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Bone remodeling disorders have been identified as potential candidates for the etiology underlying some forms of otologic disease. Here, four clinical cases are presented to demonstrate a novel approach to tinnitus management that focuses on two fundamental etiologic bases. First, is the effect of bone remodeling abnormalities of the otic capsule and second, the effect of blood sugar and insulin abnormalities upon the function of the inner ear and self-reports of tinnitus. This report presents the effect of treatment directed at bone remodeling abnormalities of the otic capsule and abnormalities of blood sugar and insulin. The treatment effects led to a substantial reduction in subjective tinnitus. These findings suggest a potential convergence between bone pathophysiology and some forms of tinnitus.

Background: Osteoporosis is a frequent complication in patients with inflammatory bowel disease. Recent studies have shown bisphosphonates to considerably reduce fracture risk in patients with osteoporosis, and preventing fractures with bisphosphonates has been reported to be cost effective in older populations. However, no studies of the cost effectiveness of these agents in preventing fractures in patients with inflammatory bowel disease are available., Objective: To investigate the cost effectiveness of the bisphosphonate ibandronate combined with calcium/colecalciferol ('ibandronate') in patients with osteopenia or osteoporosis due to inflammatory bowel disease in Germany. Treatment strategies used for comparison were sodium fluoride combined with calcium/colecalciferol ('fluoride') and calcium/colecalciferol ('calcium') alone., Study Design and Methods: A cost-utility analysis was conducted using data from a randomized controlled trial (RCT). Changes in bone mineral density (BMD) were adjusted and predicted for a standardized population receiving each respective treatment. A Markov model was developed, with probabilities of transition to fracture states consisting of BMD-dependent and -independent components. The BMD-dependent component was assessed using predicted change in BMD from the RCT. The independent component captured differences in bone quality and micro-architecture resulting from prevalent fractures or treatment with anti-resorptive drugs. The analysis was conducted for a population with a mean age of the RCT patients (women aged 36 years, men aged 38 years) with osteopenia (T-score about -2.0 at baseline), a population of the same age with osteoporosis (T-score of -3.0 at baseline) and for an older population (both sexes aged 65 years) with osteoporosis (T-score of -3.0). Outcomes were measured as costs per QALY gained from a societal perspective. The treatment duration in the RCT was 42 months. A 5-year period was assumed to follow, during which the treatment effects linearly declined to 0. The simulation time was 10 years. Prices for medication and treatment were presented as year 2004 values; costs and effects were discounted at 5%. To test the robustness of the results, univariate and probabilistic sensitivity analyses (Monte Carlo simulation) were conducted., Results: The calcium strategy dominated the fluoride strategy. When the ibandronate strategy was compared with the calcium strategy, the base-case cost-effectiveness ratios (costs per QALY gained) were between euro 407 375 for an older female population with osteoporosis and euro 6 516 345 for a younger female population with osteopenia. Univariate sensitivity analyses resulted in variations between 4% of base-case results and dominance of calcium. In Monte Carlo simulations, conducted for the various populations, the probability of an ICER of ibandronate below euro 50 000 per QALY was never greater than 20.2%., Conclusion: The ibandronate strategy is unlikely to be considered cost effective by decision makers in men or women with characteristics of those in the target population of the RCT, or in older populations with osteoporosis.

Bone is a complex organ which contains an organic matrix which serves as scaffolding, includes mineral as calcium distributed in a pattern providing structure and serves as an ion reservoir for the body. Throughout life it dynamically changes in response to changes in activity, body mass, and weight bearing. It is important to define patients at risk for bone loss, since accrued bone loss leading to osteoporosis in the older population of both men and women is unacceptable. There are many different therapies including biphosphonates which can decrease loss of bone and decrease fracture risk in patients who already have had sustained a fracture. Newer therapies such as parathyroid hormone may improve the fracture risk even more than biphosphonates over a shorter period of time.

Osteoporosis is one of the most important problems in developed societies. Unfortunately, all drugs available nowadays on the market exhibit antiresorptive action bringing only moderate benefits to patients suffering from this disease. For the last few years, the number of studies on the suggested use of anabolic therapy in the treatment of osteoporosis has been growing up. In the present study we describe in details sodium fluoride, 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins), growth hormone, insulin-like growth factor I, and parathormone and its analogues, describing their mechanism of action and adverse effects. We also show the results of experimental studies and clinical trials in which the mentioned drugs were used. On the basis of available results we are trying to establish the exact position of anabolic agents in pharmacotherapy of osteoporosis.

Objective: Data from cell culture experiments suggest that local growth factors (GFs) may mediate the effects of estrogens, calcitonin or fluor ions on the skeleton. To assess the in vivo relevance of the in vitro reports, the effect of fluor salts, hormone replacement therapy (HRT) and calcitonin on the concentrations of IGF-I, IGF-II and transforming growth factor (TGF)-beta 1 in bone matrix extracts from osteoporotic patients was evaluated., Design: Iliac crest bone biopsies were obtained from 170 patients (76 men and 94 women) with primary osteoporosis aged 55.5+/-0.8 Years., Methods: Bone matrix extraction was performed based on a guanidine-HCl/ethylendiamine-tetra-acetic acid method., Results: In comparison with age- and body mass index (BMI)-matched controls, no influence of long-term therapy with fluor ions (n=41) or calcitonin (n=16) on the bone matrix concentration of GFs was noticed. Postmenopausal women with osteoporosis on HRT (n=39) had lower skeletal IGF-I but not IGF-II levels as compared with age- and BMI-matched non-users. However, the lower rate of bone turnover in women with HRT may account for this difference, since the significance was lost after adjustment for alkaline phosphatase. Likewise, a tendency for lower TGF-beta 1 levels was observed in HRT users as compared with non-users but was lost after adjustment for bone turnover. None of the therapies influenced the serum levels of GFs when patients receiving continuous therapy for at least 1 Year before bone biopsy were considered., Conclusions: Our data suggest no direct effect of fluor therapy on skeletal GFs levels. At the concentrations used, neither HRT nor calcitonin appeared to exert any significant influence on serum or bone matrix GF levels.

Osteoporosis is a frequent complication in the course of various gastrointestinal disorders. Since its pathogenesis is complex, and incompletely understood in comparison to the well-known pathomechanism of postmenopausal osteoporosis, adequate management is difficult. We first summarize those therapeutic options which have strong evidence in postmenopausal osteoporosis and, thereafter, we review those in the context of different gastrointestinal diseases. Treatment of the underlying intestinal disorder seems to be most important to normalise altered bone metabolism and to prevent osteoporosis in patients with coeliac disease. In patients with osteoporosis associated with Crohn's disease, various treatment strategies (such as vitamin D, sodium fluoride, bisphosphonates) are discussed. In contrast to postmenopausal osteoporosis, interventional studies in secondary osteoporosis are often limited by the small study population and data about the efficacy of any treatment in prevention of fractures are therefore lacking. Well-conducted, controlled studies with the endpoint of preventing fractures are therefore required to optimise the treatment of osteoporosis in these patients.

Background: Osteoporosis is a frequent complication in Crohn's disease. Although the efficacy of both sodium fluoride and aminobisphosphonates in postmenopausal osteoporosis has been investigated in long-term therapy studies, no long-term results are available regarding the effect of these agents in the management of osteoporosis in patients with Crohn's disease., Methods: Eighty-four patients with Crohn's disease and pathological bone mineral density findings were randomized to receive either vitamin D3 (1000 IU) and calcium citrate (800 mg) daily (group A) or sodium fluoride (25 mg b.d., group B) or intravenous ibandronate (1 mg every 3 months, group C) in addition to daily calcium/vitamin D substitution. On admission to the study and after 12 and 27 months, patients underwent dual-energy X-ray absorptiometry and radiological examination of the spine., Results: Sixty-eight patients completed the 1-year observation period and were available for the intention-to-treat analysis. No new vertebral fractures were diagnosed. In group A, lumbar bone density increased by 2.6% (P = 0.066, N.S.), in group B by 5.7% (P = 0.003) and in group C by 5.4% (P = 0.003). Therapy with sodium fluoride was associated with an increase in osteocalcin (N.S.), whereas administration of ibandronate was associated with a decrease in the resorption parameter, carboxy-terminal cross-linked type-I collagen telopeptide (P < 0.05). Both sodium fluoride and ibandronate resulted in significant decreases in the serum concentration of osteoprotegerin after 9 months (P < 0.001)., Conclusions: The findings of the present study show that both sodium fluoride and ibandronate are effective in combination with calcium and vitamin D substitution in the management of osteopenia and osteoporosis in patients with Crohn's disease. Both agents are safe and well tolerated, and induce continuous increases in lumbar bone density.

Osteoporosis is a silent disease that affects 10 million Americans; 80% of those affected are women. Although the disease is more common in postmenopausal Caucasian women, all ages and races are at risk. Osteoporosis can be a debilitating disease that can cause pain, fractures, depression, and social withdrawal. Signs of osteoporosis include kyphosis, loss of height, and protrusion of the abdomen. Because symptoms generally do not occur until after the disease has progressed, clinicians should include osteoporosis screening and preventative education as part of the regular gynecologic care. Diagnosis is typically made by a dual energy x-ray absorptiometry (DEXA) scan. Treatment consists of dietary and lifestyle changes, along with pharmacologic intervention. Although hormone therapy has been shown to be effective in preventing osteoporosis, the risks of long-term treatment with HRT are discussed. The following effective treatment options for women who have been diagnosed with the disease are discussed: bisphosphonates, calcitonin, and selective estrogen receptor modulators (SERMs). Because midwives regularly care for women of all ages, they are ideal candidates to provide women with preventative education, screening, counseling, and treatment.

Purpose: To provide indications for currently approved treatments and future options for male osteoporosis, based on the pathogenetic mechanisms of bone loss in the male sex., Design: Review of the most significant data reported in the literature., Results: Unhealthy lifestyle habits should be modified. Testosterone replacement is indicated only in patients with diagnosis of hypogonadism. Based on the demonstrated pathogenetic role of estrogen lack in bone loss in men, either low doses of this hormone or selective androgen receptor modulators have been proposed for the treatment of male osteoporosis. Bisphosphonates are the only medications approved by Food and Drug Administration for idiopathic and glucocorticoid-induced osteoporosis in men. As far as anabolic treatments are concerned, there is not agreement on clinical utility of sodium fluoride. Short-term treatment with parathyroid hormone (PTH) seems to be safe and effective in patients with idiopathic osteoporosis, due to its anabolic action. Therapeutic use of growth hormone (GH) and insulin-like growth factor type I (IGF-I), both considered as potential anabolic agents, is still limited because of the high incidence of side effects and relatively transient efficacy, particularly of IGF-I., Conclusions: Treatments should be selected on the basis of anti-fracture efficacy of various medications, which has been demonstrated so far only for alendronate and risedronate. Although anabolic agents produce noticeable increase of bone mineral density, is still debated if they also reduce fracture incidence in males with osteoporosis.

All currently available, approved therapies for osteoporosis inhibit bone resorption. By acting at this site in the bone remodeling cycle, estrogens, selective estrogen receptor modulators, calcitonin, and the bisphosphonates all have the capacity to increase bone mineral density and to reduce the risk of new fractures. There can be no doubt that these agents have had an enormous impact on our diagnostic and therapeutic approach to osteoporosis. Despite their great value, the antiresorptives are generally not associated with dramatic increases in bone mass, and their action to reduce fracture risk, although highly significant, is rarely more than 50% of the baseline risk. Another approach is anabolic therapy, in which bone formation is directly stimulated. In this review we will summarize the anabolic agents that have been studied and present a current view of their current standing. Fluoride, GH, insulin-like growth factor I, the statins, and PTH will be reviewed. Although still in development, approaches to combination therapy with antiresorptives and anabolic agents are also promising.

In general, bone loss from glucocorticoid treatment occurs rapidly within the first 6 months of therapy. Glucocorticoids alter bone metabolism by multiple pathways; however, the bone loss is greatest in areas rich in trabecular bone. Preventive measures should be initiated early. It is the author's opinion that all subjects initiating treatment with prednisone at 7.5 mg or greater require calcium supplementation (diet plus supplement) at a dose of 1500 mg and vitamin D at a dose of 400 to 800 IU/d. If the patient is going to remain on this dose of glucocorticoid for more than 4 weeks, an antiresorptive agent should be started (e.g., estrogen, bisphosphonate, raloxifene). If a patient has established osteoporosis and is either initiating glucocorticoid therapy or is chronically treated with prednisone at 5 mg d or greater in addition to calcium and vitamin D supplementation, a potent antiresorptive agent (bisphosphonate) should be started. A bone mineral density measurement of either the lumbar spine or the hip may be helpful is assessing an individual's risk of osteoporosis, may improve compliance with treatment, and can be used to monitor the efficacy of the prescribed therapy. There is no reason to withhold treatment for glucocorticoid-induced bone loss until a bone mass measurement is taken, however. In motivated patients, a weight-bearing and resistance exercise program should be prescribed to help retain muscle strength and prevent depression. If hypercalciuria develops with glucocorticoid use, either thiazide diuretics or sodium restriction may be helpful. In patients who continue to lose bone or experience fracture's despite antiresorptive therapy while on glucocorticoids, bone-building anabolic agents (e.g., hPTH 1-34 or PTH 1-84) may be available someday soon.

Osteoporosis is not a significant problem in the majority of patients with primary biliary cirrhosis (PBC). However, substantial bone-related morbidity may occur in patients with advanced disease, in particular after liver transplantation. The cause of osteoporosis in PBC is multifactorial, and pathophysiological mechanisms specifically related to PBC have not been defined. In general, the principles of management followed in post-menopausal osteoporosis also apply in chronic liver disease. Dual energy X-ray absorptiometry is currently the method of choice for monitoring bone mineral density. Avoidance of conditions with potential negative effects on bone mass, and maintaining adequate serum vitamin D levels and calcium intake form the cornerstone in preventing osteoporosis. Bisphosphonates are the most logical choice when specific medical treatment of PBC-associated osteoporosis is indicated, as well as for preventing bone loss during glucocorticoid treatment and after liver transplantation. Recent studies suggest that active vitamin D analogues are effective alternatives in the post-transplant setting., (Copyright 2000 Harcourt Publishers Ltd.)

As the population ages, fragility fractures grow in importance as a public health problem. The principal goal of osteoporosis therapy is primary and secondary fracture prevention. A growing choice of therapies is now available for the treatment of osteoporosis. In this article, we review their efficacy using fracture prevention as an end point. The considerable heterogeneity among studies with regard to patient age, past fracture history, fracture site, and analytical methods precludes the possibility of performing a meaningful meta-analysis. Fracture outcomes have been reported in clinical trials with calcium supplementation, vitamin D supplementation, estrogen replacement therapy (ERT), calcitonin, etidronate, alendronate, sodium fluoride (NaF), parathyroid hormone (PTH), and raloxifene. Compelling evidence for fracture prevention has been provided for calcium and vitamin D supplementation and alendronate treatment. Evidence of fracture prevention exists for ERT, raloxifene, calcitonin, etidronate, and PTH. Data on NaF are inconsistent. Across agents, there is a trend toward greater efficacy for patients at greatest risk of fracture.

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.

We compared initial and final bone histomorphometric findings in 66 osteoporotic patients treated with sodium fluoride (NaF) according to three regimens, and in 7 osteoporotic patients who did not receive NaF. Fourteen patients received continuous NaF 75 mg/day (high-dose) with calcium 1500 mg/day for a mean of 41 months. Twenty-six patients received continuous NaF 50 mg/day (low-dose) with calcium 2000 mg/day for a mean of 15 months, either with (10 patients) or without (16 patients) vitamin D. Twenty-six patients received cyclical low-dose NaF, alternating with vitamin D, for a mean of 15 months and a total treatment duration of 28 months, of whom 14 were and 12 were not on NaF at the time of the second biopsy. Disregarding differences between regimens, there were significant increases in total and mineralized bone volume and trabecular thickness and nonsignificant decreases in these measurements in the control group. Fluoride-induced bone formation was exclusively appositional with no evidence for the creation of new trabeculae. The effect of low-dose NaF on bone structure was the same when the same total dose was given continuously or intermittently, and when the patient was or was not taking vitamin D. The increases in total and mineralized bone volume but not trabecular thickness were greater with high-dose than with low-dose NaF. Low-dose NaF caused modest but significant increases in all osteoid indices, and modest but significant declines in adjusted apposition rate and osteoid maturation rate and no change in bone formation rate. With high-dose NaF, the increase in BV/TV was greater but all indices of osteoid accumulation were much higher and all indices of impaired osteoblast function and mineralization were much lower, and 12 of 14 patients had some form of osteomalacia. This occurred also in 3 of 30 patients treated with low-dose NaF who were not taking vitamin D; the mean increase in osteoid thickness was significantly greater in these patients than in 22 low-dose patients who were taking vitamin D. We conclude: (1) The inconsistent effect of NaF in increasing bone strength is partly due to failure to restore connectivity in patients with severe bone loss and partly due to substantial osteoid accumulation. (2) Even low-dose NaF causes impaired osteoblast function, but this is much greater with high-dose prolonged therapy. (3) There is an unexplained discrepancy between the increase in bone formation implied by increases in spinal bone mineral and the lack of increase in bone formation measured histomorphometrically. (4) Defective mineralization is more closely related to the total cumulative dose of NaF than to the duration of treatment, and with low-dose treatment may be preventable by vitamin D. (5) Future clinical trials should be carried out with smaller doses of NaF and before there has been substantial loss of horizontal trabeculae in the spine.

Estrogen replacement therapy (ERT) after menopause prevents the development of osteoporosis and reduces the risk of fracture. Other potential benefits are cardioprotection--probably related to the effects of estrogen on lipid profile and fibrinogen levels--and a delay in the onset of Alzheimer's disease and perhaps amelioration of the disease. ERT, however, increases the risk of endometriosis and endometrial cancer unless given with a progestin for at least 10 days per menstrual cycle. It also results in a small but real increase in breast cancer. Alendronate, a bisphosphonate, is the first serious competitor of conjugated equine estrogen for the treatment of osteoporosis. Nearing FDA approval are so-called designer estrogens (e.g., raloxifene), which may selectively prevent osteoporosis with little or no effects on endometrial and breast tissue.

Osteoporosis is a metabolic bone disease characterized by an increased risk of fractures, especially hip, wrist and vertebral fractures. Osteoporosis occurs more commonly in women because of a bone loss after menopause. Post menopausal bone loss is prevented by estrogen replacement therapy. An adequate calcium intake remains important. Sodium fluoride and biphosphonates are the main other treatments of osteoporosis.

Objective: To investigate whether administration of sodium fluoride (NaF) in addition to cyclical etidronate has a positive effect on bone mineral density (BMD) in patients with established osteoporosis during continued treatment with corticosteroids., Patients and Methods: 47 patients who were receiving treatment with corticosteroids were included in a two year randomised, double blind, placebo controlled trial. Established osteoporosis was defined as a history of a peripheral fracture or a vertebral deformity, or both, on a radiograph. All patients were treated with cyclical etidronate, calcium, and either NaF (25 twice daily) or placebo. Vitamin D was supplemented in the case of a low serum 25 (OH) vitamin D concentration. BMD of the lumbar spine and hips was measured at baseline and at 6, 12, 18, and 24 months., Results: After two years of treatment, the BMD of the lumbar spine in the etidronate/NaF group had increased by +9.3% (95% confidence intervals (CI): +2.3% to +16.2%, p < 0.01), while the BMD in the etidronate/placebo group was unchanged: +0.3% (95% CI: -2.2% to +2.8%). The difference in the change in BMD between groups was +8.9% (95% CI: +1.9% to +16.0%, p < 0.01). For the hips, no significant changes in BMD were observed in the etidronate/NaF group after two years: -2.5% (95% CI: -6.8% to +1.8%); in the etidronate/placebo group BMD had significantly decreased: -4.0% (95% CI: -6.6% to -1.4%; p < 0.01). The difference between the groups was not significant: +1.5% (95% CI: -3.4% to +6.4%). No significant differences in number of vertebral deformities and peripheral fractures were observed between the two groups., Conclusion: The effect of combination treatment with NaF and etidronate on the BMD of the lumbar spine in corticosteroid treated patients with established osteoporosis is superior to that of etidronate alone.

In a 5-year observational study we have compared sodium fluoride (NaF) with different treatments commonly used in the treatment of osteoporosis: calcium, estrogens, androgens, and calcitonin, referred to as non-NaF. We have looked at the incidence of vertebral and nonvertebral fractures. At baseline, the NaF group, consisting of 125 patients (89% females) aged 65 +/- 10 (X +/- SE) had more crush fractures (P < 0.0001) and more months since menopause (P = 0.004) than the non-NaF group, consisting of 127 patients (90% females) aged 63 +/- 10. Fractures were evaluated by X-ray. The entire follow-up of patients treated with NaF accounted for 361 person-years, of whom 43 patients suffered one or more new vertebral fractures (68 vertebral fractures in total) and 18 patients suffered one or more new nonvertebral fractures (22 complete peripheral fractures in total); follow-up of patients treated with non-NaF regimes accounted for 382 person-years, of whom 53 patients suffered one or more new vertebral fractures (69 vertebral fractures in total) and 20 patients suffered one or more new nonvertebral fractures (27 complete peripheral fractures in total). After adjusting for significant covariates at baseline, NaF proved to be a significant protector for vertebral fractures [odds ratio (OR) 0.48, 95% confidence interval (CI) 0.2-0.9], and for peripheral fractures (QR 0.41, 95% CI 0.2-0.9). On the other hand, the probability of suffering undesired effects was much higher with NaF treatment (OR 5.04, 95% CI 2.1-11.9). We conclude that in the treatment of osteoporosis, NaF has a protective effect against vertebral and nonvertebral fractures, does not increase the risk of femoral fractures, but has a higher incidence of untoward symptomatology.

Osteoporosis is a public health scourge that is usually eminently preventable. Some risk factors, such as low calcium intake, vitamin D deficiency, and physical inactivity, are amenable to early interventions that will help maximize peak bone density. Other risk factors subject to modification are cigarette smoking and excessive consumption of protein, caffeine, and alcohol. Hip fractures are the most serious outcome of osteoporosis, with enormous personal and public health consequences. The ongoing Study of Osteoporotic Fractures has identified additional independent predictors of hip fracture risk, including maternal hip fracture, absence of significant weight gain since age 25, height, hyperthyroidism, use of long-acting benzodiazepines or anticonvulsants, spending < 4 hours a day on one's feet, inability to rise from a chair without using one's arms, poor visual depth perception and contrast sensitivity, and tachycardia. In an individual perimenopausal woman, the risk of osteoporotic fracture and the urgency of estrogen replacement therapy can be best estimated on the basis of bone mineral density, as measured by dual-energy x-ray absorptiometry, coupled with the presence or absence of existing fractures and clinical risk factors evident from the history and physical examination. Estrogen, calcitonin, and bisphosphonates have all been proved effective in retarding postmenopausal bone loss and therefore reducing the risk of fracture. The use of sodium fluoride is more controversial, although a recent study has suggested a possible role for slow-release fluoride combined with high-dose calcium supplementation.

The pathophysiology of corticosteroid-induced osteoporosis is outlined in this article. Treatment options, based upon our understanding of the pathophysiology, and a review of the available literature are offered.

To investigate whether sodium fluoride (NaF) is able to prevent bone loss in patients treated with corticosteroids (Cs), we performed a randomized double-masked, placebo-controlled trial with 44 Cs-treated patients without established osteoporosis, defined as the absence of previous peripheral fractures and vertebral deformities on radiographs. The effects of NaF (25 mg twice daily) and placebo on the bone mineral density (BMD) of the lumbar spine and hips were compared at baseline and at 6, 12, 18 and 24 months. After 2 years, the BMD of the lumbar spine had decreased in the placebo group by 3.0% (95% CI: -4.9% to -1.0%; p < 0.01); in the NaF group there was a statistically insignificant increase in BMD of 2.2% (95% CI: -0.8% to +5.3%). The difference in the changes in BMD between the two groups was +5.2% (95% CI: +1.8% to +8.6%; p < 0.01). In the hips, BMD had decreased after 2 years in both groups: in the placebo group by -3.0% (95% CI: -5.0% to -1.0%; p < 0.05) and in the NaF group by 3.8% (95% CI: -6.1% to -1.5%; p < 0.01). The difference in the changes in BMD between the two groups was not significant: +0.8% (95% CI: -2.1% to +3.8%). Three vertebral deformities were observed in the placebo group and one in the NaF group (insignificant difference), while no peripheral fractures occurred during the study period. It is concluded that in Cs-treated patients without established osteoporosis NaF prevents bone loss in the lumbar spine but does not have a positive effect on the BMD of the hips.

Osteoporosis is a leading cause of disability and death in older Americans; women are at higher risk than men. Bone is a living tissue that undergoes continuous remodeling throughout life. Several drugs-including sex hormones, bisphosphonates, calcitonin, and sodium fluoride-can arrest the progression of osteoporosis and prevent fractures. Calcium and vitamin D supplementation may prevent the development of osteoporosis in high-risk individuals and are useful adjuncts when used with other treatments.

Osteoporotic fractures constitute a major public health problem. These fractures typically occur at the hip, spine and distal forearm. Their pathogenesis is heterogeneous, with contributions from both bone strength and trauma. Water fluoridation has been widely proposed for its dental health benefits, but concerns have been raised about the balance of skeletal risks and benefits of this measure. Fluoride has potent effects on bone cell function, bone structure and bone strength. These effects are mediated by the incorporation of fluoride ions in bone crystals to form fluoroapatite, and through an increase in osteoblast activity. It is believed that a minimum serum fluoride level of 100 ng/ml must be achieved before osteoblasts will be stimulated. Serum levels associated with drinking water fluoridated to 1 ppm are usually several times lower than this value, but may reach this threshold at concentrations of 4 ppm in the drinking water. Animal studies suggest no effect of low-level (0-3 ppm) fluoride intake on bone strength, but a possible decrease at higher levels. Sodium fluoride has been used to treat established osteoporosis for nearly 30 years. Recent trials of this agent, prescribed at high doses, have suggested that despite a marked increase in bone mineral density, there is no concomitant reduction in vertebral fracture incidence. Furthermore, the increase in bone density at the lumbar spine may be achieved at the expense of bone mineral in the peripheral cortical skeleton. As a consequence, high dose sodium fluoride (80 mg daily) is not currently used to treat osteoporosis. At lower doses, recent trials have suggested a beneficial effect on both bone density and fracture. The majority of epidemiological evidence regarding the effect of fluoridated drinking water on hip fracture incidence is based on ecological comparisons. Although one Finnish study suggested that hip fracture rates in a town with fluoridated water were lower than those in a matching town without fluoride, a later study failed to show differences. Ecological studies from the United States and Great Britain have, if anything, revealed a weak positive association between water fluoride concentration and hip fracture incidence. Two studies examining hip fracture rates before and after fluoridation yielded discordant results, and are complicated by underlying time trends in hip fracture incidence. Only two studies have attempted to examine the relation between water fluoride concentration and fracture risk at an individual level. In one of these, women in a high fluoride community had double the fracture risk of women in a low fluoride community. In the other, there was no relationship between years of fluoride exposure and incidence of spine or non-spine fractures. In conclusion, the epidemiological evidence relating water fluoridation to hip fracture is based upon ecological comparisons and is inconclusive. However, several studies suggest the possibility of a weak adverse effect, which warrants further exploration. Data on the relationship between fluoride intake and hip fracture risk at the individual level, and data relating fluoridation to bone mineral density are required. Until these become available, the burden of evidence suggesting that fluoridation might be a risk factor for hip fracture is weak and not sufficient to retard the progress of the water fluoridation programme.

Osteoporosis is an increasingly prevalent chronic and debilitating disease. It is a metabolic disorder characterized by decreased bone mass that subsequently leads to bone fractures. Osteoporotic fractures occur most commonly in the hip, spine, distal radius, and ribs. Historically, pharmacologic options for the treatment of osteoporosis have been limited to hormone replacement therapy, vitamins, and mineral supplements. These previous treatments have been effective for many patients with osteoporosis. However, for many other patients, treatment with hormone replacement therapy, calcium, and vitamin D has been contraindicated or ineffective. Recently, several newly developed medications have become available for the treatment of osteoporosis in the United States. These new therapies have expanded the choices of pharmacologic options for primary health care providers and their patients. Pharmacologic therapy coupled with individualized diet, exercise, and fracture prevention counseling can help to decrease the severity and consequences of osteoporosis for growing numbers of Americans.

The judicious use of resources in the managed care setting requires that outcomes assessment be used in selecting the most cost-effective alternative strategies for preventing and treating diseases. Osteoporosis has major medical and economic costs and consequences for society, yet the most effective strategies to pursue in reducing these costs and consequences are uncertain. Selecting appropriate screening, preventive, and therapeutic strategies will require careful evaluation of data from clinical trials and from outcomes research in determining the most appropriate course of action. These issues represent a major challenge for the decision maker in the managed care setting.

Objectives: To review current knowledge of the epidemiology, pathogenesis, prevention and treatment of osteoporosis, with particular reference to issues related to the menopause., Methods: Peer-reviewed publications were assessed., Results: Much international variation exists in the prevalence of osteoporosis and the incidence of fracture. Risk fractures for osteoporosis are numerous. The menopause and other causes of hypogonadism in both women and men strongly predispose to osteoporosis. Various endocrinopathies, especially glucocorticoid excess, also are important. The contribution of family history may be explained by one or more genetic markers. Poor vitamin D and calcium nutrition, smoking, high alcohol consumption and inactivity increase risk. Reduced bone mass is a major risk factor for fracture, although the magnitude of that risk may vary between populations. In addition, bone fragility, length of the femoral neck (for hip fracture), history of prior fracture (for vertebral fracture) and falls affect fracture risk. Useful methods for measuring bone density are available for both epidemiologic surveillance and for clinical practice. Dual energy x-ray absorptiometry is the most desirable method in clinical care settings. Some risk factors can be modified for prevention of osteoporosis. Postmenopausal bone loss can be inhibited with estrogen or estrogen plus progestin therapy. Bone loss in the elderly may be moderated with calcium and vitamin D supplementation. Maintenance of muscle tone and strength through exercise may reduce falls. CONCLUSIONS. Osteoporosis is a large and growing health problem in many countries. Prevention of osteoporosis is a high priority, especially because treatment of the established disease remains sub-optimal. Prevention requires immediate, intermediate-term and long-term strategies. First line therapy for established osteoporosis in women in many countries is estrogen or estrogen plus progestin, calcium and vitamin D. Prospects for improved prevention of osteoporotic fractures are encouraging.

We now have a number of effective drugs for osteoporosis. However, close inspection of clinical trials results suggests we should aim for even better ones.

Fluoride exerts a biphasic action at the level of osteoblasts, on bone mineral, on bone structure and function, and in the treatment of osteoporosis. At low circulating concentrations, skeletal uptake of fluoride is limited and the effects are beneficial. At higher concentrations and greater skeletal uptake, fluoride may cause the formation of abnormally mineralized bone of impaired quality. A new treatment program entailing intermittent slow release sodium fluoride (SR-NaF) with continuous calcium citrate may capture desirable qualities of fluoride without toxic effects, and be therapeutically efficacious in postmenopausal osteoporosis.

We have previously demonstrated that a treatment regimen of slow-release sodium fluoride (SRNaF) and continuous calcium citrate increases lumbar bone mass, improves cancellous bone material quality, and significantly reduces vertebral fracture rate in osteoporotic patients. In order to assess whether such treatment also improves trabecular structure, we quantitated cancellous bone connectivity before and following 2 years of therapy with SRNaF in 23 patients with osteoporosis and vertebral fractures. In addition, we performed bone histomorphometry on the same sections used for connectivity measurements. There was a significant increase in L2-L4 bone mineral density during therapy (0.827 +/- 0.176 g/cm2 SD to 0.872 +/- 0.166, p = 0.0004). Significant histomorphometric changes were represented by increases in mineral apposition rate (0.6 +/- 0.4 microns/d to 1.1 +/- 0.7, p = 0.0078) and adjusted apposition rate (0.4 +/- 0.3 microns/d to 0.6 +/- 0.4, p = 0.016). On the other hand, trabecular spacing significantly declined (from 1375 +/- 878 microns to 1052 +/- 541, p = 0.05). Two-dimensional quantitation of trabecular struts on iliac crest histological sections disclosed significant increases in mean node number per mm2 of cancellous tissue area (0.22 +/- 0.12 vs. 0.39 +/- 0.27, p = 0.0077), the mean node to free-end ratio (0.23 +/- 0.21 vs. 0.41 +/- 0.46, p < 0.05), and in the mean node to node strut length per mm2 of cancellous area (0.098 +/- 0.101 vs. 0.212 +/- 0.183, p < 0.01). There were no significant changes in any of the measurements associated with free-end number or free-end to free-end strut length.(ABSTRACT TRUNCATED AT 250 WORDS)

Sodium fluoride has for more than 2 decades been a commonly used therapeutic agent for established osteoporosis because of a repeatedly documented anabolic effect on trabecular bone mass. Recently, however, three controlled trials have failed to demonstrate any therapeutic advantage of NaF over placebo with respect to vertebral fracture rate. Also, there have been several reports of an increased incidence of nonvertebral fractures during fluoride administration. Thus, the efficacy of fluoride therapy remains a controversial issue. The aim of this longitudinal study was to investigate the effect of sodium fluoride (40-60 mg per day), calcium (45 mmol), and vitamin D2 (18,000 IU) on trabecular bone strength, assessed before and after 1 or 5 years of treatment for osteoporosis. Iliac crest biopsies were taken before and after 1 year of treatment in 12 patients, and before and after 5 years of treatment in 14 patients. Measurements were made of biomechanical competence, ash content, and bone fluoride content, and bone strength parameters were normalized for ash content, thereby obtaining a measure of trabecular bone quality. Bone fluoride content was significantly increased after both 1 and 5 years of treatment, indicating that the administered fluoride had been ingested. After 1 year of treatment, no difference was observed in iliac crest trabecular bone ash content. A general trend for decreased bone strength and bone quality was observed, but this was insignificant. After 5 years of fluoride treatment, an insignificant decrease in iliac crest trabecular bone ash content was observed.(ABSTRACT TRUNCATED AT 250 WORDS)

Osteoporosis constitutes a major financial burden for society, which will increase in the near future owing to the ageing of the population. Women are the most common victims of involutional osteoporosis because of post-menopausal bone loss induced by oestrogenic deficit. Men are nevertheless not completely untouched by osteoporosis, however, compared to women, they are under less threat. Every effort should be made to curtail the financial burden on society and to improve the quality of life of sufferers. The first steps should be to increase the calcium intake, the level of exercise and to decrease the risk of falls. A preventive therapy with oestroprogestogens should be instituted at the time of the menopause, provided there is no contraindication. In the absence of fracture data, the modalities of alternative therapies like calcitonin and bisphosphonates are still debated. For people already suffering from fractures, restorative therapy should be considered. Sodium fluoride therapy is able to provoke a decrease in vertebral fracture frequency without compromising cortical bone strength provided elementary rules for its use are respected. Whether bisphosphonates can protect against fractures is still unsettled. Vitamin D has a physiological role, particularly in institutionalized elderly patients deprived of any exposure to the sun. Anabolic steroids are not devoid of side effects, and furthermore, no fracture data are so far available.

The intrinsic (material) quality of cancellous and cortical bone was evaluated in vivo from the measurement of reflection ultrasound velocities in the ulna. In cancellous bone, the reflection ultrasound velocity was inversely correlated with age in normal women (r = -0.48, p = 0.001), with a significantly lower mean value in 32 normal postmenopausal women than in 14 premenopausal women (3124 versus 3341 m/s, p < 0.0001). In 32 untreated osteoporotic women the cancellous bone velocity was lower than in normal postmenopausal subjects (2906 versus 3124 m/s, p = 0.0001). Following treatment with slow-release sodium fluoride plus calcium citrate (mean 2.4 years in 33 osteoporotic patients with no fracture during treatment), the cancellous bone velocity was significantly higher than in untreated osteoporotic women (3082 versus 2906 m/s, p = 0.0002) and was not significantly different from that in normal postmenopausal women. The cortical bone velocity displayed similar trends, but the changes did not attain statistical significance. The measurements were repeated approximately 9 months later in 9 untreated and in 20 treated patients; in 5 additional patients, the measurements were made both before and after 9 months of treatment with slow-release sodium fluoride and calcium citrate. The cancellous bone velocity increased significantly (p = 0.046) in these patients, from 3008 m/s before treatment to 3112 m/s after the first 9 months of treatment. The velocity rose significantly from 3037 to 3167 m/s (p = 0.017) in patients treated for a short time (12-30 months at first measurement), but it did not change in untreated patients or those treated for more than 30 months. Thus, the material quality of cancellous bone decreases with normal aging and is reduced further with the osteoporotic process. This impaired quality may be corrected by treatment with slow-release sodium fluoride plus calcium citrate.

The future of sodium fluoride (NaF), the most potent osteoblast stimulator known to man, is in the balance. Of three recent randomized trials of continuous NaF only one found a significant in vertebral fractures in the NaF group. When data from the first year were excluded, two of the studies (those with the largest numbers) showed a significantly reduced risk of vertebral fracture on NaF. The effect of NaF on cortical bone is poorly documented. Two studies have shown reduced forearm cortical bone density with continuous NaF. A further two (histomorphometric) studies have shown the development of increased cortical porosity on continuous NaF treatment. In one, this was selectively at the external cortex and was linearly correlated with cancellous volume increase. Our pilot study using NaF administered cyclically has shown an encouraging (though non-significant) reduction in vertebral fracture rates (excluding year 1) and no fall in forearm cortical density. Another (US) cyclical study has shown no increase in cortical porosity. A current W. Australian randomized study of 50 patients is described where NaF dosage is varied proportional to the osteoblast response, and duration is dependent on densitometric and radiographic response. The future of NaF should involve cyclical administration, in cautious initial dosage (50-60 mg/day) of enteric-coated NaF, in conjunction with a potent inhibitor of resorption such as hormone replacement, bisphosphonates or calcitonin.

The observations of familial juvenile osteoporosis, presumably of genetic origin are exceptional. The authors report the observation of a 16-year old adolescent suffering from osteoporosis, confirmed by histomorphometry and decrease in bone density (lumbar vertebrae 0.79 g/cm2 and femoral neck 0.88 g/cm2: LUNAR DPX). We prescribed fluorine and calcium therapy. Lumbar bone density increases by 11% and bone density of the thighbone neck by 7.6%. We cannot rule out growth as a factor in the changes observed, given that the propositus is only 16. A densitometric investigation performed in 4 of his 12 brothers shows a decrease in the lumbar bone mineral content (from 61 to 94% expressed as Z score). A genotypic origin seems to be conceivable, especially since no other cause could be considered (endocrinal, alimentary...). On the other hand, there is no argument in favour of osteogenesis imperfecta disease. The bone densitometry is a useful diagnostic means to detect familial forms of osteoporosis.

Radiological investigation of the vertebral column in two patients with low-back pain (53-year-old woman and a 52-year-old man) revealed unusually marked osteoporosis and sintering fractures of the 3rd, and 1st and 4th lumbar vertebrae, respectively. Biochemical tests failed to provide any evidence about metabolic or endocrinological abnormality. Iliac crest biopsy showed mastocytosis. There were no skin changes in either patient. Additional examinations excluded involvement of any internal organs. Despite treatment with calcium, sodium fluoride, vitamin D3 and calcitonin in the woman, and aspirin and chromoglycinic acid in the man the osteoporosis has slowly progressed during the last 7 and 5 years, but the disease has remained limited to the skeletal system. In a case of unusually marked osteoporosis, mastocytosis should be included in the differential diagnosis even in the absence of urticaria pigmentosa.

We evaluated the effects of intermittent slow-release sodium fluoride (SRNaF) and continuous calcium citrate therapy on cortical bone histology, reflection ultrasound velocity (material strength) and back-scattered electron image analysis (BEI) in 26 osteoporotic patients before and following therapy. All measurements were made on transiliac crest bone biopsies obtained before and following 2 years of therapy in each patient. For all 26 patients there were no significant changes in cortical bone histomorphometric parameters. In 15 patients in whom bone material quality was assessed by reflection ultrasound, there was no change in velocity (4000 +/- 227 SD to 4013 +/- 240 m/s). BEI disclosed no mineralization defects or the presence of woven bone. Mean atomic number (density) of bone increased slightly, but significantly (9.261 +/- 0.311 to 9.457 +/- 0.223, P = 0.031). While these changes are less marked than those observed for cancellous bone, they indicate that this form of therapy does not adversely affect cortical bone remodelling.

Low-bone-turnover osteoporosis is a common complication of primary biliary cirrhosis (PBC). Since sodium fluoride stimulates bone formation we assessed the effect of this drug on bone mass in a 2-year, prospective, double-blind trial including 22 women with PBC who were randomly assigned to receive sodium fluoride (50 mg/day) or placebo. All received calcium supplements and low doses of vitamin D. Bone mineral density of the lumbar spine was measured by dual-photon absorptiometry initially and every 6 months. Vertebral fractures were evaluated in thoracic and lumbar spine initially, and after 1 and 2 years. Seven patients in the fluoride group and eight in the placebo group completed the trial. In the fluoride group, bone mineral density did not change after 2 years (initial 1.05 +/- 0.07, final 1.07 +/- 0.06 g/cm2; p = n.s.). In the placebo group, however, bone mineral density decreased significantly (initial 1.00 +/- 0.07, final 0.93 +/- 0.06 g/cm2; p = 0.03). Moreover, in the fluoride group bone mineral density increased by 2.9 +/- 3.6%, and in the placebo group decreased by 6.6 +/- 2.6% (p = 0.04). None of the patients developed new vertebral or non-vertebral fractures. Treatment with sodium fluoride did not impair liver function or cholestasis in PBC. These results indicate that sodium fluoride prevents bone loss in PBC and therefore might be considered as a possible therapeutic agent for osteoporosis associated with this liver disease. Since a small number of patients completed the trial, further studies are required.

The replacement of lost trabeculae characteristic of postmenopausal osteoporosis is problematic, since a biological pathway has not been established for trabecular regeneration de novo in the healthy, intact, mature skeleton. Possible pathways for trabecular replacement may occur under pathological conditions, in particular those associated with bone hypertrophy. The topography of trabecular hypertrophy was compared in two groups of subjects with disease- or treatment-induced osteosclerosis following a period of atrophy. In Paget's disease and fluoride-treated osteoporosis a thickening of rarefied trabeculae in both was associated in Paget's disease only with an increase in the trabecular number and the transformation of a discontinuous arrangement into a more continuous network. The sequence seems to be a progression of intratrabecular resorption normally attendant upon a period of trabecular thickening. The failure of fluoride-treated bone in this respect, due to the unusual stability of the fluorotic skeleton, may provide insight to more effective anabolic regimens.

This review summarizes basic pathophysiology, epidemiology, classification and theories on the etiology of osteoporoses. Diagnostic, preventative and therapeutic aspects are discussed including the use of hormones and hormone analogues (estrogen, progestins, calcitonins, anabolic steroids), calcium, fluoride, bisphosphonates, vitamins D and their metabolites and the recently proposed "coherence therapy". Reference is made to new compounds under study including imidazoquinazolinones, methylxanthines and benzothiophenes.

A case report of a 53 year old postmenopausal woman with severe osteoporosis occurring in association with beta thalassemia trait is presented. She was found to have marked axial osteopenia with lumbar spine bone mineral density that was more than three standard deviations below the mean, but had normal bone mineral density of the proximal radius. A biopsy of the iliac crest showed evidence of high turnover osteoporosis. Bone densitometry of the spine and hip in a consecutive series of eleven asymptomatic individuals with thalassemia trait also is reported. Bone mineral density was diminished in the spine (z-score = -0.78, P less than 0.03) and hip (z-score = -0.54, P = 0.05) of patients with thalassemia trait. It is postulated that thalassemia minor may be a risk factor for osteoporosis.