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Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures
G Model JINJ 7139 No. of Pages 6
Injury, Int. J. Care Injured xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures H.K. Phillips* , S.J. Harrison, H. Akrawi, S.A. Sidhom Department of Trauma and Orthopaedics, Calderdale and Huddersfield NHS FoundationTrust, Huddersfield Royal Infirmary, Acre Street, Lindley, Huddersfield, HD3 3EA, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 21 March 2017
Introduction: Patients may be at an increased risk of atypical proximal femoral fractures with prolonged bisphosphonate use. Patients and methods: This was a retrospective review of patients who sustained a subtrochanteric fracture of the femur in our department between April 2009 and March 2014. The radiographs were reviewed for features of atypical femoral fractures as described by the American Society of Bone Mineral Research. Results: 185 patients were coded according to the National Hip Fracture Database as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients had radiographic findings consistent with an atypical subtrochanteric fracture. 5 patients were excluded as their histology confirmed malignancy. 12 patients were taking bisphosphonates on admission. All 12 patients were females taking alendronic acid on admission, who sustained the fracture as the result of minimal or no trauma and underwent long gamma nail fixation. The mean age was 71.6 years (range 62–79 years). The mean length of time on bisphosphonates prior to admission was 8.33 years (range 3–25 years). 9/12 patients had pre-existing symptoms for between 5 days and 2 years prior to admission. 1 patient sustained a broken gamma nail 14 weeks post-operatively requiring revision. The mean time to discharge from theatre was 16 days (range 5–57 days). The mean time to radiological union in the patients in whom there was evidence was 24 weeks. Conclusions: In this small group of patients, management of this fracture pattern can be complex with the potential for delayed or non-union and prodromal symptoms are common. © 2017 Published by Elsevier Ltd.
Keywords: Bisphosphonate Atypical femoral fracture Alendronic acid Subtrochanteric fracture Osteoporosis
Introduction The use of bisphosphonates has long been established to reduce the risk of hip and vertebral fractures in patients with osteoporosis, as well as in the management of metabolic bone disease such as osteogenesis imperfecta and Paget’s disease [1]. Bisphosphonates include alendronate, risedronate and zolendronic acid [2]. However, in recent years, it has been shown that with prolonged bisphosphonate use, patients may be at an increased risk of atypical proximal femoral stress fractures [3,4,5,6]. There is a suggestion that this type of fracture may be associated with slow healing and prolonged post-operative immobility [7]. Structurally, bisphosphonates have a high affinity for bone mineral and are stable analogues of pyrophosphate. Their
* Corresponding author. E-mail address: [email protected] (H.K. Phillips).
mechanism of action is to decrease bone loss by increasing apoptosis of osteoclasts [1,8]. It may be possible that over a long period of time, the bisphosphonates accumulate in bone and this may result in an over suppression of bone turnover in the long-term, This results in a decrease in new bone formation and remodelling. This dense, brittle, hypermineralised bone may have micro cracks within it and be of poor quality, therefore being more susceptible to fracture [1,9]. The aim of this study was to assess the post-operative outcomes of patients who sustained a bisphosphonate-related atypical proximal femoral fracture between April 2009 and March 2014 in a large district general hospital. Patient and methods A retrospective review of patient case notes, charts and radiographs who sustained a subtrochanteric fracture of the femur between April 2009 and March 2014 and presented to our
http://dx.doi.org/10.1016/j.injury.2017.03.025 0020-1383/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
G Model JINJ 7139 No. of Pages 6
2
H.K. Phillips et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx
department was performed. The list of patients was generated from the National Hip Fracture Database coded as ‘subtrochanteric fracture’. The radiographs of patients were reviewed for features of atypical femoral fractures as described by the American Society of Bone Mineral Research (ASBMR) [10]. The ASBMR radiological criteria state that the fracture must be located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. This is usually in the proximal 1/3 of the femoral shaft. 4 of the following 5 features must also be present:
patients heard a crack on walking. The remaining 5 (n = 5) patients fell from standing height.
1) Fracture associated with minimal or no trauma, such as a fall from standing height or less 2) The fracture line originates at the lateral cortex and is substantially transverse in orientation. It, however, may become oblique as it progresses medially across the femur. 3) Complete fractures extend through both cortices and may be associated with a medial spike, incomplete fractures involve the lateral cortex 4) The fracture is non-comminuted or minimally comminuted 5) Localised periosteal or endosteal thickening is present at the fracture site.
Two (n = 2) patients had polymyalgia rheumatica and were on long-term steroids, 2 (n = 2) patients had hypothyroidism and 1 patient had nephritic syndrome.
The case notes of patients who met the above criteria were subsequently reviewed to ascertain patient demographics upon admission, the laterality of the fracture, the mechanism of injury, mobility status, the presence of pre-existing symptoms, operation, histology results from reamings sent, length of bisphosphonate treatment prior to admission, metabolic disorders, post-operative complications, mobility on admission and discharge, and subsequent revision surgery. Exclusion criteria included patients with proximal femoral fractures due to pathological causes such as cancer, new trauma, patients with radiological features not matching the criteria set by ASBMR. Results Between April 2009 and March 2014, 185 patients were coded according to the NHFD as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients had radiographic findings consistent with an atypical subtrochanteric fracture. Of these 26 patients, 5 patients were excluded as their histology from reamings in theatre confirmed malignancy. Of the 21 patients remaining, 12 patients were documented to be taking bisphosphonates on admission. Patient demographics
Pre-existing symptoms Nine (n = 9) patients had pre-existing symptoms including ipsilateral hip, thigh or groin pain for between 5 days and 2 years prior to admission. Metabolic disorders
Operative fixation All 12 (n = 12) patients underwent long gamma nail fixation. The mean time to theatre was 1.25 days (range 0–3 days). Complications and revisions One (n = 1) patient sustained a broken gamma nail 14 weeks postoperatively and this was revised to a further long gamma nail. Mobility on admission Seven (n = 7) patients were independent on admission, 4/12 patients were mobile with 1 stick and 1 patient was mobile with a zimmer frame. Mobility on discharge One (n = 1) patient was mobile with crutches on discharge, Three (n = 3) patients were mobile with 2 sticks, Six (n = 6) patients were mobile with a zimmer frame on discharge, 1 patient (n = 1) required a wheeled walking frame and 1 (n = 1) patient required a gutter frame. The patient requiring a gutter frame had also undergone open reduction and internal fixation of a distal radius fracture. Time to discharge The mean time to discharge from theatre was 16 days (range 5–57 days) Time to union
All 12 (n = 12) patients were females and taking alendronic acid on admission. The mean age of these 12 patients was 71.6 years (range 62–79 years). The laterality of the fracture site was the right side in 6 patients and the left side in 6 patients.
Table 1 demonstrates the time to radiological union in each of the 12 (n = 12) patients and reasons for non-evidence of radiological union. The mean time to radiological union in the 7 (n = 7) patients in who there was evidence of radiological union was 24 weeks (9–56).
Length of bisphosphonate treatment prior to admission
Discussion
In 3 (n = 3) patients the length of time on bisphosphonates prior to admission was not known. In the remaining 9 (n = 9) patients, the mean length of time on bisphosphonates was 8.33 years (range 3–25 years).
In our department, between April 2009 and March 2014, 185 patients were coded according to the NHFD as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients (14.1%) had radiographic findings consistent with an atypical subtrochanteric fracture. The ASBMR radiological criteria describe the pattern of these atypical fractures as originating at the lateral cortex and being substantially transverse in orientation. There may be a medial spike associated with complete fractures and these fractures usually have nil or minimal comminution [10] as demonstrated in Fig. 1. Schilcher et al. [11] reviewed radiographs
Mechanism of injury All 12 (n = 12) patients sustained the fracture as a result of minimal or no trauma. In 3 (n = 3) patients, the leg gave way on walking. Two (n = 2) patients twisted and heard a crack. Two (n = 2)
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
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H.K. Phillips et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx Table 1 Time to radiological union in patients who have undergone gamma nail fixation for atypical subtrochanteric fractures of the femur. Patient
Time to radiological union
Notes
1
7 months following revision 14 months
No post-op X-rays showing union, 1st post op xray at 4 months shows broken gamma nail
2 3 4 5 6 7
– 15 weeks 14 weeks –
8 9 10
10 months 9 weeks –
11 12
23 weeks 14 weeks
Required bone stimulation (Exogen1) for nonunion No routine clinic follow up – – Moved out of area and lost to follow up At 9 month follow up, some callous but not sufficient, therefore referred for bone stimulation (ExogenJ). At 18 month follow up CT scan showed hypertrophic non-union, referred to tertiary referral center due to thigh pain – – No X-rays performed at 8 week follow up, clinically was mobilising well with 2 sticks – –
of 5342 patients with a femoral shaft fracture who were 55 years of age or older and found 172 (3.2%) atypical fractures according to the American Society for Bone and Mineral Research criteria. Twelve out of twenty six patients who sustained an atypical subtrochanteric femoral fracture in our study were taking bisphosphonates on admission. All of these patients were taking alendronic acid. According to efficacy trials, in women who are below the age of 80 years old and have documented osteoporosis, bisphosphonates prevent clinical fractures [11,12]. However, the use of bisphosphonates in the long term may lead to an increased risk of atypical femoral fractures. They may accumulate in the hydroxyapatite mineral phase of long bone, inhibiting apoptosis of osteoclasts. This is turn may result in suppression of bone turnover, therefore impairment of the bone’s ability to repair micro damage as a result of strain. Micro-cracks may appear and compromise the bone strength [1]. There is a high mineral-to-matrix ratio resulting in bone that is brittle, and increasing susceptibility to micro damage further [5]. Bisphosphonates can remain bound to bone for many years, and some have a higher binding affinity, therefore reside in the bone for longer. The order of binding affinity is zolendronic acid > alendronate > ibandronate > risedronate > etidronate [2]. In our study, the mean length of time on bisphosphonates was 8.33 years (range 3–25 years). It is still unclear as to the optimum duration for bisphosphonate therapy. ‘Drug holidays’ have been
3
advocated in the literature after a 3–5 year course of bisphosphonates, however, the ideal length of ‘drug holiday’ has not been clarified, and the effectiveness of treatment is unclear after restarting [1,2,12]. The American Association of Clinical Endocrinologists guidelines suggested ‘drug holidays’ after 10 years of bisphosphonate therapy in high-risk patients and after 5 years in moderate-risk patients [13]. Chiha et al. [13] did a retrospective review of 209 patients who commenced a drug holiday from bisphosphonates between 2005 and 2010 of which 5.2% patients developed a fracture [13]. Patients who are at high risk of fracture are those with a low bone mineral density < 2.5, sustained a previous vertebral fracture, more than 70 years old, have high bone turnover markers or undergoing glucocorticoid therapy. They may benefit from being commenced on a selective oestrogen receptor modulator such as teraparatide if the bisphosphonate therapy has been stopped after 5 years [14]. A drug holiday of 2–3 years may be adequate for patients who are not high risk, with monitoring of the FRAX (fracture risk assessment tool) score and bone turnover markers to guide recommencement of treatment [15]. Early clinical indicators of bisphosphonate associated fractures of the proximal femur may include prodromal symptoms of ipsilateral thigh or groin pain, and radiologically a thickened lateral proximal femoral cortex with cortical beaking [1]. A high proportion of patients in our study, 9 patients (75%) reported preceding symptoms between 5 days and 2 years prior to admission. There have been similar reports in the literature of patients having symptoms preceding bisphosphonate associated atypical femoral fracture. Kharazmi, M. et al., 2014 reported 86% patients between January 2006 and March 2013 with atypical bisphosphonate femoral fractures as having prodromal symptoms for weeks or longer [16]. Bhadada et al. [1] did a retrospective study of 8 patients between January 2010 and December 2012 who sustained atypical femoral fractures [1]. 6 patients were on alendronate and 2 were on zolendronate therapy before the fractures. 87.5% patients had prodromal symptoms prior to fracture. 25% patients were also on long-term corticosteroids for Addison’s disease and rheumatoid arthritis. This is similar to our study in which there were 17% (n = 2) patients with polymyalgia rheumatica on long-term steroids, 17% (n = 2) patients with nephritic syndrome and 8% (n = 1) patient with hypothyroidism. The surgical management of atypical subtrochanteric fractures of the femur remains a challenge due to the deforming forces of the muscular attachments on the proximal and distal fragments, the transverse fracture pattern and the bone quality [17,18]. In our study, all 12 (n = 12) patients with these atypical subtrochanteric fractures of the femur were managed surgically with a long antegrade gamma intramedullary femoral nail (Fig. 2). We found that closed reduction of transverse subtrochanteric fractures can be difficult. The proximal fragment of the fracture is often
Fig. 1. AP and lateral radiographs demonstrating the appearance of an atypical subtrochanteric fracture of the femur. The fracture is in the proximal 1/3 of the femoral shaft, transverse and minimally comminuted.
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
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Fig. 2. Post-operative AP and lateral radiographs of a patient who has undergone long anterograde gamma intramedullary nail fixation of an atypical subtrochanteric fracture of the femur.
Fig. 3. Use of a Lanes bone lever intra- operatively through the proximal skin incision to keep the proximal fragment extended.
persistently flexed due to the pull of iliopsoas. One technique that we found useful in our department intraoperatively was to utilise a Lanes bone lever through the entry incision, and pass it anteriorly to extend the proximal fragment. This should be held down by an assistant throughout the reaming process until both the gamma nail and lag screw are inserted as shown in Fig. 3. There is a potential to reduce and fix these fractures in varus due to the muscular pull of the abductors, therefore the distal fragment will need to be abducted and externally rotated. While the gamma nail is inserted, some of the traction on the traction table could be released to allow for impaction at the fracture site due to the
transverse nature of the fracture pattern. It is also useful to use the distal locking in dynamic mode (Fig. 4) and encourage early weight bearing to allow for further impaction at the fracture site. It is useful the send the intra- operative reamings from the femur for histology due to the atypical nature of these fractures which may bear similarity to metastatic bone disease. One (n = 1) patient sustained a broken gamma nail 14 weeks postoperatively and this was revised to a further long gamma nail. This was a 73 year old female with a background of polymyalgia rheumatica on both long-term steroids and bisphosphonates (Fig. 5a–c). This case demonstrates some of the pitfalls associated with the surgical management of these fractures. Fig. 5b demonstrates on the intra-operative C arm images that the fracture has been fixed with the proximal fragment still flexed, evident on the lateral view. There is distraction at the fracture site with an evident gap. The lag screw is not in the ideal position being anterior in the femoral head. Teo et al. [7] did a retrospective study of 33 female patients between May 2004 and October 2009 with bisphosphonate-associated subtrochanteric fractures. 70% patients underwent fixation with an extramedullary device. In 21% patients there was implant failure, and 30% patients required revision surgery. The mean time to union radiologically was 10.0 months and time for fracture site pain to cease was 6.2 months. In our study, 2 patients were referred for bone stimulation therapy for non-union of the fracture and in the patients who were followed up in the outpatient clinic, radiological union took between 9 weeks and 56 weeks. Despite small numbers in the studies, there may be a suggestion that intramedullary devices may be superior to extra medullary devices in this fracture type. Melin et al. [19] did a retrospective survey of between 2004 and 2011 of 9 patients (10 atypical fractures) [19]. There was shown to be a high incidence of revision surgery and delayed union. They also found poor clinical
Fig. 4. The use of the distal locking screw in dynamisation mode to encourage further impaction at the fracture site.
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
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Fig. 5. a: Pre-operative AP and lateral radiographs of a patient with polymyalgia rheumatica on long-term steroids who sustained an atypical subtrochanteric fracture of the femur. b: Intra-operative images demonstrating a gap at the fracture site and flexion of the proximal fragment. c: AP and lateral radiographs at 14 weeks post-operatively demonstrating that the gamma nail has broken.
outcomes with mean Harris Hip Scores of 58.9 and timed up-andgo test of 25.7 s at an average follow up of 36.5 months (range 10–104 months). We recognise the limitation of a study of this kind, being that we have a small sample of patients. However, given that, according to the current literature, these fractures are rare, this study adds to the growing evidence on the subject. Conclusions This study supports the current literature that bisphosphonate related atypical fractures are rare. However, in this small group of patients, management of this fracture pattern can be complex with the potential for delayed or non-union. Prodromal symptoms are common and important to be aware of in patients taking bisphosphonates. Patients with a metabolic disorder and also taking steroids may also be at increased risk of this fracture type. The technical difficulties faced during surgical management of these fractures have been identified, and it is recommended that the surgery should be performed by senior experienced surgeons to help prevent failure of fixation. In the primary care setting, patients should be assessed for their fracture risk, and be considered for a ‘drug holiday’ from bisphosphonates or switch to a selective oestrogen receptor modulator after 5 years to avoid such entity of fractures.
References [1] Bhadada S, Sridhar S, Muthukrishnan J, Mithal A, Sharma D, Bhansali A, et al. Predictors of atypical femoral fractures during long term bisphosphonate therapy: a case series and review of the literature. Indian J Med Res 2014;140 (1):46–54. [2] Brown J, Morin S, Leslie W, Papaioannou A, Cheung A, Davison K, et al. Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays. Can Fam Physician 2014;60(4):324–33. [3] Ballas E, Mavrogenis A, Karamanis E, Kokkalis Z, Mitsiokapa E, Koulalis D, et al. Low-energy femoral shaft fractures after long-term alendronate therapy: report of seven cases. Eur J Orthop Surg Traumatol 2015;25(1):181–7. [4] Rheinboldt M, Harper D, Stone M. Atypical femoral fractures in association with bisphosphonate therapy: a case series. Emer Radiol 2014;21(5):557–62. [5] Schilcher J, Sandberg O, Isaksson H, Aspenberg P. Histology of 8 atypical femoral fractures: remodelling but no healing. Acta Orthop 2014;85(3):280–6. [6] Wang Z, Ward M, Chan L, Bhattacharyya T. Adherence to oral bisphosphonates and the risk of subtrochanteric and femoral shaft fractures among female healthcare beneficiaries. Osteoporos Int 2014;25(8):2109–916. [7] Teo B, Koh J, Goh S, Png M, Chua D, Howe T. Post-operative outcomes of atypical femoral subtrochanteric fracture in patients on bisphosphonate therapy. Bone Joint J 2014;96-B(5):658–64. [8] Pazianas M, Kim S, Yuen T, Sun L, Epstein S, Zaidi M. Questioning the association between bisphosphonates and atypical femoral fractures. Ann N Y Acad Sci 2015;1335(1):1–9. [9] Reddy S. Long term bisphosphonate therapy and atypical femoral fractures: a word of caution. Indian J Med Res 2014;140(1):8–10. [10] Shane E, Burr D, Abrahamsen B, Adler R, Brown T, Cheung A, et al. Atypical subtrochanteric and diaphyseal femoral fractures: a second report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 2014;29(1):1–23.
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
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[11] Schilcher J, Koeppen V, Aspenberg P, Michaelsson K. Risk of atypical femoral fracture during and after bisphosphonate use. N Engl J Med 2014;371(10):974– 6. [12] Watts N. Long-term risks of bisphosphonate therapy. Arquivos Brasileiros de Endocrinologia Metabogia 2014;58(5):523–9. [13] Chiha M, Myers L, Ball C, Sinacore J, Camacho P. Long-term follow up of patients on drug holiday from bisphosphonates: a real world setting. Endo Pract 2013;19(6):989–94. [14] Villa J, Gianakos A, Lane J. Bisphosphonate treatment in osteoporosis: optimal duration of a therapy and the incorporation of a drug holiday. HSS J 2016;12 (1):66–73. [15] Adler R, El-Hajj Fuleihan G, Bauer D, Clarke B, Clines G, Compston J, et al. Managing osteoporosis in patients on long-term bisphosphonate treatment: report of a task force of the american society for bone and mineral research. J Bone Miner Res 2016;31(1):16–35.
[16] Kharazami M, Michaelsson K, Haliberg P. Prodromal symptoms in patients with bispshosphonate- associated atypical fractures of the femur. J Bone Miner Metab 2015;33(5):516–22. [17] Cho J, Oh C, Leung F, Park K, Wong M, Kwek E, et al. Healing of Aypical subtrochanteric femur fractures after cephalomedullary nailing: which factors predict union? J Orthop Trauma 2017;31(3):138–45. [18] Tosounidis T, Lampropoulou-Adamidou K, Kanakaris N. Intramedullary nailing of sequential bilateral atypical subtrochanteric fractures and the management of distal femoral introperative fracture. J Orthop Trauma 2015 Epub ahead of print Jun 11, 2015. [19] Meling T, Nawab A, Harboe K, Fosse L. Atypical femoral fractures in elderly women: a fracture registry-based cohort study. Bone Joint J 2014;96-B (8):1035–40.
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
Injury, Int. J. Care Injured xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Injury journal homepage: www.elsevier.com/locate/injury
Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures H.K. Phillips* , S.J. Harrison, H. Akrawi, S.A. Sidhom Department of Trauma and Orthopaedics, Calderdale and Huddersfield NHS FoundationTrust, Huddersfield Royal Infirmary, Acre Street, Lindley, Huddersfield, HD3 3EA, United Kingdom
A R T I C L E I N F O
A B S T R A C T
Article history: Accepted 21 March 2017
Introduction: Patients may be at an increased risk of atypical proximal femoral fractures with prolonged bisphosphonate use. Patients and methods: This was a retrospective review of patients who sustained a subtrochanteric fracture of the femur in our department between April 2009 and March 2014. The radiographs were reviewed for features of atypical femoral fractures as described by the American Society of Bone Mineral Research. Results: 185 patients were coded according to the National Hip Fracture Database as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients had radiographic findings consistent with an atypical subtrochanteric fracture. 5 patients were excluded as their histology confirmed malignancy. 12 patients were taking bisphosphonates on admission. All 12 patients were females taking alendronic acid on admission, who sustained the fracture as the result of minimal or no trauma and underwent long gamma nail fixation. The mean age was 71.6 years (range 62–79 years). The mean length of time on bisphosphonates prior to admission was 8.33 years (range 3–25 years). 9/12 patients had pre-existing symptoms for between 5 days and 2 years prior to admission. 1 patient sustained a broken gamma nail 14 weeks post-operatively requiring revision. The mean time to discharge from theatre was 16 days (range 5–57 days). The mean time to radiological union in the patients in whom there was evidence was 24 weeks. Conclusions: In this small group of patients, management of this fracture pattern can be complex with the potential for delayed or non-union and prodromal symptoms are common. © 2017 Published by Elsevier Ltd.
Keywords: Bisphosphonate Atypical femoral fracture Alendronic acid Subtrochanteric fracture Osteoporosis
Introduction The use of bisphosphonates has long been established to reduce the risk of hip and vertebral fractures in patients with osteoporosis, as well as in the management of metabolic bone disease such as osteogenesis imperfecta and Paget’s disease [1]. Bisphosphonates include alendronate, risedronate and zolendronic acid [2]. However, in recent years, it has been shown that with prolonged bisphosphonate use, patients may be at an increased risk of atypical proximal femoral stress fractures [3,4,5,6]. There is a suggestion that this type of fracture may be associated with slow healing and prolonged post-operative immobility [7]. Structurally, bisphosphonates have a high affinity for bone mineral and are stable analogues of pyrophosphate. Their
* Corresponding author. E-mail address: [email protected] (H.K. Phillips).
mechanism of action is to decrease bone loss by increasing apoptosis of osteoclasts [1,8]. It may be possible that over a long period of time, the bisphosphonates accumulate in bone and this may result in an over suppression of bone turnover in the long-term, This results in a decrease in new bone formation and remodelling. This dense, brittle, hypermineralised bone may have micro cracks within it and be of poor quality, therefore being more susceptible to fracture [1,9]. The aim of this study was to assess the post-operative outcomes of patients who sustained a bisphosphonate-related atypical proximal femoral fracture between April 2009 and March 2014 in a large district general hospital. Patient and methods A retrospective review of patient case notes, charts and radiographs who sustained a subtrochanteric fracture of the femur between April 2009 and March 2014 and presented to our
http://dx.doi.org/10.1016/j.injury.2017.03.025 0020-1383/© 2017 Published by Elsevier Ltd.
Please cite this article in press as: H.K. Phillips, et al., Retrospective review of patients with atypical bisphosphonate related proximal femoral fractures, Injury (2017), http://dx.doi.org/10.1016/j.injury.2017.03.025
G Model JINJ 7139 No. of Pages 6
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H.K. Phillips et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx
department was performed. The list of patients was generated from the National Hip Fracture Database coded as ‘subtrochanteric fracture’. The radiographs of patients were reviewed for features of atypical femoral fractures as described by the American Society of Bone Mineral Research (ASBMR) [10]. The ASBMR radiological criteria state that the fracture must be located along the femoral diaphysis from just distal to the lesser trochanter to just proximal to the supracondylar flare. This is usually in the proximal 1/3 of the femoral shaft. 4 of the following 5 features must also be present:
patients heard a crack on walking. The remaining 5 (n = 5) patients fell from standing height.
1) Fracture associated with minimal or no trauma, such as a fall from standing height or less 2) The fracture line originates at the lateral cortex and is substantially transverse in orientation. It, however, may become oblique as it progresses medially across the femur. 3) Complete fractures extend through both cortices and may be associated with a medial spike, incomplete fractures involve the lateral cortex 4) The fracture is non-comminuted or minimally comminuted 5) Localised periosteal or endosteal thickening is present at the fracture site.
Two (n = 2) patients had polymyalgia rheumatica and were on long-term steroids, 2 (n = 2) patients had hypothyroidism and 1 patient had nephritic syndrome.
The case notes of patients who met the above criteria were subsequently reviewed to ascertain patient demographics upon admission, the laterality of the fracture, the mechanism of injury, mobility status, the presence of pre-existing symptoms, operation, histology results from reamings sent, length of bisphosphonate treatment prior to admission, metabolic disorders, post-operative complications, mobility on admission and discharge, and subsequent revision surgery. Exclusion criteria included patients with proximal femoral fractures due to pathological causes such as cancer, new trauma, patients with radiological features not matching the criteria set by ASBMR. Results Between April 2009 and March 2014, 185 patients were coded according to the NHFD as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients had radiographic findings consistent with an atypical subtrochanteric fracture. Of these 26 patients, 5 patients were excluded as their histology from reamings in theatre confirmed malignancy. Of the 21 patients remaining, 12 patients were documented to be taking bisphosphonates on admission. Patient demographics
Pre-existing symptoms Nine (n = 9) patients had pre-existing symptoms including ipsilateral hip, thigh or groin pain for between 5 days and 2 years prior to admission. Metabolic disorders
Operative fixation All 12 (n = 12) patients underwent long gamma nail fixation. The mean time to theatre was 1.25 days (range 0–3 days). Complications and revisions One (n = 1) patient sustained a broken gamma nail 14 weeks postoperatively and this was revised to a further long gamma nail. Mobility on admission Seven (n = 7) patients were independent on admission, 4/12 patients were mobile with 1 stick and 1 patient was mobile with a zimmer frame. Mobility on discharge One (n = 1) patient was mobile with crutches on discharge, Three (n = 3) patients were mobile with 2 sticks, Six (n = 6) patients were mobile with a zimmer frame on discharge, 1 patient (n = 1) required a wheeled walking frame and 1 (n = 1) patient required a gutter frame. The patient requiring a gutter frame had also undergone open reduction and internal fixation of a distal radius fracture. Time to discharge The mean time to discharge from theatre was 16 days (range 5–57 days) Time to union
All 12 (n = 12) patients were females and taking alendronic acid on admission. The mean age of these 12 patients was 71.6 years (range 62–79 years). The laterality of the fracture site was the right side in 6 patients and the left side in 6 patients.
Table 1 demonstrates the time to radiological union in each of the 12 (n = 12) patients and reasons for non-evidence of radiological union. The mean time to radiological union in the 7 (n = 7) patients in who there was evidence of radiological union was 24 weeks (9–56).
Length of bisphosphonate treatment prior to admission
Discussion
In 3 (n = 3) patients the length of time on bisphosphonates prior to admission was not known. In the remaining 9 (n = 9) patients, the mean length of time on bisphosphonates was 8.33 years (range 3–25 years).
In our department, between April 2009 and March 2014, 185 patients were coded according to the NHFD as having sustained a subtrochanteric fracture of the femur. Of these, 26 patients (14.1%) had radiographic findings consistent with an atypical subtrochanteric fracture. The ASBMR radiological criteria describe the pattern of these atypical fractures as originating at the lateral cortex and being substantially transverse in orientation. There may be a medial spike associated with complete fractures and these fractures usually have nil or minimal comminution [10] as demonstrated in Fig. 1. Schilcher et al. [11] reviewed radiographs
Mechanism of injury All 12 (n = 12) patients sustained the fracture as a result of minimal or no trauma. In 3 (n = 3) patients, the leg gave way on walking. Two (n = 2) patients twisted and heard a crack. Two (n = 2)
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H.K. Phillips et al. / Injury, Int. J. Care Injured xxx (2016) xxx–xxx Table 1 Time to radiological union in patients who have undergone gamma nail fixation for atypical subtrochanteric fractures of the femur. Patient
Time to radiological union
Notes
1
7 months following revision 14 months
No post-op X-rays showing union, 1st post op xray at 4 months shows broken gamma nail
2 3 4 5 6 7
– 15 weeks 14 weeks –
8 9 10
10 months 9 weeks –
11 12
23 weeks 14 weeks
Required bone stimulation (Exogen1) for nonunion No routine clinic follow up – – Moved out of area and lost to follow up At 9 month follow up, some callous but not sufficient, therefore referred for bone stimulation (ExogenJ). At 18 month follow up CT scan showed hypertrophic non-union, referred to tertiary referral center due to thigh pain – – No X-rays performed at 8 week follow up, clinically was mobilising well with 2 sticks – –
of 5342 patients with a femoral shaft fracture who were 55 years of age or older and found 172 (3.2%) atypical fractures according to the American Society for Bone and Mineral Research criteria. Twelve out of twenty six patients who sustained an atypical subtrochanteric femoral fracture in our study were taking bisphosphonates on admission. All of these patients were taking alendronic acid. According to efficacy trials, in women who are below the age of 80 years old and have documented osteoporosis, bisphosphonates prevent clinical fractures [11,12]. However, the use of bisphosphonates in the long term may lead to an increased risk of atypical femoral fractures. They may accumulate in the hydroxyapatite mineral phase of long bone, inhibiting apoptosis of osteoclasts. This is turn may result in suppression of bone turnover, therefore impairment of the bone’s ability to repair micro damage as a result of strain. Micro-cracks may appear and compromise the bone strength [1]. There is a high mineral-to-matrix ratio resulting in bone that is brittle, and increasing susceptibility to micro damage further [5]. Bisphosphonates can remain bound to bone for many years, and some have a higher binding affinity, therefore reside in the bone for longer. The order of binding affinity is zolendronic acid > alendronate > ibandronate > risedronate > etidronate [2]. In our study, the mean length of time on bisphosphonates was 8.33 years (range 3–25 years). It is still unclear as to the optimum duration for bisphosphonate therapy. ‘Drug holidays’ have been
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advocated in the literature after a 3–5 year course of bisphosphonates, however, the ideal length of ‘drug holiday’ has not been clarified, and the effectiveness of treatment is unclear after restarting [1,2,12]. The American Association of Clinical Endocrinologists guidelines suggested ‘drug holidays’ after 10 years of bisphosphonate therapy in high-risk patients and after 5 years in moderate-risk patients [13]. Chiha et al. [13] did a retrospective review of 209 patients who commenced a drug holiday from bisphosphonates between 2005 and 2010 of which 5.2% patients developed a fracture [13]. Patients who are at high risk of fracture are those with a low bone mineral density < 2.5, sustained a previous vertebral fracture, more than 70 years old, have high bone turnover markers or undergoing glucocorticoid therapy. They may benefit from being commenced on a selective oestrogen receptor modulator such as teraparatide if the bisphosphonate therapy has been stopped after 5 years [14]. A drug holiday of 2–3 years may be adequate for patients who are not high risk, with monitoring of the FRAX (fracture risk assessment tool) score and bone turnover markers to guide recommencement of treatment [15]. Early clinical indicators of bisphosphonate associated fractures of the proximal femur may include prodromal symptoms of ipsilateral thigh or groin pain, and radiologically a thickened lateral proximal femoral cortex with cortical beaking [1]. A high proportion of patients in our study, 9 patients (75%) reported preceding symptoms between 5 days and 2 years prior to admission. There have been similar reports in the literature of patients having symptoms preceding bisphosphonate associated atypical femoral fracture. Kharazmi, M. et al., 2014 reported 86% patients between January 2006 and March 2013 with atypical bisphosphonate femoral fractures as having prodromal symptoms for weeks or longer [16]. Bhadada et al. [1] did a retrospective study of 8 patients between January 2010 and December 2012 who sustained atypical femoral fractures [1]. 6 patients were on alendronate and 2 were on zolendronate therapy before the fractures. 87.5% patients had prodromal symptoms prior to fracture. 25% patients were also on long-term corticosteroids for Addison’s disease and rheumatoid arthritis. This is similar to our study in which there were 17% (n = 2) patients with polymyalgia rheumatica on long-term steroids, 17% (n = 2) patients with nephritic syndrome and 8% (n = 1) patient with hypothyroidism. The surgical management of atypical subtrochanteric fractures of the femur remains a challenge due to the deforming forces of the muscular attachments on the proximal and distal fragments, the transverse fracture pattern and the bone quality [17,18]. In our study, all 12 (n = 12) patients with these atypical subtrochanteric fractures of the femur were managed surgically with a long antegrade gamma intramedullary femoral nail (Fig. 2). We found that closed reduction of transverse subtrochanteric fractures can be difficult. The proximal fragment of the fracture is often
Fig. 1. AP and lateral radiographs demonstrating the appearance of an atypical subtrochanteric fracture of the femur. The fracture is in the proximal 1/3 of the femoral shaft, transverse and minimally comminuted.
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Fig. 2. Post-operative AP and lateral radiographs of a patient who has undergone long anterograde gamma intramedullary nail fixation of an atypical subtrochanteric fracture of the femur.
Fig. 3. Use of a Lanes bone lever intra- operatively through the proximal skin incision to keep the proximal fragment extended.
persistently flexed due to the pull of iliopsoas. One technique that we found useful in our department intraoperatively was to utilise a Lanes bone lever through the entry incision, and pass it anteriorly to extend the proximal fragment. This should be held down by an assistant throughout the reaming process until both the gamma nail and lag screw are inserted as shown in Fig. 3. There is a potential to reduce and fix these fractures in varus due to the muscular pull of the abductors, therefore the distal fragment will need to be abducted and externally rotated. While the gamma nail is inserted, some of the traction on the traction table could be released to allow for impaction at the fracture site due to the
transverse nature of the fracture pattern. It is also useful to use the distal locking in dynamic mode (Fig. 4) and encourage early weight bearing to allow for further impaction at the fracture site. It is useful the send the intra- operative reamings from the femur for histology due to the atypical nature of these fractures which may bear similarity to metastatic bone disease. One (n = 1) patient sustained a broken gamma nail 14 weeks postoperatively and this was revised to a further long gamma nail. This was a 73 year old female with a background of polymyalgia rheumatica on both long-term steroids and bisphosphonates (Fig. 5a–c). This case demonstrates some of the pitfalls associated with the surgical management of these fractures. Fig. 5b demonstrates on the intra-operative C arm images that the fracture has been fixed with the proximal fragment still flexed, evident on the lateral view. There is distraction at the fracture site with an evident gap. The lag screw is not in the ideal position being anterior in the femoral head. Teo et al. [7] did a retrospective study of 33 female patients between May 2004 and October 2009 with bisphosphonate-associated subtrochanteric fractures. 70% patients underwent fixation with an extramedullary device. In 21% patients there was implant failure, and 30% patients required revision surgery. The mean time to union radiologically was 10.0 months and time for fracture site pain to cease was 6.2 months. In our study, 2 patients were referred for bone stimulation therapy for non-union of the fracture and in the patients who were followed up in the outpatient clinic, radiological union took between 9 weeks and 56 weeks. Despite small numbers in the studies, there may be a suggestion that intramedullary devices may be superior to extra medullary devices in this fracture type. Melin et al. [19] did a retrospective survey of between 2004 and 2011 of 9 patients (10 atypical fractures) [19]. There was shown to be a high incidence of revision surgery and delayed union. They also found poor clinical
Fig. 4. The use of the distal locking screw in dynamisation mode to encourage further impaction at the fracture site.
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Fig. 5. a: Pre-operative AP and lateral radiographs of a patient with polymyalgia rheumatica on long-term steroids who sustained an atypical subtrochanteric fracture of the femur. b: Intra-operative images demonstrating a gap at the fracture site and flexion of the proximal fragment. c: AP and lateral radiographs at 14 weeks post-operatively demonstrating that the gamma nail has broken.
outcomes with mean Harris Hip Scores of 58.9 and timed up-andgo test of 25.7 s at an average follow up of 36.5 months (range 10–104 months). We recognise the limitation of a study of this kind, being that we have a small sample of patients. However, given that, according to the current literature, these fractures are rare, this study adds to the growing evidence on the subject. Conclusions This study supports the current literature that bisphosphonate related atypical fractures are rare. However, in this small group of patients, management of this fracture pattern can be complex with the potential for delayed or non-union. Prodromal symptoms are common and important to be aware of in patients taking bisphosphonates. Patients with a metabolic disorder and also taking steroids may also be at increased risk of this fracture type. The technical difficulties faced during surgical management of these fractures have been identified, and it is recommended that the surgery should be performed by senior experienced surgeons to help prevent failure of fixation. In the primary care setting, patients should be assessed for their fracture risk, and be considered for a ‘drug holiday’ from bisphosphonates or switch to a selective oestrogen receptor modulator after 5 years to avoid such entity of fractures.
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