1 Introduction
Bone morphogenetic proteins (BMPs), first described by Urist in 1965,[1] [1–3] [4,5] [6] [7] [8] [9] [3,10]
ONFH is an insidious and progressive disease that accompanies the apoptosis of osteocytes, frequently leading to femoral head collapse and subsequent osteoarthritis. The preservation of the femoral head by nonvascularized bone grafting is an attractive alternative treatment in patients without head collapse or with minimal collapse.[11,12] [13,14] [15] [16] [17]
One of our previous studies has described the benefits of rhBMP-2 in the treatment of ONFH. It improves the speed and quality of bone repair inside the necrotic lesions of the femoral head.[18] [19] [20] [21]
Therefore, we investigated the use of rhBMP-2 to determine whether it would increase the risk of HO formation in selected ONFH patients with nonvascularized bone grafting surgery and enhance the surgical results of nonvascularized bone grafting in compared to patients who did not receive the intraoperative rhBMP-2.
2 Patients and methods
A total of 101 patients (150 hips) who underwent debridement and impacted bone grafting (IBG) surgery for nontraumatic ONFH at China-Japan Friendship Hospital from January 2013 to December 2015 were analyzed retrospectively. Seven patients (9 hips) who were lost to follow-up (contact information changed or lost) were excluded; the remaining 94 patients (141 hips) were included in the study. All the operations were performed or supervised by experienced surgeons specializing in osteonecrosis, joint preserving, and reconstruction (Drs Sun and Li). According to the usage of rhBMP-2 in operation, the patients were divided into 2 groups. The 1st group (N = 46, 66 hips) received the standard background surgery (debridement + IBG) in combination with rhBMP-2 application (classified as BMP-positive group), and the 2nd group (N = 48, 75 hips) received the standard background surgery (debridement + IBG) alone (classified as BMP-negative group). The minimum period of follow-up in the BMP-positive and -negative groups was 12 (average, 18; range, 12–25) months and 13 (average, 16; range, 13–25) months, respectively. All the information was obtained from the medical records. The study was approved by our Institutional Review Board.
In this study, the causes of osteonecrosis were steroid intake, alcoholism, and idiopathy, following which, the patients with traumatic ONFH were excluded. All patients included in the analysis were aged 20 to 50 years. The patients with skeletal immaturity (<18-year-old or exhibiting open epiphysis) were also excluded as they were contraindicated to BMPs therapy according to FDA. Indication for this surgery was restricted primarily to Association Research Circulation Osseous (ARCO)[22] Table 1 .
Table 1: Preoperative characteristics of patients included in the study.
Bone-grafting was performed using the “Light Bulb” procedure. The patient was anesthetized and placed in a lateral decubitus position. An incision approximately 5 to 6 cm was extended from the site over greater trochanter to the hip, in order to protect the blood supply to the femoral head. After splitting the fascia lata in the direction of the incision direction, the anterior gluteus medius could be found. A longitudinal incision was made in the capsule along the femoral head through the interval between the tensor fascia and the gluteus medius, and the head-neck junction was exposed. A nearly square bone window (length and width of 1.5 cm each and a depth of 0.5–1.0 cm) was made at the femoral head-neck junction using osteotomes. Subsequently, the necrotized lesion located at the upper and anterolateral side of the head was removed through the window using a curette and a high-speed drill. The procedure was monitored by C-arm fluoroscopy, and a minimum of 5 mm subchondral bone was retained. Multiple drilling was conducted utilizing a 3-mm drill bit in the sclerotic bone until fresh blood could be actively observed from the wound holes. The cavity was filled with an autologous cancellous bone that was harvested from the iliac external circumferential lamella mixed with the artificial bone (Shanghai Bio-lu Biomaterials Co., Ltd., Shanghai, China). These implants were compressed layer-by-layer, providing strong structural support to the head and preserving the natural hip geometry. After surgery, the originally excised bone plate was placed back and fixed to cover the bone window firmly. rhBMP-2 (4 mg, from Hangzhou Jiuyuan, China) was mixed with the implants for the patients in the 1st group. This product consisted of porous hydroxyapatite 1 to 5 mg, lecithin 15 to 30 mg, and medical gelatin 50 to 70 mg and was preserved at 4 °C until implanted. Before the joint capsule was closed, the articular cavity was flushed with copious normal saline. The rhBMP-2 was added to the therapeutic regimen randomly rather than through a double-blind design.
Postoperatively, all patients followed a strict rehabilitation training program. In the initial 12 weeks, the patients were advised to keep the toe-touch weight bearing with 2 crutches. Approximately 50% weight-bearing with a cane or crutch in the opposite hand was allowed in the following 12 weeks. Full weight-bearing was tolerated at the beginning of the 7th month and heavy physical activity (such as running) up to 12 months postoperatively. All patients were followed up at 3 months, 6 months, 9 months, and 1 year and then at every 6 months for the following year by radiographical and clinical examinations.
In the radiological evaluation, 2 authors (LS, WS) independently assessed the radiographs (X-ray, anteroposterior, and frog lateral views) for the presence of HO and evaluated the degree of ectopic bone formation employing the Brooker grading system.[23] [24]
The data were analyzed using SPSS Statistical Software version 19.0. The quantitative variables were represented as the mean ± standard deviation (SD). Continuous correction chi-square test was used to assess the differences in HO formation and Pearson chi-square test for other qualitative variables. The between-group differences in the pre- and postoperative HHS were examined by an independent samples t test; whereas, the within-group changes were evaluated by a paired t test. In order to determine whether the age, gender, BMI, stage of ONFH, and use of rhBMP-2 predicted HO and the rate of survival of the femoral head, we performed binary logistic regression analysis. A multivariate logistic regression assessed the relation between postoperative HHS (excellent, good, and fair) and preoperative demographic characteristics of the patients.
3 Results
3.1 Radiological results
Patients receiving rhBMP-2 faced a higher risk (relative risk [RR], 9.0; 95% confidence interval [CI]: 1.2–70.8; P = .023) of developing HO than those not receiving this product, as assessed by the postoperative X-rays. Patients in the BMP-positive group showed a mean of 12.1% (8/66 hips) HO formation, which was greater than the 1.3% (1/75 hips) in the BMP-negative group (Table 2 ). A total of 7/9 confirmed HO cases occurred on the right hip and 2 on the left hip. In the BMP-positive group, the HO formation as class I was observed in 3 patients, class II in 3 (Fig. 1 ), class III in 1, and class IV in 1 (Fig. 2 ). In the BMP-negative group, the HO formation occurred on the right hip and was classified as class I. We found no association (P = .031) between the variables (age, gender, BMI, and stage of ONFH) other than the use of rhBMP-2 and the development of HO.
Table 2: The specific conditions of the HO cases and clinical results of all patients.
Figure 1: A 36-year-old male patient with ARCO stage IIIa osteonecrosis of the right femoral head. Graph A and B represent the preoperative anteroposterior and frog lateral X-ray images of the right hip, respectively. Graph C and D illustrate the postoperative anteroposterior and frog lateral X-ray images, respectively, at the 4th month after surgery, showing a lamellar fragment of HO (class II) in the anterolateral soft tissues of the hip joint (white arrow). ARCO = Association Research Circulation Osseous, HO = heterotopic ossification.
Figure 2: A 45-year-old female patient with ARCO stage IIIa osteonecrosis of the right femoral head caused by large steroid intake owing to SLE. The figure represents the anteroposterior X-ray image of the right hip treated with impacted bone graft in combination with rhBMP-2 at 6 months after surgery, showing HO formation (white arrow). A bony bridge formed from the greater trochanter to the site above acetabulum (class IV). ARCO = Association Research Circulation Osseous, HO = heterotopic ossification, SLE = systemic lupus erythematosus.
The assessment of bone healing by CT scan revealed 2 hips at ARCO stage IIb and 5 hips at stage IIc both progressed to stage III, with further femoral head collapse accompanied by painful limp. In the BMP-positive group, 4 hips at ARCO stage IIIa progressed to stage IV and were subjected to total hip arthroplasty (THA). In the BMP-negative group, 4 hips at ARCO stage IIb and 5 hips at stage IIc progressed to stage III, and 6 hips at stage IIIa progressed to stage IV at the end of follow-up. Any radiological changes were not observed throughout the follow-up period in the 6 hips; however, the functional score was elevated. All the other hips in both groups of patients showed evident radiological signs of roundness and complete repair.
3.2 Clinical results
The average postoperative HHS of both groups of patients was 82.9 ± 11.2. In the BMP-positive group, clinical success was reported in 44 hips (66.7%): “excellent” and “good” scores in 36 and 8 hips, respectively, with substantial pain relief or functional improvement. Eleven hips had “fair” scores, and the survival rate of the femoral head was 83.3% (55/66 hips). The average postoperative HHS score was 84.6 ± 10.9. In the BMP-negative group, clinical success was reported in 42 hips (56.0%): “excellent” and “good” scores in 32 and 10 hips, respectively. Twelve hips had “fair” scores, and the survival rate of the femoral head was 72.0% (54/75 hips). The average postoperative HHS score was 81.4 ± 11.3.
Binary regression analysis suggested that the age, gender, BMI, and use of rhBMP-2 did not correlate with the survival rate of the femoral head (P > .05). However, it was associated with the stage of ONFH (P < .01). Thus, this surgical procedure could achieve a preferable rate of survival in patients with ARCO IIa and IIb ONFH over those with ARCO IIIa ONFH. The multiple regression analysis displayed similar results, that is, no association was found (P < .01) between the preoperative demographic characteristics (age, gender, BMI, and use of rhBMP-2), other than the stage of ONFH, and the postoperative HHS (excellent, good, and fair).
All the 7 patients in both groups diagnosed with class I and II HO formation showed neither serious pain symptoms nor severe functional impairment, obliterating the need for surgery for the removal of the extra bone. The patient with class III HO formation showed early pain, redness, and erythema around the hip joint at the 4th month after surgery, following which, minor limitations in the range of motion (ROM) of the hip joint were noted. These symptoms were resolved by aspirin administered orally for 3 months, without further deterioration in the ROM. The patient with class IV HO formation was subjected to THA due to further collapse, and the extra bone was removed simultaneously.
Significant complications, such as deep infection and other wound problems, were not observed in any patient who underwent this procedure. Three patients displayed lateral femoral cutaneous nerve lesion at the immediate follow-up (1 and 2 hips in the BMP-positive and negative group, respectively). The frequency of complications did not differ between the 2 groups of patients.
4 Discussion
BMPs are paracrine and autocrine growth factors that are involved in multiple biological processes.[25–27] [1] [28,29] [30] [31] [32] [21]
Nevertheless, our study exhibits some limitations. First, this retrospective study was restricted due to the small number of samples, short-term follow-up, and the limited number of HO cases. Accordingly, random grouping, experimental control, and prospective studies are essential to verify the complication of using rhBMP-2 in ONFH. Second, in this trial, the dose of rhBMP-2 was 4 mg/hip, and we did not investigate the association between different doses of the protein and the risk of HO in the follow-up. For improved better clinical outcomes and reduced complications, the optimal dosage of rhBMP-2 will be the focus of our future research. Third, the surgical procedure utilized the autologous iliac bone and artificial bone as the void filler for enhanced structural integrity postremoval of the necrotized bone. In addition, the composited artificial bone substitute possesses adequate osteoinductivity and osteoconductivity and can also provide an osteoconductive scaffold for supporting the new bone and vascular ingrowth. Therefore, the evaluation of the true isolated effect of rhBMP-2 in inducing the formation of new bone was challenging; however, we reported the clinical efficacy in ONFH. Moreover, a fixed ratio of artificial bone with the autogenous iliac bone was absent, and a number of mixed bone grafts were primarily based on the volume of the bone defect after the removal of the necrotic bone.
As shown in our study, the survival rate was higher in the patients who received rhBMP-2 during head-preserving surgery as compared to those without rhBMP-2 application (83.3% vs 72.0%). Although no statistical difference (P = .38) was observed, the proportion of the patients with successful surgeries was improved. Of the various treatments available for ONFH, local debridement and IBG, introduced by Rosenwasser et al[17] [12] [10,12,33] [34–36] [27] [37,38]
Although the usage of BMPs in spinal fusion, fracture healing, and ONFH has been greatly accepted by surgeons, attention should be shifted to the clinically relevant complications, especially with large doses. Of these complications, HO formation is frequently reported in spinal fusion surgery when the spinal cord is exposed to rhBMP.[39–41] [42] [18]
With respect to the carcinogenic effect of rhBMP-2, any cases of newly diagnosed tumors were not reported. The products with a high dose of BMP (rhBMP-2, 40 mg) have been associated with a high risk of cancer when used in clinical spine studies, despite limited evidence to date, indicating that BMPs are possibly carcinogenic to humans.[20,43] [44–46] [47,48] [49,50]
In conclusion, the present retrospective analysis was conducted on patients who received intraoperative rhBMP-2 and had a high risk of HO formation during the treatment of ONFH. Although the patients in the rhBMP-2 group had a high rate of femoral head preservation and HHS scores, the statistical analysis showed no significant difference. Therefore, surgeons should weigh the risks and benefits of this product before using them in patients with ONFH.
Acknowledgments
The authors thank the staff and fellows at the Centre for Osteonecrosis and Joint Preserving and Reconstruction at China–Japan Friendship Hospital for their assistance in performing the operation, caring for the patients, and participating in collecting and analyzing the experimental data.
References
[1]. Urist MR. Bone: formation by autoinduction. 1965. Clin Orthop Relat Res 2002;4–10.
[2]. Wozney JM, Rosen V, Celeste AJ, et al. Novel regulators of bone formation: molecular clones and activities. Science 1988;242:1528–34.
[3]. Ripamonti U, Petit JC. Bone morphogenetic proteins, cementogenesis, myoblastic stem cells and the induction of periodontal tissue regeneration. Cytokine Growth Factor Rev 2009;20:489–99.
[4]. Boden SD, Kang J, Sandhu H, et al. Use of
recombinant human bone morphogenetic protein-2 to achieve posterolateral lumbar spine fusion in humans: a prospective, randomized clinical pilot trial: 2002 Volvo Award in clinical studies. Spine (Phila Pa 1976) 2002;27:2662–73.
[5]. Burkus JK, Transfeldt EE, Kitchel SH, et al. Clinical and radiographic outcomes of anterior lumbar interbody fusion using
recombinant human bone morphogenetic protein-2 . Spine (Phila Pa 1976) 2002;27:2396–408.
[6]. Govender S, Csimma C, Genant HK, et al.
Recombinant human bone morphogenetic protein-2 for treatment of open tibial fractures: a prospective, controlled, randomized study of four hundred and fifty patients. J Bone Joint Surg Am 2002;84-a:2123–34.
[7]. Gautschi OP, Frey SP, Zellweger R. Bone morphogenetic proteins in clinical applications. ANZ J Surg 2007;77:626–31.
[8]. Spagnoli DB, Marx RE. Dental implants and the use of rhBMP-2. Dent Clin North Am 2011;55:883–907.
[9]. Mont MA, Ragland PS, Biggins B, et al. Use of bone morphogenetic proteins for musculoskeletal applications. An overview. J Bone Joint Surg Am 2004;86-A(Suppl 2):41–55.
[10]. Lieberman JR, Conduah A, Urist MR. Treatment of osteonecrosis of the femoral head with core decompression and human bone morphogenetic protein. Clin Orthop Relat Res 2004;139–45.
[11]. Mont MA, Marulanda GA, Seyler TM, et al. Core decompression and nonvascularized bone grafting for the treatment of early stage osteonecrosis of the femoral head. Instr Course Lect 2007;56:213–20.
[12]. Mont MA, Etienne G, Ragland PS. Outcome of nonvascularized bone grafting for osteonecrosis of the femoral head. Clin Orthop Relat Res 2003;84–92.
[13]. Ganz R, Buchler U. Overview of attempts to revitalize the dead head in aseptic necrosis of the femoral head–osteotomy and revascularization. Hip 1983;296–305.
[14]. Pizette S, Niswander L. BMPs are required at two steps of limb chondrogenesis: formation of prechondrogenic condensations and their differentiation into chondrocytes. Dev Biol 2000;219:237–49.
[15]. Boettcher WG, Bonfiglio M, Smith K. Non-traumatic necrosis of the femoral head. II. Experiences in treatment. J Bone Joint Surg Am 1970;52:322–9.
[16]. Merle D’aubigne R, Postel M, Mazabraud A, et al. Idiopathic necrosis of the femoral head in adults. J Bone Joint Surg Br 1965;47:612–33.
[17]. Rosenwasser MP, Garino JP, Kiernan HA, et al. Long term follow-up of thorough debridement and cancellous bone grafting of the femoral head for avascular necrosis. Clin Orthop Relat Res 1994;17–27.
[18]. Sun W, Li Z, Gao F, et al.
Recombinant human bone morphogenetic protein-2 in debridement and impacted bone graft for the treatment of femoral head osteonecrosis. PLoS One 2014;9:e100424.
[19]. Skillington J, Choy L, Derynck R. Bone morphogenetic protein and retinoic acid signaling cooperate to induce osteoblast differentiation of preadipocytes. J Cell Biol 2002;159:135–46.
[20]. Carragee EJ, Chu G, Rohatgi R, et al. Cancer risk after use of recombinant bone morphogenetic protein-2 for spinal arthrodesis. J Bone Joint Surg Am 2013;95:1537–45.
[21]. Kaewsrichan J, Wongwitwichot P, Chandarajoti K, et al. Sequential induction of marrow stromal cells by FGF2 and BMP2 improves their growth and differentiation potential in vivo. Arch Oral Biol 2011;56:90–101.
[22]. Sugano N, Atsumi T, Ohzono K, et al. The 2001 revised criteria for diagnosis, classification, and staging of idiopathic osteonecrosis of the femoral head. J Orthop Sci 2002;7:601–5.
[23]. Brooker AF, Bowerman JW, Robinson RA, et al. Ectopic ossification following total hip replacement. Incidence and a method of classification. J Bone Joint Surg Am 1973;55:1629–32.
[24]. Harris WH. Traumatic arthritis of the hip after dislocation and acetabular fractures: treatment by mold arthroplasty. An end-result study using a new method of result evaluation. J Bone Joint Surg Am 1969;51:737–55.
[25]. Walsh DW, Godson C, Brazil DP, et al. Extracellular BMP-antagonist regulation in development and disease: tied up in knots. Trends Cell Biol 2010;20:244–56.
[26]. Ducy P, Karsenty G. The family of bone morphogenetic proteins. Kidney Int 2000;57:2207–14.
[27]. Nolan K, Thompson TB. The DAN family: modulators of TGF-beta signaling and beyond. Protein Sci 2014;23:999–1012.
[28]. Sakou T. Bone morphogenetic proteins: from basic studies to clinical approaches. Bone 1998;22:591–603.
[29]. Cho TJ, Gerstenfeld LC, Einhorn TA. Differential temporal expression of members of the transforming growth factor beta superfamily during murine fracture healing. J Bone Miner Res 2002;17:513–20.
[30]. Giannoudis PV, Kanakaris NK, Dimitriou R, et al. The synergistic effect of autograft and BMP-7 in the treatment of atrophic nonunions. Clin Orthop Relat Res 2009;467:3239–48.
[31]. Dawson E, Bae HW, Burkus JK, et al.
Recombinant human bone morphogenetic protein-2 on an absorbable collagen sponge with an osteoconductive bulking agent in posterolateral arthrodesis with instrumentation. A prospective randomized trial. J Bone Joint Surg Am 2009;91:1604–13.
[32]. Carreira AC, Lojudice FH, Halcsik E, et al. Bone morphogenetic proteins: facts, challenges, and future perspectives. J Dent Res 2014;93:335–45.
[33]. Seyler TM, Marker DR, Ulrich SD, et al. Nonvascularized bone grafting defers joint arthroplasty in hip osteonecrosis. Clin Orthop Relat Res 2008;466:1125–32.
[34]. Tang TT, Lu B, Yue B, et al. Treatment of osteonecrosis of the femoral head with hBMP-2-gene-modified tissue-engineered bone in goats. J Bone Joint Surg Br 2007;89:127–9.
[35]. Xiao ZM, Jiang H, Zhan XL, et al. Treatment of osteonecrosis of femoral head with BMSCs-seeded bio-derived bone materials combined with rhBMP-2 in rabbits. Chin J Traumatol 2008;11:165–70.
[36]. Katiella KA, Yanru Z, Hui Z. Magnesium alloy transfected BMSCs-BMP-2 composite in repair of femoral head necrosis with assessment of visceral organs. Springerplus 2016;5:1857.
[37]. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature 2003;425:577–84.
[38]. Zhang X, Guo J, Zhou Y, et al. The roles of bone morphogenetic proteins and their signaling in the osteogenesis of adipose-derived stem cells. Tissue Eng Part B Rev 2014;20:84–92.
[39]. Joseph V, Rampersaud YR. Heterotopic bone formation with the use of rhBMP2 in posterior minimal access interbody fusion: a CT analysis. Spine (Phila Pa 1976) 2007;32:2885–90.
[40]. Wong DA, Kumar A, Jatana S, et al. Neurologic impairment from ectopic bone in the lumbar canal: a potential complication of off-label PLIF/TLIF use of bone morphogenetic protein-2 (BMP-2). Spine J 2008;8:1011–8.
[41]. Brower RS, Vickroy NM. A case of psoas ossification from the use of BMP-2 for posterolateral fusion at L4-L5. Spine (Phila Pa 1976) 2008;33:E653–5.
[42]. Boraiah S, Paul O, Hawkes D, et al. Complications of recombinant human BMP-2 for treating complex tibial plateau fractures: a preliminary report. Clin Orthop Relat Res 2009;467:3257–62.
[43]. Devine JG, Dettori JR, France JC, et al. The use of rhBMP in spine surgery: is there a cancer risk? Evid Based Spine Care J 2012;3:35–41.
[44]. Bleuming SA, He XC, Kodach LL, et al. Bone morphogenetic protein signaling suppresses tumorigenesis at gastric epithelial transition zones in mice. Cancer Res 2007;67:8149–55.
[45]. Ehata S, Yokoyama Y, Takahashi K, et al. Bi-directional roles of bone morphogenetic proteins in cancer: another molecular Jekyll and Hyde? Pathol Int 2013;63:287–96.
[46]. Caja L, Bellomo C, Moustakas A. Transforming growth factor beta and bone morphogenetic protein actions in brain tumors. FEBS Lett 2015;589:1588–97.
[47]. Langenfeld EM, Langenfeld J. Bone morphogenetic protein-2 stimulates angiogenesis in developing tumors. Mol Cancer Res 2004;2:141–9.
[48]. Raida M, Clement JH, Leek RD, et al. Bone morphogenetic protein 2 (BMP-2) and induction of tumor angiogenesis. J Cancer Res Clin Oncol 2005;131:741–50.
[49]. Koketsu K, Yoshida D, Kim K, et al. Gremlin, a bone morphogenetic protein antagonist, is a crucial angiogenic factor in pituitary adenoma. Int J Endocrinol 2015;2015:834137.
[50]. Laulan NB, St-Pierre Y. Bone morphogenetic protein 4 (BMP-4) and epidermal growth factor (EGF) inhibit metalloproteinase-9 (MMP-9) expression in cancer cells. Oncoscience 2015;2:309–16.
