Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study

A randomized controlled trial

David W. Dempster, Hua Zhou, Robert R. Recker, Jacques P. Brown, Michael A. Bolognese, Christopher P. Recknor, David L. Kendler, E. Michael Lewiecki, David A. Hanley, D. Sudhaker Rao, Paul D. Miller, Grattan C. Woodson, Robert Lindsay, Neil Binkley, Xiaohai Wan, Valerie A. Ruff, Boris Janos, Kathleen A. Taylor

Research output: Contribution to journalArticle

49 Citations (Scopus)

Abstract

Context: Recent studies on the mechanism of action (MOA) of bone-active drugs have rekindled interest in how to present and interpret dynamic histomorphometric parameters of bone remodeling. Objective: We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL). Design: This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study. Setting: The study was conducted at 12 U.S. and Canadian centers. Subjects: Healthy postmenopausal women with osteoporosis participated in the study. Interventions: Subjects received TPTD 20 μg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35). Main Outcome Measures: The primary end point was mineralizing surface/bone surface (MS/BS), a dynamic measure of bone formation, at month 6. A standard panel of dynamic and static histomorphometric indices was also assessed. When specimens with missing labels were encountered, several methods were used to calculate mineral apposition rate (MAR). Serum markers of bone turnover were also measured. Results: Among 58 subjects with evaluable biopsies (TPTD=28; ZOL=30), MS/BS was significantly higher in the TPTD group (median: 5.60 vs. 0.16%, P <0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P <0.05). TPTD significantly increased procollagen type 1 N-terminal propeptide (PINP) at months 1, 3, 6, and 12 and carboxyterminal cross-linking telopeptide of collagen type 1 (CTX) from months 3 to 12. ZOL significantly decreased PINP and CTX below baseline at all time points. Conclusions: TPTD and ZOL possess fundamentally different mechanisms of action with opposite effects on bone formation based on this analysis of both histomorphometric data and serum markers of bone formation and resorption. An important mechanistic difference was a substantially higher MS/BS in the TPTD group. Overall, these results define the dynamic histomorphometric characteristics of anabolic activity relative to antiresorptive activity after treatment with these two drugs.

Original languageEnglish
Pages (from-to)2799-2808
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Volume97
Issue number8
DOIs
StatePublished - Aug 2012

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zoledronic acid
Teriparatide
Bone
Randomized Controlled Trials
Osteogenesis
Bone and Bones
Bone Remodeling
Therapeutics
Collagen Type I
Biopsy
Minerals
Biomarkers
Bone Density Conservation Agents
Anabolic Agents
Bone Resorption
Pharmaceutical Preparations

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology
  • Biochemistry, medical
  • Endocrinology, Diabetes and Metabolism

Cite this

Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study : A randomized controlled trial. / Dempster, David W.; Zhou, Hua; Recker, Robert R.; Brown, Jacques P.; Bolognese, Michael A.; Recknor, Christopher P.; Kendler, David L.; Lewiecki, E. Michael; Hanley, David A.; Rao, D. Sudhaker; Miller, Paul D.; Woodson, Grattan C.; Lindsay, Robert; Binkley, Neil; Wan, Xiaohai; Ruff, Valerie A.; Janos, Boris; Taylor, Kathleen A.

In: Journal of Clinical Endocrinology and Metabolism, Vol. 97, No. 8, 08.2012, p. 2799-2808.

Research output: Contribution to journalArticle

Dempster, DW, Zhou, H, Recker, RR, Brown, JP, Bolognese, MA, Recknor, CP, Kendler, DL, Lewiecki, EM, Hanley, DA, Rao, DS, Miller, PD, Woodson, GC, Lindsay, R, Binkley, N, Wan, X, Ruff, VA, Janos, B & Taylor, KA 2012, 'Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study: A randomized controlled trial', Journal of Clinical Endocrinology and Metabolism, vol. 97, no. 8, pp. 2799-2808. https://doi.org/10.1210/jc.2012-1262
Dempster, David W. ; Zhou, Hua ; Recker, Robert R. ; Brown, Jacques P. ; Bolognese, Michael A. ; Recknor, Christopher P. ; Kendler, David L. ; Lewiecki, E. Michael ; Hanley, David A. ; Rao, D. Sudhaker ; Miller, Paul D. ; Woodson, Grattan C. ; Lindsay, Robert ; Binkley, Neil ; Wan, Xiaohai ; Ruff, Valerie A. ; Janos, Boris ; Taylor, Kathleen A. / Skeletal histomorphometry in subjects on teriparatide or zoledronic acid therapy (SHOTZ) study : A randomized controlled trial. In: Journal of Clinical Endocrinology and Metabolism. 2012 ; Vol. 97, No. 8. pp. 2799-2808.
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T2 - A randomized controlled trial

AU - Dempster, David W.

AU - Zhou, Hua

AU - Recker, Robert R.

AU - Brown, Jacques P.

AU - Bolognese, Michael A.

AU - Recknor, Christopher P.

AU - Kendler, David L.

AU - Lewiecki, E. Michael

AU - Hanley, David A.

AU - Rao, D. Sudhaker

AU - Miller, Paul D.

AU - Woodson, Grattan C.

AU - Lindsay, Robert

AU - Binkley, Neil

AU - Wan, Xiaohai

AU - Ruff, Valerie A.

AU - Janos, Boris

AU - Taylor, Kathleen A.

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N2 - Context: Recent studies on the mechanism of action (MOA) of bone-active drugs have rekindled interest in how to present and interpret dynamic histomorphometric parameters of bone remodeling. Objective: We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL). Design: This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study. Setting: The study was conducted at 12 U.S. and Canadian centers. Subjects: Healthy postmenopausal women with osteoporosis participated in the study. Interventions: Subjects received TPTD 20 μg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35). Main Outcome Measures: The primary end point was mineralizing surface/bone surface (MS/BS), a dynamic measure of bone formation, at month 6. A standard panel of dynamic and static histomorphometric indices was also assessed. When specimens with missing labels were encountered, several methods were used to calculate mineral apposition rate (MAR). Serum markers of bone turnover were also measured. Results: Among 58 subjects with evaluable biopsies (TPTD=28; ZOL=30), MS/BS was significantly higher in the TPTD group (median: 5.60 vs. 0.16%, P <0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P <0.05). TPTD significantly increased procollagen type 1 N-terminal propeptide (PINP) at months 1, 3, 6, and 12 and carboxyterminal cross-linking telopeptide of collagen type 1 (CTX) from months 3 to 12. ZOL significantly decreased PINP and CTX below baseline at all time points. Conclusions: TPTD and ZOL possess fundamentally different mechanisms of action with opposite effects on bone formation based on this analysis of both histomorphometric data and serum markers of bone formation and resorption. An important mechanistic difference was a substantially higher MS/BS in the TPTD group. Overall, these results define the dynamic histomorphometric characteristics of anabolic activity relative to antiresorptive activity after treatment with these two drugs.

AB - Context: Recent studies on the mechanism of action (MOA) of bone-active drugs have rekindled interest in how to present and interpret dynamic histomorphometric parameters of bone remodeling. Objective: We compared the effects of an established anabolic agent, teriparatide (TPTD), with those of a prototypical antiresorptive agent, zoledronic acid (ZOL). Design: This was a 12-month, randomized, double-blind, active-comparator controlled, cross-sectional biopsy study. Setting: The study was conducted at 12 U.S. and Canadian centers. Subjects: Healthy postmenopausal women with osteoporosis participated in the study. Interventions: Subjects received TPTD 20 μg once daily by sc injection (n = 34) or ZOL 5 mg by iv infusion at baseline (n = 35). Main Outcome Measures: The primary end point was mineralizing surface/bone surface (MS/BS), a dynamic measure of bone formation, at month 6. A standard panel of dynamic and static histomorphometric indices was also assessed. When specimens with missing labels were encountered, several methods were used to calculate mineral apposition rate (MAR). Serum markers of bone turnover were also measured. Results: Among 58 subjects with evaluable biopsies (TPTD=28; ZOL=30), MS/BS was significantly higher in the TPTD group (median: 5.60 vs. 0.16%, P <0.001). Other bone formation indices, including MAR, were also higher in the TPTD group (P <0.05). TPTD significantly increased procollagen type 1 N-terminal propeptide (PINP) at months 1, 3, 6, and 12 and carboxyterminal cross-linking telopeptide of collagen type 1 (CTX) from months 3 to 12. ZOL significantly decreased PINP and CTX below baseline at all time points. Conclusions: TPTD and ZOL possess fundamentally different mechanisms of action with opposite effects on bone formation based on this analysis of both histomorphometric data and serum markers of bone formation and resorption. An important mechanistic difference was a substantially higher MS/BS in the TPTD group. Overall, these results define the dynamic histomorphometric characteristics of anabolic activity relative to antiresorptive activity after treatment with these two drugs.

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