Guidance

Bisphosphonates: use and safety

Published 18 December 2014

1. Overview

Bisphosphonates are widely used to treat and prevent bone-related conditions. They act by inhibiting osteoclast activity and bone resorption. Individual bisphosphonates have different indications and are used:

• for the prevention and treatment of osteoporosis in postmenopausal women
• for treatment of Paget’s disease of bone
• as part of some anticancer treatment regimens, particularly for metastatic bone cancer and multiple myeloma

The oral bisphosphonate medicines prescribed in the UK are:

• alendronate (Fosamax, Fosavance)
• sodium clodronate (Bonefos, Loron)
• disodium etidronate (Didronel, Didronel PMO)
• ibandronate (Bondronat, Bonviva)
• risedronate sodium (Actonel, Actonel Once a Week)

The intravenous/injected bisphosphonates prescribed in the UK are:

• ibandronate (Bondronat, Bonviva)
• disodium pamidronate (Aredia)
• zoledronic acid (Aclasta, Zometa)

2. Important safety issues with bisphosphonates

The following sections summarise important safety issues with bisphosphonates which MHRA has investigated and issued guidance on.

Full guidance on prescribing and use of bisphosphonates, including safety information is provided in the summary of product characteristics (SPC) for healthcare professionals and the patient information leaflet (PIL) that accompanies the medicine .

2.1 Oesophageal reactions

Oral formulations of the bisphosphonates alendronate, ibandronate and risedronate are associated with serious oesophageal adverse reactions including:

• oesophagitis
• oesophageal ulcers
• oesophageal strictures
• oesophageal erosions

Warnings about the risk of oesophageal reactions with oral alendronate, ibandronate and risedronate and clear instructions on how to take these medicines are provided in their product information.

In order to reduce the risk of oesophageal reactions healthcare professionals are advised that:

• alendronate and oral ibandronate should not be given to patients with abnormalities of the oesophagus and/or other factors which delay oesophageal emptying such as stricture or achalasia and Risedronate should be used with caution in such patients
• alendronate, oral ibandronate and risedronate should be used with caution in patients with active or recent upper gastrointestinal problems
• in patients with known Barrett’s oesophagus, prescribers should consider the benefits and potential risks of alendronate and risedronate on an individual basis. Oral ibandronate should be used with caution in patients with known Barrett’s oesophagus
• patients should be advised about the importance of adhering to dosage instructions:
  • tablets should be swallowed whole with at least 200 ml of water on an empty stomach immediately after getting up in the morning
  • patients should stay fully upright for at least 30 minutes or one hour after taking the tablet and before taking any food, drink or other medicine
• patients should be advised to stop taking the tablets and to seek medical attention if they develop any symptoms of oesophageal irritation such as difficulty or pain upon swallowing, chest pain, or new or worsening heartburn

Oesophageal cancer

A 2010 study carried out by MHRA, in conjunction with the Cancer Epidemiology Unit at the University of Oxford, investigated post-marketing reports of oesophageal cancer (cancer of the gullet) in association with oral bisphosphonate use.

The results from this study suggested a small increase in the risk of oesophageal cancer in patients who had taken oral bisphosphonates for more than 5 years compared with a group who had not taken oral bisphosphonates.

The incidence rate of oesophageal cancer over 5 years in men and women aged 60 to 79 years in the general population is 0.5 women per 1000 and 1.5 men per 1000. In this study, the incidence increased with 5 years’ of bisphosphonates use to one woman per 1000, and three men per 1000.

The Commission on Human Medicines said that the evidence from this study was not strong enough to suggest a definite causal association between oral bisphosphonates and oesophageal cancer.

On the basis of these findings there is no need for patients to stop taking their bisphosphonate medicine. However, it is important to carefully follow the instructions in the patient information leaflet on how to take the medicine, and to report any signs of oesophageal irritation to the doctor, such as:

• difficulties or pain on swallowing
• chest pain or heartburn

A 2012 Europe-wide review of 4 new epidemiological studies supported the conclusion of the 2010 review.

However, as an association between bisphosphonates and oesophageal cancer cannot be excluded, caution should be used when considering nitrogen-containing bisphosphonates for oral use in patients with known Barrett’s oesophagus. Physicians should carefully consider the benefits and potential risks of treatment with alendronate, ibandronate and risedronate in these patients.

2.2 Osteonecrosis of the jaw

A Europe-wide review on the risk of osteonecrosis of the jaw (ONJ) in association with the use of bisphosphonates carried out in 2009 concluded that the risk is greater for patients receiving intravenous bisphosphonates for cancer than for patients receiving oral bisphosphonates for osteoporosis or Paget’s disease of bone.

ONJ related to bisphosphonates is defined as an area of exposed or dead bone in the jaw that has lasted for more than 8 weeks, in a patient who has been or is currently being exposed to a bisphosphonate and has not has radiation therapy on the jaw.

All patients receiving intravenous bisphosphonates should have a dental check-up before bisphosphonate treatment. Urgent bisphosphonate treatment should not be delayed, however, a dental check-up should be carried out as soon as possible.

All other patients who start oral bisphosphonates should only have a dental examination before starting treatment if they have poor dental health.

During all bisphosphonate treatments, patients should be encouraged to:

• maintain good oral hygiene
• receive routine dental check-ups
• report any oral symptoms such as dental mobility, pain, or swelling

2.3 Atrial fibrillation

Following the publication of 2 clinical trials which found an increased incidence of atrial fibrillation with zoledronic acid, and alendronate, respectively (Black et al, 2007, Cummings et al, 2007), a Europe-wide review of clinical trial data, reported cases and published literature on the risk of atrial fibrillation with all bisphosphonates was carried out in 2008.

The review concluded that although the risk seemed to be low, clinical trial results did suggest an increased risk of atrial fibrillation for zoledronic acid, pamidronate, and possibly for alendronate.

Following this review, product information for both zoledronic acid products Aclasta and Zometa, and pamidronate were updated to include atrial fibrillation as a possible side effect.

A further European review of alendronate and atrial fibrillation in April 2010 considered new studies and meta-analyses on alendronate and atrial fibrillation published since the previous European review in 2008 and concluded that at the present time, atrial fibrillation did not need to be added to the list of possible side effects of alendronate in the product information.

The review concluded that at the present time, atrial fibrillation did not need to be added to the list of possible side effects of alendronate in the product information.

However, the safety issue of atrial fibrillation and all bisphosphonates should continue to be kept under close review.

3. Atypical femoral fractures

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. The issue was kept under close review and any emerging data were evaluated.

A further Europe-wide review of bisphosphonates and atypical femoral fractures was conducted in May 2011. This review concluded that atypical fractures of the femur may occur rarely with the use of any bisphosphonate.

Atypical femoral fractures have been reported rarely with bisphosphonate therapy, mainly in patients receiving long-term treatment for osteoporosis. The fractures occurred after minimal or no trauma, and some patients experienced thigh pain weeks to months before presenting with a completed femoral fracture.

Fractures were frequently bilateral, therefore the contralateral femur should be examined in bisphosphonate-treated patients who have a femoral shaft fracture. Poor healing of these fractures was also reported.

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. 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 risk of atypical femoral fractures with all bisphosphonates will continue to be closely monitored.

4. Adverse effects on renal function

Renal toxicity is a recognised adverse reaction associated with intravenous bisphosphonates. Comprehensive warnings about renal reactions are included in the product information for all intravenous bisphosphonates.

These warnings in the product information for Aclasta (intravenous zoledronic acid 5mg used for the once-yearly treatment of osteoporosis and as a single dose for the treatment of Paget’s disease of bone) were strengthened in 2010, following reports of renal failure and renal impairment with its use.

The product information for Zometa (intravenous zoledronic acid 4mg given every 3 to 4 weeks to reduce bone damage in advanced cancer cases involving bone, and as a single dose for tumour-induced hypercalcaemia), already contains strong warnings and precautions regarding renal impairment and renal failure.

For both Aclasta and Zometa, renal function should be measured before each dose, and patients should be adequately hydrated before treatment. Renal function monitoring is recommended after use of zoledronic acid in at-risk patients—especially those with pre-existing renal impairment or other risk factors such as advanced age, dehydration or use of concomitant nephrotoxic drugs or diuretic therapy.

Use in patients with severe renal impairment is generally not recommended, but may be considered for tumour-induced hypercalcaemia, if the benefits outweigh the risks.