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

• Sponsor: Radiation Therapy Oncology Group (Other)
• Overall Status: Completed
• CT.gov ID: NCT00329797
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 109
• Locations: 88
• Arms: 2
• Duration (Months): 104
• Patients Per Site: 1.2
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis; Prostate Cancer	Dietary Supplement: Calcium; Dietary Supplement: Zoledronic acid; Radiation: radiation therapy; Drug: LHRH; Dietary Supplement: Vitamin D	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 109 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Supportive Care
• Official Title: 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
• Study Start Date: Mar 1, 2006
• Actual Primary Completion Date: Nov 1, 2014
• Actual Study Completion Date: Nov 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 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.	Dietary Supplement: Calcium; A single dose of 500 mg of elemental calcium orally each day for 3 years.; Dietary Supplement: Zoledronic 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.; Other Names: Zometa zoledronate ; Radiation: radiation 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.; Drug: LHRH; 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 Supplement: Vitamin D; 400 IU (10μg), orally each day for 3 years.
Active Comparator: Control Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Dietary Supplement: Calcium; A single dose of 500 mg of elemental calcium orally each day for 3 years.; Radiation: radiation 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.; Drug: LHRH; 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 Supplement: Vitamin D; 400 IU (10μg), orally each day for 3 years.

Outcome Measures

Primary Outcome Measures

1. Freedom From Any Bone Fracture (FABF) Rate at Three Years [From randomization to 3 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.

Secondary Outcome Measures

1. Percent Change in Bone Mineral Density at 3 Years [Baseline, 3 years from start of treatment]

   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.

2. Changes in the Functional Assessment of Cancer Therapy-General (FACT-G) at 3 Years [Baseline, 3 years from start of treatment]

   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.

3. Utility of the Use of Bisphosphonates as Assessed by Quality-adjusted Survival [From pre-treatment to 3 years from start of treatment]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Enloe Cancer Center at Enloe Medical Center	Chico	California	United States	95926
2	USC/Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90089-9181
3	Robert and Beverly Lewis Family Cancer Care Center at Pomona Valley Hospital Medical Center	Pomona	California	United States	91767
4	Radiation Oncology Center - Roseville	Roseville	California	United States	95661
5	Radiological Associates of Sacramento Medical Group, Incorporated	Sacramento	California	United States	95815
6	Penrose Cancer Center at Penrose Hospital	Colorado Springs	Colorado	United States	80933
7	St. Mary - Corwin Regional Medical Center	Pueblo	Colorado	United States	81004
8	Northeast Georgia Medical Center	Gainesville	Georgia	United States	30501
9	Saint Anthony's Hospital at Saint Anthony's Health Center	Alton	Illinois	United States	62002
10	Northwest Community Hospital	Arlington Heights	Illinois	United States	60005
11	Ingalls Cancer Care Center at Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
12	Saint James Hospital and Health Centers Comprehensive Cancer Institute - Olympia Fields	Olympia Fields	Illinois	United States	60461
13	CCOP - Carle Cancer Center	Urbana	Illinois	United States	61801
14	Center for Cancer Care at Goshen General Hospital	Goshen	Indiana	United States	46526
15	Methodist Cancer Center at Methodist Hospital	Indianapolis	Indiana	United States	46202
16	Lucille P. Markey Cancer Center at University of Kentucky	Lexington	Kentucky	United States	40536-0093
17	St. Agnes Hospital Cancer Center	Baltimore	Maryland	United States	21229
18	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21231-2410
19	Barbara Ann Karmanos Cancer Institute	Detroit	Michigan	United States	48201-1379
20	Josephine Ford Cancer Center at Henry Ford Hospital	Detroit	Michigan	United States	48202
21	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007-3731
22	CentraCare Clinic - River Campus	Saint Cloud	Minnesota	United States	56303
23	Coborn Cancer Center	Saint Cloud	Minnesota	United States	56303
24	Southeast Missouri Regional Cancer Center at Southeast Missouri Hospital	Cape Girardeau	Missouri	United States	63701
25	CCOP - Kansas City	Kansas City	Missouri	United States	64131
26	Siteman Cancer Center at Barnes-Jewish Hospital - Saint Louis	Saint Louis	Missouri	United States	63110
27	CCOP - St. Louis-Cape Girardeau	Saint Louis	Missouri	United States	63141
28	David C. Pratt Cancer Center at St. John's Mercy	Saint Louis	Missouri	United States	63141
29	St. John's Regional Health Center	Springfield	Missouri	United States	65804
30	Hulston Cancer Center at Cox Medical Center South	Springfield	Missouri	United States	65807
31	CCOP - Montana Cancer Consortium	Billings	Montana	United States	59101
32	Northern Rockies Radiation Oncology Center	Billings	Montana	United States	59101
33	Great Falls Clinic - Main Facility	Great Falls	Montana	United States	59405
34	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
35	CCOP - Nevada Cancer Research Foundation	Las Vegas	Nevada	United States	89106
36	Renown Institute for Cancer at Renown Regional Medical Center	Reno	Nevada	United States	89502
37	Kingsbury Center for Cancer Care at Cheshire Medical Center	Keene	New Hampshire	United States	03431
38	Norris Cotton Cancer Center at Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0002
39	Cancer Institute of New Jersey at Cooper University Hospital - Camden	Camden	New Jersey	United States	08103
40	Franklin & Edith Scarpa Regional Cancer Center at South Jersey Healthcare	Vineland	New Jersey	United States	08360
41	Cancer Institute of New Jersey at Cooper - Voorhees	Voorhees	New Jersey	United States	08043
42	Lourdes Regional Cancer Center	Binghamton	New York	United States	13905
43	Veterans Affairs Medical Center - Brooklyn	Brooklyn	New York	United States	11209
44	Roswell Park Cancer Institute	Buffalo	New York	United States	14263-0001
45	CCOP - Hematology-Oncology Associates of Central New York	East Syracuse	New York	United States	13057
46	Mission Hospitals - Memorial Campus	Asheville	North Carolina	United States	28801
47	Wayne Radiation Oncology	Goldsboro	North Carolina	United States	27534
48	Cancer Centers of North Carolina - Raleigh	Raleigh	North Carolina	United States	27607
49	Wilmed Radiation Oncology Services	Wilson	North Carolina	United States	27893
50	McDowell Cancer Center at Akron General Medical Center	Akron	Ohio	United States	44307
51	Summa Center for Cancer Care at Akron City Hospital	Akron	Ohio	United States	44309-2090
52	Charles M. Barrett Cancer Center at University Hospital	Cincinnati	Ohio	United States	45267
53	Cancer Research UK Medical Oncology Unit at Churchill Hospital & Weatherall Institute of Molecular Medicine - Oxford	Salem	Ohio	United States	44460
54	Precision Radiotherapy at University Pointe	West Chester	Ohio	United States	45069
55	Cancer Treatment Center	Wooster	Ohio	United States	44691
56	Rosenfeld Cancer Center at Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
57	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
58	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
59	Cancer Center of Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301-1792
60	Fox Chase Cancer Center - Philadelphia	Philadelphia	Pennsylvania	United States	19111-2497
61	Lankenau Cancer Center at Lankenau Hospital	Wynnewood	Pennsylvania	United States	19096
62	York Cancer Center at Apple Hill Medical Center	York	Pennsylvania	United States	17405
63	Christine LaGuardia Phillips Cancer Center at Wellmont Holston Valley Medical Center	Kingsport	Tennessee	United States	37662
64	Jon and Karen Huntsman Cancer Center at Intermountain Medical Center	Murray	Utah	United States	84157
65	Val and Ann Browning Cancer Center at McKay-Dee Hospital Center	Ogden	Utah	United States	84403
66	Utah Valley Regional Medical Center - Provo	Provo	Utah	United States	84604
67	Dixie Regional Medical Center - East Campus	Saint George	Utah	United States	84770
68	LDS Hospital	Salt Lake City	Utah	United States	84143
69	Norris Cotton Cancer Center - North	Saint Johnsbury	Vermont	United States	05819
70	Sentara Cancer Institute at Sentara Norfolk General Hospital	Norfolk	Virginia	United States	23507
71	Naval Medical Center - Portsmouth	Portsmouth	Virginia	United States	23708-2197
72	North Star Lodge Cancer Center at Yakima Valley Memorial Hospital	Yakima	Washington	United States	98902
73	Theda Care Cancer Institute	Appleton	Wisconsin	United States	54911
74	St. Vincent Hospital Regional Cancer Center	Green Bay	Wisconsin	United States	54307-3508
75	Bay Area Cancer Care Center at Bay Area Medical Center	Marinette	Wisconsin	United States	54143
76	Community Memorial Hospital Cancer Care Center	Menomonee Falls	Wisconsin	United States	53051
77	Vince Lombardi Cancer Clinic at Aurora St. Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
78	Medical College of Wisconsin Cancer Center	Milwaukee	Wisconsin	United States	53226
79	Veterans Affairs Medical Center - Milwaukee	Milwaukee	Wisconsin	United States	53295
80	West Allis Memorial Hospital	West Allis	Wisconsin	United States	53227
81	British Columbia Cancer Agency - Vancouver Island Centre	Victoria	British Columbia	Canada	V8R 6V5
82	Doctor H. Bliss Murphy Cancer Centre	St. John's	Newfoundland and Labrador	Canada	A1B 3V6
83	Margaret and Charles Juravinski Cancer Centre	Hamilton	Ontario	Canada	L8V 5C2
84	Cancer Care Program at Thunder Bay Regional Health Sciences	Thunder Bay	Ontario	Canada	P7B 6V4
85	Maisonneuve-Rosemont Hospital	Montreal	Quebec	Canada	H1T 2M4
86	Centre Hospitalier Universitaire de Quebec	Quebec City	Quebec	Canada	G1R 2J6
87	CHUS-Hopital Fleurimont	Sherbrooke	Quebec	Canada	J1H 5N4
88	Allan Blair Cancer Centre at Pasqua Hospital	Regina	Saskatchewan	Canada	S4T 7T1

Sponsors and Collaborators

• Radiation Therapy Oncology Group
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Colleen A. Lawton, MD, Medical College of Wisconsin
• Study Chair: Matthew R. Smith, MD, Massachusetts General Hospital
• Study Chair: Margaret Chamberlain-Wilmoth, PhD, MSS, RN, Carolinas Medical Center - University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Radiation Therapy Oncology Group
• ClinicalTrials.gov Identifier: NCT00329797
• Other Study ID Numbers: RTOG 0518; CDR0000476469; NCI-2009-00884
• First Posted: May 25, 2006
• Last Update Posted: Nov 29, 2017
• Last Verified: Oct 1, 2017

• Keywords provided by Radiation Therapy Oncology Group: osteoporosis; adenocarcinoma of the prostate; stage IIB prostate cancer; stage IIA prostate cancer; stage III prostate cancer; stage IV prostate cancer
• Additional relevant MeSH terms: Prostatic Neoplasms; Osteoporosis; Vitamin D; Zoledronic Acid; Calcium

Study Results

Participant Flow

Arm/Group Title	Zoledronic Acid	Control
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and luteinizing hormone-releasing hormone (LHRH) therapy.	Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Period Title: Overall Study
STARTED	57	52
COMPLETED	50	46
NOT COMPLETED	7	6

Baseline Characteristics

Arm/Group Title	Zoledronic Acid	Control	Total
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Total of all reporting groups
Overall Participants	50	46	96
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	70	71	71
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	50 100%	46 100%	96 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Eligible patients

Arm/Group Title	Zoledronic Acid	Control
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Measure Participants	50	46
Number (95% Confidence Interval) [percentage of participants]	98.0 196%	97.4 211.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	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.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.95
	Comments
	Method	Log Rank
	Comments

2. Secondary Outcome

Title	Percent Change in Bone Mineral Density at 3 Years
Description	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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Zoledronic Acid	Control
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Measure Participants	50	46
Lumbar	6	-5
Hip - Right	-2	-5
Hip - Left	1	-8
Femoral - Right	1	-6
Femoral - Left	3	-8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Lumbar
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Hip - right
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.47
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Hip - left
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Femoral - right
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.076
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Femoral - left
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.0007
	Comments	significance level = 0.05
	Method	t-test, 2 sided
	Comments

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Zoledronic Acid	Control
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Measure Participants	29	21
Physical Subscale	-1.03	0.06
Social Subscale	-0.69	-1.13
Emotional Subscale	1.83	1.15
Functional Subscale	-1.10	-2.76
Total	-1.00	-2.77

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Physical subscale
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.33
	Comments	significance level = 0.01
	Method	t-test, 2 sided
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Social subscale
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.82
	Comments	significance level = 0.01
	Method	t-test, 2 sided
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Emotional subscale
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.51
	Comments	significance level = 0.01
	Method	t-test, 2 sided
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Functional subscale
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.25
	Comments	significance level = 0.01
	Method	t-test, 2 sided
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Zoledronic Acid, Control
	Comments	Total
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.63
	Comments	significance level = 0.01
	Method	t-test, 2 sided
	Comments

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Zoledronic Acid	Control
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.	Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
Measure Participants	0	0

Adverse Events

Adverse Event Reporting Description	Subjects experiencing more than one of a given adverse event are counted only once for that adverse event.
Arm/Group Title	Zoledronic Acid		Control
Arm/Group Description	Zoledronic acid q 6 months plus Vitamin D and calcium supplement for 3 years in addition to concurrent radiation therapy and LHRH therapy.		Vitamin D and calcium supplement everyday for 3 years in addition to concurrent radiation therapy and LHRH therapy.
All Cause Mortality
	Zoledronic Acid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Zoledronic Acid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/50 (16%)		5/46 (10.9%)
Cardiac disorders
Left ventricular failure	1/50 (2%)		0/46 (0%)
Myocardial ischaemia	1/50 (2%)		0/46 (0%)
Restrictive cardiomyopathy	1/50 (2%)		0/46 (0%)
Eye disorders
Uveitis NOS	1/50 (2%)		0/46 (0%)
Gastrointestinal disorders
Abdominal pain NOS	1/50 (2%)		1/46 (2.2%)
Colonic haemorrhage	1/50 (2%)		0/46 (0%)
General disorders
Death NOS	0/50 (0%)		1/46 (2.2%)
Gait abnormal NOS	0/50 (0%)		1/46 (2.2%)
Injury, poisoning and procedural complications
Fracture NOS	1/50 (2%)		0/46 (0%)
Vessel injury-artery: Carotid	1/50 (2%)		0/46 (0%)
Investigations
Lymphopenia	0/50 (0%)		1/46 (2.2%)
Metabolism and nutrition disorders
Glucose tolerance impaired	0/50 (0%)		1/46 (2.2%)
Hypocalcemia	1/50 (2%)		0/46 (0%)
Hypokalemia	1/50 (2%)		0/46 (0%)
Hyponatremia	1/50 (2%)		0/46 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/50 (2%)		0/46 (0%)
Muscle weakness, generalized or specific area (not due to ne	1/50 (2%)		0/46 (0%)
Nervous system disorders
Cerebral ischaemia	0/50 (0%)		1/46 (2.2%)
Psychiatric disorders
Confusional state	0/50 (0%)		1/46 (2.2%)
Renal and urinary disorders
Pollakiuria	1/50 (2%)		0/46 (0%)
Renal/genitourinary - Other:	2/50 (4%)		0/46 (0%)
Reproductive system and breast disorders
Penile pain	1/50 (2%)		0/46 (0%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid		Control
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/50 (90%)		38/46 (82.6%)
Blood and lymphatic system disorders
Hemoglobin	13/50 (26%)		11/46 (23.9%)
Gastrointestinal disorders
Abdominal pain NOS	1/50 (2%)		3/46 (6.5%)
Constipation	7/50 (14%)		4/46 (8.7%)
Diarrhoea NOS	9/50 (18%)		8/46 (17.4%)
Dry mouth	0/50 (0%)		3/46 (6.5%)
Gastrointestinal - Other:	3/50 (6%)		1/46 (2.2%)
Hemorrhoids	3/50 (6%)		1/46 (2.2%)
Nausea	4/50 (8%)		0/46 (0%)
Proctitis NOS	3/50 (6%)		5/46 (10.9%)
Rectal hemorrhage	4/50 (8%)		9/46 (19.6%)
General disorders
Constitutional Symptoms - Other:	4/50 (8%)		2/46 (4.3%)
Edema: limb:	7/50 (14%)		2/46 (4.3%)
Fatigue	23/50 (46%)		15/46 (32.6%)
Pain - Other:	5/50 (10%)		1/46 (2.2%)
Pain NOS	3/50 (6%)		1/46 (2.2%)
Investigations
Aspartate aminotransferase increased	3/50 (6%)		1/46 (2.2%)
Blood creatinine increased	4/50 (8%)		1/46 (2.2%)
Leukopenia NOS	5/50 (10%)		2/46 (4.3%)
Lymphopenia	7/50 (14%)		5/46 (10.9%)
Metabolic/laboratory - Other:	5/50 (10%)		2/46 (4.3%)
Platelet count decreased	4/50 (8%)		1/46 (2.2%)
Weight increased	4/50 (8%)		0/46 (0%)
Metabolism and nutrition disorders
Hyperglycaemia NOS	2/50 (4%)		6/46 (13%)
Musculoskeletal and connective tissue disorders
Arthralgia	13/50 (26%)		7/46 (15.2%)
Back pain	6/50 (12%)		2/46 (4.3%)
Bone pain	8/50 (16%)		2/46 (4.3%)
Muscle weakness NOS	4/50 (8%)		2/46 (4.3%)
Musculoskeletal/soft tissue - Other:	6/50 (12%)		1/46 (2.2%)
Myalgia	5/50 (10%)		3/46 (6.5%)
Pain in extremity	5/50 (10%)		1/46 (2.2%)
Nervous system disorders
Dizziness	3/50 (6%)		2/46 (4.3%)
Headache	3/50 (6%)		0/46 (0%)
Peripheral sensory neuropathy	3/50 (6%)		3/46 (6.5%)
Psychiatric disorders
Depression	6/50 (12%)		3/46 (6.5%)
Insomnia	3/50 (6%)		2/46 (4.3%)
Libido decreased	5/50 (10%)		4/46 (8.7%)
Renal and urinary disorders
Pollakiuria	20/50 (40%)		13/46 (28.3%)
Renal/genitourinary - Other:	3/50 (6%)		4/46 (8.7%)
Urinary incontinence	5/50 (10%)		4/46 (8.7%)
Urinary retention	3/50 (6%)		5/46 (10.9%)
Reproductive system and breast disorders
Erectile dysfunction NOS	9/50 (18%)		6/46 (13%)
Gynaecomastia	7/50 (14%)		4/46 (8.7%)
Respiratory, thoracic and mediastinal disorders
Cough	4/50 (8%)		0/46 (0%)
Dyspnoea	5/50 (10%)		5/46 (10.9%)
Skin and subcutaneous tissue disorders
Dermatitis exfoliative NOS	3/50 (6%)		1/46 (2.2%)
Pruritus	4/50 (8%)		0/46 (0%)
Vascular disorders
Hot flushes NOS	27/50 (54%)		25/46 (54.3%)

Limitations/Caveats

This study stopped accrual early due to unmet targeted accrual goals with 109 subjects accrued out of 1272 planned, less than 10% than what was planned.

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

PI's are required to abide by the sponsor's publication guidelines which require review by coauthors and subsequent review and approval by the sponsor.