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Strontium ranelate stimulates trabecular bone formation in a rat tibial bone defect healing process

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Abstract

Summary

Strontium ranelate treatment is known to prevent fractures. Here, we showed that strontium ranelate treatment enhances bone healing and affects bone cellular activities differently in intact and healing bone compartments: Bone formation was increased only in healing compartment, while resorption was reduced in healing and normal bone compartments.

Introduction

Systemic administration of strontium ranelate (SrRan) accelerates the healing of bone defects; however, controversy about its action on bone formation remains. We hypothesize that SrRan could affect bone formation differently in normal mature bone or in the bone healing process.

Methods

Proximal tibia bone defects were created in 6-month-old female rats, which orally received SrRan (625 mg/kg/day, 5/7 days) or vehicle (control groups) for 4, 8, or 12 weeks. Bone samples were analyzed by micro-computed tomography and histomorphometry in various regions, i.e., metaphyseal 2nd spongiosa, a region close to the defect, within the healing defect and in cortical defect bridging region. Additionally, we evaluated the quality of the new bone formed by quantitative backscattered electron imaging and by red picosirius histology.

Results

Healing of the bone defect was characterized by a rapid onset of bone formation without cartilage formation. Cortical defect bridging was detected earlier compared with healing of trabecular defect. In the healing zone, SrRan stimulated bone formation early and laterly decreased bone resorption improving the healing of the cortical and trabecular compartment without deleterious effects on bone quality. By contrast, in the metaphyseal compartment, SrRan only decreased bone resorption from week 8 without any change in bone formation, leading to little progressive increase of the metaphyseal trabecular bone volume.

Conclusions

SrRan affects bone formation differently in normal mature bone or in the bone healing process. Despite this selective action, this led to similar increased bone volume in both compartments without deleterious effects on the newly bone-formed quality.

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Author information

Authors and Affiliations

  1. Division of Bone Diseases, Department of Internal Medicine Specialties, Geneva University Hospital, 4, rue Gabrielle-Perret-Gentil, CH-1211, Geneva 14, Switzerland

    C. Lavet, R. Rizzoli & P. Ammann

  2. GEROM-LHEA, Institut de Biologie en Santé, University of Angers, Angers, France

    G. Mabilleau & D. Chappard

  3. SCIAM, Institut de Biologie en Santé, University of Angers, Angers, France

    G. Mabilleau & D. Chappard

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  1. C. Lavet
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  2. G. Mabilleau
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Corresponding author

Correspondence to C. Lavet.

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Conflicts of interest

Lavet C, Mabilleau G, Chappard D, Rizzoli R, and Ammann P declare that they received funding from Servier Laboratory to complete this project.

Electronic supplementary material

Supplementary data 1

A-Experimental design. Seventy 6 month-old Sprague-Dawley female rats were randomly assigned to seven groups of 10 animals each. After surgery, three groups were respectively submitted to SrRan or vehicle treatment by gavage 5 days a week. The healing process was followed over time at weeks 4, 8 and 12 after surgery in one group of SrRan and control. B-Investigated compartments. In order to evaluate if SrRan could differently alter bone cellular activities in healing bone compartment (modeling and remodeling) as compared to normal bone (remodeling), we used a metaphyseal drill hole defect model in a mature animal model. Three regions of interest were investigated at the trabecular compartment: i) in the metaphyseal compartment far from the defect characterized by a normal bone remodeling (MC), ii) within the defect defined as the healing zone and submitted to both modeling and remodeling (DC) and iii) in an area close to the defect considered as a transition zone between the two first compartments potentially influenced by factor diffusion (CDC). At the cortical level the cortical shell bridging the defect (DC) was analyzed. (GIF 97 kb)

High resolution image (TIFF 52861 kb)

Supplementary data 2

Red picosirius staining under polarized lightning of the healing compartment. A- Outer bone zone. B- Cortical shell bridging the defect zone. C- Metaphyseal healing zone. Red picosirius staining used in combination with polarized microscopy is particularly useful to observe collagen network abnormalities as the large and better aligned collagen fibers appear in bright red and the thinner and/or not organized one in green or yellow. From week-4, large collagen and well organized fibers already appeared in bright red and were predominant at the cortical and trabecular compartment of the healing zone of both SrRan and control animals. Note that area A included collagen appearing in green with polarized microscopy. This area corresponded to a fibrin network at the periosteal in relation to the healing process after local surgery. (GIF 340 kb)

High resolution image (TIFF 49785 kb)

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Lavet, C., Mabilleau, G., Chappard, D. et al. Strontium ranelate stimulates trabecular bone formation in a rat tibial bone defect healing process. Osteoporos Int 28, 3475–3487 (2017). https://doi.org/10.1007/s00198-017-4156-3

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