BIOPHOSPHONATES FOR THE PREVENTION OF SKELETAL-RELATED EVENTS AND TREATMENT OF MULTIPLE MYELOMA

BPs are pyrophosphate analogues characterized by two phosphate groups linked to a P-C-P core.57 They inhibit osteoclast activity by inhibiting farnesyl pyrophosphate synthase and accumulate in the mineral phase of the bone.58 There are two groups of BPs, one that contains nitrogen and one that does not. Ibandronate, pamidronate, and ZA contain nitrogen; etidronate and clodronate do not. Nitrogen-containing BPs inhibit farnesyl pyrophosphate synthase, which is essential for osteoclast survival and activity while non-nitrogen containing BPs are metabolized to cytotoxic adenosine triphosphate analogues that induce osteoclast apoptosis.59 BPs have also been shown to stimulate the innate anti-cancer immune response by upregulating γδT-cells.60 A direct anti-MPC activity has also been described for N-BPs in vitro.61 Nitrogen-containing BPs have also been shown to inhibit RANKL-induced osteoclast formation in vitro.62 Nitrogen-containing BPs have potencies that are 100 to 10,000 times higher than BPs without nitrogen.63 Multiple clinical trials have shown the efficacy of BPs in preventing SRE in patients with MM (Table 1).

Table 1

(To view a larger version of Table 1, click here.)


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A phase III double-blind trial comparing ibandronate vs placebo in addition to anti-myeloma therapy found that ibandronate did not show significant benefits in reducing SRE in MM patients with lytic bone disease.68 Oral pamidronate (300mg/d) was evaluated in a double-blind randomized trial in patients with newly diagnosed MM. After a median duration of 18 months, no significant reduction was apparent in SRE, hypercalcemic episodes or survival between treatment arms.69 A large, randomized, double-blind study conducted to determine the effect of monthly 90mg infusions of pamidronate in patients with MM revealed that after nine cycles of therapy, 24% of pamidronate-treated patients developed a SRE compared to 41% of patients who received placebo.70 Patients who received pamidronate also had a significant decrease in bone pain, no deterioration in performance status and no increase in analgesic use at the end of 9 months. The proportion of patients developing an SRE remained significantly lower in the pamidronate group after an additional 12 cycles of treatment.71 Overall survival was increased in the subset of patients with MM receiving second-line antimyeloma therapy (21 months vs 14 months; p=0.041) compared with placebo. A double-blind randomized phase III trial comparing monthly 90mg vs 30mg of IV pamidronate found that the median time to a SRE was 9.2 months in the 90 mg group and 10.2 months in the 30 mg group (p=0.63).72 Given that a higher proportion of patients in the pamidronate 90 mg group developed osteonecrosis of the jaw (ONJ) and renal toxicity compared to patients in the 30 mg group, monthly infusion of pamidronate 30 mg was the recommended dose for prevention of bone disease in patients with MM.

A phase III trial evaluated two doses of ZA (4 and 8mg) compared with pamidronate (90mg) infused every 3 to 4 weeks for the treatment of patients with MM or breast cancer with metastatic bone disease. The results of the study showed that the proportion of patents developing SRE did not differ between the ZA (4mg) and pamidronate-treated patients.73 After 25 months of follow-up, the overall proportion of patients developing an SRE remained similar between the ZA (4mg) and pamidronate group.74 However, an additional multiple-events analysis showed that patients treated with ZA had a 16% reduction in the risk of developing an SRE compared with patients who received pamidronate.74 In a study which evaluated ZA vs pamidronate in 1,018 United States Veterans with newly diagnosed MM, patients receiving ZA had a 25% reduction in SRE as well as a 22% reduction in risk of death compared to pamidronate.75 A randomized phase III trial comparing 4 mg IV ZA every 3–4 weeks or 1600 mg oral clodronic acid (CA) daily amongst 1970 patients found that ZA reduced mortality by 16% compared to CA (p=0.0118). ZA also extended median overall survival by 5.5 months (50.0 months vs 44.5 months; p=0.04), significantly improved progression-free (PFS) survival by 12% (p=0.0179), and increased median PFS by 2.0 months (19.5 months vs 17.5 months; p=0.07) compared to CA.23 While ZA has been administered every 4 weeks in the aforementioned trials, a randomized phase III trial has shown that ZA administered every 12 weeks is noninferior to ZA administered every 4 weeks.76

BPs not only prevent SRE in MM but also provide a survival benefit possibly due to their anti-MPC properties. In vitro studies suggest that pamidronate may possess anti-MPC properties based on its ability to induce apoptosis of MPC, suppression of IL-6 production and antiangiogenesis.64,77,78 ZA has also been shown to possess antiangiogenic properties in vitro.79 In a long-term follow-up (8.6 years) of a placebo-controlled trial, the subset of CA-treated patients who did not have vertebral fractures at baseline had significantly longer OS vs patients who received placebo (median OS, 59 months vs 37 months, respectively; p=0.006).80 In a retrospective analysis of a phase III trial comparing ZA (4 mg) with pamidronate (90 mg), patients with high baseline bone-specific alkaline phosphatase levels had significantly better 25-month survival with zoledronic acid than with pamidronate (82 vs 53%, respectively; p=0.041).81 In a clinical trial in which 94 patients were randomized to receive either ZA (4mg) or not, after 49.6 months median follow-up, the ZA-treated group had superior 5-year event-free survival (80% vs 52%, p=<0.01) and 5 year OS (80% vs 46%, p=<0.01) compared to the control group.82 As aforementioned, several other trials have shown that BPs prolong survival in patients with MM.23,75 Taken together, these studies conclusively established the role of the nitrogenous BPs ZA, and to a slightly lesser extent pamidronate, for management of MBD.

By interfering with the crosstalk between MPC and osteoclasts, BPs are able to reduce SRE and prolong survival in MM patients via apoptosis of osteoclasts, immunemodulation and direct anti-MPC activity.

SIDE EFFECTS AND TOXICITY OF BIOPHOSPHONATES

Despite being effective agents for the prevention of SRE in MM patients, the long term use of BPs has come under scrutiny due to their side effects. Notable and well characterized toxicities of BPs include flu-like symptoms, renal toxicity requiring dose reduction in patients with renal insufficiency, ONJ, gastrointestinal upset, atrial fibrillation and atypical femoral fracture.8

Approximately 40% of patients will experience a flu-like syndrome with the first administration of an IV nitrogen-containing BP. Symptoms include fever, fatigue, malaise, myalgia, arthralgia and bone pain that are caused by release of cytokines from γδT cells and macrophages.83 Patients treated with alendronate for osteoporosis were noted to develop low-energy fractures associated with minor trauma, most commonly in the subtrochanteric region of the femur.84 These fractures have usually been associated with extended BP treatment duration of 4–10 years.85 In MM patients treated with IV BPs, cases of atypical fractures resembling those seen in patients on alendronate have been reported.86,87

Renal injury is a major limiting factor in BP use, with acute tubular necrosis as the main pathology.88 Nephrotoxicity is related to the dose, infusion time and maximum plasma concentration that affects the intracellular concentration of BPs.89 There is the potential for BPs with prolonged renal tissue half-life, such as ZA, to accumulate in renal tissue and cause damage. Pamidronate has been associated with collapsing focal segmental glomerulosclerosis.90 With ZA, the risk of kidney injury (rise in creatinine of 0.5 mg/dl) was observed in the initial phase III trials comparing ZA to pamidronate, prompting a dose reduction from 8mg to 4mg and increase in the duration of the infusion from 5 to 15 min.73 To minimize toxicity, the 2007 American Society of Clinical Oncology guidelines suggested dose adjustments of ZA in patients with creatinine clearance ranging from 30–60 mL/min. ZA is not recommended for patients with creatinine clearance <30 mL/min.91 For patients with severe renal impairment, pamidronate 90mg administered over 4–6 hrs is the preferred BP. This nephrotoxicity is not unique to nitrogenous BPs as in a randomized phase III trial comparing 4 mg IV ZA every 3–4 weeks or 1600 mg oral CA daily amongst 1970 patients with MM, both groups had the same rate of renal toxicity (12%).22 Dose dependence of renal toxicity was demonstrated in a phase III trial comparing monthly 90mg vs 30mg of IV pamidronate which found a greater incidence of renal toxicity in the 90mg group compared to the 30mg group (6% vs 2.7%; p=0.072).72

ONJ is defined as a lesion of exposed bone in the maxilla or mandible that persists for 8 weeks in patients treated with BPs who are not receiving radiotherapy to the craniofacial area.92 Clinical signs and symptoms of ONJ include pain, swelling and/or ulceration of the oral mucosa, loose teeth or a nonhealing socket after tooth extraction. The severity of ONJ can vary from asymptomatic forms to severe lesions complicated by the appearance of fistula or fracture.93 The incidence of ONJ in patients with MM treated with BPs has been noted to be as high as 8.5%. Ibandronate and pamidronate appear to have a better safety profile compared to ZA.94 In a study comparing ZA vs pamidronate in 1,018 United States Veterans with newly diagnosed MM, the patients who received ZA had a higher incidence of ONJ compared to patients who received pamidronate (2.6% vs 0.8%).75 The phase III trial comparing ZA to CA in 1970 patients found a higher risk of developing ONJ in the ZA group compared to the CA group (4% vs <1%).22 The phase III trial comparing monthly 90mg vs 30mg of IV pamidronate found a greater amount of ONJ in the 90mg group (2.4%) vs the 30mg group (0.5%).72 The complete removal of necrotic bone, smoothing of sharp bony

edges and careful wound closure, accompanied by perioperative antibiotic treatment is generally considered to be the most suitable approach to achieve ONJ healing.95 With surgical management, resolution with complete healing of ONJ has been noted greater than 80% of cases.96

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