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Keywords:

  • prostate carcinoma;
  • androgen-deprivation therapy;
  • bone mineral density;
  • bisphosphonate

Abstract

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

BACKGROUND:

Androgen-deprivation therapy (ADT) decreases bone mineral density (BMD) and increases fracture risk in patients with prostate carcinoma. The authors investigated the effectiveness of a single infusion of zoledronic acid initiated subsequent to ADT on BMD with hormone-naive prostate carcinoma.

METHODS:

Forty men received either a single infusion of zoledronic acid (4 mg intravenously on Day 1) or no infusion during ADT. BMD of the proximal femur and posteroanterior lumbar spine was measured by dual-energy x-ray absorptiometry and urinary N-telopeptide (u-NTx) at 6 and 12 months.

RESULTS:

At baseline, the overall BMDs demonstrated no significant difference in lumbar spine and hip regions. At 6months, mean (±standard error) BMD of the posteroanterior lumbar spine decreased 4.6% ± 1.0% in control patients and increased 5.1% ± 1.2% in patients receiving zoledronic acid, a significant difference (P = .0002). At 12 months, the change in BMD between the 2 groups was statistically significantly different at the lumbar region (P = .0004), indicating that zoledronate preserved BMD. For u-NTx, bone turnover was statistically significantly decreased in the zoledronate group compared with controls at 6 months (P < .0001), but returned to pretreatment levels at 12 months in the zoledronate group.

CONCLUSIONS:

Bone loss begins at 6 months with ADT. A single infusion of zoledronic acid in patients receiving ADT reduces bone mineral loss and maintains BMD at least at 12 months during ADT. Further study is needed to determine the best dosing schedule to prevent ADT-induced bone loss in men with hormone-naive prostate carcinoma. Cancer 2009. © 2009 American Cancer Society.

Current data from the Prostate Strategic Urologic Research Endeavor (CaPSURE) and Surveillance, Epidemiology, and End Results--Medicare database of the United States have demonstrated an increase in recent years in the proportion of patients with localized and advanced prostate carcinoma for whom androgen-deprivation therapy (ADT) is being selected.1, 2 Data on the current treatment of prostate cancer in Japan indicate that ADT is chosen to treat localized/advanced prostate cancer in an extremely high proportion of cases.3

Testosterone is the primary male hormone and is important in establishing and maintaining the typical male characteristics. Possible adverse effects (AEs) of ADT, in the form of gonadotropin-releasing hormone (GnRH) agonists, are generally related to changing levels of hormones, such as hot flushes, loss of muscle mass, erectile dysfunction, fatigue, anemia, and osteoporosis.

The results of several prospective studies show that a rapid loss of bone mineral density (BMD) occurs within the first 6 to 12 months of ADT.4, 5 The risk of skeletal fracture associated with ADT was recently reported,6 and it is important to note that a skeletal fracture in a patient with prostate carcinoma is an independent and adverse predictor of survival.7 Recent studies have shown that bisphosphonates, such as alendronate, pamidronate, risedronate, and zoledronic acid, will maintain the increased BMD in patients on ADT.8-12 However, the durable or long-term efficacy of zoledronic acid is still unknown.

We investigated the effectiveness of a single infusion of zoledronic acid initiated subsequent to ADT on BMD and biochemical markers of bone turnover in patients with hormone-naive prostate carcinoma. The main focus of this study was to evaluate the near-term effectiveness of a single infusion of zoledronic acid during the 12 months after ADT.

MATERIALS AND METHODS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Patients

Study participants were recruited at Kitasato University Hospital between September 2006 and March 2007. All patients had prostate adenocarcinoma with bone metastasis and did not receive any hormonal therapy (hormone naive) previously. Treatment with GnRH agonist was initiated at study entry in all patients. Men with metabolic bone disease, history of treatment for osteoporosis, a serum calcium level <8.4 mg/dL or >10.6 mg/dL, or a serum creatinine concentration >1.5 mg/dL were also excluded. At the screening visit, BMD of the posteroanterior lumbar spine and proximal femur was determined by dual-energy x-ray absorptiometry (DXA). T score was calculated from a Japanese male reference database.13 Patients with T score of −2.5 or less were excluded.

Study Design

This study was a randomized, prospective controlled pilot study over 12 months. Eligible patients were simply randomized by random numbers that are readily generated by computer software (Excel version 2003; Microsoft, Redmond, Wash). Forty eligible patients were randomly assigned to receive either zoledronic acid at a dose of 4 mg (Zometa; Novartis Pharmaceuticals Inc, Basel, Switzerland) intravenously on Day 1 only (n = 20) or no treatment (n = 20). The patients received zoledronic acid simultaneously with the initiation of ADT. Patients were evaluated at baseline and at 6 months and 12 months. Serum samples were obtained at each visit and stored at −80°C. BMD was measured by DXA at baseline, 6 months, and 12 months. All patients provided written informed consent.

Safety Assessment

The AEs were monitored every 3 months. Physical examinations and serum creatinine/calcium levels were monitored every 3 months. AEs were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 (NCI-CTCAE v.3.0).

Study Endpoints

BMD of the posteroanterior lumbar spine and proximal femur was determined by DXA using a Hologic QDR 4500A/SL densitometer (Hologic Inc, Waltham, Mass) in all patients. The DXA device was standardized and calibrated using the Anthropomorphic Spine Phantom (Hologic Inc). In vivo precision assessment was performed according to the International Society for Clinical Densitometry recommendation.14 By determining precision error (0.012 g/cm2) and least significant change (0.034 g/cm2 at 95% confidence interval [95% CI]), it was confirmed that sufficiently precise assessment was done in our hospital. Serum concentrations of testosterone (SRL Inc., Tokyo, Japan) were measured by radioimmunoassays. Urine concentrations of N-telopeptide (NTx; SRL Inc.) were measured by enzyme immunoassays.

Statistical Analysis

The primary study endpoint was the percentage change in the BMD of the posteroanterior lumbar spine from baseline to Months 6 and 12. Statistical analyses were performed using SPSS statistical software (version 13.0; SPSS Japan Inc., Tokyo, Japan). Values are reported as means ± standard error [SE] unless otherwise specified. All P values were 2-sided, and P < .05 was considered statistically significant.

RESULTS

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Forty eligible patients were randomly assigned to receive either zoledronic acid (n = 20) or no drug treatment (n = 20). Table 1 lists the baseline characteristics of patients in both groups. All patients were hormone naive and received treatment with a GnRH agonist after study entry.

Table 1. Clinical Characteristics of the Patients
CharacteristicsZoledronic Acid GroupControl GroupP
MeanNo.SDMeanNo.SD
  1. SD indicates standard deviation; NS, not significant; NTx, N-telopeptide; BCE, bone collagen equivalents; Cr, creatinine.

Patients treated 20  20  
Age, y (range)70.5 (53-81)  70 (60-82)  NS
Serum testosterone, ng/mL4.08 0.854.12 0.63NS
Body mass index, kg/m223.7 2.2322.3 2.8NS
Urinary NTx, nmol BCE/nmol Cr44.6 35.633.2 14.2NS
Bone mineral density, g/cm2       
 Posteroanterior lumbar spine1.026 0.230.936 0.183NS
 Total hip0.856 0.1380.859 0.174NS
 Femoral neck0.726 0.130.719 0.148NS
T score       
 Posteroanterior lumbar spine−0.23 1.42−0.41 1.19NS
 Total hip−0.66 1.11−0.39 1.30NS
 Femoral neck−1.06 1.00−1.14 1.17NS

The mean percentage changes in BMD of the posteroanterior lumbar spine, the total hip, and the femoral neck differed significantly between groups (Fig. 1). At 6 months, the mean (±SE) BMD of the posteroanterior lumbar spine decreased 4.6% ± 1.0% from baseline in control men and increased 5.1% ± 1.2% from baseline in men given zoledronic acid (P = .0002). At 12 months, the mean (±SE) BMD of the posteroanterior lumbar spine decreased 8.2% ± 1.8% from baseline in the control men and increased 3.5% ± 0.8% from baseline in the men receiving zoledronic acid (P = .0004). The between-group differences in percent change from baseline to 6 months and to 12 months were 9.7% (95% CI, 7.0%-12.4%) and 11.7% (95% CI, 9.6%-13.4%), respectively.

thumbnail image

Figure 1. Geometric mean percent changes from baseline for bone mineral density for the (A) lumbar spine, (B) total hip, and (C) femoral neck are shown. P values are between-group comparisons of the percentage change from baseline to 12 months after treatment.

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At 6 months, the mean (±SE) BMD of the total hip decreased 2.2% ± 0.5% from baseline in the controls and increased 1.1% ± 0.7% from baseline in the treatment group (P = .0025). At 12 months, the mean (±SE) BMD of the total hip decreased 4.6% ± 1.0% from baseline in controls and increased 1.1% ± 0.6% from baseline in those given zoledronic acid (P = .0008). The between-group differences in percent change from baseline to 6 months and to 12 months were 3.3% (95% CI, 2.2%-4.4%) and 5.7% (95% CI, 4.6%-6.9%), respectively.

At 6 months, the mean (±SE) BMD of the femoral neck decreased 0.7% ± 0.1% from baseline in the controls and increased 1.8% ± 0.8% from baseline in the treatment group (P = .0063). At 12 months, the mean (±SE) BMD of the femoral neck decreased 1.8% ± 0.4% from baseline in controls and increased 5.1% ± 1.3% from baseline in those given zoledronic acid (P = .0393). The between-group differences in percent change from baseline to 6 months and to 12 months were 2.5% (95% CI, 1.3%-3.7%) and 6.9%.(95% CI, 4.6%-9.2%), respectively.

Changes from baseline to 6 months in urine NTx differed significantly between the groups (Fig. 2). Mean (±SE) urine NTx increased by 70.3% ± 15.7% in control men and decreased by 9.5% ± 10.8% in the zoledronic acid group, a statistically significant difference (P < .0001). At 12 months, the mean (±SE) urine NTx increased 63.9% ± 14.3% from baseline in the control group and increased 19.7% ± 19.3% from baseline in the zoledronic acid group; these differences did not reach statistical significance (P = .0703).

thumbnail image

Figure 2. Geometric mean percent changes from baseline for urine N-telopeptide are shown. P values are between-group comparisons of the percentage change from baseline to 12 months after treatment.

Download figure to PowerPoint

AEs related to treatment in each group were never higher than grade 3 (using NCI-CTCAE v.3.0). Neither azotemia nor osteonecrosis of the jaw was reported in either group.

DISCUSSION

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

The incidence and mortality of prostate carcinoma is rapidly increasing in Japan. In 2000, the Japanese Urological Association (JUA) launched a system for registering patients who were newly diagnosed with prostate carcinoma at institutions authorized by the JUA. The compilation results of 2000 were published and surprisingly indicated that primary ADT was used in 40% of patients with T1c disease and in >50% of patients with T2 disease.3

Conversely, the US National Cancer Institute Physician Data Query and American Urological Association guidelines do not recommend hormonal therapy for treatment of localized prostate carcinoma. However, CaPSURE surveillance data have demonstrated that in recent years the use of ADT has increased for patients with all stages of prostate carcinoma.1 Furthermore, several randomized controlled trials show an overall survival benefit of neoadjuvant ADT as well as adjuvant ADT, and this combination treatment has had a large impact.15-17 Thus, ADT for prostate carcinoma is being adopted and the number of patients undergoing ADT may increase worldwide in the future. However, among men surviving at least 5 years after the diagnosis of prostate carcinoma, 19.4% of those who received ADT had skeletal fractures, and there was a statistically significant relationship between the number of doses of GnRH received during the 12 months after diagnosis and subsequent risk of fracture.18 In addition, the occurrence of skeletal-related events (SREs), including fractures, contributes significantly to the cost of care for patients with advanced prostate carcinoma.19 The average total cost of treatment was €13,051/patient over the 24-month follow-up period, which includes an average cost of €6973/patient to treat SREs. Treatment of SREs more than doubled total treatment costs, and these data suggest that bisphosphonates can reduce SREs and healthcare costs.

Recent studies have shown that bisphosphonates, such as alendronate, pamidronate, risedronate, and zoledronic acid, will maintain the increased BMD in patients on ADT.8-12 Greenspan et al reported the effect of the oral bisphosphonate alendronate given orally (70 mg) once weekly on BMD, and markers of bone turnover in patients with nonmetastatic prostate carcinoma recently initiating ADT or receiving ADT for ≥6 months evaluated in a prospective, randomized, double-blind, placebo-controlled, partial crossover trial.20 In patients treated with alendronate, BMD increased over 12 months by 3.7% (P < .001) at the spine and 1.6% (P = .008) at the femoral neck. Conversely, patients in the placebo group had losses of 1.4% (P = .045) at the spine and 0.7% (P = .081) at the femoral neck. At 12 months, the difference between the 2 groups was 5.1% (P < .001) at the spine and was 2.3% (P < .001) at the femoral neck.

Intravenous bisphosphonates also increase BMD in GnRH agonist–treated men.8, 10-12 To our knowledge, Smith et al were the first to assess the effect of zoledronic acid on BMD during ADT for nonmetastatic prostate carcinoma.8 Patients with prostate carcinoma (no metastases) who were beginning ADT were randomly assigned to receive zoledronic acid at a dose of 4 mg or placebo intravenously every 3 months for 1 year. The mean BMD in the lumbar spine increased by 5.6% in patients receiving zoledronic acid and decreased by 2.2% in those given placebo (mean difference, 7.8%; P < .001). The mean BMD of the femoral neck, trochanter, and total hip also increased in the zoledronic acid group and decreased in the placebo group after 1 year of therapy.

Israeli et al assessed the benefit of zoledronic acid in patients with pre-existing bone loss. Patients were randomized to receive zoledronic acid at a dose of 4 mg or placebo intravenously every 3 months when initiated during the first year of ADT in patients with locally advanced prostate carcinoma.11 Although all patients receiving zoledronic acid in their study experienced increases in lumbar spine and total hip BMD, patients with low baseline T scores (−1 or less and −2 or greater) experienced a greater magnitude of increase in lumbar spine BMD than patients with normal baseline T scores (more than −1) (5.8% vs 4.4%, respectively). A similar difference in the magnitude of NTx suppression was observed. Zoledronic acid–treated patients with low baseline T scores experienced greater NTx suppression than patients with normal baseline T scores (−82.7% vs −58.4%, respectively). These results suggest that patients with pre-existing bone loss may experience a greater benefit of zoledronic acid treatment.

In patients with hormone-refractory metastatic prostate carcinoma, frequent treatment with zoledronic acid (4 mg every 3 weeks) reportedly decreases the risk of SREs.21

Patients with hormone-refractory prostate carcinoma and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at a dose of 4 mg, zoledronic acid at a dose of 8 mg (subsequently reduced to 4 mg; 8/4), or placebo every 3 weeks for 15 months. The median time to first SRE (defined as pathologic bone fractures, spinal cord compression, surgery to bone, radiation therapy to bone, or a change of antineoplastic therapy to treat bone pain) was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at a dose of 4 mg (P = .011 vs placebo), and was 363 days for those who received zoledronic acid at a dose of 8/4 mg (P = .491 vs placebo). Given the results of this study, zoledronic acid (4 mg every 3-4 weeks) was approved to treat patients with hormone-refractory prostate carcinoma metastatic to bone, and this treatment remains the only known effective schedule to prevent SRE complications in patients with metastatic prostate carcinoma.

The results of the current study demonstrate that a single infusion of zoledronic acid within the first 12 months of ADT prevents bone loss and increases BMD in men with hormone-naive prostate carcinoma. Compared with the control group, zoledronic acid significantly increased lumbar spine and femoral neck BMD by 11.7% and 5.7%, respectively (P = .0004 and P = .0008, respectively). A single infusion of zoledronic acid can provide a durable effect for the hormone-naive patient for at least 12 months after ADT. When initiating ADT for hormone-naive patients with prostate carcinoma, the simultaneous use of a single infusion of zoledronic acid might have not only bone health but also compliance advantages for ADT-induced osteoporosis, because the most significant BMD loss occurs within 12 months after ADT therapy in these men.

The findings of the current study demonstrated that urinary NTx returned to the pretreatment levels at the 12-month follow-up in the zoledronate group. If the changes in the urinary NTx levels indicate BMD loss in advance, an annual infusion of zoledronate might be a lower dosage in this patient population, and an infusion every 6 months will be favorable to maintain urinary NTx levels.

Our results are consistent with the results of previously published studies,10, 12 although we evaluated only hormone-naive patients (using zoledronic acid with simultaneous ADT) and consistent timing of follow-up of BMD every 6 months. However, these results do not justify less frequent administration of zoledronic acid to prevent SREs in patients with hormone-naive prostate carcinoma, because the study was powered to demonstrate a significant change in BMD, but was not powered to assess the impact on the risk of SREs.

The prognosis of primary ADT performed in patients with prostate carcinoma is quite good, and 50% of patients were alive after primary ADT at 10-year follow-up in a Japanese population.3 Thus, we must take care of not only cancer control but also the patient's bone health based on a probably long life span for these men.

Conclusions

A single infusion of zoledronic acid increased BMD and decreased urine NTx levels in hormone-naive patients with prostate carcinoma. These effects were durable within 12 months after the initiation of ADT. However, urinary NTx returned to pretreatment levels at 12 months, and further study is needed to clarify the optimal regimen of therapy, as well as its long-term efficacy.

Acknowledgements

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

We thank Yukitoshi Ohta, RT, Erina Sato, CRC, and Mineko Uemae, RT, for helpful data management.

Conflict of Interest Disclosures

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References

Supported in part by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan.

References

  1. Top of page
  2. Abstract
  3. MATERIALS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. Conflict of Interest Disclosures
  8. References
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