Fracture risk prediction with FRAX in Slovak postmenopausal women

Introduction

Current Slovak treatment thresholds in osteoporosis are based on bone mineral density (BMD) or a previous fracture. Some patients at high risk for fractures may not be identified. FRAX (Fracture Risk Assessment Tool) is based on patient risk profile assessment and calculates 10-year fracture risks. Using FRAX, treatment initiation could be more patient-specific.

Aim of study

To evaluate the risk profile with FRAX in slovak postmenopausal women, to identify those at high risk of fracture according to NOF (National Osteporosis Foundation) intervention thresholds based on FRAX and to compare this approach to current treatment thresholds.

Methods

We measured BMD at lumbar spine, femoral neck, total hip and calculated 10-year absolute fracture risks with the slovak version of FRAX in 365 patients.

Results

Average risk of major osteoporotic fracture was 10,39% and hip fracture 3,00%. 109 patients were eligible for treatment according to actual treatment criteria (88 based on BMD and 21 with previous fracture). In addition, 57 high risk osteopenic patients were identified by NOF thresholds using FRAX, who should be also considered for treatment.

Conclusion

Using FRAX and NOF thresholds it’s possible to identify high risk patients who don’t fulfill current treatment criteria but may profit from treatment.     

绝经后妇女椎体骨折与骨密度的关系

目的探讨绝经后妇女骨质疏松性椎体骨折与骨密度(BMD)的关系。方法对骨质疏松性椎体骨折的绝经后妇女280例(骨折组)和无椎体骨折的绝经后妇女280例(对照组)行胸腰椎正侧位X线摄片,并用双能X线骨密度测量仪(DEXA)检测腰椎(L2~L4)和左髋部BMD和T值。结果骨折组腰椎及髋部BMD和T值均低于对照组(P<0.01)。随着年龄的增加,两组BMD均逐渐下降。结论绝经后妇女的骨质疏松性椎体骨折与腰椎BMD下降相关;随着年龄的增加,椎体骨折的危险性增加;对绝经后妇女应重视BMD和胸腰椎X线片检查。     

Health-economic comparison of three recommended drugs for the treatment of osteoporosis

Osteoporosis is a large and growing disease with significant health consequences. Based on an evaluation of clinical evidence, the German osteology umbrella organization DVO (Dachverband Osteologie deutschsprachiger wissenschaftlicher Fachgesellschaften) published guidelines in March 2003 for the diagnosis and treatment of osteoporosis. For prevention of fractures in women with postmenopausal and senile osteoporosis, these guidelines recommend three treatment options as first-line therapy: risedronate, alendronate and raloxifene. No evidence is currently available for the reduction of hip fractures by raloxifene. Only risedronate and alendronate, therefore, are recommended for prevention of hip fractures. Information on the cost-effectiveness of preventing and treating osteoporosis may support decision makers in more efficient allocation of resources. Accordingly, the objective of this study is the comparative assessment of the cost-effectiveness of risedronate, alendronate and raloxifene for patient populations in Germany at high risk of osteoporotic fracture due to low bone mineral density (BMD) (i.e., T-score < -2.5) and resulting from a history of at least one previous vertebral fracture, as compared to osteoporotic patients with no treatment. Target variables for the economic comparison are costs per hip fracture avoided and costs per quality-adjusted life year (QALY) gained. Hip fractures are the most costly and best-documented complication of osteoporosis. A cost-effectiveness analysis was therefore conducted, using as criteria for evaluating intervention the incremental cost per hip fracture avoided and the cost per QALY gained. We used a fracture-incidence-based Markov model of osteoporosis, with analysis of patients' transition across outcome states over time (e.g., fracture, healthy, dead). Base-case analysis was conducted on a cohort of 1,000 women aged 70 with low spine BMD and prevalent vertebral fracture, over 3 years of treatment with risedronate, alendronate or raloxifene, and with application of a 10-year analytic time horizon. Model inputs included hip and vertebral fracture incidence rates; relative risk of fracture given low BMD and prevalent vertebral fracture, fracture cost, treatment prices/day (risedronate: 35 mg, 1.76 euro; alendronate: 70 mg, 1.82 euro; raloxifene: 60 mg, 1.82 euro); health utility; and efficacy in terms of relative-risk reduction of fracture of the hip (60% risedronate; 51% alendronate; not significant raloxifene) and vertebrae (49% risedronate; 47% alendronate; 30% raloxifene). A 5% discount rate was applied to cost and outcomes. In the base case, treatment with risedronate reduces costs from the social insurance perspective with respect to both endpoints: i.e., costs per averted hip fracture and QALY. Over the 3-year treatment period and 10-year observation, furthermore, risedronate proved superior to alendronate and raloxifene (i.e., risedronate was less expensive and more effective). From the perspective of statutory health insurance, the cost per averted hip fracture is 37,348 euro for risedronate and 48,349 euro for alendronate (costs for raloxifene were not calculated due to a nonsignificant effect on prevention of hip fractures); and cost per QALY gained is 32,092 euro for risedronate, in comparison to patients in Germany with no therapy (alendronate 41,302 euro; raloxifene 1,247,119 euro). This cost-effectiveness analysis gives evidence that bisphosphonates are cost effective. Under consideration of current prices and the published clinical evidence, risedronate dominates the comparison of DVO-recommended drugs.     

Application of the WHO fracture risk assessment tool (FRAX) to predict need for DEXA scanning and treatment in patients with inflammatory bowel disease at risk of osteoporosis

Aliment Pharmacol Ther 2011; 33: 551–558

Summary

Background Although patients with inflammatory bowel disease (IBD) are at increased risk of osteoporosis, low bone mineral density (BMD) alone confers only a modest increase in risk of fracture. The FRAX score, developed by the WHO, is a free web‐based clinical scale assessing the 10‐year fracture risk and need for lifestyle advice/reassurance, dual X‐ray absorptiometry (DEXA) scanning or preventive treatment. Aim To assess the accuracy of pre‐BMD FRAX scores in identifying at risk IBD patients needing BMD measurement (intermediate risk) and/or therapy (high risk). Methods We calculated FRAX scores retrospectively in 116 consecutive IBD out‐patients (81 Crohn’s disease, 35 ulcerative colitis), who were having DEXA scans in 2005–2009 because they were considered at risk of osteoporosis. Results On DEXA scans, 47% (38/81) and 12% (10/81) patients with Crohn’s disease were osteopaenic and osteoporotic, respectively; equivalent figures for patients with UC were 34% (12/35) and 14% (5/35). The clinical FRAX score alone, when compared with the FRAX score including the BMD result, had a sensitivity of 100% (95% CI: 70–100%), specificity of 40% (95% CI: 31–50%), positive predictive value of 16% (95% CI: 9–27%) and negative predictive value of 100% (95% CI: 90–100%) in identifying those patients needing BMD measurement (intermediate risk) or preventive therapy (high risk). Conclusions In patients with IBD perceived to be at risk of osteoporosis and/or osteopaenia, the clinical FRAX score alone can predict accurately the risk of osteoporotic fracture, and thereby reduce the need for DEXA scans and unnecessary anti‐osteoporosis treatment.

     

Relationship between change in femoral neck bone mineral density and hip fracture incidence during treatment with strontium ranelate

ABSTRACT

Objective: Strontium ranelate (SR) increases bone mineral density (BMD) in postmenopausal osteoporotic women and reduces vertebral and non-vertebral fracture incidence. Hip fracture reduction has also been observed during 3-year treatment with SR in osteoporotic women at high risk of hip fracture. The objective of this study is to analyse the association between BMD changes and hip fracture incidence during treatment with SR.

Material and methods: In this post-hoc analysis, 465 women aged over 74 years with low BMD at the femoral neck (T-score ≤ –2.4 according to NHANES normative values) were selected from the population of a recently published study (the Treatment of Peripheral Osteoporosis Study – TROPOS). BMD was assessed at the femoral neck at baseline and after a follow-up of 3 years. Hip fractures were reported by study investigators.

Results: After adjusting for age, body mass index, femoral neck BMD at baseline and number of prevalent vertebral fractures, we found that for each 1% increase in femoral neck BMD observed after 3 years, the risk to experience a hip fracture after 3 years decreased by 7% (95% CI: 1–14%) (?p = 0.04). In patients experiencing a hip fracture over 3 years of treatment with SR, femoral neck BMD increased by (mean [SE]) 3.41 (1.02)% compared to 7.23 (0.81)% in patients without hip fracture (?p = 0.02).

Conclusion: In this post-hoc analysis of women undergoing 3 years of SR treatment, an increase in femoral neck BMD is associated with a decrease in hip fracture incidence.     

Full length parathyroid hormone,PTH(1-84), for the treatment of severe osteoporosis in postmenopausal women

ABSTRACT

Objective: To review and analyse the evidence supporting the use of full length parathyroid hormone, PTH(1-84), in the treatment of osteoporosis based on a search of several literature sources; articles selected for review were published between 1990 and 2008.

Background: PTH(1-84) is approved for the treatment of osteoporosis in postmenopausal women at high risk of fracture in Europe. It was well tolerated in clinical trials and demonstrated bone building properties and fracture prevention particularly for the lumbar spine in the treatment of postmenopausal women.

Results: The TOP clinical trial showed that PTH(1-84) treatment for 18 months resulted in a 61% reduction (p = 0.001) in new vertebral fracture incidence when compared with placebo and reduced the risk of a first vertebral fracture by 68% (p = 0.006) in women without a prevalent fracture at baseline. PTH(1-84) increased bone mineral density (BMD) at vertebral and non-vertebral sites the lumbar spine BMD increasing regardless of T-score, age, prior osteoporosis therapy or number of years post-menopause. The PaTH study showed that treatment with PTH(1-84) for 12 months increased BMD at the trabecular spine and hip. Lumbar spine BMD gains were largest with sequential administration of PTH(1-84) followed by alendronate but were smaller with concurrent administration involving anabolic and antiresorptive agents. Lumbar spine BMD increases were also seen in trials involving PTH with raloxifene and PTH in combination with hormone replacement therapy.

Conclusions: PTH(1-84) has demonstrated effective bone building qualities and extends the therapeutic options available to osteoporotic women. The use of PTH(1-84) followed by sequential administration of an antiresorptive has proved effective at increasing trabecular BMD and points towards new treatment regimens offering improvements in BMD and fracture prevention.     

The burden-of-illness study on osteoporosis in the Slovenian female population

Study objective This burden-of-illness study on osteoporosis was performed with the main goal to estimate the economic implications of osteoporosis for the Slovenian healthcare system. Methods A variety of sources was used to quantify the utilization of resources in 2003, and the appropriate unit costs were assigned to the identified resources. Main outcome measures The study included all direct and indirect costs that arise from treatment of osteoporosis and consequent hip, spine and wrist fractures in total Slovene postmenopausal population in 2003. Results We estimated the total burden of postmenopausal osteoporosis in Slovenia for 2003 to be over SIT 7.55 billion (approximately €31.5 million); among that, 45% or SIT 3.39 billion (€14.2 million) belong to drug expenditures for osteoporosis treatment and prevention; 29% or SIT 2.2 billion (€9.2 million) include indirect costs for osteoporosis morbidity and mortality, and 26% or SIT 1.95 billion (€8.1 million) belong to direct costs for treatment, hospitalization, and rehabilitation of osteoporotic fractures. Total costs on osteoporotic fractures were however subject to an approximation due to the expert panel-based estimate of proportion of osteoporosis-caused fractures and the limited data on resource utilization for fracture treatment. Conclusion Osteoporosis is a costly disease with a significant burden to society and needs to be viewed as an important problem with a complex long-term impact.     

应用64排128层螺旋CT骨密度测量对骨质疏松与椎体骨折的研究分析

目的本研究旨在应用64排128层螺旋CT骨密度测量探讨椎体骨质疏松与骨折的相关性。方法选择200例50岁以上中老年病例，进行骨密度（BMD）测定，分析他们脊柱QCT检查资料，将有骨折的一组作为研究组，将没有骨折的一组作为对照组，然后进行统计学处理。结果骨折组的椎骨BMD明显低于无骨折组，BMD与椎体骨折呈负相关性，BMD越低，骨质疏松的程度越严重，发生骨折的几率就越高。结论64排128层螺旋CT骨密度测定（QCT）是一种非常准确的骨密度测量方法，利用这种检查方法可早期发现骨质疏松、积极干预，从而预防椎体骨折的发生。     

骨质疏松患者骨量形态学相关性的临床研究

为探讨患者骨质疏松时骨矿物含量与骨骼形态变化的相关性,对259例骨质疏松症患者用双能X城骨密度测量仪（DEXA）同步进行骨矿物含量测定和形态学分析,并预测骨折危险性。通过骨密度（BMD）、脊柱椎体前高（A）、中高（M）和后高（P）的测量及分析得出结合指数。结果表明：当结合指数＜－5SD时,即提示出现骨质疏松骨折。     

Closing the osteoporosis management gap in primary care: a secondary prevention of fracture programme

BACKGROUND: Effective treatments are available to reduce fracture risk in patients with osteoporosis. Prioritisation of assessment and treatment for those patients at highest risk of fracture will and treatment for those patients at highest risk of fracture will will ensure the optimal utilisation of healthcare resources. OBJECTIVES: To confirm prior fracture to be a strong predictor of osteoporosis, evaluate a simple means of identifying patients with osteoporosis, assess the current management gap in this high risk patient group and to enable initiation of treatment where appropriate.Research design and methods: All women >/=65 years of age living at home and registered with a general practitioner (GP) in Coatbridge, Lanarkshire, Scotland (4045) were mailed an osteoporosis questionnaire. Participants were from an area of generally low socioeconomic background, where 16% of the population are over >/=65 years and >/=99% are Caucasian. Those who had sustained a fracture or had >/=2 osteoporosis risk factors and had not previously been screened for osteoporosis were invited for a Dual energy X-ray Absorptiometry scan. A second group of women at high risk of osteoporosis were referred by their GP for a scan. Bone mineral density (BMD) was determined and treatment was reviewed and prescribed according to national guidelines. RESULTS: 2386/4045 women returned the questionnaire (response rate 59%); 2286 were correctly completed and made up the sample size. Eight hundred and fifty two had sustained >/=1 fracture(s), of whom 43 (5%) had previously had BMD testing and 80 (9.4%) were receiving treatment. There were 1434 women with no history of fracture that had >/=2 risk factors for osteoporosis. Of 395 women referred by their GP, 113 had sustained fractures. Following the audit, 1054 women were scanned, including 463 women who had not sustained fractures that had >/=2 osteoporosis risk factors. Of the 1054, 591 women had sustained 763 fractures: 46 (6.0%) hip, 284 (37.2%) wrist, 37 (4.8%) humerus and 396 (51.9%) other bones (mainly ankle or rib). Eighty (13.5%) women with a fracture history had normal BMD, 204 (34.5%) were osteopenic and 307 (51.9%) were osteoporotic. Older women were more likely to have osteoporosis: overall, 12.8%, 46.8% and 63.0% of women were osteoporotic in age groups <65 years, 65-75 years and >75 years, respectively. Treatment was prescribed according to Lanarkshire's osteoporosis guidelines for 670 (63.6%) patients: 90.0% received bisphosphonate + calcium/vitamin D and 10% received calcium/vitamin D. CONCLUSIONS: A simple scan identified patients with prior fracture and with osteoporosis. Prior fracture was confirmed to be a strong predictor of osteoporosis; 86.4% of women with a fracture history had low BMD and 51.9% had osteoporosis. Similar disease management programmes elsewhere in primary care to identify high risk patients and ensure appropriate prescribing would, in addition to implementing national guidelines, be pharmaco-economically prudent and improve management of patients with fragility fracture across the UK.     

Raloxifene: a review of its use in postmenopausal osteoporosis

Raloxifene is a selective estrogen receptor modulator that partially mimics the effects of estrogens in bone and the cardiovascular system, while functioning as an antiestrogen in endometrial and breast tissue. In randomised placebo-controlled studies involving postmenopausal women or patients with osteoporosis, raloxifene 60 to 150 mg/day was effective in increasing bone mineral density (BMD) over 12- to 36-month periods. At the 60 mg/day recommended dosage, increases of 1.6 to 3.4%, 0.9 to 2.3% and 1.0 to 1.6% were reported in lumbar spine, femoral neck and total hip, respectively, versus < or =0.5% with placebo. Raloxifene 60 or 120 mg/day decreased the risk of vertebral fractures over a 36-month period in postmenopausal patients with osteoporosis. Significant reductions in radiographic fracture risk versus placebo (30 and 50%) occurred regardless of whether patients had existing fractures at baseline. Although raloxifene did not affect the overall incidence of nonvertebral fractures, a reduction in the incidence of ankle fracture was reported in comparison with placebo. In postmenopausal women, raloxifene 60 mg/day significantly reduced serum levels of total and low density lipoprotein cholesterol from baseline, compared with placebo. High density lipoprotein cholesterol and triglyceride levels were unaffected. Raloxifene 60 or 120 mg/day reduced the risk of invasive breast cancer by 76% during a median of 40 months' follow-up in postmenopausal patients with osteoporosis and no history of breast cancer. A relative risk reduction of 90% was reported for estrogen-receptor positive invasive breast cancers; estrogen-receptor negative cancer risk was unaffected by raloxifene. Raloxifene was generally well tolerated in clinical trials at dosages up to 150 mg/day. Adverse events thought to be related to raloxifene treatment were hot flushes and leg cramps. Venous thromboembolism was the only serious adverse event thought to be related to raloxifene treatment and a relative risk of 3.1 compared with placebo treatment was reported in patients with osteoporosis. Vaginal bleeding occurred in < or =6.4% of raloxifene-treated women but was reported by 50 to 88% of those receiving estrogens or hormone replacement therapy (HRT). Raloxifene treatment was not associated with stimulatory effects on the endometrium. CONCLUSIONS: Raloxifene significantly increases BMD in postmenopausal women and reduces vertebral fracture risk in patients with osteoporosis. In clinical trials, raloxifene was generally well tolerated compared with placebo and HRT, although its propensity to cause hot flushes precludes use in women with vasomotor symptoms. In particular, the lack of stimulatory effects on the endometrium and the reduction in invasive breast cancer incidence indicate raloxifene as an attractive alternative to HRT for the management of postmenopausal osteonorosis.     

Examining the relationship between bone mineral density and fracture risk reduction during pharmacologic treatment of osteoporosis

Osteoporosis is a skeletal disorder characterized by compromised bone strength that predisposes the patient to an increased risk for fracture. Elements of bone strength include bone mineralization, architecture, turnover, size, and bone mineral density (BMD). Measurement of BMD is the most readily available, noninvasive method for assessing osteoporotic fracture risk and is used by the World Health Organization for diagnostic purposes. Because low BMD is predictive of increased fracture risk, it was believed that changes in BMD during pharmacologic therapy for osteoporosis would strongly predict observed fracture risk reductions. We examined the relationship between changes in BMD and reduction in fracture risk during pharmacologic therapy in postmenopausal women with osteoporosis. The correlation between BMD increases and fracture risk reduction during treatment is not consistent; larger increases in BMD do not necessarily correlate with greater reductions in fracture risk. Multiple factors, in addition to BMD, appear to contribute to the increased bone strength and decreased fracture risk achieved with approved drug therapies for osteoporosis. Until the exact relationship of these factors is fully understood, clinicians should continue to evaluate drug efficacy for osteoporosis based on the fracture risk reductions from well-designed clinical trials.     

Teriparatide: new preparation. Osteoporosis: less well evaluated than alendronic acid

(1) Oral alendronic acid is the reference drug for women with osteoporosis and a previous vertebral fracture. In a placebo-controlled trial in women who were also taking calcium and vitamin D, treatment with alendronic acid for three years reduced the incidence of symptomatic vertebral fractures (2.3% versus 5%) and wrist fractures (2.2% versus 4.1%) and, albeit with a lower level of evidence, the incidence of hip fractures (1.1% versus 2.2%). (2) Teriparatide, a biotech drug, reproduces the 34 N-terminal amino acids of parathormone. It is marketed in Europe for subcutaneous treatment of "proven" postmenopausal osteoporosis. (3) The cornerstone of the clinical evaluation dossier is a randomised placebo-controlled double-blind trial in 1637 women also taking calcium and vitamin D. The two doses of teriparatide (20 micrograms/day and 40 micrograms/day), given for a median of 19 months, reduced the risk of new radiologically documented vertebral fractures (about 4% versus 14% in the placebo group) and spinal pain (about 16% versus 23% in the placebo group), but not the risk of hip fracture. (4) In a double-blind trial in 146 postmenopausal women also taking calcium and vitamin D, 40 micrograms/day teriparatide given subcutaneously for 14 months increased spinal mineral bone density significantly more than 10 mg/day alendronic acid given orally. The trial was not designed to show a difference in clinical outcome (fractures). (5) The main adverse effects of teriparatide reported to date are nausea, headache, cramp, hypercalcemia and hyperuricemia. (6) A rat study showed an increased risk of osteosarcoma. This tumour is rare in humans, and the number of patients so far enrolled in clinical trials is insufficient to document a possible increase in risk associated with teriparatide. (7) The need for daily subcutaneous injections and for refrigeration of the prefilled syringes are two notable disadvantages of teriparatide therapy. (8) In practice, alendronic acid is better assessed and remains the reference treatment, combined with calcium and vitamin D, for secondary prevention of osteoporotic fracture in postmenopausal women.     

Efficacy and safety of alendronate and risedronate for postmenopausal osteoporosis

INTRODUCTION: This paper discusses the efficacy and safety of alendronate and risedronate in the treatment of postmenopausal osteoporosis. METHODS: The literature was searched with the PubMed from 1996 to the present, with respect to strictly conducted systematic reviews with homogeneity, meta-analyses with homogeneity, and randomized controlled trials (RCTs) with narrow Confidence Interval. RESULTS: According to the results of large randomized controlled trials (RCTs), bisphosphonates (alendronate, risedronate, and ibandronate), raloxifene, calcitonin, parathyroid hormone (PTH), and strontium ranelate effectively prevent vertebral fractures in postmenopausal women with osteoporosis. Because raloxifene has been shown to be effective in preventing the initial vertebral fracture in postmenopausal osteoporotic women without prevalent vertebral fractures, it is considered in the treatment of postmenopausal women with mild osteoporosis or osteopenia with some risk factors for fractures. RCTs have also demonstrated that alendronate, risedronate, PTH, and strontium are useful to prevent non-vertebral fractures and that alendronate and risedronate prevent hip fractures, thus alendronate or risedronate are primarily considered as the first-line drugs in the treatment of elderly women with osteoporosis having some risk factors for falls. While it has been suggested that PTH may be considered in patients with severe osteoporosis, the use of PTH in the treatment for osteoporosis is limited to 2 years or less, and it may be appropriate to use other anti-resorptive drugs after the completion of PTH treatment to maintain the skeletal effects gained during the treatment. RCTs have demonstrated that the incidence of gastrointestinal tract adverse events in postmenopausal osteoporotic women treated with bisphosphonates and placebo are similar, and also the long-term efficacy and safety of alendronate and risedronate. CONCLUSION: The evidence derived from the literature, based on strict evidence-based medicine guidelines, suggests that there is long-term efficacy and safety with alendronate and risedronate in the treatment of osteoporosis in postmenopausal women.     

Denosumab: a review of its use in the treatment of postmenopausal osteoporosis

Denosumab (Prolia?) is a human recombinant monoclonal antibody that is approved for the treatment of postmenopausal osteoporosis in women at high or increased risk of fracture in the US, the EU and several other countries. Denosumab has a novel mechanism of action; it binds to receptor activator of nuclear factor κB ligand and inhibits bone resorption by inhibiting osteoclast formation, function and survival. In postmenopausal women with osteoporosis, denosumab reduced the risk of vertebral, nonvertebral and hip fractures compared with placebo over 3 years in the large, phase III FREEDOM study. In postmenopausal women with low bone mineral density (BMD) or osteoporosis, treatment with denosumab increased BMD and decreased markers of bone turnover more than alendronate in those who were essentially treatment-naive in the 1-year DECIDE study and also in the 1-year STAND study, in which women were switched from alendronate to denosumab or continued alendronate treatment. Denosumab was generally well tolerated in clinical trials, although long-term effects of very low bone turnover remain to be established. Denosumab is administered once every 6 months via subcutaneous injection, which may be a preferred method of administration and may improve adherence to treatment compared with other osteoporosis treatments. Denosumab is a valuable new option for the treatment of postmenopausal osteoporosis in women at increased or high risk of fractures, and may be useful as a first-line treatment in women at increased risk of fractures who are unable to take other osteoporosis treatments.     

Recombinant full-length parathyroid hormone (1-84)

Full-length parathyroid hormone (PTH) 1-84 is a recombinant version of human PTH. It is approved in the EU for the treatment of postmenopausal women with osteoporosis who have a high risk of fractures. Once-daily subcutaneous administration of PTH(1-84) stimulates new bone formation and increases bone mass. In the pivotal, randomised, double-blind, multicentre, 18-month TOP trial in 2532 postmenopausal women with osteoporosis, subcutaneous PTH(1-84) 100 microg/day significantly reduced the incidence of new or worsened vertebral fractures relative to placebo (primary endpoint). Moreover, the increase from baseline in bone mineral density (BMD) at the lumbar spine, total hip, femoral neck and trochanter was also significantly greater than in the placebo group. In another well designed study (PaTH; n = 238), 1 year of subcutaneous PTH(1-84) 100 microg/day followed by 1 year of alendronate 10 mg/day resulted in significantly greater increases in total spine, femoral neck and total hip BMD at 24 months compared with patients who received placebo for the second year. During the first year, PTH(1-84) in combination with alendronate was no more effective than PTH(1-84) monotherapy in terms of increasing areal lumbar spine BMD. PTH(1-84) is generally well tolerated, although patients should be monitored for elevated serum calcium.     

Alendronate: an update of its use in osteoporosis.

Alendronate (alendronic acid) is a nitrogen-containing bisphosphonate which binds to bone surfaces and inhibits bone resorption by osteoclasts. Oral alendronate 5 or 10 mg/day produces sustained increases in bone mineral density (BMD) in postmenopausal women with or without osteoporosis, in men with primary osteoporosis and in both men and women with or without osteoporosis receiving systemic corticosteroid therapy. Histomorphometric analyses have found that alendronate does not appear to impair bone quality. Alendronate reduced the risk of radiographic vertebral fracture, clinical vertebral fracture or hip fracture by 47 to 56% in postmenopausal women who had > or = 1 existing vertebral fracture and in those with no existing vertebral fractures but who had osteoporosis. In a number of comparative trials in postmenopausal women with osteoporosis, alendronate 10 mg/day was found to be more effective at inducing sustained increases in BMD than intranasal calcitonin, and at least as effective as conjugated estrogens and raloxifene. Alendronate 70 mg administered once weekly and 35 mg twice weekly are as effective at increasing BMD as 10 mg/day in this patient group. In clinical trials, alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and associated with the upper GI tract, most commonly including abdominal pain, nausea, dyspepsia, acid regurgitation and musculoskeletal pain. No statistically significant differences between alendronate 10 mg/day and placebo have been found in the incidence of upper GI adverse events in large clinical trials. However, postmarketing surveillance reported a low incidence of adverse events related to the oesophagus. Specific instructions aimed at reducing the risk of upper GI adverse events have been provided by the manufacturer. CONCLUSIONS: Alendronate is effective and generally well tolerated in the treatment of women or men with primary (including postmenopausal) or corticosteroid-induced osteoporosis and in the prevention of osteoporosis in postmenopausal women. The drug has been associated with upper GI tract adverse events, although the extent to which alendronate is responsible for these events has not been clearly established. Alendronate should be considered a treatment of choice in postmenopausal women with osteoporosis. Alendronate is also a suitable treatment option for primary osteoporosis in men and for corticosteroid-induced osteoporosis in both men and women.     

Hormone therapy for the prevention of bone loss in menopausal women with osteopenia: is it a viable option?

Osteopenia is a state of low bone mass, the appropriate clinical management of which is not always clear. The use of hormone therapy for postmenopausal bone loss has become controversial given recent data regarding the risks of therapy. Fragility fractures are common, and result in substantial morbidity and mortality. Although the fracture rate is higher among osteoporotic women, the substantially larger population of osteopenic women accounts for a higher absolute number of fractures. Osteopenia is defined solely according to the statistical properties of the distribution of bone mineral density (BMD) values, which limits its usefulness in clinical care. BMD, although inversely related to fracture risk, should not be used as the sole criterion for fracture risk. Limited data suggest that benefits of treatment seen in women with documented osteoporosis may not extend to osteopenic women. Although estrogen prevents postmenopausal bone loss, preservation of BMD does not necessarily translate into reduced fracture risk. In making decisions about whether to treat a woman with osteopenia, it is critical to estimate how treatments will affect the individual's risk of fracture. Treatment decisions should be based on whether the net benefits of treatment outweigh the anticipated risks, which will depend on the age of the patient and her risk profile. In our opinion, there is insufficient evidence to support treatment for women with a BMD in the osteopenic range in the absence of fragility fracture. For osteopenic women with higher risk, the availability of other treatments with a more favourable risk-benefit profile eliminates the role of hormone therapy for fracture prevention.     

Review of risedronate in the treatment of osteoporosis

Risedronate (Actonel^®, Procter & Gamble and Aventis) is a novel, orally administered pyridinyl bisphosphonate. Preclinical studies have shown that risedronate is a potent inhibitor of osteoclasts. Risedronate inhibited bone resorption and increased bone density in the spine and hip. Prospective, randomised, placebo-controlled trials (RCTs) in patients with postmenopausal osteoporosis (PMO) have demonstrated that risedronate decreased the risk of vertebral fractures by up to 49% and of non-vertebral fractures by up to 39% over 3 years in postmenopausal women with one or more prevalent vertebral fractures. This reduction of the risk for vertebral fractures was significant from the first year of treatment (risk reduction up to 65%). Risedronate was the first bisphosphonate to be studied in a large RCT with prevention of hip fracture as the primary end point. In this study, risedronate reduced the risk of hip fracture by 40% in elderly women with low hip bone density and one clinical risk factor for hip fracture and by 60% in women with low bone density and a prevalent vertebral fracture at baseline. Risedronate was also effective in the prevention and treatment of bone loss in glucocorticoid-induced osteoporosis (GIO), with a positive effect on vertebral fractures within the first year. Risedronate was well-tolerated with a safety profile comparable to placebo in all clinical studies. Patients with a previous or current history of upper GI illness or who were taking NSAIDs or aspirin were not excluded from these studies. Importantly, the upper GI safety profile of risedronate was shown to be similar to that of placebo in endoscopic studies. There was no evidence of acute-phase reactions or primary mineralisation defects. The most appropriate dose of risedronate was 5 mg/day.