Cardiac Arrhythmia and Heart Failure Shortly After Starting Romosozumab for Osteoporosis: A Case-Based Review.

Romosozumab is a humanized monoclonal antibody that targets the sclerostin protein, which regulates bone formation and resorption. It is a novel therapy in the treatment of post-menopausal women with osteoporosis. The evidence regarding romosozumab's cardiovascular safety is conflicting. We report the first post-marketing case demonstrating cardiac events (i.e., atrial fibrillation and congestive heart failure) in a female patient with osteoporosis likely triggered by romosozumab. A literature review on romosozumab and cardiovascular disease is discussed extensively. For osteoporotic patients with cardiovascular risk factors (e.g., hypertension, coronary artery disease, and stroke), the benefits of fracture prevention should be weighed against potential cardiovascular risks before prescribing romosozumab. Real-world data on post-marketing surveillance will shed light on the potential safety signals of romosozumab.

Bad to the bones: prescribing of drugs for the prevention and treatment of osteoporosis in patients on chronic glucocorticoids.

Of patients prescribed systemic glucocorticoids, this study identifies the proportion prescribed osteoporosis pharmacologic treatment and associated characteristics. Overall, 13.2% of patients were prescribed osteoporosis pharmacologic treatment. Predictors included documented osteoporosis, past DXA or fracture, and provision of care within a department using embedded protocols, suggesting electronic medical record-based tools may be beneficial. PURPOSE: This study aimed to identify a cohort of patients at risk for glucocorticoid-induced osteoporosis based on their prescribed glucocorticoid regimens and to quantify the proportion who were also prescribed osteoporosis pharmacologic treatment. The secondary objective was to recognize patient characteristics associated with receiving such treatment. METHODS: A retrospective single-site cohort study used prescription order data to identify 7774 adults prescribed chronic glucocorticoids and measure the proportion also prescribed osteoporosis pharmacologic treatment. RESULTS: Of the total cohort, 1026/7774 (13.2%) had osteoporosis pharmacologic treatment prescribed. Of the subgroups prescribed a prednisone-equivalent of 5, 10, or 20 mg per day or more for at least 180 days, 584/4262 (13.7%), 153/1048 (14.6%), and 47/344 (13.7%) had treatment prescribed. Factors independently associated with osteoporosis pharmacologic treatment initiation included having osteoporosis or osteopenia on the problem list (OR = 4.45, 95% CI 3.70-5.34), history of dual-energy X-ray absorptiometry (DXA) screening (OR = 2.18, 95% CI 1.82-2.62), history of fracture (OR = 1.83, 95% CI 1.54-2.167), and longer duration of glucocorticoid use (OR = 1.33, 95% CI 1.10-1.59). The prescribing department was also a significant predictor of medication initiation, with cardiac transplant (OR = 6.04, 95% CI 3.97-9.17), oncology (OR = 4.11, OR 3.28-5.14), and lung transplant (OR = 1.51, 95% CI 1.08, 2.12) being positively correlated with this outcome, and nephrology (OR = 0.51, 95% CI 0.36-0.72) and kidney transplant (OR = 0.53, 95% CI 0.37, 0.75) being negatively correlated. CONCLUSION: Prescribing rate of osteoporosis pharmacologic treatment in patients using chronic glucocorticoids is low. Examining practices with higher prescribing rates may offer insight into improving protection against osteoporosis-induced fractures.

Increased incidence among the very elderly in the 2020 Niigata Prefecture Osteoporotic Hip Fracture Study.

INTRODUCTION: A 2015 study showed a decreasing trend in the incidence of osteoporotic hip fractures in Niigata Prefecture, Japan, which had been increasing. This study aimed to investigate the incidence of osteoporotic hip fractures in 2020, determine the long-term change in the incidence of hip fractures from 1985 to 2020, and assess whether the decline in fracture incidence since 2010 has continued. MATERIALS AND METHODS: We obtained data from the registration forms submitted by hospitals and clinics of patients who lived in Niigata Prefecture and were diagnosed with osteoporotic hip fracture through a survey conducted from January 1, 2020 to December 31, 2020. RESULTS: In 2020, 3,369 hip fractures were recorded in Niigata Prefecture. Although the overall incidence of age-specific hip fractures decreased, it increased in patients aged ≥ 90 years, regardless of sex. The proportion of patients receiving anti-osteoporosis drugs prior to hip fracture increased from 7.6% in 2004 to 17.3% in 2020. Notably, surgical treatment should be performed as early as possible, and the preoperative waiting time was 2.9 days, which was mainly due to holidays. CONCLUSION: The incidence of hip fractures in Niigata Prefecture has gradually increased over the past 35 years, with an increasing change observed in the very elderly recently in 2020. Although the treatment of osteoporotic hip fractures in Niigata Prefecture is adequate, improvements may include increasing the rate of adoption of osteoporosis treatment further and decreasing the number of days of preoperative waiting.

A review and perspective on the assessment, management and prevention of fragility fractures in patients with osteoporosis and chronic kidney disease.

This article aims to review the methods used for the assessment of fracture risk and the use of osteoporosis medications for fracture prevention in the population with CKD, and highlights the difficulties faced by clinicians in the management of these patients and the latest recommendations and guidelines. Chronic kidney disease (CKD) and osteoporosis often co-exist in older adults, and they present a major healthcare challenge. CKD mineral and bone disorder (CKD-MBD) occurs as renal function declines and this syndrome affects most patients in CKD stages 4 and 5. The biochemical abnormalities of CKD-MBD, renal bone disease and risk factors associated with age-related bone loss and osteoporosis lead to a cumulative effect on fracture risk and mortality. There is a need for routine evaluation of fracture risk and fracture prevention in this population. Measurement of bone mineral density (BMD) and the use of the FRAX tool have predictive value for incident fractures in the general population and in CKD. This enables physicians to identify CKD patients most at risk of sustaining a fragility fracture and allows a more targeted approach to fracture prevention. Data analysis from the pivotal trials of therapeutic agents used in osteoporosis show that these drugs can be considered in mild and moderate CKD (stages 1-3 CKD). Off-label drug use in patients with CKD-MBD and more severe renal impairment (CKD stages 4 and 5) could offer significant benefits to sub-groups of patients when carefully tailored to each individual's bone turnover and calcium and phosphate balance. However, this requires a selective approach and treatment decisions based on inference from pathophysiology while we await further trials. Guidelines advocate the correction and/or reduction of the biochemical abnormalities of CKD-MBD before initiation of treatment with osteoporosis drugs and close monitoring during treatment.

Trends in hip and distal femoral fracture rates in Italy from 2007 to 2017.

Osteoporosis-related fractures are a growing public health concern worldwide due to high societal and economic burden. The study aims to assess trends in incidence rates of hip and distal femoral fractures and in the use of anti-osteoporosis drugs in Italy between 2007 and 2017. Patients with hip and distal femoral fractures (ICD-9-CM codes 820.x and 821.x) were identified in the Italian National Hospital Discharge Database while anti-osteoporosis medication data were retrieved from the National Observatory on the Use of Medicines Database. A joinpoint regression analysis was performed to identify the years where the trends in incidence rates of hip and distal femoral fractures changed significantly; the average annual percentage change for the period of observation was estimated. Hospitalizations for femoral fractures were 991,059, of which 91.4% were hip fractures and 76.5% occurred in women. Age-standardized hip fractures rate per 100,000 person-years decreased both in women (-8.7%; from 789.9 in 2007 to 721.5 in 2017) and in men (-4.3%; from 423.9 to 405.6), while the rate of distal femoral fractures increased by 23.9% in women (from 67.78 to 83.95) and 22.7% in men (from 27.76 to 34.06). These changes were associated with an increment in the use of anti-osteoporosis drugs from 2007 to 2011 (from 9.1 to 12.4 DDD/1000 inhabitants/day), followed by a plateau in the period 2012-2017. The use of bisphosphonates increased progressively from 2007 to 2010 (from 8.2 to 10.5 DDD/1000 inhabitants/day), followed by a plateau and then decreased from 2015 onwards. The decreasing trend of hip fractures could be related to a major intake of anti-osteoporosis medications while the increment of distal femoral fractures might be due to population aging and to the use of bisphosphonates and denosumab. Further research is needed to identify and implement interventions to prevent hip and distal femoral fractures.

Synthesis and biological activities of drugs for the treatment of osteoporosis.

Osteoporosis is an asymptomatic progressive disease. With the improvement of people's living standard and the aging of population, osteoporosis and its fracture have become one of the main diseases threatening the aging society. The serious medical and social burden caused by this has aroused wide public concern. Osteoporosis is listed as one of the three major diseases of the elderly. At present, the drugs for osteoporosis include bone resorption inhibitors and bone formation promoters. The purpose of these anti-osteoporosis drugs is to balance osteoblast bone formation and osteoclast bone resorption. With the development of anti-osteoporosis drugs, new anti osteoporosis drugs have been designed and synthesized. There are many kinds of new compounds with anti osteoporosis activity, but most of them are concentrated on the original drugs with anti osteoporosis activity, or the natural products with anti-osteoporosis activity are extracted from the natural products for structural modification to obtain the corresponding derivatives or analogues. These target compounds showed good ALP activity in vitro and in vivo, promoted osteoblast differentiation and mineralization, or had anti TRAP activity, inhibited osteoclast absorption. This work attempts to systematically review the studies on the synthesis and bioactivity of anti-osteoporosis drugs in the past 10 years. The structure-activity relationship was discussed, which provided a reasonable idea for the design and development of new anti-osteoporosis drugs.

An update on therapies for the treatment of diabetes-induced osteoporosis.

Introduction: Currently, 424 million people aged between 20 and 79 years worldwide are diabetic. More than 25% of adults aged over 65 years in North America have Type 2 diabetes mellitus (DM). Diabetes-induced osteoporosis (DM-OS) is caused by chronic hyperglycemia, advanced glycated end products and oxidative stress. The increase in the prevalence of DM-OS has prompted researchers to develop new biological therapies for the management of DM-OS. Areas covered: This review covered the current and novel biological agents used in the management of DM-OS. Data were retrieved from PubMed, Scopus, American Diabetes Association and International Osteoporosis Foundation websites, and ClinicalTrials.gov. The keywords for the search included: DM, osteoporosis, and management. Expert opinion: Several biological molecules have been examined in order to find efficient drugs for the treatment of DM-OS. These biological agents include anti-osteoporosis drugs: net anabolics (parathyroid hormone/analogs, androgens, calcilytics, anti-sclerostin antibody), net anti-resorptive osteoporosis drugs (calcitonin, estrogen, selective estrogen receptor modulators, bisphosphonates, RANKL antibody) and anti-diabetic drugs (alpha glucosidase inhibitors, sulfonylureas, biguanides, meglitinides, thiazolidinediones, GLP-1 receptor agonists, dipeptidylpeptidase-4 inhibitors, sodium glucose co-transporter-2 inhibitors, insulin). Biological medications that effectively decrease hyperglycemia and, at the same time, maintain bone health would be an ideal drug/drug combination for the treatment of DM-OS.

Age- and gender-specific epidemiology, treatment patterns, and economic burden of osteoporosis and associated fracture in Taiwan between 2009 and 2013.

This nationwide study investigated the epidemiology, treatment patterns, and economic burden of osteoporosis and associated fracture in Taiwan. The treatment of osteoporosis is alarmingly suboptimal, considering the significantly increased economic burden of major osteoporotic fracture. Osteoporosis men received lesser anti-osteoporosis drugs but had higher incremental costs attributable to osteoporotic fractures. PURPOSE: This nationwide study investigated the epidemiology, treatment patterns, and economic burden of osteoporosis and associated fracture between 2009 and 2013 in Taiwan. METHODS: We used the National Health Insurance Research Database as our data source. The prevalence of diagnosed osteoporosis and major osteoporotic fractures was calculated annually from 2009 to 2013, stratified by age and gender. Osteoporosis patients who received any prescription of anti-osteoporosis drugs during each fiscal year were defined as osteoporosis patients under treatment. Healthcare utilization and associated direct medical costs were used to quantify the economic burden of osteoporosis. For patients who encountered major osteoporotic fracture, the incremental changes of direct medical costs attributable to fracture using a pre- and post-quasi-experimental design were estimated. Furthermore, we compared the annual direct medical costs of patients who encountered major osteoporotic fracture with those diagnosed osteoporosis only and with the general population. RESULTS: The prevalence of diagnosed osteoporosis increased with age, with the highest rate among those aged 80 and older. Overall, less than one-third of women and only 10% of men received anti-osteoporosis drugs among osteoporosis patients. The annual direct medical costs for osteoporosis patients increased steadily from 2009 to 2013. The total medical costs and incremental change of direct medical costs were higher in men than those in women. CONCLUSION: We found the treatment of osteoporosis to be alarmingly suboptimal, considering the significantly increased economic burden of major osteoporotic fracture also identified in this study. Osteoporosis men received lesser anti-osteoporosis drugs but had higher incremental costs attributable to major osteoporotic fractures.

Rethinking the Appraisal and Approval of Drugs for Fracture Prevention.

Background: In January 2014, the EMA's Pharmacovigilance Risk Assessment Committee recommended that strontium ranelate no longer be used for osteoporosis. However, EMA's Committee for Medicinal Products for Human Use decided to restrict its use rather than ban it. Starting from this fact, evidence of drugs for fracture prevention over the last 30 years was reviewed and lessons to be learnt from this story are highlighted. Findings: The general belief that drug therapy may become a "solution" for fragility fractures is challenged. The key points of the article are as follows: Lessons 1-5: Bone density and morphometric vertebral compression are not reliable surrogate endpoints. In fact, clinically relevant endpoints are essential to assess harms and benefits in clinical trials. There is a need for assessing overall harm-benefit with well-designed trials, taking into account that drug therapy may not be more effective in high-risk patients. Lessons 6-10: While bisphosphonates and strontium ranelate show a questionable harm-benefit ratio on hip fracture prevention, denosumab results are inconclusive and no benefit has been proved coming from calcitonines or teriparatide. After decades of widespread use, effectiveness of drugs for osteoporosis remains uncertain, yet adverse effects are more apparent. Conclusions: Well-designed and large trials over prolonged follow-up periods, measuring clinically relevant outcomes as hip and other disabling fractures, are urgently needed in order to properly understand the harm-benefit ratio of commonly prescribed drugs. Regulatory agencies should be more transparent and make individual-patient data from all clinical trials publicly available, allowing for independent assessment and pooled analysis.

Trends in oral anti-osteoporosis drug prescription in the United Kingdom between 1990 and 2012: Variation by age, sex, geographic location and ethnicity.

INTRODUCTION: Given the expected increase in the number of patients with osteoporosis and fragility fractures it is important to have concise information on trends in prescription rates of anti-osteoporosis drugs (AOD). METHODS: We undertook a retrospective observational study using the UK Clinical Practice Research Datalink (CPRD) in the UK between 1990 and 2012 in subjects 50years or older, stratified by age, sex, geographic region and ethnicity. Yearly prescription incidence rates of any AOD and of each specific AOD were calculated as the number of patients first prescribed these AODs per 10,000person-years (py). RESULTS: In women, yearly rates of first prescription of any AOD increased from 1990 to 2006 (from 2.3 to 169.7 per 10,000py), followed by a plateau and a 12% decrease in the last three years. In men, a less steep increase from 1990 to 2007 (from 1.4 to 45.3 per 10,000py) was followed by a plateau from 2008 onwards. Yearly rates of first prescription of any AOD increased up to the age of 85-89years (248.9 per 10,000py in women and 119.3 in men). There were marked differences between ethnic groups and regions. Bisphosphonates were the most frequently prescribed AODs: etidronate till 2000, and then subsequently alendronate. CONCLUSION: We have demonstrated marked secular changes in rates of anti-osteoporosis drug prescription over the last two decades. The plateau (and decrease amongst women) in rates in recent years, set against an ever ageing population, is worrying, suggesting that the well-documented care gap in osteoporosis treatment persists. The differences in prescription rates by geographic location and ethnicity raise intriguing questions in relation to underlying fracture rates, provision of care and health behaviour. SUMMARY: We studied the prescription incidence of anti-osteoporosis drugs (AOD) from 1990 to 2012 in the UK CPRD. Overall AOD prescription incidence showed a strong increase from 1990 to 2006, followed by a plateau in both sexes and a decrease amongst women in the last three years.

OSTEOPOROSIS DRUGS MARKETED IN THE UNITED STATES: GENERIC COMPETITION, PRICING STRUCTURE, AND DISPERSION AMONG PAYERS.

BACKGROUND: Despite the cost of pharmaceuticals, studies assessing prices of osteoporosis drugs are lacking. This study examined trends in prices of osteoporosis drugs in the United States in the period 1988-2014, assessed pricing structure of osteoporosis drugs, and evaluated price trends before and after generic drugs market entry. METHODS: Data were derived from the U.S. Food and Drug Administration, the RedBook, the Centers for Medicare & Medicaid Services, and the Federal Supply Schedule (FSS). Descriptive statistics and segmented linear regression analyses were performed. RESULTS: In the period 1988-2014, osteoporosis drug prices increased faster than the inflation. The average wholesale price (AWP) of generic products at market entry represented 90 percent of the AWP for the corresponding brand. Prices of brand products continued to increase after generic entry. Drug prices showed a significant variation when compared with the brand AWP. The brand wholesale acquisition cost (WAC) was typically set at 83.3 percent of the AWP. Community pharmacies acquired osteoporosis brand drugs at a median of 80.5 percent of the brand AWP. Significant reductions in brand AWP were observed for Medicare Part B (78.5 percent of the brand AWP), generic National Average Drug Acquisition Cost (33.7 percent), and FSS (22.5 percent). CONCLUSIONS: There are significant differences in the manufacturer prices, pharmacy acquisition costs and reimbursement rates of osteoporosis drugs. Pharmaceutical companies listed prices are higher than the pharmacy actual estimated acquisitions costs, and the prices used for reimbursement to providers. Generic drugs entry significantly drives down prices; still, prices of branded drugs facing generic competition continued to increase after generic market entry.

Mortality after hip fracture with vertebral compression fracture is poor.

Due to the increasing elderly population, the prevalence of osteoporotic hip fractures in Japanese patients continues to rise. It is well established that patients with either hip fracture or both symptomatic and asymptomatic morphometric vertebral compression fracture (VCF) have a poor health prognosis compared with the general population. The purpose of this study was to retrospectively investigate vertebral fracture rates among patients with hip fracture and their influence on mortality. We examined 182 cases of osteoporotic hip fracture in patients admitted to our institution between January 2009 and May 2011. The average age at the time of fracture was 85 years. Radiographs of the lumbar spine were obtained from all of the participants and the lateral spinal radiographs were examined for evidence of VCF. The patients were classified into two groups, those with VCF and those without. A VCF was identified in approximately 78 % of the patients. The mortality rate 1 year after the hip fracture was approximately 22 % and it was significantly higher in patients with VCF. Through multivariate statistics we found that VCF, post-operative complication, loss of ambulation after operation and medication for osteoporosis were statistically significant. In other words, VCF, post-operative complication and loss of ambulation were considered to be poor prognostic factors and medication for osteoporosis was likely to improve the prognosis. We concluded that the risk of mortality after hip fracture is significantly greater in patients who also have VCF compared to patients without VCF, and that medication for osteoporosis is likely to improve prognosis.

Effect of micellar polymer PEG-PLL-OPG on osteoporosis and arteriosclerosis in mice / 实用医学杂志

Objective By using PEG-PLL and OPG-expressing plasmid to synthesize a nanocompound PEG-PLL-OPG (PPO), to investigate its effects on osteoblasts (OB) and arteriosclerosis (AS) in mice. Methods The incidences of osteoporosis (OP) and AS were studied in people. Collect people′s serum , and divide them into different groups According to the results of diagnosis, the patients were grouped into the groups of Control, AS, OP, and AS. PPO was used to deal with OB in different groups. The cell apoptosis, cell activity, the adhersion and calcification to scaffold PCL were determined by flow cytometry, MTT, alizarin red stain and SEM,respectively. PPO was also injected intp the ApoE-/-RANKL+/+ mice via caudal vein to demonstrate its effects on BMD and AS. Results PPO could increase the cell activity , inhibit OB apoptosis and promote cell adhersion and calcifica-tion on scaffold PCL in vitro. PPO could also decrease the area and calcification of atheromatous plaque , and in-crease the BMD of collum femoris in vivo. Conclusion PPO may be a new drug for OP and AS treatments.

Effect of four different anti-osteoporosis agents on the expression of matrix gla protein in primary osteoblasts of SD rat / 中华内分泌代谢杂志

Objective To observe the expression of matrix gla protein(MGP) mRNA in primary osteoblasts of Sprague-Dawley (SD) rat in vitro after treatment with anti-osteoporosis agents [vitamin K2,PTH,1,25 (OH)2D3,and alendronate],and to investigate the potential role of MGP in the pathogenesis of osteoporosis.Methods Primary osteoblasts(OBs) were derived from sequential trypsin/collagenase-digested calvaria isolated from newborn SD rat (postnastal day 1-3).OBs of the second generation were identified by Van Gieson collagen staining,alkaline phosphatase(ALP) staining and calcified nodules staining.OBs of the fourth generation were selected to interfere with vitamin K2,PTH,1,25 (OH)2D3,and alendronate,then cultured for 24 h in mediums which contained various concentrations of vitamin K2 (10-7,10-6,and 10-5 mol/L),PTH (10-9,10-8,and 10-7 mol/L),1,25 (OH) 2D3(10-10,10-9,and 10-8mol/L),alendronate(10-6,10-5,and 10-4mol/L).After being cultured for 24 h,total RNA was extracted and examined by real-time quantitative RT-PCR.Results The primary cultured cells had typical morphological characters of osteoblast.van Gieson collagen staining,ALP staining,and calcified nodules staining were all positive.Vitamin K2,PTH,1,25 (OH)2D3,and alendronate could modulate the expression of MGP mRNA in osteoblasts in a dose-dependent fashion.MGP mRNA expressions were 2.56-fold,2.12-fold,and 1.57-fold with 10-5,10-6,and 10-7 mol/L of vitamin K2 treatment,respectively.The expressions were 6.78-fold,5.31-fold,and 2.23-fold with 10-7,10-8,and 10-9mol/L of PTH(1-34) treatment,8.93-fold,6.95-fold,and 3.47-fold with 10-8 10-9,and 10-10mol/L of 1,25 (OH)2D3 treatment,and 3.47-fold,2.49-fold,and 1.98-fold with 10-4,10-5,and 10-6mol/L of alendronate treatment.Conclusion Vitamin K2,PTH,1,25 (OH)2D3,and alendronate all canregulate MGP mRNA expression in calvarial osteoblasts in a dose-dependent manner.MGP seems to be a potent target of anti-osteoporosis agents,and involved in the pathogenesis of osteoporosis.

Bone histomorphometry: a concise review for endocrinologists and clinicians / Histomorfometria óssea: uma revisão concisa para endocrinologistas e clínicos

Bone histomorphometry is a quantitative histological examination of an undecalcified bone biopsy performed to obtain quantitative information on bone remodeling and structure. Labeling agents taken before the procedure deposit at sites of bone formation allowing a dynamic analysis. Biopsy is indicated to make the diagnosis of subclinical osteomalacia, to characterize the different forms of renal osteodystrophy and to elucidate cases of unexplained skeletal fragility. Bone histomorphometric parameters are divided into structural and remodeling subgroups, with the latter being subdivided into static and dynamic categories. Metabolic bone disorders such as osteomalacia, hyperparathyroidism, hypothyroidism, osteoporosis and renal osteodystrophy display different histomorphometric profiles. Antiresorptive and anabolic drugs used for the treatment of osteoporosis also induce characteristic changes in the bone biopsy. Bone histomorphometry is an important research tool in the field of bone metabolism and provides information that is not available by any other investigative approach.

Histomorfometria óssea é uma avaliação histológica quantitativa de uma biópsia óssea calcificada realizada para obter informação sobre a remodelação e a estrutura óssea. Uma análise dinâmica é possível quando substâncias que fazem a marcação do osso são tomadas antes do procedimento e se depositam no local de formação óssea. A biópsia é indicada para diagnóstico de osteomalácia, diferentes formas de osteodistrofia renal e nos casos não explicados de fragilidade esquelética. O preparo e a análise das amostras necessitam de um laboratório especializado. A histomorfometria avalia parâmetros estruturais e de remodelação óssea, sendo o último subdividido em estático e dinâmico. Doenças osteometabólicas como osteomalácia, hiperparatireoidismo, hipoparatireoidismo, osteoporose e osteodistrofia renal apresentam parâmetros histomorfométricos distintos. Medicações antirreabsortivas e anabólicas usadas no tratamento da osteoporose também induzem alterações características na biópsia óssea. A histomorfometria óssea é uma ferramenta importante no metabolismo ósseo e oferece informação que não é possível por nenhum outro método diagnóstico.