Complications of Bisphosphonate Therapy in Multiple Myeloma: A Review

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


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


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


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].