Abstract
Background:
Ultraporous β-tricalcium phosphate (TCP) synthetic graft material (Vitoss; Orthovita) persists for a year or longer in some cases. In this study, we prospectively examined healing of cavitary defects filled with TCP versus TCP and bone marrow aspirate (TCP/BM) with the hypothesis that bone-marrow aspirate speeds incorporation of bone graft substitute.
Methods:
Fifty-five patients with a benign bone lesion undergoing surgical curettage were randomized to receive TCP (N = 26; mean duration of follow-up [and standard deviation], 20.2 ± 7.2 months) or TCP/BM (N = 29; mean duration of follow-up, 18.0 ± 7.7 months). There were no significant differences between the groups with regard to demographic or defect parameters. Clinical and radiographic evaluations were done at 1.5, three, six, twelve, eighteen, and twenty-four months, and computed tomography [CT] scans were performed at twelve months. An independent radiographic review was done to evaluate six parameters.
Results:
There was a significant (p < 0.001) increase in trabeculation through the defect and graft resorption with decreases in the persistence of the graft in both soft tissue and the defect as well as a decreased radiolucent rim around the graft over time. No significant differences were observed between the TCP and TCP/BM groups in terms of any radiographic parameter. No complications related to the graft material or BM were identified.
Conclusions:
While significant improvements in radiographic parameters were observed in both TCP groups over two years of follow-up, the addition of BM was not found to provide any significant benefit. Results should not be extrapolated to other bone graft substitutes used for this purpose.
Level of Evidence:
Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.
Following curettage of benign bone tumors, defects may be filled with autogenous bone graft, allograft, or synthetic fillers1,2. In our experience with the use of the synthetic bone-graft substitute ultraporous β-tricalcium phosphate (TCP) (Vitoss; Orthovita), the graft material, when combined with local blood alone, has performed well clinically but has sometimes persisted for a year or longer as seen on radiographs3. Prolonged persistence of the graft material may serve as a potential stress riser, although no untoward late effects have been observed to date3. Several authors have found promising results with the use of composite grafts formed from a combination of bone graft substitutes and autologous bone marrow in animal models4-8. Randomized prospective clinical trials regarding the use of bone graft fillers have been isolated to dental procedures, spinal fusions, and open reduction and internal fixation of tibial plateau fractures7,9-15. Very few studies of bone graft materials for any indication have utilized computed tomography (CT) for assessment16,17. To our knowledge, there have been no prior published studies on the effects of composite TCP and bone marrow aspirate (BM) on the healing of defects after curettage of benign bone tumors in humans, no prospective randomized studies evaluating grafting of such defects, and no prospective evaluations in which CT was utilized to assess grafted defects.
The purpose of this study was to utilize clinical, radiographic, and CT analysis to prospectively examine healing of cavitary defects treated with TCP alone compared with those treated with TCP combined with BM (TCP/BM). Our hypothesis was that radiographic measures of incorporation of the synthetic material into the native bone would improve over time and be more advanced at each time point in patients who had received BM/TCP compared with those who had received TCP alone.
The study was approved by the local institutional review board throughout patient accrual and follow-up from 2004 through 2009. It was registered at ClinicalTrials.gov (NCT00147823). Patients with any type of benign bone lesion of the extremity, pelvis, or shoulder girdle for which surgical curettage had been recommended were offered enrollment in the study. No patients with a known posttraumatic defect were included. Patients with active infection, bone marrow disorders, or other contraindications to the use of supplemental bone marrow aspiration as well as those who preferred autologous or allogeneic graft material alone or declined follow-up were excluded as well. Once consent had been obtained, the subjects were randomized according to a blocked randomization schedule (block size of four) that allocated subjects equally into the two groups.
The study was powered on the basis of a previously reported study of patients who had received TCP only for the same indications, in which the radiographic parameters used in the present study were available for a small cohort that was followed for 1.5 years3. With these data, we extrapolated two-year graft resorption and bone trabeculation data using linear regression techniques and then hypothesized linearly increasing differences from 0% to 25% for the TCP/BM group. On the basis of our observed and extrapolated effects on bone trabeculation through the defect, we hypothesized equal baseline means (mean = 1.6%; standard deviation [SD] = 7.8%) and a significantly higher mean at two years (mean, 88% versus 72%; SD = 18%) among patients randomized to receive TCP and BM (the TCP/BM group) as compared with TCP only (the TCP group). Under a 2 × 2 factorial analysis of variance (ANOVA) design, a sample size of forty-six patients (twenty-three per group) supplied at least 80% power to detect a large effect (Cohen’s d of 0.8) on bone trabeculation through the defect between the TCP/BM and TCP groups with use of a two-sided alpha of 5%. Our ANOVA model consisted of a factor for group (TCP/BM versus TCP), a factor for time (baseline versus two years), as well as an interaction effect between the two factors. Similar calculations for graft resorption resulted in a sample size of thirty-two; thus, forty-six patients provided sufficient power for both graft resorption and bone trabeculation through the defect. Predicting up to 20% attrition, we recruited fifty-six subjects to be randomized to achieve the forty-six-patient ultimate sample size. Enrollment ceased after accrual of fifty-six enrolled subjects. One patient with no postoperative data was excluded, leaving fifty-five subjects in the study group.
Those in the TCP group underwent curettage and grafting ultraporous β-tricalcium phosphate (Vitoss, Orthovita) as the filler for the created defect. The curettage procedure routinely involved intramedullary decompression to ensure eradication of the lesion and enhance healing potential. Morsellized granules of TCP were packed into the defect compactly to fill the defect completely. Those randomized to the TCP/BM group underwent, in addition to the standard curettage and grafting with morsellized TCP granules, bone marrow aspiration performed percutaneously from the anterior iliac crest with use of a standard bone marrow aspiration needle. The bone marrow aspirate was obtained in 2 to 3-cm3 aliquots per pass and with repositioning of the needle through a single entry site in the skin. Approximately 10 to 15 cm3 of bone marrow was obtained for each 30 cm3 of TCP. The aspirated marrow was mixed with the granular TCP prior to introducing the composite into the defect for the patients in this study arm. In some cases, prophylactic internal fixation was utilized in addition to the grafting procedure to minimize the risk of fracture.
Both study groups were managed with the same postoperative protocol specific to the anatomic site and the size and character of the lesion as determined by the principal investigator (T.A.D.). Typically, for patients with an upper-extremity lesion, throwing, lifting, and strength-training were restricted for a period of six weeks postoperatively and until the patient lacked pain or substantial tenderness on physical examination and the radiographs showed signs of healing of the defect. For patients with a lower-extremity lesion, the typical postoperative course entailed toe-touch weight-bearing with crutches or a walker for the first six to twelve weeks followed by gradual resumption of full weight-bearing once the patient was pain-free, had no substantial tenderness, and showed radiographic signs of healing of the defect. Patients with a lower-extremity lesion were generally allowed to return to full participation in all activities without restriction by three months postoperatively.
Each patient who completed the study underwent routine radiographic evaluation of the lesion at six weeks, three months, six months, one year, eighteen months, and two years postoperatively. Additional visits were incorporated as needed to address patients’ concerns and for those with more aggressive benign tumors, including aneurysmal bone cysts. At a single consistent time point (one year) postoperatively, each patient underwent CT of the grafted defect.
Two qualified, blinded, independent reviewers (W.S. and H.C.), both practicing radiologists, evaluated the radiographs at each time point for six criteria as previously reported2: (1) the presence of graft within the soft tissue, (2) the presence of a rim of radiolucency surrounding the grafted defect, (3) the size of the defect, (4) resorption of graft material, (5) bone trabeculation through the defect, and (6) persistence of graft material through the lesion. Each of these six parameters was rated as 0%, 25%, 50%, 75%, or 100% at each reading. Previously reported kappa analysis of these parameters has shown a moderate (κ = 0.40 to 0.59) to high (κ = 0.60 to 0.79) degree of agreement between observers for the presence of graft within soft tissue (κ = 0.76), presence (κ = 0.61) and size/circumference (κ = 0.58) of a rim of radiolucency surrounding the grafted defect, resorption of graft material (κ = 0.58), and bone trabeculation through the defect (κ = 0.67)3. In addition to the radiographic analysis, complications, both related and unrelated to the grafting procedure and including local recurrence of the underlying process, were recorded. The size of the defect was determined with radiographic analysis at baseline and during each of the follow-up evaluations.
The patient population consisted of fifty-five subjects with an average age of 23.5 years (range, three to sixty-five years). The right side was involved in thirty-three subjects and the left side, in twenty-three. A lower-extremity lesion was treated in forty-two cases and an upper-extremity lesion, in fourteen (see Appendix). The average size of the defect was 68.2 cm3. The average duration of follow-up was nineteen months, but the CT scan portion of the study was completed for only seventeen patients in each group (thirty-four in total). The two study groups (TCP and TCP/BM) did not differ significantly with respect to age, sex, size of the defect, or duration of follow-up (see Appendix). The underlying diagnoses were comparable between the groups (see Appendix). However, the average age was five years younger and the average follow-up duration was two months shorter in the TCP/BM group.
A comparison of the radiographic and CT ratings at twelve months was done to (1) attempt to assign some meaning to the radiographs on the basis of the more objective evidence provided by the CT scan at time points at which CT was not available and (2) ensure that there were no differences between the study groups (TCP versus TCP/BM) with regard to these relative interpretations (see Appendix). Because only thirty-four patients (seventeen in each group) had CT performed at the prescribed twelve-month time point, and because not all patients had radiographs obtained at the same time point for comparison, a total of twenty-eight patients was available for this analysis.
Statistical Methods
Since outcomes were repeatedly measured within a subject over time, multilevel modeling was used for statistical analysis to account for the dependence of the observations within each subject across time. Numerical and graphical exploratory data analyses were used to assess outcome distributions, the nature of outcome trajectories over time, and residuals. For analysis purposes, time was analyzed on the log scale for bone trabeculation through the defect and graft resorption, whereas persistence of the graft material in the lesion remained on its natural scale. The presence of graft within soft tissue, rim of radiolucency surrounding the grafted defect, and defect size rendered a negative binomial distribution. As displayed in graphs, all outcomes have been transformed back to the original scale.
Multilevel modeling for longitudinal data analysis allowed participants with incomplete data to be included in the analysis by providing unbiased parameter estimates under a missing at random assumption. While our sample was not large enough to conduct a rigorous analysis of the pattern of “missingness,” a sensitivity analysis was performed, verifying that the results based on our entire sample did not differ from the results generated from participants who had a full spectrum of data. Furthermore, the amount of missing data per participant was summarized and compared between the randomized groups (TCP versus TCP/BM) to ensure that the magnitude of missing data did not arise from the manipulation (intervention) of our study.
While our study was powered under a 2 × 2 factorial ANOVA design, a more sophisticated method was used to analyze our data. This more sophisticated random coefficients model includes patients with missed visits, accommodates dependence within a patient across time, and has provided adequate power to detect large effects between TCP alone and TCP/BM18.
Baseline characteristics were compared between the randomized groups with use of t tests and chi-square tests for continuous and categorical variables, respectively. All tests of hypotheses were two-tailed and performed with an alpha equal to 5%.
Source of Funding
This investigator-initiated study was sponsored by Orthovita, Inc.
In both the TCP and the TCP/BM group, there were significant changes in each of the radiographic parameters to suggest incorporation of the graft material over the duration of follow-up (Figs. 1 and 2). The value for the presence of a rim of radiolucency surrounding the grafted defect decreased over the twenty-four-month follow-up period, from an average of approximately 25% at six weeks to nearly zero by the end of the follow-up period (Fig. 3). Resorption of graft material increased most dramatically over the first twelve months, from close to zero at six weeks to slightly below 50% on average. Graft resorption continued to increase at a slower rate, to >50% on average by twenty-four months. Bone trabeculation through the defect increased most rapidly during the first twelve months but continued to increase throughout the follow-up period, to >75% on average by twenty-four months. The presence of graft within the soft tissue decreased dramatically during the first six months and was not seen beyond twelve months postoperatively (Fig. 4). Persistence of graft material through the lesion decreased progressively, from between 75% and 100% at six weeks to between 25% and 50% at the end of the twenty-four-month follow-up period on average. The size of the defect also decreased progressively over time in a similar fashion. Each of these changes over time was significant in both the TCP group and the TCP/BM group (p < 0.05).
On the basis of the twelve-month CT data alone for the thirty-four patients for whom the CT portion of the study had been completed, the TCP/BM group (as compared with TCP group) showed on average more graft within the soft tissue and graft resorption, less of a rim of radiolucency surrounding the grafted defect, less persistence of graft material through the lesion, and nearly identical bone trabeculation through the defect (see Appendix) (Fig. 4). However, the differences between the TCP and TCP/BM groups in the CT analysis at twelve months did not reach significance. Similar findings were seen on the basis of the radiographs over time, with no significant differences between the TCP and TCP/BM groups with respect to the rim of radiolucency surrounding the grafted defect, graft resorption, bone trabeculation through the defect, graft within the soft tissue, persistence of graft material through the lesion, or size of the defect remaining (Fig. 1). There were notable differences between the groups with regard to the rim of radiolucency surrounding the grafted defect, persistence of graft material through the lesion, and size of the defect (each greater on average in the TCP/BM group), but again they all lacked significance.
The comparative analysis of the two radiographic techniques used in this study showed that radiographs (as compared with the CT scans) tended to overestimate trabecular bone formation early and underestimate it when the defects were nearer to complete healing. In contrast, the CT scan did not as clearly show the radiolucencies and tended to show more remaining graft material. Statistically speaking, there was no difference between the twelve-month radiographic and CT findings with respect to graft within the soft tissue. Compared with CTs, the radiographs tended to overestimate several parameters, including (in order of decreasing magnitude of differences) the rim of radiolucency surrounding the grafted defect, graft resorption, and persistence of graft material through the lesion, in both study groups. The results for bone trabeculation through the defect and defect size were mixed between the groups with respect to overestimation/underestimation, but the absolute differences were small. There were no significant differences between the study groups with respect to the radiograph/CT comparison at twelve months for any of the parameters examined. Kappa analysis of the differences between the radiographic and CT findings at twelve months showed perfect agreement for graft within the soft tissue (κ = 1.0); agreement significantly greater than chance for the rim of radiolucency surrounding the grafted defect (κ = 0.179, 95% confidence interval [CI] = 0.026 to 0.331), bone trabeculation through the defect (κ = 0.208, 95% CI = 0.007 to 0.408), and persistence of graft material through the lesion (κ = 0.422, 95% CI = 0.183 to 0.662); and agreement better than chance but not significantly greater than chance for graft resorption (κ = 0.133, 95% CI = −0.152 to 0.418). Furthermore, the Pearson correlation between the twelve-month radiographic and CT findings was 0.747 (p ≤ 0.001); intraclass correlation coefficient [ICC] = 0.725.
No complications that were attributable to the graft material were encountered during the study period. Two patients developed early postoperative pneumonia, which was diagnosed when they were outpatients; one patient was noted to have recurrence of an intraosseous ganglion of the proximal part of the tibia and concomitant worsening arthritis; two patients had recurrence of a unicameral bone cyst; and one patient with a nonossifying fibroma had incomplete filling of a portion of the lesion.
Because of the local complications associated with autogenous bone graft and the risk of disease transmission with allograft, there has been sustained interest in developing alternative materials to fill osseous defects1,2,17,19,20. Such grafts differ in their rates of resorption, porosity, and tensile strength2,20. An ideal biodegradable material would resorb at the same rate as new bone is formed. Physical properties that increase the rate of biodegradation and bioresorption include increased porosity, larger exposed surface area, and crystal imperfections as well as decreased grain size21. Increased porosity also promotes graft resorption and bone formation as the microporosity facilitates flow of fluid containing osteoinductive substances to permeate the graft and the macroporosity supports blood vessel and osseous ingrowth22,23. However, greater porosity likely translates to decreased initial tensile strength21.
Numerous synthetic bone graft materials for use in bone voids, including calcium sulfate, hydroxyapatite, and tricalcium phosphate, are available. Reported problems concerning calcium sulfate involve occurrences of resorption outpacing osseous ingrowth3,20,21. Conversely, hydroxyapatite has been associated with an indefinite persistence of the graft material24,25. In the senior author’s (T.A.D.) experience, such persistence has been associated with late pathologic fracture through the unincorporated hydroxyapatite graft material. On the basis of clinical and animal studies, tricalcium phosphate has been suggested to have an intermediate time course of resorption between that of hydroxyapatite and that of calcium sulfate, but previous clinically available granular forms have persisted in some cases, for longer than four years in larger lesions1. Ultraporous β-tricalcium phosphate (TCP) has been purported—largely on the basis of animal studies—to provide an intermediate rate of resorption and replacement2,3, and clinical usage has been based on this premise. However, to our knowledge, there have been no published prospective studies comparing this filler alone with autologous bone graft. One prospective study of the use of graft extenders in the treatment of adolescent idiopathic scoliosis showed no significant difference between TCP and autogenous iliac crest bone graft, when added to local bone, with regard to clinical or radiographic parameters in forty patients at a mean of four years postoperatively11. Although there are published reports on the use of TCP as an allograft or autograft extender in trauma patients and in spinal fusion4,9-13,15-17,19, we know of only three studies describing its use in cavitary defects3,26,27. The first was based on our early experience, which was analyzed retrospectively and without CT examination3. In the second, an independent retrospective evaluation of sixty patients who had undergone TCP grafting of cavitary defects, the findings were similar to those in the current study, with progressively increasing resorption and trabeculation over time26. In the third, twenty-nine patients followed for a minimum of six months after TCP grafting of similar cavitary defects showed good incorporation on radiographic analysis27. Furthermore, we are not aware of any prospective analyses in which CT was utilized specifically to assess incorporation of any synthetic graft materials in cavitary defects. Only two spine studies utilized CT for assessment of graft healing16,17. Hence, to our knowledge, in addition to being the only published randomized clinical trial involving cavitary defects, this is the first prospective study not only of TCP in cavitary defects but also of CT data for analysis of grafting in cavitary defects.
In our experience with the use of TCP synthetic graft material over a three-year period beginning shortly after its release by the U.S. Food and Drug Adminstration in 2000, the graft material, when combined with local blood alone, sometimes persisted for a year or longer3. Several authors have studied the effects of composite grafts formed from a combination of bone graft substitutes and autologous bone marrow in animal models, with promising results28-30. We are not aware of any prior prospective studies in the current literature evaluating the effects of healing following use of a composite of TCP and bone marrow aspirate in cavitary bone lesions in humans. However, in the aforementioned study by Siegel et al., this combination was demonstrated to be safe and efficacious26.
The primary question posed in the current study was whether osteoinductive and/or osteogenic materials would facilitate healing of cavitary defects when those materials were combined with the synthetic TCP graft material. The study showed that the addition of bone marrow did not result in any meaningful improvement in the radiographic parameters of TCP bone graft incorporation into curetted cavitary bone defects created by removal of benign musculoskeletal tumors predominantly of the extremities. While this prospective study was adequately powered to detect large differences between randomized groups, it was not sufficiently powered to detect smaller effects. Because the study was designed with enough statistical power to detect large differences between the randomized groups, the implication is that large differences between those groups do not exist. One factor that may have influenced the outcome was the routine use of intramedullary decompression to eradicate the lesions and facilitate healing; this infusion of local bone marrow contents may have negated the potentially beneficial effects of the exogenous addition of iliac crest marrow to the graft material. Whether a higher ratio of bone marrow to synthetic graft, platelet-rich plasma, concentrated marrow, or even the addition of specific osteoinductive factors would demonstrate improvement over the use of TCP alone cannot be determined from this study.
The most novel findings described herein are the significant changes over time in the radiographic parameters analyzed. Not only the twelve-month CT analysis but also the radiographic analysis showed that the TCP product continues to be incorporated gradually over time. We did not observe any late fractures in this patient population to suggest that the persistence of the synthetic material serves as a stress riser. There were also no differences in the two treatment groups in terms of complications or clinical care postoperatively.
Limitations of this study include the use of relatively small amounts of bone marrow in the TCP/BM group, the small number of patients, loss of some patients to follow-up, and incomplete radiographic evaluation of some included patients. One notable difference between the groups was that nine of the ten patients with smaller lesions in the small bones of the hands and feet, clavicle, and proximal part of the fibula were randomized to the TCP group. On balance, there was no significant difference in the mean size of the defects between the two groups. In addition, there was a disproportionate distribution between the treatment groups for some sites, including the proximal part of the humerus, that which may have influenced the results. The manufacturer of TCP recommends a 1:1 ratio of TCP to bone marrow, but in the current study, the ratio was between 3:1 and 2:1. Power analysis suggested an 80% power to show a 25% difference. Overall follow-up and compliance was on the order of the predicted 20% attrition rate, although not all patients had the requested twelve-month CT scan (39% attrition rate), and the average duration of follow-up was considerably shorter than the twenty-four-month study design. Despite these weaknesses, this study is the first prospective analysis of benign bone defects with randomization of patients to two treatment groups and analysis of CT data on graft incorporation. Future studies should be designed to evaluate newer technologies of adding osteoinductive agents and either platelet-rich plasma or concentrated bone marrow in order to determine if there are other ways to speed up the incorporation of synthetic graft materials in these defects.
Tables showing the anatomic location of lesions according to study group, amount of BM and TCP used according to anatomic location and study group, comparison of baseline characteristics between study groups, histologic diagnoses according to study group, difference between CT and radiographic measurements at twelve months, and difference between study groups with regard to the twelve-month measurements seen on CT are available with the online version of this article as a data supplement at jbjs.org.
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