FLUORIDE 30 (2) 1997, pp 119-121	International Society for Fluoride Research	Table of Contents

ANTIRESORPTIVE THERAPY, ANABOLIC THERAPY, AND EXERCISE EFFECTS
ON BONE MASS, STRUCTURE, AND STRENGTH ASSESSED IN A RAT MODEL
Prevention and treatment of osteoporosis

Charlotte Hasselholt Søgaard MD
Aarhus, Denmark

Abstracted from PhD thesis, University of Aarhus, Denmark, 1994

Osteoporosis can be therapeutically approached in two different ways: by use of antiresorptive agents (for example estrogen and bisphosphonates) or by use of anabolic agents (for example parathyroid hormone (PTH) and fluoride). Osteoporosis becomes clinically relevant when the patient presents with a fracture. Because of a high surface to volume ratio, disproportionately more trabecular than cortical bone is lost. Consequently, the typical osteoporotic fractures are those of the spine (vertebral compression fractures), the femoral neck (hip fracture), and the distal radius (Colles' fracture); all of which are sites of large amounts of trabecular bone. The most serious osteoporotic fracture is that of the femoral neck, as it is painful, necessitates hospitalization and causes considerable morbidity and mortality.

For more than 30 years, sodium fluoride (NaF) has been a commonly used therapy for established osteoporosis. Its anabolic effect on trabecular bone mass, particularly in the spine, has been repeatedly documented. However, structural abnormalities or mineralization defects in the bone formed during fluoride administration have been demonstrated in several studies, thus indicating that the increase in bone mass is not necessarily paralleled by an improved bone quality.

Furthermore, long-term clinical investigations using fracture rate as a true end-point have now become available, and the results are conflicting. Some studies have shown that NaF reduces vertebral fracture rate. In contrast, three recent controlled trials have failed to demonstrate any therapeutic advantage of NaF over placebo with respect to vertebral fracture rate. In addition, there have been several reports of an increased incidence of non-vertebral fractures during fluoride administration.

Not much attention has been paid to fluoride's effect on bone biomechanics. Bone biopsies for measurement of bone strength in fluoride-treated osteoporotic patients are not readily available, and to our knowledge only one such investigation has been performed. In that study, a dramatic decrease in iliac crest bone strength and quality was found after 5 years of therapy (Søgaard et al. Bone 15 (4) 393-399 1994, abstract in Fluoride 27 (4) 229 1994).

There have been several animal studies focusing on bone strength during fluoride administration. No study to date has focused on the effect of fluoride on bone quality at a site of combined cortical and trabecular bone.

The vast majority of the clinical studies evaluating the effect of different preventive and therapeutic strategies in osteoporosis have used bone mass or bone histomorphometry as an end-point. This is logical, since bone biomechanical competence is not a readily available parameter in humans.

It has, however, recently become apparent that bone mass should be combined with determination of bone strength and quality when treatment regimens for osteoporosis are evaluated. In order to avoid invasive intervention in humans, bone strength can be evaluated only by making fracture rate the true end-point in clinical research. Since fracture occurs late in life, and preventive strategies should be initiated maybe 15 years ahead, such studies will be of long duration, unless they are of cross-sectional nature.

Seen in that light, longitudinal studies on small animals are attractive. Many of the animal experiments concerning the effect of various therapeutic agents or exercise on the skeleton have been based upon measurement of bone mass or on bone histomorphometry. Only a minority have focused on bone biomechanics, and then cortical bone strength has usually been the parameter measured.

To achieve a more clinically relevant evaluation, the present investigation has chosen to measure the effects of the various regimens on bone strength in the skeletal sites typical for osteoporotic fracture, namely the femoral neck and the vertebral body.

The purpose of the present investigation was to evaluate the effect on bone biomechanical competence of current therapies (fluoride and estrogen) or potential therapies (PTH, bisphosphonates, PTH co-therapy with an antiresorptive agent, and exercise) in treatment or prophylaxis of osteoporosis, assessed in either rat femoral neck and rat femoral body, or both.

SUMMARY AND CONCLUSIONS

1. The present study has confirmed that the rat skeleton is capable of reacting to mechanical and hormonal stimuli in a manner very similar to the human skeleton, and thereby it supports previous investigations finding the rat model suitable for osteoporosis research.
2. The present investigation has shown PTH to exert a highly anabolic effect on two clinically relevant sites of the rat skeleton: the vertebral body and the femoral neck. This effect is reflected in an increased bone strength as well as an increased bone quality and is independent of the presence of gonadal hormones. This study therefore provides further support for PTH being a promising agent in treatment of postmenopausal osteoporosis.
3. The present study has also shown a light, physiological, long-term exercise regimen to exert anabolic actions on the rat skeleton. This effect was most pronounced in the femoral neck, and the gain in bone strength seemed to be due partly to an increased bone mass and partly to an earlier maturation of the skeleton. But the less weight-bearing vertebral body was also found capable of responding positively to exercise, and long-term moderate physical training therefore seems promising as a part of the prevention strategy against osteoporosis. for treatment of vertebral osteoporosis.
4. In contrast, the present study has found that the apparently anabolic action of fluoride is not reflected in a concomitant increase in bone strength. Therefore this study provides further evidence for a possible detrimental effect of fluoride on bone quality, and as such agrees with previous investigations recommending discontinuance of the general use of fluoride in treatment of osteoporosis until further clinical trials, using fracture rate as an end-point, have been performed.
5. This investigation has shown only a modest effect of antiresorptive therapy on the rat skeleton. Estrogen and Risedronate seemed capable of maintaining bone mass and strength at control levels, but proved to be much less efficient than treatment with the anabolic agent PTH. When antiresorptive therapy was combined with PTH, a marked effect was found, but this was not more advantageous than treatment with PTH alone. One exception was concurrent treatment with Risedronate+PTH. This regimen showed a significant sustained increase in vertebral bone mass and strength throughout the whole treatment period, and it cannot be excluded that a long-term regimen combining PTH and bisphosphonates may prove more successful than PTH mono-therapy for treatment of vertebral osteoporosis.
6. Finally, this investigation has found the same agent to exert divergent effects on the vertebral body and on the femoral neck. This may be due partly to different ratios of cortical and cancellous bone, partly to different loading patterns at these two sites. However, the fact that the femoral neck, in contrast to the vertebral body, is not covered with periosteum and therefore can not undergo periosteal modeling (or remodeling) is an important matter that should be borne in mind when considering therapeutical intervention in osteoporosis.

Key words: Anabolic therapy, Antiresorptive therapy, Bone mass, Bone strength, Exercise, Fluoride therapy, Osteoporosis, Rat model.
Reprints: Dr Charlotte H Søgaard, Department of Connective Tissue Biology, University of Aarhus, DK-8000 Aarhus C, Denmark.

FLUORIDE 30 (2) 1997, pp 119-121	International Society for Fluoride Research
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