Summary
This study examined the imminent risk of a future fracture within 1 and 2 years following a first fracture in women aged 50 years and older and assessed independent factors associated with ...risk of subsequent fractures. The study highlights the need to intervene rapidly after a fracture to prevent further fractures.
Introduction
This study aims to determine the imminent risk of subsequent fractures within 1 and 2 years following a first fracture and to assess independent factors associated with subsequent fractures.
Methods
Retrospective, observational cohort study of women aged ≥ 50 years with a fragility fracture was identified from Swedish national registers. Clinical/demographic characteristics at the time of index fracture and cumulative fracture incidences up to 12 and 24 months following index fracture were calculated. Risk factors for subsequent fracture were identified using multivariate regression analysis.
Results
Two hundred forty-two thousand one hundred eight women (mean SD age 74 12.5 years) were included. The cumulative subsequent fracture incidence at 12 months was 7.1% (95% confidence interval CI, 6.9–7.2) and at 24 months was 12.0% (95% CI, 11.8–12.1). The rate of subsequent fractures was highest in the first month (~ 15 fractures per 1000 patient-years) and remained steady between 4 and 24 months (~ 5 fractures/1000 patient-years). Higher age was an independent risk factor for imminent subsequent fractures (at 24 months, sub-distribution hazard ratio HR, 3.07;
p
< 0.001 for women 80–89 years reference 50–59 years). Index vertebral fracture was a strong independent risk factor for subsequent fracture (sub-distribution HR, 2.72 versus hip fracture;
p
< 0.001 over 12 months; HR, 2.23;
p
< 0.001 over 24 months).
Conclusions
Our findings highlight the need to intervene rapidly after any fragility fracture in postmenopausal women. The occurrence of a fragility fracture provides healthcare systems with a unique opportunity to intervene to reduce the increased risk of subsequent fractures.
Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of ...osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis.
We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures.
As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval CI, 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab.
Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)
Summary
Romosozumab is a therapy that stimulates bone formation and reduces bone resorption. In this study of postmenopausal women with low BMD, a second course of romosozumab following a period off ...treatment or on denosumab increased or maintained BMD, respectively, and was well tolerated, providing insight into treatment sequence options.
Introduction
In patients with high fracture risk, therapies that stimulate bone formation provide rapid BMD gains; currently available agents, parathyroid hormone receptor agonists, are limited to a 2-year lifetime exposure and generally used for a single treatment course. However, for long-term osteoporosis management, a second treatment course may be appropriate. Romosozumab, a therapy with the dual effect of increasing bone formation and decreasing bone resorption, reduces fracture risk within 12 months. Here, we report efficacy and safety of a second romosozumab course.
Methods
In this phase 2, dose-finding study, postmenopausal women with low bone mass (T-score ≤ − 2.0 and ≥ − 3.5) received romosozumab or placebo (month 0–24) followed by placebo or denosumab (month 24–36); participants then received a year of romosozumab (month 36–48).
Results
Of 167 participants who entered the month 36–48 period, 35 had been initially randomized to romosozumab 210 mg monthly. In participants who received romosozumab 210 mg monthly followed by placebo, a second romosozumab course (
n
= 19) increased BMD by amounts similar to their initial treatment (month 0–12) at the lumbar spine (12.4%; 12.0%, respectively) and total hip (6.0%; 5.5%, respectively). Following denosumab, a second romosozumab course (
n
= 16) increased BMD at the lumbar spine (2.3%) and maintained BMD at the total hip. Safety profiles were similar between first and second romosozumab courses.
Conclusions
After 12 months off-treatment, a second romosozumab course again led to rapid and large BMD gains. Following denosumab, BMD gains with romosozumab were smaller than with initial treatment. No new safety findings were observed during the second course.
Summary
The FREEDOM study and its Extension provide long-term information about the effects of denosumab for the treatment of postmenopausal osteoporosis. Treatment for up to 8 years was associated ...with persistent reduction of bone turnover, continued increases in bone mineral density, low fracture incidence, and a favorable benefit/risk profile.
Introduction
This study aims to report the results through year 5 of the FREEDOM Extension study, representing up to 8 years of continued denosumab treatment in postmenopausal women with osteoporosis.
Methods
Women who completed the 3-year FREEDOM study were eligible to enter the 7-year open-label FREEDOM Extension in which all participants are scheduled to receive denosumab, since placebo assignment was discontinued for ethical reasons. A total of 4550 women enrolled in the Extension (2343 long-term; 2207 cross-over). In this analysis, women in the long-term and cross-over groups received denosumab for up to 8 and 5 years, respectively.
Results
Throughout the Extension, sustained reduction of bone turnover markers (BTMs) was observed in both groups. In the long-term group, mean bone mineral density (BMD) continued to increase significantly at each time point measured, for cumulative 8-year gains of 18.4 and 8.3 % at the lumbar spine and total hip, respectively. In the cross-over group, mean BMD increased significantly from the Extension baseline for 5-year cumulative gains of 13.1 and 6.2 % at the lumbar spine and total hip, respectively. The yearly incidence of new vertebral and nonvertebral fractures remained low in both groups. The incidence of adverse and serious adverse events did not increase over time. Through Extension year 5, eight events of osteonecrosis of the jaw and two events of atypical femoral fracture were confirmed.
Conclusions
Denosumab treatment for up to 8 years was associated with persistent reductions of BTMs, continued BMD gains, low fracture incidence, and a consistent safety profile.
Summary
Post hoc analysis of FRAME and ARCH revealed that on-study nonvertebral and vertebral fractures by Month 12 were less common in women initially treated with romosozumab versus placebo or ...alendronate. Recurrent fracture risk was also lower in romosozumab‑treated patients, and there were no fracture‑related complications. Results support continuing romosozumab treatment post‑fracture.
Purpose
Post hoc analysis evaluating efficacy and safety of romosozumab, administered in the immediate post‑fracture period, in the FRAME and ARCH phase 3 trials.
Methods
In FRAME (NCT01575834) and ARCH (NCT01631214), postmenopausal women with osteoporosis were randomized 1:1 to romosozumab 210 mg monthly or comparator (FRAME, placebo; ARCH, alendronate 70 mg weekly) for 12 months, followed by antiresorptive therapy (FRAME, denosumab; ARCH, alendronate). In patients who experienced on-study nonvertebral or new/worsening vertebral fracture by Month 12, we report the following: fracture and treatment‑emergent adverse event (TEAE) incidence through 36 months, bone mineral density changes (BMD), and romosozumab timing. Due to the sample sizes employed, meaningful statistical comparisons between treatments were not possible.
Results
Incidence of on-study nonvertebral and vertebral fractures by Month 12 was numerically lower in romosozumab- versus comparator-treated patients (FRAME, 1.6% and 0.5% versus 2.1% and 1.6%; ARCH, 3.4% and 3.3% versus 4.6% and 4.9%, respectively). In those who experienced on-study nonvertebral fracture by Month 12, recurrent nonvertebral and subsequent vertebral fracture incidences were numerically lower in patients initially treated with romosozumab versus comparator (FRAME, 3.6% 2/56 and 1.8% 1/56 versus 9.2% 7/76 and 3.9% 3/76; ARCH, 10.0% 7/70 and 5.7% 4/70 versus 12.6% 12/95 and 8.4% 8/95, respectively). Among those with on-study vertebral fracture by Month 12, recurrent vertebral and subsequent nonvertebral fracture incidences were numerically lower with romosozumab versus comparator (FRAME, 0.0% 0/17 and 0.0% 0/17 versus 11.9% 7/59 and 8.5% 5/59; ARCH, 9.0% 6/67 and 7.5% 5/67 versus 15.0% 15/100 and 16.0% 16/100, respectively). In patients with fracture by Month 12, no fracture‑related complications were reported in romosozumab-treated patients. BMD gains were numerically greater with romosozumab than comparators.
Conclusion
Data suggest support for the efficacy and safety of continuing romosozumab treatment following fracture.
Trial registrations
NCT01575834; NCT01631214.
Summary
This paper demonstrates a large post-fracture anti-osteoporosis treatment gap in the period 2005 to 2015. The gap was stable in Denmark at around 88–90%, increased in Catalonia from 80 to ...88%, and started to increase in the UK towards the end of our study. Improved post-fracture care is needed.
Introduction
Patients experiencing a fragility fracture are at high risk of subsequent fractures, particularly within the first 2 years after the fracture. Previous studies have demonstrated that only a small proportion of fracture patients initiate therapy with an anti-osteoporotic medication (AOM), despite the proven fracture risk reduction of such therapies. The aim of this paper is to evaluate the changes in this post-fracture treatment gap across three different countries from 2005 to 2015.
Methods
This analysis, which is part of a multinational cohort study, included men and women, aged 50 years or older, sustaining a first incident fragility fracture. Using routinely collected patient data from three administrative health databases covering Catalonia, Denmark, and the United Kingdom, we estimated the treatment gap as the proportion of patients not treated with AOM within 1 year of their first incident fracture.
Results
A total of 648,369 fracture patients were included. Mean age 70.2–78.9 years; 22.2–31.7% were men. In Denmark, the treatment gap was stable at approximately 88–90% throughout the 2005 to 2015 time period. In Catalonia, the treatment gap increased from 80 to 88%. In the UK, an initially decreasing treatment gap—though never smaller than 63%—was replaced by an increasing gap towards the end of our study. The gap was more pronounced in men than in women.
Conclusion
Despite repeated calls for improved secondary fracture prevention, an unacceptably large treatment gap remains, with time trends indicating that the problem may be getting worse in recent years.
Summary
This study demonstrates a substantial and persistent anti-osteoporosis treatment gap in men and women ≥50 years old who sustained major osteoporotic fracture(s) between 2005 and 2014 in ...Denmark. This was not substantially reduced by including hospital-administered anti-osteoporosis treatments. Strengthened post-fracture organization of care and secondary fracture prevention is highly needed.
Introduction
The purpose of this study was to evaluate the Danish anti-osteoporosis treatment gap from 2005 to 2014 in patients sustaining a major osteoporotic fracture (MOF), and to assess the impact of including hospital-administered anti-osteoporosis medications (AOM) on the treatment gap among these patients.
Methods
In this retrospective, registry-based study, we included men and women aged 50 years or older and living in Denmark, who sustained at least one MOF between 2005 and 2014. We applied a repeated cross-sectional design to generate cohorts of patients sustaining a first MOF, hip, vertebral, humerus, or forearm fracture, respectively, within each calendar year. We evaluated the treatment gap as the proportion of patients within each cohort not receiving treatment with AOM within 1 year of the fracture. Hospital-administered AOM was identified by SKS code.
Results
The treatment gap among MOF patients decreased from 85% in 2005 to 79% in 2014. The gap was smaller among hip and vertebral fracture patients as compared to humerus and forearm fracture patients, and it was smaller in women than in men. The use of hospital-administered AOM was relatively uncommon, with a maximum of 0.9% of MOF patients initiating hospital-administered AOM (in 2012). We observed substantial variations in this proportion between fracture types and gender. Hospital-administered AOM was most commonly used among vertebral fracture patients.
Conclusion
A significant treatment gap among patients sustaining a major osteoporotic fracture was present throughout our analysis, and including hospital-administered AOM did not significantly improve the treatment gap assessment. Improved secondary fracture prevention is urgently needed.
Summary
This position paper reviews how the National Bone Health Alliance (NBHA) will execute a project to help assure health professionals of the clinical utility of bone turnover markers; the ...current clinical approaches concerning osteoporosis and the status and use of bone turnover markers in the USA; the rationale for focusing this effort around two specific bone turnover markers; the need to standardize bone marker sample collection procedures, reference ranges, and bone turnover marker assays in clinical laboratories; and the importance of harmonization for future research of bone turnover markers.
Introduction
Osteoporosis is a major global health problem, with the prevalence and incidence of osteoporosis for at-risk populations estimated to be 44 million Americans. The potential of bone markers as an additional tool for health care professionals to improve patient outcomes and impact morbidity and mortality is crucial in providing better health care and addressing rising health care costs. This need to advance the field of bone turnover markers has been recognized by a number of organizations, including the International Osteoporosis Foundation (IOF), National Osteoporosis Foundation, International Federation of Clinical Chemistry, and Laboratory Medicine (IFCC), and the NBHA.
Methods
This position paper elucidates how this project will standardize bone turnover marker sample collection procedures in the USA, establish a USA reference range for one bone formation (serum procollagen type I N propeptide, s-PINP) and one bone resorption (serum C-terminal telopeptide of type I collagen, s-CTX) marker, and standardize bone turnover marker assays used in clinical laboratories. This effort will allow clinicians from the USA to have confidence in their use of bone turnover markers to help monitor osteoporosis treatment and assess future fracture risk. This project builds on the recommendations of the IOF/IFCC Bone Marker Standards Working Group by developing USA reference standards for s-PINP and s-CTX, the markers identified as most promising for use as reference markers.
Results
The goals of this project will be realized through the NBHA and will include its governmental, academic, for-profit, and non-profit sector stakeholders as well as major academic and commercial laboratories. Upon completion, a parallel effort will be pursued to make bone turnover marker measurements reliable and accepted by all health care professionals for facilitating treatment decisions and ultimately be reimbursed by all health insurance payers.
Conclusions
Successful completion of this project will help assure health professionals from the USA of the clinical utility of bone turnover markers and ties in with the parallel effort of the IOF/IFCC to develop worldwide bone turnover reference ranges.
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