Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON)

a multicentre, double-blind, double-dummy, randomised controlled trial

David M Reid, Jean-Pierre Devogelaer, Kenneth Saag, Christian Roux, Chak-Sing Lau, Jean-Yves Reginster, Philemon Papanastasiou, Alberto Ferreira, Florian Hartl, Taiwo Fashola, Peter Mesenbrink, Philip N Sambrook, HORIZON investigators

Research output: Contribution to journalArticle

293 Citations (Scopus)

Abstract

BACKGROUND: Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis.

METHODS: This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00100620.

FINDINGS: Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4.06% [SE 0.28] vs 2.71% [SE 0.28], mean difference 1.36% [95% CI 0.67-2.05], p=0.0001) and prevention (2.60% [0.45] vs 0.64% [0.46], 1.96% [1.04-2.88], p<0.0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup.

INTERPRETATION: A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use.
Original languageEnglish
Pages (from-to)1253-1263
Number of pages11
JournalThe Lancet
Volume373
Issue number9671
DOIs
Publication statusPublished - 11 Apr 2009

Fingerprint

zoledronic acid
Glucocorticoids
Osteoporosis
Randomized Controlled Trials
Intravenous Infusions
Bone Density
Therapeutics
Spine
Pharmaceutical Preparations
Bone and Bones
Diphosphonates
Hong Kong
Israel
Risedronate Sodium
Least-Squares Analysis
Rheumatoid Arthritis

Keywords

  • administration, oral
  • adolescent
  • adult
  • aged
  • aged, 80 and over
  • analysis of variance
  • bone density
  • bone density conservation agents
  • diphosphonates
  • double-blind method
  • drug administration schedule
  • etidronic acid
  • female
  • glucocorticoids
  • humans
  • imidazoles
  • infusions, intravenous
  • least-squares analysis
  • male
  • middle aged
  • osteoporosis
  • treatment outcome
  • young adult

Cite this

Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON) : a multicentre, double-blind, double-dummy, randomised controlled trial. / Reid, David M; Devogelaer, Jean-Pierre; Saag, Kenneth; Roux, Christian; Lau, Chak-Sing; Reginster, Jean-Yves; Papanastasiou, Philemon; Ferreira, Alberto; Hartl, Florian; Fashola, Taiwo; Mesenbrink, Peter; Sambrook, Philip N; HORIZON investigators.

In: The Lancet, Vol. 373, No. 9671, 11.04.2009, p. 1253-1263.

Research output: Contribution to journalArticle

Reid, DM, Devogelaer, J-P, Saag, K, Roux, C, Lau, C-S, Reginster, J-Y, Papanastasiou, P, Ferreira, A, Hartl, F, Fashola, T, Mesenbrink, P, Sambrook, PN & HORIZON investigators 2009, 'Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON): a multicentre, double-blind, double-dummy, randomised controlled trial', The Lancet, vol. 373, no. 9671, pp. 1253-1263. https://doi.org/10.1016/S0140-6736(09)60250-6
Reid, David M ; Devogelaer, Jean-Pierre ; Saag, Kenneth ; Roux, Christian ; Lau, Chak-Sing ; Reginster, Jean-Yves ; Papanastasiou, Philemon ; Ferreira, Alberto ; Hartl, Florian ; Fashola, Taiwo ; Mesenbrink, Peter ; Sambrook, Philip N ; HORIZON investigators. / Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON) : a multicentre, double-blind, double-dummy, randomised controlled trial. In: The Lancet. 2009 ; Vol. 373, No. 9671. pp. 1253-1263.
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abstract = "BACKGROUND: Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis.METHODS: This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00100620.FINDINGS: Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4.06{\%} [SE 0.28] vs 2.71{\%} [SE 0.28], mean difference 1.36{\%} [95{\%} CI 0.67-2.05], p=0.0001) and prevention (2.60{\%} [0.45] vs 0.64{\%} [0.46], 1.96{\%} [1.04-2.88], p<0.0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup.INTERPRETATION: A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use.",
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TY - JOUR

T1 - Zoledronic acid and risedronate in the prevention and treatment of glucocorticoid-induced osteoporosis (HORIZON)

T2 - a multicentre, double-blind, double-dummy, randomised controlled trial

AU - Reid, David M

AU - Devogelaer, Jean-Pierre

AU - Saag, Kenneth

AU - Roux, Christian

AU - Lau, Chak-Sing

AU - Reginster, Jean-Yves

AU - Papanastasiou, Philemon

AU - Ferreira, Alberto

AU - Hartl, Florian

AU - Fashola, Taiwo

AU - Mesenbrink, Peter

AU - Sambrook, Philip N

AU - HORIZON investigators

PY - 2009/4/11

Y1 - 2009/4/11

N2 - BACKGROUND: Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis.METHODS: This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00100620.FINDINGS: Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4.06% [SE 0.28] vs 2.71% [SE 0.28], mean difference 1.36% [95% CI 0.67-2.05], p=0.0001) and prevention (2.60% [0.45] vs 0.64% [0.46], 1.96% [1.04-2.88], p<0.0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup.INTERPRETATION: A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use.

AB - BACKGROUND: Persistent use of glucocorticoid drugs is associated with bone loss and increased fracture risk. Concurrent oral bisphosphonates increase bone mineral density and reduce frequency of vertebral fractures, but are associated with poor compliance and adherence. We aimed to assess whether one intravenous infusion of zoledronic acid was non-inferior to daily oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis.METHODS: This 1-year randomised, double-blind, double-dummy, non-inferiority study of 54 centres in 12 European countries, Australia, Hong Kong, Israel, and the USA, tested the effectiveness of 5 mg intravenous infusion of zoledronic acid versus 5 mg oral risedronate for prevention and treatment of glucocorticoid-induced osteoporosis. 833 patients were randomised 1:1 to receive zoledronic acid (n=416) or risedronate (n=417). Patients were stratified by sex, and allocated to prevention or treatment subgroups dependent on duration of glucocorticoid use immediately preceding the study. The treatment subgroup consisted of those treated for more than 3 months (272 patients on zoledronic acid and 273 on risedronate), and the prevention subgroup of those treated for less than 3 months (144 patients on each drug). 62 patients did not complete the study because of adverse events, withdrawal of consent, loss to follow-up, death, misrandomisation, or protocol deviation. The primary endpoint was percentage change from baseline in lumbar spine bone mineral density. Drug efficacy was assessed on a modified intention-to-treat basis and safety was assessed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov, number NCT00100620.FINDINGS: Zoledronic acid was non-inferior and superior to risedronate for increase of lumbar spine bone mineral density in both the treatment (least-squares mean 4.06% [SE 0.28] vs 2.71% [SE 0.28], mean difference 1.36% [95% CI 0.67-2.05], p=0.0001) and prevention (2.60% [0.45] vs 0.64% [0.46], 1.96% [1.04-2.88], p<0.0001) subgroups at 12 months. Adverse events were more frequent in patients given zoledronic acid than in those on risedronate, largely as a result of transient symptoms during the first 3 days after infusion. Serious adverse events were worsening rheumatoid arthritis for the treatment subgroup and pyrexia for the prevention subgroup.INTERPRETATION: A single 5 mg intravenous infusion of zoledronic acid is non-inferior, possibly more effective, and more acceptable to patients than is 5 mg of oral risedronate daily for prevention and treatment of bone loss that is associated with glucocorticoid use.

KW - administration, oral

KW - adolescent

KW - adult

KW - aged

KW - aged, 80 and over

KW - analysis of variance

KW - bone density

KW - bone density conservation agents

KW - diphosphonates

KW - double-blind method

KW - drug administration schedule

KW - etidronic acid

KW - female

KW - glucocorticoids

KW - humans

KW - imidazoles

KW - infusions, intravenous

KW - least-squares analysis

KW - male

KW - middle aged

KW - osteoporosis

KW - treatment outcome

KW - young adult

U2 - 10.1016/S0140-6736(09)60250-6

DO - 10.1016/S0140-6736(09)60250-6

M3 - Article

VL - 373

SP - 1253

EP - 1263

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9671

ER -