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Keywords:

  • BISPHOSPHONATES;
  • OSTEOPOROSIS TREATMENT;
  • OCULAR INFLAMMATION;
  • ADVERSE REACTIONS

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Ocular inflammatory reactions have been described in patients on bisphosphonate treatment. We estimated the incidence rate of ocular inflammation at 3 and 12 months in patients treated for osteoporosis using a register-based cohort linked to prescription data (hospitals and private practice) and hospital data. From January 1, 1997 to December 31, 2007, a total of 88,202 patients beginning osteoporosis therapy were identified. Of those patients, 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates. Within the first year of treatment, 4769 (5.4%) of patients on osteoporosis therapy filled one or more prescriptions for topical eye steroids (TES). TES treatment rates (per 1000 patient-years) in the first year of osteoporosis treatment were 44 (95% confidence interval [CI] 42 to 46) for alendronate, 40 (95% CI 38 to 43) for etidronate, 45 (95% CI 35 to 57) for risedronate, 32 (95% CI 27 to 37) for raloxifene, and 64 (95% CI 49 to 83) for strontium ranelate. After adjustment for age, Charlson index, and the number of comedications, pulmonary disease in men was associated with an increased use of TES (odds ratio [OR] = 1.48; 95% CI 1.17 to 1.86; p = 0.001). In women, malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04) and pulmonary disease (OR = 1.32; 95% CI 1.07 to 1.62; p = 0.01) were significant predictors at 3 months and rheumatic diseases at 12 months (OR = 1.20; 95% CI 1.10 to 1.31; p < 0.001). There was no significant difference between the different drug classes (bisphosphonates versus nonbisphosphonates, alendronate versus nonalendronate-bisphosphonates) for risk of ocular inflammation, with age and the number of comedications being the only significant predictors. Hospital-treated uveitis (48 patients, or 0.05%) showed a similar trend. In conclusion, after initiation of treatment for osteoporosis, the risk of inflammatory eye reactions requiring TES is relatively low and not significantly different between bisphosphonate and nonbisphosphonate users. Patients with a rheumatic or pulmonary disease are at increased risk. © 2013 American Society for Bone and Mineral Research.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Conjunctivitis after administration of etidronate was first recorded in spontaneous case reports. Since then, case (Table 1)1–28 and clinical studies, including most of the major randomized placebo-controlled trials,29–33 have reported inflammatory eye reactions (IERs) that include conjunctivitis, uveitis, scleritis, episcleritis, and keratitis in patients treated with nitrogen-containing bisphosphonates (including alendronate, ibandronate, and risedronate) and non-nitrogen-containing bisphosphonates (including clodronate and etidronate). However, there was a question as to whether the IERs were the result of a direct effect of bisphosphonates or of the patient's underlying disease. For example, inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, or sarcoidosis may have IERs as part of their clinical phenotype.

Table 1. Summary of Findings on Eye Inflammatory Reactions in Patients Treated With Bisphosphonates Reported in Case Studies
AuthorsNo. of casesPrimary diagnosisBP usedOnset and response to treatment
  1. ALN = alendronate; RIS = risedronate; ZOL = zolendronate; PAM = pamidronate; CLO = clodronate; D/C = discontinued; URTI = upper respiratory tract infection; h/o = history of; ADRAC = Adverse Drug Reactions Advisory Committee.

Siris11 FPaget's disease (pelvis and sacrum)Started on etidronate 400 mg/d x 6 months (no reaction)• 3 days after starting RIS responded to steroid eye drops
   RIS 30 mg/d x 84 days PAM 60 mg• <24 hours after PAM infusion responded to steroid eye drops
Ghose et al.21 MPaget's disease(pelvis)Etidronate in the pastNo reaction
Both patients: h/o eye problemsPaget's diseasePAM 65 mg in three divided infusions on alternate days• Next day after first infusion Worsened after third infusion Improved on oral steroids
1 M PAM infusion• <24 hours after PAM infusion Treated with local steroid injections
Macarol and Fraunfelder323Paget's disease and tumor–induced hypercalcemiaPAM 30–120 mg6–48 hours Recovery varied from spontaneous to requiring topical systemic steroids
 RechallengePositive in 6 (of 8) cases
Mbekeani et al.41 FOsteoporosis (?) Anti–nuclear Ab + ALN• 10 days D/C ALN + oral and topical steroids
1FOsteoporosis (?)ALN• Shortly after starting ALN D/C ALN + topical diclofenac
1FOsteoporosis (?)ALN• 3 weeks D/C ALN only
Ryan and Sampath51 MPaget's diseasePAM 90 mg ivNext day “flu like symptoms”
  Fifth day: orbital inflammation
  Improved with systemic steroids
Malik et al.61 FOsteoporosis (?)ALN 10 mg/d for a year:No reaction
   Switched to ALN 70 mg weekly2 days on ALN 70 mg/week
    ALN D/C + local steroids
Fraunfelder et al.718?PAM 30–90 mg iv6 hours to 2 days
   Rechallenge in 6 casesRelapse
Fietta et al.81 FOsteoporosisCLO 100 mg/week im5 months Recover on topical steroids
 CLO continued for a monthRelapses 24–72 hours after im weekly administrations
 Rechallenge 5 months laterRelapse
Subramanian et al.91 MMetastatic prostate cancerPAM iv• 6 days after infusion Improved on oral steroids (no more PAM infusions)
 1 MOsteopenia h/o prostate cancerPAM iv• Within 24 hours after infusion Improved on oral steroids (no more PAM infusions)
Australian ADRAC1028?BPs2 days to more than 3 years
Asensio Sanchez et al.111 FOsteoporosis (?)ALN 70 mg Rechallenge (3 weeks):Uveitis Relapse
Meaney et al.121 MMultiple myelomaPAM iv2 days after infusion
   Rechallenge (4 months)2 days after infusion
Durnian et al.131 FMGUS on HD back and leg painZol 4 mg iv48 hours Improved on oral steroids
El Saghir et al.141 FBreast cancer–R eye intraocular lens OsteoporosisZol iv24 hours–R eye Recovered on topical steroids (no more Zol infusions)
Leung et al.151 FOsteoporosisALN 70 mg/week6 weeks
 Rechallenge 6 months laterRecovery: ALN D/C + systemic steroids 4 weeks
 Recovery: ALN discontinuation only
Benderson et al.161 MMultiple myelomaZol 4 mg iv< 24 hours Recovery: systemic and topical steroids
 One month later: PAM iv ( + methylprednisolone 100 mg iv) and then monthly PAM + steroids3 days: mild conjunctivitis
 No relapse (immunological tolerance?)
Richards and Wiffen171 FOsteoporosisALNUveitis [RIGHTWARDS ARROW] corneal graft rejection
Stack and Tarr181 FOsteoporosisALN• ? Recovery: D/C ALN + oral steroids
 1 FReflex sympathetic dystrophy–leg painPAM Rechallenge 3 months later• ? Topical steroids Recovery: oral steroids
 1 MPaget'sPAM• 1 week topical steroids
Banal et al.191 MProstate cancer with bone metastasesZol 4 mg iv [RIGHTWARDS ARROW] PAM48 hours Topical steroids No relapse
Kilickap et al.201 FBreast cancer with bone metastasesZol 4 mg iv24 hours Recovery: topical steroids
Moore and Beith211 FBreast cancer and suspicion of bone metastasesZol iv3 days (already on oral steroids) Zol D/C–recovered on steroids
Phillips and Newman221 MMetastatic renal cell cancerZol 4 mg iv Monthly Zol continuedOne day 60 mg prednisone, tapered during 10 weeks of treatment No relapse (on steroids)
Sharma et al.231 MSpontaneous knee osteonecrosisZol iv3 days Improved on oral steroids
Colucci et al.241 FFrontal hyperostosis to breast cancerZol24 hours Complete recovery: Topical steroids
Tan et al.251 FOsteoporosisALN• 4 days Recovery: D/C ALN + topical steroids
 1 FOsteoporosis (?)ALN (6 months) [RIGHTWARDS ARROW] RIS (2 months)• 8 months Recovery: D/C RIS + topical steroids
McKague et al.261 FOsteoporosisALN Rechallenge with: ALN–RIS–etidronate5 months, after URTI Similar symptomatology
Procianoy and Procianoy271 FOsteoporosis h/o an episode of autoimmune thyroiditisZol (a single 5 mg iv)• Next day Symptoms resolved only after ALN D/C
Yang et al.281 F Zol 4 mg iv3 days Recovery: D/C Zol + systemic steroids

Two large cohort studies investigated the potential association between bisphosphonates and IERs with contradictory results. The first is a large US veteran cohort covering 5.7 million persons including 35,252 new bisphosphonate users (85% alendronate) and 3736 new cases of uveitis or scleritis. Overall, the prevalence of IERs was low, and similar rates of uveitis/scleritis were seen in users and nonusers of bisphosphonates.34 The 6-month rate of IERs after exposure to bisphosphonates was 7.9 new cases per 10,000 individuals, with a relative risk (RR) of 1.23 (95% confidence interval [CI] 0.85 to 1.79) compared with veterans not exposed to bisphosphonates. Nearly half of the veterans who developed IERs after treatment with bisphosphonates had a systemic diagnosis commonly associated with inflammation of the uveal tract or sclera. Conversely, the pharmaco-epidemiological cohort study from Canada comprising 934,147 individuals, including 10,827 first-time users of bisphosphonates, investigated uveitis and scleritis separately.35 First-time users of bisphosphonates had an elevated risk of both uveitis (adjusted RR of 1.45, 95% CI 1.25 to 1.68) and scleritis (adjusted RR 1.51, 95% CI 1.34 to 1.68). Adjustment for variables including age, sex, and medical conditions such as connective tissue disease, sarcoidosis, and diabetes did not change the association found. In this Canadian study, it was estimated that the number needed to harm with uveitis was 1100 and for scleritis was 370.

Despite the lack of clear epidemiological evidence for an association between bisphosphonates and IERs, a causative link between bisphosphonates and inflammatory ocular events is strengthened by the reporting of IER relapses after affected patients were rechallenged with the same or another bisphosphonate.1, 3, 7, 8, 11, 12, 15, 18, 26 In addition, no cases have been resolved without discontinuation of the bisphosphonates. The similar symptoms and clinical findings reported by all patients taking bisphosphonates, regardless of specific formulation (nitrogen or non-nitrogen-containing compounds) or route of administration, suggest that the class of drug may be the common causative agent in these events of ocular inflammation.

Overall, the incidence of IERs after bisphosphonate exposure ranges from 0.046% to 1%,3, 34 with onset occurring from a few hours after exposure up to more than 3 years, with an estimated median of 3 weeks.10

Given the widespread use of bisphosphonates, detailed knowledge on occurrence of even rare side effects is important. Moreover, drugs are, of course, often used on wider indications during clinical use than in the registration trials. Therefore, age, sex, comedication, and pattern of comorbidity and thus the risk of side effects may differ between populations in the trials and in routine use.

In view of exploring further the contradictory evidence for an association between bisphosphonates and IERs, we utilized a national prescription register to undertake a cohort study to examine the incidence of eye inflammation in the first year after initiation of treatment with bisphosphonates compared with other nonbisphosphonate treatments for osteoporosis.

Materials and Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

This register study (part of project 702538, Statistics Denmark) included all patients who began treatment with an oral bisphosphonate between January 1, 1997 and December 31, 2007, after a run-in period from January 1, 1995 (when the Danish National Prescription Database was established) to December 31, 1996 with no use of osteoporosis drugs except hormone replacement therapy (HRT). For simplicity of presentation and interpretation, we excluded patients who died within a year of beginning treatment, ensuring that the rate of first treatment year events of inflammatory eye reactions could be assessed in all subjects. We prespecified the following outcomes: filling a prescription for a topical eye steroid or a new diagnosis of conjunctivitis (ICD-10 code H10), scleritis or episcleritis (H15), keratitis (H16), and iridocyclitis (H20, H22) made at a hospital (outpatient or inpatient setting). We defined incident use of topical eye steroids as the primary outcome and hospital diagnoses as the secondary endpoint, considering that the former would have almost complete sensitivity but not perfect specificity, whereas the latter would have excellent specificity but low sensitivity, given the likelihood that patients would be treated outside the hospital system for such events. The indication for eye steroids is not coded in the prescription database. The primary analysis was that of Intention to Treat, where the first prescribed osteoporosis drug was considered the exposure of interest in patients who were exposed to more than one osteoporosis drug. Although this may perhaps seem counterintuitive, focusing instead on the most recently used osteoporosis drug may create bias in the form of reverse causality because the drug change itself may have been prompted by the onset of eye inflammation, with eye steroids only introduced when the reaction failed to resolve. As detailed below, the number of patients who changed osteoporosis drugs was small and overall conclusions were not affected by using the last prescribed drug rather than the first prescribed drug in the analysis. The National Hospital Discharge Register covers all outpatient and inpatient diagnoses in the National Health Service, whereas the National Prescription Database registers all prescriptions filled in Denmark, whether issued by a hospital, general practitioner, or private specialist. The registers do not depend on employment or insurance status, and follow-up ends only at death or emigration to outside Denmark. Zoledronate, which was only introduced for the treatment of osteoporosis in 2007, ie, at the end of the study period, is generally not captured in the prescription register because infusions are often given in the hospital setting. We used conventional descriptive statistics and multivariate logistic regression analysis. One dummy variable was introduced to capture any difference in risk between bisphosphonates and nonbisphosphonates, the latter being the reference, and an additional dummy variable was used to capture differences between alendronate, the current first-line antiresorptive agent in the country, and the other bisphosphonates. A critical p value of 0.05 was employed throughout.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Demographics of patients beginning osteoporosis treatment

We identified 88,202 new users of specific osteoporosis therapies, of which 82,404 (93%) began oral bisphosphonates and 5798 (7%) nonbisphosphonates (Table 2). The most commonly used therapies were alendronate, etidronate, and raloxifene. In general, raloxifene users were younger and healthier than the patients who began bisphosphonates. A Charlson comorbidity index of zero was seen in the majority (68.9%) of raloxifene users but only 52.3% of alendronate users, 55.7% of etidronate users, and 49.3% of patients receiving PTH analogs. Pulmonary and rheumatic diseases were particularly prevalent in bisphosphonate users. Clodronate use was extremely limited, and the majority of clodronate users had a history of malignant disease. There was no difference in the prevalence of baseline (last 12 months) use of topical eye steroids.

Table 2. Baseline Demographics of the Study Population
Drug classOral bisphosphonatesNonbisphosphonates
ATC codesM05BA04M05BA02M05BA01M05BA06M05BA07G03XC01M05BX03H05AA
DrugsAlendronateClodronateEtidronateIbandronateRisedronateRaloxifeneStrontium ranelatePTH analogs
N49,677 83 30,701 558 1385 4665 843 290 
Mean age (years)70.6 66.1 70.9 69.1 68.7 63.8 73.1 68.3 
Men, n (%)8001(16.1)19(22.9)4124(13.4)58(10.4)262(18.9)18(0.4)114(13.5)78(26.9)
Pulmonary diseases, n (%)8801(17.7)9(10.8)5072(16.5)103(18.5)241(17.4)475(10.2)136(16.1)51(17.6)
Rheumatic diseases, n (%)9763(19.7)15(18.1)6654(21.7)79(14.2)290(20.9)641(13.7)114(13.5)53(18.3)
IBD, n (%)770(1.6)3(3.6)365(1.2)8(1.4)19(1.4)46(1.0)10(1.2)10(3.4)
Diabetes, n (%)2181(4.4)5(6.0)1040(3.4)19(3.4)81(5.8)111(2.4)33(3.9)13(4.5)
Malignancy, n (%)5678(11.4)51(61.4)3365(11.0)68(12.2)162(11.7)446(9.6)97(11.5)29(10.0)
Charlson index: 0, n (%)25957(52.3)13(15.7)17090(55.7)289(51.8)694(50.1)3214(68.9)431(51.1)143(49.3)
Charlson index: 1–3, n (%)17473(35.2)47(56.6)10559(34.4)188(33.7)511(36.9)1179(25.3)302(35.8)113(39.0)
Charlson index: >3, n (%)6247(12.6)23(27.7)3052(9.9)81(14.5)180(13.0)272(5.8)110(13.0)34(11.7)
Eye steroid prescriptions
Any in last year, n (%)2543(5.1)4(4.8)1456(4.7)21(3.8)69(5.0)182(3.9)43(5.1)13(4.5)

Incidence of inflammatory eye disease treatment or diagnosis

Only for alendronate (5.9% versus 5.1%, p < 0.05) and etidronate (5.5% versus 4.7%, p < 0.05), we observed a higher number of subjects using topical eye steroids in the first year of treatment, compared with the extent of use in the year before beginning treatment (Table 3). For ibandronate, this was short of statistical significance (6.3% versus 3.8%, p = 0.07). New treatment prescriptions of topical steroids occurring in the first 3 months after the start of osteoporosis drugs in prior eye steroid nonusers were filled by 3% of bisphosphonate users, 2% of raloxifene users, and 4% of strontium ranelate users. The eye steroid treatment rates in the first year of osteoporosis treatment were 44 (95% CI 42 to 46) per 1000 patient-years for alendronate, 40 (95% CI 38 to 43) per 1000 for etidronate, 45 (95% CI 35 to 57) per 1000 for risedronate, 32 (95% CI 27 to 37) per 1000 for raloxifene, and 64 (95% CI 49 to 83) per 1000 for strontium ranelate.

Table 3. Use of Steroid–Containing Eye Medications and Hospital–Treated Inflammatory Conditions of the Eyes in the First 12 Months of Beginning Osteoporosis Treatment. Hospital Treatment Was Only Counted for Subjects Who had Not Consulted for Eye Disease in the Year Preceding the First Prescription
 Oral bisphosphonatesNonbisphosphonates
M05BA04M05BA02M05BA01M05BA06M05BA07G03XC01M05BX03H05AA
AlendronateClodronateEtidronateIbandronateRisedronateRaloxifeneStrontiumPTH analogs
  • a

    Subanalysis including only patients who had not used topical eye steroids in the last year before beginning osteoporosis treatment.

  • b

    p < 0.001.

  • c

    p < 0.01.

    An alternative approach to that used in Table 3 is to categorize patients by their last rather than first osteoporosis drug used in the exposure window. Done in this way, new prescriptions of eye steroids were filled by 4.3% of alendronate users, 1.3% of clodronate users, 4.0% of etidronate users, 6.7% of ibandronate users, 4.4% of risedronate users, 3.2% of raloxifene users, 5.5% of strontium users, and 3.9% of PTH analog users. The prespecified analysis is that shown in the tables; refer to Materials and Methods for the rationale.

 n%n%n%n%n%n%n%n%
Eye steroid prescriptions
 First 3 months
  All patients9161.811.25191.7112.0322.3511.1151.851.7
  Baseline nonusersa only6261.311.33641.271.3221.7370.8121.541.4
 First 12 months
  All patients28025.9b33.816055.5c346.3796.01874.2516.482.9
  Baseline nonusersa only20574.411.311824.0264.8594.51423.2435.462.2
 All patients (3–12 months)18863.822.410863.5234.1473.41362.9364.331.0
 Baseline nonusersa only (3–12 months)14313.000.08182.8193.5372.81052.3313.920.7
Hospital treatment for inflammatory diseases of eyes
 First 3 months
  H10 conjunctivitis150.000.060.000.000.030.100.000.0
  H15 scleritis or episcleritis00.000.010.000.000.000.000.000.0
  H16 keratitis50.000.070.000.000.000.000.000.0
  H20, H22 iridocyclitis (uveitis)80.000.030.000.000.000.000.000.0
 First 12 months
  H10 conjunctivitis490.111.3330.100.010.180.210.100.0
  H15 scleritis or episcleritis10.000.050.000.000.000.000.000.0
  H16 keratitis210.000.0230.100.010.110.000.000.0
  H20, H22 iridocyclitis (uveitis)340.100.0120.000.010.110.000.000.0

Few patients had been exposed to more than one osteoporosis drug. Thus, for the 2057 alendronate users without baseline use of steroids who went on to use eye steroids in the first year, 58 (2.8%) had also used another osteoporosis drug. Refer to the footnote in Table 3 for additional information. Evaluating the most recent rather than the originally prescribed drug (the prespecified analysis) did not alter the conclusions.

The incidence of hospital-treated uveitis (iridocyclitis, Table 3) was low, occurring in 0.07% of users of alendronate or risedronate and in 0.04% of etidronate users, ie, 0.7 (0.5 to 1.0) and 0.4 (0.2 to 0.7) cases per 1000 patient-years, respectively. There were no registered uveitis events in users of other osteoporosis drugs.

Relationship to treatment and to comorbid conditions

Patients who developed uveitis were more likely to suffer from inflammatory bowel disease (IBD), rheumatic disorders (in particular, seronegative rheumatoid arthritis), or sarcoidosis (Table 4). Hospital-treated uveitis developed in 0.11% of alendronate users with rheumatic disorders, 0.09% of alendronate users with pulmonary disease,and 0.06% of alendronate users without these conditions.

Table 4. Prevalence of Predisposing Conditions in Users of Osteoporosis Drugs Who Did or Did Not Have Eye Outcomes
 Eye steroid treatment prescribed (baseline nonusers)Hospital treatment for uveitis (iridocyclitis) (patients with no hospital contacts for eye disease in year before baseline)
 No n = 80,355Yes n = 3516No n = 85,393Yes n = 48
  • IBD = inflammatory bowel disease (Crohn's disease and ulcerative colitis).

  • a

    p < 0.01.

  • b

    p < 0.05.

(M05) Seropositive rheumatoid arthritis3.2%3.7%3.2%4.2%
(M06) Other rheumatoid arthritis3.4%4.3%a3.5%10.4%b
(M30) Polyarteritis nodosa and related conditions0.2%0.3%b0.2%2.1%
(M31) Other necrotizing vasculopathies1.9%3.8%a2.0%2.1%
(M32) Systemic lupus erythematosus0.4%0.3%0.4%2.1%
(M34) Systemic sclerosis0.2%0.3%0.2%0.0%
(M35.0) Sjögren's syndrome (Sicca syndrome)0.4%0.6%b0.4%0.0%
(D86) Sarcoidosis0.4%0.5%0.4%4.2%b
(K50, K51) IBD1.4%1.6%1.4%6.3%b

In both men and women, there was no influence of the type of osteoporosis treatment on the probability of filling prescriptions for eye steroids, neither in the first year nor the first 3 months after initiation of treatment (Table 5). After adjustment for age, Charlson index, and the number of comedications, the predictors at 3 months in women were malignant disease (OR = 1.27; 95% CI 1.02 to 1.60; p = 0.04), and pulmonary disease (OR = 1.27; 95% CI 1.03 to 1.57; p = 0.03), with baseline use of prednisolone marking an increased 12-month risk (OR = 1.46; 95% CI 1.34 to 1.60; p < 0.001). In men, where patient numbers were much lower, only baseline use of prednisolone was associated with an increased risk. This was the case both at 3 months (OR = 1.73; 95% CI 1.21 to 2.48, p < 0.01) and 12 months (OR = 1.71; 95% CI 1.40 to 2.09; p < 0.001). Diabetes was not a significant risk factor for ocular inflammation in this study population after adjustment for comorbid conditions and the number of comedications; the number of patients with diabetes in the cohort was fairly small, however. Because of the possibility that the relatively high incidence of new eye steroid use among strontium ranelate users could have masked a risk increase with bisphosphonates over nonbisphosphonates, we also conducted a non-prespecified sensitivity analysis in which we compared the most commonly used nonbisphosphonate raloxifene (low incidence of eye steroid prescriptions) with the most commonly used bisphosphonate, alendronate. This additional logistic regression analysis comprised 4466 women on raloxifene and 39,516 women on alendronate and confirmed that there was no difference in risk (3 months, adjusted OR = 1.10; 95% CI 0.76 to 1.62; p = 0.59, and 12 months OR = 0.97; 95% CI 0.81 to 1.16; p = 0.71). We have also explored to which extent patients on frequent bisphosphonate treatment for bone metastases could have affected our findings. Removal of patients with history of malignant disease from the analysis, however, did not alter the conclusions (data not shown).

Table 5. Multiple Logistic Regression Analysis With Incident Use of Steroid–Containing Eye Medications as the Dependent Variable
 At 3 months At 12 months 
WomenOdds ratiopOdds ratiop
  1. IBD = inflammatory bowel disease (Crohn's disease and ulcerative colitis).

  2. Results were mutually adjusted for the covariates shown and for age, Charlson index, number of comedications, and index year.

  3. The comparator group was users of nonbisphosphonate osteoporosis drugs (raloxifene, strontium ranelate, or PTH analogs).

Non-BP (reference)1 1 
Alendronate1.081 (0.807–1.449)0.6020.929 (0.794–1.088)0.362
Other BP1.068 (0.789–1.445)0.6710.96 (0.816–1.131)0.626
Diabetes1.159 (0.832–1.614)0.3831.153 (0.955–1.393)0.139
Malignancy1.271 (1.014–1.593)0.0371.229 (1.082–1.397)0.002
Pulmonary disease1.267 (1.025–1.566)0.0291.199 (1.064–1.352)0.003
Rheumatic disease1.089 (0.926–1.281)0.3031.096 (1.000–1.201)0.05
IBD0.809 (0.431–1.518)0.5091.117 (0.821–1.520)0.482
Prednisolone1.165 (0.989–1.372)0.0671.461 (1.336–1.599)0.001
Men    
Non-BP (reference)1 1 
Alendronate1.427 (0.347–5.877)0.6221.421 (0.621–3.251)0.405
Other BP1.741 (0.406–7.467)0.4551.569 (0.671–3.671)0.299
Diabetes1.005 (0.538–1.877)0.9881.386 (0.982–1.955)0.063
Malignancy0.775 (0.435–1.380)0.3860.793 (0.569–1.105)0.171
Pulmonary disease0.661 (0.427–1.023)0.0631.216 (0.955–1.550)0.113
Rheumatic disease0.911 (0.622–1.335)0.6330.842 (0.676–1.048)0.123
IBD0.516 (0.126–2.105)0.3561.285 (0.738–2.239)0.376
Prednisolone1.729 (1.207–2.476)0.0031.707 (1.395–2.090)0.001

There was no difference between the different drug classes (bisphosphonate versus nonbisphosphonate, alendronate versus nonalendronate-bisphosphonate) in the risk of hospital-treated uveitis, with age and the number of comedications being the only predictor (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

This study shows that the incidence of IERs requiring topical steroids after initiation of anti-osteoporosis treatment is low and the risk of severe uveitis is very low in Denmark. No difference was found in rate of IERs with bisphosphonate compared with nonbisphosphonate treatments after adjustment for underlying diseases and age. The risk of IERs was greatest among patients with seronegative rheumatoid arthritis, necrotizing vasculopathies, and Sjogren's syndrome, suggesting the underlying inflammatory disease is the most likely determinant.

Early phase animal studies reported conjunctivitis and episcleral congestion in rabbits with larger doses of pamidronate than used therapeutically (100 times), and it was identified that pamidronate is secreted into tears.36 It was also hypothesized that the well-recognized effect of some bisphosphonates to cause systemic release of cytokines and other acute phase proteins may occur in the eye, but no specific localization of these factors to the tears or orbit has been reported.9 In addition, this proposed mechanism does not explain how non-nitrogen-containing bisphosphonates also cause the same inflammatory reaction. Indeed, clodronate inhibits proinflammatory cytokine secretion from activated macrophages.37

However, approximately 10% of patients with episcleritis or scleritis presenting to secondary care have underlying rheumatoid arthritis.38 Systemic inflammatory conditions such as these often require treatment with steroids, and bisphosphonates may be used to prevent corticosteroid-induced osteoporosis, as well as treat established osteoporosis occurring as a result of systemic inflammation. In other words, many patients who begin bisphosphonates have an increased base risk of inflammatory eye disorders and additional research is needed. Accordingly, in the present study, 1 in 5 patients who began alendronate had a known rheumatic disease and 1 in 20 had been treated with topical eye steroids in the past year.

Our findings support and strengthen those of a US veteran cohort study34 but differ from those of the Canadian cohort study,35 although their absolute numbers of bisphosphonate-associated uveitis and scleritis was small. In addition, compared with our approach, the comparator group in the Canadian study was the background population, and although attempts were made to control for comorbid conditions, the estimate of the strength of association may be inflated because of undercapture of chronic inflammatory diseases. Further, the authors did not compare the rate of IERs in patients on other anti-osteoporosis medications to the rates found in patients receiving bisphosphonates.

The strengths of our study include the fact that it was a national assessment with complete capture of eye steroids prescribed and complete information about inpatient and outpatient treatment in Danish hospitals. For example, this enabled us to identify that the prevalence of pulmonary and rheumatic comorbid disease was higher in users of bisphosphonates than in users of nonbisphosphonates, thus explaining the observed association of an almost 50% higher prevalence of eye steroid use in the first year of alendronate use compared with raloxifene use. A comparison with untreated osteoporosis patients was not possible because of the low likelihood of patients being assigned the osteoporosis diagnosis code without being offered treatment. Because such an untreated subgroup would be highly biased toward more severe comorbidity, we chose to use an active comparator design instead and also to make comparisons with the eye disease rates and prescription rates in the year before patients began osteoporosis drugs. The limitations of our study include the fact that it is observational in nature and restricted to the first 12 months of osteoporosis treatment, although this is the time period during which eye reactions have most commonly been reported. Because of the limited long-term adherence to osteoporosis drugs, a 1-year study can be conducted with somewhat larger patient numbers than is currently possible for long-term exposure studies. A further limitation is that we did not have information about diagnoses of uveitis or other inflammatory disorders of the eye made in general practice or by practicing specialists in ophthalmology. Thus, mild cases that were managed by NSAID or other treatment that did not include topical steroids would not be available for analysis. Also, the capture of baseline comorbid conditions would not include rheumatological or pulmonary disorders that were exclusively treated outside the hospital system, although this is likely to be a small number of patients. This probably explains why baseline prednisolone use, serving as a proxy for rheumatic and pulmonary disorders, was associated with increased risk of eye reactions. Few patients had been exposed to more than one osteoporosis drug before the onset of an eye reaction.

In conclusion, no difference was found in rate of IERs with bisphosphonate compared with nonbisphosphonate treatments after adjustment for underlying diseases and age. The risk of IERs was greatest among patients with underlying inflammatory diseases, suggesting these are the most likely determinant.

Disclosures

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

MP has received consulting fees from Warner Chilcott. EC has received consulting fees from Eli Lilly, Servier, and P&G. PE has served on an advisory board for Nycomed, Amgen, and Novartis, and has been a member of the speakers' bureau for Amgen, GSK, and Eli Lilly. KB has served on an advisory board for Osteologic, Servier, and Amgen; received research grants from MSD; and served on speakers' bureaus for Servier, Amgen, and GSK. BA has received research grants or consulting fees from Amgen, Nycomed, and Novartis, and has been a member of speakers' bureaus for Amgen, Eli Lilly, Merck, Novartis, and Nycomed.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References

Authors' roles: All authors contributed to the writing of this article and to critical revision of the final version. The study was conceived by MP and BA. BA was responsible for the statistics and the integrity of the data analysis and had full data access.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Materials and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgements
  9. References