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Published: May 2006
ADR update

Alendronate and Inflammatory Adverse Reactions

Information on this subject has been updated. Read the most recent information.

Prescriber Update 27(1): 4–6
May 2006

Ruth Savage, Medical Assessor, CARM,
New Zealand Pharmacovigilance Centre, Dunedin

Alendronate is a potent inhibitor of bone resorption and is most commonly used in the treatment and prevention of osteoporosis.  Inflammatory eye disorders are now recognised adverse effects.  Patients with eye pain or visual loss should be referred to an ophthalmologist.  Reports to CARM indicate that alendronate may cause synovitis, which can be severe.  The risk of oesophagitis and oesophageal ulceration, which may lead to stricture or perforation, should be minimised by following advice regarding posture and adequate water intake with each dose.  Patients should report difficulty or pain when swallowing, retrosternal pain, and new or worsening dyspepsia.

Alendronate is indicated for osteoporosis and Paget’s disease
Refer if ocular pain or visual loss occurs
Myalgia and arthralgia common; synovitis rare but can be severe
Oesophagitis and oesophageal ulceration can also occur
Gastrointestinal adverse effects can be minimised
Allergy and rashes are also seen with alendronate
Inflammatory-type reactions may occur with other bisphosphonates
Other adverse reactions to alendronate
References
Bisphosphonates and osteonecrosis of the jaw

Alendronate is indicated for osteoporosis and Paget's disease

Alendronate, a bisphosphonate, is a potent inhibitor of osteoclast-mediated bone resorption.  It is indicated in postmenopausal women for the prevention and treatment of osteoporosis to prevent fractures; for the treatment of osteoporosis in men; for the treatment and prevention of glucocorticoid-induced osteoporosis; and for treatment of Paget's disease of bone.  It is given orally, usually once weekly.1  For alendronate, gastrointestinal, musculoskeletal and neurological reports comprise almost 50% of suspected adverse reactions reported to the Centre for Adverse Reactions Monitoring (CARM), and ocular reactions comprise about 4%.

Refer if ocular pain or visual loss occurs

Rare but serious ocular complications can occur with alendronate treatment.  Of these, most of the clinically significant reactions reported to CARM and internationally are ocular inflammation such as conjunctivitis, uveitis, episcleritis and scleritis.2,3  Time to onset varied from two days to three years (median of three weeks) after commencement of treatment.3  Symptoms include abnormal or blurred vision, redness, ocular pain and photophobia.2  Patients with visual loss or ocular pain need ophthalmological assessment.  Non-specific conjunctivitis seldom requires treatment and usually diminishes in intensity with subsequent exposures to alendronate.  However, alendronate may need to be discontinued for other ocular inflammation to resolve; this is always necessary for scleritis.2

Myalgia and arthralgia common; synovitis rare but can be severe

In clinical trials approximately 4% of patients treated with alendronate 10mg daily developed muscle, bone or joint pain compared with 2.5% of patients receiving placebo.  These reactions were rarely severe.  The time to onset varied from one day to several months after starting treatment.  Recovery was usual when alendronate was discontinued.  Recurrence in patients re-challenged with alendronate or another bisphosphonate has been reported.1  In some patients myalgia has occurred as part of an influenza-like syndrome that occurs in the early phase of treatment, and manifests as fever and malaise.1

CARM has received seven reports of patients experiencing synovitis while taking alendronate.  Three patients experienced recurrence on re-challenge.  In one, the synovitis was severe enough to cause carpal tunnel syndrome that required urgent decompression.4  There is one other report of severe myalgia and polyarthritis in the literature.5  If synovitis or polyarthritis occur, or there appears to be a flare of pre-existing arthritis, a trial withdrawal of alendronate is recommended.

Oesophagitis and oesophageal ulceration can also occur

Abdominal pain, nausea, vomiting, dyspepsia and diarrhoea have been frequently reported to CARM.  Oesophagitis, stomatitis and pharyngitis have also been reported.  More serious reports include oesophageal ulceration, oesophageal stricture, gastric ulceration and gastrointestinal haemorrhage.

Post-marketing studies have identified oesophageal disorders including oesophagitis, erosive oesophagitis and oesophageal ulceration as adverse reactions to alendronate.  Gastric ulcer, gastritis and gastroduodenitis have also been attributed to alendronate.6  Serious consequences of oesophageal ulceration attributed to alendronate have included stricture and perforation.1

Gastrointestinal adverse effects can be minimised

Patients should be advised to swallow alendronate tablets whole with a full glass (at least 200ml7) of plain water after rising for the day.  Food should not be eaten until 30 minutes after taking alendronate.  Patients should not lie down for at least 30 minutes and not until they have eaten their first food for the day.1  Following this advice will not prevent all alendronate-induced oesophageal events,6 therefore, patients should be instructed to seek medical attention if they have retrosternal pain, difficulty or pain when swallowing, or new onset or worsening dyspepsia.1  It is not clear if concomitant nonsteroidal anti-inflammatory (NSAID) use or previous upper gastrointestinal pathology increase the risk,6 but particular care should be taken with these patients.1

Allergy and rashes are also seen with alendronate

Urticaria, bronchospasm, angioedema and laryngeal oedema have all been reported to CARM.  A wide variety of skin exanthems have also been reported with no particular type predominating.  Post-marketing events reported include photosensitivity rashes, pruritis and, rarely, serious skin reactions including Stevens Johnson syndrome and toxic epidermal necrolysis.1

Inflammatory-type reactions may occur with other bisphosphonates

This article has focused on alendronate, which is an aminobisphosphonate.  The intravenous agents pamidronate and zoledronate belong to this same chemical class of bisphosphonates, and have also been causally associated with musculoskeletal pain, influenza-like disorders and ocular inflammation.8,9  The oral agent etidronate has a different chemical structure, lacking an amino group.10  Bisphosphonates lacking an amino group do not appear to cause oesophageal inflammation.  Conjunctivitis is the only ocular inflammation that has been reported with etidronate.2

Other adverse reactions to alendronate

In addition to inflammatory adverse reactions to alendronate, other reactions are described in the Fosamax® data sheet1 including the recently recognised one of osteonecrosis of the jaw (ONJ).  This problem is being observed in oncology patients, many of whom have been treated with high-dose monthly bisphosphonates such as pamidronate and zoledronate.  A small number of such cases have been reported worldwide in association with alendronate use11 – see boxed item below for more information about ONJ.

Competing interests (author): none declared.

References
  1. Merck Sharp & Dohme (New Zealand) Limited. Fosamax (alendronate) data sheet 17 October 2005. www.medsafe.govt.nz/profs/Datasheet/f/Fosamaxtab.pdf
  2. Fraunfelder FW, Fraunfelder FT. Bisphosphonates and ocular inflammation [Letter]. N Eng J Med 2003;348(12):1187-1188.
  3. ADRAC. Bisphosphonates and ocular inflammation. Aust Adv Drug Reactions Bull 2004;23(2). www.tga.gov.au/adr/aadrb/aadr0404.htm#3
  4. Jones DG, Savage R, Highton J. Synovitis induced by alendronic acid can present as acute carpal tunnel syndrome. BMJ 2005;330(7482):74.
  5. Gerster JC. Acute polyarthritis related to once-weekly alendronate in a woman with osteoporosis [Letter]. J Rheumatol 2004;31(4):829-830.
  6. Sharpe M, Noble S, Spencer CM. Alendronate: an update of its use in osteoporosis. Drugs 2001;61(7):999-1039.
  7. Medsafe Editorial Team. Alendronate and oesophageal ulceration. Prescriber Update 1998;No.16(Apr):32-33. www.medsafe.govt.nz/profs/PUarticles/7.htm
  8. Mayne Pharma Pty Ltd. Pamisol (pamidronate) data sheet. 7 December 2004. www.medsafe.govt.nz/profs/Datasheet/p/Pamisolinj.htm
  9. Novartis New Zealand Limited. Zometa (zoledronate) data sheet. 14 September 2005. www.medsafe.govt.nz/profs/Datasheet/z/Zometaconcinf.htm
  10. Bisphosphonates. In Sweetman SC (Ed) Martindale 34th Edn. 2005: Great Britain, p.766-768.
  11. Hay KD, Bishop PA. Association of osteonecrosis of the jaws and bisphosphonate pharmacotherapy: Dental implications. New Zealand Dental Journal 2006;102(1):4-9.

Bisphosphonates and osteonecrosis of the jaw


Information on this subject has been updated. Read the most recent information.

Prescriber Update 27(1): 6.
May 2006

Ian Reid, Professor of Medicine and Endocrinology, Faculty of Medical and Health Sciences, University of Auckland, Auckland

This is a new entity for most doctors. It refers to the development of areas of exposed, necrotic bone in either the mandible or maxilla, which persist for a number of months.  This problem is being recognised in oncology patients, many of whom have been treated with high-dose monthly bisphosphonates.  This is most commonly seen in those with metastatic breast cancer or with multiple myeloma.  The possible association with the use of bisphosphonates has raised the issue as to whether this is a problem in those who use bisphosphonates for benign indications, such as osteoporosis and Paget’s disease.  There have now been some case reports of this phenomenon, although they constitute less than five percent of the total number of cases recorded.  For instance, there have been about one hundred cases reported worldwide with alendronate in the context of twenty million patient-years of use of this medicine.  The lesions seem to develop following major dental procedures, such as extractions or dental implants, although they are sometimes associated with local trauma from dentures.  Some dentists are recommending such procedures are entirely avoided in those with a history of bisphosphonate use.  To many working in the field, this seems an over-reaction to what is, outside the context of oncological practice, a very rare event.  While the pathogenesis and aetiology of this condition are being further explored, it does seem cautious to carry out any planned major dental procedures before individuals start on bisphosphonates.  However, it must be borne in mind that substantial delays to the initiation of bisphosphonate therapy in those at a substantial risk of fracture will lead to the occurrence of preventable fractures.

 

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