We welcome the opportunity to respond to the letter by Baylink et al. Their letter makes many good points but, unfortunately, it also contains several misinterpretations of our analysis. The thesis of Baylink's letter and the paper of Einhorn et al. [1] is that fluoride incorporation into cortical bone does not impair the bone's mechanical properties. We assert that the apparent effect of fluoride on bone strength depends on how strength is defined [2, 3]. It is important to recognize the differ

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We welcome the opportunity to respond to the letter by Baylink et al. Their letter makes many good points but, unfortunately, it also contains several misinterpretations of our analysis. The thesis of Baylink’s letter and the paper of Einhorn et al. [1] is that fluoride incorporation into cortical bone does not impair the bone’s mechanical properties. We assert that the apparent effect of fluoride on bone strength depends on how strength is defined [2, 3]. It is important to recognize the difference between failure stress of bone tissue, which is an intrinsic property of bone, and the force or load required to break a bone which is an extrinsic property. That is, failure stress values are independent of the size and shape of the bone and are reported in pounds/in 2 or newtons/m 2. In contrast, failure load will vary with bone size and is reported in units of pounds or newtons. One must keep this distinction in mind. Because fluoride affects the size of the bone, failure stress and failure load can show different trends in fluoride studies. If strength is defined as failure load or torque, as it was in Einhorn study, it is not related to bone fluoride content in young, healthy rats (see Fig. 2 in [2] and Table 1 in [1]). However, failure stress or intrinsic bone strength decreases with increasing bone fluoride content (see Fig. 1 in [2]). Moreover, as we discuss below, the negative effects of fluoride on bone strength in older rats or rats fed a calciumdeficient diet are unequivocal, regardless of how bone strength is defined.

Baylink et al. claim that “we dismiss the Einhorn study,” which of course we do not, as our data (Fig. 2 in [2]) are consistent with Einhorn’s results in Table 1 [1]. They also claim that “the Einhorn data are in direct conflict” with Figure 1 of our letter [2], in which we reported bone strength as failure stress. It is difficult to see the conflict as Einhorn et al. reported strength in terms of failure torque–an extrinsic strength measure, not failure stress–an intrinsic strength measure. However, they assert that, because Einhorn et al. saw no changes in bone volume of the proximal tibia with fluoride treatment, failure torque is equivalent to intrinsic bone strength. This conclusion presumes that tibial bone volume is in some way correlated with the polar moment of inertia of the midshaft of the femur, which was not the case in our observations. As Einhorn et al. [1] did not measure intrinsic bone strength in their study, they really have no way of knowing their data are in conflict with ours. We maintain that their findings are consistent with ours.

Baylink et al. go on to criticize a study that was done previously by one of us (CHT). They claim that in this study [4], no differences in bone strength were seen between rats receiving no fluoride and those treated with 64 or 128 ppm. This claim is a bit misleading, however, because reductions in bone strength were seen in both the 64 ppm group (9% reduction) and the 128 ppm group (24% reduction) compared with rats that received no fluoride. These changes were not statistically significant, due largely to the small number of animals (n = 6) in the experimental groups, yet they are consistent with our more recent data [2].

It should be noted that controversy about fluoride effects on bone strength in experimental animals is nothing new. Low doses of fluoride most often are associated with no decrease [5-8] and, possibly, an increase in bone strength [4, 9]. High doses of fluoride are usually associated with a decrease in bone strength [2, 4, 10–12], although some studies showed no apparent effect of fluoride on bone strength, even at high doses [1, 13]. Baylink et al. correctly point out that none of these studies reported more than a modest reduction in bone strength provided that the animals had adequate calcium nutrition. The common denominator for all of these studies is that the animal subjects were young and healthy. We have shown that, in older rats exposed to chronic fluoride treatment, bone strength is decreased substantially (unpublished data; see also [14]). There are several important things to be learned from these data. First, the strength variable reported in our unpublished data (Fig. 1), i.e., failure load, represents extrinsic bone strength and can be compared to the extrinsic strength measure reported by Einhorn et al. [1]. The lack of any differences in failure load after 3 months of fluoride treatment is consistent with Einhorn’s results. However, in those animals treated with 50 ppm fluoride for 18 months, maximum load was about 20% less than controls and this difference is statistically significant (P < 0.05, Fisher’s PLSD test). Although it is possible that the fluoride-induced deficit in bone strength seen in the older animals resulted from increased fluoride accumulation into the bone, regression analyses of the data suggested that the age of the animal was the major factor in the fluoride effect. Thus, though there is controversy about fluoride effects on bone strength in young healthy animals, there is little doubt that chronic fluoride treatment decreases bone strength in older animals. Also, we could find no increase in osteoid seam width at high fluoride doses in the older rats, which suggests that the rats did not develop osteomalacia as a result of the fluoride treatment. Therefore, we conclude that the strength reduction we observed in older rats was due to a fluoride-induced mineralization defect. At this point, the molecular basis for the fluoride effect on bone strength is unknown and we agree with Baylink et al. that this issue should be addressed in future studies.

Baylink et al. point to the observation of fluoride-induced calcium deficiency and osteomalacia in clinical studies as a major causative factor for reduced bone strength and fracture risk. We agree with them that, through this mechanism, fluoride may severely reduce bone strength. In an ongoing study of fluoride effects on bone strength in young, calcium deficient rats, we have found reduced bone strength caused by both high fluoride doses and calcium deficiency (P < 0.001 for each effect by two way analysis of variance). However, the effects of fluoride on bone strength were far more dramatic in the group of rats fed a calcium-deficient diet (Fig. 2). Four months of 50 ppm fluoride treatment caused almost 40% loss in bone failure load when rats were fed a calcium-deficient diet (0.125% Ca 2 +), whereas the same fluoride treatment caused only 7% loss in bone failure load in calcium-replete rats. Others have reported similar effects of fluoride on bone strength in calcium-deficient animals [10, 15]. It is possible that the calcium-deficient rats in our study suffered from osteomalacia that was aggravated by the high fluoride treatment. We are currently performing histological evaluations of the bones from these animals to test that possibility.

The clinical significance of the reported findings in rats remains to be determined. We have shown unequivocal reductions in bone strength that were not associated with osteomalacia (manuscript in review) in old rats (Fig. 1, [14]). However, it is unknown whether the degree of strength reduction seen in fluoride-treated rats reflects a high risk of fracture in humans. We agree with Baylink et al. that, if the fluoride-induced calcium deficiency can be overcome with calcium and 1,25 Vitamin D3 supplementation, the positive effects of fluoride on bone mass may overwhelm its negative effects on intrinsic bone strength. The recent results reported by Pak et al. [16] suggest this possibility, yet they are preliminary and require confirmation.

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