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Osteoanabolic effect of alendronate and zoledronate on bone marrow stromal cells (BMSCs) isolated from aged female osteoporotic patients and its implications for their mode of action in the treatment of age-related bone loss

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Abstract

Summary

In the present study, we evaluated the potential for aminobisphosphonates to enhance the development of bone-forming osteoblasts from progenitor cells isolated from aged female osteoporotic patients. The aminobisphosphonates tested significantly enhanced osteoblast formation and thus lend further insights into their possible mode of action in the treatment of osteoporosis.

Introduction

The primary aim of this study was to evaluate the influence of aminobisphosphonates on the osteogenesis of human bone marrow stromal cells (hBMSCs) and mineralization of differentiating bone-forming cells isolated from osteoporotic patients.

Methods

The influence of aminobisphosphonate treatment on hBMSC osteogenesis was assessed by the quantitative measurement of alkaline phosphatase (ALP) activity, in addition to quantitative reverse transcription polymerase chain reaction and Western blot analysis of known osteogenic markers. Mineralized matrix formation by hBMSC-derived osteoblasts was visualized and quantified using Alizarin red staining.

Results

hBMSC cultures treated with osteogenic medium supplemented with zoledronate demonstrated a significant increase in Alizarin red staining after 3 weeks as compared to cells cultured in osteogenic medium alone. Similarly, cultures of differentiating hBMSCs isolated from patients receiving alendronate treatment also demonstrated an increased propensity for mineralization, even in the absence of further in vitro stimulation by zoledronate. The stimulatory effects of aminobisphosphonate treatment on hBMSC-derived osteoblast-mediated mineralization were independent of any alterations in ALP activity, although significant decreases in the expression levels of osteopontin (SPP1) were evident in hBMSCs following exposure to aminobisphosphonates. Further analysis including Western blotting and loss-of-function studies revealed osteopontin as having a negative influence on the mineralization of differentiating osteoporotic bone-forming cells.

Conclusions

The results presented here demonstrate for the first time that aminobisphosphonate treatment of osteoporotic hBMSCs enhances their capacity for osteoblast formation and subsequent mineral deposition, thus supporting the concept of aminobisphosphonates as having an osteoanabolic effect in osteoporosis.

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Acknowledgments

This study was supported by funding received from the Mäxi/CABMM Start-up grant, AOTrauma, Novartis Foundation, formerly Ciba-Geigy-Jubilee-Foundation, and Uniscientia. The authors would like to express their gratitude to Novartis (Vienna, Austria) for supplying the zoledronate used in this study.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Trauma Surgery and Sports Medicine, Innsbruck Medical University, Innsbruck, Austria

    R. A. Lindtner, K. Genelin, H. L. Ebner, I. Sitte & M. Blauth

  2. Bone and Stem Cell Research Group, CABMM, University of Zurich, Winterthurerstrasse 190, CH-8057, Zürich, Switzerland

    A. N. Tiaden, M. Klawitter & P. J. Richards

  3. Division of Developmental Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria

    C. Manzl

  4. Musculoskeletal Research Unit, CABMM, University of Zurich, Zurich, Switzerland

    B. von Rechenberg

  5. Zurich Center for Integrative Human Physiology (ZIHP), University of Zurich, Zurich, Switzerland

    P. J. Richards

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  1. R. A. Lindtner
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  2. A. N. Tiaden
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  3. K. Genelin
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  6. M. Klawitter
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  10. P. J. Richards
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Corresponding author

Correspondence to P. J. Richards.

Additional information

R. A. Lindtner and A. N. Tiaden contributed equally to this study.

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Lindtner, R.A., Tiaden, A.N., Genelin, K. et al. Osteoanabolic effect of alendronate and zoledronate on bone marrow stromal cells (BMSCs) isolated from aged female osteoporotic patients and its implications for their mode of action in the treatment of age-related bone loss. Osteoporos Int 25, 1151–1161 (2014). https://doi.org/10.1007/s00198-013-2494-3

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