Effects of Intravenous Zoledronic Acid Once Yearly on Bone Remodeling and Bone Structure

Authors


  • Dr Recker is a consultant for Novartis Pharmaceuticals Corp, Merck & Co, Inc, Roche Laboratories, Amgen Inc, Procter & Gamble Pharmaceuticals, Eli Lilly & Co, GlaxoSmithKline, NPS Allelix, and Wyeth Pharmaceuticals, Inc. Dr Delmas has received research grants from Procter & Gamble Pharmaceuticals, Eli Lilly & Co, and Amgen Inc. He has consulted and/or received speaker fees from Acceleron Pharma, Amgen Inc, Eli Lilly & Co, GlaxoSmithKline, Merck, Sharpe & Dohme, Novartis Pharmaceuticals Corp, Nycomed Group, Organon USA Inc, Pfizer Inc, Procter & Gamble Pharmaceuticals, Roche Laboratories, Sanofi-Aventis, Servier Laboratories, Wyeth Pharmaceuticals, and Zelos Therapeutics, Inc. Dr Reid is a consultant for Novartis Pharmaceuticals Corp, Merck & Co, Inc, and Sanofi-Aventis. Dr Lewiecki has received grants/research support from Novartis Pharmaceuticals Corp, Merck & Co, Inc, Procter & Gamble Pharmaceuticals, Eli Lilly & Co, Roche Laboratories, GlaxoSmithKline, Wyeth Pharmaceuticals, and Pfizer Inc. He is a consultant for Novartis Pharmaceuticals Corp, Merck & Co, Inc, Procter & Gamble Pharmaceuticals, Eli Lilly & Co, Roche Laboratories, GlaxoSmithKline, and Wyeth Pharmaceuticals. He owns stock in General Electric and Procter & Gamble Pharmaceuticals. Dr Miller has received scientific grants from Procter & Gamble Pharmaceuticals, Sanofi-Aventis, Roche Laboratories, Eli Lilly & Co, Merck & Co, Inc, Novartis Pharmaceuticals Corp, and Amgen Inc. He is on speaker boards, advisory boards, or is a consultant for Procter & Gamble Pharmaceuticals, Sanofi-Aventis, Merck & Co, Inc, Eli Lilly & Co, Amgen Inc, NPS Pharmaceuticals, Novartis Pharmaceuticals Corp, Roche Laboratories, and GlaxoSmithKline. Dr Hu is an employee of Novartis Pharmaceuticals, East Hanover, NJ, USA. Dr Mesenbrink owns stock, restricted stock, exercisable options, and tradable options in Novartis Pharmaceuticals Corp of East Hanover, NJ, USA, of which he is an employee. Dr Hartl is an employee of F. Hoffmann-La Roche AG, Basel, Switzerland, and a former employee of Novartis Pharma AG, Basel, Switzerland. Dr Gasser has a corporate appointment with Novartis Pharma AG, Basel, Switzerland. He also owns stock that may cause a conflict of interest. Dr Eriksen is an employee of Novartis Pharma AG, Basel, Switzerland. All other authors state that they have no conflicts of interest.

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 νCT analysis and histomorphometry.

Results: Analysis of bone structure by νCT 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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