Results

Of the patients initially enrolled in each group, 4 in group A, 4 in group B and 3 in group C withdrew during the first 6 months prior to the first control visit due to personal reasons or because of protocol violations. Of the remaining 134 women further study patients dropped out at different intervals for the following reasons: Group A (n = 45): 6 patients due to noncompliance, 2 patients because they lived too far from the study center, 3 patient due the recommendations of her own physician and 1 patient due to lower-extremity pain syndrome (LEPS). Group B (n = 44): 3 patients due to noncompliance, 2 patients because they lived too far from the study center. 3 patients due to the recommendation of their own physicians, 1 patient due to LEPS and 1 patient due to diarrhea possibly related to calcium intake. Group C (it = 45): 6 patients due to noncompliance, 2 patients because they lived too far from the study center and I patient due to renal colic (kidney stone).

Adverse Events Table 2 shows the number and type of adverse events that occurred during the study. The incidence of LEPS in group A (intermittent therapy) was only half of that in group B (continuous therapy). The other side effects in all three groups were considered to be due mainly to the calcium supplementation. The aggravation of psoriasis and the 'dry skin' are probably not directly related to the medication.

Combined Pain-Mobility Score The evolution of the CPMS during the study is shown in Fig. 1. In both fluoride-treated groups the CPMS decreased significantly compared with placebo. After 3 years the intermittent therapy schedule seemed to have reduced the CPMS better than continuous therapy.

Body Height The average changes in body height after the 3 years of therapy were  +0.9 cm in group A, -0.3 cm in group B and -2.5 cm in group C. These changes were not significant (Fisher's test for A/C: p = 0.055).

Bone Mineral Density Table 3 shows the average changes in BMD throughout the 3 years of the study expressed as percentages of baseline values. In group A we found for all six measuring sites (L2-4, femoral neck, Ward's triangle, trochanter, radius 1/3, radius 1/10) a gain in BMD after 3 years. In group B there were modest losses of BMD at the femoral neck and radius 1/3; at the other sites BMD increased. Group C showed losses of BMD at all measuring sites. The highest average gain in BMD could be seen at L2-4 in group B. The differences between the treatment groups were significant between A and B at L2-4, femoral neck and radius 1/3, and at all sites between A and C and B and C respectively. As an example Fig. 2 shows the course of BMD at the lumbar spine for the three groups.

Fracture Rates The number of new vertebral fractures occurring during the study is shown in Table 4. There was no significant difference over the 3 years between the two fluoride-treated groups. Differences can be demonstrated between group A (intermittent therapy) and C (calcium only) after the second (p=0.016) and the third year (p=0.003). The differences between groups B and C were only significant after the  third year (p=0.012). After the 3 years the differences between the treated groups and the placebo group were highly significant (A vs C:  p < 0.0001; B vs C: p = 0.0006). The relatively high number of fractures  in the first year in group B compared with group A is due to one patient who suffered five new   vertebral fractures in this year. A worsening of existing vertebral fractures (excluded in Table 4) was seen in group A for 3 vertebrae in the first year and for I vertebra in the second and third Years, respectively. In group B a progressive loss of height was observed for 8, 4 and 2 vertebrae and in group C for 2, 5 and 10 vertebral in the first, second and third years, respectively. In Table 5 the number and location of non vertebral fractures are listed. Within the 3 years we saw in group A, 9 non vertebral fractures in 8 patients, in group B, 17 in 13 patients and in group C, 30 in 22 patients. The differences between the groups for these results are significant for A vs C and B vs C (Fisher's test, two- sided: p<0.0001, p=0.0l1, respectively). These differences in non vertebral fractures reflect the different response of BMD to therapy at measuring sites where there is mainly cortical bone. For example at the femoral neck in group A, 23 patients showed a gain and 8 a loss of BMD after 3 years while in group B the relation was reversed with only 7 patients gaining and 23 patients losing bone mass. In group C all 33 patients showed losses of BMD. The individual changes at the lumbar spine and femoral neck for the patients who were examined up to month 36 are shown in Fig. 3.

Table 2 Type and rate of adverse effects observed during the 3 years of the study

	Group A               (MFP/Ca intermittent)              n %	Group B (MFP/Ca              continuous)          n %	Group C             (Ca/only)             n %
Lower– extremity pain syndrome (a)	11 24	23 52	- -
Epigastric symptoms	4 9	4 9	7 15
Diarrhea after calcium	1 2	1 2	2 4
Nausea	- -	1 2	3 6
Dry skin	1 2	- -	- -
Aggravation of psoriasis	- -	1 2	- -

(a) Disappeared 3-4 weeks after discontinuing therapy