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Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets
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Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets Roberto Caterini, MD, Associate Professor, Vito Potenza, MD, Assistant Professor, Ernesto Ippolito, MD, Professor Emeritus, Pasquale Farsetti, MD, Associate Professor* Department of Orthopaedic Surgery, University of Rome “Tor Vergata”, Viale Oxford 81, Rome, 00133, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Humeral non-union humeral shaft bone morphogenetic protein BMP-7 OP-1
Recalcitrant humeral non-union is a disabling condition that is extremely difficult to treat. The use of BMP-7 has been proposed to improve bone healing. This is a report of the results obtained in 12 patients with recalcitrant humeral non-union treated using stable fixation with a long locking compression plate and BMP-7, autologous bone graft and hydroxyapatite pellets applied at the non-union site. Patients had up to three surgical attempts at non-union healing prior to our treatment. The average time from the initial fracture to our surgery was 5.2 years. Average follow-up was 5.3 years. At follow-up, non-union had healed in all patients by an average of 7.3 months. All the patients were very satisfied with their final results, despite a restricted range of motion of the elbow and a moderate muscular atrophy, which was frequently observed. Our study shows that BMP-7 associated with autologous bone grafting and hydroxyapatite pellets after stable fixation is an effective adjuvant to stimulate bone healing in the treatment of recalcitrant humeral non-union. ã 2016 Elsevier Ltd. All rights reserved.
Introduction Non-union is a late complication of humeral shaft fractures that may occur after both conservative and surgical treatment. The incidence of non-union varies from 2% to 15%; however, it seems to be more common after surgical treatment of humeral fractures [1– 4]. The general risk factors that may predispose to non-union are obesity, alcohol abuse, use of steroids, anticoagulants and antiinflammatory drugs, poor bone quality and smoking [5,6]. Local risk factors include transverse fracture pattern, soft tissue interposition, infection and inadequate treatment [7]. Treatment of humeral shaft non-union may be difficult, and many surgical options have been reported with varying success rates. Surgical debridement of the non-union site and internal fixation with a locking compression plate combined with autologous bone grafting has been proposed as the first choice treatment for humeral shaft non-union [8–15]. However, good results have also been reported with intramedullary nailing and external fixators [11,16–23]. When traditional treatment options fail, non-union is considered resistant or recalcitrant to healing, and treatment becomes a challenge for the orthopaedic surgeon. In these cases,
* Corresponding author. E-mail address: [email protected] (P. Farsetti).
some authors have suggested the use of bone morphogenetic proteins (BMPs), which are biological osteoinductive agents that stimulate bone healing [24–26]. Recombinant BMP-7 (osteogenic protein-1 [OP-1]) represents the most common BMP utilised for treatment of non-union [27–40]. The aim of this study was to report a series of 12 recalcitrant atrophic humeral non-unions that were surgically stabilised by a locking compression plate, with the addition of BMP-7 (OP-1), autologous bone grafting and hydroxyapatite pellets, and followed-up for at least two years after treatment. Materials and Methods A total of 12 patients underwent surgery for atrophic recalcitrant non-union of the humeral shaft from 2003 to 2011. Surgery consisted of debridement of the non-union site, stabilisation with a compression plate and application of OP-1 plus autologous bone graft and hydroxyapatite pellets. There were no clinical or radiographic signs of infection in any patient. Recalcitrant was defined as a humeral shaft non-union in which at least one previous surgical treatment performed for the non-union had failed. All the patients agreed to come to our hospital for a followup evaluation. Eight patients were female and four were male; the right side was involved in five patients and the left side in seven. The initial treatment of the humeral fracture was performed in
http://dx.doi.org/10.1016/j.injury.2016.07.044 0020-1383/ã 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
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Fig. 1. A,B) Fracture of the humeral diaphysis in a 39-year-old patient surgically reduced and stabilised with a short peripheral plate. C) One year later, non-union developed and it was fixed by three retrograde anchor nails. D) Another year later, non-union was still present, and a new closed reduction and internal fixation with a single retrograde nail was performed. E) Two years later, a third surgical procedure was performed: the non-union was fixed with a short plate and cerclage wiring and cortico-cancellous bone grafts were applied, but this procedure also failed. F) Eight months later, the non-union was fixed by a long locking compression plate with an autologous bone graft, but three months later, the patient had a car accident and the plate broke (G). H,I) The patient came to our hospital, where a fourth operation was performed: the non-union was reduced again and stabilised using a new long locking compression plate, but autologous bone graft plus OP-1 and hydroxyapatite pellets were also applied. J,K) At follow-up, four years after the last operation, the non-union was healed; the patient’s elbow joint was painful after strenuous activities and a mild restriction of the elbow ROM was present, but he was very satisfied with the final result (Case 6—Table 1).
Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
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Fig. 1. (Continued)
another hospital for all patients. Initial treatment was conservative in two patients and surgical in 10: after reduction, fracture was stabilised with a peripheral plate in four patients and with an intramedullary nail in the remaining six patients. All the fractures were closed. None of the fractures had healed by nine months after the initial treatment. All 12 humeral non-unions had been treated up to three times without success using various surgical techniques either in our University hospital or in other hospitals. In many cases an autologous bone graft had been applied at the
non-union site, but BMP-7 was not used. All the patients had a final diagnosis of recalcitrant humeral non-union and underwent revision of the non-union site at our hospital using the following steps: a) removal of any remaining surgical devices that had been previously applied; b) debridement of the non-union site with proximal and distal opening of the medullary canal; c) reduction and stabilisation of the non-union with a locking compression plate; d) application to the non-union site of one unit of BMP-7 (3.5 mg of rh OP-1 + 1 g of highly purified bovine bone-derived type
Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
Type of surgery for recalcitrant non-union
Complications
Pain at follow-up (at Length of Time to the elbow joint after union follow(months) strenuous activity) up (years)
ROM of the elbow at follow-up
ATROPHIC DIAPHYSIS 2
72
NO
4
4.5
NO
NORMAL
ATROPHIC DIAPHYSIS 27
58
Revision ORIF: plate + OP1 + ABG + HP Revision ORIF: plate + OP1 + ABG + HP
POST-OP HAEMATOMA
10
9
YES
ATROPHIC DIAPHYSIS 7
7
7
9
YES
ATROPHIC DIAPHYSIS 2
69
6
6
NO
1
ATROPHIC DIAPHYSIS 2
64
Revision ORIF: plate + OP1 + ABG + HP
NO
9
9
NO
LIMITED: EXT: 25 FL: 15 LIMITED: EXT: 35 FL: 20 LIMITED: EXT: 15 FL: 5 LIMITED: EXT: 15 FL: 10
3
ATROPHIC DIAPHYSIS 5
45
Revision ORIF: plate + OP1 + ABG + HP
POST-OP HAEMATOMA
4
12
YES
1
ATROPHIC DIAPHYSIS 2
56
Revision ORIF: plate + OP1 + ABG + HP
PAIN AT THE DONOR SITE
7
6
NO
1
ATROPHIC DIAPHYSIS 2
55
Revision ORIF: plate + OP1 + ABG + HP
NO
4
9
NO
1
ATROPHIC DIAPHYSIS 3
65
Revision ORIF: plate + OP1 + ABG + HP
NO
5
4.5
NO
1
ATROPHIC DIAPHYSIS 2
35
Revision ORIF: plate + OP1 + ABG + HP
NO
2
6
YES
2 SURGICAL (ORIF: INTRAM. NAIL) SURGICAL 1 (ORIF: PLATE)
ATROPHIC DIAPHYSIS 3
44
Revision ORIF: plate + OP1 + ABG + HP
RADIAL NERVE PALSY 3
6
NO
ATROPHIC DIAPHYSIS 3
56
Revision ORIF: plate + OP1 + ABG + HP
POST-OP HAEMATOMA + PAIN AT THE DONOR SITE
2
6.
YES
Sex Side Initial treatment of the fracture
1
F
L
CONSERVATIVE 1
2
F
L
SURGICAL (ORIF: PLATE)
3
F
R
4
F
L
3 SURGICAL (ORIF: INTRAM. NAIL) CONSERVATIVE 1
5
F
R
6
M
R
SURGICAL (ORIF: 2 INTRAM. ELASTIC NAIL) SURGICAL (ORIF: PLATE)
7
F
L
8
M
L
9
M
R
10
F
R
SURGICAL (ORIF: INTRAM. NAIL) SURGICAL (ORIF: 2 INTRAM. ELASTIC NAIL) SURGICAL (ORIF: INTRAM. NAIL) SURGICAL (ORIF: PLATE)
11
F
L
12
M
L
2
ABG: autologous bone graft; HP: hydroxyapatite pellets.
Type of nonunion
Site of the non-union
Duration of the nonunion (years)
Revision ORIF: RADIAL NERVE 2 plates + OP1 + ABG + HP PALSY + PAIN AT THE DONOR SITE Revision ORIF: NO plate + OP1 + ABG + HP
LIMITED: EXT: 20 FL: 15 LIMITED: EXT: 10 FL: 10 NORMAL
LIMITED: EXT: 15 FL: 15 LIMITED: EXT: 10 FL: 10 NORMAL
LIMITED: EXT: 20 FL: 20
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Age at final surgery (years)
Number of previous surgical operations performed for the nonunion
Patient
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Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
Table 1 Patient demographics, surgical treatment and final results.
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1 collagen), plus autologous bone graft taken from the iliac crest; e) addition of hydroxyapatite pellets. Careful haemostasis was performed during the operation. Wound drainage was not implemented to avoid loss through the drainage of the BMP-7 that had been applied to the non-union site. The mean age at final surgery was 55.8 years (range: 35-72 years). Eight patients were smokers and one patient had diabetes mellitus. A functional brace was applied to all patients after surgery and was worn for six to 12 weeks. After bracing, movement of the elbow and shoulder was encouraged. Clinical and radiographic evaluations were performed routinely at 1, 3, 4.5, 6, 9 and 12 months after surgery. The average time from initial fracture to our surgical treatment was 5.2 years (range: 2–27 years). The length of follow-up ranged from two to 10 years, with an average of 5.3 years. All the patients were examined both clinically and radiographically at follow-up. Clinical examination included evaluation of pain, range of motion (ROM) of the elbow and shoulder, stability at the non-union site on manual stress, and possible deficit of the radial nerve. Radiographic examination included standard X-rays of the humerus in anteroposterior (AP) and lateral views. The non-union was considered healed when a bridging of the four cortices was present in AP and lateral views at radiographic examination. Results There were no superficial or deep post-surgical wound infections reported in any patients, although three patients developed a post-operative haematoma, which resolved spontaneously in two weeks. Radial nerve palsy was observed after surgery in two patients and was completely resolved in six to seven months. Three patients reported pain at the donor site (iliac crest) that resolved spontaneously in one to three months after surgery. There were no complications or adverse events associated with BMP-7/OP-1 application. Non-union had healed in all patients at follow-up, in an average of 7.3 months (range: 4.5–12 months) after surgery. Only two patients had undergone subsequent surgery for plate removal and this was at least one year after non-union healing. All the patients were asymptomatic at the non-union site, but five patients reported moderate pain at the elbow joint after strenuous activity. All the patients had resumed their previous daily activities after non-union healing. At follow-up, three patients were manual workers, three were white- or blue-collar employees and six were retired. The ROM of the ipsilateral elbow was restricted in all but three patients. The extension restriction ranged from 10 to 35 with an average of 16.5 , and the flexion restriction ranged from 5 to -20 , with an average of 12 . There was no significant limitation of pronation or supination of the forearm or of the ROM of the ipsilateral shoulder. There was no impairment of the peripheral nerves at follow-up. A moderate atrophy of 5–20 mm of both the arm and forearm musculature was observed in all patients and was associated with a mild-to-moderate decrease in muscular strength of the upper arm. There was no clinical instability of the humerus, as tested with manual stress at the non-union site. All the patients were very satisfied with their final result, despite the restricted ROM of the elbow and the moderate muscular atrophy observed.
Discussion The aetiology, surgical management and outcomes of long bone non-unions continue to be a subject of great interest to clinicians [41–49].
5
Open reduction and internal fixation with a locking compression plate and autologous bone grafting is considered by many authors to be the gold standard for treatment of atrophic nonunion of the humerus [8–15]. However, in some cases, despite this treatment, non-union persists (recalcitrant non-union), and its management becomes more difficult. Recalcitrant atrophic humeral non-union is a pathological condition that is difficult to treat and is usually associated with marked morbidity and functional impairment of the upper arm [30,32]. In 2001, Friedlaender et al. demonstrated the efficacy of recombinant BMP-7 (OP-1) as an osteoinductive agent and advocated its use for specific indications [24]. BMP-7 induces endochondral bone formation by stimulating local mesenchymal cells and enhancing bone collagen synthesis [50]. The results of a series of clinical studies conducted since 2001 indicate that BMP7 induces bone formation and healing of bone defects, although in many cases it was used in conjunction with autologous bone grafting or other graft types [29–39,51–53]. Only a few studies have reported specifically on the treatment of recalcitrant non-union of the humerus [30,32,38,52–53]. Bong et al. reported a seven-centre prospective study on 23 patients with atrophic diaphyseal non-union of the humerus treated using compression plate or intramedullary nail in conjunction with BMP-7 and various bone grafting techniques [32]. The authors did not specify how many of these non-unions were recalcitrant. All patients achieved union at an average time of 4.8 months (range: 2–12 months). The authors concluded that BMP-7 should be considered in conjunction with bone grafting for the treatment of atrophic and recalcitrant non-union of the humeral diaphysis. Van Houwelingen and McKee successfully treated six patients with osteopenic humeral shaft non-union stabilised by a compression plate in conjunction with humeral cortical allograft struts30. In four non-unions (two recalcitrant) a local implantation of BMP-7 was performed. Union was achieved at an average time of 3.4 months (range: 2-6 months). The authors stressed in their conclusions the importance of BMP-7 as an osteoinductive bone substitute in the treatment of persistent atrophic humeral shaft non-union. In a prospective, randomised clinical study, Calori et al. compared the bone-stimulating efficacy of BMP-7 and platelet-rich plasma (PRP) in the treatment of 120 patients with persistent fracture non-union [52]. The patients were divided into two groups of 60 patients each, according to the bone stimulating agent used. In both groups, autologous bone graft was used in approximately one-third of patients. There were 15 recalcitrant humeral non-unions in the first group and 16 in the second group. The authors concluded from their results that the effectiveness of BMP-7 is superior to that of PRP as an osteoinductive agent. Giannoudis et al. reported a study of 45 patients with atrophic aseptic non-union of long bones who were successfully treated in two separate trauma centres with a combination of BMP-7 and autologous bone graft [53]. There were seven recalcitrant humeral non-unions (15.6%) that healed by an average of 6 months (range: 3–12 months). The authors postulated a potential synergism between BMP-7 and autologous bone graft that may bring about union even in resistant atrophic non-unions. Papanna et al. reported a study of 52 patients with resistant nonunion of the upper or lower limb who were treated using BMP7 with or without revision of the fixation [38]. Ten of the patients had recalcitrant non-union of the humerus and healed by an average of 7.6 months (range: 4–19 months). The authors recommend the use of BMP-7 particularly in resistant non-unions that did not respond to previous revision surgery. The rationale for the combination of BMP-7 with autologous bone grafting and hydroxyapatite pellets is to ensure an osteoinductive action specific to BMP-7 on the mesenchymal cells present in the autologous bone graft, associated with an
Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
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osteoconductive effect exerted on the non-union site by hydroxyapatite. Our results, in accordance with the above-mentioned studies, indicate that the treatment of choice for recalcitrant nonunion of the humerus is stable fixation of the non-union site, and local application of autologous bone graft combined with BMP7 and hydroxyapatite pellets. In fact, in our study, healing of humeral non-union was achieved in all patients, in an average of 7.4 months. In several patients there was limited ROM of the elbow, particularly when the non-union had been present for many years or was located at the distal part of the humeral diaphysis. However, all the patients were very satisfied with the final results despite the restricted ROM. In fact, after the non-union had healed, all patients returned to a satisfactory lifestyle, with a marked functional improvement compared to their previous clinical condition. The best mechanical stabilisation of a non-union is obtained with a long locking compression plate, although when non-union persists, even this type of stabilisation may fail (see Fig. 1). The weakness of our study is that it is retrospective without any control group; however, our data add 12 cases to a limited number (less than 40) of reported cases of recalcitrant non-union treated using BMP-7. To the best of our knowledge, this is the first study conducted on recalcitrant non-union of the humerus treated with a homogeneous method (stabilisation of the non-union site with a long locking compression plate and apposition of autologous bone graft combined with BMP-7 and hydroxyapatite pellets) in a single institution, and followed-up for at least two years after treatment. Conclusions The application of BMP-7 seems to improve the healing rate of recalcitrant non-union of the humerus. However, in these cases, BMP-7 must be combined with autologous bone graft because the osteogenic protein enhances the intrinsic properties of the autologous bone graft and represents the best biological stimulus for bone healing (osteogenic, osteoinductive and osteoconductive). Some authors have reported a high morbidity associated with the harvest procedure, including persistent pain at the donor site, haematomas, infections and paresthesia [40,54,55]. There were no major complications in our series, except for three cases in which a transient pain was felt at the donor site and that resolved spontaneously one to three months after surgery. Considering the costs involved, however, BMP-7 should be used only in selected cases in which traditional surgical methods have failed, and the non-union has become recalcitrant. Conflict of interest The authors have no conflicts of interest for this manuscript. References [1] Rosen H. The treatment of nonunions and pseudoarthroses of the humeral shaft. Orthop Clin North Am 1990;21:725–42. [2] Sarmiento A, Zagorski JB, Zych GA, Latta LL, Capps CA. Functional bracing for the treatment of fracture of the humeral diaphysis. J Bone Joint Surg Am 2000;82A:478–86. [3] Cadet ER, Yin B, Schulz B, Ahmad CS, Rosenwasser MP. Proximal humerus and humeral shaft nonunions. J Am Acad Orthop Surg 2013;21:538–47. [4] Healy WL, White GM, Mick CA, Brooker Jr. AF, Weiland AJ. Nonunion of the humeral shaft. Clin Orthop Relat Res 1987;219:206–13. [5] Foulk DA, Szabo RM. Diaphyseal humerus fractures: natural history and occurrence of nonunion. Orthopedics 1995;18:333–5. [6] King AR, Moran SL, Steinmann SP. Humeral nonunion. Hand Clin 2007;23:449– 56. [7] Rockwood and Green’s Fractures in Adults. 6th Edition. Lippincott Williams and Wilkins, 2006. [8] Segonds JM, Alnot JY, Masmejean E. Aseptic non-union of humeral shaft fractures treated by plating and bone grafting. Rev Chir Orthop Reparatrice Appar Mot 2003;89:107–14.
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Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
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Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets Roberto Caterini, MD, Associate Professor, Vito Potenza, MD, Assistant Professor, Ernesto Ippolito, MD, Professor Emeritus, Pasquale Farsetti, MD, Associate Professor* Department of Orthopaedic Surgery, University of Rome “Tor Vergata”, Viale Oxford 81, Rome, 00133, Italy
A R T I C L E I N F O
A B S T R A C T
Keywords: Humeral non-union humeral shaft bone morphogenetic protein BMP-7 OP-1
Recalcitrant humeral non-union is a disabling condition that is extremely difficult to treat. The use of BMP-7 has been proposed to improve bone healing. This is a report of the results obtained in 12 patients with recalcitrant humeral non-union treated using stable fixation with a long locking compression plate and BMP-7, autologous bone graft and hydroxyapatite pellets applied at the non-union site. Patients had up to three surgical attempts at non-union healing prior to our treatment. The average time from the initial fracture to our surgery was 5.2 years. Average follow-up was 5.3 years. At follow-up, non-union had healed in all patients by an average of 7.3 months. All the patients were very satisfied with their final results, despite a restricted range of motion of the elbow and a moderate muscular atrophy, which was frequently observed. Our study shows that BMP-7 associated with autologous bone grafting and hydroxyapatite pellets after stable fixation is an effective adjuvant to stimulate bone healing in the treatment of recalcitrant humeral non-union. ã 2016 Elsevier Ltd. All rights reserved.
Introduction Non-union is a late complication of humeral shaft fractures that may occur after both conservative and surgical treatment. The incidence of non-union varies from 2% to 15%; however, it seems to be more common after surgical treatment of humeral fractures [1– 4]. The general risk factors that may predispose to non-union are obesity, alcohol abuse, use of steroids, anticoagulants and antiinflammatory drugs, poor bone quality and smoking [5,6]. Local risk factors include transverse fracture pattern, soft tissue interposition, infection and inadequate treatment [7]. Treatment of humeral shaft non-union may be difficult, and many surgical options have been reported with varying success rates. Surgical debridement of the non-union site and internal fixation with a locking compression plate combined with autologous bone grafting has been proposed as the first choice treatment for humeral shaft non-union [8–15]. However, good results have also been reported with intramedullary nailing and external fixators [11,16–23]. When traditional treatment options fail, non-union is considered resistant or recalcitrant to healing, and treatment becomes a challenge for the orthopaedic surgeon. In these cases,
* Corresponding author. E-mail address: [email protected] (P. Farsetti).
some authors have suggested the use of bone morphogenetic proteins (BMPs), which are biological osteoinductive agents that stimulate bone healing [24–26]. Recombinant BMP-7 (osteogenic protein-1 [OP-1]) represents the most common BMP utilised for treatment of non-union [27–40]. The aim of this study was to report a series of 12 recalcitrant atrophic humeral non-unions that were surgically stabilised by a locking compression plate, with the addition of BMP-7 (OP-1), autologous bone grafting and hydroxyapatite pellets, and followed-up for at least two years after treatment. Materials and Methods A total of 12 patients underwent surgery for atrophic recalcitrant non-union of the humeral shaft from 2003 to 2011. Surgery consisted of debridement of the non-union site, stabilisation with a compression plate and application of OP-1 plus autologous bone graft and hydroxyapatite pellets. There were no clinical or radiographic signs of infection in any patient. Recalcitrant was defined as a humeral shaft non-union in which at least one previous surgical treatment performed for the non-union had failed. All the patients agreed to come to our hospital for a followup evaluation. Eight patients were female and four were male; the right side was involved in five patients and the left side in seven. The initial treatment of the humeral fracture was performed in
http://dx.doi.org/10.1016/j.injury.2016.07.044 0020-1383/ã 2016 Elsevier Ltd. All rights reserved.
Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
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Fig. 1. A,B) Fracture of the humeral diaphysis in a 39-year-old patient surgically reduced and stabilised with a short peripheral plate. C) One year later, non-union developed and it was fixed by three retrograde anchor nails. D) Another year later, non-union was still present, and a new closed reduction and internal fixation with a single retrograde nail was performed. E) Two years later, a third surgical procedure was performed: the non-union was fixed with a short plate and cerclage wiring and cortico-cancellous bone grafts were applied, but this procedure also failed. F) Eight months later, the non-union was fixed by a long locking compression plate with an autologous bone graft, but three months later, the patient had a car accident and the plate broke (G). H,I) The patient came to our hospital, where a fourth operation was performed: the non-union was reduced again and stabilised using a new long locking compression plate, but autologous bone graft plus OP-1 and hydroxyapatite pellets were also applied. J,K) At follow-up, four years after the last operation, the non-union was healed; the patient’s elbow joint was painful after strenuous activities and a mild restriction of the elbow ROM was present, but he was very satisfied with the final result (Case 6—Table 1).
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Fig. 1. (Continued)
another hospital for all patients. Initial treatment was conservative in two patients and surgical in 10: after reduction, fracture was stabilised with a peripheral plate in four patients and with an intramedullary nail in the remaining six patients. All the fractures were closed. None of the fractures had healed by nine months after the initial treatment. All 12 humeral non-unions had been treated up to three times without success using various surgical techniques either in our University hospital or in other hospitals. In many cases an autologous bone graft had been applied at the
non-union site, but BMP-7 was not used. All the patients had a final diagnosis of recalcitrant humeral non-union and underwent revision of the non-union site at our hospital using the following steps: a) removal of any remaining surgical devices that had been previously applied; b) debridement of the non-union site with proximal and distal opening of the medullary canal; c) reduction and stabilisation of the non-union with a locking compression plate; d) application to the non-union site of one unit of BMP-7 (3.5 mg of rh OP-1 + 1 g of highly purified bovine bone-derived type
Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044
Type of surgery for recalcitrant non-union
Complications
Pain at follow-up (at Length of Time to the elbow joint after union follow(months) strenuous activity) up (years)
ROM of the elbow at follow-up
ATROPHIC DIAPHYSIS 2
72
NO
4
4.5
NO
NORMAL
ATROPHIC DIAPHYSIS 27
58
Revision ORIF: plate + OP1 + ABG + HP Revision ORIF: plate + OP1 + ABG + HP
POST-OP HAEMATOMA
10
9
YES
ATROPHIC DIAPHYSIS 7
7
7
9
YES
ATROPHIC DIAPHYSIS 2
69
6
6
NO
1
ATROPHIC DIAPHYSIS 2
64
Revision ORIF: plate + OP1 + ABG + HP
NO
9
9
NO
LIMITED: EXT: 25 FL: 15 LIMITED: EXT: 35 FL: 20 LIMITED: EXT: 15 FL: 5 LIMITED: EXT: 15 FL: 10
3
ATROPHIC DIAPHYSIS 5
45
Revision ORIF: plate + OP1 + ABG + HP
POST-OP HAEMATOMA
4
12
YES
1
ATROPHIC DIAPHYSIS 2
56
Revision ORIF: plate + OP1 + ABG + HP
PAIN AT THE DONOR SITE
7
6
NO
1
ATROPHIC DIAPHYSIS 2
55
Revision ORIF: plate + OP1 + ABG + HP
NO
4
9
NO
1
ATROPHIC DIAPHYSIS 3
65
Revision ORIF: plate + OP1 + ABG + HP
NO
5
4.5
NO
1
ATROPHIC DIAPHYSIS 2
35
Revision ORIF: plate + OP1 + ABG + HP
NO
2
6
YES
2 SURGICAL (ORIF: INTRAM. NAIL) SURGICAL 1 (ORIF: PLATE)
ATROPHIC DIAPHYSIS 3
44
Revision ORIF: plate + OP1 + ABG + HP
RADIAL NERVE PALSY 3
6
NO
ATROPHIC DIAPHYSIS 3
56
Revision ORIF: plate + OP1 + ABG + HP
POST-OP HAEMATOMA + PAIN AT THE DONOR SITE
2
6.
YES
Sex Side Initial treatment of the fracture
1
F
L
CONSERVATIVE 1
2
F
L
SURGICAL (ORIF: PLATE)
3
F
R
4
F
L
3 SURGICAL (ORIF: INTRAM. NAIL) CONSERVATIVE 1
5
F
R
6
M
R
SURGICAL (ORIF: 2 INTRAM. ELASTIC NAIL) SURGICAL (ORIF: PLATE)
7
F
L
8
M
L
9
M
R
10
F
R
SURGICAL (ORIF: INTRAM. NAIL) SURGICAL (ORIF: 2 INTRAM. ELASTIC NAIL) SURGICAL (ORIF: INTRAM. NAIL) SURGICAL (ORIF: PLATE)
11
F
L
12
M
L
2
ABG: autologous bone graft; HP: hydroxyapatite pellets.
Type of nonunion
Site of the non-union
Duration of the nonunion (years)
Revision ORIF: RADIAL NERVE 2 plates + OP1 + ABG + HP PALSY + PAIN AT THE DONOR SITE Revision ORIF: NO plate + OP1 + ABG + HP
LIMITED: EXT: 20 FL: 15 LIMITED: EXT: 10 FL: 10 NORMAL
LIMITED: EXT: 15 FL: 15 LIMITED: EXT: 10 FL: 10 NORMAL
LIMITED: EXT: 20 FL: 20
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Age at final surgery (years)
Number of previous surgical operations performed for the nonunion
Patient
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Table 1 Patient demographics, surgical treatment and final results.
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1 collagen), plus autologous bone graft taken from the iliac crest; e) addition of hydroxyapatite pellets. Careful haemostasis was performed during the operation. Wound drainage was not implemented to avoid loss through the drainage of the BMP-7 that had been applied to the non-union site. The mean age at final surgery was 55.8 years (range: 35-72 years). Eight patients were smokers and one patient had diabetes mellitus. A functional brace was applied to all patients after surgery and was worn for six to 12 weeks. After bracing, movement of the elbow and shoulder was encouraged. Clinical and radiographic evaluations were performed routinely at 1, 3, 4.5, 6, 9 and 12 months after surgery. The average time from initial fracture to our surgical treatment was 5.2 years (range: 2–27 years). The length of follow-up ranged from two to 10 years, with an average of 5.3 years. All the patients were examined both clinically and radiographically at follow-up. Clinical examination included evaluation of pain, range of motion (ROM) of the elbow and shoulder, stability at the non-union site on manual stress, and possible deficit of the radial nerve. Radiographic examination included standard X-rays of the humerus in anteroposterior (AP) and lateral views. The non-union was considered healed when a bridging of the four cortices was present in AP and lateral views at radiographic examination. Results There were no superficial or deep post-surgical wound infections reported in any patients, although three patients developed a post-operative haematoma, which resolved spontaneously in two weeks. Radial nerve palsy was observed after surgery in two patients and was completely resolved in six to seven months. Three patients reported pain at the donor site (iliac crest) that resolved spontaneously in one to three months after surgery. There were no complications or adverse events associated with BMP-7/OP-1 application. Non-union had healed in all patients at follow-up, in an average of 7.3 months (range: 4.5–12 months) after surgery. Only two patients had undergone subsequent surgery for plate removal and this was at least one year after non-union healing. All the patients were asymptomatic at the non-union site, but five patients reported moderate pain at the elbow joint after strenuous activity. All the patients had resumed their previous daily activities after non-union healing. At follow-up, three patients were manual workers, three were white- or blue-collar employees and six were retired. The ROM of the ipsilateral elbow was restricted in all but three patients. The extension restriction ranged from 10 to 35 with an average of 16.5 , and the flexion restriction ranged from 5 to -20 , with an average of 12 . There was no significant limitation of pronation or supination of the forearm or of the ROM of the ipsilateral shoulder. There was no impairment of the peripheral nerves at follow-up. A moderate atrophy of 5–20 mm of both the arm and forearm musculature was observed in all patients and was associated with a mild-to-moderate decrease in muscular strength of the upper arm. There was no clinical instability of the humerus, as tested with manual stress at the non-union site. All the patients were very satisfied with their final result, despite the restricted ROM of the elbow and the moderate muscular atrophy observed.
Discussion The aetiology, surgical management and outcomes of long bone non-unions continue to be a subject of great interest to clinicians [41–49].
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Open reduction and internal fixation with a locking compression plate and autologous bone grafting is considered by many authors to be the gold standard for treatment of atrophic nonunion of the humerus [8–15]. However, in some cases, despite this treatment, non-union persists (recalcitrant non-union), and its management becomes more difficult. Recalcitrant atrophic humeral non-union is a pathological condition that is difficult to treat and is usually associated with marked morbidity and functional impairment of the upper arm [30,32]. In 2001, Friedlaender et al. demonstrated the efficacy of recombinant BMP-7 (OP-1) as an osteoinductive agent and advocated its use for specific indications [24]. BMP-7 induces endochondral bone formation by stimulating local mesenchymal cells and enhancing bone collagen synthesis [50]. The results of a series of clinical studies conducted since 2001 indicate that BMP7 induces bone formation and healing of bone defects, although in many cases it was used in conjunction with autologous bone grafting or other graft types [29–39,51–53]. Only a few studies have reported specifically on the treatment of recalcitrant non-union of the humerus [30,32,38,52–53]. Bong et al. reported a seven-centre prospective study on 23 patients with atrophic diaphyseal non-union of the humerus treated using compression plate or intramedullary nail in conjunction with BMP-7 and various bone grafting techniques [32]. The authors did not specify how many of these non-unions were recalcitrant. All patients achieved union at an average time of 4.8 months (range: 2–12 months). The authors concluded that BMP-7 should be considered in conjunction with bone grafting for the treatment of atrophic and recalcitrant non-union of the humeral diaphysis. Van Houwelingen and McKee successfully treated six patients with osteopenic humeral shaft non-union stabilised by a compression plate in conjunction with humeral cortical allograft struts30. In four non-unions (two recalcitrant) a local implantation of BMP-7 was performed. Union was achieved at an average time of 3.4 months (range: 2-6 months). The authors stressed in their conclusions the importance of BMP-7 as an osteoinductive bone substitute in the treatment of persistent atrophic humeral shaft non-union. In a prospective, randomised clinical study, Calori et al. compared the bone-stimulating efficacy of BMP-7 and platelet-rich plasma (PRP) in the treatment of 120 patients with persistent fracture non-union [52]. The patients were divided into two groups of 60 patients each, according to the bone stimulating agent used. In both groups, autologous bone graft was used in approximately one-third of patients. There were 15 recalcitrant humeral non-unions in the first group and 16 in the second group. The authors concluded from their results that the effectiveness of BMP-7 is superior to that of PRP as an osteoinductive agent. Giannoudis et al. reported a study of 45 patients with atrophic aseptic non-union of long bones who were successfully treated in two separate trauma centres with a combination of BMP-7 and autologous bone graft [53]. There were seven recalcitrant humeral non-unions (15.6%) that healed by an average of 6 months (range: 3–12 months). The authors postulated a potential synergism between BMP-7 and autologous bone graft that may bring about union even in resistant atrophic non-unions. Papanna et al. reported a study of 52 patients with resistant nonunion of the upper or lower limb who were treated using BMP7 with or without revision of the fixation [38]. Ten of the patients had recalcitrant non-union of the humerus and healed by an average of 7.6 months (range: 4–19 months). The authors recommend the use of BMP-7 particularly in resistant non-unions that did not respond to previous revision surgery. The rationale for the combination of BMP-7 with autologous bone grafting and hydroxyapatite pellets is to ensure an osteoinductive action specific to BMP-7 on the mesenchymal cells present in the autologous bone graft, associated with an
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osteoconductive effect exerted on the non-union site by hydroxyapatite. Our results, in accordance with the above-mentioned studies, indicate that the treatment of choice for recalcitrant nonunion of the humerus is stable fixation of the non-union site, and local application of autologous bone graft combined with BMP7 and hydroxyapatite pellets. In fact, in our study, healing of humeral non-union was achieved in all patients, in an average of 7.4 months. In several patients there was limited ROM of the elbow, particularly when the non-union had been present for many years or was located at the distal part of the humeral diaphysis. However, all the patients were very satisfied with the final results despite the restricted ROM. In fact, after the non-union had healed, all patients returned to a satisfactory lifestyle, with a marked functional improvement compared to their previous clinical condition. The best mechanical stabilisation of a non-union is obtained with a long locking compression plate, although when non-union persists, even this type of stabilisation may fail (see Fig. 1). The weakness of our study is that it is retrospective without any control group; however, our data add 12 cases to a limited number (less than 40) of reported cases of recalcitrant non-union treated using BMP-7. To the best of our knowledge, this is the first study conducted on recalcitrant non-union of the humerus treated with a homogeneous method (stabilisation of the non-union site with a long locking compression plate and apposition of autologous bone graft combined with BMP-7 and hydroxyapatite pellets) in a single institution, and followed-up for at least two years after treatment. Conclusions The application of BMP-7 seems to improve the healing rate of recalcitrant non-union of the humerus. However, in these cases, BMP-7 must be combined with autologous bone graft because the osteogenic protein enhances the intrinsic properties of the autologous bone graft and represents the best biological stimulus for bone healing (osteogenic, osteoinductive and osteoconductive). Some authors have reported a high morbidity associated with the harvest procedure, including persistent pain at the donor site, haematomas, infections and paresthesia [40,54,55]. There were no major complications in our series, except for three cases in which a transient pain was felt at the donor site and that resolved spontaneously one to three months after surgery. Considering the costs involved, however, BMP-7 should be used only in selected cases in which traditional surgical methods have failed, and the non-union has become recalcitrant. Conflict of interest The authors have no conflicts of interest for this manuscript. References [1] Rosen H. The treatment of nonunions and pseudoarthroses of the humeral shaft. Orthop Clin North Am 1990;21:725–42. [2] Sarmiento A, Zagorski JB, Zych GA, Latta LL, Capps CA. Functional bracing for the treatment of fracture of the humeral diaphysis. J Bone Joint Surg Am 2000;82A:478–86. [3] Cadet ER, Yin B, Schulz B, Ahmad CS, Rosenwasser MP. Proximal humerus and humeral shaft nonunions. J Am Acad Orthop Surg 2013;21:538–47. [4] Healy WL, White GM, Mick CA, Brooker Jr. AF, Weiland AJ. Nonunion of the humeral shaft. Clin Orthop Relat Res 1987;219:206–13. [5] Foulk DA, Szabo RM. Diaphyseal humerus fractures: natural history and occurrence of nonunion. Orthopedics 1995;18:333–5. [6] King AR, Moran SL, Steinmann SP. Humeral nonunion. Hand Clin 2007;23:449– 56. [7] Rockwood and Green’s Fractures in Adults. 6th Edition. Lippincott Williams and Wilkins, 2006. [8] Segonds JM, Alnot JY, Masmejean E. Aseptic non-union of humeral shaft fractures treated by plating and bone grafting. Rev Chir Orthop Reparatrice Appar Mot 2003;89:107–14.
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Please cite this article in press as: R. Caterini, et al., Treatment of recalcitrant atrophic non-union of the humeral shaft with BMP-7, autologous bone graft and hydroxyapatite pellets, Injury (2016), http://dx.doi.org/10.1016/j.injury.2016.07.044