Fluoride Therapy For Osteoporosis Research Articles

Molecular mechanism of action of fluoride on bone cells.

Fluoride is an effective anabolic agent to increase spinal bone density by increasing bone formation, and at therapeutically relevant (i.e., micromolar) concentrations, it stimulates bone cell proliferation and activities in vitro and in vivo. However, the fluoride therapy of osteoporosis has been controversial, in large part because of a lack of consistent antifracture efficacy. However, information regarding the molecular mechanism of action of fluoride may improve its optimum and correct usage and may disclose potential targets for the development of new second generation drugs that might have a better efficacy and safety profile. Accordingly, this review will address the molecular mechanisms of the osteogenic action of fluoride. In this regard, we and other workers have proposed two competing models, both of which involve the mitogen activated protein kinase (MAPK) mitogenic signal transduction pathway. Our model involves a fluoride inhibition of a unique fluoride-sensitive phosphotyrosine phosphatase (PTP) in osteoblasts, which results in a sustained increase in the tyrosine phosphorylation level of the key signaling proteins of the MAPK mitogenic transduction pathway, leading to the potentiation of the bone cell proliferation initiated by growth factors. The competing model proposes that fluoride acts in coordination with aluminum to form fluoroaluminate, which activates a pertussis toxin-sensitive Gi/o protein on bone cell membrane, leading to an activation of cellular protein tyrosine kinases (PTKs), which in turn leads to increases in the tyrosine phosphorylation of signaling proteins of the MAPK mitogenic signal transduction pathway, ultimately leading to a stimulation of cell proliferation. A benefit of our model, but not the other model, is that it accounts for all the unique properties of the osteogenic action of fluoride. These include the low effective fluoride dose, the skeletal tissue specificity, the requirement of PTK-activating growth factors, the sensitivity to changes in medium phosphate concentration, the preference for undifferentiated osteoblasts, and the involvement of the MAPK. Unlike fluoride, the mitogenic action of fluoroaluminate is not specific for skeletal cells. Moreover, the mitogenic action of fluoroaluminate shows several important, different characteristics than that of fluoride. Thus, it is likely that our model of a fluoride-sensitive PTP represents the actual molecular mechanism of the osteogenic action of fluoride.

THE ROLE OF FLUORIDE IN THE PREVENTION OF OSTEOPOROSIS

Osteoporosis defined as low bone mass and increased susceptibility to fracture is a reflection of the sum of peak bone mass and any bone that has been lost once peak mass has been attained. Several strategies have been applied to optimize peak bone mass and to prevent bone loss. Fluoride has greatest potential as a therapy for osteoporosis once bone has been lost. It has been demonstrated both experimentally and clinically to stimulate bone formation directly and to increase bone mass in patients who already have osteoporosis. Several bone formation/stimulation therapies are under development, and some of these have reached the stage of clinical trial. None of these therapies has been as extensively studied as fluoride, and none is sufficiently advanced in development to be clinically available in the next 3 to 5 years. Fluoride therapy for osteoporosis is already performed in many countries, and approval for use in osteoporosis in the United States is pending. The first clinical trials of NaF therapy for osteoporosis were reported by Rich and Ensinck in 1961. Since then, hundreds of reports on the successes and failures of fluoride therapy have appeared in the literature. At first glance, it seems disappointing and inexplicable that, after 40 years of research, fluoride is still considered an experimental drug in the United States. One plausible explanation is that much of the early research on this drug was suboptimal, including the author's contributions. Fluoride as a naturally occurring element is difficult to patent, and this has kept major pharmaceutical companies from investing heavily in fluoride therapy despite its obvious potential. As a result, pharmacologic and pharmacokinetics studies of fluoride are limited in scope, as are phase I and phase II human toxicology and dose-finding studies. Most early studies of large doses of plain NaF were unable to demonstrate a consistent effect on fracture rate despite a consistent and dramatic effect on bone density. Once this became obvious and as new technologies for measuring bone density became available, it became equally clear that future clinical trials would have to be performed using different formulations of fluoride and lower doses. This approach has not resulted in uniformly positive clinical trials, and one must look elsewhere for answers. The most compelling explanation is that the trials have included patients with different severity of disease, suggesting that there is point in the bone loss spectrum at which even a potent bone-stimulating agent such as fluoride is ineffective. This possibility should provoke a reappraisal of the earlier negative studies: was the failure a result of the drug or of patient selection? The answer to this question is crucial, because these failures have cast a long shadow over the safety of fluoride and are contributing more to the absence of this drug from the pharmacopoeia than any other factor.

Reductions in bone strength after fluoride treatment are not reflected in tissue-level acoustic measurements.

Acoustic velocity measurements are used to estimate tissue-level bone strength after fluoride therapy for osteoporosis. However, acoustic measurements provide information about elasticity, not strength, and bone elasticity does not necessarily correlate with bone strength at a tissue level. The current study was undertaken to evaluate the effects of fluoride treatment on tissue-level acoustic velocities, and to determine the relationship between acoustic velocity and bone strength measured in the femur, femoral neck, and spine. Young adult rabbits were treated with either 0 or 100 parts per million of fluoride in their drinking water for six months. After treatment, the bones were harvested for measurement of tissue fluoride, bone strength, and acoustic properties. Acoustic velocities were measured in the femoral midshaft using an acoustic microscope with a 50 MHz transducer. Both longitudinal and transverse velocities were measured. After the initial acoustic measurements the bone specimens were treated to remove either the organic matrix or mineral, and the acoustic measurements were repeated. Fluoride treatment increased bone fluoride levels 7-8 fold and reduced all biomechanical parameters. Most notably the fracture force of the femoral neck was reduced by 25% (p < 0.005), and the fracture stress of the L-5 vertebra was reduced by 19% (p < 0.05). Fluoride treatment had no significant effect on any of the measured acoustic velocities. The elastic anisotropy of the bone was decreased by demineralization (p < 0.0001) and increased by removal of the organic matrix (p < 0.0001), but unaffected by fluoride treatment. Acoustic measurements were not correlated with bone strength in the femoral neck or femoral midshaft. There was a positive correlation between the longitudinal velocity measured in the femur and the vertebral fracture stress, but this was the only positive association between acoustic velocities and strength measurements. These data cast doubt on the utility of high frequency (>2 MHz) acoustic measurements for evaluating the efficacy of fluoride therapy, especially in the hip.

Concomitant phenytoin therapy doubles the osteogenic and densitometric effect of fluoride therapy in osteoporosis

Concomitant phenytoin therapy doubles the osteogenic and densitometric effect of fluoride therapy in osteoporosis

Spinal fractures during fluoride therapy for osteoporosis: relationship to spinal bone density.

Recent studies report that fluoride therapy for osteoporosis increases spinal bone density without improving vertebral fracture rate, challenging the notion that restoration of bone mass improves bone fragility. To further evaluate this issue, the relationship between spinal bone density and vertebral fracture rate was examined in a large number of fluoride-treated, osteoporotic patients. A retrospective assessment was made of clinical data collected from our observations of 389 osteoporotics treated with fluoride 30 +/- 8 mg/day (mean +/- SD) (equivalent to 66 +/- 17 mg NaF/day) and calcium 1500 mg/day for 28 +/- 18 months. Fracture rate and bone density were assessed in the same region of the spine (i.e., T12 through L4) using quantitative computed tomography (QCT). Spinal bone density increased with time on fluoride, but the relationship was hyperbolic (r = 0.99, p less than 0.0001; asymptote = 167 mg/cc on double-reciprocal plot), suggesting a plateau in the response. The spinal fracture rate decreased as a function of time on therapy (r = -0.83, p less than 0.01), and was inversely related to spinal bone density during fluoride therapy (r = 0.70, p less than 0.001 on arithmetic plot; r = -0.79, p less than 0.001 on semi-log plot). The subgroup of patients who responded to treatment with a significant increase in spinal bone density had a 48% reduction in spinal fracture rate compared with non-responders (p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Etidronate — Sodium fluoride therapy for osteoporosis

Etidronate — Sodium fluoride therapy for osteoporosis

Fluoride therapy for osteoporosis: A review of dose response, duration of treatment, and skeletal sites of action

Osteoporosis is a disease characterized by a reduction in bone density which predisposes to fracture after even minimal trauma. Fluoride, because it has consistently been shown to stimulate bone formation and increase trabecular bone density, has been widely studied for the treatment of osteoporosis. The article focuses on the dose response, duration of treatment, and skeletal sites of action of fluoride; we also include comments on the effect of fluoride on vertebral and appendicular fracture rates. The skeletal response to fluoride doses, ranging from 15 to 43 mg elemental fluoride per day, included a linear increase in spinal bone density at an average rate of 1.25 +/- 0.91 mg/cm3 per month. The rate of increase in spinal bone density was related to the dose of fluoride (r = 0.34, P less than 0.03). Spinal bone density had increased above the fracture threshold in 44% of patients treated with fluoride for 32 +/- 10 months. The time required to achieve this goal was, however, influenced by the pretreatment spinal bone density and interpatient variation in response to fluoride treatment. Patients whose spinal bone density remained below the fracture threshold had lower pretreatment bone densities and/or slower rates of increase in spinal bone density (P less than 0.001). The osteogenic effect of fluoride was not limited to the spine. After 2 years of fluoride therapy, we found bone density in the femoral condyle (measured by QCT) to have increased by 13 +/- 2.6 mg/cm3 (n = 38, P less than 0.001); bone density in the hip (measured by DPA) was increased by 0.0261 +/- 0.015 g/cm2 (n = 55, P less than 0.025).(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Fragility of the Peripheral Skeleton During Fluoride Therapy for Osteoporosis

Bone fragility during fluoride therapy for osteoporosis was observed in 24 (37.5%) of 64 patients treated with sodium fluoride, calcium, and vitamin D for 2.5 years who developed episodes of lower-limb pain during treatment. Eighteen (28%) of these patients had clinical and roentgenographic features of 41 stress fractures and 12 new spinal fractures. There were 26 periarticular, six femoral neck, three pubic rami, three tibia and fibula, one greater trochanter, and two subtrochanteric fractures. Vertebral fractures appeared first, then periarticular, then femoral neck, and lastly long-bone shaft fractures. All fractures were spontaneous in onset. The peripheral fracture rate during treatment was three times that in untreated osteoporosis. Roentgenograms must be repeated at intervals of three to four weeks before the pathognomonic callus becomes visible, and the diagnosis can be made. Trabecular stress fractures tend to occur in the first 18 months of treatment, and cortical stress fractures occur after 30 months of therapy.

90072368 The effect of prolonged fluoride therapy for osteoporosis: Bone composition and histology

90072368 The effect of prolonged fluoride therapy for osteoporosis: Bone composition and histology

Fluoride Therapy and Parathyroid Hormone Activity in Osteoporosis

1. To determine the relationships between parathyroid hormone activity and long-term sodium fluoride therapy in osteoporosis, cytochemical bioassays (for biologically active parathyroid hormone) were performed in 22 osteoporotic control patients and in 18 patients after 15 +/- 10 months of treatment (60 mg of sodium fluoride daily). Ten patients were studied longitudinally by repeated metabolic balances and were therefore common to both groups. All patients were receiving mineral supplements. 2. Cross-sectional data showed a fourfold mean increase in biologically active parathyroid hormone on fluoride treatment (P less than 0.005) together with a 51% increase in serum alkaline phosphatase (P less than 0.005). Longitudinal data showed, in addition, a significant increase in the calcium balance of 2.4 +/- 1.2 (SEM) mmol daily (P less than 0.05) and the development of a positive phosphorus balance (P less than 0.02). 3. Fluoride-treated patients were then analysed in two groups according to the level of biologically active parathyroid hormone. Thirty-two per cent of values were above the upper limit of normal (18 pg/ml). The mean serum alkaline phosphatase level in this group showed no elevation above that of the control patients, the overall rise being accounted for entirely by patients with normal levels of biologically active parathyroid hormone. High levels of biologically active parathyroid hormone were also associated with relative hypophosphataemia (P less than 0.01), relative hypercalciuria (P less than 0.05) and an increased urine/faecal calcium ratio (P less than 0.025). 4. Results show that long-term fluoride and calcium therapy increase biologically active parathyroid hormone in osteoporosis and that excessive parathyroid hormone activity may account for certain features of the refractory state.

Journal of Bone and Mineral Research

The aim of the study was to investigate the usefulness of urinary fluoride excretion in evaluating fluoride therapy. In a prospective study, 35 patients with osteoporosis were treated for about 44 months with a mean dosage of 31.4 mg fluoride ion per day. Urinary fluoride excretion and serum alkaline phosphatase activity were measured at 3-month intervals. Bone mineral content (BMC) was measured in L2-L4 with dual-photon absorptiometer. The mean number of BMC measurements was 5.7 per patient. The interindividual reproducibility for measurements in 10 patients was 2.1%. For each individual, the regression coefficient of BMC for the period of treatment was calculated. Responders were defined as those who had a positive value and nonresponders had 0 or a negative value. The percentage responders was 83%. Between responders and nonresponders no differences were found for age, fluoride dosage, duration of treatment, or changes in serum alkaline phosphatase activity. Urinary fluoride excretion was higher in responders than in nonresponders (p less than 0.001) and a positive correlation (p less than 0.001) was obtained between the changes in BMC and urinary fluoride excretion. In the responders, 90% had a urinary fluoride excretion greater than 8 mg/24 h. All nonresponders had a urinary fluoride excretion less than 8 mg/24 h. Urinary fluoride excretion is a valuable predictor of BMC response during fluoride therapy for osteoporosis.

Journal of Bone and Mineral Research

We attempted to identify risk factors for the development of lower limb stress fractures during fluoride therapy for osteoporosis (OP). We compared 18 patients who developed 41 such fractures (26 periarticular, 6 femoral neck, 5 long bone shaft, 1 greater trochanter and 3 pubic rami fractures) during fluoride therapy, with 24 similarly treated patients who did not develop stress fractures. Treatment consisted of sodium fluoride 0.99 mg/kg per day, elemental calcium 1 g/day, and vitamin D. We obtained a previous fracture history, annual radiographs of the spine (fractures), hands (metacarpal cortical index, MCI) and pelvis (Singh index, femoral cortical index), three-monthly serum fluoride and alkaline phosphatase levels, and pretreatment transiliac bone biopsies (routine histomorphometry). The stress fracture group was found to have, before treatment: lower MCI (p less than 0.05), lower trabecular bone volume (p less than 0.05), a lower number of trabeculae (p less than 0.05), greater trabecular separation (p less than 0.05), less extensive eroded surfaces (p less than 0.05), a lower double/single tetracycline label ratio (p less than 0.05); and during treatment: more new spinal fractures (p less than 0.05) and higher serum alkaline phosphatase levels (p less than 0.01). We conclude that stress fracture patients had more severe trabecular and cortical OP and possibly a poorer bone-forming capacity before therapy than patients without stress fractures. We suspect that fluoride therapy may temporarily further weaken bone and so lead to stress fractures in severely osteoporotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Bone and Mineral Research

Eighty one women with vertebral osteoporosis were treated for up to 2 years with fluoride administered either as monofluorophosphate (MFP, 200 mg/day, i.e., 26.4 mg fluoride-ion) or sodium fluoride (NaF, 50 mg/day, i.e., 22.6 mg fluoride-ion). All patients received calcium supplementation (1 g of Ca2+/day) taken apart from NaF and in the same tablet for MFP. Despite almost similar fluoride dosage of both regimens, the early increase in the bone mineral density (BMD) of the lumbar spine was higher with MFP than with NaF, reaching 11% and 4%, respectively, at 1 year (p = 0.007), and 21% and 6%, respectively, at 18 months (p less than 0.001). The incidence of lower extremity pain syndrome related to benign stress microfractures was also higher with MFP than with NaF (35% and 15%, respectively, p less than 0.01). Urinary fluoride levels were higher in the MFP than in the NaF group (9.6 +/- 3.5 vs. 6.8 +/- 3.4 at one year, p = 0.003), suggesting that this difference in efficacy and tolerance is related to a better bioavailability of fluoride provided by MFP than by NaF. The occurrence of a stress microfracture could not be predicted by any clinical, biochemical, or densitometric parameter before treatment, but patients presenting with a stress microfracture during the course of the treatment had a higher gain in bone mass than those without stress fractures (at 1 yr+11 vs. +5%, p = 0.03 and at 18 months +18 vs. +6.9%, p less than 0.02). In conclusion, there is a clear correlation between the efficacy and the occurrence of side effects of fluoride therapy in osteoporosis.(ABSTRACT TRUNCATED AT 250 WORDS)

Journal of Bone and Mineral Research

This report reviews some aspects of fluoride pharmacokinetics in relation to the treatment of osteoporosis. The bioavailability of conventional plain NaF tablets has been shown to be close to 100, for sustained-release NaF tablets close to 90%, and for enteric-coated NaF tablets 65%. The simultaneous intake of food and/or calcium tablets reduces the bioavailability by 30 to 40%. Fluoride renal clearance is influenced by both urinary pH and flow and the clinical consequences of this is discussed. Studies on plasma kinetics of fluoride during chronic fluoride intake suggests that a plasma sample taken at mid-dosage intervals will give reproducible "mean steady-state" levels. It is suggested that improvements of the clinical benefit of fluoride therapy in osteoporosis might be achieved if the dosage regimen were based on the pharmacokinetic properties of the fluoride preparation used as well as plasma fluoride monitoring.

Journal of Bone and Mineral Research

Since osteoporosis is a disease of diminished bone density, and since osteoporotic fractures occur most commonly in the spine, the ideal therapeutic agent for osteoporosis is one which can increase spinal bone density and thereby reduce the risk for vertebral fractures. In the current study we sought to examine the effect of fluoride therapy on spinal bone density utilizing quantitative computed tomography to measure changes in vertebral trabecular bone density during treatment with fluoride. A group of 61 postmenopausal osteoporotic females, aged 70 +/- 9 years, were treated with 34 +/- 7 mg elemental fluoride/day (equivalent to 75 +/- 15 mg NaF/day) and 1500 mg calcium/day for 19 +/- 6 months. Spinal bone density was increased within the first 6 months of fluoride therapy by 42% or 10 +/- 13 mg/cm3 (p less than 0.001) and continued to increased throughout 2 years of observation. The skeletal response to fluoride therapy was also associated with an early increase in serum alkaline phosphatase activity (p less than 0.001), which was related to the increase in spinal bone density (r = .58, p less than 0.001). Large interpatient variation was observed in the spinal bone response to fluoride therapy, which was not explained by variations in the pretreatment spinal bone density (r = .04), age of the patient (r = .15), or dose of fluoride (r = .16). Results from these studies demonstrate (1) the therapeutic value of fluoride to increase trabecular bone density linearly for 2 years in the osteoporotic spine and (2) the clinical value of measuring spinal bone density and/or serum alkaline phosphatase activity as indices of the skeletal response to fluoride.

Assessment of osteoporotic spine deformity

For the objective assessment of the severity and progression of osteoporotic deformities of the spine, a mathematical model has been developed which permits evaluation of a single set of radiographs of the spine without reference to absolute values of vertebral height. The model was based on measurements of anterior, central and posterior heights of the vertebrae Th4 to L5 of 50 subjects, aged 20 to 50 years, without a history or radiologic signs of osteoporosis or other metabolic bone disease and without traumatic deformities. The model follows a simple sinusoidal function which describes the general form of the spine, adapted to the individual's height and build. A spine fracture index (SFI) is produced and the method allows calculation of the total number of vertebral deforming events (VDE), manner. The method has been used prospectively in 178 spine radiographs of 109 subjects (60 healthy early postmenopausal women and 49 with osteoporosis). Sensitivity and specificity of SFI in identifying osteoporotic patients were 94 and 88% respectively. In all 109 persons, densitometry of the spine was performed by dual photon absorptiometry at the same time. In the osteoporotic patients the examination was repeated once or twice during fluoride therapy for osteoporosis. The SFI and the total score of VDE and VDS correlated significantly with lumbar bone mineral content (r = -0.38 P less than 0.001). The method offers the advantage of being objective, not dependent on projection errors, and adaptable to the shape of the individual spine.

Iliac bone biopsies at the time of periarticular stress fractures during fluoride therapy: Comparison with pretreatment biopsies

We attempted to establish whether systemic changes in trabecular bone explain the development of stress fractures in the lower limbs during fluoride therapy for osteoporosis. To this end we compared transiliac bone biopsies obtained before treatment with those taken around the time of stress fractures after 14.3 +/- 10.9 (SD) months of therapy in six patients (group A). Biopsies from a comparable group of six patients without stress fractures at the time of the second biopsy (after 11.9 +/- 2.7 months of treatment) served for comparison (group B). The biopsies were processed undecalcified and examined by routine histomorphometry. The second biopsies did not show any significant improvement in mean bone volume or trabecular architecture. Although the second biopsies in group A had increased erosion surfaces (p less than 0.05) and greater osteoid volume (p less than 0.05), group B biopsies showed no difference in erosion surfaces but an increase in all osteoid parameters: osteoid volume (p less than 0.05), osteoid surface (p less than 0.05), and osteoid seam thickness (p less than 0.01). We reached the following conclusions: (1) the combination of increased erosion and replacement of removed bone by as yet unmineralized osteoid in the stress fracture group must have weakened bone and allowed the development of stress fractures. (2) Stress fracture patients may have mounted a less vigorous osteoblast response to fluoride than non-stress fracture patients. Under these conditions microfractures are likely to heal poorly and propagate to develop into full stress fractures. (3) Renal failure is a contraindication to fluoride therapy.

P9. Significance of raised parathyroid hormone activity during fluoride therapy in osteoporosis

P9. Significance of raised parathyroid hormone activity during fluoride therapy in osteoporosis

The effect of prolonged fluoride therapy for osteoporosis: Bone composition and histology

To examine the long-term effects of fluoride therapy in osteoporosis, we obtained iliac crest biopsies from 11 osteoporotic patients 6 to 12 years after they had started fluoride therapy. Although basal biopsies were not obtained, nine subjects had been biopsied 4 years prior to the second biopsy. In addition, 4 subjects had stopped fluoride therapy prior to the second biopsy. Biopsy samples were divided and analyzed: (a) histomorphometrically for bone formation and mineralization; and (b) for mineral content. Parameters of bone formation were increased in the first biopsy of all patients; they remained elevated in the second biopsy of subjects still receiving fluoride, but decreased to normal values in subjects who stopped fluoride therapy. Parameters of mineralization (i.e., osteoid width and osteocytic osteoid) were elevated in the first biopsy, but had decreased in the second biopsy whether fluoride was stopped or not. There was no woven bone in these biopsies. Bone mineral content, whether measured as density or by summation of the individual ions (% mineral), was higher than normal in all subjects, whether or not they were still receiving fluoride. These results suggest that prolonged fluoride therapy of osteoporosis continues to stimulate bone formation, but does not cause a progressive mineralization defect. Mineral content is acutely increased following fluoride therapy, and persists after therapy is discontinued.

Fluoride therapy in osteoporosis: Acute effects on parathyroid and mineral homoeostasis

1. Acute metabolic effects of sodium fluoride therapy were analysed among 41 osteoporotic patients already receiving large calcium supplements, 33 of whom underwent simultaneous metabolic balance studies. 2. Mean serum calcium fell transiently within 24-48 h by 0.03 +/- 0.07 (SD) mmol/l (P less than 0.01) and phosphorus by 0.06 +/- 0.08 (SD) mmol/l (P less than 0.001). In a subgroup, ionized calcium fell and biologically active parathyroid hormone (bio-PTH) rose more than fivefold (P less than 0.01). Urine calcium rose after an insignificant fall. 3. Pretreatment calcium and phosphorus balances were significantly positive and did not change overall during the first 8 days of treatment. However, on analysing balances in two groups relative to serum changes, in patients whose serum levels changed least sodium fluoride increased faecal calcium (P less than 0.025) and phosphorus (P less than 0.01) and reduced calcium balance (P less than 0.01), giving a mean balance difference between the two groups of 2.1 mmol daily (P less than 0.001). 4. Very small changes in serum levels therefore indicate well-marked metabolic responses: sodium fluoride acutely stimulates bio-PTH activity and must also enhance mineral uptake from circulation into tissue(s). By separate and opposing action(s) it inhibits intestinal calcium and phosphorus absorption, predominantly in those whose serum levels remain stable. All these effects may be relevant to long-term therapeutic results.