What are the risks of ocular adverse effects with bisphosphonate treatment?
Prepared by UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals
Before using this Q&A, read the disclaimer at
Date prepared:6th June 2017
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].
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)[3].
Serious ocular adverse effects associated with bisphosphonate therapy appear to be rare and inflammatory in nature. Uveitis and scleritis are the most commonly reported2.
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[4]. 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[5].
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 sclera2,5,6.
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 2,[6].
It was initially thought that non-nitrogen containing bisphosphonates (such as clodronate) were not associated with ocular effects7, but reports have since emerged to suggest otherwise[7]. 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.2Parenteral exposure appears to lead to a more rapid onset than oral exposure[8].
Incidence
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 incidenceAlendronic acid (Fosamax)[9] / Uncommon / Uncommon
Pamidronate (Aredia)[10] / Uncommon / Very rare
Ibandronic acid (Bonviva)[11] / Rare / Rare
Risedronate (Actonel)[12] / Unknown / Not listed
Clodronate (Loron)[13] / Unknown - post marketing reports / Not listed
Zoledronic acid (Aclasta)[14]. / 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 2,13,14,16. Most of the published information consists 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, non- significant 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 physicians8.
No of cases of uveitis/scleritis per 10,000 prescriptionsBisphosphonates / 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 study8.
The study which prompted press attention in 2012 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 data2.
Incidence rate (per 10,000 person years)Condition / Bisphosphonate users / Non-users / Adjusted RR (95%CI)
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 study2.
Case Studies:
Uveitis
A retrospective case series identified 18 patients who had uveitis and who took bisphosphonates. Mean age of uveitis diagnosis was 64.9 years (38-82). A combination of pain and redness was the most common clinical presentation (56% of cases). In 61% of cases, the patients were being concurrently treated with alendronate, and risedronate was being taken in 39% of cases.[15]
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 days[16].
Two case reports describe patients developing uveitis following the administration of parenteral zoledronic acid infusion for postmenopausal osteoporosis. One case report described a 66 year old woman that developed bilateral uveitis and right macular oedema 24 hours afterdose administration. Another described a 63 year old woman who developed unilateral uveitis and vitreal haze 48 hours after doseadministration. Both cases were treated with steroids and subsequently resolved.[17],[18]
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 bisphosphonates7.
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 dechallenge6. 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 therapy[19].
Other Eye Disorders
Conjunctivitis and iritis have also been reported due to bisphosphonate therapy[20]. 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 usage19.
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 medication[21].
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.2 Prompt discontinuation of the bisphosphonate and symptomatic treatment should lead to symptom resolution. Other supportive and symptomatic measures, such as steroid therapy, should be used as required8,18.
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 Causality of an adverse effect does not need to have been established to report to the scheme[22].
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
Much of the available data is limited to case reports or case series.
Quality Assurance
Prepared byUmair Hamid (based on previous work by H.Johnson) Senior Pharmacist: Pharmacovigilance, Regional Drug and Therapeutics Centre, Newcastle Upon Tyne
Date Prepared
6th June 2017
Checked by
Maxine Goldsbrough, Senior Pharmacist: Medicines Information, Regional Drug and Therapeutics Centre, Newcastle Upon Tyne
Date of check
19th July 2017
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
*UVEITIS AND *ALENDRONATE OR *"RISEDRONATE SODIUM" OR *"CLODRONIC ACID" OR *"ETIDRONIC ACID" OR *DIPHOSPHONATES
eMC
MHRA
References
1
Available through Specialist Pharmacy Service at
[1] Clinical Knowledge Summaries (2013) Osteoporosis- Prevention of fragility fractures.Accessed via [March 2016] on 6th June 2017
[2] 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
[3] Daily Mail: Popular osteoporosis drug ‘raises risk of sight problems in elderly’. Published online 2nd April 2012. Accessed via on 6th June 2017
[4] Uveitis: Medline Plus Health Topic Page last updated on 20/08/2016. Accessed via on 6th June 2017
[5] Scleritis: Medline Plus Health Topic Page last updated on 20/08/2016. Accessed via on 6th June 2017
[6]Tabbara K. Nodular Scleritis following Alendronate Therapy. Ocular immunology and inflammation 2008; 16: 99-101
[7] Health Canada. Canadian Adverse Reaction Newsletter 2003; 13(4): 1-2
[8]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
[9]Summary of Product Characteristics – Fosamax (alendronate sodium). MSD Ltd. Accessed via on 06/06/17. Last updated on the eMC: 13/06/16
[10] Summary of Product Characteristics – Disodium Pamidronate. Wockhardt UK Ltd. Accessed via on 06/06/17. Last updated on the eMC: 20/12/16
[11]Summary of Product Characteristics – Bonviva (ibandronic sodium monohydrate). Roche Ltd. Accessed via on 06/06/17. Last updated on the eMC: 05/05/16.
[12] Summary of Product Characteristics – Actonel (risedronate sodium). Warner Chilcott UK Ltd. Accessed via on 06/06/17. Last updated on the eMC: 03/03/16
[13] Summary of Product Characteristics – Loron (diclodronate sodium). Intrapharm Laboratories Ltd. Accessed via on 06/06/17. Last updated on the eMC: 18/01/17
[14] Summary of Product Characteristics – Aclasta (zoledronic acid). Novartis Ltd. Accessed via on 06/06/17. Last updated on the eMC: 28/04/17
[15] Sifuentes Giraldo W, Macis Villa C, Bachiller Corral J et al. Uveit
s associated with bisphosphonate treatment: a case series of 18 patients (conference abstract). Annals of the Rheumatic Diseases 2013; 72: 0003-4967
[16] Richards J, Wiffen S. Corneal graft rejection precipitated by uveitis secondary to Alendronate sodium therapy. Cornea 2006; 25(9): 1100-1101
[17]Freitas-Neto CA, de Oliveira Fagundes WB, Ribeiro M Jr et al. Unilateral Uveitis with Vitreous Haze Following Zoledronic Acid Therapy for Osteoporosis. Seminars in Ophthalmology 2015; 30(3) 232-234
[18]Tian Y, Wang R, Liu L et al.Acute bilateral uveitis and right macular edema induced by a single infusion of zoledronic acid for the treatment of postmenopausal osteoporosis as a substitution for oral alendronate: a case report. BMC Musculoskeletal Disorders 2016; 17:72
[19] Leung S, Ashar B, and Miller R. Bisphosphonate-associated scleritis: a case report and review. Southern Medical Journal 2005; 98(7): 733-735
[20]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
[21] Patient Information Leaflet- Fosamax (alendronate sodium). MSD Ltd. Last updated on the eMC: 13/06/16. Accessed via on 06/06/17
[22] MHRA Yellow card scheme information. Accessed via 06/06/17