Bisphosphonates are bone resorption inhibitors widely used to treat osteoporosis, bone metastases of malignant tumors, and Paget’s disease. They suppress the function of osteoclasts responsible for bone resorption and help maintain bone density.
Uveitis (iridocyclitis), scleritis, episcleritis, orbital inflammation, blepharitis, and conjunctivitis are known ocular complications. Bisphosphonates are one of the important causative drugs for drug-induced uveitis and scleritis 1), and confirming the history of administration is important. The 2019 Guidelines for the Management of Uveitis also mention them as a major causative drug for drug-induced uveitis 2).
| Dosage form | Representative drugs | Main target diseases |
|---|---|---|
| Oral | Alendronate (Bonalon®, Fosamax®), Risedronate (Actonel®, Benet®), Minodronate (Bonoteo®), Ibandronate (Bonviva®) | Osteoporosis |
| Intravenous | Zoledronic acid (Zometa®, Reclast®), Pamidronate, Ibandronate (Bonviva IV®) | Bone metastases, Paget’s disease, Osteoporosis |
Intravenous formulations (especially zoledronic acid and pamidronate) have the highest frequency of ocular complications and occur earlier than oral formulations. The risk is highest at the first administration and tends to decrease with repeated doses.
Bisphosphonates (such as Bonaron® and Zometa®) can cause eye inflammation. These drugs are an important cause of drug-induced uveitis and scleritis, and particularly with intravenous administration (zoledronic acid), acute anterior uveitis has been reported at a frequency of 0.8%7). If redness, eye pain, or decreased vision occur within one week after administration, please consult an ophthalmologist promptly.
The main symptoms are hyperemia and eye pain (tenderness, throbbing severe pain). Visual acuity loss is often noticed when the condition progresses to severe cases (necrotizing scleritis). It may also be accompanied by photophobia, lacrimation, and foreign body sensation. Influenza-like syndrome (acute phase reaction: fever, malaise, myalgia, arthralgia) and ocular inflammation may appear simultaneously 5).
Anterior Uveitis
Features: Mild to moderate anterior chamber inflammatory cells and flare are observed.
Associated findings: May be accompanied by keratic precipitates (KP).
Onset: AAU after zoledronic acid infusion has been reported to occur 1–7 days (mean 3 days) after administration7).
Symptoms: Photophobia, conjunctival injection, and decreased visual acuity appear.
Scleritis
Features: Anterior diffuse and nodular types are common. Deep injection (dark red) is observed.
Examination findings: Hyperemia does not resolve with epinephrine eye drops (due to deep involvement). Tenderness and throbbing pain are severe.
Severity: If it progresses to necrotizing scleritis, the blindness rate reaches 40%. Recurrence is frequent, and complete cure may take several years.
Episcleritis
Features: Mainly transient irritation, warmth, and foreign body sensation; no pain or tenderness.
Differentiation: The nodule is mobile, and hyperemia subsides with epinephrine eye drops (important for distinguishing from scleritis).
Course: Most cases resolve spontaneously within days to weeks without treatment.
Orbital Inflammation and Others
Orbital inflammation: Presents with proptosis, diplopia, and eye pain. There are multiple case reports after intravenous zoledronic acid 8) and after intravenous pamidronate 5, 9).
Others: Conjunctivitis, eye pain, blurred vision, etc. have also been reported 5).
Imaging evaluation: MRI confirms extraocular muscle enlargement and orbital fat inflammation.
If eye pain and redness appear within 1 to 7 days after intravenous bisphosphonates such as zoledronic acid or pamidronate, suspect bisphosphonate-induced anterior uveitis or scleritis1, 7). If accompanied by flu-like symptoms (acute phase reaction) such as fever, malaise, and joint pain during the same period, the causal relationship with the drug is even more strongly suggested. Consider discontinuing the suspected drug in collaboration with the prescribing orthopedics, endocrinology, or oncology department.
The diagnosis of drug-induced uveitis is suspected based on the temporal relationship between bisphosphonate use and symptom onset, and is confirmed by improvement after discontinuation of the suspected drug. Causal assessment using the Naranjo criteria is useful 1):
The following screening tests are performed2):
| Disease | Key differentiating features |
|---|---|
| HLA-B27-associated acute anterior uveitis | HLA-B27 positive, history of ankylosing spondylitis, psoriasis, or inflammatory bowel disease |
| ANCA-associated scleritis (GPA/MPA) | c-ANCA (anti-PR3 antibody) positive, ear/nose/throat, lung, and kidney involvement |
| Rheumatoid arthritis-associated scleritis | Positive RF and anti-CCP antibodies, history of RA |
| Infectious uveitis | Syphilis serology, tuberculin test, anterior chamber paracentesis (infection markers) |
| Behçet’s disease | Hypopyon, oral aphthae, genital ulcers, skin lesions |
The basis of diagnosis is to confirm the temporal relationship between bisphosphonate administration and ocular inflammation (1–7 days after intravenous zoledronic acid, and attention to onset after first use with oral medications) 1). To rule out infectious and autoimmune diseases, blood tests (CRP, RF, ANCA, HLA-B27) and tuberculosis screening are performed 2). Improvement of symptoms after discontinuation of the suspected drug strongly suggests a causal relationship. Recurrence upon rechallenge is almost diagnostic, but rechallenge is generally not performed because it causes recurrence of symptoms.
Discontinuation of the suspected drug (bisphosphonate) is the first-line treatment1, 3). Most cases improve within weeks after discontinuation. Consult with the prescribing physician in orthopedics, endocrinology, or oncology; if osteoporosis treatment is needed, consider alternatives to bisphosphonates.
Alternative drug options:
Most cases resolve spontaneously within days to weeks without treatment, but to differentiate from scleritis, steroid and antibiotic eye drops are used:
Anterior uveitis
Localized scleritis (diffuse/nodular)
Steroids are the mainstay of treatment:
When there is no response to local treatment:
Circumferential/severe scleritis:
Mild cases (episcleritis, mild anterior uveitis):
Re-administration of the same drug after improvement of bisphosphonate-induced ocular inflammation may cause recurrence of ocular inflammation 5). Switching to a different bisphosphonate also carries a risk of recurrence, so it is generally recommended not to continue bisphosphonate therapy in patients who have experienced ocular inflammation. If continued treatment for osteoporosis is necessary, consult with an orthopedic surgeon or endocrinologist about switching to a drug with a different mechanism, such as denosumab or teriparatide.
Multiple mechanisms are thought to be involved in bisphosphonate-induced ocular inflammation.
Intravenous bisphosphonates may cause systemic symptoms such as fever and myalgia as an acute phase reaction, and ocular inflammation can also appear early after administration 5, 7). Although mechanisms involving immune cell activation and inflammatory cytokines are presumed, in individual cases the decision is made based on the temporal relationship with drug administration, exclusion of other diseases, and improvement after discontinuation 1).
Increased production of inflammatory cytokines (IL-6, TNF-α, IFN-γ) disrupts the blood-eye barrier, allowing circulating immune complexes and inflammatory cells to infiltrate the eye 3). Direct toxicity of bisphosphonates themselves (at high concentrations) may also contribute as damage to vascular endothelial cells.
Immune complex deposition in the uvea and sclera triggers local inflammation via complement activation. Cross-reactivity to proteoglycan antigens common to bone, uvea, and sclera has also been proposed as a hypothesis.
Scleritis can occur idiopathically as an isolated condition, or arise from systemic diseases (e.g., autoimmune diseases such as rheumatoid arthritis), infection, or after ophthalmic surgery. The mechanism of endogenous scleritis is thought to involve immune processes, and bisphosphonate-induced scleritis is also categorized within this framework.
In cases switched from bisphosphonates to denosumab (anti-RANKL antibody), fewer reports of ocular inflammation recurrence have been noted. However, large-scale prospective comparative data are limited, and continued monitoring after switching is necessary.
A cohort analysis by Pazianas 2013 using a national prescription database also examined inflammatory ocular complications during osteoporosis treatment10). Future challenges include prospectively verifying the incidence in Japan, the necessity of baseline ophthalmologic evaluation before initial administration, and risk stratification.
Bisphosphonates, while recognizing their side effects, benefit many patient populations in preventing fractures. After the onset of ocular inflammation, it is important to transition to appropriate alternative therapies through multidisciplinary collaboration (ophthalmology, orthopedics, endocrinology, oncology).
