Burkholderia sp. JD-TRS-9

 
National Institutes of Health

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1990-2016
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2012
2012
A rare case of neonatal Ebstein's anomaly with circular shunting was reported. A two-stage surgical procedure was performed, and… (More)
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2011
2011
zygous hypercholesterolaemias. Curr Opin Lipidol 2004;15:413–422. 34. Marais AD, Raal FJ, Stein EA, Rader DJ, Blasetto J, Palmer… (More)
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2009
2009
Fenstermacher JD. In normal rat, intraventricularly administered insulin-like growth factor-1 is rapidly cleared from CSF with… (More)
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2008
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2008
The first computer users were all programmers, and the field of Human-Computer Interaction started, in part, with a focus on… (More)
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2005
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2005
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Selective Estrogen Receptor Modulators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 5. Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6. Peptides from the Parathyroid Hormone Family . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 7. Strontium Ranelate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 8. Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 Several chemical entities have shown their ability to reduce axial and/or appendicular fractures in patients Abstract with osteoporosis. Since patients who have experienced a previous fracture are at high risk for subsequent vertebral or hip fracture, it is of prime importance to treat such patients with medications that have unequivocally demonstrated their ability to reduce fracture rates in patients with prevalent fractures. Results obtained with calcium and vitamin D, in this particular population, are not fully satisfactory and these medications are probably better used in conjunction with other therapeutic regimens. Bisphosphonates have shown their ability to reduce vertebral (alendronate, risedronate, ibandronate) and non-vertebral (alendronate, risedronate) fractures in patients with established osteoporosis. Raloxifene has also shown similar properties, notwithstanding its effect on non-vertebral fractures, which has only been derived from a post-hoc analysis limited to patients with prevalent severe vertebral fractures at baseline. This compound also has interesting non-skeletal benefits, including effects on the breast and heart. Teriparatide, a bone-forming agent, promptly reduces the rate of vertebral and all non-vertebral fractures, without significant adverse effects. Strontium ranelate, the first agent shown to concomitantly decrease bone resorption and stimulate bone formation, has also shown its ability to reduce rates of vertebral and non-vertebral fractures in patients with established osteoporosis. It significantly reduces hip fractures in elderly individuals at high risk for such events. Its safety profile is also excellent. Osteoporosis is characterized by bone fragility due to low bone the WHO defines osteoporosis as a condition characterized by a mass and modifications of the internal bone structure, with alteraBMD value at least 2.5 standard deviations below the mean for a tions of its micro-architecture.[1] Low bone mineral density (BMD) young healthy population (BMD T-score less than –2.5). In the is considered the single best predictor of risk for an individual to presence of a BMD T-score less than –2.5 and a prevalent fracture, subsequently present with an osteoporotic fracture. Consequently, the condition is called severe or established osteoporosis.[1] Of the A U T H O R P R O O F 2 Reginster & Sarlet various fragility fractures, which represent the major complication reduced incident radiographic vertebral fractures (relative risk of the disease, vertebral and hip fractures are associated with [RR] 0.58; 95% CI 0.3, 0.97) after a mean duration of 4.3 years.[6] pronounced morbidity and increased mortality.[1] Only one-third In vitamin D-replete elderly patients (mean age 78.4 years) with a of all radiologic vertebral fractures (morphometric fractures) genprevious hip fracture, a daily intake of calcium 800 mg/day in two erate symptoms (clinical vertebral fractures). In the appendicular different forms yielded incident rates of new vertebral fractures of skeleton, fractures occurring at the clavicle, humerus, wrist, pelvis, 100% and 50% above those observed in women without prevalent hip, and lower leg are considered major non-vertebral fractures. fractures, regardless of whether they were receiving calcium supAlthough several agents have been used for many years to prevent plementation. Whereas the authors concluded that oral calcium or treat osteoporosis, methodologically sound, randomized consupplementation lowered fracture rates in elderly patients, the trolled trials assessing anti-fracture efficacy at axial (vertebral) design of the study (which lacked a placebo treatment group in and appendicular (non-vertebral) sites of the skeleton have only patients with hip fractures) makes it difficult to extrapolate this become available within the last 15 years. Most of these trials have statement to women with previous hip fractures.[7] recently been summarized in evidence-based[1-3] or quantitative A recently published study, RECORD (Randomized Evaluasystematic (meta-analysis) reviews.[4] People who have had one tion of Calcium OR vitamin D), addressed specifically this issue fracture are at high risk of another. It seems, therefore, important by assigning a large cohort of people aged 70 years or older, who to provide these individuals with treatments that have unequivowere mobile before developing a low-trauma fracture, to oral cally demonstrated their ability to reduce fracture risk, in the colecalciferol 800 IU/day, calcium 1000 mg/day, both of these presence of prevalent vertebral or non-vertebral fractures. agents, or a placebo, for a follow-up that varied between 24 This article reviews the pharmacologic treatment options for months and 62 months. The incidence of new low-trauma fracture severe postmenopausal osteoporosis and secondary fracture predid not differ between patients who were receiving calcium and vention. It summarizes the available clinical evidence with respect those who were not (hazard ratio [HR] 0.94; 95% CI 0.81, 1.09), to safety and efficacy of both currently available and emerging those receiving colecalciferol or not (HR 1.02; 95% CI 0.88, 1.19), agents for the treatment of patients with severe disease. We based and those receiving the combination treatment or placebo (HR our review on studies published between 1975 and 2005 that 1.01; 95% CI 0.75, 1.36).[8] However, it should be noted that, in reported results, with a follow-up of at least 1 year, of the radiologthe RECORD study, the compliance with medication was poor. It ic or clinical evidence of fracture. declined to 63% after 2 years and might have been as low as 45% when non-responders to the questionnaire about compliance were included. Compliance and adherence are widely recognized as 1. Calcium and Vitamin D major factors affecting outcomes in osteoporosis management, and extreme caution should be used when extrapolating the results Calcium and/or vitamin D deficiency is associated with seconof the RECORD study to other settings where the adherence would dary hyperparathyroidism, increased bone turnover, and bone loss be better.[9] with increased fracture risk. Calcium deficiency is most often Calcium and/or vitamin D supplementation has been repeatedlinked to inadequate intake of dietary calcium, while factors that ly[10,11] but not systematically[12] suggested to be an effective way contribute to low vitamin D levels include low exposure to sunto reduce osteoporotic fractures (mainly at non-vertebral sites) in light, decreased synthesis in skin, and reduced intestinal absorpelderly patients at increased risk; however, similar positive effects tion related to aging and limited dietary sources.[5] Whereas severhave not been clearly established in patients with prevalent fracal randomized controlled trials and/or meta-analyses have been tures. Currently available results are more supportive of their use performed to assess the efficacy and safety of calcium and/or in combination with another therapeutic regimen in this particular vitamin D supplementation in the prevention of osteoporotic fracindication.[2] tures in elderly individuals, few of them were designed to answer this question in individuals who had already experienced a previous fracture. Between 1975 and 2004, only two studies assessed 2. D-Hormones (Active Metabolites of Vitamin D) incident fracture rates in women with severe osteoporosis receiving calcium supplementation. In women over the age of 60 years Alfacalcidol [1-α(OH)D3] and calcitriol [1.25(OH)2D3] have with prevalent vertebral fractures who were consuming <1 g/day been investigated for more than 2 decades in patients with severe of calcium, supplementation with calcium carbonate 1200 mg/day osteoporosis but, in most studies, the methodology used either for  2006 Adis Data Information BV. All rights reserved. Treat Endocrinol 2006; 5 (1) A U T H O R P R O O F Treatment of Severe Postmenopausal Osteoporosis 3 selection of patients or for the assessment of the fracture outcomes ture outcomes in primary osteoporosis[21] or in older people,[22] makes it rather difficult to draw unequivocal conclusions.[13] two recent meta-analyses yielded conflicting results, suggesting either a lower adjusted global RR for fracture when patients were In Japanese women (mean age 71.9 years), with low bone mass allocated to hydroxylated forms[21] or no evidence of advantages of and prevalent fractures at baseline, 1 μg/day of alfacalcidol rethe D-hormone compared with native vitamin D.[22] The latter duced new vertebral fracture rates after 1 year. However, the meta-analysis concluded that the risk of hypercalcemia was particcontrol patients had 1.89 fractures/patient at baseline whereas the ularly high with calcitriol (RR 14.94; 95% CI 2.95, 75.61) comtreated patients had only 1.24 fractures/patient at baseline.[14] pared with placebo or calcium. There was no evidence that vitaConsequently, some of the observed differences between the min D (plain or hydroxylated) increased gastrointestinal sympgroups may be attributed to baseline differences in fracture sustoms (RR 1.03; 95% CI 0.79, 1.36) or renal disease (RR 0.80; 95% ceptibility between the treatment and placebo groups, rather than CI 0.34, 1.87).[22] to the effects of the treatment.[15] A recent re-analysis of the results A number of results, either from randomized controlled trials or of this study did not reach similar conclusions and questioned the meta-analyses, suggest that active vitamin D metabolites, mainly axial (RR 0.37; 95% CI 0.09, 1.44) and appendicular (RR 1.10; alfacalcidol, may exert a preventive effect on fracture recurrence 95% CI 0.02, 2) anti-fracture efficacies of alfacalcidol.[16] Another in women with established osteoporosis. Besides their actions Japanese study showed a positive effect of alfacalcidol (1 μg/day) through the classical pathway of interfering with bone strength, on vertebral fracture rates (RR 0.46; 95% CI 0.31, 0.69) but the some recent data also suggested that alfacalcidol might reduce the information provided in the original publication[17] does not aupropensity of elderly individuals to fall.[23] thoritatively confirm the prevalence of fractures in all individuals at baseline. Pharmacologic management of established osteoporosis with calcitriol yielded conflicting results. A mean dosage 3. Calcitonin of 0.43 μg/day given to postmenopausal women with vertebral compression fractures did not provide a significant benefit comCalcitonin is an endogenous polypeptidic hormone that inhibits pared with placebo (RR for new vertebral fracture 1.46; 95% CI osteoclastic bone resorption.[2] The vast majority of clinical trials 0.59, 3.62 and RR for non-vertebral fracture 2.20; 95% CI 0.52, have been performed with salmon calcitonin, which is 40–50 times 9.24) after 2 years.[16,18] In addition, no differences between the more potent than human calcitonin.[2] Most of the initial studies groups were observed for vertebral fractures in a study assessing using injectable[24,25] or intranasal[26,27] salmon calcitonin that were calcitriol (dose adjusted to maintain serum calcium <11 mg/dL) in performed in women with established osteoporosis were of insufwomen with vertebral fractures (RR 0.90; 95% CI 0.42, 1.83).[19] ficient size to draw significant conclusions. The PROOF (Prevent However, these two studies were largely underpowered to assess Recurrence Of Osteoporotic Fracture) study randomized 1255 an effect of the tested medication on fracture rates (including n = women with prevalent fractures to salmon calcitonin nasal spray 86[18] and n = 50[19] patients, respectively). In a larger single-blind, (100, 200, or 400 IU/day) or placebo for 5 years. Despite an randomized controlled trial (n = 622), women who received calciimportant proportion of patients lost to follow-up (59.3%), the triol (0.50 μg/day) and calcium (1 g/day) for 3 years had fewer PROOF study concluded that there was a borderline significant fractures than those who received calcium alone. The reduction in reduction in vertebral fracture rates (RR 0.79; 95% CI 0.62, 1) for vertebral fracture rate was significant (RR 0.43; 95% CI 0.31, the 200 IU/day group, while no significant effects were observed 0.61) overall, but mainly driven by an unexplained increase in for the 100 IU/day and 400 IU/day groups.[28] With regard to nonfracture rates observed during the second and third years in women vertebral fractures, the pooled effect did not reach statistical receiving calcium alone. This beneficial effect of calcitriol was significance (RR 0.80; 95% CI 0.59, 1.09). The absence of a evident only in women who had no more than five vertebral clearcut dose dependence for fracture prevention is a seriously fractures at baseline. The author claimed a significant difference in troubling feature in this study. Generally speaking, the tolerance of the number of peripheral fractures but further reassessment of the nasal salmon calcitonin was good but the reporting of adverse results showed this to be of only borderline statistical significance events was rather poor.[2,28] A recent meta-analysis suggested a (RR 0.50; 95% CI 0.25, 1).[16,20] non-significant increase in rhinitis (RR 1.72; 95% CI 0.92, 3.23) in treated patients.[29] The respective beneficial effects of native or hydroxylated forms of vitamin D were not directly compared in women with Calcitonin is likely to reduce the risk of vertebral fractures in prevalent fractures. However, considering all trials reporting fracpatients with established osteoporosis. However, the marginal  2006 Adis Data Information BV. All rights reserved. Treat Endocrinol 2006; 5 (1) A U T H O R P R O O F 4 Reginster & Sarlet effect size of the reduction, the absence of proven efficacy against fracture efficacy of raloxifene 60 mg/day. During the fourth year, non-vertebral fractures, and the prohibitive costs of the nasal if results in the fourth year were considered separately, the risk of a formulation make its interest at least questionable. new vertebral fracture was reduced by 48% (RR 0.52; 95% CI 0.35, 0.78) in patients who had a prevalent vertebral fracture before starting the study.[34] 4. Selective Estrogen Receptor Modulators The MORE study was continued for an additional 4 years (CORE [Continuing Outcomes Relevant to Evista]). The risk of at Selective estrogen receptor modulators are non-hormonal comleast one new non-vertebral fracture was similar in the placebo pounds that have the property of binding to estrogen receptors in (22.9%) and raloxifene (22.8%) groups. The incidence of at least various tissues. They behave like estrogen agonists towards some one new non-vertebral fracture at six major sites (clavicle, humetarget tissues (e.g. bone, liver), but they exert an estrogen antagorus, wrist, pelvis, hip, lower leg) was 17.5% in both groups. nistic action on the breast and/or (according to the drug) an action However, a decreased risk at six major non-vertebral sites was on other female sexual organs, such as the uterus, that may or may seen in women with prevalent vertebral fractures (RR 0.78; 95% not be agonistic. CI 0.63, 0.96).[35] Some extraskeletal effects have been observed In the MORE (Multiple Outcomes of Raloxifene Evaluation) with raloxifene. After 3 years of therapy, 13 cases of breast cancer study,[30] 7705 postmenopausal women (who were at least 2 years’ developed in the 5129 women receiving raloxifene versus 27 cases postmenopausal) received raloxifene 60 mg/day or 120mg/day or in the 2576 women receiving placebo (RR 0.24; 95% CI 0.13, placebo. All women received calcium (500 mg/day) and vitamin D 0.44). Raloxifene reduced the risk of estrogen receptor-positive (400 IU/day) supplementation. The main endpoint of MORE was breast cancer by 90% (RR 0.10; 95% CI 0.04, 0.24), but did not the reduction in the percentage of women developing a new reduce the risk of estrogen receptor-negative invasive breast canvertebral fracture when receiving raloxifene. The secondary cer (RR 0.88; 95% CI 0.26, 3).[36] In the MORE study, there was endpoints assessed the RR for non-vertebral fractures, breast canno significant difference in the incidence of combined coronary cer, and cardiovascular events. After the 3-year study period, the and cerebrovascular complications between raloxifene and placeRR of incident vertebral fracture was significantly decreased in bo recipients in the overall cohort. However, in 1035 women with women with prevalent vertebral fractures (RR 0.70; 95% CI 0.56, increased cardiovascular risk at baseline, a decrease of 40% in the 0.86).[30] Raloxifene, at a dosage of 60 mg/day, reduced the risk of incident clinical vertebral fracture by 66% during the first year of risk of cardiovascular complications was observed in those receivtherapy (RR 0.34; 95% CI 0.11, 0.77) in the group of women with ing raloxifene (RR 0.60; 95% CI 0.38, 0.95).[37] Hot flashes were prevalent vertebral fractures.[31] The risk of a non-vertebral fracthe most frequent adverse effect, leading to withdrawal from ture was not significantly different between the group of patients therapy in 0.1%, 0.7%, and 0.5% of women receiving placebo, treated with either raloxifene 60 mg/day or 120 mg/day and those raloxifene 60mg, and raloxifene 120mg, respectively. Leg cramps treated with placebo (RR 0.9; 95% CI 0.8, 1.1). However, in a were more frequent in those women receiving raloxifene (7% in post-hoc analysis, a subgroup of patients who had a severe vertethe 60mg group and 6.9% in the 120mg group) than in those bral fracture (semi-quantitative grade 3) before starting the study receiving placebo (3.7%).[30] After 3 years, raloxifene was associ(n = 614) experienced a significant decrease in the risk of nonated with an increased risk of venous thromboembolic complicavertebral fractures within the 3 years of the study. In this group tions (RR 3.1; 95% CI 1.5, 6.2) but did not increase the risk of with severe osteoporosis, raloxifene 60 mg/day allowed a reducendometrial cancer (RR 0.8; 95% CI 0.2, 2.7).[30] tion of 26% in the risk of new vertebral fracture (RR 0.74; 95% CI Raloxifene at the dosage of 60 mg/day, the dose approved for 0.54, 0.99) and a reduction of 47% in the non-vertebral fracture therapy, is able to prospectively produce a significant decrease in risk (clavicle, humerus, wrist, pelvis, hip, and leg) [RR 0.53; 95% the vertebral fracture risk in postmenopausal women with estabCI 0.29, 0.99].[32] During the 3 years of the MORE study, raloxlished osteoporosis.[2,30] There are some convergent, but retrospecifene led to a significant 37% decrease (RR 0.63; 95% CI 0.49, tive, data tending to demonstrate that raloxifene could also prevent 0.83) in the occurrence of one new moderate or severe vertebral non-vertebral fractures in patients with severe osteoporosis.[32] fracture in women with at least one prevalent vertebral fracture Raloxifene might also confer some extraskeletal advantages, such before initiation of therapy.[33] Moreover, the extension of the MORE study to a fourth year confirmed the persistence of the antias prevention of breast cancer and cardiovascular events.[36,37]  2006 Adis Data Information BV. All rights reserved. Treat Endocrinol 2006; 5 (1) A U T H O R P R O O F Treatment of Severe Postmenopausal Osteoporosis 5 5. Bisphosphonates been compared in a double-blind, 1-year study involving a total of 1258 postmenopausal osteoporotic women.[40] This study included both patients with low BMD and patients with prevalent vertebral Bisphosphonates are synthetic analogs of the naturally occuror hip fractures. The increases in BMD at the lumbar spine, hip, ring pyrophosphates. Bisphosphonates localize preferentially to and total body were similar for the three regimens and the fall in sites of active bone remodeling.[2] They act directly on mature bone turnover markers was also quite similar. The gastrointestinal osteoclasts, decreasing their bone resorption activity. Moreover, tolerability of the once-weekly regimen and daily administration bisphosphonates can induce osteoclast apoptosis.[2] were similar.[40] The anti-fracture efficacy of the weekly formulaEtidronate is administered intermittently (400 mg/day for 2 tion is assumed to be similar to that of the daily formulation, but weeks every 3 months) for 3–5 years. Several studies of similar this has not been formally tested. design have examined the anti-fracture efficacy of cyclical Risedronate efficacy has been extensively tested in doubleetidronate in postmenopausal women with prevalent vertebral blind, placebo-controlled trials. Risedronate at a dosage of 5 mg/ fractures.[2] Methodologic problems with fracture assessment, limday for 3 years has thus been shown to significantly reduce the ited statistical power, potential toxicity of the compound with vertebral fracture risk in established osteoporosis compared with regard to bone mineralization, the necessity to perform post-hoc placebo.[41,42] In women with at least one vertebral fracture at analyses to show an effect regarding the prevention of new vertebaseline, the relative reduction in new vertebral fractures was 41% bral fractures in postmenopausal women with low bone mass, and (RR 0.59; 95% CI 0.42, 0.82), and a 39% reduction was seen for patients with multiple prevalent vertebral fractures led to the non-vertebral fractures (RR 0.61; 95% CI 0.39, 0.94).[41] In woconclusion that etidronate was a largely obsolete form of thermen with at least two vertebral fractures at baseline, the risk of apy.[2] new vertebral fractures was reduced by 49% (RR 0.51; 95% CI Oral alendronate for the treatment of osteoporosis has been 0.36, 0.73) but, in this study, the effect on new non-vertebral extensively studied under randomized controlled trial conditions. fractures was not significant (RR 0.67; 95% CI 0.44, 1.04).[42] In In an initial 3-year study, alendronate significantly increased BMD both studies, the effect on the vertebral fracture rate was signifiand reduced the incidence of new vertebral deformities when cant after 1 year. Pooling of both studies showed that after 1 year given in different doses to osteoporotic women, 20% of whom had of treatment, the risk of new vertebral fractures was reduced by prevalent vertebral deformities.[38] At the end of 3 years, one or 62% (RR 0.38; 95% CI 0.25, 0.56) and the risk of multiple new more new vertebral fractures had occurred in 6.2% of women in vertebral fractures was reduced by 90% (RR 0.10; 95% CI 0.04, the placebo group and in 3.2% of women treated with alendronate. 0.26).[43] The European study[41] was continued blindly in a subset Alendronate reduced the vertebral fracture rate by 48% (RR 0.52; of the population and the anti-fracture efficacy was maintained for 95% CI 0.28, 0.95).[38] The anti-fracture efficacy of alendronate at least 5 years.[44] More recently, vertebral fracture risk reduction has been best established in two large populations of postmewith risedronate was confirmed in women aged >80 years with nopausal women, one with and one without pre-existing vertebral documented osteoporosis (RR 0.56; 95% CI 0.39, 0.81).[45] The fractures.[2,39] The daily dose of alendronate was 5mg for the first 2 vertebral fracture efficacy of risedronate has recently been shown years and 10mg thereafter. In the study including 2027 women to be largely independent of the presence of clinical risk factors for with established osteoporosis (i.e. with at least one prevalent osteoporotic fractures.[46] vertebral fracture at baseline), alendronate reduced the incidence of new vertebral fractures by 47% (RR 0.53; 95% CI 0.41, 0.68). Risedronate has also been shown to decrease the incidence of The incidence of vertebral fractures with clinical symptoms was hip fractures in a controlled trial specifically designed for that similarly reduced (RR 0.46; 95% CI 0.28, 0.75). There was no purpose.[47] However, hip fracture reduction was only observed in reduction in the overall risk of non-vertebral fractures (RR 0.80; women with documented osteoporosis. In this placebo-controlled 95% CI 0.63, 1.01), but hip fracture incidence was also reduced study involving 5445 women aged 70–79 years who had osteo(RR 0.49; 95% CI 0.23, 0.99) as was wrist fracture risk (RR 0.52; porosis and risk factors for falls, it was shown that risedronate 2.5 95% CI 0.31, 0.87).[39] mg/day or 5 mg/day for 3 years (the actual mean duration of Daily compliance with 10mg of alendronate is uncertain and treatment was 2 years) lowered the risk of hip fracture by 40% (RR difficult to maintain in routine clinical practice. The efficacy and 0.6; 95% CI 0.4, 0.9). There was no dose effect and, interestingly, safety of treatment with oral, once-weekly alendronate 70mg, the effect was greater in the group of women who had a vertebral twice-weekly alendronate 35mg, and daily alendronate 10mg have fracture at baseline (RR 0.4; 95% CI 0.2, 0.8). However, in the  2006 Adis Data Information BV. All rights reserved. Treat Endocrinol 2006; 5 (1) A U T H O R P R O O F 6 Reginster & Sarlet same study there was no significant effect of risedronate in 3886 monthly oral ibandronate in the treatment of postmenopausal women aged ≥80 years (RR 0.8; 95% CI 0.6, 1.2), but these osteoporosis. patients were essentially selected on the basis of the presence of at Bisphosphonates have been shown to reduce vertebral fractures least one risk factor for hip fracture, such as difficulty standing (alendronate, risedronate, ibandronate) and hip fractures (alenfrom a sitting position or a poor tandem gait, rather than on the dronate, risedronate) in women with established osteoporosis (low basis of low BMD or prevalent fractures.[47] BMD and prevalent fractures). There is currently no compelling Like alendronate, risedronate has also shown a good safety evidence for significant differences in the magnitude of treatment profile in clinical trials.[1,2] The safety profile of risedronate was effects between bisphosphonates. similar to that of placebo, despite the fact that, unlike in the alendronate trials, patients with a history of gastrointestinal dis6. Peptides from the Parathyroid Hormone Family ease or long-term use of NSAIDs were not excluded from the Peptides from the parathyroid hormone (PTH) family have risedronate studies. A weekly formulation of risedronate has also been investigated in the management of osteoporosis for more been developed and, as for alendronate, has been shown to be than 30 years. Continuous endogenous production or exogenous therapeutically equivalent to the daily formulation as judged by administration of PTH, as is the case in primary or secondary the effects on bone density and on bone turnover.[48] hyperparathyroidism, can lead to deleterious consequences on the A large, 3-year, multinational, double-blind, placebo-conskeleton, particularly on cortical bone.[1,2,53] However, daily adtrolled, phase III, fracture prevention study (BONE [iBandronate ministration of PTH (e.g. through daily subcutaneous injections) Osteoporosis vertebral fracture trial in North America and Euresults in an increase of the number and activity of osteoblasts, rope])[49] explored the efficacy and safety of daily (2.5mg) and leading to an increase in bone mass and an improvement in intermittent (between course interval >2 months; 20mg every skeletal architecture, at both the trabecular and cortical skeleton. other day for 12 doses every 3 months) oral ibandronate in the This treatment also increases cortical bone width. treatment of postmenopausal osteoporosis. The BONE study enIn order to assess the effects of teriparatide (the 1–34 aminorolled 2946 postmenopausal women with a BMD T-score at the terminal fragment of PTH) on fractures, 1637 postmenopausal lumbar spine of less than or equal to –2 and one to four prevalent women with prior vertebral fractures were randomly assigned to vertebral fractures. Both regimens were similarly effective and receive 20μg or 40μg of teriparatide or placebo, self-administered significantly reduced the rate of new morphometric vertebral subcutaneously daily.[53] fractures by 62% (RR 0.38; 95% CI 0.25, 0.59) and 50% (RR 0.50; New vertebral fractures occurred in 14% of women in the 95% CI 0.34, 0.74), respectively, versus placebo; the difference placebo group and in 5% and 4%, respectively, of women in the between the two treatment regimens was not statistically signifi20μg and 40μg dose groups. The RRs for fracture compared with cant. As well as reducing the risk of new morphometric vertebral the placebo group were 0.35 and 0.31 (95% CI 0.22, 0.55 and 0.19, fractures, oral daily and intermittent ibandronate reduced the risk 0.50), respectively. New non-vertebral fragility fractures occurred of new and worsening vertebral fractures (62% and 50%, respecin 6% of women in the placebo group and 3% of women in each tively) to a statistically significant extent and decreased the risk of teriparatide group (RR 0.47 and 0.46; 95% CI 0.25, 0.88 and 0.25, new clinical vertebral fractures (by 49% and 48%, respectively), 0.86, respectively). relative to placebo, after 3 years.[49] Teriparatide had only minor side effects (occasional nausea and The overall population was at a low risk for osteoporotic headache).[53] fractures. Consequently, the incidence of non-vertebral fractures The anti-fracture efficacy of teriparatide with regard to the was similar between the ibandronate and placebo groups after 3 spine was not modulated by the age of the individuals (<65 years, years (9.1%, 8.9%, and 8.2% in the daily, intermittent, and placebo 65–75 years, or >75 years), prevalent spinal BMD values (T-score groups, respectively; difference between arms not significant). A less than or equal to –2.5 or greater than or equal to –2.5), or the post-hoc analysis reported a 69% reduction in non-vertebral fracnumber of prevalent fractures (one or two or more fractures).[54] tures in the daily treatment group when considering high-risk patients with a femoral neck T-score less than –3.[50] At the end of this trial, patients were followed for an additional 18-month period without teriparatide, during which they were A monthly oral formulation of ibandronate (150mg) was reallowed to use any anti-osteoporotic medication considered approcently shown to be highly effective in decreasing bone turnover[51] priate by their caregiver. While the proportion of patients who and increasing BMD,[52] suggesting a potential role for once 2006 Adis Data Information BV. All rights reserved. Treat Endocrinol 2006; 5 (1) A U T H O R P R O O F Treatment of Severe Postmenopausal Osteoporosis 7 received an inhibitor of bone resorption was slightly higher among FIRST (Fracture International Run-in Strontium ranelate Trials). those previously in the placebo group than those who received 20 Throughout the studies, the patients received calcium/vitamin D μg/day of teriparatide, the reduction of non-vertebral fractures supplements that were individually adapted according to their observed in the teriparatide group during the initial trial was deficiencies (500mg or 1000mg of calcium, and 400IU or 800IU confirmed during the 18-month period of follow-up (RR 0.59; of colecalciferol). From more than 9000 osteoporotic postme95% CI 0.42, 0.85).[55] All participants in this trial were invited to nopausal women who took part in FIRST, 1649 patients were participate in an additional follow-up, to assess non-vertebral included in SOTI, with a mean age of 69 years, and 5091 patients fragility fractures for an overall 50-month period including treatwere included in TROPOS, with a mean age of 77 years.[57,58] ment and follow-up. The HR for non-vertebral fragility fractures At the end of the first year of the vertebral fracture study, there in each teriparatide group relative to placebo was statistically was a 49% lower risk of a new vertebral fracture in the strontium significant for the 50-month period (20 μg/day: HR 0.62; 95% CI ranelate group than in the placebo group (RR 0.51; 95% CI 0.36, 0.41, 0.93 and 40 μg/day: HR 0.52; 95% CI 0.34, 0.82). In the 0.74), and a 52% lower risk of symptomatic fracture (RR 0.48; follow-up period, the HR indicated a significant difference be95% CI 0.29, 0.80). Over the entire 3-year study period, the tween the 40μg group versus the placebo group but not between strontium ranelate group had a 41% lower risk of a new vertebral the 20μg group versus the placebo group. However, the 20μg and fracture than the placebo group (RR 0.59; 95% CI 0.48, 0.73). The 40μg groups were not significantly different from each other. The proportion of patients with more than one new vertebral fracture analysis of time to fracture showed that the fracture incidence in over the 3-year period was 6.4% in the strontium ranelate group the former placebo and teriparatide groups diverged during the and 9.8% in the placebo group (RR 0.64; 95% CI 0.44, 0.93). 50-month period that included teriparatide treatment and followThere was a 38% lower risk of symptomatic vertebral fracture in up (p = 0.009).[56] the strontium ranelate group than in the control group over a Treatment of postmenopausal osteoporosis with teriparatide period of 3 years (RR 0.62; 95% CI 0.47, 0.83; p < 0.001).[58] decreases the risk of vertebral and non-vertebral fractures, and is Strontium ranelate was well tolerated, without any specific well tolerated. The 40μg dose increases BMD more than the 20μg adverse events, and no deleterious effects on the rates of nondose but has similar effects on the risk of fractures and is more vertebral fractures were observed.[58] likely to have adverse effects (such as transient hypercalcemia, In the whole population of the non-vertebral fracture study, which was of no concern with the 20 μg/day dosage). strontium ranelate was associated with a 16% risk reduction for all non-vertebral fractures over a 3-year follow-up period (RR 0.84; 95% CI 0.70, 0.99) and with a 19% reduction in the risk of major 7. Strontium Ranelate non-vertebral osteoporotic fractures (RR 0.81; 95% CI 0.66, 0.98). Strontium ranelate appears to have a particular profile characIn the high-risk fracture subgroup (women aged ≥74 years and terized by an inhibition of bone resorption and a stimulation of with femoral-neck BMD T-scores less than or equal to –3), treatbone formation, suggesting that, for the first time, a chemical ment was associated with a 36% reduction in the risk of hip entity used in the treatment of osteoporosis could be targeted to an fracture (RR 0.64; 95% CI 0.41, 0.99). A reduction in the risk for uncoupling of the bone remodeling process. new vertebral fracture of 39% over 3 years was obtained in the strontium ranelate group (RR 0.61; 95% CI 0.51, 0.73) with a 45% Strontium ranelate has been investigated in a large phase III reduction (RR 0.55; 95% CI 0.39, 0.77) over the first year of program that included two extensive clinical trials in the treatment treatment. In these 3640 patients, 66.4% had no prevalent vertebral of severe osteoporosis: SOTI (Spinal Osteoporosis Therapeutic fracture at inclusion. In the subgroup of patients with at least one Intervention) and TROPOS (TReatment Of Peripheral OSteoprevalent fracture (n = 1224; 587 in the strontium ranelate group porosis) aimed at evaluating the effect of strontium ranelate on and 637 in the placebo group), the risk of experiencing a new spinal and peripheral (non-spinal) fractures.[17,57] Both studies vertebral fracture was reduced by 32% (RR 0.68; 95% CI 0.53, were randomized, double-blind, placebo-controlled and multina0.85).[57] tional with two parallel groups (strontium ranelate 2 g/day vs placebo), with a study duration of 5 years, with the main statistical Treatment was well tolerated; the incidence of adverse events analysis planned after 3 years. was well balanced between the two groups (87.9% in the strontium All patients included in these two studies had previously particranelate group and 88.9% in the placebo group), as was the ipated in a normalization of calcium and vitamin D study called occurrence of serious adverse events (24.7% in the strontium  2006 Adis Data Information BV. All rights reserved. Treat Endocrinol 2006; 5 (1) A U T H O R P R O O F 8 Reginster & Sarlet Evaluation of Calcium Or Vitamin D, RECORD): a randomised placeboranelate group and 24.4% in the placebo group) and withdrawals controlled trial. Lancet 2005; 365: 1621-8 due to adverse events (24.2% in the strontium ranelate group and 9. Sambrook P. Vitamin D and fractures: quo vadis? Lancet 2005; 365: 1599-600 10. Chapuy MC, Arlot ME, Delmas PD, et al. Effect of calcium and cholecalciferol 21.6% in the placebo group).[57,58] Nausea (7.2% vs 4.4%), diartreatment for three years on hip fractures in elderly women. BMJ 1994; 308: rhea (6.7% vs 5%), headache (3.4% vs 2.4%), and dermatitis and 1081-2 eczema (5.5% vs 4.1%) were reported more commonly in the 11. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. strontium ranelate group, but only during the first 3 months of JAMA 2005; 293: 2257-64 treatment; after 3 months there was no difference between groups 12. Porthouse J, Cockayne S, King C, et al. Randomised controlled trial of calcium and supplementation with cholecalciferol (vitamin D3) for prevention of fractures concerning nausea and diarrhea. Upper gastrointestinal symptoms in primary care. BMJ 2005; 330: 1003-8 were comparable between the two groups (incidence of gastritis: 13. Richy F, Ethgen O, Bruyère O, et al. Efficacy of alphacalcidol and calcitriol in 2.3% in the strontium ranelate groups and 2.7% in the placebo primary and corticosteroid-induced osteoporosis: a meta-analysis of their effects on bone mineral density and fracture rate. Osteoporos Int 2004; 15: 301-10 group).[57] 14. Orimo H, Shiraki M, Hayashi Y, et al. Effect of 1 alpha-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postme8. Conclusion nopausal osteoporosis. Calcif Tissue Int 1994; 54: 370-6 15. Blank RD, Bockman RS. A review of clinical trials of therapies for osteoporosis using fracture as an end point. J Clin Densitom 1999; 2: 435-52 Several chemical entities have shown their ability to signifi16. Papadimitropoulos E, Wells G, Shea B, et al. VIII: meta-analysis of the efficacy of cantly reduce both vertebral and all non-vertebral and/or hip vitamin D treatment in preventing osteoporosis in postmenopausal women. Endocr Rev 2002; 28: 560-9 fractures in women with established osteoporosis. Inhibitors of 17. Orimo H, Shiraki M, Hayashi T, et al. Reduced occurrence of vertebral crush bone resorption (selective estrogen receptor modulators, bisphosfractures in senile osteoporosis treated with 1 alpha (OH)-vitamin D3. Bone phonates, calcitonin), anabolic agents (teriparatide), or agents with Miner 1987; 3: 47-52 18. Ott SM, Chesnut CH. Calcitriol treatment is not effective in postmenopausal<lb>a dual mode of action (strontium ranelate) should be combined<lb>osteoporosis. Ann Intern Med 1989; 110: 267-74<lb>with an adequate supplementation of calcium and vitamin D.<lb>19. Gallagher JC, Goldar D. Treatment of postmenopausal osteoporosis with high<lb>doses of synthetic calcitriol: a randomized controlled study. Ann Intern Med<lb>1990; 113: 649-55<lb>Acknowledgments<lb>20. Tilyard MW, Spears GF, Thomson J, et al. Treatment of postmenopausal osteo-<lb>porosis with calcitriol or calcium. N Engl J Med 1992; 326: 357-62<lb>No sources of funding were used to assist in the preparation of this review.<lb>21. Richy F, Schacht E, Bruyère O, et al. Vitamin D analogs versus native vitamin D in<lb>Dr Reginster has been on the advisory boards of and has received consulting<lb>preventing bone loss and osteoporosis-related fractures: a comparative meta-<lb>fees from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline,<lb>analysis. Calcif Tissue Int 2005; 76: 176-86<lb>Roche, Merckle, Nycomed, NPS, and Theramex; has received lecture fees 22. Avenell A, Gillespie W, Gillespie L, et al. Vitamin D and vitamin D analogues for<lb>preventing fractures associated with involutional and post-menopausal osteo-<lb>from Merck Sharp and Dohme, Lilly, Rottapharm, IBSA, Genevrier, Novartis,<lb>porosis. Cochrane Database Syst Rev 2005; (3): CD000227<lb>Servier, Roche, Merckle, Teijin, Analis, Theramex, Nycomed, and Novo-<lb>23. Schacht E, Richy F, Reginster JY. The therapeutic effects of alfacalcidol on bone<lb>Nordisk; and grant support from Bristol Myers Squibb, Fondation Leon<lb>strength, muscle metabolism and prevention of falls and fractures. J Muscu-<lb>Frédéricq (Liège), Standard de Liège, Merck Sharp & Dohme, Novartis,<lb>loskelet Neuronal Interact 2005; 5: 273-84<lb>Roche, and GlaxoSmithKline. Dr Sarlet has no conflicts of interest that are 24. Rico H, Revilla M, Hernandez ER, et al. Total and regional bone mineral content<lb>directly relevant to the content of this review.<lb>and fracture rate in postmenopausal osteoporosis treated with salmon<lb>calcitonin: a prospective study. Calcif Tissue Int 1995; 56: 181-5 25. Gennari C, Chierichetti SM, Bigazzi S, et al. Comparative effects on bone mineral<lb>References<lb>content of calcium plus salmon calcitonin given in two different regimens in<lb>postmenopausal osteoporosis. Curr Ther Res 1995; 38: 455-62<lb>1. Delmas PD. Treatment of postmenopausal osteoporosis. Lancet 2002; 359: 2018-<lb>26<lb>26. Hizmetli S, Elden H, Kaptanoglu E, et al. The effect of different doses of calcitonin<lb>2. Boonen S, Body JJ, Boutsen Y, et al. Evidence-based guidelines for the treatment<lb>on bone mineral density and fracture risk in postmenopausal osteoporosis. Int J<lb>of postmenopausal osteoporosis: a consensus document of the Belgian Bone<lb>Clin Pract 1998; 52: 453-5<lb>Club. Osteoporos Int 2005; 16: 239-54<lb>27. Abellan Perez M, Bayina Garcia FJ, Calabozo M, et al. Multicenter comparative<lb>3. Reginster JY. Treatment of postmenopausal osteoporosis. BMJ 2005; 330: 859-60<lb>study of synthetic salmon calcitonin administered nasally in the treatment of<lb>established postmenopausal osteoporosis. An Med Interna 1995; 12: 12-6<lb>4. Cranney A, Guyatt G, Griffith L, et al. IX: summary of meta-analyses of therapies<lb>for postmenopausal osteoporosis. Endocr Rev 2002; 23: 570-8<lb>28. Chesnut CH, Silverman S, Andriano K, et al. A randomized trial of nasal spray<lb>5. Reginster JY. The high prevalence of inadequate serum vitamin D levels and<lb>salmon calcitonin in postmenopausal women with established osteoporosis: the<lb>implications for bone health. Curr Med Res Opin 2005; 21: 579-86<lb>Prevent Recurrence Of Osteoporotic Fractures study. Am J Med 2000; 109:<lb>267-76<lb>6. Recker RR, Hinders S, Davies KM, et al. Correcting calcium nutritional deficiency<lb>prevents spine fractures in elderly women. J Bone Miner Res 1996; 11: 1961-6 29. Cranney A, Tugwell P, Zytaruk N, et al. VI: meta-analysis of calcitonin for the<lb>treatment of postmenopausal osteoporosis. Endocr Rev 2002; 28: 540-51<lb>7. Chevalley T, Rizzoli R, Nydegger V, et al. Effects of calcium supplements on<lb>femoral bone mineral density and vertebral fracture rate in vitamin-D-replete 30. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in<lb>elderly patients. Osteoporos Int 1994; 4: 245-52<lb>postmenopausal women with osteoporosis treated with raloxifene: results from<lb>8. Grant AM, Avenell A, Campell MK, et al. Oral vitamin D3 and calcium for<lb>a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation<lb>secondary prevention of low-trauma fractures in elderly people (Randomised<lb>(MORE) Investigators. JAMA 1999; 282: 637-45  2006 Adis Data Information BV. All rights reserved.<lb>Treat Endocrinol 2006; 5 (1) A<lb>U<lb>T<lb>H<lb>O<lb>R<lb>P<lb>R<lb>O<lb>O<lb>F<lb>Treatment of Severe Postmenopausal Osteoporosis<lb>9 31. Maricic M, Adachi JD, Sarkar S, et al. Early effects of raloxifene on clinical 46. Kanis JA, Barton IP, Johnell O. Risedronate decreases fracture risk in patients<lb>vertebral fractures at 12 months in postmenopausal women with osteoporosis.<lb>selected solely on the basis of prior vertebral fracture. Osteoporos Int 2005; 16:<lb>Arch Intern Med 2002; 162: 1140-3<lb>475-82 32. Delmas PD, Genant HK, Crans GG, et al. Severity of prevalent vertebral fractures 47. McClung MR, Geusens P, Miller PD, et al. Effect of risedronate on the risk of hip<lb>and the risk of subsequent vertebral and nonvertebral fractures: results from<lb>fracture in elderly women. N Engl J Med 2001; 344: 333-40<lb>MORE trial. Bone 2003; 33: 522-32<lb>48. Brown JP, Kendler DL, McClung MR, et al. The efficacy and tolerability of<lb>33. Siris E, Adachi JD, Lu Y, et al. Effects of raloxifene on fracture severity in<lb>risedronate once a week for the treatment of postmenopausal osteoporosis.<lb>postmenopausal women with osteoporosis: results from the MORE study.<lb>Calcif Tissue Int 2002; 71: 103-11<lb>Multiple Outcomes of Raloxifene Evaluation. Osteoporos Int 2002; 13: 907-13<lb>49. Delmas PD, Recker RR, Chesnut CH, et al. Daily and intermittent oral ibandronate<lb>34. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral<lb>normalize bone turnover and provide significant reduction in vertebral fracture<lb>fracture risk reduction in postmenopausal women with osteoporosis: four-year<lb>risk: results from the BONE study. Osteoporos Int 2004; 15: 792-8<lb>results from a randomized clinical trial. J Clin Endocrinol Metab 2002; 87:<lb>3609-17<lb>50. Chesnut CH, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis.<lb>35. Siris ES, Harris ST, Eastell R, et al. Skeletal effects of raloxifene after 8 years:<lb>J Bone Miner Res 2004; 19: 1241-9<lb>results from the continuing outcomes relevant to Evista (CORE) study. J Bone<lb>Miner Res 2005; 20: 1514-24<lb>51. Reginster JY, Wilson KM, Dumont E, et al. Monthly oral ibandronate is well<lb>36. Cummings SR, Eckert S, Krueger KA, et al. The effect of raloxifene on risk of<lb>tolerated and efficacious in postmenopausal women: results from the Monthly<lb>breast cancer in postmenopausal women: results from the MORE randomized<lb>Oral Pilot Study. J Clin Endocrinol Metab 2005; 90: 5018-24<lb>trial. Multiple Outcomes of Raloxifene Evaluation. JAMA 1999; 281: 2189-97<lb>52. Miller PD, McClung MR, Macovei L, et al. Monthly oral ibandronate therapy in<lb>37. Barrett-Connor E, Grady D, Sashegyi A, et al. Raloxifene and cardiovascular<lb>postmenopausal osteoporosis: 1-year results from the MOBILE study. J Bone<lb>events in osteoporotic postmenopausal women: four-year results from the<lb>Miner Res 2005; 20: 1315-22<lb>MORE (Multiple Outcomes of Raloxifene Evaluation) randomized trial. JAMA<lb>53. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1–34)<lb>2002; 287: 847-57<lb>on fractures and bone mineral density in postmenopausal women with osteo-<lb>38. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral<lb>porosis. N Engl J Med 2001; 344: 1434-41<lb>density and the incidence of fractures in postmenopausal osteoporosis: the<lb>Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 54. Marcus R, Wang O, Satterwhite J, et al. The skeletal response to teriparatide is<lb>1995; 333: 1437-43<lb>largely independent of age, initial bone mineral density, and prevalent vertebral<lb>fractures in postmenopausal women with osteoporosis. J Bone Miner Res 2003;<lb>39. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alen-<lb>18: 18-23<lb>dronate on risk of fracture in women with existing vertebral fractures. Lancet<lb>1996; 348: 1535-41<lb>55. Lindsay R, Scheele WH, Neer R, et al. Sustained vertebral fracture risk reduction<lb>40. Schnitzer T, Bone HG, Crepaldi G, et al. Therapeutic equivalence of alendronate<lb>after withdrawal of teriparatide in postmenopausal women with osteoporosis.<lb>70mg once-weekly and alendronate 10mg daily in the treatment of osteo-<lb>Arch Intern Med 2004; 164: 2024-30<lb>porosis. Aging 2000; 12: 1-12<lb>56. Prince R, Sipos A, Hossain A, et al. Sustained nonvertebral fragility risk reduction<lb>41. Harris ST, Watts NB, Genant HK, et al. Effects of risedronate treatment on<lb>after discontinuation of teriparatide treatment. J Bone Miner Res 2005; 20:<lb>vertebral and nonvertebral fractures in women with postmenopausal osteo-<lb>1507-13<lb>porosis: a randomized controlled trial. JAMA 1999; 282: 1344-52<lb>57. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the<lb>42. Reginster JY, Minne HW, Sorensen OH, et al. Randomized trial of the effects of<lb>risk of nonvertebral fractures in postmenopausal women with osteoporosis:<lb>risedronate on vertebral fractures in women with established postmenopausal<lb>TRreatment Of Peripheral OSteoporosis (TROPOS) study. J Clin Endocrinol<lb>osteoporosis. Osteoporos Int 2000; 11: 83-91<lb>Metab 2005; 90: 2816-22<lb>43. Watts NB, Josse RG, Hamdy RC, et al. Risedronate prevents new vertebral<lb>58. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk<lb>fractures in postmenopausal women at high risk. J Clin Endocrinol Metab 2003;<lb>of vertebral fracture in women with postmenopausal osteoporosis. N Engl J<lb>88: 542-9<lb>Med 2004; 29: 459-68<lb>44. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a<lb>5-year placebo-controlled clinical experience. Bone 2003; 32: 120-6 45. Boonen S, McClung MR, Eastell R, et al. Safety and efficacy of risedronate in Correspondence and offprints: Dr Jean-Yves Reginster, WHO Collaborating<lb>reducing fracture risk in osteoporotic women aged 80 and older: implications<lb>Center for Public Health Aspects of Rheumatic Diseases, Liège, Belgium.<lb>for the use of antiresorptive agents in the old and oldest old. J Am Geriatr Soc<lb>E-mail: jyreginster@ulg.ac.be<lb>2004; 52: 1832-9  2006 Adis Data Information BV. All rights reserved.<lb>Treat Endocrinol 2006; 5 (1) 
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