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. 2010 Jan;46(1):101-11.
doi: 10.1016/j.bone.2009.09.002. Epub 2009 Sep 9.

Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations

Jeffrey S Willey  1 , Eric W Livingston, Michael E Robbins, J Daniel Bourland, Leidamarie Tirado-Lee, Hope Smith-Sielicki, Ted A Bateman
Affiliations

Risedronate prevents early radiation-induced osteoporosis in mice at multiple skeletal locations

Jeffrey S Willey et al. Bone. 2010 Jan.

Abstract

Introduction: Irradiation of normal, non-malignant bone during cancer therapy can lead to atrophy and increased risk of fracture at several skeletal sites, particularly the hip. This bone loss has been largely attributed to damaged osteoblasts. Little attention has been given to increased bone resorption as a contributor to radiation-induced osteoporosis. Our aims were to identify if radiation increases bone resorption resulting in acute bone loss and if bone loss could be prevented by administering risedronate.

Methods: Twenty-week-old female C57BL/6 mice were either: not irradiated and treated with placebo (NR+PL); whole-body irradiated with 2 Gy x-rays and treated with placebo (IR+PL); or irradiated and treated with risedronate (IR+RIS; 30 microg/kg every other day). Calcein injections were administered 7 and 2 days before sacrifice. Bones were collected 1, 2, and 3 weeks after exposure. MicroCT analysis was performed at 3 sites: proximal tibial metaphysis, distal femoral metaphysis, and the body of the 5th lumbar vertebra (L5). Osteoclasts were identified from TRAP-stained histological sections. Dynamic histomorphometry of cortical and trabecular bone was performed. Circulating TRAP5b and osteocalcin concentrations were quantified.

Results: In animals receiving IR+PL, significant (P<0.05) reduction in trabecular volume fraction relative to non-irradiated controls was observed at all three skeletal sites and time points. Likewise, radiation-induced loss of connectivity and trabecular number relative to NR+PL were observed at all skeletal sites throughout the study. Bone loss primarily occurred during the first week post-exposure. Trabecular and endocortical bone formation was not reduced until week 2. Loss of bone volume was absent in animals receiving IR+RIS. Histology indicated greater osteoclast numbers at week 1 within IR+PL mice. Serum TRAP5b concentration was increased in IR+PL mice only at week 1 compared to NR+PL (P=0.05). Risedronate treatment prevented the radiation-induced increase in osteoclast number, surface, and TRAP5b.

Conclusions: This study demonstrated a rapid loss of trabecular bone at several skeletal sites after whole-body irradiation. Changes were accompanied by an increase in osteoclast number and serum markers of bone loss. Risedronate entirely prevented bone loss, providing further evidence that an increase in bone resorption likely caused this radiation-induced bone loss.

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Figures

Figure 1
Figure 1
Bone volume fracture (BV/TV), trabecular connectivity (Conn.D), and structure model index (SMI) as quantified using microCT within the secondary spongisa from the proximal tibia, distal femur, or fifth lumbar vertebra (L5) from mice. Animals either received a 2 Gy whole-body dose of X-rays together with placebo injections of PBS (IR+PL; red triangle symbols) or injections of risedronate (IR+RIS; green circles) throughout the study; or served as non-irradiated controls receiving PBS (NR+PL; blue squares). * Indicates significant difference compared to NR+PL within a given time point as determined by two-way ANOVA (P < 0.05). For data different from NR+PL within each time point, the percentage above each symbol represents the difference from non-irradiated controls. aIndicates significant difference compared to Week 1 data within a treatment group (P < 0.05); b Indicates significant difference compared to Week 2 data within a treatment group (P < 0.05). Differences between IR+PL and IR+RIS are not illustrated as they are significant for every comparison execpt: for Weeks 1 and 2 SMI at the proximal tibia; Weeks 1 and 2 SMI at the distal femur; and Weeks 1, 2 and 3 Conn.D at L5.
Figure 2
Figure 2
MicroCT images of trabecular bone in the proximal tibial metaphysis (Tibia), distal femoral metaphysis (Femur), and within the vertebral body of the fifth lumbar (L5) vertebrae from mice sacrificed at Week 1 after receiving: a 2 Gy dose of X-rays with a PBS placebo injected subcutaneously (IR+PL); a 2 Gy dose and subcutaneous risedronate injections (IR+RIS); and non-irradiated animals receiving PBS (NR+PL). The scale bar represents 500 μm.
Figure 3
Figure 3
Bone volume fracture (BV/TV), trabecular connectivity (Conn.D), and structure model index (SMI) as quantified using microCT within the secondary spongisa from the proximal tibia, distal femur, or fifth lumbar vertebra (L5) from mice. Animals either received a 2 Gy whole-body dose of X-rays together with placebo injections of PBS (IR+PL; red triangle symbols) throughout the study or served as non-irradiated controls receiving PBS (NR+PL; blue squares). The equation of the regression line from Week 1 to Week 3 is provided. * P < 0.05 Indicates a difference between the slopes of the lines as determined by linear regression.
Figure 4
Figure 4
The number of osteoclasts (Oc.N) relative to the bone surface (BS) within the proximal tibial metaphysis of mice at Week 1, 2, and 3 after initiating the experiment where mice either received a 2 Gy whole-body dose of X rays then daily injections of PBS (IR+PL; open triangles); 2 Gy X-rays with daily injections of risedronate (IR+RIS; open circles); or served as non-irradiated controls (NR+PL; open squares). * Indicates significant difference compared to NR+PL within a given time point; # Indicates a difference between IR+RIS and IR+PL within a given time point as determined by two-way ANOVA (P < 0.05).
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References

    1. Aziz NM, Rowland JH. Trends and advances in cancer survivorship research: challenge and opportunity. Semin Radiat Oncol. 2003;13:248–66. - PubMed
    1. Oeffinger KC, Mertens AC, Sklar CA, Kawashima T, Hudson MM, Meadows AT, Friedman DL, Marina N, Hobbie W, Kadan-Lottick NS, Schwartz CL, Leisenring W, Robison LL. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572–82. - PubMed
    1. Society TAC. Cancer Facts & Figures 2007. Atlanta: American Cancer Society; The American Cancer Society;
    1. Zhao W, Diz DI, Robbins ME. Oxidative damage pathways in relation to normal tissue injury. Br J Radiol. 2007;80(Spec No 1):S23–31. - PubMed
    1. Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem. 2009;16:130–43. - PubMed

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