types of calcium phosphate cement, the differences in the chemical composition, mechanical properties, and resorptive properties of the types of calcium phosphate cement limit the generalizability of the ndings of this meta-analysis for all products of calcium phosphate cement. Despite differences among the studies, our ndings suggest that, across varying implants, product providers, and perioperative care regimes, calcium phosphates consistently lead to improvements in terms of pain and loss of reduction as compared with alternative approaches. A major difculty that faces authors of meta-analyses is the inadequacy of reporting of the results of randomized controlled trials, which limits their ability to pool results across trials. The Consolidated Standards of Reporting Trials (CONSORT) Statement is a twenty-two-item checklist of the minimum recommendations for reporting randomized controlled trials developed by the CONSORT Group to alleviate such limitations46.

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This statement was adopted by major journals, which will eventually improve the reporting of randomized trials, and hence, the conduct of meta-analyses. Relevant Literature Synthetic bone materials, such as different types of calcium phosphate bone cement, have been used more frequently over the last few years to ll fracture voids. Synthetic materials have the advantages of ready availability and reasonable biological and mechanical characteristics of osseointegration and osteoconduction that make them a promising alternative to autograft. It would appear that, in contained metaphyseal defects, the advantage of osteoinduction provided by autograft is not required to achieve excellent outcomes. More importantly, calcium phosphate bone cement lacks the disadvantage of donor-site morbidity associated with autograft and the disadvantages of potential infection and disease transmission associated with allograft. Although calcium phosphate bone cement lacks the osteoinduction and osteogenesis of autograft and is mechanically weaker than autograft or allograft, promising biomechanical and clinical results have been documented in the literature in multiple studies that have assessed this type of bone cement21-27,29,40,43. The results of this meta-analysis conrm the favorable mechanical properties of calcium phosphate bone cement as used in those studies, which resulted in a lower prevalence of loss of fracture reduction as compared with autograft. Various validated functional outcome measures (SF-36, DASH) have been reported inconsistently; however, the results of three separate studies have suggested improved functional outcome scores in association with the use of calcium phosphate bone cement as compared with no grafting material in the control group21,29,30. Among patients with distal radial fractures, infection rates were signicantly lower when calcium phosphate bone cement was used as opposed to when no graft was used. However, this nding should be interpreted with caution because it was a subgroup analysis and because of the fact that the condence interval is wide. Overview The present meta-analysis of fourteen randomized controlled trials suggested that the use of calcium phosphate bone cement for the treatment of fractures in adult patients is associated with a lower incidence of pain, a decreased risk of losing fracture reduction, lower infection rates in patients with radial fractures, and likely improved functional outcomes. The methodological limitations of the available studies and the lack of patient-relevant outcomes (validated functional outcomes and quality-of-life measures) dictate the planning and performance of a sufciently sized, methodologically sound study with clinically relevant outcome measures. Our meta-analysis provides the best estimate of the effect of calcium phosphate bone

cement use in fracture management; however, these benecial effects of calcium phosphate bone cement should be interpreted with caution until conrmed by large, denitive randomized trials. Appendix Figures showing the search strategy and sensitivity analyses of the outcomes of pain and loss of reduction are available with the electronic versions of this article, on our web site at jbjs.org (go to the article citation and click on Supplementary Material) and on our quarterly CD-ROM (call our subscription department, at 781-449-9780, to order the CD-ROM). n
NOTE: The authors thank Drs. Leighton, Larsson, and Buckley and their coauthors for providing the full unpublished manuscripts of their meeting abstracts and Drs. Kopylov and Mattsson and their coauthors for providing additional information regarding their studies. They also thank Dr. Bashar Alolabi for assistance with reviewing articles.

Sohail S. Bajammal, MBChB, MSc, FRCSC Richard Buckley, MD, FRCSC Division of Orthopaedic Surgery, University of Calgary, 3330 Hospital Drive N.W., Calgary, AB T2N 4N1, Canada Michael Zlowodzki, MD Amy Lelwica, MD 2450 Riverside Avenue South, R200, Minneapolis, MN 55454 Paul Tornetta III, MD Boston University Medical Center, 850 Harrison Avenue, Boston, MA 02118 Thomas A. Einhorn, MD 720 Harrison Avenue, Suite 808, Boston, MA 02118. E-mail address: thomas.einhorn@bmc.org Ross Leighton, MD, FRCSC Suite 4873 HI Site QE II HSC, Halifax, Nova Scotia, B3H 3A7, Canada Thomas Russell, MD 240 LaGrange Creek Drive, Eads, TN 38028 Sune Larsson, MD, PhD Department of Orthopedics, Uppsala University Hospital, S-751 85 Uppsala, Sweden Mohit Bhandari, MD, MSc, FRCSC Division of Orthopaedic Surgery, McMaster University, Hamilton General Hospital, 6 North Trauma, 237 Barton Street East, Hamilton, ON L8L 2X2, Canada. E-mail address: bhandam@mcmaster.ca

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