Bisphosphonates: atypical femoral fractures

Atypical femoral fractures reported rarely with bisphosphonate therapy, mainly in patients receiving long-term treatment for osteoporosis.

Article date: June 2011

Individual bisphosphonates have different indications, and are used for:

  • prophylaxis and treatment of osteoporosis
  • treatment of Paget’s disease
  • as part of some cancer regimens, particularly for bone metastases and multiple myeloma

In 2008, a Europe-wide review of bisphosphonates and atypical stress fractures concluded that alendronic acid use was associated with an increased risk of atypical stress fractures of the proximal femoral shaft and a warning was subsequently added to alendronic acid product information. At that time, the available data neither supported nor refuted a possible class effect, and the issue was kept under close review and any emerging data evaluated (see Drug Safety Update March 2009).

A further Europe-wide review has now been completed, which included data from the published literature and that provided by the marketing authorisation (licence) holders (including preclinical studies, clinical trials, and case reports) as well as reports produced by professional organisations.1 2 The key findings and advice for healthcare professionals from this review are given below.

Key findings:

  • atypical femoral fractures have been reported rarely with bisphosphonate therapy, mainly in patients receiving long-term treatment for osteoporosis; atypical femoral fractures are considered a class effect of bisphosphonates
  • they can occur after minimal or no trauma - some patients experience thigh or groin pain, often associated with features of stress fractures on radiograph, weeks to months before presenting with a completed femoral fracture; poor healing of these fractures has been reported
  • the overall balance of risks and benefits of individual bisphosphonates in their authorised indications remains favourable - the absolute number of atypical fractures reported is far lower than the number of osteoporotic fractures prevented3

Advice for healthcare professionals includes:

  • atypical femoral fractures are often bilateral; therefore the contralateral femur should be examined in bisphosphonate-treated patients who have sustained a femoral shaft fracture
  • discontinuation of bisphosphonate therapy in patients suspected to have an atypical femur fracture should be considered while they are evaluated, and should be based on an assessment of the benefits and risks of treatment for the individual
  • during bisphosphonate treatment, patients should be advised to report any thigh, hip, or groin pain. Any patient who presents with such symptoms should be evaluated for an incomplete femur fracture
  • the optimum duration of bisphosphonate treatment for osteoporosis has not been established. The need for continued treatment should be re-evaluated periodically based on the benefits and potential risks of bisphosphonate therapy for individual patients, particularly after 5 or more years of use

The risk of atypical femoral fractures with bisphosphonates will be kept under close review in Europe.

To facilitate future case reporting and research, the European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has adopted a definition of atypical femoral fracture based on the American Society for Bone and Mineral Research (ASBMR) provisional case definition of atypical femoral fracture1 —major and minor features (a):

Major features(b):

  • located anywhere along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare
  • associated with no trauma or minimal trauma, as in a fall from a standing height or less
  • transverse or short oblique configuration
  • complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex

Minor features:

  • noncomminuted
  • localised periosteal reaction of the lateral cortexc
  • generalised increase in cortical thickness of the diaphysis
  • prodromal symptoms such as dull or aching pain in the groin or thigh
  • bilateral fractures and symptoms
  • delayed healing
  • comorbid conditions (eg, vitamin D deficiency, rheumatoid arthritis, hypophosphatasia)
  • use of pharmaceutical agents (eg, bisphosphonates, glucocortoids, proton pump inhibitors)

(a) Specifically excluded are fractures of the femoral neck, intertrochanteric fractures with spiral subtrochanteric extension, pathologic fractures associated with primary or metastatic bone tumours, and periprosthetic fractures.
(b) All major features are required to satisfy the case definition of atypical femoral fracture. None of the minor features are required, but sometimes have been associated with these fractures (c) Often referred to in the literature as ‘beaking’ or ‘flaring’

Further information is available from the European Medicines Agency

See also BNF section 6.6.2 Bisphosphonates and other drugs affecting bone metabolism

Article citation: Drug Safety Update June 2011, vol 4 issue 11: A1.

  1. Shane E, et al. J Bone Miner Res 2010; 25: 2267–94. 2

  2. Rizzoli R, et al. Osteoporos Int 2011; 22: 373–90.

  3. Schilcher J and Aspenberg P. N Engl J Med 2011; 364 : 1728–37.

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