Efficacy in Reducing Fractures and Safety of Zoledronic Acid in Men With Osteoporosis

A Two Year Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Evaluate the Fracture Efficacy and Safety of Intravenous Zoledronic Acid 5 mg Annually for the Treatment of Osteoporosis in Men

This study will investigate if the drug zoledronic acid given once yearly is safe and has beneficial effects in treating osteoporosis by reducing bone loss and fractures in men with osteoporosis.

Study Overview

• Status: Completed
• Conditions: Male Osteoporosis
• Intervention / Treatment: Drug: Zoledronic acid 5 mg iv; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 1199
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina
    • Novartis Investigative Site
  • Cordoba, Argentina
    • Novartis Investigative Site
  • Mar del Plata, Argentina
    • Novartis Investigative Site
  • San Miguel de Tucuman, Argentina
    • Novartis Investigative Site
• Australia
  • Geelong-VIC, Australia
    • Novartis Investigative Site
  • Maroochydore-QLD, Australia
    • Novartis Investigative Site
  • Randwick-NSW, Australia
    • Novartis Investigative Site
• Austria
  • Graz, Austria
    • Novartis Investigative Site
  • Vienna, Austria
    • Novartis Investigative Site
• Belgium
  • Bruxelles, Belgium
    • Novartis Investigative Site
  • Diepenbeek, Belgium
    • Novartis Investigative Site
  • Genk, Belgium
    • Novartis Investigative Site
  • Godinne, Belgium
    • Novartis Investigative Site
  • Gozee, Belgium
    • Novartis Investigative Site
  • Jette, Belgium
    • Novartis Investigative Site
  • Laeken, Belgium
    • Novartis Investigative Site
  • Leuven, Belgium
    • Novartis Investigative Site
  • Liege, Belgium
    • Novartis Investigative Site
  • Merksem, Belgium
    • Novartis Investigative Site
  • Wilrijk, Belgium
    • Novartis Investigative Site
• Brazil
  • Brasilia, Brazil
    • Novartis Investigative Site
  • Curitiba, Brazil
    • Novartis Investigative Site
  • Rio de Janeiro, Brazil
    • Novartis Investigative Site
  • Sao Paulo, Brazil
    • Novartis Investigative Site
• Czechia
  • Ceske Budejovice, Czechia
    • Novartis Investigative Site
  • Hradec Kralove, Czechia
    • Novartis Investigative Site
  • Plzen, Czechia
    • Novartis Investigative Site
  • Prague, Czechia
    • Novartis Investigative Site
  • Praha, Czechia
    • Novartis Investigative Site
• Denmark
  • Aalborg, Denmark
    • Novartis Investigative Site
  • Arhus, Denmark
    • Novartis Investigative Site
  • Glostrup, Denmark
    • Novartis Investigative Site
  • Hvidovre, Denmark
    • Novartis Investigative Site
  • Odense C, Denmark
    • Novartis Investigative Site
• Finland
  • Helsinki, Finland
    • Novartis Investigative Site
  • Tampere, Finland
    • Novartis Investigative Site
  • Turku, Finland
    • Novartis Investigative Site
• Germany
  • Aachen, Germany
    • Novartis Investigative Site
  • Bad Bentheim, Germany
    • Novartis Investigative Site
  • Bad Pyrmont, Germany
    • Novartis Investigative Site
  • Braunfels, Germany
    • Novartis Investigative Site
  • Dresden, Germany
    • Novartis Investigative Site
  • Essen, Germany
    • Novartis Investigative Site
  • Frankfurt, Germany
    • Novartis Investigative Site
  • Hamburg, Germany
    • Novartis Investigative Site
  • Hannover, Germany
    • Novartis Investigative Site
  • Heidelberg, Germany
    • Novartis Investigative Site
  • Kempen, Germany
    • Novartis Investigative Site
  • Leverkusen, Germany
    • Novartis Investigative Site
  • Magdeburg, Germany
    • Novartis Investigative Site
  • Marburg, Germany
    • Novartis Investigative Site
  • München, Germany
    • Novartis Investigative Site
  • Würzburg, Germany
    • Novartis Investigative Site
• Hungary
  • Budapest, Hungary
    • Novartis Investigative Site
  • Debrecen, Hungary
    • Novartis Investigative Site
  • Gyula, Hungary
    • Novartis Investigative Site
  • Szekesfehervar, Hungary
    • Novartis Investigative Site
  • Veszprem, Hungary
    • Novartis Investigative Site
• Iceland
  • Kopavogur, Iceland
    • Novartis Investigative Site
• Italy
  • Arenzano, Italy
    • Novartis Investigative Site
  • Siena-SI, Italy
    • Novartis Investigative Site
  • Valeggio Sul Mincio, Italy
    • Novartis Investigative Site
• Norway
  • Elverum, Norway
    • Novartis Investigative Site
  • Gjettum, Norway
    • Novartis Investigative Site
  • Hamar, Norway
    • Novartis Investigative Site
  • Oslo, Norway
    • Novartis Investigative Site
  • Paradis, Norway
    • Novartis Investigative Site
  • Trondheim, Norway
    • Novartis Investigative Site
• Poland
  • Bialystok, Poland
    • Novartis Investigative Site
  • Warszawa, Poland
    • Novartis Investigative Site
• Portugal
  • Lisbon, Portugal
    • Novartis Investigative Site
  • Ponte de Lima, Portugal
    • Novartis Investigative Site
• Romania
  • Bucharest, Romania
    • Novartis Investigative Site
  • Cluj Napoca, Romania
    • Novartis Investigative Site
• Russian Federation
  • Moscow, Russian Federation
    • Novartis Investigative Site
  • St. Petersburg, Russian Federation
    • Novartis Investigative Site
  • Tyumen, Russian Federation
    • Novartis Investigative Site
  • Yaroslavl, Russian Federation
    • Novartis Investigative Site
  • Yekaterinburg, Russian Federation
    • Novartis Investigative Site
• Slovakia
  • Banska Bystrica, Slovakia
    • Novartis Investigative Site
  • Bratislava, Slovakia
    • Novartis Investigative Site
  • Kosice, Slovakia
    • Novartis Investigative Site
  • Lubochna, Slovakia
    • Novartis Investigative Site
  • Piestany, Slovakia
    • Novartis Investigative Site
• South Africa
  • Cape Town, South Africa
    • Novartis Investigative Site
  • Rosebank-Johannesburg, South Africa
    • Novartis Investigative Site
  • Western Cape, South Africa
    • Novartis Investigative Site
• Spain
  • Alicante, Spain
    • Novartis Investigative Site
  • Barcelona, Spain
    • Novartis Investigative Site
  • Cordoba, Spain
    • Novartis Investigative Site
  • Granada, Spain
    • Novartis Investigative Site
  • Hospitalet de Llobregat, Spain
    • Novartis Investigative Site
  • Madrid, Spain
    • Novartis Investigative Site
  • Malaga, Spain
    • Novartis Investigative Site
  • Merida, Spain
    • Novartis Investigative Site
  • Oviedo, Spain
    • Novartis Investigative Site
  • Sabadell, Spain
    • Novartis Investigative Site
  • Salamanca, Spain
    • Novartis Investigative Site
  • Santander, Spain
    • Novartis Investigative Site
  • Sevilla, Spain
    • Novartis Investigative Site
  • Valencia, Spain
    • Novartis Investigative Site
  • Villajoyosa, Spain
    • Novartis Investigative Site
• Sweden
  • Gothenburg, Sweden
    • Novartis Investigative Site
  • Linkoeping, Sweden
    • Novartis Investigative Site
  • Lund, Sweden
    • Novartis Investigative Site
  • Malmo, Sweden
    • Novartis Investigative Site
  • Orebro, Sweden
    • Novartis Investigative Site
  • Stockholm, Sweden
    • Novartis Investigative Site
  • Umea, Sweden
    • Novartis Investigative Site
  • Uppsala, Sweden
    • Novartis Investigative Site
• Switzerland
  • Aarau, Switzerland
    • Novartis Investigative Site
  • Baden, Switzerland
    • Novartis Investigative Site
  • Basel, Switzerland
    • Novartis Investigative Site
  • Bern, Switzerland
    • Novartis Investigative Site
  • Geneve, Switzerland
    • Novartis Investigative Site
  • Lausanne, Switzerland
    • Novartis Investigative Site
  • Sion, Switzerland
    • Novartis Investigative Site
  • Zuerich, Switzerland
    • Novartis Investigative Site
• United Kingdom
  • Aberdeen, United Kingdom
    • Novartis Investigative Site
  • Chorley, United Kingdom
    • Novartis Investigative Site
  • Glasgow, United Kingdom
    • Novartis Investigative Site
  • Kent, United Kingdom
    • Novartis Investigative Site
  • Liverpool, United Kingdom
    • Novartis Investigative Site
  • Manchester, United Kingdom
    • Novartis Investigative Site
  • Middx, United Kingdom
    • Novartis Investigative Site
  • Newcastle Upon Tyne, United Kingdom
    • Novartis Investigative Site
  • Nottingham, United Kingdom
    • Novartis Investigative Site
  • Penarth, United Kingdom
    • Novartis Investigative Site
  • Reading-Berkshire, United Kingdom
    • Novartis Investigative Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 48 years to 83 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Osteoporosis as defined by very low bone mineral density in the hip and spine or low bone mineral density in the hip combined with presence of 1-3 mild or moderate fractures of the vertebrae

Exclusion Criteria:

• Low Vitamin D
• Renal insufficiency
• Previous treatment with certain anti-osteoporotic therapies (except after certain washout periods): calcitonin, bisphosphonates, parathyroid hormone (PTH), sodium fluoride, strontium ranelate,
• Previous treatment with testosterone, anabolic steroids or growth hormone
• Chronic use of systemic corticosteroids (oral or i.v.) within the last year
• History of any cancer or metastases within the last 5 years
• History of brittle bone disease, multiple myeloma, or Paget's disease, or any other metabolic bone disease, except osteoporosis
• Bilateral hip replacements

Other protocol-defined inclusion/exclusion criteria may apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zoledronic Acid; 5 mg/100 ml administered via a peripheral intravenous site as a slow infusion over 15 minutes. The intravenous (i.v.) infusion was delivered via vented infusion line (to allow constant flow) and 20-22 gauge angiocatheter, and preceded and followed by a 10 ml normal saline flush of the intravenous line for a total volume infused of 120 ml once a year.	Drug: Zoledronic acid 5 mg iv; Zoledronic acid 5 mg iv given once a year.; Other Names: Reclast; Aclasta,
Placebo Comparator: Placebo; 100 ml Placebo administered via a peripheral intravenous site as a slow infusion over 15 minutes. The i.v. infusion was delivered via vented infusion line (to allow constant flow) and 20-22 gauge angiocatheter, and preceded and followed by a 10 ml normal saline flush of the intravenous line for a total volume infused of 120 ml once a year.	Drug: Placebo; Placebo intravenous (i.v.) once a year

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least One New Morphometric Vertebral Fracture Over 24 Months	Vertebral fracture (VF) was assessed based on morphometry. QM(quantitative morphometry) incident VF(QM positive) is defined by at least 20% decrease in vertebral height of at least 4mm. If participant had QM positive at any vertebrae at any visit, x-rays from visits for participants were evaluated using Genant semi-quantitative method for VF assessment: Grade1 Mild VF is defined as 20-24% decrease in anterior, middle, and/or posterior vertebral height. Grade2 moderate VF is defined as 25-40% decrease in vertebral height. Grade3 Severe VF is defined as more than 40% decrease in vertebral height	24 Months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants With at Least One New Morphometric Vertebral Fracture Over 12 Months	Vertebral fracture (VF) was assessed based on morphometry. QM(quantitative morphometry) incident VF(QM positive) is defined by at least 20% decrease in vertebral height of at least 4mm. If participant had QM positive at any vertebrae at any visit, x-rays from visits for participants were evaluated using Genant semi-quantitative method for VF assessment: Grade1 Mild VF is defined as 20-24% decrease in anterior, middle, and/or posterior vertebral height. Grade2 moderate VF is defined as 25-40% decrease in vertebral height. Grade3 Severe VF is defined as more than 40% decrease in vertebral height	12 Months
Percentage of Participants With at Least One New Moderate or Severe Morphometric Vertebral Fracture Over 12 Months	Moderate or severe vertebral fracture (VF) was assessed based on morphometry. A QM (quantitative morphometry) incident VF(QM positive) was defined by at least a 20% decrease in any vertebral height (at least 4 mm). If a participant had a QM positive at any vertebrae at any visit,x-rays from all visits for participants were evaluated using Genant semi-quantitative (SQ) method for VF assessment. Grade 2 moderate VF was defined as a 25-40% reduction in any vertebral height.Grade 3 Severe: VF was defined as more than 40% reduction in any vertebral height.	12 months
Percentage of Participants With at Least One New Moderate or Severe Morphometric Vertebral Fracture Over 24 Months	Moderate or severe vertebral fracture (VF) was assessed based on morphometry. A QM (quantitative morphometry) incident VF(QM positive) was defined by at least a 20% decrease in any vertebral height (at least 4 mm). If a participant had a QM positive at any vertebrae at any visit,x-rays from all visits for participants were evaluated using Genant semi-quantitative (SQ) method for VF assessment. Grade 2 moderate VF was defined as a 25-40% reduction in any vertebral height.Grade 3 Severe: VF was defined as more than 40% reduction in any vertebral height.	24 Months
Percentage of Participants With at Least One New or Worsening Morphometric Vertebral Fracture Over 12 Months	Worsening vertebral fracture (VF) was assessed based on morphometry. QM (quantitative morphometry) incident VF(QM positive) was defined by at least a 20% decrease in any vertebral height (at least 4 mm). If a participant had a QM positive at any vertebrae at any visit, x-rays from all visits for participants were evaluated using Genant semi-quantitative (SQ) method for VF assessment. A worsening fracture was defined as an SQ reading that was greater than the baseline SQ reading, which was at least 1 (prevalent fracture)	Baseline, 12 months
Percentage of Participants With at Least One New or Worsening Morphometric Vertebral Fracture Over 24 Months	Worsening vertebral fracture (VF) was assessed based on morphometry. A QM (quantitative morphometry) incident VF(QM positive) was defined by at least a 20% decrease in any vertebral height (at least 4 mm). If a participant had a QM positive at any vertebrae at any visit,x-rays from all visits for participants were evaluated using Genant semi-quantitative (SQ) method for VF assessment. A worsening fracture was defined as an SQ reading that was greater than the baseline SQ reading, which was at least 1 (prevalent fracture)	Baseline, Month 24
Mean Change in Height From Baseline	Height was measured using a stadiometer. Two measurements were taken in millimeters (mm), and repeated if the two measurements differed by greater than 4 mm. The average of the two (or four) height measurements was used for analysis	from Baseline to 12 months and 24 months
Number of Participants With First Clinical Vertebral Fracture	Clinical vertebral fracture is a painful vertebral fracture which came to clinical attention, e.g., with increased back pain, impairment of mobility or functional limitations. Subjects who did not experience a fracture event were censored at the end of study. End of study was defined as the last visit or date of death, whichever was earlier.	24 months
Number of Participants With First Clinical Fracture	Clinical fracture is painful fracture in any site which came to clinical attention, e.g., with increased pain, impaired mobility or functional limitations. Subjects who did not experience fracture were censored at end of study. End of study was defined as the earlier of last visit or date of death.	24 months
Number of Participants With First Non-vertebral Fracture	Non-vertebral fracture is any fracture which was not of the vertebrae. Subjects who did not experience a fracture event were censored at the end of study. End of study was defined as the last visit or date of death, whichever was earlier.	24 months
Percentage Change From Baseline in Lumbar Spine Bone Mass Density (BMD)	Dual energy x-ray absorptiometry (DXA) Least Square Means (LSM) were analyzed using an ANCOVA model with treatment and baseline value as explanatory variables. Percent change in BMD at lumbar spine at Months 6, 12, and 24 relative to baseline as measured by DXA in a subset of at least 100 evaluable subjects at selected sites. Percentage change from baseline = 100*(endpoint - baseline)	Month 6, Month 12, Month 24
Percentage Change From Baseline in Total Hip BMD (g/CM^2)	Dual energy x-ray absorptiometry (DXA) Least Square Means (LSM) were analyzed using an ANCOVA model with treatment and baseline value as explanatory variables. Percent change in total hip BMD at Months 6, 12, and 24 relative to baseline as measured by DXA in a subset of at least 100 evaluable subjects at selected sites. Percentage change from baseline = 100*(endpoint - baseline)	Month 6, Month 12, Month 24
Percentage Change From Baseline in Femoral Neck BMD (g/CM^2)	Dual energy x-ray absorptiometry (DXA) Least Square Means (LSM) were analyzed using an ANCOVA model with treatment and baseline value as explanatory variables. Percent change in total femoral neck BMD at Months 6, 12, and 24 relative to baseline as measured by DXA in a subset of at least 100 evaluable subjects at selected sites. Percentage change from baseline = 100*(endpoint - baseline)	Month 6, Month 12, Month 24
Serum Beta C-terminal Telopeptides of Type I Collagen(b-CTx) by Visits		Baseline, Month 3, Month 6, Month 12, Month 15, month 18, Month 24

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals
• Investigators: Principal Investigator: Novartis Pharmaceuticals, Novartis; Principal Investigator: Novartis Pharmaceuticals, Novartis Argentina; Principal Investigator: Novartis Pharmaceuticals, Novartis Belgium; Principal Investigator: Novartis Pharmaceuticals, Novartis Brazil; Principal Investigator: Novartis Pharmaceuticals, Novartis Czech Republic; Principal Investigator: Novartis Pharmaceuticals, Novartis Denmark; Principal Investigator: Novartis Pharmaceuticals, Novartis Finland; Principal Investigator: Novartis Pharmaceuticals, Novartis Germany; Principal Investigator: Novartis Pharmaceuticals, Novartis Hungary; Principal Investigator: Novartis Pharmaceuticals, Novartis Norway; Principal Investigator: Novartis Pharmaceuticals, Novartis Portugal; Principal Investigator: Novartis Pharmaceuticals, Novartis Romania; Principal Investigator: Novartis Pharmaceuticals, Novartis Spain; Principal Investigator: Novartis Pharmaceuticals, Novartis Slovakia; Principal Investigator: Novartis Pharmaceuticals, Novartis Sweden; Principal Investigator: Novartis Pharmaceuticals, Novartis United Kingdom; Principal Investigator: Novartis Pharmaceuticals, Novartis Australia; Principal Investigator: Novartis Pharmaceuticals, Novartis Italy; Principal Investigator: Novartis Pharmaceuticals, Novartis Austria; Principal Investigator: Novartis Pharmaceuticals, Novartis Iceland; Principal Investigator: Novartis Pharmaceuticals, Novartis Poland; Principal Investigator: Novartis Pharmaceuticals, Novartis Russia; Principal Investigator: Novartis Pharmaceuticals, Novartis (South Africa)

Publications and helpful links

General Publications

• Boonen S, Reginster JY, Kaufman JM, Lippuner K, Zanchetta J, Langdahl B, Rizzoli R, Lipschitz S, Dimai HP, Witvrouw R, Eriksen E, Brixen K, Russo L, Claessens F, Papanastasiou P, Antunez O, Su G, Bucci-Rechtweg C, Hruska J, Incera E, Vanderschueren D, Orwoll E. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med. 2012 Nov 1;367(18):1714-23. doi: 10.1056/NEJMoa1204061.

Study record dates

Study Major Dates

• Study Start: December 1, 2006
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): October 1, 2010

Study Registration Dates

• First Submitted: February 22, 2007
• First Submitted That Met QC Criteria: February 22, 2007
• First Posted (Estimate): February 23, 2007

Study Record Updates

• Last Update Posted (Actual): April 21, 2017
• Last Update Submitted That Met QC Criteria: April 19, 2017
• Last Verified: October 1, 2011

More Information

Terms related to this study

• Keywords: Osteoporosis; bone biomarkers; bone mineral density; zoledronic acid; vertebral fractures; males; clinical fractures
• Additional Relevant MeSH Terms: Metabolic Diseases; Musculoskeletal Diseases; Bone Diseases; Bone Diseases, Metabolic; Osteoporosis; Physiological Effects of Drugs; Bone Density Conservation Agents; Zoledronic Acid
• Other Study ID Numbers: CZOL446M2309