Efficacy and Safety of Transdermal Abaloparatide in Postmenopausal Women with Osteoporosis: A Randomized Study.

Anabolic therapies, recommended for patients at very high fracture risk, are administered subcutaneously (SC). The objective of this study was to evaluate the efficacy and safety of the abaloparatide microstructured transdermal system (abaloparatide-sMTS) as an alternative to the SC formulation. This phase 3, noninferiority study (NCT04064411) randomly assigned postmenopausal women with osteoporosis (N = 511) 1:1 to open-label abaloparatide administered daily via abaloparatide-sMTS or SC injection for 12 months. The primary comparison between treatment groups was the percentage change in lumbar spine bone mineral density (BMD) at 12 months, with a noninferiority margin of 2.0%. Secondary endpoints included percentage change in total hip and femoral neck BMD, bone turnover markers, dermatologic safety, and new clinical fracture incidence. At 12 months, percentage increase from baseline in lumbar spine BMD was 7.14% (SE: 0.46%) for abaloparatide-sMTS and 10.86% (SE: 0.48%) for abaloparatide-SC (treatment difference: -3.72% [95% confidence interval: -5.01%, -2.43%]). Percentage change in total hip BMD was 1.97% for abaloparatide-sMTS and 3.70% for abaloparatide-SC. Median changes from baseline at 12 months in serum procollagen type I N-terminal propeptide (s-PINP) were 52.6% for abaloparatide-sMTS and 74.5% for abaloparatide-SC. Administration site reactions were the most frequently reported adverse events (abaloparatide-sMTS, 94.4%; abaloparatide-SC, 70.5%). Incidence of serious adverse events was similar between groups. Mild or moderate skin reactions occurred with abaloparatide-sMTS with no identifiable risk factors for sensitization reactions. Few new clinical fractures occurred in either group. Noninferiority of abaloparatide-sMTS to abaloparatide-SC for percentage change in spine BMD at 12 months was not demonstrated; however, clinically meaningful increases from baseline in lumbar spine and total hip BMD were observed in both treatment groups. © 2023 Radius Health, Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

The Efficacy and Safety of Abaloparatide-SC in Men With Osteoporosis: A Randomized Clinical Trial.

Abaloparatide significantly increased bone mineral density (BMD) in women with postmenopausal osteoporosis and decreased risk of vertebral, nonvertebral, and clinical fractures compared with placebo. The Abaloparatide for the Treatment of Men with Osteoporosis (ATOM; NCT03512262) study evaluated the efficacy and safety of abaloparatide compared with placebo in men. Eligible men aged 40 to 85 years with osteoporosis were randomized 2:1 to daily subcutaneous injections of abaloparatide 80 µg or placebo for 12 months. The primary endpoint was change from baseline in lumbar spine BMD. Key secondary endpoints included BMD change from baseline at the total hip and femoral neck. A total of 228 men were randomized (abaloparatide, n = 149; placebo, n = 79). Baseline characteristics were similar across treatment groups (mean age, 68.3 years; mean lumbar spine BMD T-score, -2.1). At 12 months, BMD gains were greater with abaloparatide compared with placebo at the lumbar spine (least squares mean percentage change [standard error]: 8.48 [0.54] versus 1.17 [0.72]), total hip (2.14 [0.27] versus 0.01 [0.35]), and femoral neck (2.98 [0.34] versus 0.15 [0.45]) (all p < 0.0001). The most common (≥5%) treatment-emergent adverse events were injection site reaction, dizziness, nasopharyngitis, arthralgia, bronchitis, hypertension, and headache. During 12 months of abaloparatide treatment, men with osteoporosis exhibited rapid and significant improvements in BMD with a safety profile consistent with previous studies. These results suggest abaloparatide can be considered as an effective anabolic treatment option for men with osteoporosis. © 2022 Radius Health Inc and The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Romosozumab efficacy and safety in European patients enrolled in the FRAME trial.

In this post hoc analysis, we assessed romosozumab efficacy and safety in European patients enrolled in FRAME. Romosozumab treatment through 12 months, followed by denosumab for a further 24 months, resulted in early and sustained risk reduction for major fracture categories, associated with large gains in bone mineral density. INTRODUCTION: In the multinational FRAME phase 3 trial of romosozumab in postmenopausal women with osteoporosis, marked differences between clinical and non-vertebral fracture outcomes were observed among patients from Central and Southern America versus rest of world. This post hoc analysis assessed romosozumab efficacy and safety in European patients enrolled in the FRAME trial and extension study. METHODS: In FRAME (NCT01575834), patients were randomised 1:1 to romosozumab 210 mg or placebo monthly (QM) for 12 months, followed by open-label denosumab 60 mg Q6M to month 36, including a 12-month extension study. We report incidence of major fracture outcomes, bone mineral density (BMD) change from baseline and safety for European patients enrolled in FRAME. RESULTS: In FRAME, 3013/7180 (41.96%) patients were European; 1494 received romosozumab and 1519 received placebo. Through 12 months, romosozumab reduced fracture risk versus placebo for non-vertebral fracture (1.4% versus 3.0%; p = 0.004), clinical fracture (1.4% versus 3.6%; p < 0.001), new vertebral fracture (0.4% versus 2.1%; p < 0.001) and major osteoporotic fracture (0.9% versus 2.8%; p < 0.001), with results sustained through 36 months following transition to denosumab. Hip fractures were numerically reduced with romosozumab at month 12 (0.2% versus 0.6%; p = 0.092). Romosozumab increased BMD versus placebo at month 12; all patients in the romosozumab and placebo groups experienced further increases by month 36 after transition to denosumab. Adverse events were balanced between groups. CONCLUSIONS: Among European patients in FRAME, romosozumab resulted in early and sustained risk reduction for all major fracture categories, associated with large BMD gains that continued after transition to denosumab.

Prevalence of FRAX risk factors and the osteoporosis treatment gap among women ≥ 70 years of age in routine primary care across 8 countries in Europe.

We studied whether elderly women at risk for fractures receive primary care treatment to prevent fracture. We found that across Europe, women at risk are often not identified, and less than half of such women receive appropriate treatment. Finally, women diagnosed with osteoporosis are much more likely to receive treatment. PURPOSE: To examine the relationship between risk factors for fragility fracture (FF) and osteoporosis (OP) treatment gap in elderly women across Europe, and compare the prevalence of risk factors between countries. METHODS: Demographic and clinical information was collected from women ≥ 70 years visiting primary care physicians in Belgium, France, Germany, Ireland, Poland, Slovakia, Switzerland, and the UK. Increased risk of FF was defined by the presence of 1 or more criteria (history of fracture, 10-year fracture probability, or T-score ≤ - 2.5). RESULTS: There were 3798 women in total. Treatment gap (proportion at increased risk of FF not receiving treatment for OP) varied from 53.1 to 90.8% across countries, and the proportion of patients at increased risk of FF varied from 41.2 to 76.1%. Across countries, less than 50% of patients with increased risk of FF had a diagnosis of OP. Previous fracture was the most common risk factor, with similar prevalence across most countries; other risk factors varied widely. The treatment gap was reduced in patients with an OP diagnosis in all countries, but this reduction varied from 36.5 to 79.4%. The countries with the lowest rates of bone densitometry scans (Poland, France, and Germany; 8.3-12.3%) also had the highest treatment gap (82.2 to 90.8%). CONCLUSIONS: This study highlights differences across Europe in clinical risk factors for fracture, rates of densitometry scanning, and the rates of OP diagnosis. More emphasis is needed on risk assessment to improve the identification and treatment of elderly women at risk for fracture.

Guidelines of prevention, recognition and treatment of osteoporotic bone fractures.

Population aging makes osteoporotic fractures (OP) an increasingly serious healthcare problem. It is estimated that there are approximately 2,200,000 people with an osteoporotic fracture in Poland, and according to the NFZ (National Health Found) report 126,100 new fractures were registered in 2018, including 34,700 fractures of the proximal femur (PFF). Surgical treatment of OP fractures is difficult due to local conditions and the general health condition of the patients. Reduced bone strength makes it difficult to achieve permanent bone fixation and union.The current "Guidelines for the prevention, diagnosis and treatment of osteoporotic bone fractures" is an update of the 2017 version (previous versions: 2007, 2012) taking into account the progress made in this area of knowledge and practice. The latest principles of conduct have been created on the basis of contemporary world standards and publications. The recommended methods of treating fractures will be discussed: of the PFF, distal end of the radius, proximal end of the humerus and the spine. Particular attention has been paid to the management of patients with PFF, because the average age - 80 years causes that an average of 29.4% of patients in Poland die within a year after the fracture (data from the National Health Fund). After sustaining a fracture, the risk of a consecutive one increases 210 times, so the surgeon is required not only to treat the fracture, but also to implement fracture prophylaxis. The study will also present the principles of diagnosis and treatment of osteoporosis.The presented guidelines were adopted in August 2022 as an official document of the National Consultant in the field of Orthopedics and Traumatology of the bone and joints system and the President of the Polish Society of Orthopedics and Traumatology. The leading author was Prof. dr hab. med. Edward Czerwiski.

Relation between risk of falls, sarcopenia and parameters assessing quality of skeletal muscles in a group of postmenopausal women.

INTRODUCTION: Involutional changes that occur in skeletal muscle are a feature that characterizes the aging process. In women, age-related decreases in muscle mass and function of skeletal muscles occur more rapidly with the onset of menopause. Progressive muscle dysfunction has been directly linked with an increased probability of falls, fractures, disability and mortality. AIM OF THE STUDY: To assess the relationship between the risk of falls and parameters of skeletal muscle assessment in a group of postmenopausal women together with the identification of patients with sarcopenia. MATERIAL AND METHODS: This study was carried among 122 women over 60 years of age. Patients had their muscular system tested with the emphasis on the sarcopenia diagnosis using: Total Body Composition, handgrip and physical performance tests. Patients also underwent a questionnaire survey assessing occurrence of falls. RESULTS: The analysis showed an over 2-fold increase (OR 2.4; 95% CI, 1.02-5.56) in risk of falls in a year among subjects with decreased muscle mass. No such correlation was noted with parameters such as falls in the last 12 months and decrease of muscle strength as well as physical performance. Sarcopenia is more likely to be diagnosed with European Working Group on Sarcopenia in Older People (EWGSOP1) criteria than EWGSOP2 (updated in 2018) (18% vs. 4.1% respectively). The increased risk of falls has not been proven in women with sarcopenia. CONCLUSIONS: The decrease of muscle mass is significantly correlated with the risk of falls in the last year in postmenopausal women. Impact of sarcopenia on the risk of falls depends on diagnostic criteria.

Contemporary Management of Osteoporotic Fractures.

With aging of the population, osteoporotic fractures are becoming an increasing medical problem world-wide. It has been estimated that 2,700,000 patients experienced a low energy fracture in the Polish population in 2010. On the basis of contemporary world standards and publications in the field of orthopaedics and trau-matic surgery, a summary of the principles of management of osteoporotic fractures is presented. Both general problems of fracture treatment in elderly patients as well as difficulties in surgical and conservative treatment resulting from osteoporotic bone abnormalities are discussed. Special attention is paid to preoperative and postoperative procedures in patients with proximal femur fractures. Also presented is a contemporary strategy for the treatment of fractures of the distal forearm, proximal humerus and vertebrae. General principles of diagnosis and treatment of osteoporosis are discussed.

Vertebral fracture assessment, trabecular bone score and handgrip in a group of postmenopausal women with vertebral fractures - preliminary study.

OBJECTIVES: The aim of our study was to determine a possible correlation between vertebral fractures (indicated by VFA - vertebral fracture assessment), TBS (trabecular bone score) and muscle strength (measured by means of handgrip strength test results) in a group of postmenopausal women. MATERIAL AND METHODS: The study was conducted between 2014 and 2015 in a group of patients of Krakow Medical Centre (KMC). Women who participated in the study were referred to KMC by an attending physician for suspected vertebral fracture. Apart from VFA, patients were additionally tested for bone density (including TBS), muscle strength (by means of a handgrip strength test) and height loss. Altogether 35 patients with an average age of 69.7 years (49-95, SD = 10.49) were included in the study. RESULTS: In the group of 35 women, VFA analysis demonstrated vertebral fractures in 17 patients (40%). Vertebral height loss suggesting a fracture was revealed in 77 vertebrae. The mean result of the TBS was 1.195 (0.982-1.409, SD = 0.09), which suggests high risk of fracture. The majority of the subjects (65.7%) displayed major bone microarchitecture degradation (TBS < 1.23) and also the highest number of fractures (n = 62, 80.5% of all). There was no correlation between the spine bone mineral density (BMD) score and the TBS result, which confirms studies showing that subjects with the same bone density may have completely different TBS. Bone density (spine BMD) was similar (osteopenic) in groups with or without vertebral fracture (in VFA). We noted a significant correlation (r = 0.45, p < 0.05) between the number of fractured vertebrae and the handgrip score. CONCLUSIONS: VFA should be a part of a standard diagnostic procedure for patients with osteoporotic fractures. When it comes to identifying patients at risk of fracturing vertebrae, muscle strength (handgrip) may have potential use in clinical practice. The predictive value of the TBS in reference to vertebral fractures should be evaluated in bigger randomized studies.

Trabecular Bone Score (TBS) in Clinical Practice - Rewiev.

Bone mineral density (BMD) assessment is the basic method for assessing fracture risk and diagnosing osteoporosis according to the World Health Organization (WHO). Osteoporosis is diagnosed when the T-score at the proximal femur or spine is T≤-2.5; however, 70% of fractures occur in patients who do not fulfil this criterion. As BMD alone does not adequately predict fracture risk, additional methods supporting risk assessment are needed [3,4]. In 2012, the US Food and Drug Administration (FDA) adopted the Trabecular Bone Score (TBS) as another diagnostic method for osteoporosis. The aim of this study is to evaluate the use of TBS in clinical practice with particular attention to fracture risk assessment, differential diagnosis and assessment of treatment outcomes in patients suffering from primary or secondary osteoporosis. Literature analysis points to the increasing use of TBS in clinical practice. It has been found that, in different subjects with the same BMD, structural bone health is better differentiated using TBS. Additionally, it is valuable to use the DXA along with TBS analysis for improved prediction of fracture risk. Indirect assessment of bone structure with TBS is also helpful in assessing the effect of medications. In conclusion, TBS analysis is a valuable tool in the assessment of bone fracture risk and in the differential diagnosis of structural bone disorders in secondary osteoporosis.

10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.

BACKGROUND: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis. METHODS: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov. FINDINGS: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius. INTERPRETATION: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. FUNDING: Amgen.

Romosozumab Treatment in Postmenopausal Women with Osteoporosis.

BACKGROUND: Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. METHODS: We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. RESULTS: At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. CONCLUSIONS: In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).

Fracture Liaison Services - Polish Experience. Methods of Secondary Prevention of Osteoporotic Fractures.

BACKGROUND: Fragility fractures are a major challenge to health systems around the world. The risk of a subsequent fracture may increase even 11-fold after one's first fracture event. A coordinator-based system (Fracture Liaison Services) was established in Poland in order to fill the gap in the care of patients with osteoporotic fractures. In the past years, the FLS has become a crucial part of orthopaedic facilities worldwide, bringing benefits to patients and savings to health systems' budgets. MATERIAL AND METHODS: In 2015, the European Foundation of Osteoporosis and Musculoskeletal Diseases (EFOM) implemented the FLS in Poland under the name "System Zapobiegania Zlamaniom (SZZ)". It was established in 16 centres in different parts of Poland. During the preparation phase, 42 healthcare professionals from 17 sites participated in courses organized by EFOM. RESULTS: A total of 1,579 patients were included in the SZZ, with a total of 746 DXA scans performed in that group. Patients were educated about osteoporotic fractures, including the methods of prevention (causes of fractures, problem of falls, vitamin D and calcium supplementation). The number of patients receiving antiresorptive treatment increased by 74.1%. The percentage of patients taking vitamin D and calcium supplements increased by an average of 10.8%. Although all the participating patients had suffered a fragility fracture, only 42% fulfilled the WHO clinical criteria for osteoporosis. CONCLUSIONS: 1. The implementation of the Fracture Liaison Service concept in Poland is possible and beneficial for the patients and healthcare system. 2. The current WHO definition of osteoporosis might be insufficient. 3. The use of an integrated database in different facilities, in terms of fracture epidemiology, significantly improves the quality of data being collected.

Possibilities for Implementing Fracture Liaison Service in Poland in the Light of a Visit to Glasgow Western Infirmary.

Osteoporosis remains one of the top challenges for health services all over the world. Osteoporotic changes in bone structure along with the aging of society result in rapid growth of osteoporotic fractures. Statistics show that approximately 25% of women and 20% of men will suffer a subsequent fracture within 5 years of an initial one. In order to deal with the problem, a novel program in secondary fracture prevention was developed in Scotland in the late 1990's. The system was based on a coordinator and focused on identifying, diagnosing and treating patients with osteoporotic fractures. After just a few years, the system, known as Fracture Liaison Services (FLS), proved to be a cost-effective success. For the last several years, FLS has been implemented in countries all over the world. The Glasgow Western Infirmary, where the program started, continues to be one of the top exemplary facilities in the United Kingdom. Each year the Bone Metabolism Unit proves its effectiveness by providing 4000 DXA scans and taking care of 2500 fractures a year. In 2015, the European Foundation of Osteoporosis and Musculoskeletal Diseases successfully implemented a coordinator-based Fracture Liaison Service in Poland.

Cost-effectiveness analysis of treatment of osteoporotic fractures in relation to FRAX algorithm in a sample of Polish population.

BACKGROUND: The increasing incidence of osteoporotic fractures is becoming a growing burden on the health service. Due to the high cost of treatment, these fractures require a broader look at the underlying problem. The aim of the study was to assess the 10-year probability of hip fracture or any other major osteoporotic fracture at which the treatment becomes cost-effective. MATERIAL AND METHODS: This was a retrospective study of a group of 1,024 patients. The cost-effectiveness of pharmacological low-energy fracture prevention was analyzed by means of the medication defined as the reimbursement limit basis in the reimbursement limit group 147.0. (medications used in bone diseases) in July 2013 (Alendrogen 70 mg). 3- and 5-year therapies were analysed. The outcome was compared with the results of FRAX® (of the Polish and British population) in every patient. RESULTS: The model for calculating cost-effectiveness showed that treatment after the age of 50 until the age of 60-65 years is cost-effective at a similar level of 10-year major fracture probability (regardless of treatment duration). After the age of 65, there is a clear decline in the profitability of the therapy. The results indicate that, for the population of women aged >50 years, the treatment is cost-effective when the 10-year major fracture probability equals 5.1% and 6% for a 3- and 5-year therapy, respectively. CONCLUSIONS: 1. The study showed pharmacological treatment to be cost-effective in a large group of patients forming the study population. 2. The analysis also revealed a strong correlation between study results and the specific tool employed to define fracture probability.

A 24-month study evaluating the efficacy and safety of denosumab for the treatment of men with low bone mineral density: results from the ADAMO trial.

CONTEXT: One in 4 men in the United States aged >50 years will have an osteoporosis-related fracture. Fewer data are available on osteoporosis treatment in men than in women. OBJECTIVE: The purpose of this study was to evaluate denosumab therapy in men with low bone mineral density (BMD). DESIGN: This was a phase 3 study with 2 treatment periods: a previously reported 12-month double-blind, placebo-controlled phase and a 12-month open-label phase. SETTING: This was a multicenter study conducted in North America and Europe. PARTICIPANTS: A total of 228 men entered the open-label phase and 219 completed the study. INTERVENTION: Men from the original denosumab (long-term) and placebo (crossover) groups received 60 mg of denosumab sc every 6 months. MAIN OUTCOME MEASURES: BMD, serum collagen type I C-telopeptide, and safety were measured. RESULTS: During the open-label phase, continued BMD increases occurred with long-term denosumab treatment (2.2% lumbar spine, 0.9% total hip, 1.3% femoral neck, 1.3% trochanter, and 0.2% 1/3 radius), resulting in cumulative 24-month gains from baseline of 8.0%, 3.4%, 3.4%, 4.6%, and 0.7%, respectively (all P < .01). The crossover group showed BMD gains after 12 months of denosumab treatment similar to those of the long-term denosumab group during the first treatment year. Significant reductions in serum collagen type I C-teleopeptide were observed after denosumab administration. Adverse event rates were similar between groups, and no new safety signals were identified. CONCLUSIONS: In men with low BMD, denosumab treatment for a second year continued to increase BMD, maintained reductions in bone resorption, and was well tolerated. BMD increased in men initiating denosumab during the second year. These effects were similar to those previously seen in postmenopausal women with osteoporosis and in men with prostate cancer receiving androgen deprivation therapy.

[The causes of falls and injuries after falls in women over the age of 50 living alone in Krakow]. / Przyczyny upadków i urazów po upadkach u kobiet powyzej 50 roku zycia zyjacych samodzielnie w Krakowie.

INTRODUCTION: Falls are one of the most devastating health problems of elderly people. The identification of causes of falls helps to establish proper prevention strategies. MATERIAL AND METHOD: The study was based on a group of community-dwelling, independent women aged over 50 years. The frequency of falls was calculated on the basis of a retrospective analysis of 1326 cases. 100 women were chosen for a telephone questionnaire to identify causes and consequences of falls. The average age was 63.9 (SD 8.6) and the average BMI was 27.6 (SD 5.4). RESULTS: Approximately 31% of 1326 women reported at least one fall a year. In the year preceding the questionnaire 62% of the participants reported one fall, 26%--two falls, 8%--three falls and 5%--four and more falls. In the surveyed group of 100 women 72% of falls occurred outdoors, which is 2.5 times more often than at home (28%). 68% of falls occurred between 12 pm and 6 pm. Summer is the season of the highest occurrence of falls (37%). In winter, the frequency of outdoor falls increases, whereas during summer the frequency of falls happening in and outdoors does not differ. The most frequent cause of falls, both in and outdoors, was slipping. Other important risk factors include: hypnotic drugs, walking impairments, balance deficit, vertigo, analgesics. Most of the falls had various intrinsic and extrinsic causes. KEY POINTS: We found that 30% of women aged over 50 years falls at least once a year. Both at home and outside falls resulted from slipping. For almost 80% of falls as a consequence of an injury. The majority of falls had intrinsic and extrinsic origins.

The effect of three or six years of denosumab exposure in women with postmenopausal osteoporosis: results from the FREEDOM extension.

CONTEXT: The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) extension is evaluating the long-term efficacy and safety of denosumab for up to 10 years. OBJECTIVE: The objective of the study was to report results from the first 3 years of the extension, representing up to 6 years of denosumab exposure. DESIGN, SETTING, AND PARTICIPANTS: This was a multicenter, international, open-label study of 4550 women. INTERVENTION: Women from the FREEDOM denosumab group received 3 more years of denosumab for a total of 6 years (long-term) and women from the FREEDOM placebo group received 3 years of denosumab (crossover). MAIN OUTCOME MEASURES: Bone turnover markers (BTMs), bone mineral density (BMD), fracture, and safety data are reported. RESULTS: Reductions in BTMs were maintained (long-term) or achieved rapidly (crossover) after denosumab administration. In the long-term group, BMD further increased for cumulative 6-year gains of 15.2% (lumbar spine) and 7.5% (total hip). During the first 3 years of denosumab treatment, the crossover group had significant gains in lumbar spine (9.4%) and total hip (4.8%) BMD, similar to the long-term group during the 3-year FREEDOM trial. In the long-term group, fracture incidences remained low and below the rates projected for a virtual placebo cohort. In the crossover group, 3-year incidences of new vertebral and nonvertebral fractures were similar to those of the FREEDOM denosumab group. Incidence rates of adverse events did not increase over time. Six participants had events of osteonecrosis of the jaw confirmed by adjudication. One participant had a fracture adjudicated as consistent with atypical femoral fracture. CONCLUSION: Denosumab treatment for 6 years remained well tolerated, maintained reduced bone turnover, and continued to increase BMD. Fracture incidence remained low.

Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial.

OBJECTIVE: To compare the efficacy and safety of denosumab to ibandronate in postmenopausal women with low bone mineral density (BMD) previously treated with a bisphosphonate. METHODS: In a randomized, open-label study, postmenopausal women received 60 mg denosumab subcutaneously every 6 months (n=417) or 150 mg ibandronate orally every month (n=416) for 12 months. End points included percentage change from baseline in total hip, femoral neck, and lumbar spine BMD at month 12 and percentage change from baseline in serum C-telopeptide at months 1 and 6 in a substudy. RESULTS: At month 12, significantly greater BMD gains from baseline were observed with denosumab compared with ibandronate at the total hip (2.3% compared with 1.1%), femoral neck (1.7% compared with 0.7%), and lumbar spine (4.1% compared with 2.0%; treatment difference P<.001 at all sites). At month 1, median change in serum C-telopeptide from baseline was -81.1% with denosumab and -35.0% with ibandronate (P<.001); the treatment difference remained significant at month 6 (P<.001). Adverse events occurred in 245 (59.6%) denosumab-treated women and 230 (56.1%) ibandronate-treated women (P=.635). The incidence of serious adverse events was 9.5% for denosumab-treated women and 5.4% for ibandronate-treated women (P=.046). No clustering of events in any organ system accounted for the preponderance of these reports. The incidence rates of serious adverse events involving infection and malignancy were similar between treatment groups. CONCLUSION: In postmenopausal women previously treated with a bisphosphonate and low BMD, denosumab treatment resulted in greater BMD increases than ibandronate at all measured sites. No new safety risks with denosumab treatment were identified.

Fracture risk prediction in outpatients from Krakow Region using FRAX tool versus fracture risk in 11-year follow-up.

INTRODUCTION: FRAX is a an algorithm accepted by WHO for evaluating fragility fracture risk of women aged 40 years or more. The aim of this study was to use the FRAX tool to verify the risk of fractures in a population of women from the Cracow region in an 11-year follow-up. MATERIALS AND METHODS: The study was a retrospective cohort survey evaluating the incidence of fragility fractures over 11 years of follow-up. 5,092 women aged 50 years and more were randomly chosen from a group of 100,000 female patients of the Cracow Medical Centre who came to the Centre for densitometric examination between 1997 and 2001. Finally, 1024 patients were randomized into the study. After an average of 11 years a follow-up telephone survey was conducted among a randomly selected group of patients using a questionnaire corresponding to the one applied in the first survey. 10-year fracture risk was calculated for each patient using FRAX based on the BMI (Body Mass Index) and for 886 women using FRAX based on BMD (Bone Mineral Density) at the femoral neck. The Polish version of FRAX was validated by comparing the predicted risk with the actual incidence of fractures during the 11-year follow-up. RESULTS: The 10-year probability of a major osteoporotic fracture calculated using FRAX based on BMI for the entire group was 5.3% (median, 1st/3rd quartile: 3.5-8.5%) and the probability of a proximal femur (hip) fracture was 1.3% (median, 1st-3rd quartile: 0.7% -2.4%). In 886 women whose BMD T-score at the femoral neck was available, the mean probability of a major osteoporotic fracture was 4.9% (3.3-7.9%) and of a hip fracture 0.9% (0.3-2.3%). The actual absolute fracture risk calculated on the basis of the number of patients who had experienced a fracture during the follow-up was surprisingly much higher than the predicted figure. The risk of a major fracture in the study group was 17.7% and of a proximal femur fracture, 3%. CONCLUSION: In our opinion, FRAX is a very good screening tool, but not a precise diagnostic tool.

A randomized, placebo-controlled study of the effects of denosumab for the treatment of men with low bone mineral density.

CONTEXT: Men with low bone mineral density (BMD) were treated with denosumab. OBJECTIVE: Our objective was to investigate the effects of denosumab compared with placebo in men with low BMD after 1 yr of treatment. DESIGN, SUBJECTS, AND INTERVENTION: This was a placebo-controlled, phase 3 study to investigate the efficacy and safety of denosumab 60 mg every 6 months vs. placebo in men with low BMD. MAIN OUTCOME MEASURE: The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at month 12. RESULTS: Of the 242 randomized subjects (mean age 65 yr), 228 (94.2%) completed 1 yr of denosumab therapy. After 12 months, denosumab resulted in BMD increases of 5.7% at the LS, 2.4% at the total hip, 2.1% at the femoral neck, 3.1% at the trochanter, and 0.6% at the one third radius (adjusted P ≤ 0.0144 for BMD percent differences at all sites compared with placebo). Sensitivity analyses done by controlling for baseline covariates (such as baseline testosterone levels, BMD T-scores, and 10-yr osteoporotic fracture risk) demonstrated that the results of the primary endpoint were robust. Subgroup analyses indicate that treatment with denosumab was effective across a spectrum of clinical situations. Treatment with denosumab significantly reduced serum CTX levels at d 15 (adjusted P < 0.0001). The incidence of adverse events was similar between groups. CONCLUSIONS: One year of denosumab therapy in men with low BMD was well tolerated and resulted in a reduction in bone resorption and significant increases in BMD at all skeletal sites assessed.