Original articlesDoes suppression of bone turnover impair mechanical properties by allowing microdamage accumulation?
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.
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