Vertebral Fracture Rate Research Articles

Vertebral fractures in Beijing, China: the Beijing Osteoporosis Project.

Women in China have much lower risk of hip fracture than women in Europe or North America but their risk of vertebral fractures is not known. Lateral spine radiographs, hip and lumbar spine bone density, and potential risk factors for and consequences of vertebral fractures were assessed in a random sample of 402 women age 50 years or older living in Beijing, China. The prevalence of vertebral fractures, defined by vertebral morphometry, increased from 5% (95% CI, 1-9%) in 50- to 59-year olds to 37% (27-46%) among women age 80 years or older. The age-standardized prevalence of vertebral fractures was 5.5% lower than found by similar methods for women in Rochester, MN, U.S.A. Each SD lower spine bone mineral density (BMD) was associated with a 2.4-fold (1.7-3.5) increased odds of having a vertebral fracture. Women with a history of heavy physical labor had a lower risk of vertebral fractures. Vertebral fractures were associated with decreased height loss and limited physical function but not chronic back pain. Women in Beijing, China have lower bone density and a slightly lower rate of vertebral fracture than white women in the United States. Low bone density and more sedentary occupations increase the risk of fracture in women living in urban China.

Gender differences in fracture risk and bone mineral density

We have investigated gender-related differences of bone mineral density and fracture threshold in 136 males (age, 60.7±9.3 years) and 337 females (age, 59.7±7.8 years) without evidence of secondary osteoporosis. Women and men were examined for total amount of spine fractures and bone mineral density by quantitative computed tomography (QCT) of three non-fractured vertebral bodies L1–L5. Females with lumbar fractures ( n=96) when compared with non-fracture women ( n=241) were older and had lower bone density at their vertebral sites. Males with vertebral fractures ( n=52) were older and had a significantly reduced bone mineral density of the spine when compared with healthy males ( n=84). When we compared gender-related vertebral fracture rates, we observed a significantly higher prevalence of vertebral fractures in the male population. After matching males and females for age and bone mineral density to exclude an influence of either variable, we compared the prevalence of vertebral fracture risk in both sexes with logistic regression analysis. Data of estimated fracture risk, differed very significantly for sex and bone density at the vertebral site, indicating that men present fracture at a higher bone density level compared with females; in 10% of study population fractures occurred at a QCT level of 105 mg/cm 3 in women and 120 mg/cm 3 in men. The estimated odds ratio for sex of 3.1 (95% CI) means a three-fold increased risk for vertebral fractures compared to males at a given density level. These results underline that a decreased bone mineral density leads to the occurrence of spine fractures in females and males as well.

Fluoride for the Treatment of Postmenopausal Osteoporotic Fractures: A Meta-Analysis

We conducted an effectiveness meta-analysis to determine the efficacy of fluoride therapy on bone loss, vertebral and nonvertebral fractures and side effects in postmenopausal women. A literature search was conducted on MEDLINE, Current Contents and the Cochrane Controlled Trial Registry. Two independent reviewers selected randomized controlled trials which met predetermined inclusion criteria. They independently extracted data using predetermined forms and assessed the methodologic quality of the trials using a validated scale. For dichotomous outcomes, the relative risk (RR) was calculated, and for continuous outcomes, the weighted mean difference (WMD) of percentage change from baseline was calculated. Where heterogeneity existed (determined by a chi-square test) a random effects model was used. Eleven studies (1429 subjects) met the inclusion criteria. The increase in lumbar spine bone mineral density (BMD) was found to be higher in the treatment group than in the control group with a WMD 8.1% (95% CI: 7.15, 9.09) after 2 years of treatment and 16.1% (95% CI: 14.65, 17.5) after 4 years. The RR for new vertebral fractures was not significant at 2 years [0.87 (95% CI: 0.51, 1.46)] or at 4 years [0.9 (95% CI: 0.71, 1.14)]. The RR for new nonvertebral fractures was not significant at 2 years [1.2 (95% CI: 0.68, 2.10)] but was increased at 4 years in the treated group [1.85 (95% CI: 1.36, 2.50)], especially if used at high doses and in a non-slow-release form. The RR for gastrointestinal side effects was not significant at 2 years [2.18 (95% CI: 0.86, 1.21)] but was increased at 4 years in the treated group [2.18 (95% CI: 1.69, 4.57)], especially if fluoride was used at high doses and in a non-slow-release form. The number of withdrawals and dropouts was not different between treated and control groups at 2 and 4 years. Thus, although fluoride has an ability to increase bone mineral density at the lumbar spine, it does not result in a reduction in vertebral fractures. Increasing the dose of fluoride increases the risk of nonvertebral fractures and gastrointestinal side effects without any effect on the vertebral fracture rate.

The potential role of bisphosphonates as adjuvant therapy in the prevention of bone metastases.

Bisphosphonates (BPs) reduce bone resorption rates by inhibiting osteoclast function, although direct antineoplastic effects and poorly understood effects on bone pain also may occur. Within the family of BPs there are more similarities in pharmacologic effects than differences, although side effect profiles, rates of oral absorption, and potency do differ. Oral clodronate and intravenous pamidronate reduce skeletal complications in patients with bone metastases from breast carcinoma (as well as in myeloma). Uncontrolled trials of prostate carcinoma also suggest clinical benefit. Animal studies show that BPs can reduce the rate of development of bone metastases (for example, in Walker 256 carcinoma), but there is little evidence of an effect at nonosseous sites. The hypothesis that the growth of subclinical osseous metastases is augmented by products of bone resorption (a "vicious cycle") and may be diminished by a local reduction of these substances has led to trials of BPs involving patients with no clinical evidence of bone metastases. These trials are critically assessed in this review. In patients with recurrent breast carcinoma but no overt bone metastases, oral clodronate reduced the number of diagnosed bone metastases; but the number of patients who had relapses in bone, though smaller, was not significantly different from the number among patients who took placebo. In a trial of oral pamidronate, no effect was seen, but compliance was a problem because of gastrointestinal side effects. Patients treated for operable breast carcinoma have four or five times the normal rate of vertebral fracture, and BPs do reduce the rate of bone loss. Three adjuvant clodronate trials have been reported. The first, an open-label controlled trial (Diel et al.), showed a reduction in osseous and nonosseous recurrences and an increase in disease free and overall survival with 2 years of clodronate. A second open-label trial (Saarto et al.) of similar size involving lymph node positive breast carcinoma patients showed no effect on the rate of bone metastasis relapse and a deleterious effect on relapse rates of nonosseous metastases with 3 years of clodronate. A third placebo-controlled trial involving 1079 patients reported, in an interim analysis, a reduction in osseous metastases during treatment with 2 years of clodronate, but no effect on nonosseous metastases or survival. A confirmatory clinical trial is required for two interrelated reasons: 1) scientifically, it is important to demonstrate that an agent that has its dominant effect on a normal tissue cell, the osteoclast, can influence the growth of neoplastic cells; and 2) from the perspective of patient care, it must be unequivocally shown that a reduction in the rate of osseous recurrence translates into an improvement in disease free survival or an improvement in quality of life through reduction of adverse skeletal events. The National Surgical Adjuvant Breast Project has committed to conducting this study and including women with operable breast carcinoma.

Raloxifene reduced vertebral fractures in postmenopausal women

(1999) JAMA 282, 637. Ettinger B, Black DM, Mitlak BH, et al, . for the Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. . Reduction of vertebral fracture risk in postmenopausal...

Bone matters: are density increases necessary to reduce fracture risk?

As aconsequence of the exponential BMD/fracture risk relationship,very small increases in BMD can be expected to have very largeeffects on reducing fracture rates (Fig. 1). It is not necessary todouble BMD to reduce fractures by a factor of 2.On the basis of the established relationships betweenBMD, bone strength, and fracture risk, current therapies forreducing fractures have been targeted at reversing bone lossto increase bone strength. Several different therapies havebeen shown to increase bone density and reduce frac-tures.

Bone disease in multiple myeloma.

Bone disease in multiple myeloma.

A Four-Year Randomized Controlled Trial of Hormone Replacement and Bisphosphonate, Alone or in Combination, in Women with Postmenopausal Osteoporosis

PURPOSE: Hormone replacement therapy (HRT) with estrogen and treatment with bisphosphonates have been shown to increase bone mineral density (BMD) in postmenopausal women. This 4-year prospective randomized study was carried out to assess the effectiveness of the combined HRT plus etidronate on BMD in postmenopausal women with established osteoporosis. PATIENTS AND METHODS: Seventy-two postmenopausal women (mean age 64.9 ± 0.5 years) attending metabolic bone disease outpatient clinics with established osteoporosis were randomly allocated into one of four treatment groups and monitored for 4 years. All patients enrolled in this study including the control group (n = 18) received 1.0 g elemental calcium and 400 units vitamin D per day. The HRT group (n = 18) received cyclical estrogen and progesterone; the etidronate group (n = 17) received intermittent cyclical etidronate; and the combined therapy group (n = 19) received both HRT and etidronate. BMD was measured in the lumbar spine and the hip before treatment and at 2 and 4 years after treatment. Changes in height were recorded, and the occurrence of new vertebral fractures were documented in comparison with the baseline radiographic evaluation. In 40 patients (10 patients per group), analysis of bone histomorphometry was carried out after 4 years of treatment. RESULTS: In patients who received the combined therapy, BMD increased in the lumbar spine by 10.4% ( P <0.001) and in the hip by 7.0% ( P <0.001) at 4 years. For patients treated with ICE, these increases were 7.3% ( P <0.001) and 0.9% ( P <0.05), and with HRT, the increases were 7.0% ( P <0.001) and 4.8% ( P <0.01) in the vertebrae and femora, respectively. The group treated with calcium and vitamin D lost 2.5% ( P <0.05) and 4.4% ( P <0.01) of BMD in the vertebrae and femora, respectively, after 4 years. Patients who received combined therapy had significantly higher BMD in both the vertebrae and in the femora ( P <0.05) in comparison with patients who were treated with HRT or etidronate alone after 4 years. In comparison with patients in the control group, there was a trend toward a lower rate of new vertebral fractures in the treatment groups. Height loss was significantly less in all three active treatment groups (HRT [ P <0.001], etidronate [ P <0.02], and combined therapy group [ P <0.0001]), in comparison with the control group. The combined therapy group did not have a significant height loss, in comparison with the HRT ( P <0.02) and the etidronate ( P <0.001) groups. None of the patients had histomorphometric evidence of osteomalacia. CONCLUSION: This 4-year randomized study showed an additive effect of etidronate and HRT on hip and spine BMD in postmenopausal women with established osteoporosis.

Fluoride Salts are no Better at Preventing New Vertebral Fractures than Calcium-Vitamin D in Postmenopausal Osteoporosis: The FAVOStudy

Although fluoride salts have been shown to be capable of linearly increasing spinal bone mineral density (BMD) in postmenopausal osteoporosis, the effects of this gain in density on the vertebral fracture rate remain controversial. We conducted a 2-year multicenter, prospective, randomized, double-masked clinical trial in 354 osteoporotic women with vertebral fractures (mean age 65.7 years). They received either fluoride (208 patients), given as sodium fluoride (50 mg/day) or as monofluorophosphate (200 mg/day or 150 mg/day), or a placebo (146 patients). All patients received daily supplements of 1 g of calcium (Ca) and 800 IU of vitamin D2 (D). A 1-year open follow-up on Ca-D was obtained in 124 patients. After 2 years the fluoride group and the Ca-D group had increased their lumbar BMD by 10.8% and 2.4% respectively (p = 0.0001). However, the rate of patients with at least one new vertebral fracture, defined by semiquantitative assessment and evaluable on an intention-to-treat basis in 89% of patients, was similar in the fluoride groups and the Ca-D group. No difference between the three fluoride regimens was found. The percentage of patients with nonvertebral fractures was not different in the fluoride and Ca-D groups (1.9% and 1.4% respectively for hip fractures). A lower limb pain syndrome occurred more frequently in the fluoride groups. In the 124 patients followed for 1 year after cessation of fluoride therapy, the percentage of patients with at least one new vertebral fracture after 36 months was identical to the percentages in the previous fluoride group and the Ca-D group. We conclude that fluoride-Ca-D regimen was no more effective that Ca-D supplements for the prevention of new vertebral fractures in women with postmenopausal osteoporosis.

Benefits of growth hormone treatment on bone metabolism, bone density and bone strength in growth hormone deficiency and osteoporosis

Bone mass is reduced in patients with GH deficiency (GHD) leading to an increased vertebral fracture rate and clinically significant osteoporosis. Patients with GHD of juvenile onset have reduced skeletal mineralization. When substituting GH in patients with GHD, bone turnover is increased and bone mineral density initially decreases during the first year due to the increase in remodelling space. From the experience in patients with acromegaly, cortical bone mass is increased and trabecular bone mass is normal in eugonadal or decreased in the hypogonadal patients. However, bone mineral content and bone area are increased leading to a higher biomechanical competence of bone as shown in rats. In patients with GHD of juvenile onset, mineralization and bone maturation are achieved during treatment with GH in adult life after having reached final body height leading to an increase in bone mass. The GH/ IGF-I system is dysregulated in patients with post-menopausal osteoporosis. This is shown by reduced systemic IGF and IGFBP-3-levels in osteoporosis suggesting a decrease of endogenous GH-secretion or a dysregulation of the GH receptor system which is beyond the normal ageing process of the GH/IGF system, the "somatopause". A premature somatopause may be responsible for the dysregulation in some patients with osteoporosis. However, 24-h GH profiles do not differ between patients suffering from osteoporosis or osteoarthritis. Treatment of osteoporosis with GH might be beneficial due to the increased bone metabolism and improved bone geometry which occurs with GH. The substantial increase of bone remodelling achieved with GH may be helpful during late post-menopause with decreased bone turnover and impaired osteoblastic function. Using GH to prevent physiological bone loss that occurs with age seems possible, but has to be discussed on an ethical and economic basis.

Growth Hormone Deficiency in Adults

Although growth hormone has been in clinical use for almost 40 years to promote linear growth in children with growth hormone deficiency, replacement therapy in adults was previously not deemed clinically indicated. However, intensive research over the past decade has led to important advances in our medical knowledge and improvements in the care for patients with growth hormone deficiency. Well-controlled clinical trials have demonstrated beneficial effects of replacement therapy with recombinant human prion-free growth hormone (rhGH; somatropin). The most important restoration parameters include reduction of cardiovascular risk factors and improved lipid profile, normalised body composition, improved exercise capacity and bone mass, as well as enhanced psychological well-being. Some important issues regarding growth hormone deficiency and long term somatropin treatment are unresolved, such as diagnostic criteria and the potential for malignancy and impaired glucose tolerance. Furthermore, the effect on hard end-points such as life expectancy or vertebral fracture rate is unknown, but is expected to emerge from physician-managed, multinational databases. Consequently, at this point somatropin therapy should be given in conjunction with clinical trials.

A risk-benefit assessment of alendronate in the treatment of involutional osteoporosis.

Osteoporosis is the most frequent metabolic condition experienced by elderly individuals. It is characterised by a low bone mass and microarchitectural deterioration of bone tissue leading to an increase in bone fragility and susceptibility to fracture. Osteoporosis constitutes a significant financial burden for health services as well as a source of pain and disability and a cause of a decrease in the quality of life for patients with the condition. Effective therapy for osteoporosis is, therefore, urgently needed. Currently, a number of different therapeutic approaches exist that have more or less proven positive effects on the incidence of fractures, for example estrogen replacement therapy, calcitonin, fluoride salts, calcium plus vitamin D supplementation and the first-generation bisphosphonate etidronate (etidronic acid). Alendronate (alendronic acid) is an alkylaminobisphosphonate with a very potent antiresorptive capability. In contrast to etidronate, alendronate possesses an excellent ratio between its potency for inhibiting bone resorption and its potency for impairing bone formation. In addition, no case of focal or generalised osteomalacia has so far been observed with alendronate. The bioavailability of oral alendronate is poor and the agent has to be taken in a fasting state, at least 30 minutes before breakfast, with a full glass of water. Alendronate has demonstrated its ability to increase bone mass significantly above the placebo values at any studied skeletal site in a wide variety of patient subgroups regardless of age, race, baseline rate of bone turnover or baseline bone mineral density. Alendronate is the only medication with a demonstrated positive effect on symptomatic and asymptomatic vertebral fracture rate, as well as on nonvertebral fracture rate. In clinical trials, alendronate was generally well tolerated and no significant clinical or biological adverse experiences were observed. However, postmarketing data have included reports of oesophageal lesions compatible with the diagnosis of alendronate-induced chemical oesophagitis, in around 1% of patients taking the agent. However, in the vast majority of cases alendronate tablets had been taken incorrectly. Therefore, with proper use, that is, use complying with the manufacturers administration recommendations, this potentially dangerous complication should be minimised and should not outweigh the overall positive benefit of alendronate in the prevention of fractures.

Bisphosphonates in bone diseases.

Bisphosphonates are a class of drugs which are strongly attracted to the bone where they influence the calcium metabolism, mainly by inhibition of the osteoclast-mediated bone resorption. This property makes these compounds suited for the treatment of several diseases of the bone. In Paget's disease, several bisphosphonates can reduce bone pain and decrease the bone turnover 60-70%. Cyclical oral etidronate and daily oral alendronate both proved to reduce the vertebral fracture rate for postmenopausal osteoporotic woman, while most investigated bisphosphonates can increase spinal bone mass in osteoporosis. Bisphosphonates can help lowering serum calcium and reverse skeletal complications in malignancy mediated bone diseases. Oral and intravenous administration of therapeutic doses is relatively safe. In general, gastrointestinal disturbances are described most often and the oldest, least potent, bisphosphonate etidronate can induce osteomalacia. The various characteristics of bisphosphonates: physicochemical, biological, therapeutic and toxicological, vary greatly depending on the structure of the individual bisphosphonate. Even small changes in the structure can lead to enormous differences in potency. Overall, this class of drugs offers several prospects for the future.

Cyclical Etidronate in the Treatment of Postmenopausal Osteoporosis: Efficacy and Safety After Seven Years of Treatment

PURPOSE: To determine the efficacy and safety of cyclical etidronate for up to 7 years in the treatment of postmenopausal osteoporosis and to examine the effects of discontinuing treatment after 2 or 5 years of therapy.PATIENTS AND METHODS: Patients were randomized at entry into the original study in 1986 to blinded treatment for 2 years with either a calcium (placebo) or an intermittent cyclical etidronate regimen, which most patients continued for a third year. Following this phase of the study, patients were enrolled into an open-label, follow-up study (years 4 and 5), during which all patients received cyclical etidronate treatment. In the present double-blind study (years 6 and 7), patients were rerandomized to receive intermittent cyclical therapy with either etidronate or placebo; all patients received calcium. The treatment regimen consisted of 400 mg/day etidronate or placebo for 14 days, followed by 76 days of elemental calcium (500 mg/day); this cycle was repeated approximately 4 times in each year. Of the 193 patients who continued in years 6 and 7 of the study, 93 were randomized to receive cyclical etidronate and 100 were randomized to receive calcium only. For purposes of efficacy analyses, patients were categorized by their total years of cumulative etidronate treatment (7, 5, 4, or 2 years). There were 51, 46, 42, and 54 patients in the 7-, 5-, 4-, and 2-year groups, respectively. Annual assessments included lumbar spine bone mineral density (BMD), as measured by densitometry, and vertebral radiographs.RESULTS: The groups receiving cyclical etidronate during this 2-year study period (7- and 4-year groups) had statistically significant mean percent increases in spinal BMD of 1.8% and 2.2%, respectively (P <0.05) at the week 104 observation time. The 5- and 2-year groups, which did not receive etidronate during this period, had mean values of 1.4% and 0.2%, respectively (not significant) at week 104. In the 7-, 5-, 4-, and 2-year groups, the increases in spinal BMD at the end of 7 years were 7.6%, 8.6%, 8.1%, and 3.9%, respectively; these values were statistically significant for all groups compared with original baseline (year 0) (P <0.05). BMD of the femur and wrist was maintained throughout the 7-year period. The incidence and rate of vertebral fractures were lowest in patients with the longest exposure to etidronate. Etidronate was well tolerated during the study, with low incidences of gastrointestinal side effects and nonvertebral fractures.CONCLUSIONS: Long-term cyclical etidronate is a safe, effective, and well-tolerated treatment for postmenopausal osteoporosis. Bone mass is maintained for at least 2 years after treatment with etidronate is stopped; however, further gains in spinal bone mass are seen in patients who continue therapy.

Epidemiology of spinal osteoporosis.

Approximately 30% of postmenopausal white women in the United States have osteoporosis, and 16% have osteoporosis of the lumbar spine in particular. Bone density of the spine is positively associated with greater height and weight, older age at menopause, a history of arthritis, more physical activity, moderate use of alcoholic beverages, diuretic treatment, and current estrogen replacement therapy, whereas later age at menarche and a maternal history of fracture are associated with lower levels of density. Low bone density leads to an increased risk of osteoporotic fractures. Fracture risk also increase with age. Vertebral fractures affect approximately 25% of postmenopausal women, although the exact figure depends on the definition used. Recent data show that vertebral fracture rates are as great in men as in women but, because women live longer, the lifetime risk of a vertebral fracture from age 50 onward is 16% in white women and only 5% in white men. Fracture rates are less in most nonwhite populations, but vertebral fractures are as common in Asian women as in those of European heritage. Other risk factors for vertebral fractures are less clear but include hypogonadism and secondary osteoporosis; obesity is protective of fractures as it is of bone loss. Compared with hip fractures, vertebral fractures are less disabling and less expensive, costing approximately $746 million in the United States in 1995. However, they have a substantial negative impact on the patient's function and quality of life. The adverse effects of osteoporotic fractures are likely to increase in the future with the growing number of elderly people.

Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis

Small increases in bone mass are commonly seen with existing treatments for osteoporosis, which reduce bone remodelling and primarily prevent bone loss. Since these drugs reduce but do not eliminate risk of fractures, an anabolic agent that would increase bone mass and potentially cure the underlying skeletal problem is needed. We did a 3-year randomised controlled trial to find out the effects of 1-34 human parathyroid hormone (hPTH [1-34], 400 U/25 micrograms daily subcutaneously) in postmenopausal women with osteoporosis taking hormone-replacement therapy (n = 17). The controls were women taking hormone-replacement therapy only (n = 17). The primary outcome was bone-mineral density of the lumbar vertebrae, with bone-mineral density at other sites and vertebral fractures as secondary endpoints. Patients taking hormone-replacement therapy and PTH (1-34) had continuous increase in vertebral bone-mineral density during the 3 years, whereas there was no significant change in the control group. The total increase in vertebral bone-mineral density was 13.0% (p < 0.001); 2.7% at the hip (p = 0.05); and 8.0% in total-body bone mineral (p = 0.002). No loss of bone mass was found at any skeletal site. Increased bone mass was associated with a reduction in the rate of vertebral fractures, which was significant when fractures were taken as a 15% reduction in vertebral height (p = 0.04). During the first 6 months of treatment, serum osteocalcin concentration, which reflects bone formation, increased by more than 55%, whereas excretion of crosslinked n-telopeptide, which reflects bone resorption, increased by only 20%, which suggests some uncoupling of bone formation and resorption. By 6 months, there were similar increases in both markers, which gradually returned towards baseline as the study progressed. Vertebral bone-mineral density increased most during the first year of PTH treatment. We found that PTH has a pronouned anabolic effect on the central skeleton in patients on hormone-replacement therapy. PTH also increases total-body bone mineral, with no detrimental effects at any skeletal site. The increased vertebral mass was associated with a reduced rate of vertebral fracture, despite increased bone turnover. Bone-mass changes may be consistent with a reduction in all osteoporotic fractures. If confirmed in larger studies, these data have important implications for the treatment of postmenopausal osteoporosis.

Osteoporosis: Trials and tribulations

A 30–50% reduction in fracture risk produced by a drug is biologically “worthwhile.” The detection of this benefit, when truly present, is a challenge requiring large studies of 3–5 years' duration, because only a small number of women at risk actually sustain a fracture during this time. For example, in any year, fractures occur in 1–2 per 100 women approximately 65 years of age, 6–10 per 100 women approximately 75 years of age, and only 1–2 per 2,000 of the 15% of women <60 years of age with osteoporosis. An appreciation of this low annual event rate is important because (1) it helps patients to understand their illness, (2) it determines the power of clinical trials, (3) it underscores the large numbers of patients that must be treated to prevent one fracture, and (4) it underscores the need for safety, particularly in groups at low absolute risk of fracture; all are exposed to drug side effects, and the vast majority derive no benefit from treatment because they would not have had a fracture without it, despite being at risk. Few studies have met the design requirements needed to identify the antifracture efficacy of a drug when it really exists, namely, (1) large patient samples randomized to treatment or placebo for 3–4 years, (2) blinding throughout follow-up, (3) statistical analyses of preplanned comparisons using intention to treat, and (4) avoidance of statistical analyses of associations discovered by post hoc analyses. Moreover, (5) few studies have assessed long-term safety and quality of life. Consequently, the uncertainty regarding efficacy and safety of available treatments may be more of a problem of the design, execution, and interpretation of the clinical studies than of the drugs themselves. In the reduction of vertebral fracture risk, the greatest optimism exists for hormone replacement therapy (HRT) and the bisphosphonates. HRT reduces bone turnover, increases bone mineral density (BMD), and decreases vertebral fracture rates by approximately 40%, even in women > 70 years of age. Reduction in hip fracture risk with HRT has been reported in observational studies. Two rigorously conducted studies provide credible evidence that the bisphosphonate alendronate reduces the risk of vertebral and hip fractures by approximately 40–50%. Etidronate, calcitonin, and 1,25-dihydroxyvitamin D 3 may reduce risk of vertebral fracture; however, problems in study design leave uncertainty. Although 2 trials using fluoride suggest a reduction in fracture rates, the more rigorously conducted trials do not, despite having adequate power to do so. Calcium supplements are likely to slow bone loss, but reduction in fracture risk is uncertain. Vitamin D and calcium supplementation reduce risk of hip fracture in nursing home residents but not in community residents. There have been no studies of the efficacy of any treatment to prevent hip or vertebral fractures in men or in corticosteroid-related osteoporosis. The treatment of osteoporosis is becoming a reality. HRT and the bisphosphonates, particularly alendronate, appear to be the best options at present.

Fewer bone histomorphometric abnormalities with intermittent than with continuous slow-release sodium fluoride therapy.

To help resolve the uncertainty whether sodium fluoride (NaF) therapy should be given intermittently or continuously, we examined iliac crest bone biopsies (before and after treatment) and fragility fracture rates in 35 intermittently treated (group I) and 69 continuously treated (group C) patients; all received calcium. The following statistically significant results were obtained. Reduction in vertebral fracture rate was similar in the two groups. Trabecular thickness and the structurally more important mineralized thickness increased only in group I. Group I also accumulated less excess osteoid (surface, volume). Mean osteoid thickness did not change in either group because of a bimodal distribution of wide seams with osteoblasts and double tetracycline labels, and thin seams without osteoblasts or labels. Osteoid was lamellar. Osteoid in abnormal sites (within bone marrow or bone, or around osteocytes) was found less frequently in group I. Adjusted apposition rate declined and mineralization lag time increased in both groups because of extended unlabelled osteoid seams. Erosion surface increased only in group C. Hook and/or tunnel erosion was seen less frequently in group I; it was closely associated with osteoid in abnormal sites and correlated with osteoid surface. Extended osteoid surface may have forced osteoclasts to hollow out trabeculae, leaving the empty osteoid shell in marrow. Excess osteoid volume and eroded surface and osteoid and erosion in abnormal sites correlated with bone fragility in group C. We conclude that intermittent therapy is to be preferred because it (1) increased mineralized trabecular thickness, (2) did not cause excessive osteoid accumulation and erosion, (3) showed less osteoid and erosion in abnormal sites and (4) led to a similar reduction in the vertebral fracture rate as did continuous treatment. The question of whether intermittency of therapy has some other effect independent of the cumulative dose of fluoride administered cannot be answered by this study.

Fluoride Therapy for Bone Disease

The use of fluoride in the treatment of osteoporosis remains very controversial, despite its registration in many countries. Fluoride has been convincingly demonstrated to have a potent anabolic effect on osteoblastic trabecular bone formation, with a subsequent sustained increase in axial bone mass. However, its ability to reduce the vertebral fracture rate in established spinal osteoporosis is still debated, and questions have been raised regarding a potential negative effect on cortical bone mass and an increase in fractures of the peripheral skeleton, especially hip fractures. These data, including some very recent studies, are reviewed to draw some perspectives and recommendations for the use of fluoride in the treatment of osteoporosis.

Effect of Long-term Treatment with 1α (OH)D&lt;SUB&gt;3&lt;/SUB&gt;-hydroxyvitamin D&lt;SUB&gt;3&lt;/SUB&gt; on Postmenopausal Osteoporosis

The effects of long-term treatment with 1α3-hydroxyvitamin D3[1α(OH)D3] on bone mineral density, fracture incidence and chemical parameters in postmenopausal osteoporosis were examined.Thirty two postmenopausal women were divided into 2 groups: Group 1 (n=10) as the control group and Group 2 (n=22) which was given 1μg of 1α(OH)D3 per day without supplemental calcium for two to three years.Lumbar (L2-L4) bone mineral density (BMD) determined by dual energy X-ray absorptiometry was maintained for the first year and increased two and three years after the treatment with 1α(OH)D3, while BMD of controol group decreased yearly for three years. Percent change of corrected L2-L4 BMD increased by 2.55% with 1α(OH)D3 treatment and decreased by 1.32% with the control group after two years. This difference was significant (P=0.014). In all younger postmenopausal patients (55-65 years old) except for two patients, 1α(OH)D3 treatment increased the percent change of L2-L4 BMD.The vertebral fracture rate in the treated group was 39/1000 patient years and that in the control group was 111/1000 patient years although there was no significant difference in fracture rate between them. There were no patients who showed hypercalcemia nor an abnormally high serum creatinine level in both groups during the study period. These results indicate that 1α(OH)D3 treatment is effective for increasing lumber BMD without any serious adverse effects in postmenopausal osteoporosis.