Low-energy femoral shaft fractures after long-term alendronate therapy: report of seven cases

  • Efstathios G. Ballas
  • Andreas F. Mavrogenis
  • Eirineos Karamanis
  • Zinon T. Kokkalis
  • Evanthia Mitsiokapa
  • Demetrios Koulalis
  • Demetrios Mastrokalos
  • Panayiotis J. Papagelopoulos
Original Article

Abstract

Background

There is increasing evidence suggesting a high incidence of low-energy fractures of the diaphysis or the proximal femur in patients receiving bisphosphonates for a long time. Bisphosphonate-related femoral fractures occur after low-energy trauma and have a typical simple transverse or oblique radiographic pattern, with focal or generalized increased cortical thickness, cortical beaking, and medial spiking.

Materials and methods

This article presents six female patients who experienced seven transverse femoral diaphysis and subtrochanteric fractures with cortical thickening and beaking; all patients had alendronate treatment for 4–10 years (average, 9 years) before their fracture.

Results

The typical radiographic findings, long-term administration of alendronate, low-energy mechanism of fracture, and related literature support the fact that the fractures in the patients presented in this series should be related to alendronate treatment.

Conclusion

Until definite evidence is available, alendronate treatment in patients with osteoporosis is not now prohibited by the healthcare authorities, probably because its beneficial influence outweighs the adverse effects. However, this adverse effect deserves attention of medical practitioners; physicians should be alert on alendronate’s possible suppressive effect on bone turnover, which in turn may be responsible for the occurrence of femoral fractures.

Keywords

Bisphosphonates Alendronate Femoral fractures 

Introduction

Bisphosphonates have been widely used for the treatment of osteoporosis; they improve bone mineral density, decrease markers of bone turnover, and reduce the risk of vertebral and nonvertebral osteoporotic fractures [1]. However, there is increasing evidence suggesting a high incidence of low-energy fractures of the diaphysis or the proximal femur in patients receiving bisphosphonates for a long time [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14].

Bisphosphonate-related femoral fractures occur after low-energy trauma and have a typical radiographic pattern; the fractures are simple transverse or oblique, with focal or generalized increased cortical thickness, cortical beaking, and medial spiking [2, 3, 4]. This type of fracture is considered 98 % specific to long-term alendronate therapy [2]. Although bisphosphonate-related low-energy femoral fractures of the aforementioned typical pattern have been reported with various bisphosphonates such as ibandronate, risedronate, or zoledronic acid [6, 7, 8], most cases have been reported after long-term administration of alendronate. The etiology for this observation is unclear.

To enhance the literature, this article presents six female patients, who experienced seven low-energy fractures of the femoral diaphysis and subtrochanteric region after long-term alendronate treatment (Table 1), and discusses the etiology, imaging and treatment for these fractures. The purpose of the study is to provide additional data concerning the incidence of atypical femoral fractures in patients on bisphosphonate therapy, the preoperative symptoms, and postoperative surgical and medical management of these patients.
Table 1

Details of the female patients included in this series

Patients no.

Age (years)

Co-morbidities

Time of alendronate treatment (70 mg/week)

Fracture location

Prodromal pain

Surgical treatment

1

73

Hypertension

8 years

Femoral diaphysis

No

Intramedullary hip nailing

2

83

Hypothyroidism

10 years

Femoral diaphysis

No

Lost to follow-up

3

65

Hypothyroidism

6 years

Subtrochanteric

No

Intramedullary hip nailing

4

57

None

4 years

Femoral diaphysis

Yes

Intramedullary hip nailing

5

74

Hypertension, diabetes mellitus

10 years

Femoral diaphysis (right)

No

Intramedullary hip nailing

 

75

  

Femoral diaphysis (left)

  

6

70

Hypertension, coronary artery heart disease

6 years

Femoral diaphysis

No

ORIF (plate and screws)

ORIF open reduction and internal fixation

Patients and methods

Case 1

A 73-year-old woman was admitted with a fracture of the diaphysis of the right femur after a fall from standing position. Past medical history revealed hypertension treated with an angiotensin-converting-enzyme inhibitor, and postmenopausal osteoporosis diagnosed 8 years before and treated since then with 70 mg/week alendronate and daily calcium and vitamin D supplementation. She did not have any other medication. She denied any preexisting pain at her right thigh.

Radiographs showed a transverse right femoral diaphysis fracture with thickening of the cortex and a medial cortical spike (Fig. 1a). The biochemical markers of bone formation and resorption were not assessed. Static locked intramedullary nailing was done. Alendronate treatment was discontinued and replaced by denosumab. At 12-month follow-up, the patient was asymptomatic without pain or discomfort during weight bearing; radiographs showed bridging callus formation (Fig. 1b).
Fig. 1

Anteroposterior radiograph of the right femur shows a midshaft transverse femoral fracture with thickening of the diaphyseal cortex (arrow heads) and a medial cortical spike (arrow) (a). Anteroposterior radiograph of the right femur 12 months after static locked intramedullary nailing (b)

Case 2

An 83-year-old woman was admitted with acute pain and inability to stand and weightbear on her left leg. She suddenly experienced extreme pain on her left thigh while walking, without a history of trauma or a fall. Past medical history revealed hypothyroidism under levothyroxine therapy, left total hip replacement for arthritis performed 15 years before, left total knee replacement for arthritis performed 10 years before, an osteoporotic vertebral fracture, and postmenopausal osteoporosis diagnosed 10 years before and treated since then with 70 mg/week alendronate and daily calcium and vitamin D supplementation. She did not have any other medication. She denied any preexisting pain in her left thigh, but she reported intermittent diffuse musculoskeletal pain episodes.

Radiographs showed a transverse left femoral diaphysis fracture with hypertrophy and beaking of the cortex (Fig. 2). There was no evidence of radiolucency at the bone–cement interface of the femoral prosthesis; the femoral stem of the hip prosthesis, and the femoral component of the knee prosthesis were stable. Surgical treatment was suggested; however, the patient refused further treatment at our institution and was discharged from hospital at her own will.
Fig. 2

Anteroposterior radiograph of the left femur shows a transverse left femoral diaphysis fracture with thickening (arrow heads) and beaking (arrow) of the cortex, between a total hip and knee prosthesis

Case 3

A 65-year-old woman was admitted with acute pain and inability to stand and weight bear on her left leg after trying to lift her elderly mother from a chair. Past medical history revealed hypothyroidism under levothyroxine therapy, and postmenopausal osteoporosis diagnosed 6 years before and treated since then with 70 mg/week alendronate and daily calcium supplementation. She did not have any other medication. She denied any preexisting pain at her left hip or thigh.

Radiographs showed a transverse left femoral subtrochanteric fracture with thickening and beaking of the cortex (Fig. 3a). Intramedullary hip nail fixation was done. Alendronate treatment was discontinued and replaced by denosumab. At 12-month follow-up, radiographs showed delayed fracture healing (Fig. 3b, c). The patient has returned almost completely to her previous level of activity with minimal thigh pain.
Fig. 3

Anteroposterior radiograph of the left hip shows a subtrochanteric transverse femoral fracture with thickening (arrow heads) and beaking (arrow) of the cortex (a). Anteroposterior (b) and lateral (c) radiographs of the left hip 12 months after intramedullary hip nail fixation show delayed fracture healing

Case 4

A 57-year-old woman was admitted with acute pain and inability to weight bear on her right leg after a fall from standing position. Past medical history revealed postmenopausal osteoporosis diagnosed 4 years before and treated since then with 70 mg/week alendronate and daily calcium and vitamin D supplementation. She did not have any other medication. She denied any preexisting pain at her right thigh.

Radiographs showed a right femoral diaphysis fracture with thickening and medial beaking of the cortex (Fig. 4a). Static locked intramedullary nailing was done (Fig. 4b). Alendronate treatment was discontinued and replaced by denosumab. At 18-month follow-up, the patient has returned completely to her daily activities; radiographs showed bone healing.
Fig. 4

Anteroposterior radiograph of the right femur shows a midshaft femoral fracture with thickening (arrow heads) and beaking (arrow) of the cortex (a) treated with static locked intramedullary nailing (b)

Case 5

A 74-year-old woman was admitted with acute pain and inability to weight bear on her left leg while walking. Past medical history revealed hypertension, diabetes mellitus, and postmenopausal osteoporosis diagnosed 10 years before and treated since then with 70 mg/week alendronate and daily calcium and vitamin D supplementation. A year before she experienced a similar fracture at her right femoral diaphysis after a fall from standing position, which was treated with intramedullary hip nail fixation. At that time, alendronate treatment was discontinued and replaced by denosumab. She denied any previous pain at her right or left thighs.

Radiographs showed a left femoral diaphysis fracture with thickening and medial beaking of the cortex (Fig. 5). Static locked intramedullary nailing was done; denosumab treatment was continued. At 9-month follow-up, she reported minimal pain at her left thigh during walking; radiographs showed bridging callus formation.
Fig. 5

Anteroposterior radiograph of the pelvis shows a left midshaft femoral fracture with thickening (arrow heads) and beaking (arrow) of the cortex and intramedullary right hip nailing for a similar fracture 1 year before

Case 6

A 70-year-old woman was admitted with a right femoral diaphysis fracture after a fall while walking at her home. Past medical history revealed hypertension and coronary artery heart disease under antihypertensive and antiplatelet medication, and postmenopausal osteoporosis diagnosed 7 years before and treated since then with 70 mg/week alendronate. She denied any preexisting pain at her right thigh.

Radiographs showed a transverse fracture with thickening and beaking of the cortex (Fig. 6a). Open reduction and internal fixation were done (Fig. 6b). Alendronate treatment was discontinued and replaced by strontium ranelate. At 6-month follow-up, she reported minimal pain at her right thigh during walking; radiographs showed delayed bone healing.
Fig. 6

Anteroposterior radiograph of the left femur shows a transverse midshaft fracture with thickening (arrow heads) and beaking (arrow) of the cortex (a) treated with open reduction and internal fixation (b)

Discussion

Alendronate reduces bone resorption by inducing osteoclast apoptosis [15]. However, the effect of long-term alendronate treatment on bone metabolism is under research [2, 3, 4, 14, 15, 16, 17]. Although a previous large observational study failed to show a link between bisphosphonate long-term use and risk of femoral fractures [5], an emerging number of case reports, small case series, and experimental studies have emphasized on long-term alendronate-therapy-related femoral fractures [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 16] of low-energy and typical radiographic pattern [2, 3, 4, 5]. This article presents six female patients who experienced seven transverse femoral diaphysis and subtrochanteric fractures with cortical thickening and beaking; all patients had alendronate treatment for 4–10 years before their fracture. The typical radiographic findings, long-term administration of alendronate, low-energy mechanism, and related literature [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13] support the fact that these fractures should be considered alendronate related.

We see two limitations in this series. First, the sample size is small. However, to our knowledge, there is no study available in the literature taking into account the total preoperative and postoperative management, presence of prodromal pain, surgical, and postoperative medical treatment for osteoporosis for patients with bisphosphonate-related femoral fractures. Additionally, we report the first case of a bisphosphonate-related femoral diaphysis fracture occurring between a total hip and a total knee prosthesis. Second, five of the six patients including in this study were switched to denosumab treatment for their osteoporosis after the occurrence of the fracture. At that time, we were not aware of the possible risk for denosumab-related femoral diaphysis fractures; therefore, careful follow-up of these patients is currently performed for the possible risk of similar fractures.

Bisphosphonate-related femoral fractures of the specific radiographic pattern have been reported after long-term treatment with ibandronate, risedronate, or zoledronic acid [6, 7, 8]. However, interestingly, the majority of patients who sustained this type of femoral fractures had been administered long-term alendronate [2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13]. Odvina et al. [16] was among the first who reported severe suppression of bone turnover in nine patients with spontaneous nonspinal fractures after >3 years alendronate treatment [16]. Neviaser et al. [2] reported on 25 patients on alendronate treatment for an average of 6.9 years who sustained low-energy femoral shaft fractures; 76 % of the fractures were transverse femoral diaphysis fractures with cortical hypertrophy and medial spiking [2]. Kwek et al. [3] identified 17 patients with low-energy subtrochanteric fractures after an average of 4.8 years of alendronate treatment [3]. All fractures had the typical bisphosphonate-related radiographic pattern; nine patients had bilateral involvement and 13 reported prodromal thigh pain [3]. More recently, Ward et al. [7] reported 16 patients on bisphosphonate treatment for 3–10 years who sustained a total of 24 diaphyseal and subtrochanteric femoral fractures. Half of the patients who were treated with intramedullary nailing required a reoperation because of delayed union or nonunion [7]. Several case reports have offered additional evidence regarding bisphosphonate-related femoral fractures [13]. Whether these observations reflect a different effect of the various bisphosphonates on bone metabolism or are due to the longer duration of alendronate availability on the market is still to be addressed. Yet, since there is no conclusive evidence available, a possible elevated risk of low-energy femoral fractures should be taken into account when prescribing bisphosphonates for osteoporosis.

Current evidence suggests increased mineralization and microdamage accumulation as a possible mechanism of alendronate-related femoral fractures [14]. Possible risk factors include associated chronic glucocorticosteroid treatment, concurrent use of proton-pump inhibitors, or other antiresorptive agents such as estrogen, young age, and normal bone mineral density at the beginning of bisphosphonate therapy [6, 17]. Asian descent, rheumatoid arthritis, and diabetes mellitus have also been associated with this type of fractures [18]. The exact duration of alendronate treatment that may cause a suppressive effect on bone turnover is also in question. The presence of prodromal symptoms including pain and discomfort in the limb 1 week–2 years [3, 4] before the occurrence of the bisphosphonate-related fracture has been reported in 56–76 % of the patients [3, 4, 7, 8, 10, 11, 12]. Prodromal pain may be localized in the groin, the anterior, or the lateral thigh [3, 4], or it may be characterized as weakness in the leg rather than pain [3]. Most patients with prodromal symptoms are in the early menopause and had led relatively active lifestyles at the time of injury [4]. Prodromal symptoms have not been reported in patients who had other than alendronate treatment for their osteoporosis [4]. During the period of prodromal symptoms, thickening of the cortex is usually diagnosed in the subtrochanteric region on the fractured side [11]. A contralateral bisphosphonate-related femoral fracture make occur in up to 44.2 % of the cases [14, 20]. Therefore, physicians should screen patients on alendronate for prodromal symptoms and obtain radiographs for early detection of thickening of the femoral cortex [3, 11].

The management of the patients with bisphosphonate-related femoral fractures consists of surgical treatment of the fracture, cessation of the bisphosphonate, and administration of an anabolic agent along with calcium and vitamin D supplementation [18, 19, 20]. Denosumab is a RANK ligand inhibitor human monoclonal antibody. Similarly to bisphosphonates, denosumab appears to be implicated in increasing risk of jaw osteonecrosis and more recently in low-energy femoral diaphysis fractures [19]. No data exist comparing plate versus nail fixation for bisphosphonate-related femoral fractures, but possibly the role of intramedullary nailing to ensure endochondral repair for these fractures should be supported. In any case, close monitoring of these patients is mandatory for the occurrence of delayed union or a contralateral femoral fracture, as in one patient each in this series.

Until definite evidence is available, alendronate treatment in patients with osteoporosis is not prohibited by the healthcare authorities, probably because its beneficial influence outweighs the adverse effects. However, physicians should be alert on the possible suppressive effect of alendronate on bone turnover, which in turn may be responsible for the occurrence of femoral fractures.

Notes

Conflict of interest

None of the authors had any financial or personal relationships with other people or organizations that could inappropriately influence (bias) their work.

References

  1. 1.
    Black DM, Thompson DE, Bauer DC et al (2000) Fracture risk reduction with alendronate in women with osteoporosis: the fracture intervention trial. J Clin Endocrinol Metab 85:4118–4124PubMedCrossRefGoogle Scholar
  2. 2.
    Neviaser AS, Lane JM, Lenart BA, Edobor-Osula F, Lorich DG (2008) Low-energy femoral shaft fractures associated with alendronate use. J Orthop Trauma 22:346–350PubMedCrossRefGoogle Scholar
  3. 3.
    Kwek EB, Goh SK, Koh JS, Png MA, Howe TS (2008) An emerging pattern of subtrochanteric stress fractures: a long-term complication of alendronate therapy? Injury 39:224–231PubMedCrossRefGoogle Scholar
  4. 4.
    Goh SK, Yang KY, Koh JS et al (2007) Subtrochanteric insufficiency fractures in patients on alendronate therapy: a caution. J Bone Joint Surg Br 89:349–353PubMedCrossRefGoogle Scholar
  5. 5.
    Abrahamsen B, Eiken P, Eastell R (2009) Subtrochanteric and diaphyseal femur fractures in patients treated with alendronate: a register-based national cohort study. J Bone Miner Res 24:1095–1102PubMedCrossRefGoogle Scholar
  6. 6.
    Odvina CV, Levy S, Rao S, Zerwekh JE, Rao DS (2010) Unusual mid-shaft fractures during long-term bisphosphonate therapy. Clin Endocrinol (Oxf) 72(2):161–168CrossRefGoogle Scholar
  7. 7.
    Ward WG Jr, Carter CL, Wilson SC, Emory CL (2012) Femoral stress fractures associated with long-term bisphosphonate treatment. Clin Orthop Relat Res 470(3):759–765PubMedCentralPubMedCrossRefGoogle Scholar
  8. 8.
    Glennon DA (2009) Subtrochanteric stress fractures in six patients on long-term bisphosphonate therapy: a case series. Bone 44(Suppl 1):S77–S78CrossRefGoogle Scholar
  9. 9.
    Schilcher J, Aspenberg P (2009) Incidence of stress fractures of the femoral shaft in women treated with bisphosphonate. Acta Orthop 80(4):413–415PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Capeci CM, Tejwani NC (2009) Bilateral low-energy simultaneous or sequential femoral fractures in patients on long-term alendronate therapy. J Bone Joint Surg Am 91:2556–2561PubMedCrossRefGoogle Scholar
  11. 11.
    Cermak K, Shumelinsky F, Alexiou J, Gebhart MJ (2010) Case reports: subtrochanteric femoral stress fractures after prolonged alendronate therapy. Clin Orthop Relat Res 468(7):1991–1996PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Ha YC, Cho MR, Park KH, Kim SY, Koo KH (2010) Is surgery necessary for femoral insufficiency fractures after long-term bisphosphonate therapy? Clin Orthop Relat Res 468(12):3393–3398PubMedCentralPubMedCrossRefGoogle Scholar
  13. 13.
    Goddard MS, Reid KR, Johnston JC, Khanuja HS (2009) Atraumatic bilateral femur fracture in long-term bisphosphonate use. Orthopedics 32(8)Google Scholar
  14. 14.
    Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces biomechanical properties in dog rib. J Bone Miner Res 15:613–620PubMedCrossRefGoogle Scholar
  15. 15.
    Nancollas GH, Tang R, Phipps RJ et al (2006) Novel insights into actions of bisphosphonates on bone: differences in interactions with hydroxyapatite. Bone 38(5):617–627PubMedCrossRefGoogle Scholar
  16. 16.
    Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301PubMedCrossRefGoogle Scholar
  17. 17.
    Armamento-Villareal R, Napoli N, Diemer K et al (2009) Bone turnover in bone biopsies of patients with low-energy cortical fractures receiving bisphosphonates: a case series. Calcif Tissue Int 85:37–44PubMedCrossRefGoogle Scholar
  18. 18.
    Cosman F, Curtis JR, Dell R et al (2010) American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res 25(11):2267–2294PubMedCrossRefGoogle Scholar
  19. 19.
    Shane E, Ebeling PR, Abrahamsen B, et al (2013) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. J Bone Miner Res. doi:10.1002/jbmr.1998. (Epub ahead of print)
  20. 20.
    Lo JC, Huang SY, Lee GA, Khandewal S, Provus J, Ettinger B, Gonzalez JR, Hui RL, Grimsrud CD (2012) Clinical correlates of atypical femoral fracture. Bone 51(1):181–184PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag France 2014

Authors and Affiliations

  • Efstathios G. Ballas
    • 1
  • Andreas F. Mavrogenis
    • 1
  • Eirineos Karamanis
    • 1
  • Zinon T. Kokkalis
    • 1
  • Evanthia Mitsiokapa
    • 1
  • Demetrios Koulalis
    • 1
  • Demetrios Mastrokalos
    • 1
  • Panayiotis J. Papagelopoulos
    • 1
  1. 1.First Department of Orthopaedics, ATTIKON University HospitalAthens University Medical SchoolAthensGreece

Personalised recommendations