Safety Alerts
Bisphosphonates and atypical fracture risk. An update on label warnings and local ADR reports
16 December 2010
Audiences
Healthcare professional
Industry member
Product-type
Therapeutic Products
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HSA would like to draw healthcare professionals' attention to a recent implementation of label warnings regarding the risk of atypical femur fractures associated with the bisphosphonate class of drugs that are used in the treatment of osteoporosis. The bisphosphonate products that are affected by this label warning in Singapore include risedronate (Actonel® and Risedronate Mevon®), alendronate (Fosamax®, Apo-alendronate® and Tevanate®), ibandronate (Bonviva®) and zoledronic acid (Aclasta®). Bisphosphonates that are licensed for treatment of Paget's disease or high blood calcium levels due to malignancies are not affected by these additional labelling requirements.
Atypical femur fractures
Atypical femur fractures can occur anywhere in the femoral shaft, from just below the lesser trochanter to above the supracondylar flare, and are transverse or short oblique in orientation without evidence of comminution. The fractures can be complete (involving both cortices) or incomplete (involving the lateral cortex only), and may be bilateral. Many patients report parodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. The exact incidence of atypical femoral fractures is unknown but appears to be uncommon, accounting for less than 1% of hip and femoral fractures overall.
Review by US Food and Drug Administration (FDA)
Early this year, the US FDA embarked on reviewing the risk of atypical thigh bone fractures associated with the use of bisphosphonates in the treatment of osteoporosis.¹ In its recently completed review, the US FDA recommended that the package inserts of all bisphosphonates that are indicated for the treatment of osteoporosis be updated with precautions on the potential risk of these atypical femur fractures. This label change describes the uncertainty of the optimal duration of bisphosphonate use for the treatment of osteoporosis as this information has not been elucidated. Although the mechanism of this adverse event is not known, these atypical fractures may be related to long term bisphosphonate use.
Local experience
A spike in local cases reporting atypical fractures associated with the use of alendronate was first brought to HSA's attention in early 2007. Acting on this safety signal, HSA solicited for similar reports from physicians and reviewed the local case reports together with published medical literature. Although the review did not establish that the fractures were directly associated with the use of alendronate, HSA published an article on this issue in March 2007 to alert healthcare professionals on this emerging safety issue. The article also highlighted the Ministry Of Health Clinical Practice Guidelines (MOH CPG) for Osteoporosis as it was noted that a large portion of patients who experienced atypical fractures did not have clinically diagnosed osteoporosis (defined by MOH CPG for Osteoporosis as a Bone Mass Density (BMD) T-score of -2.5 or lower) when they were prescribed alendronate. Considering that alendronate was the only bisphosphonate implicated in the local reports pertaining to atypical fractures at that time, the package inserts of all alendronate-containing products in Singapore were updated to include precautionary statements on this safety issue in 2008.
Current Situation
There are currently 14 registered bisphosphonate-containing products in Singapore that are indicated for the treatment of osteoporosis. To date, there are 82 local ADR reports of subtrochanteric fractures associated with bisphosphonates (78 with alendronate, two with risedronate and one with zoledronate). Majority of the patients who suffered fractures were female (~77%) and aged 60 years old and above (~83%). Where information on the duration of use was available, the onset of fractures ranged from two to eight years following the initiation of bisphosphonates therapy. The BMD T-score was reported for 15 of the patients; 12 of them had a BMD T-score higher than -2.5 prior to the initiation of bisphosphonates, i.e. from -2 to -1.3. These cases did not meet the criteria defined by MOH CPG for Osteoporosis as clinically diagnosed osteoporosis.
HSA is working with the licence holders of these products to strengthen the package inserts of all bisphosphonates licensed for osteoporosis treatment with warnings regarding the risk of atypical fractures.
Considering that atypical femoral fractures have been associated with long-term bisphosphonate use, healthcare professionals are encouraged to conduct periodic re-evaluation of the need for continued bisphosphonate therapy and to evaluate any patient who presents with new thigh or groin pain so as to rule out a femoral fracture. Healthcare professionals are encouraged to keep in mind the MOH CPG Guidelines for Osteoporosis when prescribing bisphosphonates for the treatment of osteoporosis. All serious adverse effects especially fractures suspected to be associated with bisphosphonates should be reported to the Vigilance Branch of HSA.