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Zoledronate in Preventing Osteoporosis and Bone Fractures in Patients With Locally Advanced Nonmetastatic Prostate Cancer Undergoing Radiation Therapy and Hormone Therapy

A Phase III Randomized Study to Evaluate the Efficacy of Zometa® for the Prevention of Osteoporosis and Associated Fractures in Patients Receiving Radiation Therapy and Long Term LHRH Agonists for High-Grade and/or Locally Advanced Prostate Cancer

Status
Completed
Phases
Phase 3
Study type
Interventional
Source
ClinicalTrials.gov
Registry ID
NCT00329797
Enrollment
109
Registered
2006-05-25
Start date
2006-03-31
Completion date
2014-11-30
Last updated
2017-11-29

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Osteoporosis, Prostate Cancer

Keywords

osteoporosis, adenocarcinoma of the prostate, stage IIB prostate cancer, stage IIA prostate cancer, stage III prostate cancer, stage IV prostate cancer

Brief summary

RATIONALE: Zoledronate may prevent bone loss in patients with prostate cancer undergoing radiation therapy and hormone therapy. It is not yet known whether zoledronate is more effective than calcium and vitamin D alone in preventing osteoporosis and bone fractures in patients with prostate cancer. PURPOSE: This randomized phase III trial is studying zoledronate to see how well it works compared to calcium and vitamin D alone in preventing osteoporosis and bone fractures in patients with locally advanced nonmetastatic prostate cancer undergoing radiation therapy and hormone therapy.

Detailed description

OBJECTIVES: Primary * Compare the potential benefit of bisphosphonate therapy comprising zoledronate plus vitamin D and calcium supplement vs standard therapy with vitamin D and calcium supplement in the prevention of osteoporosis and associated bone fractures in patients with locally advanced nonmetastatic adenocarcinoma of the prostate undergoing radiotherapy and luteinizing hormone-releasing hormone (LHRH) agonist therapy. Secondary * Evaluate the potential benefit of these regimens on quality of life in these patients. * Evaluate the potential benefit in bone mineral density over a period of 3 years for patients treated with these regimens. OUTLINE: This is randomized multicenter study. Patients are stratified according to T score of the hip by dual x-ray absorptiometry (DXA) scan (\< -1.0 but \> -2.5 vs ≥ - 1.0) and planned duration of luteinizing hormone-releasing hormone (LHRH) agonist therapy (1-2½ years vs \> 2½ years). Patients are randomized to 1 of 2 treatment arms. Quality of life is assessed at baseline and every 6 months during treatment.

Interventions

DIETARY_SUPPLEMENTCalcium

A single dose of 500 mg of elemental calcium orally each day for 3 years.

DIETARY_SUPPLEMENTZoledronic acid

Patients receive IV over 15 minutes once every 6 months for 3 years. The goal dose of zoledronic acid is 4 mg, but the selection of dose is determined based on calculated creatinine clearance at baseline.

RADIATIONradiation therapy

Patients must receive external beam irradiation, brachytherapy (HDR or LDR), or a combination of external beam irradiation and brachytherapy at the discretion of the treating physician. Dose/duration also will be at the discretion of the treating physician; however, dose will not exceed 45 Gy to 100% of the proximal femur, and no proximal femur will receive ≥ 60 Gy.

DRUGLHRH

LHRH therapy must take place for a minimum of one year. Choice of LHRH agonist, dose, and duration are at the discretion of the treating physician.

DIETARY_SUPPLEMENTVitamin D

400 IU (10μg), orally each day for 3 years.

Sponsors

National Cancer Institute (NCI)
CollaboratorNIH
Radiation Therapy Oncology Group
Lead SponsorNETWORK

Study design

Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
SUPPORTIVE_CARE
Masking
NONE

Eligibility

Sex/Gender
MALE
Age
18 Years to No maximum
Healthy volunteers
No

Inclusion criteria

Eligibility criteria: * Pathologically (histologically or cytologically) proven diagnosis of adenocarcinoma of the prostate within 12 months of registration; * Any one of the following clinical stages: * T3 disease, any N stage, M0 with any Gleason score and any prostate-specific antigen (PSA); \< T3 stage, any N stage, M0 with Gleason's score ≥ 8 and any PSA; \< T3 stage, any N stage, M0 with Gleason's score 7 and PSA ≥ 15 nanograms/ml; \< T3 stage, any N stage, M0 with Gleason score \< 7 and PSA ≥ 20 nanograms/ml. * A negative bone scan for metastatic disease; * It is mandatory that the treating physician determine the planned duration of LHRH therapy prior to the site registering the patient (minimum 1 year of therapy); If patient is receiving pre-treatment LHRH therapy, it must have begun ≤ 6 months prior to registration. If pelvic radiation therapy (RT) has started, it must have begun ≤ 8 weeks prior to registration; * Appropriate stage for protocol entry, including no distant metastases, based upon the following minimum diagnostic workup to be done within 16 weeks prior to registration: * History/physical examination; * Dental evaluation, including history of dental surgery (e.g., extraction or implant); * Bone scan; * T and L spine films; * DXA scan: To be eligible the patient must have a scan on Lunar, Hologic, or Norland equipment only and the T scores in both the L spine and total hip must be \> negative 2.5; * Zubrod Performance Status 0-1 within 16 weeks prior to registration; (8/16/07) * Age ≥ 18; * Serum creatinine within 4 weeks prior to registration (8/16/07) * Corrected serum calcium ≥ 8.4 and ≤ 10.6 mg/dl within 8 weeks prior to registration; note: for patients with an albumin of 4.0, corrected calcium=measured calcium. The formula for corrected calcium if serum albumin value is above or below 4.0 is as follows: Corrected calcium (mg/dl) = (4 - \[patient's albumin (g/dl)\] x 0.8) + patient's measured calcium (mg/dl) * Patients who are sexually active must be willing/able to use medically acceptable forms of contraception, as the treatment involved in this study may be significantly teratogenic. * Patient agrees to refrain from using all products listed in Section 9.2, Non-permitted Supportive Therapy; * Post-prostatectomy patients are eligible. * Patient must sign study specific informed consent prior to study entry. Ineligibility criteria: * Prior invasive malignancy (except non-melanomatous skin cancer) unless disease free for a minimum of 3 years; e.g., carcinoma in situ of the breast or oral cavity are permissible; * Patients with baseline T scores of ≤ -2.5 are excluded. * Patients with baseline calculated creatinine clearance \< 30 mL/min (estimated by Cockcroft-Gault formula below) are excluded. creatinine clearance male = \[(140 - age) x (wt in kg)\] / \[(serum creatinine) x (72)\] * Prior bisphosphonate therapy; * Prior pelvic radiation (other than for current prostate cancer) or prior systemic radiotherapeutic agents, such as strontium or samarium; * Patients receiving systemic chemotherapy, steroids, growth hormones, or calcitonin; * Patients with a history of Paget's disease or with uncontrolled thyroid or parathyroid dysfunction or with other diseases that influence bone metabolism; * Known hypersensitivity to zoledronic acid or other bisphosphonates; * Active dental problems at study entry, including infection of the teeth or jawbone; dental or fixture trauma; or a current or prior diagnosis of osteonecrosis of the jaw, exposed bone in the mouth, or slow healing after dental procedures; * Recent or planned

Design outcomes

Primary

MeasureTime frameDescription
Freedom From Any Bone Fracture (FABF) Rate at Three YearsFrom randomization to 3 yearsThe time of failure was measured from the date of randomization to the date of documented bone fractures, defined as any fracture of the bone. The three-year FABF rate will be estimated by the Kaplan-Meier method.

Secondary

MeasureTime frameDescription
Percent Change in Bone Mineral Density at 3 YearsBaseline, 3 years from start of treatmentBone mineral density (BMD) was measured by DXA scan (Dual X-ray absorptiometry) for five locations: lumbar, right total hip, left total hip, right femoral neck, and left femoral neck. The percent change at 3 years was calculated for each location by the following formula: Percent Change BMD = (BMD\_3 years - BMD\_Baseline)/ BMD\_Baseline \* 100.
Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsBaseline, 3 years from start of treatmentThe FACT-G is a validated, 27-item measure. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, with 0=Not a lot and 4=Very much. All items in a subscale are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range from 0-108 for the FACT-G total score, 0-28 for the physical, social and functional subscales, and 0-24 for the emotional subscale. Certain items, identified on the FACT-G scoring guides, must be reversed before it is added by subtracting the response from 4. All subscale totals are added together to form the FACT-G total score. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL.
Utility of the Use of Bisphosphonates as Assessed by Quality-adjusted SurvivalFrom pre-treatment to 3 years from start of treatmentThe EQ-5D is a standardized instrument for measuring generic health status used to generate health utilities, used to derive quality adjusted survival. Quality adjusted survival is computed using the weighted sum of times in different health states added up to a total quality-adjusted survival time. The log-rank test is used to compare quality-adjusted survivals between the treatment arms.

Countries

Canada, United States

Participant flow

Participants by arm

ArmCount
Zoledronic Acid
Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.
50
Control
Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
46
Total96

Withdrawals & dropouts

PeriodReasonFG000FG001
Overall StudyProtocol Violation10
Overall StudyWithdrawal by Subject66

Baseline characteristics

CharacteristicZoledronic AcidControlTotal
Age, Continuous70 years71 years71 years
Sex: Female, Male
Female
0 Participants0 Participants0 Participants
Sex: Female, Male
Male
50 Participants46 Participants96 Participants

Adverse events

Event typeEG000
affected / at risk
EG001
affected / at risk
deaths
Total, all-cause mortality
— / —— / —
other
Total, other adverse events
45 / 5038 / 46
serious
Total, serious adverse events
8 / 505 / 46

Outcome results

Primary

Freedom From Any Bone Fracture (FABF) Rate at Three Years

The time of failure was measured from the date of randomization to the date of documented bone fractures, defined as any fracture of the bone. The three-year FABF rate will be estimated by the Kaplan-Meier method.

Time frame: From randomization to 3 years

Population: Eligible patients

ArmMeasureValue (NUMBER)
Zoledronic AcidFreedom From Any Bone Fracture (FABF) Rate at Three Years98.0 percentage of participants
ControlFreedom From Any Bone Fracture (FABF) Rate at Three Years97.4 percentage of participants
Comparison: The study is designed to show a 40% relative reduction in the yearly ABF hazard rate, equivalent to an improvement in a 3-year FABF rate from 88% to 92.6%. A sample size of 1030 analyzable patients with a one-sided log-rank test at α = 0.05, was calculated to provide 80% statistical power, with one interim analysis and a final analysis for efficacy using Haybittle-Peto boundaries.p-value: 0.95Log Rank
Secondary

Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years

The FACT-G is a validated, 27-item measure. In addition to a total QOL score, subscale scores for physical, functional, social and emotional well-being are produced. There are 5 responses options, with 0=Not a lot and 4=Very much. All items in a subscale are added together, multiplied by the number of items in the subscale, then divided by the number of items answered to obtain subscale totals. Scores range from 0-108 for the FACT-G total score, 0-28 for the physical, social and functional subscales, and 0-24 for the emotional subscale. Certain items, identified on the FACT-G scoring guides, must be reversed before it is added by subtracting the response from 4. All subscale totals are added together to form the FACT-G total score. Each subscale requires at least 50% of the items to be completed while the overall response rate must be greater than 80%. If items are missing, the subscale scores can be prorated. A higher score indicates better QOL.

Time frame: Baseline, 3 years from start of treatment

Population: Eligible patients with baseline and 3-year FACT-G data

ArmMeasureGroupValue (MEAN)
Zoledronic AcidChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsSocial Subscale-0.69 units on a scale
Zoledronic AcidChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsFunctional Subscale-1.10 units on a scale
Zoledronic AcidChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsEmotional Subscale1.83 units on a scale
Zoledronic AcidChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsTotal-1.00 units on a scale
Zoledronic AcidChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsPhysical Subscale-1.03 units on a scale
ControlChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsTotal-2.77 units on a scale
ControlChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsPhysical Subscale0.06 units on a scale
ControlChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsSocial Subscale-1.13 units on a scale
ControlChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsEmotional Subscale1.15 units on a scale
ControlChanges in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 YearsFunctional Subscale-2.76 units on a scale
Comparison: Physical subscalep-value: 0.33t-test, 2 sided
Comparison: Social subscalep-value: 0.82t-test, 2 sided
Comparison: Emotional subscalep-value: 0.51t-test, 2 sided
Comparison: Functional subscalep-value: 0.25t-test, 2 sided
Comparison: Totalp-value: 0.63t-test, 2 sided
Secondary

Percent Change in Bone Mineral Density at 3 Years

Bone mineral density (BMD) was measured by DXA scan (Dual X-ray absorptiometry) for five locations: lumbar, right total hip, left total hip, right femoral neck, and left femoral neck. The percent change at 3 years was calculated for each location by the following formula: Percent Change BMD = (BMD\_3 years - BMD\_Baseline)/ BMD\_Baseline \* 100.

Time frame: Baseline, 3 years from start of treatment

Population: Eligible patients with baseline and 3-year BMD data at respective location

ArmMeasureGroupValue (MEAN)
Zoledronic AcidPercent Change in Bone Mineral Density at 3 YearsHip - Right-2 percentage of baseline value
Zoledronic AcidPercent Change in Bone Mineral Density at 3 YearsFemoral - Right1 percentage of baseline value
Zoledronic AcidPercent Change in Bone Mineral Density at 3 YearsHip - Left1 percentage of baseline value
Zoledronic AcidPercent Change in Bone Mineral Density at 3 YearsFemoral - Left3 percentage of baseline value
Zoledronic AcidPercent Change in Bone Mineral Density at 3 YearsLumbar6 percentage of baseline value
ControlPercent Change in Bone Mineral Density at 3 YearsFemoral - Left-8 percentage of baseline value
ControlPercent Change in Bone Mineral Density at 3 YearsHip - Right-5 percentage of baseline value
ControlPercent Change in Bone Mineral Density at 3 YearsHip - Left-8 percentage of baseline value
ControlPercent Change in Bone Mineral Density at 3 YearsFemoral - Right-6 percentage of baseline value
ControlPercent Change in Bone Mineral Density at 3 YearsLumbar-5 percentage of baseline value
Comparison: Lumbarp-value: <0.0001t-test, 2 sided
Comparison: Hip - rightp-value: 0.47t-test, 2 sided
Comparison: Hip - leftp-value: 0.0002t-test, 2 sided
Comparison: Femoral - rightp-value: 0.076t-test, 2 sided
Comparison: Femoral - leftp-value: 0.0007t-test, 2 sided
Secondary

Utility of the Use of Bisphosphonates as Assessed by Quality-adjusted Survival

The EQ-5D is a standardized instrument for measuring generic health status used to generate health utilities, used to derive quality adjusted survival. Quality adjusted survival is computed using the weighted sum of times in different health states added up to a total quality-adjusted survival time. The log-rank test is used to compare quality-adjusted survivals between the treatment arms.

Time frame: From pre-treatment to 3 years from start of treatment

Population: Eligible patients with baseline and follow-up EQ-5D scores, resulting in only 59 patients (no deaths), less than half of enrolled patients (and less than 5% of planned enrollment), which is extremely problematic as it can lead to selection bias, especially with even fewer patients with follow-up scores. Therefore analysis was not conducted.

Source: ClinicalTrials.gov · Data processed: Feb 4, 2026