Elsevier

Bone

Volume 27, Issue 1, July 2000, Pages 13-20
Bone

Original articles
Does suppression of bone turnover impair mechanical properties by allowing microdamage accumulation?

https://doi.org/10.1016/S8756-3282(00)00284-2Get rights and content

Abstract

One plausible purpose of bone turnover is to repair bone microdamage. We hypothesized that suppression of bone turnover impairs bone quality by allowing accumulation of microdamage. We investigated the effect of high-dose etidronate (EHDP) on bone’s mechanical properties and microdamage accumulation. Skeletally mature beagles, 1–2 years old at the beginning of the study, were treated with daily injections of vehicle or EHDP at 0.5 mg/kg per day or 5.0 mg/kg per day for 1 year. X-rays were taken at baseline and monthly from 7 to 12 months. Bones were taken upon sacrifice and biomechanical tests, histomorphometry, and microdamage analyses were performed. Fractures of ribs and/or thoracic spinous processes were found in 10 of 11 dogs treated with the higher dose EHDP. Only one fracture of a thoracic spinous process was found in dogs treated with the lower dose EHDP, and no fractures were found in the vehicle controls. Biomechanical tests showed reduced mechanical strength in ribs and lumbar vertebrae, but not in the femoral diaphysis or thoracic spinous process in the higher dose EHDP group. Histomorphometric measurements showed a significant reduction of cancellous bone turnover in both EHDP-treated groups compared with controls. In dogs treated with the higher dose EHDP, activation frequency was reduced to zero in both cortical and cancellous bone. Osteoid volume increased significantly, especially in trabecular bone, resulting in reduced mineralized bone volume in the higher dose EHDP group. Microcrack numerical density (Cr.Dn) increased significantly only in the lumbar vertebral body in the higher dose EHDP group, but not in the rib or thoracic spinous process where fractures occurred. These findings show that suppression of bone turnover using high doses of EHDP is associated with fractures of the ribs and spinous processes in dogs. This is most likely the result of excessive amounts of unmineralized bone produced by the inhibition of mineralization at these high doses, rather than by the accumulation of microdamage.

Introduction

Bisphosphonates are used to treat osteoporosis because they reduce fracture risk, and increase bone mass by reducing bone turnover.6 Human trials show that one bisphosphonate, alendronate, increases bone mass by 7%–9% within 3 years.7, 28 However, experiments in dogs that were given etidronate subcutaneously found that high doses (0.5–10 mg/kg per day) were associated with an increase in spontaneous fractures of thoracic spinous process, rib, and pelvis, but a lower dose (0.1 mg/kg per day) was not.10, 11 Etidronate (EHDP) reduces bone turnover but also can inhibit mineralization at the doses given. Thus, fractures could have been caused either by the accumulation of unrepaired microdamage, or by the presence of large amounts of unmineralized bone. However, in that study, neither microdamage accumulation nor strength were measured at the sites where fractures occurred. Although microdamage has been proposed as a contributing cause for fragility fractures,3, 16 no data exist to show that reduced bone turnover leads to a concomitant increase in microdamage, or that microdamage influences bone fragility in vivo.

The primary goal of this study was to determine whether a significant reduction in bone turnover caused by treatment with high-dose EHDP is associated with an increased risk for fracture. If so, we sought to determine whether treatment with EHDP reduces bone strength and whether this occurs by allowing microdamage accumulation, inhibiting mineralization of new bone, or through a combination of these.

Section snippets

Experimental design

Thirty-one female beagles, aged 1–2 years, were randomly assigned to three weight-matched groups (Table 1): a control group (n = 8; saline vehicle); a lower dose EHDP (Procter & Gamble Pharmaceuticals) group (n = 12; 0.5 mg/kg per day); or a higher dose EHDP group (n = 11; 5.0 mg/kg per day). The solutions were prepared by adding the powder form of the compound to saline and passing the solution through sterilizing filters and into sterile containers.

All dogs were acclimated for a period of 1

Body weight and age

Although final body weight increased significantly compared with initial body weight in all groups (p < 0.01), there were no significant differences among the three groups in initial and final body weight, body weight gain, or age at start of treatment (Table 1).

Fracture incidence

No fractures were found either by X-ray or on postmortem inspection in the control group, and only a single fracture was found in a thoracic spinous process in the lower dose EHDP group (Table 2). In the higher dose EHDP group, 21

Discussion

The purpose of this study is not to comment on the efficacy or safety of EHDP as a treatment for osteoporosis. The doses of EHDP used here are higher than the clinical dose for postmenopausal osteoporosis. EHDP was used only as an agent to reduce bone turnover and inhibit mineralization, to enable examination of the relative effects of impaired mineralization and microdamage accumulation on bone strength. It was also used because we considered it important to examine the reasons for the earlier

Acknowledgements

The authors acknowledge Mary Hooser, Diana Jacob, and Thurman Alvey for assistance with histological procedures. This study was supported by NIH Grant 2PO1AG05793. Etidronate was kindly provided by Procter & Gamble Pharmaceuticals, Inc.

References (31)

  • T.M. Boyce et al.

    Damage type and strain mode associations in human compact bone bending fatigue

    J Orthop Res

    (1998)
  • D.B. Burr et al.

    Bone microdamage and skeletal fragility in osteoporotic and stress fractures

    J Bone Miner Res

    (1997)
  • R. Candield et al.

    Dipshosphonate therapy of Paget’s disease

    Clin Endocrinol Metab

    (1977)
  • S.R. Cummings et al.

    Effect of alendronate on risk of fracture in women with low bone density but without vertebral fracturesResults from the Fracture Intervention Trial

    JAMA

    (1998)
  • G.A.M. Finerman et al.

    Diphosphonate treatment of Paget’s disease

    Clin Orthop

    (1976)
  • Cited by (86)

    • Biomechanical mechanisms of atypical femoral fracture

      2021, Journal of the Mechanical Behavior of Biomedical Materials
    • On the evolution and contemporary roles of bone remodeling

      2020, Marcus and Feldman’s Osteoporosis
    • 2.10 Bone as a material

      2017, Comprehensive Biomaterials II
    • Osteoporosis and Bone Biology

      2015, Williams Textbook of Endocrinology
    View all citing articles on Scopus
    View full text