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Department of Medicine (I.R.R., T.C., A.B.G., A.H., J.C., R.A., B.J.O.-W., F.W., M.C.E., G.D.G.), University of Auckland, Auckland, New Zealand; and Pathology Laboratory (A.K.), Middlemore Hospital, Auckland, New Zealand
Address all correspondence and requests for reprints to: Prof. Ian Reid, Faculty of Medical and Health Sciences, University of Auckland, Private Bag 92019, Auckland, New Zealand. E-mail: i.reid{at}auckland.ac.nz.
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Abstract |
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Experimental Subjects: Subjects included 80 women with postmenopausal osteoporosis who had been taking estrogen for at least 1 yr.
Methods: Subjects were randomized to receive monofluorophosphate (MFP) (fluoride content of 20 mg/d) or placebo over 4 yr in a double-blind trial.
Results and Discussion: There were progressive increases in lumbar spine bone density over the duration of the study (MFP, 22%; placebo, 6%; P < 0.0001). In the trabecular bone of L3, these increases were even greater (MFP, 49%; placebo, 2.5%; P < 0.0001). In the proximal femur, there were smaller but significant treatment effects (P = 0.015). Total body scans and their subregions also showed significantly greater increases in the MFP group. Bone formation markers increased significantly in the MFP group at yr 1. Hyperosteoidosis was present in biopsies from five of seven MFP subjects, with osteomalacia in two of seven. The hazards ratio for vertebral fractures was 0.20 (95% confidence interval, 0.05–1.30), and the incidence rate ratio was 0.12 (95% confidence interval, 0.06–0.23; P < 0.01). The hazards ratio for nonvertebral fractures was 3.3 (95% confidence interval, 0.8–12.0).
Conclusions: We conclude that fluoride at 20 mg/d produces substantial increases in bone mineral density but still interferes with bone mineralization. This indicates that most previous studies with this ion have used toxic doses and that much lower doses should be assessed to find a safe dose window for the use of this powerful anabolic agent.
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Introduction |
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In light of these considerations, we hypothesized that the efficacy of fluoride could be optimized by its use in low doses, in patients already taking an antiresorptive agent. We have now tested this possibility directly in a randomized controlled trial, assessing the efficacy of adding glutamine monofluorophosphate (MFP) or placebo to preexisting treatment with hormone replacement therapy and calcium supplementation.
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Subjects and Methods |
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Postmenopausal women with osteoporosis were recruited from a hospital clinic. They were required to have at least one vertebral fracture (i.e. a reduction in the anterior, middle, or posterior relative height of a vertebra of more than 3 SDs in relation to the vertebra-specific normal values (3) or a bone mineral density (BMD) T-score in the lumbar spine (L2–L4) of less than –2.5). In addition, all subjects had been receiving estrogen for at least 12 months before study entry. Subjects were ineligible if they had disorders of calcium metabolism other than osteoporosis, thyroid or hepatic dysfunction, or serum creatinine of more than 0.20 mmol/liter. No subjects had previously used calcitonin or fluoride, and none had used bisphosphonates in the previous year.
Eighty women entered the study. Their characteristics at study entry are given in Table 1
. Two subjects in the placebo group died, and five discontinued study medication for personal reasons and seven for intercurrent illness. In the MFP group, there were no deaths, and eight discontinued study medication for personal reasons and seven for intercurrent illness. Durations of follow-up were 3.1 ± 1.3 yr (mean ± SD) in the placebo group and 2.9 ± 1.7 yr in those randomized to MFP (P = 0.32). Mean trial medication compliance (based on tablet counts) was 86 ± 17.3% (mean ± SD) in the placebo group and 81 ± 15.2% in the active arm (P = 0.28).
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Before entry to the study, a full medical history was taken, dietary calcium intake was assessed using a food frequency questionnaire (4), and customary physical activity was assessed by questionnaire (5). Height and weight were measured at study entry and six monthly using a Harpenden stadiometer and an electronic balance, respectively.
Women were randomized to receive tablets of either glutamine MFP with calcium (Tridin; Rottapharm SpA, Monza, Italy) or identical tablets containing calcium alone. Tablets were taken with the morning and evening meals and provided daily doses of 20 mg elemental fluoride and 600 mg calcium (half as the citrate and half as the gluconate). Compliance was checked at each clinic visit by tablet counts. All patients also took a nightly supplement containing 500 mg elemental calcium as the carbonate. Subjects continued on their current estrogen regimen, usually continuous conjugated equine estrogens (0.3- 0.625 mg/d) plus medroxyprogesterone acetate (2.5–5 mg/d). Vitamin D3 (400–800 IU/d) was given to any patient whose serum 25-hydroxyvitamin D level was less than 50 nmol/liter, either initially or at the annual checks. Patients were seen at trial entry, at 3 and 6 months, and then six monthly to 4 yr.
Serum fluoride concentrations (at least 12 h after the last MFP dose) were monitored at each visit, with the intention of maintaining levels less than 12.5 µmol/liter (6). Results were monitored by a staff member who had no contact with the participants; all other study personnel and the study subjects were blinded to treatment allocation. In 10 subjects, an MFP dose reduction was required. To maintain blinding, a dose reduction was also notified by the monitor to the study doctor looking after a randomly selected placebo-treated patient. The study was approved by the local ethics committee, and each subject gave written informed consent.
Measurements
BMD was assessed at trial entry and annually using a Lunar (Madison, WI) DPX-L dual-energy x-ray absorptiometer. Separate scans of the total body, lumbar spine in the anteroposterior projection, third lumbar vertebra in the lateral projection, proximal femur, and distal forearm were undertaken. For all lumbar spine scans, only those vertebral bodies demonstrated not to be fractured on plain radiographs were included in the analysis. Bone turnover markers were assessed using standard methods, as described previously (7)
Lateral radiographs of the thoracic and lumbar spines were performed at trial entry and annually, using a film-tube distance of 100 cm. An incident vertebral fracture was defined as a decrease in an anterior, middle, or posterior vertebral height of at least 20% and at least 4 mm.
Statistics
Data were analyzed on an intention to treat basis. Continuous variables (e.g. BMD, biochemical measurements) were analyzed using a mixed models approach to repeated measures (Proc Mixed; SAS Institute, Cary NC). Significant interaction effects were further explored using the method of Tukey to preserve an overall 5% significance level. Time to first fracture was compared between treatment and control arms using a proportional hazards model, and results are presented as the hazard ratio and 95% confidence interval. Fractures were also expressed as fractures per 1000 patient years at risk, and the incidences were compared between groups assuming a Poisson distribution. All analyses were performed using procedures of SAS version 9.1 (SAS Institute).
The study was powered to assess effects on both lumbar spine BMD and vertebral fractures. A study of this size has greater than 90% power to detect a difference in the absolute change in lumbar spine BMD between treated and control groups of at least 5%. Assessment of power to detect effects on vertebral fractures was based on the study of Riggs et al. (8), who found a fracture rate of 181 in 1000 person years in women treated with estrogen compared with 53 in 1000 person years for women receiving estrogen plus fluoride. Based on these figures, 80 subjects yield a power of 90% to detect this difference (
= 0.05) and a power of 80% to detect a halving of fracture numbers.
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Results |
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There were substantial and progressive increases in lumbar spine BMD over the duration of the study (Fig. 1). In the anteroposterior projection, the MFP group increased 22%, whereas the placebo group was only 6% above baseline at the end of the study. These changes were most marked in trabecular bone, as reflected in the assessments of the third lumbar vertebra in the lateral projection in which the MFP group increased 49% compared with a nonsignificant change of +2.5% in the placebo. In both projections, the between-groups comparisons were highly significant (P < 0.0001).
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). In the femoral neck, BMD increased 4.6% above baseline by yr 4 in the MFP group, having decreased slightly in the placebo group (time-treatment interaction, P = 0.015). In the trochanter, there was also an upward trend in those on MFP, although this was not quite significant (data not shown).
Figure 2 shows the changes in the total body scans and their major subregions. In the whole skeleton, there were significant increases in both groups, which were significantly greater in the MFP group. The trunk and legs regions were analyzed separately to determine whether fluoride was having a positive effect on both trabecular bone and cortical bone. In the trunk, the difference between MFP and placebo groups was 6.9%, whereas in the legs it was only 2.5%, although this was still significant.
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Biochemical parameters
At the end of the study, 20 subjects from each group were randomly selected for assay of bone turnover markers. These data are shown in Fig. 3 and indicate a significant stimulation of bone formation with no change in bone resorption. Total alkaline phosphatase was measured annually throughout the study and again showed a sustained effect of MFP treatment. The stimulation of bone formation was substantially attenuated at yr 4.
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). PTH levels were comparable at baseline, subsequently tended to be higher in the MFP group (Ptime x treatment = 0.06) but only reached significance at yr 3. Serum fluoride levels were maintained at approximately 7 µmol/liter in the active group.
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During follow-up, five patients assigned to placebo had new vertebral fractures, three in one patient (one in each of 3 different years), and one in each of the others. These occurred during 116 patient-years follow-up, giving a fracture rate of 60.3 per 1000 patient years. One MFP subject had a single fracture during 102 patient-years follow-up, fracture rate 9.8 per 1000 patient years. A Poisson regression gives an incidence rate ratio of 0.12 (95% confidence interval, 0.06–0.23; P < 0.01). Analysis of the time to first fracture showed a hazards ratio of 0.20 (95% confidence interval, 0.05–1.30).
Height loss tended to be greater in the placebo group (0.46 ± 0.10 cm compared with 0.24 ± 0.10 cm in the MFP group at 4 yr), but this was not significant over the whole study period (P = 0.45).
Six nonvertebral fractures occurred in the MFP group (scaphoid, wrist, hip, metatarsal, humerus, and rib) and two (hip and wrist) in those randomized to placebo (hazards ratio, 3.3; 95% confidence interval, 0.8–12.0).
Bone biopsies
All subjects were invited to undergo a transiliac bone biopsy at the end of the study, and nine placebo subjects and seven taking MFP agreed. Fifteen biopsies were suitable for quantitative histomorphometry. In the MFP subject whose biopsy was not able to be quantified, there was qualitative evidence of hyperosteoidosis. In the remaining six MFP-treated subjects, osteoid surface and osteoid volume were both above the reference ranges in four, whereas these parameters were within normal in all placebo subjects (Fig. 4). Thus, five of the MFP-treated subjects and none of the placebo-treated subjects had hyperosteoidosis (significantly different between groups, P = 0.005). Double-tetracycline labels were found in three of the MFP-treated subjects with hyperosteoidosis. In these subjects, the mineralization lag time was prolonged (94, 134, and 175 days: normal, <30 d; Osteomalacia, >100 d).
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Safety
Adverse events occurred with comparable frequencies in the placebo and MFP groups: gastrointestinal, 27 and 21%; back pain, 15 and 18%; lower limb pain, 10 and 5%, respectively. In the MFP group, three women discontinued study medication because of gastrointestinal complaints and one because of lower limb pain. In the placebo group, one woman discontinued because of a gastrointestinal complaint.
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Discussion |
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Unlike most previous studies of fluoride, the present trial has provided estrogen to both study groups. This is likely to account for the significant positive changes in BMD in the placebo group at most sites despite the fact that these women had been using estrogen for some years before the inception of the study. This provides additional evidence for the substantial long-term beneficial effects of estrogen on the skeleton. Alexandersen et al. (17) reported a similar study in which estrogen and fluoride were administered, using a factorial design. In that study, estrogen was initiated at the same time as fluoride. Again, additivity of these two interventions was demonstrated, with the MFP-treated subjects having spine BMD increments 15% higher at 2 yr than subjects receiving estrogen alone. Additivity was also demonstrable in the total body scans, but both interventions were without substantial effects in the hip and forearm. Both studies indicate that there is additivity of the effects of fluoride and estrogen, in marked contrast to the most extensively studied anabolic-antiresorptive combination, alendronate and PTH (15). However, there does appear to be additivity between PTH and estrogen (18), so the induction of resistance to anabolic therapies may not be a factor common to all antiresorptives. Because most patients with osteoporosis are treated initially with antiresorptive agents, it is important that additional studies are conducted to determine which combinations of antiresorptives and anabolic agents permit additive changes in BMD.
The changes in bone turnover markers in the present study are what would be expected with an anabolic agent, in that the three osteoblast indices showed evidence of significant stimulation, whereas there was no change in bone resorption. The effects on both formation and resorption markers are less than has been reported recently with PTH (15) but comparable with those reported by Alexandersen et al. (17) in their comparison of MFP plus estrogen with estrogen alone and by others (11, 19) assessing fluoride monotherapy. The difference between groups for all markers tended to decrease over time, which may account for the slower rate of increase in bone density later in the study. Reginster et al. (11) observed a similar phenomenon, although others have not (17, 19). The fact that it is seen in only some studies suggests that it might be related to declining compliance over time. The positive changes in a variety of indices of osteoblast function confirm that fluoride does activate osteoblast activity and is not just artifactually changing BMD as a result of changes in the crystal structure of bone.
Despite the small number of events, fracture data from the present study are in keeping with those summarized in a recent metaanalysis (20). Thus, there is a trend toward fewer vertebral fractures but a trend in the opposite direction for nonvertebral fractures. The metaanalysis suggested a relative risk of vertebral fracture of 0.87 at 2 yr and 0.90 at 4 yr, neither being significant. For nonvertebral fractures, the relative risks were 1.2 at 2 yr and 1.85 at 4 yr, the latter figure being significantly different from 1. Within this group of studies, the use of low-dose fluoride was associated with a reduced vertebral fracture risk (relative risk, 0.29), and the trials that included some women using estrogen also showed a significant vertebral fracture reduction associated with the further addition of fluoride (relative risk, 0.30). There are other data to suggest that low-dose fluoride has greater antifracture efficacy. Riggs et al. (21) reported a post hoc reanalysis of their previous study (14) in which women were initially allocated to elemental fluoride doses of 41 mg/d but, in many cases, received much lower doses because of side effects. The post hoc analysis suggested that the rapid increases in BMD associated with high doses of fluoride were also associated with increased fracture risk, whereas more modest increments in BMD were protective. Somewhat similar data have since been published by Ringe et al. (1) in which a daily elemental fluoride dose of 11 mg was compared with 20 mg/d or with placebo. Although the higher fluoride dose was associated with the biggest increases in BMD, fracture rates were lowest in the low-dose fluoride group, and pain-mobility scores reflected these trends. In contrast to the metaanalysis, the Ringe et al. study also showed significantly fewer nonvertebral fractures, with the protective effects tending to be greater in the low-dose fluoride group.
An additional recent randomized trial of slow-release sodium fluoride has been published by Rubin et al. (19). These subjects received 23 mg/d elemental fluoride together with 945 mg calcium. Surprisingly, there were no significant effects on bone density in either the spine or proximal femur, but a reduction in vertebral fracture rate was observed, with similar numbers of nonvertebral fractures in the fluoride and placebo groups. Although the study used a medium dose of fluoride, the bioavailability of the slow-release preparation is lower than that of many other preparations, and the coadministration of a substantial calcium dose is likely to have reduced fluoride absorption further. The absence of dramatic increases in BMD in this study certainly suggests that the absorbed dose of fluoride was low. Thus, this study is consistent with other recent evidence indicating that doses of fluoride less than 20 mg/d are more likely to demonstrate antifracture efficacy.
In contrast to most recent studies, the present investigation included assessment of bone histology in a subset of patients. The biopsies clearly demonstrate accumulation of osteoid in the majority of MFP-treated subjects. In two of seven, these values remained within the normal range, but, in two others, the diagnostic criteria for osteomalacia were met. These results are similar to those reported by a number of other groups (22, 23, 24), although many of the patients reported by those authors were receiving substantially higher doses of elemental fluoride. In contrast, one group has reported improvements in mineral apposition rates and connectivity, without any increases in osteoid indices (25). The accumulation of fluoride within bone results in an abnormal crystal structure on the bone surface (26) and is associated with diminished strength on biomechanical testing of bone biopsy cores (27). These adverse changes in bone strength despite increases in bone mass have been blamed for the failure of fluoride therapy to consistently reduce fracture rates. The present findings indicate that abnormal mineralization is still a problem, even when the elemental fluoride dose is as low as 20 mg/d. Therefore, it seems inappropriate to recommend the widespread use of the dosing regimen used in the current study. Rather, it would be of interest to explore the use of lower doses still, because even a much smaller increase in BMD would still represent a substantial therapeutic benefit. Indeed, Balena et al. (22) have reported that elemental fluoride doses of approximately 10 mg/d are not associated with the development of mineralization defects, and this was the approximate dose level that Ringe et al. (1) suggested was optimal in terms of fracture prevention. The present study has used MFP in the same dose as that used by Meunier et al. (10), which may account for the absence of antifracture efficacy in that trial. The high rate of abnormal histology in the present study also emphasizes that the much higher doses used in many previous studies were likely to have been associated with significant impairment of mineralization, so their failure to prevent fractures is not surprising.
Fluoride ion is a potent stimulator of osteoblast activity that is affordable and, therefore, potentially more widely available than other anabolic interventions for osteoporosis. If its therapeutic potential is to be realized, additional pilot studies of even lower fluoride doses are needed. Assessment of daily fluoride ion intakes in the region of 5–10 mg would seem an appropriate next step. The aim of future studies of fluoride should be to seek a therapeutic window that harnesses its potent anabolic effect without significant impairment of bone mineralization.
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Acknowledgments |
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Footnotes |
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Disclosure Statement: The authors have nothing to disclosure.
First Published Online April 17, 2007
Abbreviations: BMD, Bone mineral density; MFP, monofluorophosphate.
Received October 17, 2006.
Accepted April 5, 2007.
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References |
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