Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure

Robert R. Recker, Pierre D. Delmas, Johan Halse, Ian R. Reid, Steven Boonen, Pedro A. Garcia-Hernandez, Jerzy Supronik, E. Michael Lewiecki, Luis Ochoa, Paul Miller, Huilin Hu, Peter Mesenbrink, Florian Hartl, Juerg Gasser, Erik F. Eriksen

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Abstract

In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained. Introduction: In the HORIZON pivotal fracture trial (PFT), enrolling 7736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1652). Materials and Methods: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for μCT analysis and histomorphometry. Results: Analysis of bone structure by μCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p <0.0001) and reduced mineralizing surface (MS/BS; p <0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p <0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid. Conclusions: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.

Original languageEnglish
Pages (from-to)6-16
Number of pages11
JournalJournal of Bone and Mineral Research
Volume23
Issue number1
DOIs
StatePublished - Jan 2008

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zoledronic acid
Bone Remodeling
Bone and Bones
Placebos
Biopsy
Postmenopausal Osteoporosis
tibolone
Diphosphonates
Tetracycline
Therapeutics
Osteoporosis

All Science Journal Classification (ASJC) codes

  • Surgery

Cite this

Recker, R. R., Delmas, P. D., Halse, J., Reid, I. R., Boonen, S., Garcia-Hernandez, P. A., ... Eriksen, E. F. (2008). Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. Journal of Bone and Mineral Research, 23(1), 6-16. https://doi.org/10.1359/jbmr.070906

Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. / Recker, Robert R.; Delmas, Pierre D.; Halse, Johan; Reid, Ian R.; Boonen, Steven; Garcia-Hernandez, Pedro A.; Supronik, Jerzy; Lewiecki, E. Michael; Ochoa, Luis; Miller, Paul; Hu, Huilin; Mesenbrink, Peter; Hartl, Florian; Gasser, Juerg; Eriksen, Erik F.

In: Journal of Bone and Mineral Research, Vol. 23, No. 1, 01.2008, p. 6-16.

Research output: Contribution to journalArticle

Recker, RR, Delmas, PD, Halse, J, Reid, IR, Boonen, S, Garcia-Hernandez, PA, Supronik, J, Lewiecki, EM, Ochoa, L, Miller, P, Hu, H, Mesenbrink, P, Hartl, F, Gasser, J & Eriksen, EF 2008, 'Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure', Journal of Bone and Mineral Research, vol. 23, no. 1, pp. 6-16. https://doi.org/10.1359/jbmr.070906
Recker, Robert R. ; Delmas, Pierre D. ; Halse, Johan ; Reid, Ian R. ; Boonen, Steven ; Garcia-Hernandez, Pedro A. ; Supronik, Jerzy ; Lewiecki, E. Michael ; Ochoa, Luis ; Miller, Paul ; Hu, Huilin ; Mesenbrink, Peter ; Hartl, Florian ; Gasser, Juerg ; Eriksen, Erik F. / Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure. In: Journal of Bone and Mineral Research. 2008 ; Vol. 23, No. 1. pp. 6-16.
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abstract = "In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63{\%} and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99{\%} of biopsies obtained. Introduction: In the HORIZON pivotal fracture trial (PFT), enrolling 7736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70{\%}, 77{\%}, 41{\%}, and 25{\%}, respectively. Whereas 79{\%} of patients received zoledronic acid/placebo only (stratum I, n = 6113), 21{\%} received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1652). Materials and Methods: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for μCT analysis and histomorphometry. Results: Analysis of bone structure by μCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6{\%} versus 12.8{\%}; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63{\%} median (71{\%} mean) reduction of the activation frequency (Ac.f; p <0.0001) and reduced mineralizing surface (MS/BS; p <0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p <0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid. Conclusions: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63{\%} (mean, 71{\%}) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.",
author = "Recker, {Robert R.} and Delmas, {Pierre D.} and Johan Halse and Reid, {Ian R.} and Steven Boonen and Garcia-Hernandez, {Pedro A.} and Jerzy Supronik and Lewiecki, {E. Michael} and Luis Ochoa and Paul Miller and Huilin Hu and Peter Mesenbrink and Florian Hartl and Juerg Gasser and Eriksen, {Erik F.}",
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T1 - Effects of intravenous zoledronic acid once yearly on bone remodeling and bone structure

AU - Recker, Robert R.

AU - Delmas, Pierre D.

AU - Halse, Johan

AU - Reid, Ian R.

AU - Boonen, Steven

AU - Garcia-Hernandez, Pedro A.

AU - Supronik, Jerzy

AU - Lewiecki, E. Michael

AU - Ochoa, Luis

AU - Miller, Paul

AU - Hu, Huilin

AU - Mesenbrink, Peter

AU - Hartl, Florian

AU - Gasser, Juerg

AU - Eriksen, Erik F.

PY - 2008/1

Y1 - 2008/1

N2 - In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained. Introduction: In the HORIZON pivotal fracture trial (PFT), enrolling 7736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1652). Materials and Methods: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for μCT analysis and histomorphometry. Results: Analysis of bone structure by μCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p <0.0001) and reduced mineralizing surface (MS/BS; p <0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p <0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid. Conclusions: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.

AB - In a substudy of the HORIZON pivotal fracture trial, in which yearly intravenous zoledronic acid 5 mg was found to significantly reduce risk of various fracture types in patients with postmenopausal osteoporosis, 152 patients underwent bone biopsy. Zoledronic acid reduced bone turnover by 63% and preserved bone structure and volume, with evidence of ongoing bone remodeling in 99% of biopsies obtained. Introduction: In the HORIZON pivotal fracture trial (PFT), enrolling 7736 women with postmenopausal osteoporosis, three annual intravenous infusions of the bisphosphonate zoledronic acid (5 mg) significantly reduced morphometric vertebral, clinical vertebral, hip, and nonvertebral fractures by 70%, 77%, 41%, and 25%, respectively. Whereas 79% of patients received zoledronic acid/placebo only (stratum I, n = 6113), 21% received concomitant treatment with other antiresorptive drugs, excluding other bisphosphonates, PTH, and strontium (stratum II, n = 1652). Materials and Methods: To determine effects on bone remodeling and bone architecture, iliac crest bone biopsies were obtained in 152 patients on active treatment or placebo at 3 yr after double tetracycline labeling. In five patients, only qualitative histology was performed, leaving 147 biopsy cores (79 on active treatment and 68 on placebo) for μCT analysis and histomorphometry. Results: Analysis of bone structure by μCT revealed higher trabecular bone volume (BV/TV) in the zoledronic acid group (median, 16.6% versus 12.8%; p = 0.020). In addition, patients treated with zoledronic acid exhibited higher trabecular numbers (p = 0.008), decreased trabecular separation (p = 0.011), and a trend toward improvement in connectivity density (p = 0.062), all indicating better preservation of trabecular structure after treatment with zoledronic acid. Qualitative analysis revealed presence of tetracycline label in 81 of 82 biopsies from patients on zoledronic acid and all 70 biopsies from placebo patients, indicative of continued bone remodeling. No bone pathology was observed. Zoledronic acid induced a 63% median (71% mean) reduction of the activation frequency (Ac.f; p <0.0001) and reduced mineralizing surface (MS/BS; p <0.0001) and volume referent bone formation rate (BFR/BV) versus placebo, indicating reduced bone turnover. Mineral appositional rate was higher in the zoledronic acid group (p = 0.0002), suggesting improved osteoblast function compared with placebo. Mineralization lag time was similar in the two groups, whereas osteoid volume (OV/BV; p <0.0001) and osteoid thickness (O.Th; p = 0.0094) were lower in zoledronic acid-treated patients, indicating normal osteoid formation and mineralization of newly formed bone. Concomitant administration of other antiresorptive osteoporosis therapies (e.g., raloxifene, tamoxifen, tibolone, ipriflavone) did not significantly alter the tissue level response to zoledronic acid. Conclusions: Annual dosing for 3 yr with zoledronic acid 5 mg intravenously resulted in a median 63% (mean, 71%) reduction of bone turnover and preservation of bone structure and mass without any signs of adynamic bone. Concomitant treatment with other osteoporosis therapies did not significantly affect the bone response to zoledronic acid.

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