Skip to main content

Advertisement

SpringerLink
Log in

Sequential Treatment of Estrogen Deficient, Osteopenic Rats with Alendronate, Parathyroid Hormone (1–34), or Raloxifene Alters Cortical Bone Mineral and Matrix Composition

  • Original Research
  • Published:
Calcified Tissue International Aims and scope Submit manuscript

Abstract

Anti-resorptive and anabolic treatments can be used sequentially to treat osteoporosis, but their effects on bone composition are incompletely understood. Osteocytes may influence bone tissue composition with sequential therapies because bisphosphonates diffuse into the canalicular network and anabolic treatments increase osteocyte lacunar size. Cortical bone composition of osteopenic, ovariectomized (OVX) rats was compared to that of Sham-operated rats and OVX rats given monotherapy or sequential regimens of single approved anti-osteoporosis medications. Adult female Sprague–Dawley rats were OVX (N = 37) or Sham–OVXd (N = 6). After 2 months, seven groups of OVX rats were given three consecutive 3-month periods of treatment with vehicle (V), h-PTH (1–34) (P), alendronate (A), or raloxifene (R), using the following orders: VVV, PVV, RRR, RPR, AAA, AVA, and APA. Compositional properties around osteocyte lacunae of the left tibial cortex were assessed from Raman spectra in perilacunar and non-perilacunar bone matrix regions. Sequential treatments involving parathyroid hormone (PTH) caused lower mean collagen maturity relative to monotherapies. Mean mineral:matrix ratio was 2.2% greater, mean collagen maturity was 1.4% greater, and mean carbonate:phosphate ratio was 2.2% lower in the perilacunar than in the non-perilacunar bone matrix region (all P < 0.05). These data demonstrate cortical bone tissue composition differences around osteocytes caused by sequential treatment with anti-osteoporosis medications. We speculate that the region-specific differences demonstrate the ability of osteocytes to alter bone tissue composition adjacent to lacunae.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Gasser JA, Ingold P, Venturiere A et al (2008) Long-term protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat. J Bone Miner Res 23:544–551. https://doi.org/10.1359/jbmr.071207

    Article  CAS  PubMed  Google Scholar 

  2. Cosman F (2014) Anabolic and antiresorptive therapy for osteoporosis: combination and sequential approaches. Curr Osteoporos Rep 12:385–395. https://doi.org/10.1007/s11914-014-0237-9

    Article  PubMed  Google Scholar 

  3. Mosekilde L, Danielsen CC, Søgaard CH et al (1995) The anabolic effects of parathyroid hormone on cortical bone mass, dimensions and strength-assessed in a sexually mature, ovariectomized rat model. Bone 16:223–230. https://doi.org/10.1016/8756-3282(94)00033-V

    Article  CAS  PubMed  Google Scholar 

  4. Amugongo SK, Yao W, Jia J et al (2014) Effects of sequential osteoporosis treatments on trabecular bone in adult rats with low bone mass. Osteoporos Int 25:1735–1750. https://doi.org/10.1007/s00198-014-2678-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Amugongo S, Yao W, Jia J et al (2014) Effect of sequential treatments with alendronate, parathyroid hormone (1–34) and raloxifene on cortical bone mass and strength in ovariectomized rats. Bone 67:257–268. https://doi.org/10.1097/OPX.0b013e3182540562

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Boskey A, Mendelsohn R (2005) Infrared analysis of bone in health and disease. J Biomed Opt 10:31102. https://doi.org/10.1117/1.1922927

    Article  CAS  Google Scholar 

  7. Acevedo C, Bale H, Gludovatz B et al (2015) Alendronate treatment alters bone tissues at multiple structural levels in healthy canine cortical bone. Bone 81:352–363. https://doi.org/10.1016/j.bone.2015.08.002

    Article  CAS  PubMed  Google Scholar 

  8. Burr DB, Allen MR, Miller LM et al (2011) Bisphosphonates do not alter the rate of secondary mineralization. Bone 49:701–705. https://doi.org/10.1016/j.bone.2011.05.009

    Article  CAS  PubMed  Google Scholar 

  9. Bala Y, Depalle B, Farlay D et al (2012) Bone micromechanical properties are compromised during long-term alendronate therapy independently of mineralization. J Bone Miner Res 27:825–834. https://doi.org/10.1002/jbmr.1501

    Article  CAS  PubMed  Google Scholar 

  10. Burket JC, Brooks DJ, MacLeay JM et al (2013) Variations in nanomechanical properties and tissue composition within trabeculae from an ovine model of osteoporosis and treatment. Bone 52:326–336. https://doi.org/10.1016/j.bone.2012.10.018

    Article  CAS  PubMed  Google Scholar 

  11. Paschalis EP, Burr DB, Mendelsohn R et al (2003) Bone mineral and collagen quality in humeri of ovariectomized cynomolgus monkeys given rhPTH (1–34) for 18 months. J Bone Miner Res 18:769–775. https://doi.org/10.1359/jbmr.2003.18.4.769

    Article  CAS  PubMed  Google Scholar 

  12. Saito M, Marumo K, Kida Y et al (2011) Changes in the contents of enzymatic immature, mature, and non-enzymatic senescent cross-links of collagen after once-weekly treatment with h-PTH (1–34) for 18 months contribute to improvement of bone strength in OVX monkeys. Osteoporos Int 22:2373–2383. https://doi.org/10.1007/s00198-010-1454-4

    Article  CAS  PubMed  Google Scholar 

  13. Eswaran SK, Gupta A, Adams MF, Keaveny TM (2006) Cortical and trabecular load sharing in the human vertebral body. J Bone Miner Res 21:307–314. https://doi.org/10.1359/JBMR.051027

    Article  CAS  PubMed  Google Scholar 

  14. Stern A, Yao X, Wang Y et al (2018) Effect of osteoporosis treatment agents on the cortical bone osteocyte microenvironment in adult estrogen-deficient, osteopenic rats. Bone Rep 8:115–124. https://doi.org/10.1016/j.bonr.2018.02.005

    Article  PubMed  PubMed Central  Google Scholar 

  15. Tazawa K, Hoshi K, Kawamoto S et al (2004) Osteocytic osteolysis observed in rats to which parathyroid hormone was continuously administered. J Bone Miner Metab 22:524–529. https://doi.org/10.1007/s00774-004-0519-x

    Article  CAS  PubMed  Google Scholar 

  16. Gardinier JD, Al-Omaishi S, Rostami N et al (2018) Examining the influence of PTH (1–34) on tissue strength and composition. Bone 117:130–137. https://doi.org/10.1016/j.bone.2018.09.019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Roelofs AJ, Stewart CA, Sun S et al (2012) Influence of bone affinity on the skeletal distribution of fluorescently labeled bisphosphonates in vivo. J Bone Miner Res 27:835–847. https://doi.org/10.1002/jbmr.1543

    Article  CAS  PubMed  Google Scholar 

  18. Wysolmerski JJ (2013) Osteocytes remove and replace perilacunar mineral during reproductive cycles. Bone 54(2):230–236. https://doi.org/10.1016/j.bone.2013.01.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Qing H, Bonewald LF (2009) Osteocyte remodeling of the perilacunar and pericanalicular matrix. Int J Oral Sci 1(2):59–65. https://doi.org/10.4248/ijos.09019

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tsourdi E, Jähn K, Rauner M, Busse B, Bonewald LF (2018) Physiological and pathological osteocytic osteolysis. J Musculoskelet Neuronal Interact 18(3):292–303

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Nicolella DP, Moravits DE, Gale AM et al (2006) Osteocyte lacunae tissue strain in cortical bone. J Biomech 39:1735–1743. https://doi.org/10.1016/j.jbiomech.2005.04.032

    Article  PubMed  Google Scholar 

  22. Gardinier JD, Al-Omaishi S, Morris MD, Kohn DH (2016) PTH signaling mediates perilacunar remodeling during exercise. Matrix Biol 52–54:162–175. https://doi.org/10.1016/j.matbio.2016.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Mandair GS, Morris MD (2015) Contributions of Raman spectroscopy to the understanding of bone strength. BoneKEy 4:1–8. https://doi.org/10.1038/bonekey.2014.115

    Article  CAS  Google Scholar 

  24. Gamsjaeger S, Masic A, Roschger P et al (2010) Cortical bone composition and orientation as a function of animal and tissue age in mice by Raman spectroscopy. Bone 47:392–399. https://doi.org/10.1016/j.bone.2010.04.608

    Article  PubMed  Google Scholar 

  25. Taylor EA, Lloyd AA, Salazar-Lara C, Donnelly EL (2017) Raman and FT-IR mineral to matrix ratios correlate with physical chemical properties of model compounds and native bone tissue. Appl Spectrosc 71(10):2404–2410. https://doi.org/10.1177/0003702817709286

    Article  CAS  PubMed  Google Scholar 

  26. Gamsjaeger S, Robins SP, Tatakis DN et al (2017) Identification of pyridinoline trivalent collagen cross-links by Raman microspectroscopy. Calcif Tissue Int 100(6):565–574. https://doi.org/10.1007/s00223-016-0232-5

    Article  CAS  PubMed  Google Scholar 

  27. Beattie JR, Sophocleous A, Caraher MC et al (2019) Raman spectroscopy as a predictive tool for monitoring osteoporosis therapy in a rat model of postmenopausal osteoporosis. J Mater Sci Mater Med 30(2):25. https://doi.org/10.1007/s10856-019-6226-x

    Article  CAS  PubMed  Google Scholar 

  28. de Souza RA, Xavier M, da Silva FF et al (2012) Influence of creatine supplementation on bone quality in the OVX rat model: an FT-Raman spectroscopy study. Lasers Med Sci 27(2):487–495. https://doi.org/10.1007/s10103-011-0976-0

    Article  PubMed  Google Scholar 

  29. Boskey A, Mendelsohn R (2005) Infrared analysis of bone in health and disease. J Biomed Opt 10:031102. https://doi.org/10.1117/1.1922927

    Article  CAS  PubMed  Google Scholar 

  30. Saito M, Marumo K (2015) Effects of collagen crosslinking on bone material properties in health and disease. Calcif Tissue Int 97(3):242–261. https://doi.org/10.1007/s00223-015-9985-5

    Article  CAS  PubMed  Google Scholar 

  31. Bala Y, Seeman E (2015) Bone’s material constituents and their contribution to bone strength in health, disease, and treatment. Calcif Tissue Int 97(3):308–326. https://doi.org/10.1007/s00223-015-9971-y

    Article  CAS  PubMed  Google Scholar 

  32. Garnero P (2012) The contribution of collagen crosslinks to bone strength. BoneKey Rep 1:182. https://doi.org/10.1038/bonekey.2012.182

    Article  PubMed  PubMed Central  Google Scholar 

  33. Gamsjaeger S, Buchinger B, Zoehrer R et al (2011) Effects of one year daily teriparatide treatment on trabecular bone material properties in postmenopausal osteoporotic women previously treated with alendronate or risedronate. Bone 49:1160–1165. https://doi.org/10.1016/j.bone.2011.08.015

    Article  CAS  PubMed  Google Scholar 

  34. Boskey AL, Spevak L, Weinstein RS (2009) Spectroscopic markers of bone quality in alendronate-treated postmenopausal women. Osteoporos Int 20:793–800. https://doi.org/10.1007/s00198-008-0725-9

    Article  CAS  PubMed  Google Scholar 

  35. Durchschlag E, Paschalis EP, Zoehrer R et al (2006) Bone material properties in trabecular bone from human iliac crest biopsies after 3- and 5-year treatment with risedronate. J Bone Miner Res 21:1581–1590. https://doi.org/10.1359/jbmr.060701

    Article  CAS  PubMed  Google Scholar 

  36. Gamsjaeger S, Buchinger B, Zwettler E et al (2011) Bone material properties in actively bone-forming trabeculae in postmenopausal women with osteoporosis after three years of treatment with once-yearly zoledronic acid. J Bone Miner Res 26:12–18. https://doi.org/10.1002/jbmr.180

    Article  CAS  PubMed  Google Scholar 

  37. Gallant MA, Brown DM, Hammond M et al (2015) Bone cell-independent benefits of raloxifene on the skeleton: a novel mechanism for improving bone material properties. Bone 61:191–200. https://doi.org/10.1016/j.bone.2014.01.009.Bone

    Article  Google Scholar 

  38. Roschger P, Lombardi A, Misof BM et al (2010) Mineralization density distribution of postmenopausal osteoporotic bone is restored to normal after long-term alendronate treatment: qBEI and sSAXS data from the fracture intervention trial long-term extension (FLEX). J Bone Miner Res 25:48–55. https://doi.org/10.1359/jbmr.090702

    Article  CAS  PubMed  Google Scholar 

  39. Ou-Yang H, Paschalis EP, Mayo WE et al (2001) Infrared microscopic imaging of bone: spatial distribution of CO3(2−). J Bone Miner Res 16:893–900. https://doi.org/10.1359/jbmr.2001.16.5.893

    Article  CAS  PubMed  Google Scholar 

  40. Donnelly E, Meredith DS, Nguyen JT et al (2012) Reduced cortical bone compositional heterogeneity with bisphosphonate treatment in postmenopausal women with intertrochanteric and subtrochanteric fractures. J Bone Miner Res 27:672–678. https://doi.org/10.1002/jbmr.560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shah FA, Stoica A, Cardemil C, Palmquist A (2017) Multiscale characterisation of cortical bone composition, microstructure, and nanomechanical properties in experimentally-induced osteoporosis. J Biomed Mater Res 106(4):997–1007. https://doi.org/10.1002/jbm.a.36294

    Article  CAS  Google Scholar 

  42. Miyagawa K, Kozai Y, Ito Y et al (2011) A novel underuse model shows that inactivity but not OVX determines the deteriorated material properties and geometry of cortical bone in the tibia of adult rats. J Bone Miner Metab 29(4):422–436. https://doi.org/10.1007/s00774-010-0241-9

    Article  PubMed  Google Scholar 

  43. Paolillo FR, Romano RA, de Matos L et al (2018) Short-term and long-term effects of osteoporosis on incisor teeth and femoral bones evaluated by Raman spectroscopy and energy dispersive X-ray analysis in OVX rats. J Bone Miner Metab 37(1):18–27. https://doi.org/10.1007/s00774-018-0903-6

    Article  PubMed  Google Scholar 

  44. Paschalis EP, Gamsjaeger S, Condon K, Klaushofer K, Burr D (2019) Estrogen depletion alters mineralization regulation mechanisms in an OVX monkey animal model. Bone 120:279–284. https://doi.org/10.1016/j.bone.2018.11.004

    Article  CAS  PubMed  Google Scholar 

  45. Paschalis EP, Gamsjaeger S, Hassler N, Klaushofer K, Burr D (2017) Ovarian hormone depletion affects cortical bone quality differently on different skeletal envelopes. Bone 95:55–64. https://doi.org/10.1016/j.bone.2016.10.029

    Article  CAS  PubMed  Google Scholar 

  46. Gourion-Arsiquaud S, Burket JC, Havill LM et al (2009) Spatial variation in osteonal bone properties relative to tissue and animal age. J Bone Miner Res 24:1271–1281. https://doi.org/10.1359/jbmr.090201

    Article  PubMed  PubMed Central  Google Scholar 

  47. Qing H, Ardeshirpour L, Pajevic PD et al (2012) Remodeling in mice during lactation. J Bone Miner Res 27:1018–1029. https://doi.org/10.1002/jbmr.1567

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kaya S, Basta-Pljakic J, Seref-Ferlengez Z et al (2017) Lactation-induced changes in the volume of osteocyte lacunar-canalicular space alter mechanical properties in cortical bone tissue. J Bone Miner Res 32:676–680. https://doi.org/10.1002/jbmr.3090

    Article  CAS  Google Scholar 

  49. Bonewald LF, Johnson ML (2008) Osteocytes, mechanosensing and Wnt signaling. Bone 42:606–615. https://doi.org/10.1016/j.bone.2007.12.224

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Rath Bonivtch A, Bonewald LF, Nicolella DP (2007) Tissue strain amplification at the osteocyte lacuna: a microstructural finite element analysis. J Biomech 40:2199–2206. https://doi.org/10.1016/j.jbiomech.2006.10.040

    Article  Google Scholar 

  51. Lane NE, Yao W, Balooch M et al (2006) Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res 21:466–476. https://doi.org/10.1359/JBMR.051103

    Article  CAS  PubMed  Google Scholar 

  52. Baylink DJ, Wergedal JE (1971) Bone formation by osteocytes. Am J Physiol 221:669–678

    Article  CAS  Google Scholar 

  53. Villanueva AR, Ramser JR, Frost HM et al (1966) Tetracycline-based quantitative measurements of the tissue and cell dynamics in 10 cases of osteoporosis. Clin Orthop Relat Res 46:203–217

    CAS  PubMed  Google Scholar 

  54. Frost HM (1969) Tetracycline-based histological analysis of bone remodeling. Calcif Tissue Res 3:211–239

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We acknowledge Lynn Johnson, PhD, of the Cornell Statistical Consulting Unit for assistance with statistical analysis. This work was funded by National Institutes of Health Grants #’s R01 AR043052-07, 1 P50 AR03043, P50 AR060752NIH to NEL; The Endowment for Aging Research at UC Davis to NEL; and the Center for Musculoskeletal Health at UC Davis.

Author information

Authors and Affiliations

  1. Sibley School of Mechanical and Aerospace Engineering, Cornell University, Ithaca, NY, USA

    Erik A. Taylor

  2. Department of Materials Science and Engineering, Cornell University, Ithaca, NY, USA

    Eve Donnelly

  3. Research Division, Hospital for Special Surgery, New York, NY, USA

    Eve Donnelly

  4. Department of Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA

    Xiaomei Yao & Mark L. Johnson

  5. Center for Musculoskeletal Health, University of California Davis Medical Center, Sacramento, CA, USA

    Sarah K. Amugongo & Nancy E. Lane

  6. Department of Physiological Sciences, University of Florida, Gainesville, FL, USA

    Donald B. Kimmel

  7. Health Center, University of California At Davis, 4625 Second Avenue, Suite 2006, Sacramento, CA, 95817, USA

    Nancy E. Lane

Authors
  1. Erik A. Taylor
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Eve Donnelly
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xiaomei Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mark L. Johnson
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sarah K. Amugongo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Donald B. Kimmel
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Nancy E. Lane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nancy E. Lane.

Ethics declarations

Conflict of interest

Erik A. Taylor, Eve Donnelly, Xiaomei Yao, Mark L. Johnson, Sarah K. Amugongo, Donald B. Kimmel, and Nancy E. Lane declare that they have no conflict of interest or disclosures.

Human and Animal Rights and Informed Consent

We present no data from groups of human patients or individual human participants in this study. All applicable international, national, and institutional guidelines for the care and use of animals were followed. All procedures performed during studies involving animals were in accordance with the ethical standards of practice at the University of California, Davis. This study only reports data from animal experiments for which the statement on animal welfare is included.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1597 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Taylor, E.A., Donnelly, E., Yao, X. et al. Sequential Treatment of Estrogen Deficient, Osteopenic Rats with Alendronate, Parathyroid Hormone (1–34), or Raloxifene Alters Cortical Bone Mineral and Matrix Composition. Calcif Tissue Int 106, 303–314 (2020). https://doi.org/10.1007/s00223-019-00634-w

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00223-019-00634-w

Keywords

Search

Navigation