Ibandronate produces significant,similar antifracture efficacy in North American and European women: new clinical findings from BONE

ABSTRACT

Objectives: BONE (oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe) determined whether less frequent dosing of ibandronate (dose-free interval > 2?months) provided similar antifracture efficacy to daily dosing. As osteoporosis medications must be effective across different populations, an additional objective of BONE was to investigate and report the effect of oral ibandronate in North American and European women, as described here.

Patients and methods: BONE was a randomized, double-blind, placebo-controlled, fracture-prevention study in 2946 postmenopausal women (age 55?years?80?years; ≥ 5?years since menopause) with osteoporosis (low lumbar spine bone mineral density and one to four prevalent vertebral fractures [T4?L4]). Participants received daily calcium (500?mg) and vitamin D (400?IU) plus either placebo, oral daily ibandronate (2.5?mg) or oral intermittent ibandronate (20?mg every other day for 12 doses every 3?months). The efficacy and tolerability of ibandronate were assessed independently in both North American and European populations.

Results: Consistent, significant efficacy was observed in the North American (new vertebral fracture risk reduction: 60% and 54% with daily and intermittent ibandronate, respectively) and European patient populations (50% and 48%, respectively). Both ibandronate regimens also significantly reduced the incidence of new, worsening, and acute clinical, vertebral fractures. Daily and intermittent ibandronate significantly increased bone density at the spine in both North American (5.4% and 4.4% vs. baseline with daily and intermittent ibandronate, respectively) and European (7.1% and 6.3% vs. baseline, respectively) populations. Significant increases were also observed for total hip bone density (2.6% and 3.7% vs. baseline for daily, and 2.5% and 3.1% for intermittent; North American and European populations, respectively). Comparable, significant decreases in biochemical markers of bone turnover (reductions in urinary excretion of C-telopeptide levels of 53.5% and 67.1% vs. baseline for daily, and 50.0% and 53.8% for intermittent; North American and European populations, respectively) were also observed in both populations (?p < 0.004 for all cited measurements in each ibandronate group vs. placebo). Oral ibandronate was well tolerated in both North American and European patients, with a safety profile similar to placebo.

Conclusions: Oral ibandronate, administered daily or intermittently, effectively reduced vertebral fracture risk in North American and European women with postmenopausal osteoporosis. These results demonstrate the efficacy of ibandronate administered with extended dose-free intervals, regardless of patients’ geographical origin. Research investigating other less frequent ibandronate regimens, such as once-monthly oral administration, is underway.     

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.     

Relationship between bone mass,invasive breast cancer incidence and raloxifene therapy in postmenopausal women with low bone mass or osteoporosis

ABSTRACT

Objective: To evaluate the relationship between bone mass and risk of breast cancer and to determine the effect of raloxifene therapy on breast cancer incidence in women categorized by bone mass into low bone mass and osteo­porosis subgroups.

Design: In this post hoc analysis, data were analyzed from the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, enrolling postmenopausal women with low bone mass (N = 7705), and the Continuing Outcomes Relevant to Evista (CORE) trial, a follow-up to MORE enrolling 4011 MORE participants. Total follow-up was for up to 8 years. Women with a total hip bone mineral density (BMD) T-score <?–1 to >?–2.5 or T-score ≤?–2.5 (referent, NHANES III database) were classified as having low bone mass or osteoporosis, respectively. Women with a pre-existing vertebral fracture were considered as having osteoporosis irrespective of BMD T-score. Analyses were performed for invasive breast cancers and invasive estrogen-receptor (ER) positive breast cancers.

Results: Women with low bone mass (N = 3829) had a twofold higher incidence of invasive ER-positive breast cancer than those with osteoporosis (N = 3836) (HR 2.13, 95% CI 1.12–4.03). The incidence of all invasive breast cancers did not differ significantly between the bone mass groups. The incidences of invasive and invasive ER-positive breast cancers were 65–78% lower in women assigned raloxifene versus placebo in both the low bone mass and osteoporosis groups (?p < 0.05).

Conclusions: In this post hoc analysis of postmeno­pausal women participating in MORE and CORE, bone mass was a predictor of invasive ER-positive breast cancer. Raloxifene treatment reduced the risk of invasive and invasive ER-positive breast cancers in women with low bone mass and those with osteoporosis. Since participants were older postmenopausal women with low bone mass, whether these findings can be generalized to other postmenopausal women is unclear.     

Risk factors for osteoporosis

SUMMARY

Background: Although postmenopausal African–American women are at lower risk for osteoporosis-related fractures compared with white women, fractures in African–American women are associated with significantly higher morbidity and mortality. Therefore, early diagnosis and treatment of osteoporosis in this population is just as important as it is for other ethnic groups and worthy of the attention of physicians and healthcare organizations.

Objective: The purpose of this study was to evaluate risk factors for osteoporosis in postmenopausal African–American women.

Design: This was a retrospective, case-control study in 201 postmenopausal African–American women at a community-based osteoporosis center. Spine and hip bone mineral density measurements were obtained by dual-energy x-ray absorptiometry. Patient and family medical history, past and present pharmaceutical use, and dietary and exercise habits were collected using a patient self-administered questionnaire.

Results: Using the manufacturer's African–American referent database, 56 women had osteoporosis, 99 had osteopenia, and 46 had normal bone mineral density. Risk factors more common in the osteoporotic group compared with the normal group included sedentary lifestyle (P < 0.03), family history of osteoporosis (P < 0.03), low body mass index (P < 0.05), and history of bilateral oophorectomy (P < 0.03). Polyarthritis was more prevalent in the normal versus the osteoporotic group (P < 0.001). In addition, premenopausal use of oral contraceptives (P < 0.005) and postmenopausal use of estrogen therapy (P < 0.05) were more common in the normal compared with the osteoporotic group.

Conclusions: Many risk factors for osteoporosis in African–American women are similar to those in white women and can aid in the selection of patients in need of bone density testing.     

Cost-effectiveness of bisphosphonate therapies for women with postmenopausal osteoporosis: implications of improved persistence with less frequently administered oral bisphosphonates

ABSTRACT

Objective: Studies have shown that weekly bisphosphonate dosing results in improved persistence compared to daily dosing among patients with postmenopausal osteoporosis, yet more than 50% of patients discontinue therapy within a year. An oral, less frequent administration bisphosphonate provides an opportunity to improve persistence, a parameter not well modeled in previous cost-effectiveness analyses of osteoporosis therapies.

Research design and methods: We developed a Markov model to estimate the effect of improved persistence on the cost-effectiveness of bisphosphonates among postmenopausal women with established osteoporosis (vertebral fracture and bone mineral density T-score ≤ –2.5) and an average age of 78 years. Fracture risks, clinical efficacy, mortality, resource use, costs, and utilities were obtained from the published literature. Persistence rates were derived primarily from a published clinical trial. Approximately 50% greater persistence with a monthly versus a weekly therapy was assumed on the basis of the PERSIST study, a 6-month, randomized, head-to-head prospective study that investigated treatment persistence in postmenopausal osteoporotic women on monthly versus weekly bisphosphonate therapy. Persistence was extrapolated to a maximum of 5 years. Following discontinuation, treatment benefit declined linearly and proportionally to the duration of active treatment.

Results: Based on model estimates, more fractures were avoided (versus no treatment) with monthly bisphosphonate (58.1 per 1000 treated women) than with weekly bisphosphonates (33.8 per 1000 treated women), resulting in lower fracture care costs per woman ($7317 and $7548, respectively). The incremental cost per quality-adjusted life-year gained was lower with a monthly bisphosphonate ($13?749) than with weekly bisphosphonates ($16?657) when compared to no treatment. The incremental cost per quality-adjusted life-year of a monthly bisphosphonate was $9476 when compared to a weekly bisphosphonate.

Conclusions: In postmenopausal women with established osteoporosis, improvement in persistence with a less frequently administered oral bisphosphonate therapy could augment the fracture benefit and thereby improve cost-effectiveness. Further studies are required to refine the estimates of cost-effectiveness in order to address limited availability of adherence and fracture risk data.     

Long dosing intervals in the treatment of postmenopausal osteoporosis

ABSTRACT

Background: Osteoporosis is a common disease associ­ated with diminished bone strength and increased risk of fracture. With the aging of the population, the number of people with osteoporosis, particularly postmenopausal women, is expected to increase. There are excellent tools for diagnosing osteoporosis and widely available treat­ments that are safe and effective. Nevertheless, osteo­porosis is underdiagnosed and undertreated. Even among those who are diagnosed and treated, widespread non­adherence with treatment regimens undermines the efficacy of osteoporosis therapy.

Purpose: To examine the pharmacological options for the treatment of postmenopausal osteoporosis and the influence of extended dosing intervals upon outcomes, medication adherence, and patient preference.

Methods: A Medline and Cochrane Review database search was conducted for appropriate clinical trials, meta-analyses, and systematic reviews published between 1987 and 2007.

Findings: The causes of nonadherence include poor understanding of the consequences of a silent disease, concern regarding potential side-effects of medications, the inconvenience associated with administration of some osteoporosis medications, and medication costs. The recent development of effective oral and injectable osteo­porosis medications that can be given with long dosing intervals may improve patient adherence. Less frequent dosing lessens the inconvenience of administration, and dosing by injection assures that the medication is 100% bioavailable. Osteoporosis patients have shown a preference for monthly bisphosphonate dosing compared with weekly dosing.

Conclusion: Enhanced adherence with new dosing regimens can be expected to improve treatment efficacy, reduce fracture risk, and lessen the burden of osteo­porosis on patients and society. Further study is required to fully elucidate the relationship between extended dosing, adherence, and positive outcomes.     

Clinical use of denosumab for the treatment for postmenopausal osteoporosis

Abstract

Denosumab is a fully human monoclonal antibody with high affinity and specificity for human receptor activator of nuclear factor kappa B ligand (RANKL), the principal regulator of osteoclastic bone resorption. By binding to RANKL, denosumab prevents it from binding to its receptor on the cell surface of pre-osteoclasts and mature osteoclasts, thereby reducing the formation, activity, and survival of osteoclasts and inhibiting osteoclastic bone resorption. In a large, randomized, placebo-controlled clinical trial in postmenopausal women with osteoporosis, denosumab 60?mg administered subcutaneously every 6 months reduced levels of bone turnover markers, increased bone mineral density, and reduced the risk of vertebral fractures, hip fractures, and non-vertebral fractures. There was no significant difference between denosumab and placebo in the overall risk of adverse events or serious adverse events. Denosumab was associated with a significant increase in the risk of eczema and cellulitis, and a significant decrease in the risk of falling and concussions. Denosumab recently received regulatory approval for the treatment of postmenopausal women with osteoporosis at high risk for fracture, with no dose adjustment in patients with renal impairment. Denosumab is a new therapeutic option to reduce fracture risk in women with postmenopausal osteoporosis, especially for those with impaired renal function or with intolerance or poor response to oral therapy.     

A comparison of teriparatide and calcitonin therapy in postmenopausal Asian women with osteoporosis: a 6‐month study

ABSTRACT

Objective: The number of hip fractures is expected to double in the next 20 years, with current estimates that Asia will account for 37% of these cases. As bone mineral density (BMD) may be used as a measure of fracture risk, we sought to compare the effects of teriparatide with salmon calcitonin treatment on changes in BMD, biochemical bone markers, and safety in postmenopausal Asian women with osteoporosis.

Methodology: A total of 104 patients (?n = 47 teriparatide [20?µg/day subcutaneously] and n = 57 calcitonin [100?IU/day subcutaneously]) were enrolled in Hong Kong, Singapore, Philippines, Malaysia, and Thailand. Calcium (≥ 500?mg/day) and vitamin D (200–400?IU/day) supplements were taken throughout the 6‐month controlled, randomized study.

Results: Teriparatide was associated with a 5.03 ± 4.77% increase in lumbar spine BMD (?p < 0.0001, mean ± SD change from baseline), whereas changes in lumbar spine BMD for patients on calcitonin were not statistically significant (mean change of 0.36 ± 4.12%, p = 0.16). Comparison of the two groups indicated that teriparatide treatment improved lumbar spine BMD statistically significantly more than calcitonin (?p < 0.0001). No statistically significant changes were observed for total hip or femoral neck BMD. Serum bone-specific alkaline phosphatase (BSAP) increased by 55.9% (median change from baseline, p < 0.0001) in the teriparatide group, and remained stable with calcitonin (5.0% change, p = 0.24); osteocalcin increased by 156.15% (median change from baseline, p < 0.0001) with teriparatide, and decreased with calcitonin (–15.25%, p = 0.03). Similar rates of adverse events were observed, with nausea and dizziness the most commonly reported for both groups (teriparatide versus calcitonin, 13.0% versus 23.2% p = 0.21, 10.9% versus 21.4% p = 0.19, respectively). There were no clinically relevant changes observed in laboratory parameters.

Conclusions: Both treatments were similarly tolerated, however teriparatide was associated with greater increases in lumbar spine BMD and bone formation markers, demonstrating the unique mechanism of action and safety of this treatment for osteoporosis in these Asian women.     

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.     

Prevention of vertebral fractures in osteoporosis: mixed treatment comparison of bisphosphonate therapies

ABSTRACT

Objective: The objective was to compare the efficacy of bisphosphonates regarding the prevention of vertebral fractures in postmenopausal women with osteoporosis.

Methods: Seven randomized placebo controlled trials investigating the effects of zoledronic acid (one study), alendronate (three studies), ibandronate (one study), and risedronate (two studies) in terms of fractures with a follow-up of 3 years were identified with a systematic literature search. The endpoint of interest was vertebral fractures. Results of all trials were analyzed simultaneously with a Bayesian mixed treatment comparison (MTC). With MTC the relative treatment effect of one intervention to another can be obtained in the absence of head-to-head evidence. MTC can be considered a valid method when included studies are comparable regarding effect modifying baseline patient and study characteristics.

Results: There is a 98% probability that zoledronic acid shows the greatest reduction in vertebral fractures of all four bisphophonates compared. Zoledronic acid showed an OR of 0.28 (95% Credible Interval 0.22; 0.35) relative to placebo, an OR of 0.57 (0.36; 0.92) relative to ibandronate, an OR of 0.54 (0.39; 0.75) relative to alendronate, and an OR of 0.49 (0.34; 0.69) relative to risedronate. Alendronate, ibandronate, and risedronate showed comparable vertebral fracture reductions. Indirect comparisons using a conservative random effects model supported these findings.

Conclusion: An indirect comparison of findings from placebo controlled randomized studies indicates that zoledronic acid provides a greater vertebral fracture risk reduction in postmenopausal women with osteoporosis than ibandronate, alendronate, or risedronate.     

The effects of teriparatide on the incidence of back pain in postmenopausal women with osteoporosis

ABSTRACT

Objectives: Back pain is a major cause of suffering, disability, and cost. The risk of developing back pain was assessed following treatment with teriparatide [rh(PTH 1–34)] in postmenopausal women with osteoporosis.

Research design and methods: A secondary analysis of back pain findings from the global, multi-site Fracture Prevention Trial was conducted where postmenopausal women with prevalent vertebral fractures were administered teriparatide 20?µg (?n = 541) or placebo (?n = 544) for a median of 19 months. Treatment-emergent back pain data were collected during adverse event monitoring, and spine radiographs were obtained at baseline and study endpoint.

Main outcome measures: The risk of back pain stratified by severity of new or worsening back pain and the risk of back pain associated with both number and severity of new vertebral fractures.

Results: Women randomized to teriparatide 20?µg had a 31% reduced relative risk of moderate or severe back pain (16.5% vs. 11.5%, P = 0.016) and a 57% reduced risk of severe back pain (5.2% vs. 2.2%, P = 0.011). Compared with placebo, teriparatide-treated patients experienced reduced relative risk of developing back pain associated with findings of: one or more new vertebral fractures by 83% (6.5% vs. 1.1%, P < 0.001), two or more new vertebral fractures by 91% (2.5% vs. 0.20%, P = 0.004), and one or more new moderate or severe vertebral fractures by 100% (5.1% vs. 0.0%, P < 0.001).

Conclusions: Teriparatide-treated women had reduced risk for moderate or severe back pain, severe back pain, and back pain associated with vertebral fractures. The mechanism of the back pain reduction likely includes the reduction both in severity and number of new vertebral fractures.     

European women's preference for osteoporosis treatment: influence of clinical effectiveness and dosing frequency

ABSTRACT

Objective: To determine participant preference for weekly versus monthly bisphosphonate therapy for osteoporosis after being informed about differences in fracture efficacy.

Design: 20‐minute, semi-structured, face-to-face or telephone interviews. Two bisphosphonate choices were presented on the basis of block randomization: weekly therapy with proven efficacy to reduce fracture risk at the spine and hip, or monthly therapy with proven efficacy to reduce fracture risk at the spine but not the hip.

Subjects: Women from the UK, Germany, France, Spain and Italy, with postmenopausal osteoporosis and aged ≥ 55 years. Fifty percent were currently taking a weekly bisphosphonate; 50% had no history of taking any bisphosphonate.

Measures: An efficacy rating scale and an intention-to-use rating scale were developed for this study. The primary endpoint was preference for weekly or monthly therapy. Reasons for preference were recorded.

Results: A preference was recorded for 1248 women (1253 were recruited). More women preferred weekly to monthly therapy (82% vs. 18%, respectively; p < 0.001). Among women who preferred weekly therapy, efficacy was the most commonly cited reason (65%). Ninety-two percent of the total cohort rated the efficacy of the weekly therapy as ‘excellent/good’ versus 38% for monthly (?p < 0.001). Sixty-nine percent intended to use weekly bisphosphonates compared with 34% for monthly (?p < 0.001).

Conclusions: When informed about differences in fracture efficacy in weekly and monthly bisphosphonates, a significantly greater proportion (82%) of women preferred a weekly bisphosphonate with proven fracture efficacy at the spine and hip over a monthly bisphosphonate with proven fracture efficacy only at the spine.     

Skeletal pain in postmenopausal women with osteoporosis: prevalence and course during raloxifene treatment in a prospective observational study of 6 months duration

ABSTRACT

Objective: To assess the prevalence of skeletal pain in postmenopausal women before the onset of raloxifene treatment and the further course of pain during treatment in a naturalistic setting.

Research design and methods: Prospective, uncontrolled, multicentre, 6‐month, observational study in Germany. Clinical, diagnostic and pain data were collected at baseline, 6 weeks and 6 months of raloxifene treatment from 3299 female outpatients with postmenopausal osteoporosis. Physicians assessed the presence or absence of back pain, joint pain and diffuse bone pain at each visit, perceived sleep quality and the use of analgesics. Patients assessed intensity and frequency of pain using a 100?mm visual analogue scale (VAS) and a 5‐point scale (from ‘rarely’ to ‘permanently’), respectively.

Results: At baseline, patients had mean (SD) age 67.6 (9.3) years, 89.4% were reported to have reduced bone mineral density, 39.8% had pre-existing fractures and 93.4% had skeletal pain (physician assessment): 85.1% had back pain, 41.8% joint pain and 32.5% diffuse bone pain. Median pain intensity on VAS was 66.0?mm. After 6 months of raloxifene treatment, the frequency and intensity of pain and use of analgesics for skeletal pain decreased consistently by approximately 50%. Pain frequency decreased in 58.2% and increased in 2.3% of patients. The median decrease in pain intensity from baseline to 6 months was 27.0?mm (46%). Patients’ subjective quality of sleep improved: the proportion of patients who were reported to sleep well increased from 21.3% at baseline to 46.7% at 6 months. The decrease in relative pain frequency was greatest with diffuse pain (67.6%) followed by joint pain (36.9%) and back pain (32.5%).

Conclusion: Raloxifene treatment in postmenopausal women with osteoporosis was associated with a marked reduction of skeletal pain and analgesic consumption and an improvement in subjective sleep quality. Further investigation in a randomised, placebo-controlled trial is warranted.     

Oral nitrogen-containing bisphosphonates: a systematic review of randomized clinical trials and vertebral fractures

ABSTRACT

Background: Vertebral fractures are the most common osteoporotic fracture. They are associated with increased morbidity and mortality, and also predict future vertebral and non-vertebral fracture risk. Bisphosphonates are the current mainstay for the treatment of postmenopausal osteoporosis. Health authority guidelines request that assessment of vertebral fracture risk reduction is part of the evaluation of bisphosphonate efficacy. In this review, we compare the published evidence for the efficacy of the nitrogen-containing oral bisphosphonates in reducing the risk of vertebral fractures.

Methods: A review of publications in the treatment of postmenopausal osteoporosis and the most frequently prescribed oral bisphosphonate therapies (alendronate, ibandronate and risedronate) was carried out using the Dialog (Embase and Medline) and Cochrane online scientific citation databases. Eligible publications were those reporting randomized, placebo-controlled trials that included vertebral fracture as the primary or secondary endpoint (any time-point).

Results: Of 159 publications identified, six studies assessing alendronate, ibandronate and risedronate met the pre-defined eligibility criteria. In total, 14?083 women were included in the studies, with 8182 patients receiving active treatment. Most studies were 3?years in duration. Discontinuation rates varied from 11 to 45%, being highest in those studies that specified one or more vertebral fracture as part of the inclusion criteria. Across these studies, the reduction in the risk of vertebral fractures ranged from 41 to 62% (44–48% for alendronate; 41–49% for risedronate; 62% for ibandronate).

Conclusions: Nitrogen-containing oral bisphosphonates effectively reduce the risk of osteoporotic vertebral fracture, with the magnitude of effect ranging from 41 to 62%.     

Characterization of patients in the European Forsteo Observational Study (EFOS): postmenopausal women entering teriparatide treatment in a community setting

ABSTRACT

Objective: The European Forsteo^* Observational Study (EFOS) study was primarily designed to assess fracture incidence, degree of pain, health-related quality of life (HRQoL) and compliance in women prescribed teriparatide in a community setting. This report describes the design of the study and characteristics of the patients at entry.

Methods: At entry, 1645 postmenopausal women with a diagnosis of osteoporosis and about to initiate teriparatide treatment were enrolled in eight European countries. Baseline data were collected on demographic characteristics, medical and osteoporosis history, disease status, prior use of medications and HRQoL.

Results: The mean (standard deviation [SD]) age of patients was 71.5 (8.4) years, lumbar spine bone mineral density (BMD) T?score was –3.3 (1.2), the mean number of previous fractures reported after 40 years of age was 2.9 (2.0), 70% had two or more vertebral deformities and 91.7% were pre-treated with bisphosphonates. HRQoL, evaluated by the health state value (HSV) (median: 0.59, Q1; Q3: 0.08; 0.71) and visual analogue scale (VAS) (median 50.0, Q1; Q3: 35.0; 69.0) status of the European quality of life questionnaire (EQ?5D) was poor. Extreme problems were reported by 31% of patients for the pain/discomfort dimension, mobility was limited in 69% and anxiety/depression was reported by 57% of patients. Chronic or intermittent back pain was reported by 91% of patients, which occurred every day or almost every day within the last month in 66% of patients.

Conclusions: The post-menopausal women prescribed teriparatide were severely osteoporotic, with a high fracture risk and poor HRQoL, despite previous therapy for osteoporosis. Moderate to severe back pain was very common.     

Cost-effectiveness of alternative treatments for women with osteoporosis in Canada

ABSTRACT

Background: During the years following menopause, estrogen levels decline leading to accelerated bone loss and an increased risk of osteoporosis and osteoporosis-related fractures.

Methods: Using a Markov model and decision analytic techniques, the long-term costs and outcomes of five treatment and secondary prevention strategies for osteoporosis were compared: ‘no intervention’, alendronate, etidronate, risedronate, and raloxifene. The base case analysis examined postmenopausal (65 year old) osteoporotic women without prior fracture. Probabilistic sensitivity analysis (PSA) was used to incorporate the impact of parameter uncertainty, and deterministic sensitivity analysis (DSA) was used to compare alternative patient populations and modeling assumptions. Life years and Quality Adjusted Life Years (QALYs) were used as measures of effectiveness.

Results: In the base case analysis, risedronate was dominated by etidronate and alendronate. Alendronate and etidronate were projected to have similar costs and QALYs, and the efficiency frontier was represented by ‘no intervention’, etidronate, alendronate, and raloxifene (Can$32?571, Can$38?623 and Can$114?070 per QALY respectively). Alternative assumptions of raloxifene's impact on CHD and breast cancer, alternative discount rates and alternative patient risk factors (e.g., starting age of therapy, CHD risk, and prior fracture risk) had significant impacts on the overall cost-effectiveness results for both the bisphosphonates and raloxifene.

Discussion: Using conventionally quoted benchmarks and compared to no therapy, alendronate, etidronate, and raloxifene would all be considered cost-effective alternatives for treating women with osteoporosis. Potential limitations of this study include the usual caveats and cautions associated with long-term projection models and the fact that not all inputs into the model are Canadian data sources.     

Bone density after teriparatide in patients with or without prior antiresorptive treatment: one-year results from the EUROFORS study*

Objective: Recombinant teriparatide, a bone anabolic agent, is given to treatment-naïve and pre-treated patients with severe osteoporosis, but few data exist comparing the response to teriparatide in these groups. EUROFORS (the EUROpean study of FORSteo?) enrolled postmenopausal women with established osteoporosis who were either treatment-naïve or had prior antiresorptive (AR) treatment with or without documented inadequate clinical response. The objective of the secondary analysis described here was to evaluate the interim bone mineral density (BMD) response in these groups after one year of open-label teriparatide therapy.

Research design and methods: Postmenopausal women with established osteoporosis who enrolled in a prospective, randomized, controlled trial received open-label teriparatide 20 µg/day for the first year. With respect to their prior osteoporosis treatment history, they were retrospectively allocated to one of three groups: treatment-naïve (n = 204), prior treatment with an antiresorptive drug (AR-pretreated) (n = 240), or prior antiresorptive treatment with inadequate response (inadequate AR-responders) (n = 421). BMD was measured by dual energy x-ray absorptiometry.

Results: Lumbar spine BMD increased from baseline (p < 0.001) in the three groups (mean, 95% CI); treatment-naïve: 8.4% (7.4%, 9.3%); AR-pretreated: 7.1% (6.3%, 7.9%); inadequate AR-responders: 6.2% (5.6%, 6.9%). Total hip BMD increased from baseline in the treatment-naïve (p < 0.001): 1.8% (1.1%, 2.5%) but did not change in the AR-pretreated: 0.4% (?0.2%, 1.1%) or inadequate AR-responders: ?0.3% (?0.9%, 0.2%). Treatment-emergent adverse events were similar in the three groups.

Conclusion: One year of teriparatide significantly (p < 0.001) increased spine BMD in all groups, and total hip BMD in the treatment-naïve group. Because of the limitations of this interim analysis (most importantly, the short duration of treatment and lack of a control group), further study is needed to determine the optimal treatment duration to reach the potential BMD gains at the proximal femur in patients with prior antiresorptive drug use (mostly bisphosphonates).

Clinical trial registration: clinicaltrials.gov, nct00191425     

Emerging drugs for the management of cancer treatment induced bone loss

Areas covered in this review: We focus our attention on data on the efficacy of currently available and emerging drugs for the management of cancer treatment induced bone loss (CTIBL) found in a PubMed research from 1997 till today.

Importance of the field: One of the most common and severe safety issues of the antihormonal therapy in both sexes is the CTIBL and the related fragility fractures. In postmenopausal women with estrogenic receptor positive breast cancer, the third-generation aromatase inhibitors (AIs) are the standard therapy. Observational retrospective studies have found that AIs treated patients had a high rate of bone loss and fracture risk (RR 1.3). Also in men with prostate cancer receiving androgen deprivation therapy, the increase in bone turnover and the consequent bone loss are very rapid and sustained significantly increasing the fracture risk.

What the reader will gain: The aim of our review is to provide the current evidences for the management of bone loss and fracture risk in this subpopulation.

Take home message: The very high rate of bone loss and the high incidence of fractures indicate that cancer patients at risk of CTIBL need to be carefully monitored and stratified for fracture risk. Although there is a strong evidence of efficacy in prevention of bone loss and reduction of fracture risk for many drugs approved for postmenopausal osteoporosis (PMO) and male osteoporosis, for CTIBL there are actually no drugs approved for this indication.