Single Dosing of Zoledronic Acid in Cancer Therapy Induced Bone Loss (CTIBL)

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00712985
• Collaborator: Novartis (Industry)
• Enrollment: 18
• Location: 1
• Arm: 1
• Duration (Months): 65.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this research is to establish if a once a year dose of Zoledronic Acid is sufficient to suppress and maintain urine and serum bone density markers (NTx) and serum CTx within normal range at 12 months post-dosing in postmenopausal early breast cancer patients receiving additional treatment with non-steroidal aromatase inhibitors.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer	Drug: Zometa	Phase 3

Detailed Description

Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. Skeletal complications due to metastatic disease include (severe) bone pain, spinal cord compromise, pathological fractures, and hypercalcemia.

Zoledronic acid is a member of a class of compounds known as bisphosphonates. Bisphosphonates are effective inhibitors of osteoclastic bone resorption and have demonstrated therapeutic efficacy in the treatments of hypercalcemia of malignancy, lytic bone disease associated with multiple myeloma, and mixed lytic and blastic bone metastases associated with breast cancer. The precise mechanism by which bisphosphonates inhibit osteoclast function is not fully understood, but may include a direct toxic effect on mature osteoclasts, an inhibition of osteoclast production from precursor cells, and an impairment of osteoclast chemotaxis to sites of active bone resorption. Osteoclasts are specialized bone cells which erode mineralized bone by secreting acids and lysosomal enzymes. In normal bone remodeling, osteoclastic bone resorption is coupled to and is in equilibrium with osteoblastic bone formation. The lytic bone destruction associated with malignant bone metastases develops because tumor cells synthesize and release soluble factors that stimulate osteoclasts to resorb bone. The osteoclastic activating factors released by tumor cells include parathyroid hormone-related peptide (PTHrP), growth factors, and cytokines. The malignant activation of osteoclasts results in a disruption of normal bone remodeling wherein the equilibrium between bone resorption and bone formation is shifted toward increased bone resorption. This relative increase in osteoclastic bone resorption results in a net loss of bone. Thus, the predominant role of the osteoclast in the pathogenesis of bone destruction and the inhibitory effects of bisphosphonates on osteoclast function have formed the rationale for the use of bisphosphonates in the treatment of osteolytic bone metastases. The common role, regardless of tumor type, of the osteoclast as the mediator of bone destruction in metastatic skeletal disease is indicated by the inhibitory effects of bisphosphonates on tumor-induced osteolysis in animal models utilizing various malignant cell lines and the effectiveness of bisphosphonates in the therapy of tumor-induced hypercalcemia arising from any type of cancer. Moreover, recent studies have specifically shown that therapy with the bisphosphonate pamidronate (Aredia) combined with antineoplastic therapy significantly reduces the proportion of patients having skeletal complications due to the lytic bone disease associated with multiple myeloma and breast cancer compared to antineoplastic therapy alone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 18 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Prevention
• Official Title: Single Dosing of Zoledronic Acid in Cancer Therapy Induced Bone Loss (CTIBL)
• Study Start Date: Sep 1, 2005
• Actual Primary Completion Date: Mar 1, 2011
• Actual Study Completion Date: Mar 1, 2011

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Zometa (Zoledronic Acid) X 1 dose Zometa (Zoledronic Acid) 5 mg IV X 1 dose	Drug: Zometa; Zometa (Zoledronic Acid) 5 mg IV over 15 minutes in a one time dose; Other Names: Zoledronic Acid

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Urine and Serum NTx and Serum CTx Within Normal Range at 12 Months [One year]

   17 women with early breast cancer receiving adjuvant Aromatase Inhibitor (AI) therapy were treated with a single 5 mg IV dose of zoledronic acid. Urine and serum NTx and serum CTx were measured at baseline and month 12.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Postmenopausal women with Stage I, II or IIIa breast cancer being treated with a non-steroidal Aromatase Inhibitor (AI) .Negative bone scan (no bone metastases).

• Calculated creatinine clearance > 40 ml/min

• Documented T score of less than or equal to -1.5 on Dual Energy X-ray Absorptiionmetry (DXA) scan at the lumbar spine or femoral neck within 3 months prior to screening.

• Urine NTx > 50 nano moles(nM)based on second morning void.

• Signed informed consent.

• Ambulatory patients at least 18 years of age.

• Eastern Cooperative Oncology Group (ECOG)0-2.

• Ability to comply with trial requirements.

Exclusion Criteria:

• Bone Metastases.

• Any woman of child bearing potential.

• Patients with fractures occurring within three months prior to randomization. - Greater than a 2+ protein on urine dipstick without evidence of contamination or bacteriuria (may be repeated one time, at least a day apart).

• Calculated creatinine clearance less than 30 mL/min at screening.

• Serum calcium > 2.75 mmol/L (11.0 mg/dL) or < 2.00 mmol/L (8.0 mg/dL).

• Liver Function tests (LFT)> 2.0 x upper limit of normal (ULN).

• Serum alkaline phosphatase > 1.5 x ULN. History of hypersensitivity to bisphosphonates.

• Evidence of vitamin D deficiency (serum 25-(OH) D of less than 15 ng/ml).

• History of uveitis or iritis, except when secondary to trauma, and must have resolved

2 years prior to entry.

• A history of invasive malignancy of any organ system, treated or untreated, within the past 12 months prior to screening; excluding, basal cell or squamous cell carcinoma of the skin, colonic polyps with non-invasive malignancy which have been removed, Ductal Carcinoma in-situ (DCIS) that has been surgically removed, and Carcinoma in-situ (CIS) of the uterine cervix that has been surgically removed.

• Previous major solid organ transplant recipient or on a transplant waiting list.

• Treatment with any investigational drug within 30 days prior to randomization.

• History of hyperparathyroidism, hypoparathyroidism, Osteogenesis imperfecta, Paget's disease or any metabolic bone disease other than osteoporosis.

• Any medical condition which would interfere with the action of the study drug or limit life expectancy to less than 6 months.

• Any medical or psychiatric condition which, in the opinion of the investigator, would preclude the participant from adhering to the protocol or completing the trial.

• Prior treatment with IV bisphosphonates within the last 2 years.

• Previous use of oral bisphosphonates within the past 2 years (unless used for less than 8 weeks*). *NOTE: If used less than 8 weeks, the washout period is 6 months.

• Treatment with raloxifene, calcitonin, tibolone or hormone replacement therapy. The washout period for these medications is 6 months prior to randomization.

• Any treatment with strontium ranelate, samarium, sodium fluoride or parathyroid hormone.

• Use of systemic high dose corticosteroids at an average dose of > 7.5 mg per day of oral prednisone or equivalent for a period of three months or more prior to screening.

• Known hypersensitivity to zoledronic acid or other bisphosphonates.

• Current active dental problems including infection of the teeth or jawbone (maxilla or mandibular); dental or fixture trauma, or a current or prior diagnosis of osteonecrosis of the jaw (ONJ), of exposed bone in the mouth, or of slow healing after dental procedures.

• Recent (within 6 weeks) or planned dental or jaw surgery (e.g.. extraction, implants).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Penn State Milton S. Hershey Medical Center	Hershey	Pennsylvania	United States	17033

Sponsors and Collaborators

• Milton S. Hershey Medical Center
• Novartis

Investigators

• Principal Investigator: Allan Lipton, MD, Milton S. Hershey Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Baum M, Budzar AU, Cuzick J, Forbes J, Houghton JH, Klijn JG, Sahmoud T; ATAC Trialists' Group. Anastrozole alone or in combination with tamoxifen versus tamoxifen alone for adjuvant treatment of postmenopausal women with early breast cancer: first results of the ATAC randomised trial. Lancet. 2002 Jun 22;359(9324):2131-9. Erratum in: Lancet 2002 Nov 9;360(9344):1520.
• BIG 1-98 Collaborative Group. Letrozole versus tamoxifen as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer. BIG 1-98: a prospective randomized double-blind phase III study. Breast. 2005;14:Suppl 1:S3. Abstract.
• Coombes RC, Hall E, Gibson LJ, Paridaens R, Jassem J, Delozier T, Jones SE, Alvarez I, Bertelli G, Ortmann O, Coates AS, Bajetta E, Dodwell D, Coleman RE, Fallowfield LJ, Mickiewicz E, Andersen J, Lønning PE, Cocconi G, Stewart A, Stuart N, Snowdon CF, Carpentieri M, Massimini G, Bliss JM, van de Velde C; Intergroup Exemestane Study. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004 Mar 11;350(11):1081-92. Erratum in: N Engl J Med. 2004 Dec 2;351(23):2461. N Engl J Med. 2006 Oct 19;355(16):1746. van de Velde, Cornelius [added].
• Goss PE, Ingle JN, Martino S, Robert NJ, Muss HB, Piccart MJ, Castiglione M, Tu D, Shepherd LE, Pritchard KI, Livingston RB, Davidson NE, Norton L, Perez EA, Abrams JS, Therasse P, Palmer MJ, Pater JL. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003 Nov 6;349(19):1793-802. Epub 2003 Oct 9.
• Smith MR, Eastham J, Gleason DM, Shasha D, Tchekmedyian S, Zinner N. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol. 2003 Jun;169(6):2008-12.
• Walsh PC. Intravenous zoledronic acid in postmenopausal women with low bone mineral density. J Urol. 2002 Oct;168(4 Pt 1):1643.

• Responsible Party: Allan Lipton, MD, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00712985
• Other Study ID Numbers: CZOL446H US113
• First Posted: Jul 11, 2008
• Last Update Posted: Apr 24, 2014
• Last Verified: Mar 1, 2014

• Keywords provided by Allan Lipton, MD, Milton S. Hershey Medical Center: Breast cancer; aromatase inhibitors
• Additional relevant MeSH terms: Breast Neoplasms; Zoledronic Acid

Study Results

Participant Flow

Recruitment Details	Recruitment period was from 1/10/2007 for first patient consented to 12/29/2009 last patient consented. The patients were all seen in the Milton S. Hershey Medical Center Oncology clinic & were treated from first patient Day 1 of 1/16/2007 to last patient month 12 of 2/01/2011.
Pre-assignment Detail	Following consent, this trial only had 1 arm & all patients were given a one time dose of Zoledronic Acid 5 mg IV. All 17 patients were then followed for 12 months from day 1 & their urine & serum were collected in order to evaluate the urine N-telopeptide (NTx) & serum NTx & C-telopeptide (CTx) levels.

Arm/Group Title	Zoledronic Acid 5 mg IV
Arm/Group Description	Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose. Follow-up at month 1 & every 2 months to month 12 for serum & urine markers of bone destruction (NTx & CTx).
Period Title: Overall Study
STARTED	18
COMPLETED	13
NOT COMPLETED	5

Baseline Characteristics

Arm/Group Title	Zoledronic Acid 5 mg IV
Arm/Group Description	Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose. Follow-up at month 1 & every 2 months to month 12 for serum & urine markers of bone destruction (NTx & CTx).
Overall Participants	18
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	14 77.8%
>=65 years	4 22.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	56 (9.89)
Sex: Female, Male (Count of Participants)
Female	18 100%
Male	0 0%
Region of Enrollment (participants) [Number]
United States	18 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Urine and Serum NTx and Serum CTx Within Normal Range at 12 Months
Description	17 women with early breast cancer receiving adjuvant Aromatase Inhibitor (AI) therapy were treated with a single 5 mg IV dose of zoledronic acid. Urine and serum NTx and serum CTx were measured at baseline and month 12.
Time Frame	One year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Zoledronic Acid 5 mg IV
Arm/Group Description	Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose. Follow-up at month 1 & every 2 months to month 12 for serum & urine markers of bone destruction (NTx & CTx).
Measure Participants	13
Number [participants]	13 72.2%

Adverse Events

Time Frame	Monthly for 1 year
Arm/Group Title	Zoledronic Acid 5 mg IV
Arm/Group Description	Zometa (Zoledronic Acid) 5 mg IV given over 15 minutes as a one time dose. Follow-up at month 1 & every 2 months to month 12 for serum & urine markers of bone destruction (NTx & CTx).
All Cause Mortality
	Zoledronic Acid 5 mg IV
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Zoledronic Acid 5 mg IV
	Affected / at Risk (%)	# Events
Total	0/17 (0%)
Other (Not Including Serious) Adverse Events
	Zoledronic Acid 5 mg IV
	Affected / at Risk (%)	# Events
Total	0/17 (0%)

Limitations/Caveats

18 patients were able to be enrolled in this trial & only 13 were able to be analyzed. This was an insufficient number to analyze/interpret data.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.