Many cancers metastasize to bone specifically breast, prostate and Multiple Myeloma. Bisphosphonates and other systemic agents that inhibit osteoclast activity can prevent, reduce, and delay cancer-related and treatment-related skeletal complications in patients with both early and advanced malignancies [1]. Patients with metastatic cancer are at substantial risk for skeletal complications from bone metastases and bone loss (osteoporosis), which is often treatment-related. Skeletal complications of bone metastases, often referred to as skeletal-related events (SREs), include fracture, skeletal instability/loss of skeletal integrity, spinal cord compression, the need for surgery or radiation therapy for a symptomatic bone metastasis, and hypercalcaemia..These are usually associated with lytic lesions.
Bisphosphonates have become an integral component of cancer treatment in patients who have metastatic bone disease. Bisphosphonates reduce the morbidity of metastatic bone disease, mainly by decreasing the prevalence of SREs [1,2].
In addition, bisphosphonates are widely used for the prevention and treatment of bone loss (osteoporosis), both treatment-related and non-treatment-related.This includes the osteoporosis associated with aromatse inhibitors.
Bisphosphonates decrease bone resorption and increase mineralization by inhibiting osteoclast activity [1,3].
There are two classes of bisphosphonates, non-nitrogen containing and nitrogen containing, with somewhat different effects in killing osteoclast cells. The nitrogen containing bisphosphonates are more potent osteoclast inhibitors. Etidronate, clodronate, and tiludronateare non-nitrogen containing bisphosphonates, and the nitrogen containing bisphosphonates include pamidronate, alendronate, ibandronate, risedronate, and zoledronic acid.
Bisphosphonates have a direct apoptotic effect on osteoclasts, affect their differentiation and maturation, and thereby act as potent inhibitors of bone resorption. In preclinical models, the bisphosphonates have also been shown to influence macrophages, gamma delta T cells, osteoblasts, and tumor cells.
In addition to their effects on osteoclast inhibition, bisphosphonates may also have antitumor and/or antiangiogenic effects, but this is a controversial area. Investigations are ongoing to better define the clinically relevant effects of bisphosphonates in patients with cancer [4,5]
Quality of evidence and Clinical efficacy:
Definition of Skeletal Related Events:-
Breast cancer—For patients with breast cancer and bone metastases, bisphosphonate therapy can prevent and/or delay skeletal complications, and palliate bone pain. A survival benefit has not been shown. In women with metastatic breast cancer without clinically evident bone metastases, bisphosphonates do not reduce the incidence of skeletal events. Consequently, therapy with bisphosphonates is recommended to begin after the identification of osseous metastases, unless as part of a clinical trial.
The first studies were done in the 1990ties and reported in the early 2000.For metastastic breast cancer the risk of a skeletal event is approximately 64% at 2 years. This can be reduced to 33% with pamidronate and to 20% with zoladronic acid [6].
A meta-analysis of nine trials, which included 2189 women with metastatic breast cancer and bone metastases, showed that intravenous bisphosphonates (pamidronateand zoledronic acid) reduced the risk of developing a skeletal event by 17 percent (relative risk, RR 0.83; 95% CI 0.78-0.89) [7]. A meta-analysis of trials that used oral bisphosphonates (clodronateand ibandronate) showed a reduction in the risk of developing a skeletal event by 16 percent (RR 0.84 95% CI 0.76-0.93) [7].
Bisphosphonates can also prevent treatment-related bone loss in women receiving chemotherapy or aromatase inhibitors for breast cancer. In addition, improvements in disease free survival and breast cancer recurrence seen in some adjuvant therapy trials in which women received hormone therapy plus a bisphosphonate compared to hormone therapy alone suggest potential antitumor effects. However, the results of additional clinical trials are needed before it can be concluded that bisphosphonates improve breast cancer outcomes.
Prostate cancer—Bisphosphonates have been studied in men with advanced prostate cancer to delay or prevent the complications of skeletal progression (fractures, need for radiation therapy, hypercalcemia, spinal cord compression, pain), to prevent the development of bone metastases, and to protect against the bone loss associated with androgen deprivation therapy (ADT).
The results of randomized clinical trials and observational studies in patients with prostate cancer bone metastases indicate that the effectiveness of different bisphosphonates varies substantially [8,9].
The strongest data supporting benefit for bisphosphonates is with zoledronic acid, which is approved by the United States Food and Drug Administration (FDA) for use in prostate cancer in men with bone metastases who are progressing on hormone therapy. The European Committee for Proprietary Medicinal Products has approved zoledronic acid for all men with prostate cancer and bone metastases.
The benefit of zoledronic acidin men with bone metastases from prostate cancer is supported by a trial in 643 men bone metastases that were progressing while on ADT [10]. Men were randomly assigned to one of two doses of zoledronic acid (4 mg or 8 mg) or placebo, each given every three weeks. The 8 mg dose of zoledronic acid was reduced to 4 mg early in the trial because of excessive renal toxicity.
At an average follow-up of 24 months, there was a significant reduction in the frequency of SREs in men receiving zoledronic acidcompared to placebo (38 versus 49 percent), and the median time to develop an SRE was significantly longer with zoledronic acid (488 versus 321 days) [11]. Pain and analgesic scores were significantly higher in men who received placebo than in those who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. A second placebo-controlled randomized trial with zoledronic acid also demonstrated a statistically significant benefit in pain control [12].
In contrast to these results with zoledronic acid, trials with clodronatehave yielded equivocal results [13], and two trials with pamidronatehave failed to define a statistically significant benefit in terms of SREs or pain control [14.
Prevention of bone metastases—Given that the predominant site of metastases in prostate cancer is the bone, and that some preclinical data suggest an antitumor effect of bisphosphonates, adjuvant use of bisphosphonates has been studied in men with prostate cancer but without metastatic disease. In the largest trial addressing this issue, in which 508 men with nonmetastatic prostate cancer were randomly assigned to clodronateor placebo, there was no decrease in the incidence of bone metastases (80 events versus 68 events with placebo) [19]. High-potency bisphosphonates have not been studied in this setting.
Multiple myeloma
The efficacy of bisphosphonates in multiple myeloma was initially evaluated in a study in which 377 patients with stage III multiple myeloma and at least one lytic lesion were treated with antimyeloma therapy plus either placebo or pamidronate(90 mg) as a four-hour intravenous infusion given every four weeks for nine cycles [15]. The proportion of patients who had any skeletal events (pathologic fracture, irradiation of or surgery on bone, and spinal cord compression) was significantly lower in the pamidronate group (24 versus 41 percent). Pamidronate therapy was also associated with a significant reduction in bone pain. [15].
Recent evidence has shown a survival advantage as well
Morgan et al 2010 MRC Myeloma IX study randomize controlled study[18]. Lancet 2010 10 ;62051
1970 patients enrolled: 1960 eligible for intention to treat analysis : 981 in the zoladronic acid group :979 in the clodronic acid group
In both groups there was an initial subdivision into those patients who received intensive chemotherapy with the intention to treat with transplantation. This was followed by another subdivision into the zoledronic acid and clodronic acid groups
Median treatment with bisphosphonate was for 350 days
Median follow up was for 3.7 years
Zoledronic acid reduced mortality by 16% vs clodronic acid
HR 0.84 95% CI 0.74-0.96 p=0.0118
Extended median overall survival by 5.5 months (50 mo vs 44.5 p=0.04)
Increase PFS by 2.0 mo(19.5 vs 17.5 months) 12% increase HR 0.88 95% CI 0.88-0.98 p=0.0179
ONJ rate was 4% with zoledronic acid and 1% with clodronic acid
Intravenous bisphosphonate therapy is recommended for patients with multiple myeloma and any of the following:
Similar results were obtained in a randomized, double-blind phase III trial in 1648 patients with advanced multiple myeloma or breast cancer [16]. Patients were randomly assigned to receive one of two different doses of zoledronic acid(4 or 8 mg administered IV over 5 or 15 minutes) or pamidronate(90 mg IV over two hours); infusions were repeated every three to four weeks for 12 months. All participants received a daily 500 mg calcium supplement and 400 to 500 IU of vitamin Dthroughout the study. The following findings were noted:
In contrast, monthly intravenous ibandronate(Bondronate®), a high potency bisphosphonate, has not been associated with reduced skeletal-related events in patients with myeloma. In a randomized trial, 214 patients receiving conventional chemotherapy for stage II or III myeloma were randomly assigned to receive ibandronate (2 mg IV monthly for 24 months) or placebo [16]. Neither the rate of occurrence, nor the time to first skeletal-related event differed significantly between the two groups. However, the dose of ibandronate may have been too low; others have shown efficacy for 6 mg but not 2 mg monthly doses in patients with metastatic breast cancer [17].
Safety concerns:
Therapy with bisphosphonates is generally well tolerated. The most common complications are acute phase reactions, ocular inflammation, renal insufficiency, electrolyte imbalance, and osteonecrosis of the jaw (ONJ).
Osteonecrosis of the jaw can be mitigated with dental hygiene programmes before the start of the treatment with bisphosphonates, and by the use of prophylactic antibiotics during treatment. [19].
The acute phase reaction, a flu-like syndrome often with fever, chills, myalgia and arthralgias, may occur, in some degree, in approximately 50 percent of patients. When it occurs, it is typically within the first 48 hours of infusion and is self limited within 24 to 48 hours. Premedication with acetaminophenor non-steroidal antiinflammatory drugs may help [8]. On subsequent dosing, the risk of the acute phase reaction and its intensity decreases.
Bisphosphonates can be associated with other inflammatory reactions including phlebitis and ocular toxicities such as conjunctivitis, uveitis, scleritis, and orbital inflammation. Ocular inflammation often requires a formal ophthalmologic evaluation and further treatment with the offending bisphosphonate is often not recommended [8].
The nephrotoxicity of bisphosphonates is both dose- and infusion time-dependent, and renal function should be monitored regularly in patients being treated with these agents. Renal toxicity can be reduced by observing recommended infusion durations, optimizing hydration prior to bisphosphonate therapy and avoiding concurrent nephrotoxic medications. Serum calcium, magnesium, and phosphate should be measured regularly during therapy.
Calcium and vitamin D supplementation—If there are no contraindications, patients receiving bisphosphonates should receive calcium and vitamin D supplementation. Calcium and vitamin D supplementation decrease the risk of bisphosphonate-induced hypocalcemia and are important to maintaining bone health. For these reasons, many of the clinical studies investigating the bisphosphonates for metastatic bone disease incorporated calcium and vitamin D supplementation as part of the treatment regimen, and supplementation may be needed to replicate the outcomes seen in these studies.
In addition, patients with breast cancer are at risk for vitamin D deficiency. In a review of 321 breast cancer patients treated with bisphosphonates for either low bone mass or for metastatic disease, over 50 percent were vitamin D deficient [9]. Individuals with vitamin D deficiency are at increased risk for hypocalcemia, a known side effect of bisphosphonate therapy
