Unwanted effects and precautions

Unwanted effects include:

• oral bisphosphonates commonly cause gastrointestinal disturbances
  • for example - diarrhoea, constipation, indigestion and abdominal pain
  • alendronate - severe oesophageal effects have been reported e.g. oesophagitis, oesophageal ulcers, oesophageal strictures and exacerbation of peptic ulcers has been reported (1)
  • risedronate - reported to result in fewer gastric ulcers than alendronate but this may reflect fewer post-marketing data for risedronate than alendronate
• atypical fractures of the femur have been reported rarely after long term use. The incidence is 3.2 to 50 cases per 100,000 person-years, and the risk increases with the duration of exposure to bisphosphonates. (2)
• rare ocular adverse effects, including uveitis, conjunctivitis, and scleritis, have been reported with all bisphosphonates (3)

Precautions include:

• calcium and mineral metabolism disturbances (e.g. parathyroid hormone dysfunction, vitamin D deficiency) should be corrected before starting a bisphosphonate
• if dietary intake is inadequate then calcium and vitamin D supplements should be given with alendronate and risedronate
• bisphosphonates should not be administered in renal impairment (creatinine clearance < 30ml/L)
• alendronate - contraindicated if delay in oesophageal emptying e.g. achalasia, stricture. If active gastrointestinal problems (e.g. dysphagia, oesophageal disease, gastritis, duodenitis, ulcers) then manufacturer advises should be used with "caution" and patients should be advised to stop alendronate and consult doctor if symptoms such as dysphagia, worsening or new heartburn, retrosternal pain or pain on swallowing develop
  • alendronate should be taken first thing in the morning and at least 30 minutes before food, drink (other than water) or medicines(e.g. antacids and mineral supplements containing calcium)
• etidronate - advised to be taken at a point 2 hours before and 2 hours after meals or medicines containing calcium, magnesium, aluminium or iron
• risedronate - according to manufacturer, the drug should be used with "special caution" if a history of oesophageal disorders that delay oesophageal emptying or transit
  • can be taken at least 30 minutes before going to bed, or first thing in the morning (like alendronate) or between meals (like etidronate)
• upper gastrointestinal effects can be reduced by taking a bisphosphonate tablet with a full glass of water, while standing or sitting upright, and by remaining upright for at least 30 minutes after taking the bisphosphonate tablet

Note:

• failure to take bisphosphonates correctly may result in an apparent lack in efficacy - this is because of their low bioavailability
• patients who are on bisphosphonate therapy should be advised to report any thigh, hip, or groin pain and if these symptoms are present, the patient should be evaluated for an incomplete femur fracture (2).
• one of the most severe adverse effects is bisphosphonate-related osteonecrosis of the jaw (BRONJ). Most cases of BRONJ have occurred in patients with multiple myeloma and breast cancer treated with high doses of intravenous bisphosphonates. It has also been reported in patients taking bisphosphonates for osteoporosis with an incidence of approximately 1 in 10,000 to 1 in 100,000. (4)

Reference:

1. Graham DY, Malaty HM. Alendronate and naproxen are synergistic for development of gastric ulcers. Arch Intern Med. 2001 Jan 08;161(1):107-10.
2. Medicines and Healthcare products Regulatory Agency (MHRA). Bisphosphonates: atypical femoral fractures. Drug Safety Update 2011;4(11)
3. Pazianas M et al. Inflammatory eye reactions in patients treated with bisphosphonates and other osteoporosis medications: cohort analysis using a national prescription database. J Bone Miner Res. 2013 Mar;28(3):455-63
4. Khan AA et al. International Task Force on Osteonecrosis of the Jaw. Diagnosis and management of osteonecrosis of the jaw: a systematic review and international consensus. J Bone Miner Res. 2015 Jan;30(1):3-23.