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The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies.

ABSTRACT: This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.

Introduction

This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate treatment response and if the risk of a subsequent fracture decreases with continuing denosumab treatment.

Methods

In FREEDOM, a clinical trial to evaluate the efficacy and safety of denosumab, postmenopausal women with osteoporosis were randomized to placebo or denosumab for 3 years. In the 7-year FREEDOM Extension, all participants were allocated to receive denosumab. Here we compare subsequent osteoporotic fracture rates between denosumab-treated subjects during FREEDOM or the Extension and placebo-treated subjects in FREEDOM.

Results

During FREEDOM, 438 placebo- and 272 denosumab-treated subjects had an osteoporotic fracture. Exposure-adjusted subject incidence per 100 subject-years was lower for denosumab (6.7) vs placebo (10.1). Combining all subjects on denosumab from FREEDOM and the Extension for up to 10 years (combined denosumab), 794 (13.7%) had an osteoporotic fracture while on denosumab. Of these, one or more subsequent fractures occurred in 144 (18.1%) subjects, with an exposure-adjusted incidence of 5.8 per 100 subject-years, similar to FREEDOM denosumab (6.7 per 100 subject-years) and lower than FREEDOM placebo (10.1 per 100 subject-years). Adjusting for prior fracture, the risk of having a subsequent on-study osteoporotic fracture was lower in the combined denosumab group vs placebo (hazard ratio [95% CI]: 0.59 [0.43-0.81]; P?=?0.0012).

Conclusions

These data demonstrate that denosumab decreases the risk of subsequent fracture and a fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.

SUBMITTER: Kendler DL

PROVIDER: S-EPMC6331737 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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Publications

The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies.

Kendler D L DL Chines A A Brandi M L ML Papapoulos S S Lewiecki E M EM Reginster J-Y JY Muñoz Torres M M Wang A A Bone H G HG

Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 20180922 1

This post-hoc analysis queried whether women experiencing fracture on denosumab indicates inadequate treatment response or whether the risk of subsequent fracture remains low with continuing denosumab. Results showed that denosumab decreases the risk of subsequent fracture and fracture sustained while on denosumab is not necessarily indicative of inadequate treatment response.<h4>Introduction</h4>This analysis assessed whether a fracture sustained during denosumab therapy indicates inadequate tr ...[more]

PMID: 30244369

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Project description:Limited data exist on the efficacy of long-term therapies for osteoporosis. In osteoporotic postmenopausal women receiving denosumab for 7 years, nonvertebral fracture rates significantly decreased in years 4-7 versus years 1-3. This is the first demonstration of a further benefit on fracture outcomes with long-term therapy for osteoporosis.This study aimed to evaluate whether denosumab treatment continued beyond 3 years is associated with a further reduction in nonvertebral fracture rates.Participants who completed the 3-year placebo-controlled Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) study were invited to participate in an open-label extension. The present analysis includes 4,074 postmenopausal women with osteoporosis (n?=?2,343 long-term; n?=?1,731 cross-over) who enrolled in the extension, missed ?1 dose during their first 3 years of denosumab treatment, and continued into the fourth year of treatment. Comparison of nonvertebral fracture rates during years 1-3 of denosumab with that of the fourth year and with the rate during years 4-7 was evaluated.For the combined group, the nonvertebral fracture rate per 100 participant-years was 2.15 for the first 3 years of denosumab treatment (referent) and 1.36 in the fourth year (rate ratio [RR]?=?0.64; 95 % confidence interval (CI)?=?0.48 to 0.85, p?=?0.003). Comparable findings were observed in the groups separately and when nonvertebral fracture rates during years 1-3 were compared to years 4-7 in the long-term group (RR?=?0.79; 95 % CI?=?0.62 to 1.00, p?=?0.046). Fracture rate reductions in year 4 were most prominent in subjects with persisting low hip bone mineral density (BMD).Denosumab treatment beyond 3 years was associated with a further reduction in nonvertebral fracture rate that persisted through 7 years of continuous denosumab administration. The degree to which denosumab further reduces nonvertebral fracture risk appears influenced by the hip bone density achieved with initial therapy.

Project description:ImportanceHead-to-head randomized clinical trials showed greater efficacy of denosumab vs alendronate in improving bone mineral density. Although there is an association of changes in bone mineral density with reductions in fracture risk, the magnitude of the association is not well established.ObjectiveTo compare the risk of hip and any fracture in patients treated with denosumab and alendronate in routine practice settings.Design, setting, and participantsThis Danish nationwide, population-based, historical cohort study of a population with universal access to health care used prospectively collected, individually linked data from Danish health registries with complete follow-up. Cohorts consisted of 92 355 individuals 50 years or older who were new users of denosumab (n = 4624) or alendronate (n = 87 731) from May 2010 to December 2017 after at least 1 year without an antiosteoporosis medication dispensing.ExposuresInitiation of denosumab or alendronate.Main outcomes and measuresThe primary outcome was hospitalization for hip fracture, and the secondary outcome was hospitalization for any fracture. Inverse probability of treatment weights and the intention-to-treat approach were used to calculate cumulative incidences and adjusted hazard ratios (aHRs) with 95% CIs.ResultsOf the 92 355 included patients, 75 046 (81.3%) were women, and the mean (SD) age was 71 (10) years. The denosumab cohort had a lower proportion of men than the alendronate cohort (12.7% [589] vs 19.0% [16 700]), while age distributions were similar in the 2 cohorts. Within 3 years of follow-up, initiation of denosumab or alendronate was associated with cumulative incidences of 3.7% and 3.1%, respectively, for hip fracture and 9.0% and 9.0%, respectively, for any fracture. Overall, the aHRs for denosumab vs alendronate were 1.08 (95% CI, 0.92-1.28) for hip fracture and 0.92 (95% CI, 0.83-1.02) for any fracture. The aHR of denosumab vs alendronate for hip fracture was 1.07 (95% CI, 0.85-1.34) among patients with a history of any fracture and 1.05 (95% CI, 0.83-1.32) among patients without history of fracture. The aHR for any fracture for denosumab vs alendronate was 0.84 (95% CI, 0.71-0.98) among patients with a history of any fracture and 0.77 (95% CI, 0.64-0.93) among patients with no history of fracture.Conclusions and relevanceTreatment with denosumab and alendronate was associated with similar risks of hip or any fracture over a 3-year period, regardless of fracture history.

Project description:BackgroundWith the aging of the world's population, the social and economic implications of osteoporotic fractures are at epidemic proportions. This study was performed to test the hypothesis that a proximal humeral fracture is an independent risk factor for a subsequent hip fracture and that the risk of the subsequent hip fracture is highest within the first five years after the humeral fracture.MethodsA cohort of 8049 older white women with no history of a hip or humeral fracture who were enrolled in the Study of Osteoporotic Fractures was followed for a mean of 9.8 years. The risk of hip fracture after an incident humeral fracture was estimated with use of age-adjusted Cox proportional hazards regression analysis with time-varying variables; women without a humeral fracture were the reference group. Cox regression analysis was used to evaluate the timing between the proximal humeral and subsequent hip fracture. Risk factors were determined on the basis of a review of the current literature, and we chose the variables that were most predictive and easily ascertained in a clinical setting.ResultsThree hundred and twenty-one women sustained a proximal humeral fracture, and forty-four of them sustained a subsequent hip fracture. After adjustment for age and bone mineral density, the hazard ratio for hip fracture for subjects with a proximal humeral fracture relative to those without a proximal humeral fracture was 1.83 (95% confidence interval = 1.32 to 2.53). After multivariate adjustment, this risk appeared attenuated but was still significant (hazard ratio = 1.57; 95% confidence interval = 1.12 to 2.19). The risk of a subsequent hip fracture after a proximal humeral fracture was highest within one year after the proximal humeral fracture, with a hazard ratio of 5.68 (95% confidence interval = 3.70 to 8.73). This association between humeral and hip fracture was not significant after the first year, with hazard ratios of 0.87 (95% confidence interval = 0.48 to 1.59) between one and five years after the humeral fracture and 0.58 (95% confidence interval = 0.22 to 1.56) after five years.ConclusionsIn this cohort of older white women, a proximal humeral fracture independently increased the risk of a subsequent hip fracture more than five times in the first year after the humeral fracture but was not associated with a significant increase in the hip fracture risk in subsequent years.

Dataset Information

The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies.

Introduction

Methods

Results

Conclusions

Publications

The risk of subsequent osteoporotic fractures is decreased in subjects experiencing fracture while on denosumab: results from the FREEDOM and FREEDOM Extension studies.

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