Mini Review
Ann Hematol Oncol. 2015;2(5): 1040.
Complications of Bisphosphonate Therapy in Multiple Myeloma: A Review
Tamburrelli FC*, Cucchi F, Di Geronimo E, Proietti L, Scaramuzzo L, Rossi E and De Stefano V
Spinal Surgery Department, Catholic University of Rome, Italy
*Corresponding author: Tamburrelli FC, Spinal Surgery Department, Catholic University of Rome, Largo A. Gemelli 1 00168 Rome, Italy,
Received: April 24, 2015; Accepted: May 30, 2015; Published: June 04, 2015
Abstract
Background: Patients affected by Multiple Myeloma (MM), osteoporosis and oncologic diseases characterized by bone damage are successfully treated with Bisphosphonates (BPs), a very powerful inhibitors of bone resorption able to correct tumoral hypercalcaemia and to prevent pathological fractures. Among the adverse effects of the pharmacologic treatment, Osteonecrosis of the Jaw (ONJ) is known as the most typical and the worst. Recently, ocular involvement associated with BPs therapy has been suggested: uveitis and scleritis are the most commonly reported events.
Methods: We reviewed scientific literature to determine possible adverse ocular side effects associated with the use of BPs. Clinical studies were collected by using key-words (BPs, zoledronic acid, ocular effects, uveitis, eye and BPs). The World Health Organization’s Causality Assessment Guide was used to categorize an adverse ocular drug reaction.
Conclusion: Although the present review was inconclusive in determining the real incidence of the ocular related events, patients that need a treatment with BPs, should be informed on the possibility to develop ocular side effects, which are probably sustained by an inflammatory mechanism which involves IL- 6, TNFa, and other similar cytokines. Uveitis and scleritis are the most frequent, but they can be successfully managed with corticosteroid treatment.
Keywords: Bisphosphonates; Zoledronic acid; Ocular effects; Uveitis; Eye and bisphosphonates
Abbreviations
MM: Multiple Myeloma; BPs: Bisphosphonates; ONJ: Osteonecrosis of the Jaw; SRE: Skeletal-Related Events; PPi: Inorganic Pyrophosphate; RANKL: Receptor Activator of Nf-κb Ligand; OPG: Osteoprotegerin; ETI: Etidronate; CLO: Clodronate; PAM: Pamidronate; ZOL: Zoledronate
Introduction
Bisphosphonates represent an effective class of drugs used for patients affected by osteoporosis, hypercalcaemia, oncologic diseases with bone involvement (breast, lung, prostate cancer and Multiple Myeloma), and Paget disease. They can be also used to manage other conditions, such as osteogenesis imperfecta and fibrous dysplasia, resulting in the reduction of bone damage.
In particular, nearly 50% of the patients affected by Multiple Myeloma (MM) may develop complications known as Skeletal- Related Events (SRE) (i.e. bone pain, hypercalcemia, pathological and fragility fractures, spinal cord compression, radiotherapy requirement and surgery for pathological fracture) [1,2].
For these patients the use of bisphosphonates has become the standard of care, and represents an important strategy to reduce about 30-40% of SRE [2-5].
BPs decrease resorptive effects of the metastatic disease process and correct tumoral hypercalcemia; they prevent the occurrence of pathological fractures and, as a consequence, they increase quality of life. The use of BPs reduces bone pain, analgesic consumption and delays skeletal complications. MM patients treated with chemotherapy associated with BP therapy have better clinical outcomes, compared to patients treated with chemotherapy alone [6].
Bisphosphonates activity
Bisphosphonates are potent inhibitors of bone resorption and are widely used in the treatment of many diseases that cause bone mass loss.
BPs are synthetic, stable analogues of Inorganic Pyrophosphate (PPi) and bind quickly and specifically to hydroxyapatite, especially in regions where resorption is occurring. When osteoclasts break down bone, BPs accumulate in the resorption space under these cells, exposing them to high BP concentrations [7].
BPs can down-regulate “Receptor Activator of NF-κB Ligand” (RANKL) and M-CSF expression: this is one mechanism by which BPs—indirectly—affect resorption by the inhibition of osteoclast recruitment, differentiation and maturation.
They also up-regulate Osteoprotegerin (OPG) in osteoblasts; as a consequence they might therefore inhibit osteoclastogenesis preventing the development of monocytes into osteoclasts, inducing osteoclasts apoptosis, interrupting their attachment to the bone and resorptive activity [8-10].
There are two main types of BPs: nitrogen containing BPs and non-nitrogen containing BPs. The first generation of BPs are non-nitrogen-containing compounds such as Etidronate (ETI) and Clodronate (CLO), which are metabolized to cytotoxic ATP analogues, which induce osteoclast cell death [11].
Among intravenous N-BPs, the most commonly used in MM are zoledronic acid and pamidronate [12].
With regards to potency, Pamidronate (PAM) is less effective than Alendronate which is less effective than Risedronate. Risedronate is less effective than Zoledronate (ZOL). Pamidronate appears to be much less effective than other BPS while Zoledronate is the most effective drug. Nevertheless PAM and ZOL have been approved for use in MM patients in Europe [6,13].
Zoledronate can normalize cytokines pattern, through the inhibition of IL-6, the most potent survival factor for the MM clone, from the diseased bone-marrow stroma [14,15].
Superiority of any N-bisphosphonate (zoledronate or pamidronate) versus non-ammino bisphosphonates has not been demonstrated yet.
However zoledronate seems to be superior to placebo and nonnitrogen BPs and seems to give a major advantage on overall survival [16].
Adverse effects of BPs
It is well known that BPs are generally well tolerated, but they are also associated with potential adverse effects. The most common are gastrointestinal complications, like diarrhea, nausea and esophagitis, inflammatory reactions at the injection site, acute phase reactions following i.v. use, hyperthermia, hypocalcemia and hypophosphatemia and renal impairment [17]. The major complication is ONJ that seems to be correlated with BP treatment duration and has been shown to be 5%-15% at 4 years [18,19]. In the last years an increase in the incidence of subtrochanteric stress fractures (atypical fractures) has been reported [20].
Adverse ocular effects with bisphosphonate therapy
Among the adverse effects, scientific literature has recently reported some forms of ocular inflammation secondary to both intravenous and oral use of BPs: conjunctivitis, scleritis, episcleritis, iritis, keratitis and uveitis as major side effects, and eye dryness and red eye, edema and ptosis as minor side effects. Overall, the incidence of ocular adverse events after bisphosphonate exposure is difficult to be estimated because of the absence of reviews about this problem. In fact most reports in literature are simple case reports and data from voluntary drug-reporting system. Usually the onset of ocular symptoms, that are tipically unilateral, occurs in about 72 hours from administration of the bisphosphonate, and symptoms generally improve after cessation of drug use. The pathogenesis is not clear, but with high doses of topic/oral corticosteroids pain symptoms and inflammatory damage resolve, probably because inflammatory factors (TNF, IL-1, IL-6, IL-2, IFNa) may play a role in inducing eye inflammation [21-25]. Also Pazianas et al. seem to confirm this inflammatory ipothesis, as they found that uveitis onset is frequently associated with inflammatory bowel disease, rheumatic disorders (especially seronegative rheumatoid arthritis), sarcoidosis, rheumatoid arthritis and Sjogren syndrome [26]. These ocular complications have been initially associated with N-bisphosphonates; alendronate, pamidronate, risedronate and zoledronate, and nonammino bisphosphonates as well, seem to have therefore a certain role in the pathogenesis of ocular problems. However, the clinical trials do not explain if inflammation is the result of direct effect of drugs, or the expression of patient’s background disease. It is also possible that ocular structure is temporary involved by more inflammatory processes (for example episcleritis associated with uveitis), a situation to be treated with therapy interruption and expert ophthalmologist’s advice.27 The popularity of single drugs among the population probably explains the variance in the number of ocular inflammations reported for each type of bisphosphonate (Tables 1 & 2) [28].
Description
Breast cancer
Zoledronate, 4mg/6 months
Unilateral anterior uveitis
[1]
[2]
Alendronate for 6 months, followed by Risedronate for 2 months
[2]
[3]
Tyy Lai et al.
934?147 patients
Patients visited by ophtalmologist, which are asked about BP use
Cohort Study
Mahyar et al.
13?643 patients
Osteoporosis and Paget’s disease
Dry eye, conjunctivitis, 2 cases of iritis and 2 cases of episcleritis, 1 case of keratitis
Cohort Study
[4]
Zoledronateev
Right orbital pain, edema e proptosis, conjunctival chemosis
B Barlogie et al.
[5]
[3]
Zoledronate
[6]
Posterior scleritis (following Zoledronate) and conjunctivitis (following Pamidronate)
Resolution with homatropine drops and 2-hourly prednisolone acetate/phenylephrine hydrochloride drops
[7]
58-year-old woman
Osteoporosis
Zoledronate 5mg ev
Acute anterior uveitis
Case Report
Resolution of symptoms within 4 weeks with prednisolone acetate 1% and dexamethasone
[8]
73-year-old woman
Osteoporosis
Risedronate, 35 mg orally/ week (2007)
Risedronate, 150mg orally/ month(2009)
Scleritis
Case Report
First exposure to Risedronate in 2007, with recurrence of scleritisupon Risedronate exposure again in 2009
Improvement of symptoms with methylprednisolone 125 mg
intravenously (IV) four times daily
IHemmati et al.
48-year-old woman
Breast cancer with bone metastasis
Zoledronate, 4mg ev
Unilateral anterior uveitis
Case Report
Resolution of symptoms within one week with topical prednisolone acetate (1%)
[9]
47-year-old male
?
Zoledronate ev
Acute retinal pigment epitheliitis
Case Report
[10]
woman
Frontal hyperostosis secondary to breast cancer
Zoledronate ev
Unilateral anterior uveitis
Case Report
Complete resolution of symptoms after one month with topical prednisone and cycloplegic eye drops
[11]
67-year-old woman
Osteoporosis
Alendronate, 70 mg orally once/week
Panuveitisin right eye and anterior uveitis in the left
Case Report
Resolution with steroids and recurrence of symptoms with new administration of Alendronate
Sanchez et al.
86-year-old woman
Osteoporosis
Alendronate
Scleritis in right eye
Case Report
Resolution with Prednisone
[12]
54-year-old male
?
Alendronate sodium 70 mg orally once per week
Inferonasal nodular scleritis
Case Report
Resolution with 4 mg of subtenon's triamcinolone acetate; recurrence of symptoms after rechallenge
[13]
57-year-old woman
History of esophageal, breast, and lung cancers, and postmenopausal osteoporosis
Intravenous Ibandronate for 6 infusions, later changed to Zoledronate infusion
Orbital inflammatory disease:
painfully swollen left eye with photophobia and edema of the left upper lid
Case Report
Swelling and erythema disappeared completely in 2 weeks after she started on 2 methylprednisolone dose packs
[14]
2 Men
Paget’s disease
Pamidronate 65 mg in three divided
infusions on alternate days
Uveitis
Case Report
Next day after infusion
worsened;
improved on oral steroids
[15]
55- year-old man
Metastatic renal cell
cancer
Zol 4 mg iv Monthly
Orbital inflammatory disease
Case Report
One day 60mg prednisone,
tapered during 10 weeks of
treatment; no relapse
(on steroids)
[16]
62-year-old woman
MGUS with back and leg pain
Zol 4 mg iv
Bilateral acute uveitis and conjunctivitis
Case report
Improved on oral steroids
[17]
Woman
Osteoporosis
Alendronate
Uveitis ?corneal graft rejection
Case Report
[18]
64-year-old man and 65-year-old man
Metastatic prostate cancer
Pamidronate ev
Orbital inflammation
Case Report
Improved on oral steroids
[19]
71-year-old man
Paget’s disease
Pamidronate 90 mg ev
Right-sided proptosis, conjunctival chemosis and diplopia
Case Report
Next day ��flu like symptoms’’
Fifth day: orbital inflammation
improved with systemic
steroids
[20]
57, 71 and 77-year-old women
Osteoporosis
Alendronate
Posterior scleritis and anterior nodular
scleritis with possible contiguous
orbital inflammation and
myositis
Case Report
Resolution e with steroids
Mbekani et al.
Woman
Osteoporosis
Alendronate
Uveitis
Case Report
Oral steroids
[21]
Man
Paget’s disease
Pamidronate
Uveitis
Case Report
1 week topical steroids
[21]
18 patients
?
Pamidronate 30-90 mg ev; rechallenge in 6 cases
heterogeneous ocular effects
Cohort Study
6 hours to 2 days relapse
[22]
Woman
Osteoporosis(?)
Alendronate 10 mg/die for 1 year, then switched to Alendronate 70 mg weekly
Bilateral acute anterior uveitis
Case Report
Use of local steroids
[23]
60-year-old woman
Osteoporosis
Zoledronate, 5 mg (single dose)
Orbital inflammatory disease
Case Report
Resolution with oral prednisone
[24]
Woman
?
Zoledronate, 4 mg ev
Orbital inflammatory disease
Case Report
Systemic steroids
[25]
77-year-old man
Multiple myeloma
Pamidronateev
Diplopia and chemosis
Case Report
Symptoms 2 days after infusion
[26]
68-year-old male
Metastatic prostate cancer
Zoledronate
Orbital inflammation and anterior ischemic optic neuropathy
Case Report
Resolution with oral prednisone, 100 mg daily, and ibuprofen,
400 mg daily
[27]
75-year-old woman
Osteoporosis
Zoledronate
Unilateral orbital inflammation and bilateral anterior uveitis
Case Report
Intravenous methylprednisolone leads to a complete regression of the inflammatory process within days
[28]
Woman
Osteoporosis
Alendronate
Acute non granulomatous anterior uveitis
Case Report
The symptoms disappeared abruptly after anti-inflammatory therapy and discontinuation of alendronate
[29]
59-year-old man
Metastatic prostate cancer
Pamidronate
Acute retinal pigment epithelial detachment
Case Report
[30]
Post marketing surveillance
study conducted on a large cohort of veterans
Oral Alendronate(70 or 35 mg or 70 ml solution) and parenteral Pamidronate (30mg)
Uveitis, scleritis, iridocyclitis, iritis
Cohort study
Most patients had reumathological pathologies (ankylosing spondylitis, rheumatoid arthritis, polychondritis, ecc.); the interval between exposure and symptoms
tends to be less with intravenous administrations; inability to confirm
whether ocular inflammation improved once bisphosphonate
drugs were stopped or whether any
rechallenge tests were performed.
[31]
84-year-old woman
Osteoporosis
Zoledronate ev
Giant cell arteritis, complete vision loss of left eye, pain and swelling in left eye, left sided jaw pain and temporal headache
Case Report
Symptoms resolution with methylprednisolone
Metyas et al.
63 year-old man
Multiple myeloma
Zoledronate ev???
Cicatricial ectropion of the lower eyelid, without exposure keratopathy; extensive destruction of bone with an infraorbital fracture surrounded by sclerotic bony changes
Case Report
Resolution with discontinuation of bisphosphonate therapy and topical ocular lubricants
[23]
Table 1: Nitrogen-containing bisphosphonates.
Patient
BP used
Ocular effects
Type of study
Description
Authors
438 cases of ocular effects reported in the National Registry of drug-induced ocular side effects
Multiple myeloma, bone metastasis of breast cancer, Paget’s disease, osteoporosis
[22]
Woman
Paget’s disease (pelvis and sacrum)
Started on etidronate 400 mg/d x 6 months (no reaction), Risedronate 30 mg/d x 84 days; Pamidronate 60 mg
Iritis
Case Report
3 days after starting Risedronate responded to steroid e<24 hours after Pamidronate infusion
responded to steroid eye drops
[32]
68-year-old woman
Osteoporosis
CLO 100 mg/week im
Bilateral anterior acute uveitis
Case Report
5 months recover on topical
steroids
Fiettaet al.
28 patients
?
BPs
Eterogeneous ocular effects
Cohort study
Onset and response to treatment:2 days to more than 3 years
[33]
Pamidronate, Alendronate,Zoledronate and Risedronate (nitroge-containing bisphosphonates),Etidronate (non nitrogen-containing bisphosphonates)
Bilateral uveitis and/or unilateral
scleritis and episcleritis
Review
[34]
Literature up to mid-2014
Osteoporosis
Nitrogen and non nitrogen-containing BPs, selective estrogen receptor modulators, strontium, denosumab, teriparatide
Conjunctivitis, uveitis, scleritis, episcleritis, keratitis
Review (case reports, case series, cohort studies)
The drug
is secreted into the tears by the lacrimal gland and could cause irritation to the mucous
membranes with subsequent release of inflammatory mediators, similar to the systemic
response typically seen after infusion of bisphosphonates
Clark E. et Durup D.
Table 2: Non nitrogen-containing bisphosphonates.
Different ocular effects associated with Bps use can be classified as follows (World Health Organization Classification of Bisphosphonates and Ocular Side Effects) (Table 3):
Certain
Possible
Blurred vision
Ocular irritation
Nonspecific conjunctivitis
Pain
Epiphoria
Photophobia
Conjunctivitis
Uveitis
Scleritis
Episcleritis
Periocular lid and/or orbital edema
Retrobulbar neuritis
Yellow vision
Diplopia
Cranial nerve palsy
Ptosis
Visual hallucinations
Table 3: Side effects.
Side effects as conjunctivitis or episcleritis generally have a complete resolution of symptoms [21] whereas uveitis, scleritis or orbital inflammation can cause serious complications like synechiae or ipopion, determining ocular lasting damages. Scleritis is the most frequently BPs-associated ocular side effect; it occurs within 48 hours from the infusion, and a new administration can cause recurrence in the same eye in the majority of cases. With each infusion patients can develop tolerance, so the inflammatory reaction can decrease in intensity [23,29]. According to several clinical studies, a causal relation between BPs administration and suspension can be hypothesized on the onset and disappearance of symptoms [21].
Our experience
As reported in 2012, we followed-up for at least one year 50 MM patients: those who were treated with zoledronate had a better clinical outcome and quality of life versus patients not treated with BPs [30]. In this group of patients we evaluated too, if zoledronic acid could be the cause of any major or minor ocular effects (unpublished data). The data are reported in Table 4.
#
Sex
Age
BP
Dosage
Duration
Ocular effects
Ophthalmologist’s assessment
1
Male
77
Zoledronate
1 fl
1 year
Left eye Best maculopathy
Vit E, Vit B, lutein 1/die
2
Male
81
Zoledronate
1 fl
3 years
Blurredvision (senile cataracts)
Assessment for cataracts
3
Male
60
Zoledronate
1fl/month
24 months
Visus reduction (diagnosis: presbyopia)
4
Male
70
Zoledronate
1fl/month
23 months
Visus reduction
Assessment for cataracts
5
Female
60
Zoledronate
1fl/month
14 months
Right uveitis, eye dryness, photophobia and red eye
Therapy with ophthalmic solution and liposomial spray
Table 4: Cases.
Among our series of patients, we found a 77-year old man (#1) affected by left eye Best maculopathy, treated with zoledronate (1 fl/month) for 1 year; the ophthalmologist’s advice was vit. E, lutein and vit. B administration. However the not inflammatory nature and the long latency between appearance of symptoms and the start of the therapy disavow a possible correlation between zoledronate and maculopathy.
Two patients were diagnosed with cataracts (#2, #4), supposedly of senile nature, and one patient (#3) had a visus reduction caused by phisiologic presbyopia, and not because of BPs.
A 60-year old woman (#5) developed right eye uveitis after fourteen administrations. The patient complained eye dryness and red eye, photophobia and sting, treated with sodium ialuronate and liposomial spray, with complete resolution of clinical symptoms. Although the temporal relationship between ocular event and BP therapy, we think that this ocular involvement is not strongly related to BPs, because of the long latency of symptoms and the history of sclerodermia by which the patient was affected. It’s well known, in clinical practice, the relationship between sclerodermia and xeroftalmia.
Conclusion
Adverse effects strongly correlated with BPs therapy, including ONJ (which is considered to be the most dangerous), have long been known. Recently several cases of ocular events have been reported in literature in patients who are having drug treatment. At the moment the real incidence of the complication and the existence of a real relationship between drug administration and adverse effect is not strongly proved.
The aim of the present paper was that to review the literature with the specific topic to update the knowledge’s on the pathogenesis of the complication and to estimate, if possible, the real incidence of the complication.
The inflammatory origin of the complication seems to be the most suitable explanation of the disease at the moment. In fact, the interruption of BPs therapy and the administration of corticosteroids are generally followed by a prompt recovery of the symptoms with the avoidance of the worsening of the complications.
At the moment, the real incidence of the complications is impossible to establish due to the lack of sufficient data in literature. For the future, it is advisable a more careful attention focused on the possible relationship between BPs and adverse ocular events through a strict survey of patients belonging to large case series such as those who are followed in oncology centers. We also evaluated our own data belonging to an omogeneous group of patients affected by multiple myeloma and treated with zoledronate. Zoledronic acid is the most effective and powerful bisphosphonate widely used in MMs patients for its proved capacity to reduce skeletal related events. In our case series we do not recognize major ocular complication. Only five patient’s complaint minor events not clearly related to the drug therapy.
In conclusion we think that, even in the absence of a clear pathogenic relationship between BPs and side ocular events, patients should be always advised about the possibility, even rare, to develop ocular disease during the therapy.
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