This Article Abstract Full Text (PDF) CME: Take the course for this article: The Use of Bisphosphonates in Elderly Cancer Patients eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gridelli, C. Search for Related Content PubMed PubMed Citation Articles by Gridelli, C.

Geriatric Oncology

The Use of Bisphosphonates in Elderly Cancer Patients

Division of Medical Oncology, SG Moscati Hospital, Avellino, Italy

Key Words. Bone metastases • Clodronate • Ibandronate • Pamidronate • Zoledronic acid • Elderly

Correspondence: Cesare Gridelli, M.D., Division of Medical Oncology, SG Moscati Hospital, Contrada Amoretta, 83100 Avellino, Italy. Telephone: 39-0825-203574; Fax: 39-0825-2035556; e-mail: cgridelli{at}libero.it

Received June 14, 2006; accepted for publication September 20, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
After completing this course, the reader will be able to:

1. Discuss the role of bisphosphonate therapy in the management of metastatic bone disease.
   
2. Describe the differences between individual bisphosphonates with regard to safety and route of administration.
   
3. List the reasons for including elderly patients in clinical trials of bisphosphonates for the management of metastatic bone disease.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
As life expectancy increases throughout the 21st century, the size of the elderly population will also expand. This will have a marked effect on the number of patients with cancer who are classified as elderly. Despite this, the design of most clinical studies of cancer therapies excludes those patients who are >70 years of age.

Bisphosphonates are an example of a cancer therapy that has not been examined in randomized clinical trials of elderly patients. These agents are used for the prevention of skeletal complications and the relief of bone pain in patients with bone metastases. When deciding which bisphosphonate to prescribe to an elderly patient, each drug should be considered on its individual merits. Examples of areas of concern with bisphosphonates in elderly patients include their relative renal safety profiles and propensity for osteonecrosis of the jaw. Another consideration when choosing the most appropriate formulation is the preferred method of administration (oral or i.v.), which may affect patient compliance with therapy.

As the use of bisphosphonates increases, the need for data on their use in elderly patients also becomes greater. Clinical trials of bisphosphonates in this patient population are currently under way, and their results are keenly awaited.

	INTRODUCTION

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
As the life expectancy of the general population has increased, the number of elderly patients with cancer has risen as well. This number is predicted to increase further throughout the 21st century. Estimates suggest that between one fifth and one quarter of the population in the Western world will be 65 years of age by the year 2020 [1]. As the majority of cancers and cancer-related deaths will occur in the elderly, there is a significant and growing need for effective and appropriate treatment for cancer in these patients.

Patient age presents a number of challenges when prescribing medications. Factors such as comorbid conditions, declining organ function, and general frailty can substantially limit the effectiveness of treatment. Furthermore, elderly patients may already be taking a number of concomitant prescription medications that are associated with drug-drug interactions, which can increase toxicity or reduce treatment efficacy. In particular, elderly patients with cancer may be taking several medications such as chemotherapeutic and supportive care agents at any one time.

If the patients have metastatic bone disease (MBD), these prescription medications may also include a bisphosphonate. These agents are regarded as the standard of care for bone metastases. Four bisphosphonates are currently used for the treatment of MBD: clodronate (Bonefos^®, Schering AG, Berlin; and Ostac^® and Loron^®, F. Hoffmann-La Roche Ltd., Basel, Switzerland), pamidronate (Aredia^®, Novartis Pharmaceuticals Corporation, East Hanover, NJ), zoledronic acid (Zometa^®; Novartis Pharmaceuticals Corporation), and ibandronate (Bondronat^®; F. Hoffmann-La Roche Ltd.). Although the benefits of these agents are well documented, no randomized trial has been conducted in elderly patients with MBD to date. Without these data, it is not possible to predict the exact effects of bisphosphonates in this population. Bisphosphonate safety profiles are also relevant; side effects such as renal toxicity and osteonecrosis of the jaw (ONJ) must be considered. This article reviews clinical data on bisphosphonates when used for the treatment of MBD and highlights characteristics of individual agents that have particular relevance when treating elderly patients.

	BISPHOSPHONATES AND MBD

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
MBD is a common and significant complication of metastatic cancers. It occurs in up to 95% of patients with multiple myeloma (MM); 75% of patients with breast and prostate cancer; and 15%–40% of patients with lung, colon, or kidney cancers [2, 3]. Bone metastases are associated with a number of debilitating sequelae, including severe pain, pathologic fractures that may require palliative radiation therapy, and spinal cord compression. The most common events are pathologic fractures and the need for radiation therapy [4]. Bisphosphonates inhibit osteoclast-mediated bone resorption and thereby reduce the incidence of skeletal complications. Since elderly patients are at an increased risk of skeletal events due to osteoporosis or other age-related comorbidities, treatment with a bisphosphonate is important.

The four bisphosphonates currently used for the treatment of MBD are summarized in Table 1. Clodronate, the first bisphosphonate to be used for treating bone metastases, is approved for use in an oral formulation for the treatment of osteolytic lesions, hypercalcemia, and bone pain in patients with carcinoma of the breast or MM. Pamidronate, a nitrogen-containing, intravenously administered bisphosphonate, is indicated for bone pain and osteolytic lesions in patients with breast cancer or MM. More recently, two newer-generation bisphosphonates, i.v. zoledronic acid and ibandronate, have become available. Zoledronic acid is a double-nitrogen, cyclic bisphosphonate available as an i.v. formulation. It is approved for the prevention of skeletal complications in patients with MM or bone metastases secondary to any solid tumors. Ibandronate is a single-nitrogen bisphosphonate, available in both i.v. and oral formulations, which has been approved for the prevention of skeletal events in patients with bone metastases from breast cancer.

Clodronate

SREs
Clinical trials of oral clodronate established its efficacy in patients with breast cancer and MM more than 10 years ago [6, 7]. More recently, two large, randomized, placebo-controlled trials designed to assess the efficacy of oral clodronate in the prevention of SREs were conducted. In the first trial, 100 patients with metastatic breast cancer (median age, 53 years) received either oral clodronate (800 mg) twice daily for 2 years or placebo. Treatment with clodronate resulted in a significantly lower occurrence of fractures (p = .023) and a significantly longer time to first SRE compared with placebo (p = .015). However, the effect of clodronate decreased with time; the need for radiation therapy increased in the clodronate group after 15 months (p = .069) [8]. In the other trial, 144 patients with breast cancer and osteolytic bone metastases (median age: clodronate, 57 years; placebo, 59.5 years) received either oral clodronate (1,600 mg/day) or placebo for 1 year. Median time to first bone event increased significantly with clodronate treatment (p = .05) [9].

Bone Pain
Oral clodronate appears to be less effective than i.v. pamidronate in reducing bone pain. This was demonstrated in a small (n = 51; age, ~60 years), comparative trial of oral clodronate (1,600 mg daily) versus i.v. pamidronate (90 mg monthly) [10]. More patients on pamidronate experienced symptomatic pain relief than did those on clodronate.

Pamidronate

SREs
Three trials established the efficacy of the recommended 90-mg dose of i.v. pamidronate in patients with breast cancer and bone metastases [11–14]. In a long-term efficacy and safety trial, patients with metastatic breast cancer and osteolytic bone lesions (age not provided in publication) were randomized to either pamidronate or placebo every 3–4 weeks for 2 years [11]. Significantly fewer patients on pamidronate reported any skeletal complication at 15, 18, 21, and 24 months compared with placebo (p <.001). Similarly, in a placebo-controlled trial of pamidronate in patients receiving hormonal treatment who had breast cancer and 1 lytic bone lesion (mean age: pamidronate, 60 years; placebo, 62 years), a significant reduction in SMR was observed at cycles 12, 18, and 24 [12]. Compared with placebo, the number of patients who experienced skeletal complications at 24 cycles was reduced significantly (56% vs. 67%; p = .027). In patients with advanced MM and 1 lytic lesion (age: pamidronate, 64 years; placebo, 63 years), a significantly lower proportion of patients who received nine cycles of pamidronate had any skeletal event compared with those on placebo (24% vs. 41%; p < .001) [13]. Furthermore, the clinical benefit of pamidronate was still significant after a preplanned 21 cycles of additional treatment [14].

Bone Pain
The effect of i.v. pamidronate on bone pain has been investigated in several randomized trials. In patients with breast cancer or MM, i.v. pamidronate (90 mg every 3 or 4 weeks) decreased pain scores [11, 12]. However, in a combined analysis of two placebo-controlled studies of men with prostate cancer (age, ~71.5 years), no significant/sustained differences in self-reported pain, analgesic use, or mobility were found between patients treated with pamidronate and those given placebo [15].

Zoledronic Acid

SREs
The efficacy of i.v. zoledronic acid (4 mg every 3 or 4 weeks) for the prevention of SREs has been demonstrated in a number of pivotal phase III trials involving patients with breast cancer, MM, hormone-refractory prostate cancer (HRPC), and other solid tumors [16–20]. Results from these trials are presented in Table 2.

In the phase III prostate cancer trial, significantly fewer patients on zoledronic acid experienced SREs compared with those on placebo [18]. Zoledronic acid reduced the risk for SREs by 36% (p = .002) [19]. In the phase III trial in patients with solid tumors, although the primary endpoint (the number of patients with SREs at 9 months) was reduced in the zoledronic acid group, this did not reach statistical significance when compared with the placebo group. The risk of SREs was reduced by 27% with zoledronic acid (p = .017) [20].

Bone Pain
In the comparative trial, both zoledronic acid (4 mg) and pamidronate (90 mg) resulted in decreases in pain scores at 12 months (<1-point decrease in Brief Pain Inventory composite pain scores compared with baseline). Use of analgesics either remained stable or decreased [17]. In the Japanese trial, zoledronic acid significantly reduced Brief Pain Inventory pain scores compared with baseline and placebo (no p value reported) [21]. The reduction of pain intensity was obtained 4 weeks after the first infusion of zoledronic acid. Similarly, patients with HRPC and bone metastases reported fewer increases in pain and analgesic scores with zoledronic acid than with placebo [18, 19]. In the solid tumor trial by Rosen et al., the mean composite pain score increased from baseline in the zoledronic acid and placebo groups, indicating increases in pain. However, the mean composite pain score was reduced in those patients on zoledronic acid who had pain at baseline [20]. The pain-relieving effects of i.v. zoledronic acid have also been demonstrated in three nonblinded studies in patients with MBD resulting from various primary malignancies [22–24]. Blinded studies confirming the pain efficacy of zoledronic acid are warranted.

Ibandronate

SREs
Both i.v. and oral ibandronate have been evaluated for the prevention of SREs in patients with breast cancer and bone metastases (Table 3) [25–27]. The efficacy of i.v. ibandronate (6 mg via 1–2-hour infusions every 3 or 4 weeks) was demonstrated in a phase III, placebo-controlled trial of 312 patients with breast cancer [28]. After 2 years of treatment, patients treated with i.v. ibandronate (6 mg) had a significantly lower SMPR (p = .004) than patients who received placebo. Andersen-Gill multiple-event analysis showed that i.v. ibandronate significantly reduced the risk for SREs by 29% (p = .0183) [27]. Oral ibandronate (50 mg/day) was also effective in preventing SREs compared with placebo. In the combined analysis of two trials reported by Body et al. [29], oral ibandronate significantly reduced SMPR (p = .004). Moreover, oral ibandronate was associated with a 38% lower risk for SREs than placebo (Andersen-Gill multiple-event analysis, p = .0183) [27]. Similar results were obtained when risk reductions were calculated by Poisson regression method (i.v. ibandronate: 40%, p = .0033; oral ibandronate: 38%, p = .0001) [25].

Bone Pain
In the phase III trials, both formulations of ibandronate significantly reduced pain scores compared with baseline for up to 2 years [33, 26]. The maximal relief of bone pain was obtained after approximately 12 weeks of treatment with standard i.v. and oral ibandronate dosing. Analgesic use was lower only in the ibandronate treatment groups, reaching statistical significance for oral ibandronate (p =.019 vs. placebo) [33].

A number of small phase II studies suggest that intensive dosing schedules of ibandronate may achieve rapid pain relief within 3 days in patients with moderate-to-severe bone pain [33–36]. Two of the trials reported by Heidenreich et al. have assessed the effects of i.v. ibandronate as loading and maintenance dosing. In those trials, patients with prostate cancer (n = 25) or urologic cancer (n = 53; prostate, renal, or bladder cancer) received i.v. ibandronate (6 mg) on 3 consecutive days (the loading dose) followed by standard i.v. ibandronate therapy for 20 weeks (6 mg every 3–4 weeks). In the prostate cancer trial, 92% of patients experienced significantly reduced pain scores (p < .001) [34]. Similarly, in the urologic cancer trial, 83% of patients experienced pain relief, with 25% of patients becoming pain-free. The reduction in pain scores was statistically significant at day 3 (from 7.5 at baseline to 3 at day 3) and remained below baseline during the maintenance phase [35].

Effects of Bisphosphonates on Quality of Life
In total, eight trials have assessed improvements in the quality of life resulting from treatment with bisphosphonates. These have been reviewed in full in Pavlakis et al. [37]. Of these, only the pivotal ibandronate trials reported a statistically significant improvement compared with placebo. Diel and colleagues found a statistically significant difference in global functioning between i.v. ibandronate (6 mg) and placebo groups (p = .004) [33]. Similarly, patients on oral ibandronate (50 mg) had a significantly better quality of life than those on placebo in the two oral trials (p = .032) [26].

	SAFETY OF BISPHOSPHONATES IN MBD

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
Bisphosphonates can be used to treat bone metastases in elderly cancer patients, but age-related conditions and co-morbidities must be taken into consideration. For example, many elderly patients have age-related renal function impairment or renal insufficiency (creatinine clearance <60 ml/minute). These individuals may be at increased risk for renal toxicity if treated with certain i.v. bisphosphonates.

Occasionally, the deterioration of renal function can be severe, resulting in acute renal failure, dialysis, and, in some cases, death [38]. Elderly patients may also have renal impairment as a result of their cancer. For example, renal failure is a major complication of MM [39], and bladder cancer can be associated with hydronephrosis [40]. Concomitant medications such as aminoglucoside antibiotics and some chemotherapy drugs (mainly cisplatin and, less extensively, its analogs) may also induce renal toxicity [41]. The administration of bisphosphonates via the i.v. route is also associated with transient acute-phase reactions, usually occurring after the first infusion [42]. Some oral dosing regimens are associated with upper gastrointestinal problems.

Clinical Trial Data

Clodronate
Noncompliance with oral clodronate therapy is often a result of the relatively high incidence of gastrointestinal adverse events associated with this bisphosphonate. In a 2-year trial of oral clodronate (1,600 mg/day) in patients with breast cancer, gastrointestinal adverse events were significantly more common in the clodronate group than in the placebo group (66% vs. 56%; p < .05) [43].

Pamidronate
Long-term treatment with pamidronate in elderly patients (median age, 73 years; n = 22) with bone metastases resulting from breast cancer, prostate cancer, or MM was found to be effective and well tolerated [44]. Adverse events of fever, nausea, and diarrhea were reported in 23%, 18%, and 14% of patients, respectively. There were two cases (9%) of reversible acute renal insufficiency. However, this was unexpected, because long-term pamidronate use is usually associated with deterioration in renal function [45].

Zoledronic Acid
Although zoledronic acid is well tolerated, renal toxicity appears to be more common with this agent than with any other bisphosphonate [45]. In the pivotal phase III trials, approximately 10%–15% of patients experienced renal impairment [16, 18, 20]. The incidence of renal dysfunction with zoledronic acid may be higher in routine clinical practice. For example, in a retrospective review of medical charts, 38% of patients with MM had renal impairment with zoledronic acid therapy [46]. As a result of concerns over the renal safety of zoledronic acid, the product labeling now mandates regular monitoring of renal function prior to each infusion, adequate hydration, and treatment discontinuation in the event of further deterioration in renal function [47, 48]. Dose reductions are also required in patients with mild or moderate renal impairment (creatinine clearance, 30 to >60 ml/minute).

Ibandronate
Unlike the other intravenously administered bisphosphonates, data suggest that the renal safety profile of ibandronate is similar to that of placebo. Using data from the pivotal i.v. trial, Body et al. conducted a post hoc Kaplan-Meier analysis of time to serum creatinine increase with ibandronate [49]. The definition for an increase in serum creatinine was identical to that used in the comparative trial of zoledronic acid and pamidronate [16, 17]. After 96 weeks of treatment, fewer patients on ibandronate had defined serum creatinine increases (6% vs. 12% with placebo, p = .22). Furthermore, in a 2-year extension of the phase III trial, there were no clinically relevant renal adverse events, and in both groups, serum creatinine levels were similar for up to 4 years [50]. Intensive dosing with i.v. ibandronate does not appear to compromise renal safety, including in patients with urologic cancer and compensated renal insufficiency [51]. Few studies have investigated the efficacy of ibandronate in patients with MM [52, 53]. However, available data suggest that ibandronate is well tolerated in this indication, even in elderly patients with pre-existing renal failure [53, 54].

Because renal toxicity is not a concern with oral bisphosphonate therapy, the oral formulation of ibandronate may be a viable alternative for elderly patients who have renal safety issues using i.v. bisphosphonates. The pooled safety results from the two phase III trials demonstrated that oral ibandronate is well tolerated [29]. The incidence of mild treatment-related upper gastrointestinal adverse events was low (7.0%) and only slightly higher in the ibandronate group than in the placebo group.

The acute-phase reactions and flu-like symptoms that can occur during the first 3 days following i.v. administration of bisphosphonates are likely to have a particularly detrimental effect in elderly patients and lead to increased incapacitation. In the comparative bone marker trial, fewer patients in the oral ibandronate group experienced adverse events than those in the zoledronic acid group. Importantly, there was a lower incidence of treatment-related pyrexia and flu-like symptoms during the first 3 days for oral ibandronate (2% vs. 27% with zoledronic acid) [30]. Similar results were obtained in a small 12-week study of i.v./oral ibandronate and i.v. zoledronic acid in 77 patients with breast cancer or MM. In that trial, patients in the ibandronate group received the i.v. formulation on day 1 (15-minute infusion) followed by oral ibandronate (50 mg) from day 2 onward. The incidence of pyrexia and flu-like symptoms experienced during days 1–3 was lower in the ibandronate group (13% vs. 26% with zoledronic acid) [55].

Osteonecrosis of the Jaw
In recent years, ONJ has emerged as a complication of bisphosphonate therapy [56–58]. Current reports suggest that bisphosphonates may vary in their propensity to cause ONJ. Zoledronic acid and pamidronate appear to be associated with a higher risk for ONJ compared with ibandronate [57]. In a review of medical records from 252 cancer patients, 17 (6.7%) developed ONJ. All occurrences of ONJ were diagnosed in patients who were treated with zoledronic acid alone (seven patients; 2.8%), after pamidronate (nine patients; 3.6%), or preceding ibandronate (one patient; 0.4%) [57]. Length of exposure to bisphosphonates appears to be the most important risk factor for occurrence [45]. Furthermore, dental procedures/use of dentures may increase the risk for ONJ. This is particularly relevant to elderly patients, since this population is more prone to dental problems than their younger counterparts.

	MANAGEMENT ISSUES IN ELDERLY PATIENTS

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
Administration of bisphosphonates via the i.v. route may be more suitable for certain elderly cancer patients. Treatment can be combined with other drugs, such as chemotherapy, guaranteeing compliance; however, oral formulations do have a number of benefits. Oral bisphosphonates are not associated with adverse effects on renal function. Moreover, patients do not need to visit the hospital for their therapy, which is an important advantage for elderly patients who may have mobility problems and would prefer the convenience of at-home treatment. One of the main issues with oral administration is patient compliance, and this is particularly relevant in elderly patients. Oral clodronate tablets are large and difficult for some patients to swallow. In a study of clodronate in patients with metastatic bone pain (n = 55), 11% of patients discontinued treatment because of difficulty swallowing the capsules [59]. In contrast, oral ibandronate is a small tablet (approximately 1 cm in length) administered once daily. In the phase III and open-label extension trials, no patients withdrew due to difficulties with swallowing [29, 60]. In some countries, oral medications may not be reimbursed; this means that the cost of the drug needs to be paid out of the patients’ own pockets. Oral ibandronate is reimbursed in most European countries and other markets, with the exception of France, where oral ibandronate is not available.

	IBANDRONATE CLINICAL TRIALS IN THE ELDERLY

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
As has been discussed, there are many issues associated with the effective treatment and supportive care of elderly cancer patients. However, a lack of evidence from clinical trials means that the specific needs and requirements of this population are not currently being addressed. The results from phase II studies indicate that loading-dose ibandronate achieves rapid pain relief in patients who have pain despite opioid use and radiation therapy. In an attempt to define more clearly the effects of bisphosphonate therapy in elderly patients with MBD, we have designed a randomized, 6-month, phase II study of the efficacy and safety of loading-dose ibandronate followed by i.v. or oral ibandronate maintenance therapy in 126 patients 70 years of age. The primary endpoint is the effect of ibandronate on bone pain. Secondary endpoints include improvements in quality of life and World Health Organization performance status score. Results are expected in January 2007. In Germany, a clinical study is evaluating the effects of adjuvant treatment with ibandronate with or without capecitabine in elderly patients (65 years of age) with early breast cancer. The primary endpoint is event-free survival.

	SUMMARY

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
The four bisphosphonates approved for use in patients with MBD have differing efficacy and safety profiles. Currently, there are no data from randomized clinical trials on the effects of bisphosphonates in elderly patients with cancer. There have been a number of clinical trials with bisphosphonates that have included substantial numbers of elderly patients, particularly in trials of multiple myeloma or prostate cancer patients [7, 15, 18, 19, 22, 23]. Safety results from these studies vary; a study of MM patients reported that safety of clodronate was comparable with that of placebo [7], whereas in a placebo-controlled study of zoledronic acid [18], there was a greater incidence of fatigue, anemia, myalgia, fever, and lower-limb edema (>5% more patients experiencing these adverse events), along with increased renal deterioration in the zoledronic acid groups. Until randomized head-to-head safety data in elderly patients become available, physicians will have to use what is known about the use of these agents in the general population to select the most appropriate bisphosphonate for this cohort of patients.

Clinical trials to assess the role of bisphosphonate therapy in other indications, for example, the adjuvant setting and in the prevention of cancer treatment-induced bone loss, are currently in progress. If successful, this may result in bisphosphonates being used in even more elderly patients with cancer. Such increased use raises concerns about the overall safety of bisphosphonates in elderly patients, whose response to therapy may be affected by factors such as co-morbidity, decreased organ function, and polypharmacy. Specific safety precautions should be taken with regard to renal toxicity and ONJ, which are associated with the use of some bisphosphonates and are of particular concern when treating elderly patients.

There are also management issues associated with the use of these therapies, such as route of administration. Both oral and i.v. formulations are available, and an assessment should be made by the physician as to which is the most appropriate, based on the needs of the individual patient.

Awareness of the importance of including elderly patients in clinical trials is increasing. For example, one trial has recently been designed specifically to identify the effects of loading-dose ibandronate in patients 70 years of age. Metastatic bone pain accounts for a large part of the morbidity associated with skeletal metastases [61, 62]. Patients have decreased mobility and are often bedridden, ultimately experiencing poor quality of life. Since aging is generally associated with a loss of mobility, the effects of metastatic bone pain can have a substantial impact on the lives of elderly patients. The pain-relieving effects of loading-dose ibandronate may allow patients to resume activities of daily living and no longer be confined to the hospital/home. The results of the ibandronate trial are keenly awaited.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 
C.G. has acted as a consultant for Roche, AstraZeneca, Eli Lilly, and Dompe Biotec.

	REFERENCES

Top Learning Objectives Abstract Introduction Bisphosphonates and MBD Safety of Bisphosphonates in... Management Issues in Elderly... Ibandronate Clinical Trials in... Summary Disclosure of Potential... References

 

1. Yancik R, Ries LA. Aging and cancer in America. Demographic and epidemiologic perspectives. Hematol Oncol Clin North Am 2000;14:17–23.[CrossRef][Medline]
2. Roodman GD. Mechanisms of bone metastasis. N Engl J Med 2004;350: 1655–1664.[Free Full Text]
3. Coleman RE. Metastatic bone disease: Clinical features, pathophysiology and treatment strategies. Cancer Treat Rev 2001;27:165–176.[CrossRef][Medline]
4. Coleman RE. Bisphosphonates: Clinical experience. The Oncologist 2004; 9(suppl 4):14–27.[Abstract/Free Full Text]
5. Clemons M, Dranitsaris G, Cole D et al. Too much, too little, too late to start again? Assessing the efficacy of bisphosphonates in patients with bone metastases from breast cancer. The Oncologist 2006;11:227–233.[Abstract/Free Full Text]
6. Paterson AHG, Powles TJ, Kanis JA et al. Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:59–65.[Abstract]
7. Lahtinen R, Laakso M, Palva I et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 1992;340:1049–1052.[CrossRef][Medline]
8. Kristensen B, Ejlertsen B, Groenvold M et al. Oral clodronate in breast cancer patients with bone metastases: A randomized study. J Intern Med 1999; 246:67–74.[CrossRef][Medline]
9. Tubiana-Hulin M, Beuzeboc P, Mauriac L et al. Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases [in French]. Bull Cancer 2001;88:701–707.[Medline]
10. Jagdev SP, Purohit P, Heatley S et al. Comparison of the effects of intravenous pamidronate and oral clodronate on symptoms and bone resorption in patients with metastatic bone disease. Ann Oncol 2001;12: 1433–1438.[Abstract/Free Full Text]
11. Hortobagyi GN, Theriault RL, Lipton A et al. Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. Protocol 19 Aredia Breast Cancer Study Group. J Clin Oncol 1998;16: 2038–2044.[Abstract]
12. Theriault RL, Lipton A, Hortobagyi GN et al. Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: A randomized, placebo-controlled trial. Protocol 18 Aredia Breast Cancer Study Group. J Clin Oncol 1999;17:846–854.[Abstract/Free Full Text]
13. Berenson JR, Lichtenstein A, Porter L et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996;334:488–493.[Abstract/Free Full Text]
14. Berenson JR, Lichtenstein A, Porter L et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myleoma Aredia Study Group. J Clin Oncol 1998;16:593–602.[Abstract]
15. Small EJ, Smith MR, Seaman JJ et al. Combined analysis of two multi-center, randomized, placebo-controlled studies of pamidronate disodium for the palliation of bone pain in men with metastatic prostate cancer. J Clin Oncol 2003;21:4277–4284.[Abstract/Free Full Text]
16. Rosen LS, Gordon D, Kaminski M et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: A phase III, double-blind, comparative trial. Cancer J 2001;7:377–387.[Medline]
17. Rosen LS, Gordon D, Kaminski M et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: A randomized, double-blind, multicenter, comparative trial. Cancer 2003;98:1735–1744.[CrossRef][Medline]
18. Saad F, Gleason DM, Murray R et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst 2002;94:1458–1468.[Abstract/Free Full Text]
19. Saad F, Gleason DM, Murray R et al. Long-term efficacy of zoledronic acid for the prevention of skeletal complications in patients with metastatic hormone-refractory prostate cancer. J Natl Cancer Inst 2004;96:879–882.[Abstract/Free Full Text]
20. Rosen LS, Gordon D, Tchekmedyian S et al. Zoledronic acid versus placebo in the treatment of skeletal metastases in patients with lung cancer and other solid tumors: A phase III, double-blind, randomized trial—the Zoledronic Acid Lung Cancer and Other Solid Tumors Study Group. J Clin Oncol 2003;21:3150–3157.[Abstract/Free Full Text]
21. Kohno N, Aogi K, Minami H et al. Zoledronic acid significantly reduces skeletal complications compared with placebo in Japanese women with bone metastases from breast cancer: A randomized, placebo-controlled trial. J Clin Oncol 2005;23:3314–3321.[Abstract/Free Full Text]
22. Fulfaro F, Arcara C, Badalamenti G et al. The use of zoledronic acid in the treatment of painful bone metastases from prostate cancer. Proc Am Soc Clin Oncol 2003;22:428a.
23. Vogel CL, Yanagihara RH, Wood AJ et al. Safety and pain palliation of zoledronic acid in patients with breast cancer, prostate cancer, or multiple myeloma who previously received bisphosphonate therapy. The Oncologist 2004;9:687–695.[Abstract/Free Full Text]
24. Wardley A, Davidson N, Barrett-Lee P et al. Zoledronic acid significantly improves pain scores and quality of life in breast cancer patients with bone metastases: A randomised, crossover study of community vs hospital bisphosphonate administration. Br J Cancer 2005;92:1869–1876.[CrossRef][Medline]
25. Body JJ, Kanis J, Diel I et al. Risk reductions in metastatic breast cancer: Multivariate Poisson regression analyses of oral and i.v. ibandronate. Proc Am Soc Clin Oncol 2003;22:46a.
26. Body JJ, Diel IJ, Bell R et al. Oral ibandronate improves bone pain and preserves quality of life in patients with skeletal metastases due to breast cancer. Pain 2004;111:306–312.[CrossRef][Medline]
27. Tripathy D, Budde M. Assessing the efficacy of ibandronate for the prevention of skeletal-related events (SREs) in metastatic bone disease: A methodological comparison. Bone 2004;34(suppl 1):S91.[CrossRef]
28. Body JJ, Diel IJ, Lichinitser MR et al. Intravenous ibandronate reduces the incidence of skeletal complications in patients with breast cancer and bone metastases. Ann Oncol 2003;14:1399–1405.[Abstract/Free Full Text]
29. Body JJ, Diel IJ, Lichinitzer M et al. Oral ibandronate reduces the risk of skeletal complications in breast cancer patients with metastatic bone disease: Results from two randomised, placebo-controlled phase III studies. Br J Cancer 2004;90:1133–1137.[CrossRef][Medline]
30. Body JJ, Lichinitser M, Tjulandin S et al. Oral ibandronate and intravenous zoledronic acid in metastatic breast cancer patients: Comparative bone turnover marker and safety data. Bone 2006;38(suppl 1):69a
31. Barrett-Lee P, Murray N. Zoledronic acid versus ibandronate comparative evaluation in breast cancer patients with bone metastases: The NCRI ZICE trial. Bone 2006;38(suppl 1):67a.
32. Rivkin S. Oral ibandronate versus intravenous zoledronic acid for breast cancer patients with skeletal complications: The SWOG trial. Bone 2006; 38(suppl 1):82a.
33. Diel IJ, Body JJ, Lichinitser MR et al. Improved quality of life after long-term treatment with the bisphosphonate ibandronate in patients with metastatic bone disease due to breast cancer. Eur J Cancer 2004;40:1704–1712.[CrossRef][Medline]
34. Heidenreich A, Elert A, Hofmann R. Ibandronate in the treatment of prostate cancer associated painful osseous metastases. Prostate Cancer Prostatic Dis 2002;5:231–235.[CrossRef][Medline]
35. Heidenreich A, Ohlmann C, Olbert P et al. High-dose ibandronate is effective and well tolerated in the treatment of pain and hypercalcaemia due to metastatic urologic cancer. Eur J Cancer 2003;1(suppl 5):S270.
36. Mancini I, Dumon JC, Body JJ. Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: A pilot study. J Clin Oncol 2004;22:3587–3592.[Abstract/Free Full Text]
37. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Co-chrane Database Syst Rev 2005 Jul 20;(3):CD003474.
38. Chang JT, Green L, Beitz J. Renal failure with the use of zoledronic acid. N Engl J Med 2003;349:1676–1679.[Free Full Text]
39. Goldschmidt H, Lannert H, Bommer J et al. Multiple myeloma and renal failure. Nephrol Dial Transplant 2000;15:301–304.[Free Full Text]
40. Haleblian GE, Skinner EC, Dickinson MG et al. Hydronephrosis as a prognostic indicator in bladder cancer patients. J Urol 1998;160:2011–2014.[CrossRef][Medline]
41. Patterson WP, Reams GP. Renal toxicities of chemotherapy. Semin Oncol 1992;19:521–528.[Medline]
42. Zojer N, Keck AV, Pecherstorfer M. Comparative tolerability of drug therapies for hypercalcaemia of malignancy. Drug Saf 1999;21:389–406.[CrossRef][Medline]
43. Atula S, Powles T, Paterson A et al. Extended safety profile of oral clodronate after long-term use in primary breast cancer patients. Drug Saf 2003; 26:661–671.[CrossRef][Medline]
44. Tralongo P, Repetto L, Di Mari A et al. Safety of long-term administration of bisphosphonates in elderly cancer patients. Oncology 2004;67:112–116.[CrossRef][Medline]
45. Tanvetyanon T, Stiff PJ. Management of the adverse effects associated with intravenous bisphosphonates. Ann Oncol 2006;17:897–907.[Abstract/Free Full Text]
46. Antrás L, Smith M, Neary M et al. Comparison of renal impairment in multiple myeloma patients treated with zoledronic acid or ibandronate: A retrospective medical records review. Bone 2006;38(suppl 1):87a.[CrossRef]
47. Novartis Pharmaceuticals Corporation. Zometa^® (zoledronic acid). US summary of product characteristics. East Hanover, NJ: Novartis Pharmaceuticals Corporation, November 2004.
48. Novartis International AG. Zometa^® (zoledronic acid). EU summary of product characteristics. Basel, Switzerland: Novartis International AG, May 2005.
49. Body JJ, Diel IJ, Tripathy D et al. Intravenous ibandronate does not affect time to renal function deterioration in patients with skeletal metastases from breast cancer: Phase III trial results. Eur J Cancer Care 2006; 15:299–302.[CrossRef]
50. Pecherstorfer M, Rivkin S, Body JJ et al. Long-term safety of intravenous ibandronate for up to 4 years in metastatic breast cancer: An open-label trial. Clin Drug Invest 2006;26:315–322.[CrossRef]
51. Heidenreich A, Ohlmann C, Bergner R. Renal safety of loading dose ibandronate in urologic patients with compensated renal insufficiency. Cancer Treat Rev 2005;31(suppl 1):S50.
52. Menssen HD, Sakalova A, Fontana A et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 2002;20:2353–2359.[Abstract/Free Full Text]
53. Henrich D, Bergner R, Hoffmann M et al. Ibandronate in the treatment of hypercalcemia or nephrocalcinosis in patients with multiple myeloma and acute renal failure. Support Care Cancer 2005;13:463;21a–150a.
54. Henrich D, Bergner R, Hoffman M et al. Renal safety of ibandronate in elderly myeloma patients with pre-existing renal deterioration. Paper presented at: Sixth Conference of the International Society for Geriatric Oncology; September 29–October 1, 2005; Geneva.
55. Bergström B, Lichinitser M, Body JJ. Intravenous and oral ibandronate have better safety and tolerability profiles than zoledronic acid: Evidence from comparative phase II/III trials. Bone 2006;38(suppl 1):68a–69a.
56. Migliorati CA, Schubert MM, Peterson DE et al. Bisphosphonate-associated osteonecrosis of mandibular and maxillary bone. An emerging complication of supportive cancer therapy. Cancer 2005;104:83–93.[CrossRef][Medline]
57. Bamias A, Kastritis E, Bamia C et al. Osteonecrosis of the jaw in cancer after treatment with bisphosphonates: Incidence and risk factors. J Clin Oncol 2005;23:8580–8587.[Abstract/Free Full Text]
58. Badros A, Weikel D, Salama A et al. Osteonecrosis of the jaw in multiple myeloma patients: Clinical features and risk factors. J Clin Oncol 2006;24: 945–952.[Abstract/Free Full Text]
59. Robertson AG, Reed NS, Ralston SH. Effect of oral clodronate on metastatic bone pain: A double-blind, placebo-controlled study. J Clin Oncol 1995;13:2427–2430.[Abstract/Free Full Text]
60. McLachlan S-A, Cameron D, Murray R et al. Safety of oral ibandronate in the treatment of bone metastases from breast cancer: Long-term follow-up experience. Clin Drug Invest 2006;26:43–48.[CrossRef]
61. Fulfaro F, Casuccio A, Ticozzi C et al. The role of bisphosphonates in the treatment of painful metastatic bone disease: A review of phase III trials. Pain 1998;78:157–169.[CrossRef][Medline]
62. Janjan N. Bone metastases: Approaches to management. Semin Oncol 2001;28:28–34.[Medline]

This Article Abstract Full Text (PDF) CME: Take the course for this article: The Use of Bisphosphonates in Elderly Cancer Patients eLetters: Submit a response to this article Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services E-mail this article link to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints/Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Gridelli, C. Search for Related Content PubMed PubMed Citation Articles by Gridelli, C.