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.

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.

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 .).

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.

[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.

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).

Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib.

BACKGROUND: In a multicenter clinical trial in North America and Europe that tested the cathepsin K (catK) inhibitor balicatib for the treatment of osteoporosis, several patients developed hardening of the skin. OBJECTIVE: We sought to characterize these observed adverse events. METHODS: Patients with skin hardening were examined by a local dermatologist. All of those patients except one had at least one biopsy specimen taken from affected skin, which was read by local and two central dermatopathologists. Workup was directed for consideration of systemic scleroderma. RESULTS: Nine patients of 709 treated with balicatib developed skin hardening and were given a diagnosis of morphea-like skin changes. No such events were observed in patients taking placebo or the lowest balicatib dose. After discontinuation of balicatib, skin changes resolved completely in 8 and partially in one patient. LIMITATIONS: Each patient was seen by a different dermatologist in 6 different countries. CONCLUSIONS: These observations are likely dose-related adverse effects of balicatib. Although catK was originally thought to be expressed only in osteoclasts, it has more recently also been found in lung and dermal fibroblasts and been implicated in the degradation of the extracellular matrix in the lung and the skin. It is therefore plausible that the observed dermal fibrosis in balicatib-treated patients is a result of impaired degradation of extracellular matrix proteins and may represent a class effect of catK inhibitors. We recommend that further exploration of catK inhibition for the treatment of osteoporosis or cancer should include monitoring for similar adverse effects.

Sex- and age-related changes of trabecular bone of tibia in growing domestic geese (Anser domesticus).

An analysis of radiological images of the spongious substance of the tibiotarsal bones in domestic goose (120 individuals) was performed for the first time. Based on radiographs obtained from radiological examinations conducted in the region of interest (80 x 90 mm2) of the proximal metaphysis, an analysis of the spongious substance of the tibia was performed with the Trabecula programme in order to construct a map of trabeculae and identify their number, volume and density. The results were evaluated statistically using two-way ANOVA. Changes in the number, volume and density of radiological trabeculae of the tibiotarsal bone (TB) in geese from 4 to 16 weeks old were observed. The lowest number (6.34 per mm2), volume (1.50% mm) and density (33.73%) of radiological trabeculae in the proximal metaphysis of TB was reported in male geese at the age of 6 weeks. Similar tendencies were observed in females as well. It should be noted that the volume and density of radiological trabeculae of the tibiotarsal bone achieved a maximum value in males 12 weeks of age, whereas in females at 8 weeks of age. An inverse relationship between body weight and the number of trabeculae in domestic geese (r = - 0.28; P < or = 0.05) was found. We also found a positive relationship between body weight and the volume of radiological trabeculae in domestic geese (r = 0.43; P < or = 0.05). During posthatching development, from the 4th week to slaughter maturity, a decrease in relative bone mass was observed. Negative changes in the trabecular structure combined with high weight gain could lead to bone deformities and locomotor problems in the studied geese.

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.

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.

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).

Atypical subtrochanteric fractures after long-term bisphosphonate therapy.

There have been many reports published in recent years on atypical subtrochanteric fractures after long-term bisphosphonates therapy. In a description of a few series of cases, fractures of typical clinical course and radiological image have been documented. These fractures are estimated as very rare (2.3 per 10,000 patient-years). It is suggested that a subsequent use of steroids or proton pump inhibitors with bisphosphonates may increase the risk of fracture occurrence.

Feasibility of simultaneous measurement of bone formation and bone resorption markers to assess bone turnover rate in postmenopausal women: an EPOLOS study.

BACKGROUND: One of the most important risk factors for osteoporotic fractures in postmenopausal women is elevated bone turnover (EBT), occurring in 25-30% of this population. This study's aim was to find a correlation between bone resorption and bone formation markers to assess bone turnover rate and qualify an individual postmenopausal woman as a possible EBT subject. MATERIAL/METHODS: Three hundred twenty postmenopausal women (> or = one year after the last menstruation, < or = 70 years old) were enrolled at seven clinical sites in this cross-sectional observational study conducted within the EPOLOS. The group was a random sample of the population. The study was performed in a referral center involved in the diagnosis and treatment of osteoporosis. The exclusion criteria included pregnancy, cancer, fracture in the last year, and overweight (> 100 kg). Bone mineral density (BMD) measurements of the lumbar spine, total hip, trochanter, and femoral neck regions were performed. Bone resorption and formation rates were evaluated by serum levels of C-terminal telopeptide of type I collagen (CTX) and osteocalcin (OC), respectively. RESULTS: Using logistic regression to correlate the concentrations of CTX and OC it was possible not only to distinguish the EBT subgroup, but also to construct a simple nomogram for easy classification of individual patients as possible EBT subjects. EBT patients showed generally decreased BMD values and increased bone formation and resorption rates. CONCLUSIONS: Evaluation of both CTX and OC levels enables a more proper indication for EBT. The proposed nomogram may assist in evaluating outcome from the two markers of bone turnover.

Causes of falls in women in Krakow population.

INTRODUCTION: Falls rank among the most serious medical problems in elderly persons, having psychological as well as social consequences. With several hundred fall risk factors known at present, it is necessary to select those that occur most frequently in a particular population. Only then will it be possible to implement effective fall prevention programmes with the aim of increasing awareness of the causes and consequences of falls in elderly persons. The aim of the study was to identify the profile of circumstances of falls in the population of women from Krakow above 50 years of age. MATERIAL AND METHODS: This paper presents the results of a pilot study carried out as a telephone survey. RESULTS: The study population of 50 women experienced 77 falls. The results served to estimate that over half of the women fell once in a year, with most falls occurring in summer as well as during the day. Among the environmental causes of falls outdoors, over 70% were attributable to slippery ground and uneven surface. 56% of the women were taking antihypertensive and cardiovascular drugs and 54% received at least two medications at the same time. Environmental causes were more important than health-related causes of falls. CONCLUSIONS: 1. A fall is most frequently the result of several causes. 2. While the study data need to be verified against a bigger study population, they are an important source and basis for further studies.

Epidemiology, clinical significance, costs and fall prevention in elderly people.

Falls are the fifth most frequent cause of death among elderly people. They are one of the main causes of disability and reduction in the quality of life in this age group. Falls are the direct cause of the majority of limb and femoral neck fractures. Fall prevention is a difficult, expensive and underestimated problem in Poland. 30-40% of women aged 65 years or older experience a fall at least once a year. Falls lead directly to fractures in 5% of those living on their own and 20% of hospital inpatients. Underlying a fall are dysfunctions of multiple organs and the influence of external factors. About 400 different fall risk factors have been described. It has been demonstrated that the risk of falls can be decreased by as much as 40% provided that the patient is treated by a multidisciplinary team of specialists. Standard procedures of care have already been developed in Europe and in the world. This paper presents current knowledge on the epidemiology, significance and costs of treatment of complications of falls in elderly people.

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.

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.

Current understanding of osteoporosis according to the position of the World Health Organization (WHO) and International Osteoporosis Foundation.

The study documents a general change of position on osteoporosis (definition, diagnosis, aim of treatment). Taking into consideration a multifactorial nature of bone fragility in osteoporosis we do not diagnose "osteoporosis" but a total, individual 10-year fracture risk (AR-10) on the basis of independent and self-sufficient risk factors. These are: advanced age, prior fragility fracture, parental history of proximal femur fracture, low BMI, low bone mass, glicocortycosteroids treatment, rheumatoid arthritis, smoking, overuse of alcohol. The treatment should be implemented in persons burdened with a fracture risk higher than a population risk. The intervention threshold is a result of an agreement and a result of work of various working groups of experts. According to Johnell AR-10 below 8% does not require a therapeutical intervention; above 14% justifies the treatment independently of BMD measurement. AR-10 between 8% and 14% is an indication for BMD measurement precising fracture risk. The aim of the treatment is to decrease fracture risk. It combines a limitation of fracture risk factors effects including fall prevention and improvement of bone quality with applying pharmacotherapy. This study highlights that a bone mineral measurement, so far accepted as a criteria for diagnosis of osteoporosis or its exclusion should not be made in aim of diagnosis but to evaluate an absolute fracture risk. Spinal X-rays are performed in aim to diagnose vertebral fractures, which mean a multiple increase of risk of further fractures. The principles of low bone mass differential diagnosis and current possibility of pharmacological treatment are also described. Guidelines for fall avoidance in fracture prevention are described.

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.