Medicines Q&As
Q&A 406.1
What are the risks of ocular adverse effects with bisphosphonate
treatment?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Date prepared: 8th May 2012
Background
Bisphosphonates are a group of drugs which are widely used for prevention and treatment of
osteoporosis. They inhibit bone resorption by changing the activation and function of osteoclasts 1.
The most common adverse effects are transient and gastro-intestinal in nature, but they are also
known to be associated with serious long-term adverse effects such as atypical fractures,
arrhythmias, and oesophageal and colon cancers 2,3.
In April 2012, some media coverage emerged regarding an increased risk of sight problems
associated with bisphosphonates. This story was based on a retrospective cohort study published in
the Canadian Medical Association Journal and appeared to suggest a 45% increased risk for both
uveitis and scleritis (see below for more details)4.
Serious ocular adverse effects associated with bisphosphonate therapy appear to be rare and
inflammatory in nature. Uveitis and scleritis are the most commonly reported3.
Answer
What are Uveitis and Scleritis?
Uveitis consists of swelling and irritation of the middle layer of the eye (uvea), leading to symptoms
such as pain and redness, light sensitivity, and dark floaters in the vision 5. Scleritis is an inflammation
of the white outer wall of the eye (sclera), causing symptoms such as blurred vision, light sensitivity,
watery eyes, pain and tenderness, and red patches on the white of the eye 6.
Rapid recognition and treatment of uveitis and scleritis is important, as if left untreated they can lead
to permanent visual damage by causing glaucoma, cataracts, macular oedema, or perforation of the
sclera3,5,6.
Mechanism
Bisphosphonates stimulate the release of inflammatory mediators, leading to inflammatory events
such as uveitis or scleritis. Nitrogen-based aminobisphosphonates (alendronate and risedronate),
which are more potent than other bisphosphonates, are also involved in release of tumour necrosis
factor, α-interleukin-6 and other cytokines and so could be expected to increase susceptibility to
development of inflammatory ocular diseases 3,7.
It was initially thought that non-nitrogen containing bisphosphonates (such as clodronate and
etidronate) were not associated with ocular effects7, but reports have since emerged to suggest
otherwise8. It is therefore probable that ocular adverse reactions are a class effect, but theoretically
may be less likely with non-amine bisphosphonates.
Timescales
In most cases of reported uveitis or scleritis associated with bisphosphonates, the condition has
developed rapidly following initiation of therapy and has resolved following discontinuation of therapy.
This is likely to be due to a “surge” in inflammatory mediators 3Error! Bookmark not defined..
Parenteral exposure appears to lead to a more rapid onset than oral exposure (from six hours postintravenous administration and within several days following oral use) 9.
Incidence
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Medicines Q&As
The incidence rates cited in manufacturer’s Summary of Product Characteristics vary for each of the
bisphosphonates. They are summarised in table 1.
Drug
Uveitis Incidence
Scleritis incidence
Alendronic acid (Fosamax) 10
Rare
Rare
Etidronate (Didronel)11
Not listed
Not listed
Pamidronate (Aredia) 12
Uncommon
Very rare
Ibandronic acid (Bonviva) 13
Rare
Rare
Risedronate (Actonel) 14
Unknown
Not listed
Clodronate (Loron) 15
Not Listed
Not listed
Zoledronic acide (Aclasta) 16.
Rare
Not known
Table 1: Manufacturer’s reported incidence rates of uveitis and scleritis.
Due to the rarity of this type of adverse reaction, incidence rates are difficult to estimate at this time.
Ocular adverse effects were not identified during controlled trials of bisphosphonates 3,13,14,16. Most of
the published information consist of case reports or case series and post-marketing surveillance.
Cohort studies
A post-marketing surveillance study based on a national American veteran cohort found a small, nonsignificant increase in relative risk of uveitis and scleritis. During the study period, 35,252 new
prescriptions for bisphosphonates were dispensed in the study population and there were 3,736 new
diagnoses of uveitis and scleritis. An overall relative risk of 1.23 (95% CI: 0.85-1.79) within six months
of starting treatment was found, with an absolute risk of 7.9 cases per 10,000 prescriptions
dispensed. The results from this study are summarised in table 2. This study is limited by its design as
causality could not be established for each case and no dechallenge or rechallenge data was
available to the authors. The conclusion was that serious ocular effects associated with
bisphosphonates were uncommon, but warranted awareness by physicians9.
No of cases of uveitis/scleritis per 10,000 prescriptions
Bisphosphonates
Control
30 days
2.6 (95% CI: 1.2-4.5)
180 days
7.9 (95% CI: 5.2-11)
6.45 (95% CI: 66.25-6.66)
Table 2: Summarised results of French et al’s post-marketing surveillance study9.
The study which prompted recent press attention comprised of 934,147 people in British Columbia.
Only first time users of oral bisphosphonates were included in the study. Results were adjusted to
take into account factors such as age, sex, other inflammatory diseases, sulpha-containing
medicines, and non-steroidal anti-inflammatory use. The results of this study are summarised in table
3. The authors concluded that, although the absolute risk was low, numbers of patients affected could
be significant due to the widespread prescribing of this group of drugs. This study was limited by the
lack of ability to verify diagnoses, and that actual drug intake could not be ascertained from
dispensing data3.
Incidence rate (per 10,000 person years)
Bisphosphonate
Non-users
Adjusted RR (95%CI)
users
Uveitis
29
20
1.45 (1.25-1.68)
Scleritis
63
36
1.51 (1.34-1.68)
Table 3: Summarised results from Etminan et al’s retrospective cohort study3.
Condition
Case Studies:
Uveitis
One case report describes a 77 year old woman who suffered from severe uveitis leading to rejection
of a corneal graft. The patient was found to be negative for herpes or bacterial infections. Following
withdrawal of Alendronate, her symptoms improved within 10 days17.
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
Scleritis
Scleritis appears to be most commonly related to the use of pamidronate, but cases do appear in the
literature describing the condition following use of other nitrogen containing bisphosphonates 7.
A 54 year old man suffered pain and redness of the eye which started eight weeks following
commencement of Alendronate 70mg weekly. He was found to have right eye nodular scleritis which
completely resolved two weeks following discontinuation of the alendronate. After a three month
period, symptoms returned following rechallenge, and disappeared on dechallenge7. Another case
report also describes a similar positive dechallenge and rechallenge scenario in an 86 year old female
who developed scleritis six weeks after starting alendronate therapy18.
Other Eye Disorders
Conjunctivitis and iritis have also been reported due to bisphosphonate therapy19. Mild conjunctivitis
only often does not require treatment and is usually transient without requiring bisphosphonate
discontinuation. Patients may present with more than one ocular effect at the same time8. Reports of
optic neuropathy, peripapillary atrophy, cataracts, and corneal opacities have been linked to
pamidronate usage18.
Management
The possibility of inflammatory eye disorders is not highlighted in all patient information leaflets (PILs)
for bisphosphonates. The PIL for Fosamax simply lists “blurred vision; pain or redness in the eye” as
uncommon side effects of the medication20.
As uveitis and scleritis require prompt treatment by an ophthalmologist, it would be prudent to ensure
that patients are carefully counselled on initiation of therapy with bisphosphonate therapy. Patients
should be advised of the signs and symptoms of ocular inflammatory diseases and that they should
seek medical attention immediately should symptoms occur 3. Prompt discontinuation of the
bisphosphonate and symptomatic treatment should lead to symptoms resolving. Other supportive and
symptomatic measures, such as steroid therapy, should be used as required8,17.
There is no clear guidance for whether switching to a different bisphosphonate will be possible once
the inflammatory disease has subsided.
Yellow Card Reporting
Any cases of serious eye disorders which may be related to use of bisphosphonates should be
reported to the MHRA via their Yellow Card Scheme. More information on the scheme can be found
at www.yellowcard.mhra.gov.uk . Causality of an adverse effect does not need to have been
established to report to the scheme21.
Summary
There appears to be a link between bisphosphonate use and an increased risk of serious
inflammatory ocular disorder such as uveitis and scleritis. The absolute risk of such events remains
low, but there is currently little data on which to estimate incidence rates.
Non-nitrogen containing bisphosphonates may theoretically be less likely to cause ocular effects than
those which contain nitrogen groups.
Patients who develop eye pain or vision disturbances should receive prompt treatment.
Discontinuation of the bisphosphonate is likely to be required. .
Limitations
Is there anything about your answer that makes it not generally applicable? Is there anything about
what you have written that makes you concerned about it being read by anyone on the Internet?
Disclaimer
 Medicines Q&As are intended for healthcare professionals and reflect UK practice.
 Each Q&A relates only to the clinical scenario described.
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Medicines Q&As
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Quality Assurance
Prepared by
Hayley Johnson, Regional Drug and Therapeutics Centre, Newcastle upon Tyne
Date Prepared
8th May 2012
Checked by
Sarah Smith, Regional Drug and Therapeutics Centre, Newcastle upon Tyne
Date of check
31/08/2012
Search strategy
Embase
*BISPHOSPHONIC ACID DERIVATIVE AND *uveitis
*ALENDRONIC ACID/ OR *ETIDRONIC ACID/ OR *PAMIDRONIC ACID/ Or *IBANDRONIC
ACID/ Or *RISEDRONIC ACID Or *CLODRONIC ACID/ OR *ZOLEDRONIC ACID/ AND
*uveitis
Medline
*diphosphonates AND *uveitis
*ALENDRONATE/ OR *ETIDRONIC ACID/ OR pamidronate.af OR (ibandronic AND acid).af
OR risedronate.af OR *CLODRONIC ACID OR (zoledronic AND acid).af AND *UVEITIS/
*diphosphonates AND *scleritis
*ALENDRONATE/ OR *ETIDRONIC ACID/ OR pamidronate.af OR (ibandronic AND acid).af
OR risedronate.af OR *CLODRONIC ACID OR (zoledronic AND acid).af AND *scleritis
eMC
MHRA
References
1
PRODIGY (2012) Osteoporosis- primary and secondary prevention of fragility fractures. PRODIGY.
http://prodigy.clarity.co.uk/osteoporosis_prevention_of_fragility_fractures/prescribing_information/pres
cribing_information/bisphosphonates#-485542 [23rd July 2012]
2 Whitehall J. Bisphosphonates Patient.co.uk information leaflet (2011). Accessed via
http://www.patient.co.uk/printer.asp?doc=27001950 on 24th July 2012
3 Etminan M, Forooghian F, and Maberley D. Inflammatory ocular adverse events with the use of oral
bisphosphonates: a retrospective cohort study. CMAJ 2012; DOI: 10.1503/cmaj.111752
4 Daily Mail: Popular osteoporosis drug ‘raises risk of sight problems in elderly’. Published online 2nd
April 2012. Accessed via http://www.dailymail.co.uk/health/article-2124073/Popular-osteoporosisdrug-raises-risk-sight-problems-elderly.html on 9th May 2012
5 Uveitis: Medline Plus Health Topic Page accessed via
http://www.nlm.nih.gov/medlineplus/ency/article/001005.htm on 9th May 2012
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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Medicines Q&As
6
Scleritis: Medline Plus Health Topic Page accessed via
http://www.nlm.nih.gov/medlineplus/ency/article/001003.htm on 09/05/2012
7 Tabbara K. Nodular Scleritis following Alendronate Therapy. Ocular immunology and inflammation
2008; 16: 99-101
8 Health Canada. Canadian Adverse Reaction Newsletter 2003; 13(4): 1-2
9 French D and Margo C. Postmarketing Surveillance rates of uveitis and scleritis with
bisphosphonates among a national veteran cohort. Retina, The Journal of Retinal and Vitreous
Diseases. 2008; 28(6): 889-893
10 Summary of Product Characteristics – Fosamax (alendronate sodium). MSD Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC: 26/12/2011
11 Summary of Product Characteristics – Didronel (etidronate). Warner Chilcott UK Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC: 07/06/2011
12 Summary of Product Characteristics – Aredia (pamidronate disodium). Novartis Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC: 18/06/2012
13 Summary of Product Characteristics – Bonviva (ibandronic acid). Roche Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC: 24/08/2011
14 Summary of Product Characteristics – Actonel Once a Week (risedronate sodium). Warner Chilcott
UK Ltd. Accessed via http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC:
15/11//2011
15 Summary of Product Characteristics – Loron (diclodronate sodium). Roche Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC: 18/01/2012
Summary of Product Characteristics last updated on the eMC: 18/01/2012
16 Summary of Product Characteristics – Aclasta (zoledronic acid). Novartis Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/12. Last updated on the eMC: 04/05/2012
17 Richards J, Wiffen S. Corneal graft rejection precipitated by uveitis secondary to Alendronate
sodium therapy. Cornea 2006; 25(9): 1100-1101
18 Leung S, Ashar B, and Miller R. Bisphosphonate-associated scleritis: a case report and review.
Souther Medical Journal 2005; 98(7): 733-735
19 Moore M and Beith J. Acute unilateral anterior uveitis and scleritis following a single infusion of
zoledronate for metastatic breast cancer. The Medical Journal of Australia 2008: 188(6); 370-371
20 Patient Information Leaflet- Fosamax (alendronate sodium). MSD Ltd. Accessed via
http://emc.medicines.org.uk on 23/07/2012
21 MHRA Yellow card scheme information. Accessed via http://yellowcard.mhra.gov.uk/the-yellowcard-scheme/ on 23/07/2012
From the National Electronic Library for Medicines. www.nelm.nhs.uk
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