Background
Zoledronic acid is generally well-tolerated in the management of osteoporosis and other metabolic bone diseases [
1]. The most frequent adverse event is acute phase reaction (APR), which occurs in nearly half of the patients after zoledronate infusion, but usually lasts for a short time with less severity [
2]. Zoledronic acid-induced uveitis (ZAIU) is rare; the incidence was reported to be 0.8–1.1 % [
3,
4]. Some severe cases have presented with transient reduced visual acuity [
5‐
14]. Previously, other bisphosphonates (pamidronate [
15,
16], alendronate [
17], and clodronate [
18]) have also been reported to be associated with acute uveitis. Uveitis is not commonly considered to be part of the APR, but they occur within the same time frame, suggesting that it may have a similar pathogenesis [
2,
19,
20]. Stepwise regression of a phase three clinical trial showed less APR after zoledronate infusion in previous users of oral bisphosphonates [
21].
Due to the low incidence [
3,
4], even a prospective randomized study failed to document the risk factors of ZAIU [
3]. Presently, only 15 individual cases have been reported [
5‐
14,
22‐
25]. We describe a case accompanied with right macular edema occurring during the management of postmenopausal osteoporosis with the substitution of the more convenient orally administered alendronate. To our knowledge, this is the first report of ZAIU with macular edema, as well as the first report of ZAIU after long-term alendronate tolerance.
Discussion
According to the Naranjo adverse drug reaction probability scale, in our case study a score of 8 indicates a probable association between zoledronic acid and uveitis. Regarding previously published cases, a probable [
10] to definite [
5] causality has been reported.
The National Osteoporosis Foundation (NOF) recommends that any eye inflammation related to bisphosphonate should be reported to the healthcare provider as soon as possible [
26]. However, due to the low prevalence and lack of recognition, although recommended by an ophthalmologist, the correct diagnosis was made 2 days after the onset of eye irritations, which worsened the ocular symptoms of our patient, and eye drops of antivirals were inappropriately prescribed. Fortunately, all the ocular manifestations recovered promptly, including the right macular edema.
Clinical features of 16 published cases (including our case) with ZAIU are shown in Table
1. Eight cases suffered from osteoporosis (including our case) [
5‐
8,
13,
22,
23], four with bone metastasis from malignant tumors [
9‐
11,
24], one with frontal hyperostosis and breast cancer [
25], one with back and femur pain from the treatment of monoclonal gammopathy of undetermined significance (MGUS) [
14], and the remaining two cases had risks of osteopenia due to leuprolide treatment for prostate cancer [
12]. All the ocular manifestations occurred in 3 days. Only two out of 16 patients had a past ocular history. Bilateral eye involvement appeared in one-third of the patients, corresponding to a previous study [
8]. The main ocular symptoms and signs included eye pain, blurred vision, diplopia, photophobia, lid edema, proptosis, conjunctival chemosis, hyperemia, and ophthalmoplegia. Nearly half of the patients presented with systemic symptoms. Posterior synechiae was observed in 6 patients, and most of the cases were cured. Choroidal folds [
6] and vitreous haze [
5] presented in some unusual cases. However, abnormal fundus was rarely reported, especially macular edema, as described in our case.
Table 1
Clinical features of the 16 published cases (including our case) with zoledronic acid induced uveitis
| 66 | unilateral | 2d | postmenopausal osteoporosis | no |
| 75 | unilateral | 2d | osteoporosis | no |
| 58 | unilateral | NA | osteoporosis | no |
| 58 | unilateral | 10 h | osteoporosis | no |
| 56 | unilateral | 12 h | postmenopausal osteoporosis | no |
| 70 | unilateral | 1d | frontal hyperostosis after breast cancer | no |
| 54 | bilateral | 1d | breast cancer with bone matastasis | no |
| 78 | unilateral | 48 h | prostate cancer with bone matastasis | no |
| 48 | unilateral | 24 h | breast cancer with bone matastasis | no |
| 54 | unilateral | 3d | breast cancer with lung and bone matastasis | no |
| 56 | bilateral | 72 h | prostate cancer treated with leuprolide | no |
| 68 | bilateral | 60 h | prostate cancer treated with leuprolide | no |
| 60 | unilateral | 24 h | osteoporosis and breast cancer | yes |
| 62 | bilateral | 48 h | back and femur pain in MGUS | no |
| 59 | unilateral | 2d | osteoporosis | no |
16a | 63 | bilateral | 24 h | postmenopausal osteoporosis | yes |
Corticosteroids are usually necessary for treatment. Topical steroids and adequate treatment often lead in most cases to full recovery, but a small portion of patients only respond well to systemic use of steroids [
8,
14]. No deterioration of osteoporosis has been reported to be related with steroid treatment.
Further use of bisphosphonates is not fully contraindicated. From our review of previous reports, in five patients given zoledronic acid with or without the protection of steroids, no additional ocular problems were reported [
4,
12,
20]. Pamidronate was also prescribed to another patient, and a tolerance effect was also observed with a prior combination of steroids [
27]. Interestingly, our patient developed uveitis soon after administration of intravenous zoledronate after a 2-year tolerance to oral alendronate. This is the first report of ZAIU after long-term alendronate tolerance.
Patel et al. retrospectively reported that 0.8 % of postmenopausal women with osteopenia receiving zoledronate developed mild to severe anterior acute uveitis [
4]. More recently, the incidence of ZAIU was prospectively reported to be 1.1 % [95 % confidence interval (CI) 0.5–2.1] in a secondary analysis of a randomized controlled trial of early postmenopausal women [
3]. Regarding oral bisphosphonates, a retrospective cohort study reported the incidence rate to be 29/10,000 person-years for uveitis in 10,827 first time users [
28]. The true incidence might be higher, because some mild to moderate patients may fail to seek treatment.
APR is the most frequent adverse event after bisphosphonate use, usually including fever, fatigue, nasopharyngitis, musculoskeletal pain, and gastrointestinal symptoms. All APR components had a peak onset within 1 day, and the median duration of the APR was 3 days [
21]. Recently, acute uveitis is being considered as part of APR after bisphosphonate dispensing, due to its similar time of occurrence [
4,
8]. Bisphosphonates have been shown to share homologies with γ/δ T-cell ligands by stimulating cytokine release by γ/δ lymphocytes, and by inhibiting farnesyl diphosphate synthase to increase the intracellular accumulation of isopentenyl pyrophosphate [
29]. These activities may contribute to the development of APR and uveitis.
Reid et al. investigated 7,765 postmenopausal women with osteoporosis, using a stepwise logistic regression analysis, and showed that APRs were less common in smokers, diabetics, calcitonin users, and previous oral bisphosphonate users [
21]. Because uveitis is a part of APR, it seems to develop less frequently after oral bisphosphonate tolerance, as described in our case study. Additional and larger case studies and single case reports are still needed to confirm the risk factors of ZAIU after previous bisphosphonate use.
Competing interests
The authors’ declare that they have no competing interests.
Authors’ contributions
YT: drafted the manuscript and critically revised it for important intellectual content. RW, QL, and FY: in made the final diagnosis of the patient, and revised the manuscript critically for important intellectual content. LL: and CM: performed the systemic steroids treatment on the patient, and made substantial contributions to the acquisition of data. All authors read and approved the final manuscript.
Lianyuan Liu used to be a clinical doctor of the First Hospital of Qinhuangdao, now he is Chief of Liaison Office.