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|Year : 2011 | Volume
| Issue : 3 | Page : 210-218
A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis
Krishnangshu Bhanja Choudhury1, Chandrani Mallik2, Shyam Sharma1, Debangshu Bhanja Choudhury3, Sumana Maiti1, Chhaya Roy1
1 Department of Radiotherapy, Institute of Post Graduate Medical Education and SSKM Hospital, Kolkata, West Bengal, India
2 Department of Radiotherapy , Burdwan Medical College, Burdwan, West Bengal, India
3 Department of General Surgery, Calcutta National Medical College and Hospital, Kolkata, West Bengal, India
|Date of Web Publication||28-Jan-2012|
Krishnangshu Bhanja Choudhury
Department of Radiotherapy, Institute of Post Graduate Medical Education and SSKM Hospital, Kolkata, West Bengal
Source of Support: None, Conflict of Interest: None
Introduction: The prospective interventional single-institution randomized control study was carried out to compare the pain relieving efficacy among different bisphosphonates at the cost of incidence of skeletal-related events (SRE).
Materials and Methods: During June 2008 and May 2011, 256 patients with painful bone metastasis in solid tumors with a pain score of at least 5 were randomized into three arms: zoledronic acid (4 mg, i.v.), ibandronate (6 mg, i.v.) and pamidronate (90 mg, i.v.). Radiation was given to all patients, either 800 cGy single fraction or 20 Gy in five fractions. The ANOVA test was used for analysis. The Pearson test was used to correlate pain scores with proportions of responders as statistical estimation of pain relief.
Results: With a mean baseline pain score of 6.5 ± 1.2, there was no difference in pain scores among the three treatment arms, assessed at 3 months and at the end of the study. However, the pain scores at 6 months were statistically reduced in zoledronic acid-receiving patients (1.5 ± 0.4) unlike the scores in patients receiving ibandronate (3.1 ± 0.5) and pamidronate (2.3 ± 0.4), with a P-value of 0.024. The response was statistically significant at 6 months (0.039) and at the end of the study (0.023), in favor of zoledronic acid. Pearson's correlation demonstrated a statistically significant positive correlation between pain scores and response rates. There were no statistical differences in the narcotic scores among the treatment arms during the study period. The overall duration of pain relief was not different in any of treatment arms. The time of detection of hypercalcemia was no different; however, the incidence of hypercalcemia was significantly less in the zoledronic acid arm (28.3%) against 44.6% and 50% in ibandronate and pamidronate arms, respectively, with a P-value of 0.041.
Conclusion: The use of bisphosphonates for 6 months or more results in a statistical significant improvement in bone pain, more so with zoledronic acid. Hypercalcemia, an SRE, was significantly less in the zoledronic acid arm.
Keywords: Bisphosphonates, Ibandronate, Pamidronate, Painful bone metastasis, Skeletal-related events, Zoledronic acid
|How to cite this article:|
Choudhury KB, Mallik C, Sharma S, Choudhury DB, Maiti S, Roy C. A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis. Indian J Palliat Care 2011;17:210-8
|How to cite this URL:|
Choudhury KB, Mallik C, Sharma S, Choudhury DB, Maiti S, Roy C. A randomized controlled trial to compare the efficacy of bisphosphonates in the management of painful bone metastasis. Indian J Palliat Care [serial online] 2011 [cited 2020 Sep 20];17:210-8. Available from: http://www.jpalliativecare.com/text.asp?2011/17/3/210/92338
| » Introduction|| |
Palliative care is defined by the World Health Organization as the active total care of patients whose disease is not responsive to curative treatment. Bone is the third most common organ to which cancer metastasizes, after the lungs and liver. In 75% of the patients with bone metastases, pain is the dominant symptom. An adequate management of this group of patients is important for a number of reasons as bone pain secondary to metastasis is the most common pain syndrome requiring palliative treatment in cancer patients; patients with predominant bone metastasis have longer duration of survival than patients with predominantly visceral metastasis, and complications of bone metastasis are common and produce high morbidity.
Many clinical trials evaluating pain outcomes have relied on between-group comparisons or mean change-from-baseline scores on a continuous measure of pain. A recent Cochrane review of bisphosphonates for the relief of pain secondary to bone metastases, Wong  recommended against the use of mean pain scores, which was the methodology applied in the analysis by Saad et al suggesting instead that investigators examine the proportions of patients with pain relief. This recommendation is consistent with assertions by Farrar et al.  that comparing proportions of responders between groups provides findings with greater clinical relevance.
This study was carried out with the intentions of comparing the pain relieving efficacy among different bisphosphonates at the cost of incidence of skeletal-related events (SREs). The study was also intended to correlate the responders using pain scores with proportions of responders as the statistical estimation of pain relief.
| » Materials and Methods|| |
During June 2008 and May 2011, 280 patients with painful bone metastasis arising from solid tumors were selected for this single institutional, open label, interventional, randomized control study. The inclusion criteria were age (more than 18 years), solid tumors with at least one metastatic bone lesion, normal renal (serum creatinine less than 1.5 mg/dl) and hepatic function, ECOG performance status 1-4, life expectancy of at least 3 months, normal serum calcium or asymptomatic hypercalcemia, pain score of at least 5 [pain assessed with the worst pain score from the Brief Pain Inventory (BPI): patients must have a 'worst pain score' of ≥5 on a scale of 10 (as scored on the BPI question no. 3: 0 = no pain; 10 = worst possible pain)], pain corresponding to the area of bone metastases and willing to give consent for participation in trial as per Helsinki declaration. Patients were excluded if they were taking nephrotoxic drugs or osteoclast activity modulators, with the target lesions that were not detectable by conventional techniques, the painful area had received prior radiation or surgery, pathologic fracture, clinical or radiographic evidence of spinal cord compression or cauda equina syndrome, with hematological malignancy, with pregnancy or lactation and if were unlikely to cooperate fully during the study. The bone lesions were demonstrated on conventional imaging of plain radiographs, computed tomograms or magnetic resonance studies.
The primary endpoint was reduction in bone pain and reduced analgesic use. The secondary endpoint was measurement of SREs which included pathologic bone fractures, spinal cord compression and surgery to bone (surgery to treat or prevent pathologic fracture or spinal cord compression) or hypercalcemia. Also, an attempt was made to correlate the pain scores with response rates.
On the basis of criteria, 256 patients were randomized into three arms: zoledronic acid (4 mg, i.v., every 3-4 weeks), ibandronate (6 mg, i.v., every 3-4 weeks) and pamidronate (90 mg, i.v., every 3-4 weeks). Basic demographic variables were collected prior to simple randomization, along with clinical variables including time of cancer diagnosis, site and date of diagnosis of metastases other than bone at initial diagnosis, primary site of cancer, history of skeletal morbidities prior to study entry, serum creatinine level, prostate-specific antigen and baseline Eastern Cooperative Oncology Group (ECOG) performance status. A switchover among different drugs was not allowed. Patients with a switchover from zoledronic acid to others due an elevated creatinine level (more than 1.5 mg/dl) were left out of the study. Radiation were given to all patients in any of the two fractionation schedules, either single fraction of 800 cGy or 20 Gy in five fractions, using a Cobalt-60 radiation machine, using anterior-posterior or tangential radiation portals, as applicable, with a source-to-skin distance of 80 cm. Hemibody irradiation was avoided for any patient receiving 800 cGy. Palliative chemotherapy was considered as per institution protocol for chemotherapy naïve or refractory patients with a multiple drug combination for ECOG performance status of 1 and 2, single drug for ECOG score 3 and best supportive care for patients with an ECOG score of 4. Hormonal therapy for breast and prostate cancer was considered as appropriate for the patient. Those patients already receiving chemotherapy or hormones at the time of inclusion into the study were continued as per discretion of doctors and patient status. All patients received narcotics and non-narcotic analgesics as per the WHO 'analgesic ladder', three-tier analgesic and adjuvant drug combination protocol.
At each visit scheduled at 1, 2, 3 and 6 months and thereafter every 6 months, till the end of the study, patients were provided with a questionnaire and asked to rate their pain since the previous study visit on a scale from 1 to 10. Each visit was considered as a scheduled visit if made within 5 days before and after the expected date of visit as per study protocol. The questionnaire was part of a pain assessment tool, the Brief Pain Inventory. The outcomes were determined according to the response to pain defined by the 'International Bone Metastases Consensus'. The responses were compared with those in the previous visit. A complete response (CR) was defined as the worst pain score of 0 at the treated site with no increase in the analgesic intake. A partial response (PR) was defined as (i) reduction in the worst pain score of 2 or more at the treated site without any analgesic increase, or (ii) analgesic reduction of 25% or more from the previous score without an increase in pain. A stable response was defined as a one-point change in the pain score in either direction. Individuals who experienced pain progression or who did not fall into one of the response categories outlined by the consensus were considered nonresponders. Pain progression was defined as an increase of two or more points above the previous score at the treated site. Patients who had missing pain scores or analgesic intake were not included in the analysis. The narcotic scores were measured at baseline and at subsequent visits. The narcotic score was calculated by multiplying pain medication [none = 0, analgesic = 1 (paracetamol, ibuprofen), mild narcotic = 2 (dextropropoxyphene), moderate narcotic =3 (tramadol) and strong narcotic = 4 (morphine)] and frequency of medication administration [none = 0, less than daily = 1 (p.r.n.), once per day = 2, 2-4 times per day = 3 and more than 4 times = 4]. Baseline and monthly serum calcium (corrected value using serum albumin) were estimated to detect hypercalcemia. The measurement of time of diagnosis of hypercalcemia was done by using corrected serum calcium either at the end of the study or at their last visit whichever was later.
SPSS, version 17, was used for statistical analysis for ANOVA (with LSD, Bonferroni) tests, with a P-value less than 0.05 as significant. Patients with incomplete questionnaires were excluded from the final analysis. Continuous variables were reported as means ± SEs. Pearson's correlation test was used to correlate the pain score with the degree of response.
| » Results|| |
Out of 256 patients randomized, 187 patients were eligible for final analysis [Figure 1]: zoledronic acid, n = 60 (4 mg, i.v., every 3-4 weeks), ibandronate, n = 65 (6 mg, i.v., every 3-4 weeks) and pamidronate, n = 62 (90 mg, i.v., every 3-4 weeks). The groups were matched for age, gender, site of primary tumor, site and number of bone metastases and number of irradiated sites [Table 1]. The onset of pain relief was same in all arms with a mean of 1.626 ± 0.067 weeks (P-value 0.610). Without placebo, the definitive comment on the initial response whether contributed by bisphosphonates or radiation could not be made.
With a mean baseline pain score of 6.5 ± 1.2, there was no difference in pain scores among the three treatment arms, assessed at 3 months and at the end of the study. However, the pain scores at 6 months were statistically reduced in zoledronic acid-receiving patients (1.5 ± 0.4) unlike the scores in patients receiving ibandronate (3.1 ± 0.5) and pamidronate (2.3 ± 0.4), with a P-value of 0.024 [Table 2].
The response assessments defined by the 'International Bone Metastases Consensus' were statistically significant at 6 months (P-value 0.039) and at the end of study (P-value 0.023; [Table 3]. This clearly demonstrated the difference among the pain score and the response assessment. However, Pearson's correlation was performed which demonstrated a statistically significant positive correlation between pain scores and response rates [Table 4].
|Table 3: Response assessment to evaluate the pain relief for different bisphosphonate arms at different times during the study|
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|Table 4: Pearson's correlation test to correlate the pain scores and response at 3, 6 months and end of the study|
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While it has been established that there are differences in pain scores and response assessments, a repeated measures ANOVA with a Greenhouse-Geisser correction determined that the mean pain score changed statistically significantly between time points [F (4.097, 294) = 2.764; P-value 0.028]. Post-hoc tests using the Bonferroni correction revealed that bisphosphonates elicited a reduction in pain scores from baseline to scores at 3 months (6.5 ± 0. 1 vs. 1.9 ± 0.3, respectively, P-value <0.001) and in scores from 3 months to 6 months (1.9 ± 0.3 vs. 1.2 ± 0.2, P-value < 0.001). However, pain scores were elevated from 6 months till the end of the study (1.2 ± 0.2 vs. 3.562 ± 0.3, P-value < 0.001; [Figure 2]. This increase was due to pain resulting from the progression of metastatic disease, contributed by both visceral and osseous lesions.
There were no statistical differences in the narcotic scores among the treatment arms measured at different times [Table 5]. A repeated measures ANOVA with a Greenhouse-Geisser correction determined that the mean narcotic score did not change statistically between time points [F (3.427, 294) = 1.024, P-value 0.390]. Post-hoc tests using the Bonferroni correction revealed that bisphosphonates elicited a reduction in narcotic scores from baseline to score at 3 months (9.2 ± 0.3 vs. 3.8 ± 0.3, respectively, P-value < 0.001) and in scores from 3 months to 6 months (3.8 ± 0.3 vs. 3.1 ± 0.2, respectively, P-value 0.012). However, narcotic scores at the end of the study (3.0 ± 0.2) were not statistically different from those at 6 months (3.1 ± 0.2, P-value 1.000; [Figure 3].
|Figure 2: Comparing the change in pain scores over baseline in different treatment arms|
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|Figure 3: Comparing the change of narcotic scores over baseline in different treatment arms|
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The duration of pain relief was not different among the treatment arms with zoledronic acid showing 5.7 ± 2.6 months, ibandronate 5.45 ± 2.2 months and pamidronate 5.2 ± 2.1 months, with a P-value of 0.451 [Figure 4]. Similarly, the time at detection of hypercalcemia (in months) was no different with zoledronic acid showing 6.0 ± 2.5 versus 6.3 ± 2.0 in the ibandronate arm and 6.1 ± 2.1 in the pamidronate arm, with a P-value of 0.678 [Figure 5].
|Figure 4: No difference in the duration of pain relief (months) among three arms (P-value, 0.451)|
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|Figure 5: Time of detection of hypercalcemia (months) with no difference among the three treatment arms (P-value, 0.678)|
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However, the incidence of hypercalcemia was significantly less in the zoledronic acid arm (28.3%) against 44.6% and 50% in ibandronate and pamidronate arms (P-value 0.041; [Table 6]). There was no difference in toxicity profiles among patients in different arms [Table 7].
|Table 6: Incidence of skeletal-related events among different bisphosphonate arms|
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|Table 7: Frequency of commonly occurring adverse events using CTCAEv3 combing all grades of toxicities|
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| » Discussion|| |
Palliation of painful bone metastases requires a significant portion of cancer care, with an estimated $900 million spent each year on palliative radiation therapy as reported by Hanks.  Bone metastasis is a major clinical concern that can cause severe pain, bone fractures, spinal cord compression, hypercalcemia and rapid degradation in the quality of life (QoL) for patients. In the majority of patients, Neilson  states that the primary tumor is in thebreast, prostate or lungs. In addition, colon, stomach, thyroid and renal carcinoma metastasize to bone in approximately 20-30% of cases, as mentioned by Coleman et al.  Mercadante  described that the management of bone secondaries includes a multidisciplinary approach which is essentially palliative with radiation as the cornerstone in the treatment. For the majority of patients, external beam radiotherapy providesexcellent palliation for localized metastatic bone pain. It has been reported to be effective in preventing impending fractures and promoting healing in pathological fractures. Inmost clinical situations, this can be achieved with a short treatmentschedule of one to five fractions. Over the past 10 years, bisphosphonates have been established as a valuable adjunct to the range of current treatments. Bisphosphonates reduce both the symptomsand complications of bone involvement as stated by Heidenreich. 
All bisphosphonates are characterized by a phosphorus-carbon-phosphorus(P-C-P)-containing central structure, which promotes their bindingto the mineralized bone matrix, and a variable R' chain whichdetermines the relative potency, side effects, and probablyalso the precise mechanism of action. Following administration,bisphosphonates bind avidly to exposed bone mineral around reabsorbingosteoclasts leading to very high local concentrations of bisphosphonatesin the reabsorption lacunae (up to 1000 μM). On releasefrom the bone surface, bisphosphonates are internalized by theosteoclasts, where they cause disruption of the biochemical processesinvolved in bone resorption. There are two types of bisphosphonates, non-nitrogen and nitrogen. Bisphosphonates also cause osteoclast apoptosis. Recent studies by Hillner  suggestthat bisphosphonates may have direct apoptotic effects on tumorcells. It is currently recommended to initiate bisphosphonate therapy at first diagnosis of bone lesions and to continue it because the clinical benefits of bisphosphonate-based therapy in reducing pathological SREs are also well documented. Ashcroft  said that with regular dosing, bisphosphonates reduce metastatic bone pain and thereby improve QoL after 8-12weeks of regular use.
Oral clodronate and pamidronate infusions are the two most widely used bisphosphonates inoncology. However, a small percentage (<5%) of an oral doseof clodronate is absorbed and for some patients, thesize and number of capsules limited the compliance, whileinfusions of pamidronate are costly, time-consuming and placeadditional demands on already overworked intravenous therapyunits. This leads to the development of more potent bisphosphonates to simplify treatment and possibly improve the therapeuticeffectiveness of bisphosphonate therapy. 
Intravenous ibandronate, 4 mg administered monthly, was compared with 90 mg pamidronate over a 10-month period in multiple myeloma patients. Although both bisphosphonates decreased levels of bone resorption and disease activity markers from baseline, Terpos  concluded that superior scores were observed in the pamidronate group. Heras  recently performed trial included a subset of 15 patients with colorectal cancer metastatic to bone treated with 6 mg, i.v., ibandronate for 9 months. Treatment with ibandronate resulted in a significantly lower proportion of patients with an SRE (39% vs 78% for placebo; P = 0.019) and prolonged the time to first event by 6 months (median > 279 days for ibandronate and 93 days for placebo; P = 0.009). The mean skeletal morbidity rate was also lower (2.36 vs 3.14 for placebo; P = 0.018).
Most experience with bisphosphonates for bone pain is from theiruse for skeletal metastases from advanced breast cancer. Themajority of early studies were open uncontrolled studies, butsubsequent randomized controlled trials of intravenous pamidronate,clodronate, ibandronate and zoledronate have all demonstrateduseful pain relief.  To obtain optimal effects, the intravenousroute is necessary, at least until more potent and well-toleratedoral bisphosphonates have been developed. It has not been convincinglydemonstrated that any of the currently available oral bisphosphonates,in the absence of systemic anticancer treatment, can significantlyreduce metastatic bone pain.Zoledronic acid is a third-generation nitrogen-containing bisphosphonate. Its core bisphosphonate moiety attaches to bone while its imidazole ring containing two nitrogen atoms confirms its potency. Zoledronate is the most potent bisphosphonate in clinical development, and in in vitro systems has around 100-1000 times the potencyof pamidronate. A phase I study in 30 patients with hypercalcemiaindicated that dose levels as low as 0.02 mg/kg (1-2 mg total dose)were effective in achieving normocalcemia.This has shown more rapid and complete control of hypercalcemiawith zoledronate at doses of 4-8 mg. Significant and sustained reductions in bone pain and related complications were achieved using intermittent zoledronic acid for as long as 2 years.
In a placebo-controlled registration study in breast cancer patients, zoledronic acid reduced the bone pain index (approximately −0.8 relative to baseline) throughout the whole study from 4 to 52 weeks according to Clemons.  The results are supported by a recently published study on patients with progressive bone metastases who were pretreated with oral clodronate or intravenous pamidronate. After a switch to intravenous zoledronic acid, a relevant palliative benefit in sense of pain reduction was demonstrated after the switch, where a large decrease in the worst bone pain was recorded which was confirmed by Rosen. 
The effect of bisphosphonates on pain seems to be independentof the nature of the underlying tumor or radiographic appearanceof the metastases, with sclerotic lesions responding similarlyto lytic metastases. Additionally, there appears to be an importantlink between metastatic bone pain and the rate of bone resorption,with subjective response correlating with the biochemical response as noted by Clemons.  The aim of bisphosphonate treatment should be to restorethe rate of bone resorption to normal.
Evidence suggests that standard-dose bisphosphonates reduce metastatic bone pain to a greater or lesser degree depending on the drug used, primary tumor burden and bone pain. It is likely to take at least 4-12 weeks after the start of bisphosphonate therapy before a significant decline in bone pain is recorded. In addition to standard recommended doses, several studies have evaluated the analgesic potential of intensive bisphosphonate therapy for the relief of metastatic bone pain. Results to date have been promising. For example, an early trial in prostate cancer patients where intravenous clodronate was administered as a loading dose (300 mg/day for 8 days) followed by standard high-dose oral clodronate 1600 mg/day demonstrated palliation of pain. The mean pain score significantly declined (P< 0.001) in 64 out of 85 patients, and 22% became pain free without the need for additional analgesics. The first analgesic effect of clodronate was seen on day 4 of parenteral therapy. Because of severe side effects and poor tolerance, this regimen was discontinued.
| » Conclusion|| |
The small number of patients in this study in each subgroup with relevant data limited our ability to explore the most effective bisphosphonates and their relative effectiveness for different primary neoplasms. There is evidence to support the effectiveness of bisphosphonates in providing pain relief for bone metastases. There is insufficient evidence to recommend bisphosphonates for an immediate effect, as first-line therapy, to define the most effective bisphosphonates or their relative effectiveness for different primary neoplasms. Bisphosphonates should be considered alongside analgesics and/or radiotherapy for the management of painful bone metastases and also reducing the incidence of SREs.
| » References|| |
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|10.||Ashcroft AJ, Davies FE, Morgan GJ. Etiology of bone disease and the role of bisphosphonates in multiple myeloma. Lancet Oncol 2003;4:284-92. |
|11.||Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, et al. Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: A pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 2001;19:558- 67. |
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]
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