Original Article Clinics in Orthopedic Surgery 2020;12:151-157 • https://doi.org/10.4055/cios19033 Core Decompression Combined with Implantation of Autologous Bone Marrow Concentrate with Tricalcium Phosphate Does Not Prevent Radiographic Progression in Early Stage Osteonecrosis of the Hip Alejandro Hernandez, PhD, Jorge H. Nuñez, MD, Andrea Sallent, MD, Albert Gargallo-Margarit, MD, Irene Gallardo-Calero, MD, Victor Barro, MD Hip Unit, Department of Orthopedic Surgery, University Hospital of Vall d’Hebron, Universitat Autónoma de Barcelona, Barcelona, Spain Background: Untreated osteonecrosis of the femoral head ultimately leads to secondary coxarthrosis. The aim of this study was to determinate if the core decompression of the femoral head combined with implantation of autologous bone marrow concentrate with tricalcium phosphate could be used to prevent radiographic progression of early stage osteonecrosis of the hip. We also sought to determine whether this treatment improved clinical outcomes and reduced the need for total hip arthroplasty. Methods: Eighteen hips were included in the present study. All of them underwent core decompres­sion of the femoral head combined with implantation of autologous bone marrow concentrate with tricalcium phosphate between 2007 and 2012. The cell concentrate was obtained from the posterior iliac crest and processed and implanted during the same surgical procedure. Patient demographic data, clinical data including modified Harris hip score, and radiological data were collected preoperatively, postop- eratively, and during the follow-up period. Also, survival endpoints were analyzed: time of femoral head collapse and need for total hip arthroplasty. Results: The mean age of patients was 37.8 years (standard deviation [SD], 9.31 years). The mean follow-up was 68.9 months (SD, 15.0 months). In most cases (70.6%), the etiology of the osteonecrosis of the femoral head was corticosteroid use; in the remaining cases, secondary to alcohol use. Core decompression of the femoral head combined with implantation of autologous bone marrow concentrate with tricalcium phosphate did not prevent progression to collapse (< 80% at 5 years) although modified Harris hip scores improved. Overall median survival with the total hip arthroplasty as endpoint was 23 months (95% confidence interval [CI], 14.9 to 31.1 months). Overall median survival time with any degree of collapse as endpoint was 7 months (95% CI, 2.0 to 12.0 months). Conclusions: The results obtained in this study suggest that core decompression combined with implantation of autologous bone marrow concentrate and tricalcium phosphate will not prevent radiographic progression of early stage osteonecrosis of the hip. These finding also suggest that the absence of indications for hip replacement alone is not an indicator of good response to the treatment, and it is important to note the radiological results. Keywords: Hip, Osteonecrosis, Orthopedic procedures, Bone marrow, Bone substitutes Received March 11, 2019; Accepted September 3, 2019 Correspondence to: Jorge H. Nuñez, MD Hip Unit, Department of Orthopedic Surgery, University Hospital of Vall d’Hebron, Universitat Autónoma de Barcelona, Barcelona 08035, Spain Tel: +34-934893000, Fax: +34-934894401, E-mail: j.nunez@vhebron.net Copyright © 2020 by The Korean Orthopaedic Association This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Clinics in Orthopedic Surgery • pISSN 2005-291X eISSN 2005-4408 152 Hernandez et al. Bone Marrow Concentrate with Tricalcium Phosphate in Hip Osteonecrosis Clinics in Orthopedic Surgery • Vol. 12, No. 2, 2020 • www.ecios.org Osteonecrosis of the femoral head (ONFH) commonly af- with ONFH; and (3) patients with Association Research fects patients in the third to fifth decades of life.1) Although Circulation Osseous (ARCO) classification stages I or II the ultimate goal of treatment of ONFH is preservation of confirmed by magnetic resonance imaging (MRI). The the femoral head to avoid a total hip arthroplasty (THA), following exclusion criteria were used: (1) patients with this pathology accounts for up to 46.9% of THAs in these previous surgery in the hip; (2) patients with previous age groups.2,3) Moreover, more than 50% of patients will medical treatments for ONFH; and (3) patients with a develop bilateral ONFH.3) follow-up less than 2 years. Although numerous risk factors for ONFH have been identified (e.g., corticosteroids, alcohol use, sickle- Surgical Technique cell disease, Caisson disease, dyslipidemia, and coagulation The same hip orthopedic surgery specialist (AH) per- disorders), the etiology and pathogenesis of this disease re- formed all operations. One hour before the core decom- main unclear.2,4) ONFH permanently alters the bone mass, pression operation, the patient was turned into a prone producing a weak mineral structure that tends to collapse position and 60 mL of bone marrow was aspirated from the femoral head and destroy the hip joint.5) Although the posterosuperior iliac spine on both sides (Fig. 1). For some nonsurgical treatment modalities have been report- 15 minutes, the bone marrow was centrifuged to collect ed, surgery is the standard treatment approach. However, buffy coat by using a cell separator at Hematology De- the optimal surgical method to preserve the femoral head partment Laboratory. From the 60 mL of bone marrow, remains unclear.1,2) we obtained a concentrate of 10 mL of progenitor stem Various hip preserving procedures have been de- cells. After the concentrated marrow was sent back to the scribed, including the standard core decompression of operating room, CDFH was performed by drilling, under the femoral head (CDFH), osteotomies, and bone graft- fluoroscopic guidance, with a 2-mm threaded needle. The ing (vascularized or nonvascularized). 2,6,7) Emerging needle was placed from the lateral cortex of the femur to techniques include CDFH combined with instillation of the center of the necrotic area. mesenchymal stem cells (MSC) of autologous bone mar- Next, an 8-mm drill bit was used to drill the cortex row and growth factors applied to the necrotic area.8,9) The and medulla and a spoon-shaped curette was used to com- rationale underlying this combined approach is the de- plete the curettage of necrotic bone. Then, through the crease in the number and quality of stem cells in the bone drill hole, the patient was injected with the concentrated marrow of patients with ONFH.10-12) However, to date, bone marrow aspirate and tricalcium phosphate matrix none of these treatments that aim to delay the need for (Cellplex 100–400-µm porosity; Wright Medical Technol- THA has produced significantly superior outcomes com- ogy, Arlington, TN, USA) (Fig. 2). After the injection, pared to core decompression alone.2,8) Moreover, the fact the entrance hole was obliterated by directing the core that CDFH is done with a variety of techniques and with needle tangentially to collapse the core hole by cancellous supplemental bone graft procedures suggests that surgeons bone and prevent leakage of the combined concentrate. have not been completely satisfied with the results.6) Postoperatively, all patients started the same physical re- In this context, the aim of the present study was to habilitation program. Six weeks of non–weight-bearing determine if CDFH and implantation of autologous bone with bilateral crutches was advised to all patients. Patients marrow concentrate with tricalcium phosphate could pre- were allowed to engage in physical activities and sports 6 vent radiographic progression in patients with early stage hip osteonecrosis. Secondarily, we sought to determine if this treatment approach improves clinical outcomes and decreases the need for THA. METHODS A case series study of patients with a diagnosis of ONFH was performed between 2009 and 2014. The study was approved by the hospital ethics commit­tee (IRB No. ID- RTF055), and all patients gave their informed consent prior to inclusion in the study. The inclusion criteria were Fig. 1. The patient was placed in prone position, and 60-mL bone marrow as follows: (1) patients aged >18 and <45 years; (2) patients was aspirated from the posterosuperior iliac spine on both sides. 153 Hernandez et al. Bone Marrow Concentrate with Tricalcium Phosphate in Hip Osteonecrosis Clinics in Orthopedic Surgery • Vol. 12, No. 2, 2020 • www.ecios.org A B Fig. 2. (A) Core decompression of the femoral head was performed by drilling, under fluoroscopic guidance, with a 2-mm threaded needle. Next, an 8-mm drill bit was used to drill the cortex and medulla to complete curettage of the necrotic bone. (B) Through the drill hole, the patient was injected with the concentrated bone marrow aspirate and tricalcium phosphate matrix (Cellplex 100–400-µm porosity; Wright Medical Technology, Arlington, TN, USA) under fluoroscopic guidance. A B C Fig. 3. (A) Preoperative anteroposterior hip radiograph. (B) One-month postoperative anteroposterior hip radiograph. (C) Twelve-month postoperative anteroposterior hip radiograph. months after surgery. (crescent fracture) or loss of femoral head morphology was observed in radiographic or MRI evaluation. Follow-up and Outcome Measures Demographic, clinical, and radiological data were col- Statistical Analysis lected preoperatively, postoperatively, and during the Statistical analysis was conducted using IBM SPSS ver. follow-up period (1, 3, 6, and 12 months postoperatively 20.0 (IBM Corp., Armonk, NY, USA). Descriptive statis- and every 6 months thereafter). The clinical data from 24 tics were used to present the results by mean or median months of follow-up from each patient were used for anal- and range. Pre- and postoperative mHHS was compared ysis. All scores were measured by the same observer (AS). by using paired t-tests. Differences with p-values < 0.05 Demographic and clinical data included the patient's age were considered statistically significant. The Kaplan-Meier at the time of surgery, sex, etiology of the ONFH, ARCO estimator was used to determine survival. The survival classification of the ONFH, and modified Harris hip score analysis was based on two endpoints: time to femoral head (mHHS). Radiological analysis included radiographic collapse and time to THA. (preoperative and every postoperative follow-up) and MRI evaluation (preoperative, 6 months postoperative, and every 12 months thereafter). During follow-up, the radio- RESULTS logic increase of the lesion, measured by the Kerboul an- There were 20 hips in 13 patients who underwent CDFH gle, and the development of a femoral head collapse were combined with implantation of autologous bone marrow evaluated by a single expert radiologist (RD) in musculo- concentrate with tricalcium phosphate. However, two pa- skeletal pathology (Fig. 3). Collapse of the femoral head tients were excluded from the study because they were lost was considered to have occurred if subchondral fracture in the follow-up and one patient was excluded because he 154 Hernandez et al. Bone Marrow Concentrate with Tricalcium Phosphate in Hip Osteonecrosis Clinics in Orthopedic Surgery • Vol. 12, No. 2, 2020 • www.ecios.org developed a subtrochanteric fracture after surgery, requir- ondary to alcohol use. By ARCO stage, 11 hips were clas- ing osteosynthesis with an intramedullary nail. It is worth sified as stage I and six hips, as stage II. The size of femoral noting that these patients did not develop femoral head necrotic lesion was measure by the Kerboul angle (Table collapse while they were followed up. The mean age of the 2). Edema in MRI of the femoral head was a usual sign in final sample (10 patients, 17 hips) was 37.8 years (standard our patients. The mean postoperative mHHS at 24 months deviation [SD], 9.3 years). There were seven men and of follow-up was 85.2 (SD, 11.4). The mHHS at 24 months three women. The mean follow-up was 68.9 months (SD, of follow-up improved statistically significantly (p < 0.05) 15.0 months) (Table 1). (Table 1). In most cases (12 of 17 hips), the etiology of ONFH Nevertheless, 15 of 17 hips progressed to ARCO was corticosteroid use; in the remaining five cases, sec- stage III, and they underwent collapse or subchondral fracture during the follow-up. Nine of 15 hips underwent THA due to severe pain or disability. The probability of not presenting femoral head collapse in the first 15 months Table 1. Patient Demographics and Clinical Data was 33%. The overall median survival time (with THA as Total ARCO stage I ARCO stage II endpoint) was 23 months (95% confidence interval [CI], Variable (N = 10) (n = 6) (n = 4) 14.9 to 31.1 months) (Fig. 4). Overall median survival Sex time for any degree of collapse or progression to stage III Male 7 (70) 4 (66.6) 3 (75) Female 3 (30) 2 (33.4) 1 (25) 1.0 Survival function Age (yr) 37.8 ± 9.3 37.2 ± 9.1 38.1 ± 9.6 Censored 0.8 Etiology Cumulative survival Corticosteroid use 6 (60) 4 (66.6) 2 (50) 0.6 Alcohol use 4 (40) 2 (33.4) 2 (50) 0.4 Modified Harris hip score Preoperative 76.7 ± 9.8 78.2 ± 9.1 74.6 ± 10.1 0.2 Postoperative 85.2 ± 11.4 86.2 ± 12.4 84.3 ± 10.9 Follow-up (mo) 68.9 ± 15.0 68.7 ± 14.2 70.5 ± 13.8 0 20 40 60 80 Values are presented as number (%) or mean ± standard deviation. Survival time (mo) ARCO: Association Research Circulation Osseous. Fig. 4. Median 5-year survival time with total hip arthroplasty as an endpoint. Table 2. Classification According to the Location and Size of the Femoral Necrotic Lesion 1.0 Survival function Censored Subclassification Kerboul angle (°) Number 0.8 Cumulative survival Total Total 17 Central I (<200) 0 0.6 II (200–249) 2 0.4 III (250–299) 3 IV (>300) 0 0.2 Lateral I (<200) 1 II (200–249) 4 0 20 40 60 80 Survival time (mo) III (250–299) 2 Fig. 5. Median 5-year survival time with collapse of the femoral head as IV (>300) 5 an endpoint. 155 Hernandez et al. Bone Marrow Concentrate with Tricalcium Phosphate in Hip Osteonecrosis Clinics in Orthopedic Surgery • Vol. 12, No. 2, 2020 • www.ecios.org disease was 7 months (95% CI, 2.0 to 12.0 months) (Fig. 5). marrow con­centrate embedded in tricalcium phosphate did not prevent femoral head collapse in most cases (> 80%) at 5-year follow-up. The treatment failure rate in the present DISCUSSION study was higher than the rates reported in some studies ONFH is a devastating condition affecting relatively young (6%–25%).16,20,21) However, we are not the first to report patients whereby the femoral head is necrotic, resulting in such high failure rates. For example, Chotivichit et al.22) significant pain, articular surface collapse, and eventual evaluated 13 cases of stage I or II ONFH and found ra- osteoarthritis.1-3) The main aim of the present study was to diological progression indicative of femoral head collapse determine if CDFH with adjuvant implantation of autolo- in 72% of the patients at a mean follow-up of 3.6 years. gous bone marrow concentrate and tricalcium phosphate We believe that the high failure rate in our study can be could prevent radiographic progression of early stage os- explained by the presence of important, ongoing risk fac- teonecrosis of the hip. We also sought to determine wheth- tors such as steroid use and alcohol consumption. In the er this treatment improved clinical outcomes and reduced follow-up, the steroid treatment and alcohol consump- the need for THA. The overall median survival for the two tion were stopped in our patients. Additionally, the use of study endpoints—need for THA and femoral head col- MRI, which is more sensitive and specific than standard lapse—were 23 months and 7 months, respectively. radiography, to assess the increase in the lesion size and We used autologous bone marrow concentrate be- the development of femoral head collapse could have led cause previous studies have suggested that treatment re- to higher failure rates given that several of the aforemen- sults of ONFH are better in patients who receive implanta- tioned studies with better results did not use MRI.3,16,17) tion of bone marrow concentrate than those who do not.13) In those studies, they used X-ray in the follow-up, which In our study, we combined the autologous bone marrow is an important limitation. Indeed, we chose to use MRI concentrate with tricalcium phosphate—a synthetic bio- because of its high sensitivity and specificity, which is why compatible, resorbable, osteoconductive material—to MRI is considered the benchmark for the diagnosis and improve defect filling, cell transportation, and mechanical follow-up of osteonecrosis.2) Another important difference structural support, all of which are considered to play an between our study and other studies that also used autolo- essential role after core decompression and during revas- gous bone marrow concentrate with porous bone filler cularization.14) Most previous studies have evaluated the is that those studies had substantially shorter follow-up outcomes of CDFH with supplementation of stem cells periods (< 3 years).17,18) In our study, we had a minimum and growth factors but without the use of porous bone follow-up of 5 years. filler.2,15,16) The first authors who described this technique The disparity between our findings and other stud- with porous bone filler were Liu et al.,17) who retrospec- ies could also be related to the surgical technique used tively analyzed the effectiveness of core decompression for CDFH. In our case, the diameter of the drill hole was and implantation of porous hydroxyapatite bone filler with 8 mm in all patients. The number and diameter of drill- or without autologous bone marrow concentrate for the ings can vary widely depending on the specific CDFH treatment ONFH. At a mean follow-up of 26 months, they technique.8,23,24) For that reason, the number and diameter found that the collapse rate was lower in the group that of the drillings determine the bone marrow concentrate received autologous bone marrow concentrate than the implantation method in the necrotic area.19,20,25,26) Al- group that did not receive this adjuvant treatment (17.5% though some authors postulate that multiple small-di­ vs. 59.3%).17) Yamasaki et al.18) reported a 10% collapse ameter drillings are superior to the classic 8–10 mm drill- rate after 18 months of follow-up in patients treated with ings, there is no clear evidence regarding the superiority a combination of hydroxyapatite particles and autologous of that approach.8,23,24,27,28) Some studies have suggested bone marrow concentrate versus a 75% collapse rate in that small-diameter multichannel core decompression is patients treated with hydroxyapatite particles alone. In a suitable for pre-collapsed lesions.15) For example, Lim et similar study, Kang et al.19) used an autologous iliac crest al.27) compared a CDFH technique using large-diameter graft associated with MSCs to fill the debrided cavity in 61 drillings, curettage, and bone graft versus multiple 3-mm hips, reporting a 65.7% success rate (clinical and radiologi- perforations and autologous bone marrow concentrate im- cal results) in stage II patients; however, the collapse rate plantation, reporting no statistically significant differences was not specified. between the two techniques at the 5-year follow-up. At In the present study, we found that performing our center, we prefer large-diameter core decompression CDFH, debridement, and implantation of autologous bone because it offers two important advantages: high pressure 156 Hernandez et al. Bone Marrow Concentrate with Tricalcium Phosphate in Hip Osteonecrosis Clinics in Orthopedic Surgery • Vol. 12, No. 2, 2020 • www.ecios.org within the necrotic femoral head could achieve sufficient trate implantation with porous material for the treatment decompression, and progressively expanding reamers can of ONFH. Second, MRI was used in the follow-up. We be used to completely remove the sequestrum and fatty recommend that future studies should be long-term pro- marrow within the necrotic area. spective studies that involve a large sample size. Moreover, It is worth noting that clinical success did not cor- they should compare and evaluate different surgical treat- respond closely with radiographic success in this study. ments including the use of different porous materials (such Even though some of our patients experienced radio- as hydroxyapatite composite bone) used for the treatment graphic progression, their mHHS at 24 months of follow- of this pathology. up significantly improved, as was previously reported by In our study, we found that core decompression Baksi et al.29) and Sallam et al.3) We think that this could be combined with implantation of autologous bone marrow because even in stage I and II, the femoral head remains concentrate and tricalcium phosphate did not prevent without collapse and the pain is related to edema and high radiographic progression of early stage osteonecrosis of bone pressure. Also, the size of the necrotic lesion was the hip. We found that it did not prevent progression of large (200 or more degrees) in 16 of the 17 hips evaluated. disease to collapse (< 80% at 5 years) although Harris hip In our study, the median survival time (defined as time scores improved. These findings suggest that the absence until THA) was 23 months. Nine of the patients eventually of indications for hip replacement alone is not an indicator required a THA during follow-up. Despite the encourag- of good response to the treatment, and it is important to ing clinical results and lower THA conversion rates report- note radiological results. ed in the literature with bone marrow concentration, it is important to note that the studies that had longer follow- up times (including ours) have found a higher rate of CONFLICT OF INTEREST radiological progression of femoral head collapse as time No potential conflict of interest relevant to this article was passes.9,16) This is important because prosthetic surgery reported. in hip joint arthrosis does not rely solely on the degree of radiological involvement. In other words, although hip replacement may not be indicated, this does not imply a ACKNOWLEDGEMENTS good treatment response. We would like to thank the Department of Radiology of This study has several limitations. First, the sample University Hospital of Vall d’ Hebron, Barcelona, Spain. It size was relatively small mainly due to the low incidence provided all hip computer tomographic images of the pa- of detecting ONFH in the ARCO stages I and II, which is tients included in our study. consistent with other published studies (between 0% and We would like to thank Rosa Dominguez-Oronoz 2%). Another potential limitation is that we did not have (Department of Radiology, University Hospital of Vall d’ a control group. Despite these limitations, this study has Hebron, Barcelona, Spain), who was the radiologist who also several unique attributes. First, to our knowledge, our analyzed all hip magnetic resonance images of the patients study presents the longest follow-up (> 68 months) after included in our study. core decompression and autologous bone marrow concen- REFERENCES 1. Rajpura A, Wright AC, Board TN. Medical management of 4. Mont MA, Jones LC, Hungerford DS. Nontraumatic osteo- osteonecrosis of the hip: a review. 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