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Too Much, Too Little, Too Late to Start Again? Assessing the Efficacy of Bisphosphonates in Patients with Bone Metastases from Breast Cancer

^a Division of Medical Oncology and ^c Department of Clinical Pathology, Sunnybrook and Women’s College Health Sciences Centre, Toronto, Canada; ^b Cancer Care Ontario, Toronto, Canada

Key Words. Bisphosphonates • Bone metastases • Breast cancer • Bone pain • Efficacy • Skeletal-related events

Correspondence: Mark Clemons, M.B., B.S., M.D., M.R.C.P., Division of Medical Oncology, Sunnybrook and Women’s College Health Sciences Centre, 2075 Bayview Avenue, Toronto, Ontario M4N3M5, Canada. Telephone: 416-480-5847; Fax: 416-480-6002; e-mail:mark.clemons{at}sw.ca

Received November 29, 2005; accepted for publication January 17, 2006.

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

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

1. Articulate the natural history of bone metastasis in the setting of advanced breast cancer.
   
2. Describe the role of bisphosphonates in managing bone metastases in the setting of breast cancer.
   
3. Discuss clinical end points used to determine whether bisphosphonates are useful in this setting.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

 
The diagnosis of bone metastases can be a devastating occurrence for any woman with breast cancer. In this setting, bone metastases can result in skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, and hypercalcemia. Several trials have confirmed the ability of bisphosphonates to reduce or delay these skeletal complications, and they should now be considered standard care for these women.

The analysis of SREs is the typical primary end point in bisphosphonate studies. While not undermining their importance, the definition of SREs does not include complications important to patients, such as pain and immobility. It is these symptoms that are most frequently reported by patients, and bone pain and quality of life (QoL) are often measured as secondary end points in these trials. Bone pain and QoL measures are not standardized and are difficult to compare among patient populations. We do not yet know the true efficacy of bisphosphonates as analgesics or how they impact QoL.

This paper reviews the current efficacy measures used in recent bisphosphonate trials and discusses their benefits and limitations. It also explores the role of bone biomarkers and their potential use in monitoring treatment response.

	INTRODUCTION

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

 
The occurrence of metastatic bone disease is not only devastating to breast cancer patients but also leads to adverse outcomes in terms of greater morbidity and mortality. An estimated 70% of women with advanced breast cancer develop bone metastases. If they remain untreated, half of these patients will subsequently develop a skeletal-related event (SRE). SREs are generally defined as including one or more of the following: pathologic fracture, radiotherapy for bone complications (uncontrolled bone pain/impending fracture), surgery for bone complications (fractures or impending fractures), or spinal cord compression. It has been estimated that up to 40% of breast cancer patients with bone metastases will suffer a pathologic fracture, 18% will require radiation to bone, and 1% will require surgery, while <10% will develop spinal cord compression [1, 2]. However, pain is the most common symptom of bone metastases in actual practice, occurring in 50%–90% of patients [1, 3].

The treatment of breast cancer patients with bone metastases requires a multidisciplinary approach. Systemic treatment options include analgesics, hormonal therapy, chemotherapy, and biological agents such as trastuzumab and bisphosphonates [4]. Bisphosphonates such as clodronate, ibandronate, pamidronate, and zoledronic acid are now standard care for metastatic bone disease with proven ability to reduce the risk for predefined SREs [5]. A systematic review of five trials among patients with breast cancer confirms the beneficial effects of bisphosphonates over placebo. Treatment significantly reduced the odds ratio for nonvertebral fractures (0.8; 95% confidence interval [CI], 0.64–0.99), combined fractures (0.75; 95% CI, 0.61–0.93), radiotherapy (0.65; 95% CI, 0.54–0.79), orthopedic surgery (0.59; 95% CI, 0.43–0.83), and hypercalcemia (0.43; 95% CI, 0.29–0.63) [6].

The role of bisphosphonates in the treatment of metastatic bone pain is not as clearly defined. In a randomized crossover trial of i.v. clodronate in patients with pain from bone metastases, Ernst et al. [7] reported a significant difference in daily morphine dose scores (p = .03) but no significant difference in scores from visual analogue scales (p = .51) between the placebo and clodronate groups. In a combined analysis of two studies of pamidronate, the mean pain scores at last visit increased in both the placebo and treatment groups. However, they increased significantly less in the treatment group (p < .001), with fewer patients experiencing an overall increase in pain (40% vs. 52%; p = .003) [8]. A review of phase III trials of ibandronate demonstrated that both the oral and i.v. formulations reduced bone pain to below baseline levels over 2 years (p = .001 vs. placebo) [9]. In a phase III study of zoledronic acid versus placebo, while pain scores in the treatment group were consistently lower, they were not significantly different [2].

Guidelines from the American Society of Clinical Oncology (ASCO) suggest that i.v. pamidronate or zoledronic acid may be useful in the treatment of pain caused by bone metastases when used with concurrent systemic chemotherapy and/or hormonal therapy. However, there is insufficient evidence to support a role as adjunctive therapy to radiation therapy when no other systemic treatment is being used [10]. A systematic review by Wong and Wiffen [11] concluded that, although evidence supported their effectiveness in providing some pain relief for bone metastases, there were insufficient data to recommend bisphosphonates as first-line therapy, to define the most effective bisphosphonate, or to define the relative effectiveness of one agent or another against various different primaries.

A recent survey reported that 31% of physicians in Europe and Canada consider bisphosphonates (on their own or in combination with other therapies) to be ineffective in controlling pain [12]. Furthermore, although patients seek rapid pain relief, the reality is that the onset of the analgesic effect is slow with standard doses of bisphosphonates. Despite the uncertainty regarding analgesic benefit, there has been a trend toward initiating bisphosphonates before delivery of palliative radiation therapy. A study by Enright et al. [13] reported that, before 1998, 42.9% of patients received palliative radiation treatment as initial therapy for bone metastases, whereas in 2001, only 27.8% of patients received palliative radiation treatment upfront.

Clinicians need better methods of evaluating the effect of bisphosphonates on bone metastases in order to estimate their true efficacy and palliative value. Most studies depend on the number and timing of SREs to compare the treatment and placebo arms. The definition of an SRE does not include end points that are important to patients: pain, immobility, analgesic use, and nonhospital costs such as those of physiotherapy [5]. In addition, many studies use serial plain radiographs in the form of skeletal surveys to detect asymptomatic fractures, thereby detecting SREs but ignoring pain. Pain scores, analgesic consumption, and quality of life (QoL) scores are all subject to observer bias and are difficult to compare among different patient populations. To allow true estimation of analgesic and palliative benefits of bisphosphonates, we need a standardized pain measurement and QoL instrument that includes domains that are important to the patient. This paper reviews the current efficacy measures used in bisphosphonate trials and discusses their limitations.

	END POINTS IN BISPHOSPHONATE TRIALS

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

 
The U.S. Food and Drug Administration’s "regular approval" is based on end points that demonstrate that a drug provides a longer or better life or that it has a favorable effect on an established surrogate [14]. Regulatory approvals for currently available bisphosphonates were based on various clinical efficacy end points used to assess the occurrence of SREs.

SRE Measures
Although SREs are the most frequently used primary end points in bisphosphonate trials (Table 1) [2, 8, 15–27], many different SRE scores are available, making comparisons among trials difficult.

Typically, a patient’s risk of experiencing an SRE increases with time as metastatic disease progresses. For this reason, the impact of treatment on skeletal morbidity is best captured by methods that measure multiple events over time. The mean skeletal morbidity rate (SMR) can be defined as the number of SREs per patient divided by the patient’s time on study (in years) and has been reported and analyzed in trials of zoledronic acid and pamidronate. However, patients with bone metastases exhibit considerable variation in frequency and timing of SREs since some patients experience isolated events while others experience them in clusters [28]. When skeletal complications are temporally clustered, they are more likely related, but this clustering is not expressed in the SMR because it assumes that all SREs are independent of one another.

An alternative measure is the skeletal morbidity period rate (SMPR), which also has been reported in phase III trials of i.v. and oral ibandronate. The SMPR accounts for the inter-dependence of events by counting events only once within a given time period and is defined as the number of periods with new events divided by the total number of periods on study per patient. The time periods chosen are typically on the order of 12 weeks. Because the SMPR accounts for the interdependence of skeletal events, it is increasingly being used in place of the SMR to report the findings of clinical trials. One important practical limitation of both the SMR and SMPR statistics is the difficulty in transforming these end points into a form that patients can understand when confronted with a decision to initiate a bisphosphonate.

Multiple event analysis, such as the Andersen-Gill method [29], has been used to analyze SREs as secondary end points in clinical trials of zoledronic acid and ibandronate. The method examines all SREs and their timing throughout the course of the disease, taking variability in event rates among patients into account (including clustering), and allowing rates to vary over time [28]. It is a statistically robust method that accounts for all skeletal events and for the timing of events throughout the course of the disease. However, it does not fully account for between-group differences of patients’ time on study. For example, it is difficult to distinguish between groups in terms of patients who die or withdraw from the study for other reasons and are still at risk for an SRE. Cook and Lawless [30] have developed a multiple-event method that takes mortality into account, while Ghosh and Lin [31] have described another method that is useful in analyzing the cumulative number of events.

Bone Pain Measures
As with SREs, many different methods have been used to assess metastatic bone pain in bisphosphonate trials, and there is no universally accepted or validated instrument. Most trials use a combination of bone pain and analgesic count. Early trials did not make a formal assessment of bone pain because of the inadequacy of pain assessment methodology for patients with bone metastases. Instead, it was indirectly assessed by estimating the radiation requirement for pain, and radiation therapy was undertaken as clinically required [21]. The requirement for radiotherapy to the bone is considered an SRE in the composite end points of bisphosphonate trials. This requirement represents a significant part of the SRE end point. Therefore, in a roundabout way, SRE outcomes in these trials do incorporate some measure of pain relief. However, there is a need for a more direct assessment of metastatic bone pain relief.

Randomized, placebo-controlled studies of pamidronate used a scoring system that measured both the severity (graded 0–3) and frequency (graded 0–3) of pain [8, 24]. The final bone pain score was equal to the product of the two individual scores. A score of 0 indicated no pain, while a score of 9 indicated severe, constant pain. Analgesic use was also estimated using a composite score. A final score was obtained by multiplying a score for the type of medication by a score for the frequency at which it was administered.

Phase III trials of i.v. and oral ibandronate used a simple, five-point scale—0 (no pain), 1 (mild pain), 2 (moderate pain), 3 (severepain), and 4 (intolerablepain)—that patients were asked to complete every 3–4 weeks, during each study visit, to evaluate bone pain over the previous week [15, 16, 25, 32, 33]. Analgesic use was scored on a seven-point scale: 0 (none), 1 (mild analgesia; e.g., paracetamol or nonsteroidal anti-inflammatory drugs [NSAIDs]), 2 (mild analgesia and NSAIDs), 3 (moderate analgesia; e.g., codeine), 4 (opiates, morphine equivalent of <40 mg daily), 5 (opiates, =40 mg but <100 mg morphine equivalent daily), and 6 (=100 mg morphine equivalent daily).

The Brief Pain Inventory comprises a composite of four pain scores (worst, least, and average pain over the last week and current pain) and is validated for cancer pain rather than metastatic bone pain [34]. This was used in the placebo-controlled trial of zoledronic acid and a randomized comparative study of zoledronic acid versus pamidronate [2]. A five-point scale was used to measure analgesic use, ranging from 0 (no analgesic use) to 4 (strong narcotics).

A range of other scales for both bone pain and analgesic use has been used by other studies. These include a visual analogue scale [19], variants of pain–point scales [17], and analgesic use on a four- or five-point scale [19, 20]. While all these instruments represent an improvement in pain relief by a decrease in pain score, scale variations make it difficult for clinicians to estimate if the effect on pain relief differs among drugs.

QoL Measures
QoL measurements are subjective, multidimensional constructs reflecting functional status, psychosocial well-being, health perceptions, and disease- and treatment-related symptoms from the patient’s perspective. They incorporate expectation, satisfaction, a value system, and many other aspects of a patient’s life. In general, QoL has been poorly estimated in bisphosphonate studies.

Pamidronate studies have used the Spitzer QoL instrument [35], which is intended to be completed by a health care professional and consists of only five items; activity, daily living, health, support, and outlook. This instrument was designed to assess the relative benefits and risks of various treatments for serious illness and of supportive programs, such as palliative care or hospice care. It is not suitable for measuring the QoL in ostensibly healthy people. Studies of clodronate [20] and ibandronate [32, 33] used the European Organization for Research and Treatment of Cancer Quality-of-Life Questionnaire (EORTC QLQ-C30) [36]. This instrument is composed of modules that assess QoL for specific cancers in clinical trials. The current instrument consists of 30 items with five functional scales: physical function, role function, cognitive function, emotional function, and social function.

However, neither the Spitzer nor the European instrument addresses in depth the QoL issues related to the complications of bone metastases, such as mobility, functional impairment, and the side effects of bony progression, (such as pathological fractures, hypercalcemia, and spinal cord compression). There is an urgent need to develop a QoL instrument specific to bone metastases that addresses these issues. A Canadian-led group proposes to develop a specific module for patients with bone metastases that will be administered concurrently with the EORTC QLQ-C30 core questionnaire (Edward Chow, personal communication). When developed and used in future clinical trials, it will allow for more accurate self-assessment of the palliative benefits of bisphosphonate treatments.

Bone Markers
Markers of bone turnover (Table 2) are now frequently measured as secondary end points in bisphosphonate studies. Such markers seem to hold the most promise in identifying patients likely to respond to and benefit from bisphosphonate treatment [37]. Among them, urinary N-terminal cross-linked type 1 collagen telopeptide (uNTx) and C-terminal cross-linked type 1 collagen telopeptide (CTX) are the most widely used [38]. Elevated NTx levels predict subsequent SREs, and conversely, normalization of excretion rates is associated with a reduction in SREs and improvement of symptoms.

Lipton et al. [41] reported a link between SREs and bone markers in breast cancer patients treated with pamidronate for 6 months. NTx excretion was significantly reduced (p = .002) in patients receiving pamidronate compared with those randomized to placebo. In the pamidronate group, normalized NTx levels were associated with a lower but nonsignificant, incidence of fractures than seen in patients with NTx levels that remained elevated (42% vs. 89%).

In a phase II randomized trial involving patients with breast cancer or multiple myeloma treated with different bisphosphonate regimens, greater reductions in NTx levels were obtained following treatment with the two highest dose levels of zoledronic acid and the single dose level of pamidronate than with the lowest dose of zoledronic acid, and the reductions correlated with a lower incidence of SREs [42].

Evidence for a relationship between bone markers and metastatic bone pain is limited. In a randomized trial of pamidronate for treating bone pain related to metastatic bone disease from breast or prostate cancer, symptomatic response was observed during the first 4 weeks of treatment with pamidronate but not with placebo (p < .05) [43]. Among the 52 patients treated with pamidronate, clinical response (defined as a >20% decrease in pain score on at least two consecutive measurements) was closely correlated with the rate of bone resorption assessed by a bone biomarker.

Jagdev and colleagues [44] compared the effects of pamidronate and oral clodronate on pain symptoms and bone resorption in patients with metastatic bone disease from breast, prostate, renal, lung, thyroid, or other solid tumors. Pain scores in the pamidronate group improved significantly compared with those in the clodronate group after 3 months of treatment (p < .01) and at the last assessment (4 months; p < .05). Changes in levels of bone markers were correlated with changes in pain scores (p = .01).

These results suggest that bone turnover is correlated with SREs in patients with metastatic bone disease and that bone markers appear to serve as adequate surrogates for the anti-SRE efficacy of bisphosphonates. Because of the lack of sufficient, rigorous, prospective phase III data, current ASCO guidelines for bisphosphonates in breast cancer advise against using biochemical markers to monitor treatment routinely [10]. Despite these reservations, the potential benefits of using bone markers in managing patients with metastatic bone disease is not inconsiderable. Indeed, the ASCO guidelines acknowledge the potential clinical value of bone markers as prognostic or predictive factors of bisphosphonate response. It has been recommended that the prognostic value of bone markers be confirmed by prospective clinical trials involving comprehensive bone tumor assessments with a combination of bone imaging and bone turnover measurements [45].

	CONCLUSION

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

 
Bisphosphonates are now the treatment of choice for patients with bone metastases from breast cancer because they can delay or prevent SREs. In breast cancer patients, bisphosphonates reduce the risk for developing a skeletal event by 17% (RR 0.83; 95% CI, 0.78–0.89) [46]. But this is not enough. At the clinical level, we need to understand what impact they have on each individual patient on a daily basis. It has been estimated that 90% of patients continue on bisphosphonates until death [47]. This can have serious financial and emotional implications. Moreover, they must return to the cancer center for treatment when terminally ill, and we do not currently assess the impact this has on them or their families.

The true efficacy of bisphosphonates as analgesics and their impact on QoL are not really known. Most bisphosphonate clinical trials focus on end points such as SREs and not so much on bone pain. SRE scores do not include QoL issues important to patients. Different scores for SREs are available, making comparisons among different trials and different bisphosphonates difficult. Still, there is increasing evidence that sensitive biochemical measures of bone turnover can act as surrogate measures for treatment response in metastatic bone disease. However, the correlation between bone markers and response to treatment is only now being defined and needs further assessment in a randomized trial setting. Finally, bone pain measures are frequently not standardized and are subject to observer bias.

As pain is the most frequently reported symptom from patients with metastatic bone disease, effective and rapid pain management is essential to improving levels of functioning and QoL. Pain and QoL instruments designed specifically for patients with bone metastases are urgently needed to assess the true efficacy of treatment. Recent studies have shown that rapid relief of bone pain may be achieved with loading doses of i.v. ibandronate [48]. Phase III studies are under way that will further investigate this treatment protocol in comparison with standard doses of i.v. zoledronic acid.

In order to optimize patient care, we need to correlate QoL scores specific to bone metastases with information obtained from conventional trial end points. Pinpointing the nature of the correlation among traditional end points, bone markers, bone pain measures, and QoL will help guide optimal, individualized treatment strategies for patients.

	DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

 
Mark Clemons and George Dranitsaris have acted as consultants for Novartis within the past 2 years.

	REFERENCES

Top Learning Objectives Abstract Introduction End Points in Bisphosphonate... Conclusion Disclosures of Potential... References

 

1. Diel IJ. Bisphosphonates in the prevention of bone metastases: current evidence. Semin Oncol 2001;28(suppl 11):75–80.[CrossRef][Medline]
2. 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]
3. LoRusso P. Analysis of skeletal-related events in breast cancer and response to therapy. Semin Oncol 2001;28(suppl 11):22–27.[Medline]
4. Clemons M. Should all breast cancer patients with symptomatic bone metastases be treated with bisphosphonates? The case in support. Clin Oncol (R Coll Radiol) 2004;16:108–111.
5. Gainford MC, Dranitsaris G, Clemons M. Recent developments in bisphosphonates for patients with metastatic breast cancer. BMJ 2005;330:769–773.[Free Full Text]
6. Ross JR, Saunders Y, Edmonds PM et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003;327:469–475.[Abstract/Free Full Text]
7. Ernst DS, Brasher P, Hagen N et al. A randomized controlled trial of intravenous clodronate in patients with metastatic bone disease and pain. J Pain Symptom Manage 1997;13:319–326.[CrossRef][Medline]
8. Lipton A, Theriault R, Hortobagyi GN et al. Pamidronate prevents skeletal complications and is effective palliative treatment in women with breast carcinoma and osteolytic bone metastases: long-term follow-up of two randomized, placebo-controlled trials. Cancer 2000;88:1082–1090.[CrossRef][Medline]
9. Tripathy D, Body JJ, Bergstrom B. Review of ibandronate in the treatment of metastatic bone disease: experience from phase III trials. Clin Ther 2004;26:1947–1959.[Medline]
10. Hillner BE, Ingle JN, Chlebowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol 2003;21:4042–4057.[Abstract/Free Full Text]
11. Wong R, Wiffen PJ. Bisphosphonates for the relief of pain secondary to bone metastases. Cochrane Database Syst Rev 2002;(2):CD002068.
12. McPartland C, Grosjean L. Treatment of painful bone metastases in Europe and Canada: the role of bisphosphonates. Ann Oncol 2004;15(suppl 3):iii50.
13. Enright K, Clemons M, Chow E. Utilization of palliative radiotherapy for breast cancer patients with bone metastases treated with bisphosphonates–Toronto Sunnybrook Regional Cancer Centre experience. Support Care Cancer 2004;12:48–52.[Medline]
14. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol 2003;21:1404–1411.[Abstract/Free Full Text]
15. 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]
16. 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]
17. Conte PF, Latreille J, Mauriac L et al. Delay in progression of bone metastases in breast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. J Clin Oncol 1996;14:2552–2559.[Abstract]
18. Hortobagyi GN, Theriault RL, Porter L et al. Efficacy of pamidronate in reducing skeletal complications in patients with breast cancer and lytic bone metastases. N Engl J Med 1996;335:1785–1791.[Abstract/Free Full Text]
19. Hultborn R, Gundersen S, Ryden S et al. Efficacy of pamidronate in breast cancer with bone metastases: a randomized, double-blind placebo-controlled multicenter study. Anticancer Res 1999;19:3383–3392.[Medline]
20. 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]
21. Paterson AH, 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]
22. 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]
23. Rosen L, Gordon DH, Dugan W Jr et al. Zoledronic acid is superior to pamidronate for the treatment of bone metastases in breast carcinoma patients with at least one osteolytic lesion. Cancer 2004;100:36–43.[CrossRef][Medline]
24. Theriault RL, Lipton A, Hortobagyi GN et al. Pamidronate reduces skeletalmorbidityinwomenwithadvancedbreastcancerandlyticbonelesions: a randomized, placebo-controlled trial. J Clin Oncol 1999;17:846–854.[Abstract/Free Full Text]
25. Tripathy D, Lichinitzer M, Lazarev A et al. Oral ibandronate for the treatment of metastatic bone disease in breast cancer: efficacy and safety results from a randomized double-blind, placebo-controlled trial. Ann Oncol 2004;15:743–750.[Abstract/Free Full Text]
26. Tubiana-Hulin M, Beuzeboc P, Mauriac L et al. [Double-blinded controlled study comparing clodronate versus placebo in patients with breast cancer bone metastases.] Bull Cancer 2001;88:701–707. French.[Medline]
27. van Holten-Verzantvoort AT, Kroon HM, Bijvoet OL et al. Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol 1993;11:491–498.[Abstract/Free Full Text]
28. Major PP, Cook R. Efficacy of bisphosphonates in the management of skeletal complications of bone metastases and selection of clinical endpoints. Am J Clin Oncol 2002;25(suppl 1):s10–s18.
29. Anderson PK, Gill RD. Cox’s regression model for counting processes: a large sample study. Ann Stat 1982;10:1100–1120.
30. Cook RJ, Lawless JF. Marginal analysis of recurrent events and a terminating event. Stat Med 1997;16:911–924.[CrossRef][Medline]
31. Ghosh D, Lin DY. Nonparametric analysis of recurrent events and death. Biometrics 2000;56:554–562.[CrossRef][Medline]
32. 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]
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. Cleeland CS, Ryan KM. Pain assessment: global use of the Brief Pain Inventory. Ann Acad Med Singapore 1994;23:129–138.[Medline]
35. Spitzer WO, Dobson AJ, Hall J et al. Measuring the quality of life of cancer patients: a concise QL-index for use by physicians. J Chronic Dis 1981;34:585–597.[CrossRef][Medline]
36. Aaronson NK, Ahmedzai S, Bergman B et al. Quality of Life: Assessment, Analysis, and Interpretation. New York: John Wiley, 2000:21.
37. Gainford MC, Dranitsaris G, Clemons M. Systemic treatment of bone metastases from breast cancer: Is it all that it’s cracked up to be? J Clin Oncol 2005;23:4802–4803.[Free Full Text]
38. Clamp A, Danson S, Nguyen H et al. Assessment of therapeutic response in patients with metastatic bone disease. Lancet Oncol 2004;5:607–616.[CrossRef][Medline]
39. Brown JE, Thomson CS, Ellis SP et al. Bone resorption predicts for skeletal complications in metastatic bone disease. Br J Cancer 2003;89: 2031–2037.[CrossRef][Medline]
40. Coleman RE, Major P, Lipton A et al. Predictive value of bone resorption and formation markers in cancer patients with bone metastases receiving the bisphosphonate zoledronic acid. J Clin Oncol 2005;23:4925–4935.[Abstract/Free Full Text]
41. Lipton A, Demers L, Curley E et al. Markers of bone resorption in patients treated with pamidronate. Eur J Cancer 1998;34:2021–2026.[CrossRef][Medline]
42. Berenson JR, Rosen LS, Howell A et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001;91:1191–1200.[CrossRef][Medline]
43. Vinholes JJ, Purohit OP, Abbey ME et al. Relationships between biochemical and symptomatic response in a double-blind randomized trial of pamidronate for metastatic bone disease. Ann Oncol 1997;8:1243–1250.[Abstract/Free Full Text]
44. Jagdev SP, Purohit OP, 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]
45. Gainford MC, Dranitsaris G, Clemons M et al. Systemic treatment of bone metastases from breast cancer: is it all that it’s cracked up to be? J Clin Oncol 2005;23:4802–4803; author reply 4803.[Free Full Text]
46. Pavlakis N, Schmidt R, Stockler M. Bisphosphonates for breast cancer. Cochrane Database Syst Rev 2005;(3):CD003474.
47. Clemons M, Enright K, Cesta A et al. Do physicians follow systemic treatment and funding policy guidelines? Can J Clin Pharmacol 2004;11: e168–e178.[Medline]
48. 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.

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This Article Abstract Full Text (PDF) CME: Take the course for this article: Too Much, Too Little, Too Late to Start Again? Assessing the Efficacy of Bi... 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 HighWire Citing Articles via Google Scholar Google Scholar Articles by Clemons, M. Articles by Gainford, M. C. Search for Related Content PubMed PubMed Citation Articles by Clemons, M. Articles by Gainford, M. C.