Prolonged Efficacy of a Single Dose of the Bisphosphonate Zoledronic Acid Janet E

Cancer Therapy: Clinical

Prolonged Efficacy of a Single Dose of the Bisphosphonate Zoledronic Acid Janet E. Brown,1Susan P. Ellis,1James E. Lester,1Sandra Gutcher,1Tina Khanna,1 Om-Prakesh Purohit,1Eugene McCloskey,2 and Robert E. Coleman1

Abstract Purpose: Bisphosphonates play a central role in the management of bone loss due to a range of disorders, including metastatic bone disease, cancer treatment ^ induced bone loss, and postmenopausal osteoporosis.With potent bisphosphonates, such as zoledronic acid, it may be possible to maintain efficacy with relatively infrequent administration. Experimental Design: Sixty-six patients who were osteopenic at >1 year following curative cancer therapy received a single i.v. 4 mg dose of the bisphosphonate zoledronic acid. Bone mineral density (BMD) was measured using double-beam X-ray absorptiometry scan and the bone resorption marker N-telopeptide of type II collagen was determined using a chemiluminescence ELISA assay. Results: The single dose of zoledronic acid induced mean increases in bone BMD at the lumbar spine of 3.1%, 5.2%, and 5.3% and at the total hip of 2.7%, 3.5%, and 4.3% after 12, 24, and 36 months of follow-up, respectively (P < 0.001at all time points). By 36 months, 84% of patients had achieved increase in BMD at the spine and 90% at the hip.The mean percentage decrease in the bone resorption marker N-telopeptide was f58% at 6 weeks and 42%, 33%, and 31% at 12, 24, and 36 months, respectively (P < 0.001). Conclusions: A single dose of zoledronic acid in patients with low BMD results in a sustained increase in BMD and a corresponding decrease in bone resorption.Very infrequent administration of zoledronic acid may have clinical benefits in terms of convenience, reduced toxicity, improved compliance, and cost.

Bisphosphonates play a central role in the management of disease (6–8). The clinical decision to use a bisphosphonate, bone loss due to a range of disorders, including metastatic bone especially over prolonged periods, must therefore be made with disease, cancer treatment–induced bone loss, Paget’s disease, clear risk/benefit assessment. In recent years, development of and, notably, postmenopausal osteoporosis. Bisphosphonates the more potent nitrogen-containing bisphosphonates has led are therefore very widely used, with many patients receiving to the possibility of relatively infrequent dosing, with consid- continuous treatment for years and potentially decades. The erable potential benefits in compliance, efficacy, adverse event drugs have proven benefit, not only in preventing bone loss but profile, convenience, and cost (9, 10). also in prevention of fragility fractures (1, 2). There are increasing numbers of long-term cancer survivors Although generally well tolerated, bisphosphonates are not who have received adjuvant chemotherapy and hormonal without associated problems, such as gastrointestinal toxicity, therapies. Initial attention has focused on treatment of the poor absorption, and suboptimal compliance of oral agents malignancy, but the possible long-term effects of such cancer (3), as well as acute phase reactions and occasional nephro- treatments on the skeleton, with accelerated bone loss, which toxicity with i.v. administration (4, 5). The occurrence of may lead to osteoporosis and fragility fractures, have been osteonecrosis of the jaw is also of growing concern, especially highlighted recently (11–15). In cancer treatment–induced when nitrogen-containing bisphosphonates are given i.v., once bone loss, less frequent dosing with bisphosphonates is every three to four weeks over a long period for metastatic bone beginning to be explored. A study in 401 patients by Gnant et al. (16)showed that breast cancer patients receiving the severe potential insult to bone from concomitant ovarian Authors’ Affiliations: 1Academic Unit of Clinical Oncology,Weston Park Hospital suppression and an aromatase inhibitor experienced a bone and 2Metabolic Bone Unit, University of Sheffield, United Kingdom mineral density (BMD)loss of 14.4% after 36 months Received 1/30/07; revised 6/15/07; accepted 7/5/07. (P < 0.001). By contrast, in patients receiving the same The costs of publication of this article were defrayed in part by the payment of page endocrine therapy with 6 monthly zoledronic acid, BMD charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. remained stable. In prostate cancer patients receiving androgen Requests for reprints: Janet E. Brown, Cancer Research UK Clinical Centre in deprivation therapy, zoledronic acid given every 3 months Leeds, JIF Building, St. James’ University Hospital, Beckett Street, Leeds LS9 resulted in an increase in BMD of 5.6% after 1 year compared 7TF, United Kingdom. Phone: 44-113-2064184; Fax: 44-113-2460136; E-mail: with a decrease of 2.2% over the same time period in patients [email protected]. F 2007 American Association for Cancer Research. not given zoledronic acid, an overall difference of 7.8% doi:10.1158/1078-0432.CCR-07-0247 (P < 0.001; ref. 17).

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In postmenopausal osteoporosis, exposure to high i.v. doses within the postmenopausal reference range (see below). All patients of alendronate over 4 days induced a 5% increase in BMD at who completed the main 2-year study were invited to participate in the 1 year and had a sustained effect on bone resorption for at least extension study, which involved a further BMD and NTX assessment 1 year (18, 19), whereas monthly oral ibandronate resulted in at 36 months. All patients gave written informed consent and the study was approved by the local Ethics Committee. On meeting the entry 6.6% and 4.2% increases in BMD after 2 years at the spine and criteria, patients were given a single 15-min i.v. infusion of 4 mg hip, respectively (20). Reid et al. (9) showed that a single zoledronic acid. All patients were prescribed daily oral calcium i.v. infusion of zoledronic acid produced mean increases in (500 mg)and vitamin D (400 IU). BMD 1 year later of 4.6% and 3.3% at lumbar spine and hip, BMD was measured at the lumbar spine (L1-L4)and nondominant respectively, and that this was as effective as more frequent hip using a Lunar Expert DXA Scanner (GE Lunar; ref. 22). The dosing. In this latter study, the bone resorption marker urinary precision using the EXPERT-XL is 0.01 to 0.03 g/cm2, depending on the N-telopeptide/creatinine ratio [N-telopeptide of type II collagen site measured, with precision for the spine being greater than that for (NTX)] decreased rapidly following zoledronic acid and the proximal femur. Daily quality assurance was done whenever a remained suppressed after 1 year. Very recently, preliminary patient was to be scanned, using a phantom, following the manufac- results of a large phase III trial of an annual schedule of 5 mg turer’s guidelines. Measurements were made at baseline and then at 6, 12, 18, 24, and 36 months following zoledronic acid infusion. zoledronic acid indicated that this schedule was able to reduce NTX was measured at weeks 6 and 12, and 3 months thereafter until the risk of osteoporotic fractures in spine, hip, and other 24 months and then at 36 months on a second voided morning urine nonvertebral sites (21). sample. These measurements were made by a chemiluminescence assay These studies have raised the possibility that a single dose using a Vitros ECI analyzer (23)and urinary creatinine was measured of a potent bisphosphonate in patients with low BMD may lead using a dry slide method, in both cases using reagents from Ortho- to a long-term decrease in bone resorption with increases in Clinical Diagnostics (Rochester, NY). The NTX reference ranges used in BMD beyond 1 year. In this exploratory open study, we report, our center were 16 to 107 nmol/mmol creatinine for males and 32 to for the first time, the long-term effects (up to 3 years)of a single 124 nmol/mmol creatinine for postmenopausal females (coefficient of i.v. infusion of zoledronic acid on BMD in long-term survivors variation, 6.8-14.9%). Testosterone was determined using the Vitros from cancer with osteopenia. assay (reference range, 7.1-24.1 nmol/L). Estradiol was measured by the Elecsys assay systems (reference range, 5-54.7 pg/mL for postmenopausal females; Elecsys 2010 immunoanalyzer, Roche Diagnostics Patients and Methods GmbH). Blood samples were taken for safety measurements, including full blood count (hemoglobin, total white cell, neutrophil, and platelet Sixty-six cancer survivors with osteopenia, based on double-beam count), urea and electrolytes, liver function tests, alkaline phosphatase, X-ray absorptiometry scan WHO T-score criteria (-1 SD to -2.5 SD from calcium and adjusted calcium, and inorganic phosphate, and any the sex-matched young adult mean, WHO Technical Report 1994), were adverse events were recorded at each clinical visit. Spinal X-rays were recruited to a single-arm, open, phase II single center study. For this not routinely carried out and only symptomatic fractures were recorded. study, all patients in our center who were eligible (see below)and who Changes in urine NTX and BMD were examined using a mixed model were osteopenic on double-beam X-ray absorptiometry scanning were linear regression and analysis of covariance using SPSS for Windows invited to participate. Recruitment commenced in October 2001 and (version 11.5.0). The analysis allows for missing values. Data from was completed in December 2004. Only patients at least 1 year after a patients who withdrew from the study were included in the analyses up complete response of cancer to surgery F chemotherapy and/or to the time of withdrawal. Significance of changes between baseline radiotherapy with no evidence of metastases were included. Other and individual time points were assessed by paired t tests. Where entry criteria included confirmation of postmenopausal status data were not normally distributed, statistics were conducted on log- (females), Eastern Cooperative Oncology Group performance status transformed data. Figures of percentage changes from baseline are V 2, no previous bisphosphonate treatment, no treatment with anabolic shown as means (SE). steroids, fluoride, or calcitonin or change in endocrine therapy within the last 6 months, and absence of abnormal renal function and of other disorders of bone metabolism. For female patients, postmenopausal Results status was not only documented primarily by lack of menstruation for >1 year but was also assessed biochemically by using a combination of Forty-five females and 21 males were recruited (44 breast serum follicle-stimulating hormone z15 mU/mL and estradiol levels cancer, 11 testicular cancer, and 11 lymphoma). The mean ages

Table 1. Baseline characteristics

Overall population Women Men No. patients 66 45 21 Mean age (range), y 50 (21-78) 54 (32-78) 42 (21-78) Mean time since last cancer therapy (range), y 4.3 (1-27) 4.2 (1-27) 4.5 (1-11) Cancer type Breast 44 44 0 Lymphoma 11 1 10 Testicular 11 0 11 Mean estradiol (range), pg/mL N/A 15.3 (0.5-27.0) N/A Mean testosterone (range), nmol/L N/A N/A 11.5 (4.1-23.7)

Abbreviation: N/A, not applicable.

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spine but Fig. 2 shows that the rate of gain and the magnitude of the gain were greater at the spine than at the hip. At the spine, only 3.8% patients lost >3% in BMD (maximum individual loss, 5.8%)over 24 months, although 1 patient lost 9% at 3 years. At the hip, only one patient (1.9%)lost >3% in BMD (actual value, 3.5%)at 24 months. Figure 3 shows an early and substantial mean percentage decrease in NTX of f60% at 6 weeks. This reduction was substantially maintained for the rest of the study period, with around a 40% reduction at 12 months and a 32% reduction maintained at 24 months. Even at 3 years, the reduction remained at f30% (P < 0.001 at all time points). Because the study population contained a mix of men and women, we have analyzed the BMD changes overall and by gender. These analyses are reported in Table 2 for 12, 24, and Fig. 1. Mean percentage change (SE) in BMD at the spine and the hip with time 36 months. For both men and women, the differences between following a single infusion of zoledronic acid.The number of patients contributing to BMD values at all time points and those at baseline were highly each time point is indicated. The number falls with time, in part because of patient significant (P < 0.001). Moreover, statistical analysis showed drop out and in part because some patients are still to be assessed at the 36-mo time point. Points, mean; bars, SE. that there was no significant sex-time interaction for spine (P = 0.285)or for hip (P = 0.629). Corresponding analyses for the NTX changes in men and women are also shown in and mean times since last cancer treatment (with ranges)are shown in Table 1, along with gonadal hormone levels at baseline. Eighteen patients (all breast cancer)had received concomitant endocrine treatment. Of these, 13 had received tamoxifen alone (8 had completed tamoxifen before the study and the remaining 5 had been on tamoxifen for more than 2 years)and 5 had received tamoxifen and then an aromatase inhibitor. Two of these patients had completed aromatase inhibitor (anastrazole)treatment before study entry and three patients continued throughout the study. Using the lower limit of the reference range of testosterone (7.1 nmol/L), 3 of the 21 men were hypogonadal at baseline. Two of these were more elderly men with lymphoma and one was a younger man who had had testicular cancer. Ten patients did not complete the 2-year main study with four withdrawing in the first 6 months and a further three by 12 months. In 2 patients, withdrawal was due to disease recurrence (1 lymphoma and 1 breast)and 8 due to patient logistical reasons (3 lymphoma, 3 testicular, and 2 breast). Figure 1 shows the mean percentage change in BMD at the spine and hip, relative to baseline, at various times. For the spine, there was a mean increase in BMD at 12 months of 3.1% (range, -9.0% to 11.1%). By 24 months, a mean increase in BMD of 5.2% (range, -5.8% to 15.4%)was achieved and this was sustained at 3 years, with a mean increase of 5.3% (range, -1.5% to 15.8%). At all time points, the increases relative to baseline were highly significant (P < 0.001). At the hip, the BMD also increased steadily by 2.7%, 3.5%, and 4.3% (ranges, -4.6% to 11.0%, -3.5% to 12.0%, and -2.9% to 12.1%)after 12, 24, and 36 months, respectively ( P < 0.001 at all time points). The distribution of the change in BMD with time is shown in Fig. 2 in terms of the proportions of patients who suffered a loss in BMD, up to 3% increase in BMD and >3% increase in BMD, following the single infusion of zoledronic acid. The majority of patients already showed an increase in BMD by 6 months and this proportion increased with time on study (76%, 85%, and 84% at the spine and 87%, 85%, and 90% at the hip, Fig. 2. The distribution of the change in BMD at spine and hip with time in terms of recorded at 12, 24, and 36 months, respectively). The numbers the proportions of patients who suffered a loss in BMD, up to 3% increase in BMD of patients gaining BMD were higher at the hip than at the and >3% increase in BMD, following the single infusion of zoledronic acid.

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Discussion

This is the first demonstration of a sustained increase in BMD over several years from a single dose of a bisphosphonate in patients with cancer treatment–induced bone loss or, indeed, in any condition resulting in low BMD. The results in the current study are consistent with the shorter study by Reid et al. (9), which reported similar increases at the spine and at the hip 1 year after an infusion of 4 mg zoledronic acid in postmenopausal women with low BMD, but provide additional information on the duration of action of a single treatment. Correspondingly, in 40 men with prostate cancer receiving a GnRH agonist, Michaelson et al. (24)have shown very recently that a single treatment with zoledronic acid significantly increased BMD relative to placebo 1 year later (spine, 4.0% increase Fig. 3. Mean percentage change (SE) in NTX with time following a single infusion compared with a loss of 3.1% in placebo, P < 0.001; hip, 0.7% of zoledronic acid. The number of patients contributing to each time point is P indicated.The number falls with time, in part because of patient drop out and in part increase compared with 1.9% loss in placebo, = 0.004). because some patients are still to be assessed at the 36-mo time point. Points, We believe that our data represent the longest-lasting effect of mean; bars, SE. a single dose of a bisphosphonate yet reported. It is noteworthy that BMD continued to increase after 1 year, and it was not simply that the early increase was sustained with f85% patients Table 2, including 6 weeks (by which time the maximum achieving an increase at spine and 90% at the hip after 3 years. change had occurred)and 6, 12, 24, and 36 months. Again, for Because the study population was of mixed gender, it was both men and women, at all time points, the differences important to determine if there was any sex-linked dependence compared with baseline were highly significant (P < 0.001). of the response to zoledronic acid. Our results show clearly that Further statistical analysis showed that there was no significant there was no such dependence. Although tamoxifen therapy sex-time interaction (P = 0.637). These data therefore show that itself is known to have a slight beneficial effect on BMD in there is no significant difference in BMD and NTX change postmenopausal women, recent studies have shown that most between men and women in the response to zoledronic acid. of this gain occurs within the first 2 years of therapy (25). In the There were no serious drug-related adverse events, including current study, 18 women had received tamoxifen therapy, all renal toxicity or reported osteonecrosis of the jaw. No patient for at least 2 years, and the majority had completed tamoxifen required hospital admission due to drug toxicity. Reported before study entry. drug toxicities included flu-like symptoms (63%), nausea The large reduction in urinary NTX levels after 6 weeks (6%), headache, bone ache, and itching (each <5%). One (f60%)is consistent with other studies following infusion of patient suffered a low trauma Colles wrist fracture while on 4 mg zoledronic acid (26)but, remarkably, the mean NTX study. suppression below baseline was still 30%, even 3 years after

Table 2. Mean BMD and NTX levels according to gender, following the single administration of zoledronic acid

Time after zoledronic All Women Men acid (mo) Mean percentage gain in BMD F SE(no. patients contributing to mean) SPINE 12 3.09 F 0.55 (59) 3.05 F 0.7 (42) 3.21 F 0.87 (17) 24 5.18 F 0.68 (53) 4.99 F 0.84 (40) 5.75 F 1.06 (13) 36 5.26 F 0.89 (38) 5.45 F 1.19 (27) 4.81 F 1.03 (11)

Mean percentage gain in BMD F SE(no. patients contributing to mean)

HIP 12 2.67 F 0.41 (59) 2.97 F 0.52 (42) 1.93 F 0.60 (17) 24 3.52 F 0.46 (53) 3.69 F 0.57 (40) 3.00 F 0.69 (13) 36 4.27 F 0.65 (38) 4.27 F 0.84 (27) 4.28 F 0.91 (11)

Mean percentage reduction in NTX F SE(no. patients contributing to mean)

NTX 1.5 58.0 F 3.2 (53) 58.5 F 4.0 (39) 56.5 F 5.3 (14) 6 45.7 F 3.3 (51) 46.3 F 4.2 (37) 44.1 F 4.9 (14) 12 42.2 F 3.9 (52) 42.8 F 4.9 (36) 40.6 F 6.22 (16) 24 32.6 F 4.1 (41) 34.6 F 5.12 (27) 28.8 F 7.2 (14) 36 31.4 F 6.4 (33) 28.6 F 8.58 (23) 37.9 F 7.4 (10)

www.aacrjournals.org 5409 Clin Cancer Res 2007;13(18) September 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2007 American Association for Cancer Research. Cancer Therapy: Clinical treatment. Based on known correlations between BMD, nates. Such studies also serve to show the potential lasting reduction in bone resorption as reflected by NTX, and fracture effects of bisphosphonate therapy. rate (27–29), it seems likely that infrequent zoledronic acid The duration of effect of a single dose of zoledronic acid administration would translate into clinical benefit, with found in the current study is unexpectedly long and a full reduced skeletal morbidity. biological explanation will require further studies. However, No placebo group was used in this study. We have justified it is known that the duration of action of individual bisphos- this based on data from the study by Fleisch (3), where no phonates varies according to their binding affinity to bone. increase in BMD was observed in the placebo group and also This is extremely high for zoledronic acid compared with, for because, because it is the norm for a gradual reduction in BMD example, residronate (32). Following the acute effects of a with age, particularly in the early postmenopausal years, the bisphosphonate on local osteoclast function, the drug is benefits of zoledronic acid over no treatment are more likely to presumably internalized by deposition of new bone but be underestimated rather than overestimated in our study. becomes biologically active again as this area undergoes Although there is some evidence that calcium and vitamin D subsequent remodeling months or years later. The high affinity supplementation may lead to a small reduction in bone of zoledronic acid for bone may result in the majority of this markers of f10% (9, 30), there is no convincing evidence remobilized drug readhering to the bone surface and the that this alone can lead to an increase in BMD. consequent effects on bone cell function. Recently, Black et al. (31)reported data from a double blind Although this study was done in a patient population with a trial in which 1,099 postmenopausal women were randomized history of cancer, it seems likely that our findings would apply to receive either alendronate weekly for 10 years or alendronate also to accelerated bone loss from other causes, including weekly for 5 years followed by 5 years on placebo. Compared postmenopausal osteoporosis. The findings have opened up the with continuing alendronate, switching to placebo for 5 years intriguing possibility of very infrequent use of a bisphospho- resulted in declines of BMD at the hip and spine of -2.4% nate to prevent accelerated bone loss, perhaps once every 2 to (P < 0.001)and -3.7% ( P < 0.001), respectively, but mean 3 years. This may be especially applicable in those patients with levels remained at or above the pretreatment levels 10 years a milder degree of bone loss, with all the advantages that would earlier. This work has raised the possibility of providing a ’drug accrue in terms of convenience, reduced toxicity, improved holiday‘ for those patients who are on long-term bisphospho- compliance, and cost.

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Janet E. Brown, Susan P. Ellis, James E. Lester, et al.

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