Anabolic Therapy and Optimal Treatment Sequences for Patients With Osteoporosis at High Risk for Fracture

Objective: Provide an update regarding anabolic medications for osteoporosis, which are often considered to be the last resort for patients with osteoporosis, after multiple fractures have already occurred and other medications have already been administered.Methods: Literature review and discussion.Results: Recent pivotal trial data for anabolic agents and randomized trials comparing anabolic and antiresorptive medications suggest that three anabolic agents (teriparatide, abaloparatide, and romosozumab) reduce nonvertebral and vertebral fractures faster and to a greater extent than potent antiresorptive treatments. Furthermore, bone density accrual is maximized when patients are given anabolic agents first, followed by potent antiresorptive therapy. Since total hip bone density during or after osteoporosis treatment has emerged as an excellent surrogate for future fracture risk, attaining a greater hip bone mineral density is a treatment goal for high-risk osteoporosis patients.Conclusion: This review defines the highest-risk patients and summarizes the rationale for the evolving role of anabolic therapy in the management of postmenopausal women at high risk for fracture.Abbreviations: ACTIVE = Abaloparatide Comparator Trial in Vertebral Endpoints; ARCH = Active Controlled Fracture Study in Postmenopausal Women with Osteoporosis at High Risk; BMD = bone mineral density; FRAME = Fracture Study in Postmenopausal Women with Osteoporosis; FRAX = Fracture Risk Assessment Tool; PTH = parathyroid hormone; TBS = trabecular bone score     

Management of osteoporosis

Osteoporosis or osteopenia occurs in about 44 million Americans, resulting in 1.5 million fragility fractures per year. The consequences of these fractures include pain, disability, depression, loss of independence, and increased mortality. The burden to the healthcare system, in terms of cost and resources, is tremendous, with an estimated direct annual USA healthcare expenditure of about $17 billion. With longer life expectancy and the aging of the baby-boomer generation, the number of men and women with osteoporosis or low bone density is expected to rise to over 61 million by 2020. Osteoporosis is a silent disease that causes no symptoms until a fracture occurs. Any fragility fracture greatly increases the risk of future fractures. Most patients with osteoporosis are not being diagnosed or treated. Even those with previous fractures, who are at extremely high risk of future fractures, are often not being treated. It is preferable to diagnose osteoporosis by bone density testing of high risk individuals before the first fracture occurs. If osteoporosis or low bone density is identified, evaluation for contributing factors should be considered. Patients on long-term glucocorticoid therapy are at especially high risk for developing osteoporosis, and may sustain fractures at a lower bone density than those not taking glucocorticoids. All patients should be counseled on the importance of regular weight-bearing exercise and adequate daily intake of calcium and vitamin D. Exposure to medications that cause drowsiness or hypotension should be minimized. Non-pharmacologic therapy to reduce the non-skeletal risk factors for fracture should be considered. These include fall prevention through balance training and muscle strengthening, removal of fall hazards at home, and wearing hip protectors if the risk of falling remains high. Pharmacologic therapy can stabilize or increase bone density in most patients, and reduce fracture risk by about 50%. By selecting high risk patients for bone density testing it is possible to diagnose this disease before the first fracture occurs, and initiate appropriate treatment to reduce the risk of future fractures.     

Osteoporosis Treatment After Osteoporotic Fractures: Data From a Single Medical Center

ObjectiveMost patients do not receive osteoporosis treatment after osteoporotic fracture. This study reviewed osteoporosis treatment after osteoporotic fractures in a center without a Fracture Liaison Service.MethodsWe identified all patients with hip, vertebral, humeral or radial fractures, evaluated in Meir Medical Center, in 2017. The exclusion criteria were not a Clalit Health Services member, high-energy fracture or 30-day postoperative mortality. The primary endpoint was osteoporosis drugs issued within 12 months of fracture. Secondary endpoints included bone densitometry and 1-year mortality.ResultsFive-hundred-eighty-two patients (average age 78.6 ± 11.1 years, 75.8% women) were included. There were 321 (55.5%) hip, 84 (14.1%) humeral, 33 (5.6%) vertebral, and 144 (24.7%) radial fractures. Osteoporosis drugs were issued to 26.5% of the patients; those with humeral fractures received the least (21.4%) and vertebral, the most (30.3%; P = .51). Bone densitometry was performed in 23.2% of patients. One-year mortality after hip fracture was 12.1%, followed by humeral (3.6%; P < .05). Logistic regression showed that previous treatment (odds ratio [OR] = 7.4; 95% confidence interval [CI] 3.6–15.2), bone densitometry (OR = 4.4; 95% CI 2.6–7.4) and endocrinology visit (OR = 2.6; 95% CI, 1.4–4.6) were the most important factors associated with treatment.ConclusionFewer than one third of patients received pharmacotherapy within 1 year after fracture. Because pharmacotherapy reduces future fractures and mortality, we recommend that medical staff who care for patients with fracture adopt practical and effective strategies to increase treatment rates among patients with osteoporotic fractures.     

Osteoporosis: the current status of mesenchymal stem cell-based therapy

Osteoporosis, or bone loss, is a progressive, systemic skeletal disease that affects millions of people worldwide. Osteoporosis is generally age related, and it is underdiagnosed because it remains asymptomatic for several years until the development of fractures that confine daily life activities, particularly in elderly people. Most patients with osteoporotic fractures become bedridden and are in a life-threatening state. The consequences of fracture can be devastating, leading to substantial morbidity and mortality of the patients. The normal physiologic process of bone remodeling involves a balance between bone resorption and bone formation during early adulthood. In osteoporosis, this process becomes imbalanced, resulting in gradual losses of bone mass and density due to enhanced bone resorption and/or inadequate bone formation. Several growth factors underlying age-related osteoporosis and their signaling pathways have been identified, such as osteoprotegerin (OPG)/receptor activator of nuclear factor B (RANK)/RANK ligand (RANKL), bone morphogenetic protein (BMP), wingless-type MMTV integration site family (Wnt) proteins and signaling through parathyroid hormone receptors. In addition, the pathogenesis of osteoporosis has been connected to genetics. The current treatment of osteoporosis predominantly consists of antiresorptive and anabolic agents; however, the serious adverse effects of using these drugs are of concern. Cell-based replacement therapy via the use of mesenchymal stem cells (MSCs) may become one of the strategies for osteoporosis treatment in the future.     

Overview of osteoporosis.

Osteoporosis is a common age-related disorder manifested clinically by skeletal fractures, especially fractures of the vertebrae, hip, and distal forearm. The major cause of these fractures is low bone mass, although an increase in trauma due to falls in the elderly also contributes. There are multiple causes for the low bone mass which, in any given individual, may contribute differently to the development of the osteopenia. The most important groups of causes are failure to achieve adequate peak bone mass, slow bone loss due to processes relating to aging, the menopause in women, and a variety of sporadic behavioral, nutritional, and environmental factors that affect bone mass in some but not in other individuals. The most important approach is prevention. Drugs and behavioral factors known to cause bone loss should be eliminated and perimenopausal women should be evaluated for possible preventive administration of estrogen. For patients with fractures due to established osteoporosis, the only drugs approved by the Food and Drug Administration are the antiresorptive agents calcium, estrogen, and calcitonin. Formation-stimulating regimens, however, are being developed and may be available for clinical use in the foreseeable future. These regimens may be capable of increasing bone mass to above the fracture threshold, thereby resulting in a clinical cure of the osteoporosis.     

Risk factors and prevention of osteoporosis-related fractures

In order to effectively prevent osteoporosis-related fractures, one must aim to prevent both osteoporosis, as well as the events and circumstances that may lead to injury, ultimately resulting in fracture. Among all the osteoporotic fractures that can occur, hip fractures are associated with a severe decrease in quality of life and high mortality, which reaches 51% at one year post-fracture in nonagenarians. Prevention of osteoporosis should ideally begin in childhood, aiming to achieve high peak bone mass accompanied by an inherently healthy lifestyle throughout life, in order to minimize bone loss during middle and third age, and in parallel to avoid or diminish other fracture risk factors. There are numerous fracture risk factors, including age, gender, race, lifestyle and concomitant medical conditions, which either cannot or can be modified, to a greater or lesser degree. Falls consist a previously underestimated risk factor, responsible for a large percentage of fractures. International and national strategies aimed at public awareness, early identification of those at increased risk for fracture and preventive or therapeutic intervention may succeed in subduing the currently increasing prevalence of osteoporotic fractures.     

A review of anabolic therapies for osteoporosis

Osteoporosis results from a loss of bone mass and bone structure such that the bone becomes weak and fractures with very little trauma. Until recently, the approved osteoporosis therapies prevented more bone loss by altering osteoclast activity and lifespan. Recently, attention has turned away from osteoclast inhibition to agents that can stimulate the osteoblast to form new bone, or anabolic agents. This article reviews both approved and experimental anabolic agents that improve bone mass by improving osteoblast activity, or increasing osteoblast number. The use of the anabolic agents to improve bone mass and strength followed by agents that prevent the new bone mass from being lost may offer the ability to cure osteoporosis and reduce bone fracture healing time.     

Stéroides sexuels et ostéoporose chez l'homme

Several epidemiological studies have shown that about 25 per cent of hip fractures and 20 per cent of symptomatic vertebral fractures occur in men. The lifetime risk of hip fracture was estimated to be about 6 to 8 per cent and the risk of any osteoporotic fracture was estimated to be about 18 per cent in 50-year-old white men. In about 60% of cases in men, bone loss is secondary to several pathological conditions, such as long-term steroid therapy, severe hypogonadism, smoking or alcohol abuse or gastrointestinal disorders. In 40% of cases, osteoporosis is primary or idiopathic in men between the ages of 40 and 60 years. Genetic factors, a defect of boneforming cells or abnormal serum levels of bioavailable sex steroids could explain bone loss and fragility fractures in these men. It has been shown that hypogonadism is associated with a marked increase in bone remodelling and particularly in bone resorption with a dramatic loss in trabecular bone. It is now known that testosterone is partly transformed into estradiol by aromatase. Testosterone may therefore act on bone in two ways: it directly stimulates bone formation and estradiol regulates bone remodelling and inhibits bone resorption. Finally, in men over the age of 60 without hypogonadism, it has been shown that bone mineral density and fracture risk were better correlated with serum levels of bioavailable estradiol and Sex Hormone Binding Globulin than with serum testosterone levels.     

PKP治疗骨质疏松性椎体压缩骨折的预后评价及继发危险因素分析

目的:分析椎弓根入路行椎体后凸成形术(PKP)治疗骨质疏松性椎体压缩骨折的预后评价及继发危险因素分析。方法:选择2016年2月-2018年2月我院收治的骨质疏松性椎体压缩骨折患者85例纳入本次研究,采用随机数表法分为观察组(n=43)和对照组(n=42)。对照组使用经皮椎体成形术进行治疗,观察组采用PKP进行治疗。比较两组患者手术情况、术后情况、椎体前缘高度丢失率、Cobb角、继发性骨折发生情况及分析骨质疏松性椎体压缩骨折患者术后继发骨折的危险因素。结果:观察组手术时间、透视次数、骨水泥注入量、术中出血量均显著低于对照组,差异显著(P0.05);观察组疼痛缓解时间、下地时间及住院时间均显著低于对照组,差异显著(P0.05);治疗前,两组椎体前缘高度丢失率、Cobb角比较,无显著差异;治疗后,两组患者的椎体高度丢失率明显下降,但两组术后7 d、术后6月两组椎体前缘高度丢失率、Cobb角比较无显著差异;观察组术后12月椎体前缘高度丢失率、Cobb角低于对照组,差异显著(P0.05);所有患者均随访12月,其中22例(25.88%)发生继发性椎体骨折,进行单因素分析,结果发现,两组患者性别、骨折部位、局部矢状面后凸角度、骨水泥量、椎体高度恢复、术后抗骨质疏松治疗差异无统计学意义(P0.05);骨质疏松原因、骨水泥椎间隙渗漏、术后支具佩戴、原发骨折类型与骨质疏松性椎体压缩骨折患者术后发生继发骨折相关(P0.05)。多因素Logistic分析显示,骨质疏松原因、骨水泥椎间隙渗漏、术后支具佩戴、原发骨折类型均是骨质疏松性椎体压缩骨折患者术后发生继发骨折的独立危险因素(P0.05)。结论:在骨质疏松性椎体压缩骨折患者中应用PKP可有效改善手术情况,随着时间的延长,PKP更有利于维持患者椎体高度;骨质疏松原因、骨水泥椎间隙渗漏、术后支具佩戴、原发骨折类型是骨质疏松性椎体压缩骨折患者术后发生继发骨折的危险因素,临床上对于具有危险因素的患者引起重视,并采取干预措施。     

The prospective evaluation of the osteoporotic vertebral fractures incidence in a random population sample

Introduction Osteoporotic vertebral fractures are mostly incidental but in some patients may lead to clinical symptoms, characteristic deformations of the vertebral column and increase total mortality. The aim of the study was to evaluate the prevalence of osteoporotic vertebral fractures and risk factors for osteoporosis in a random sample of Szczecin inhabitants aged over 50 in the relation to the whole European population examined in the frame of EVOS (European Vertebral Osteoporosis Study) and its prospective phase - EPOS (European Prospective Osteoporosis Study). At the baseline, 607 persons were studied, including 301 women and 306 men. Material and methods The questionnaire on the risk factors for osteoporosis and the spine X-rays analysed by morphometry, were taken in all subjects. The incidence of osteoporotic vertebral deformity in the studied population was similar in both sexes (12.6% women and 10,3% men) but in men aged 50-64 fracture incidence was significantly higher in comparison with women. The prevalence of new vertebral fractures examined after 4 years was higher in women than in men (9.1 vs 6.4/1000 persons years). Among the risk factors for osteoporosis, low physical activity and prolonged immobilization in women significantly influenced the incidence of vertebral deformities. Conclusions: 1) The study shows the high incidence of risk factors and osteoporotic vertebral deformities in the population of Szczecin inhabitants aged over 50. 2) Visual assessment only with a combination with morphometry is an optimal tool for detection of incident vertebral fractures.     

In-Vivo Assessment of Femoral Bone Strength Using Finite Element Analysis (FEA) Based on Routine MDCT Imaging: A Preliminary Study on Patients with Vertebral Fractures

PurposeTo experimentally validate a non-linear finite element analysis (FEA) modeling approach assessing in-vitro fracture risk at the proximal femur and to transfer the method to standard in-vivo multi-detector computed tomography (MDCT) data of the hip aiming to predict additional hip fracture risk in subjects with and without osteoporosis associated vertebral fractures using bone mineral density (BMD) measurements as gold standard.MethodsOne fresh-frozen human femur specimen was mechanically tested and fractured simulating stance and clinically relevant fall loading configurations to the hip. After experimental in-vitro validation, the FEA simulation protocol was transferred to standard contrast-enhanced in-vivo MDCT images to calculate individual hip fracture risk each for 4 subjects with and without a history of osteoporotic vertebral fractures matched by age and gender. In addition, FEA based risk factor calculations were compared to manual femoral BMD measurements of all subjects.ResultsIn-vitro simulations showed good correlation with the experimentally measured strains both in stance (R² = 0.963) and fall configuration (R² = 0.976). The simulated maximum stress overestimated the experimental failure load (4743 N) by 14.7% (5440 N) while the simulated maximum strain overestimated by 4.7% (4968 N). The simulated failed elements coincided precisely with the experimentally determined fracture locations. BMD measurements in subjects with a history of osteoporotic vertebral fractures did not differ significantly from subjects without fragility fractures (femoral head: p = 0.989; femoral neck: p = 0.366), but showed higher FEA based risk factors for additional incident hip fractures (p = 0.028).ConclusionFEA simulations were successfully validated by elastic and destructive in-vitro experiments. In the subsequent in-vivo analyses, MDCT based FEA based risk factor differences for additional hip fractures were not mirrored by according BMD measurements. Our data suggests, that MDCT derived FEA models may assess bone strength more accurately than BMD measurements alone, providing a valuable in-vivo fracture risk assessment tool.     

Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.

OBJECTIVE--To determine the ability of measurements of bone density in women to predict later fractures. DESIGN-- Meta-analysis of prospective cohort studies published between 1985 and end of 1994 with a baseline measurement of bone density in women and subsequent follow up for fractures. For comparative purposes, we also reviewed case control studies of hip fractures published between 1990 and 1994. SUBJECTS--Eleven separate study populations with about 90,000 person years of observation time and over 2000 fractures. MAIN OUTCOME MEASURES--Relative risk of fracture for a decrease in bone mineral density of one standard deviation below age adjusted mean. RESULTS--All measuring sites had similar predictive abilities (relative risk 1.5 (95% confidence interval 1.4 to 1.6)) for decrease in bone mineral density except for measurement at spine for predicting vertebral fractures (relative risk 2.3 (1.9 to 2.8)) and measurement at hip for hip fractures (2.6 (2.0 to 3.5)). These results are in accordance with results of case-control studies. Predictive ability of decrease in bone mass was roughly similar to (or, for hip or spine measurements, better than) that of a 1 SD increase in blood pressure for stroke and better than a 1 SD increase in serum cholesterol concentration for cardiovascular disease. CONCLUSIONS--Measurements of bone mineral density can predict fracture risk but cannot identify individuals who will have a fracture. We do not recommend a programme of screening menopausal women for osteoporosis by measuring bone density.     

Role of endocrine-immune dysregulation in osteoporosis, sarcopenia, frailty and fracture risk

Osteoporosis, a key predictor of hip fractures can be treated using a variety of safe and effective interventions. Nevertheless, optimally effective strategies for the prevention of hip fractures must also incorporate efforts to address a broad range of other potentially reversible factors. Hyperthyroidism, anticonvulsants, caffeine and smoking may decrease bone mass and increase fracture risk at any age. In older individuals it is important to also consider additional risk factors, including long-acting benzodiazepines, poor vision and sarcopenia. The presence of sarcopenia, an age-related decline in muscle bulk and quality enhances the risk of frailty and possibly also hip fracture, particularly if associated with diminished functional mobility, lower quadriceps strength and poor balance or body sway. In this review we examine evidence which indicates the presence of endocrine-immune dysregulation in both osteoporosis and sarcopenia. Post-menopausal declines in serum estrogen and androgen levels contribute to increases in local bone levels of cytoclastic cytokines, followed by increased osteoclastogenesis and bone loss. Similarly, the presence of decreased gonadal hormones and IGF-1, combined with unusually high peripheral levels of cytokines, inflammatory mediators and coagulation markers all enhance the risk of sarcopenia and frailty. We propose that a translational research approach which emphasizes common pathophysiologic mechanisms in osteoporosis and sarcopenia could accelerate the speed of discovery of effective strategies for both frailty and hip fracture prevention.     

IL-6 Contributes to the Defective Osteogenesis of Bone Marrow Stromal Cells from the Vertebral Body of the Glucocorticoid-Induced Osteoporotic Mouse

Osteoporosis is one of the most prevalent skeletal system diseases. It is characterized by a decrease in bone mass and microarchitectural changes in bone tissue that lead to an attenuation of bone resistance and susceptibility to fracture. Vertebral fracture is by far the most prevalent osteoporotic fracture. In the musculoskeletal system, osteoblasts, originated from bone marrow stromal cells (BMSC), are responsible for osteoid synthesis and mineralization. In osteoporosis, BMSC osteogenic differentiation is defective. However, to date, what leads to the defective BMSC osteogenesis in osteoporosis remains an open question. In the current study, we made attempts to answer this question. A mouse model of glucocorticoid-induced osteoporosis (GIO) was established and BMSC were isolated from vertebral body. The impairment of osteogenesis was observed in BMSC of osteoporotic vertebral body. The expression profiles of thirty-six factors, which play important roles in bone metabolisms, were compared through antibody array between normal and osteoporotic BMSC. Significantly higher secretion level of IL-6 was observed in osteoporotic BMSCs compared with normal control. We provided evidences that IL-6 over-secretion impaired osteogenesis of osteoporotic BMSC. Further, it was observed that β-catenin activity was inhibited in response to IL-6 over-secretion. More importantly, in vivo administration of IL-6 neutralizing antibody was found to be helpful to rescue the osteoporotic phenotype of mouse vertebral body. Our study provides a deeper insight into the pathophysiology of osteoporosis and identifies IL-6 as a promising target for osteoporosis therapy.     

Comparison of osteoporosis and calcium intake between Japan and the United States.

The number of osteoporotic females in Japan with vertebral bone mineral density measured by dual energy x-ray absorptiometry, defined as less than -3 SD of the peak bone mass, is approximately 10,000,000, corresponding to 8% of the whole population of Japan. While this value approximately corresponds to the prevalence of low bone mineral density in the United States, the incidence of hip fracture appears to be much less in Japan than in the United States, 50,000 per 125,000,000 per year compared with 250,000 for a population twice as large. This seems to be paradoxical because of the lower bone mineral density and lower calcium intake in Japan, with 400-500 mg/day mainly as soybean products, small fish with bones, and vegetables. The difference in hip fracture incidence, however, may not actually be as wide as it seems when the larger number of bedridden elderly subjects in Japan is taken into consideration. In these bedridden subjects with severe immobilization osteoporosis, hip fracture is only prevented by the fact that they are not ambulatory. Life-style difference may also offer an explanation. Sitting on a tatami mattress on completely flexed knees with frequent standing up, along with other household work, in a narrow home space may ensure a marked development of hip musculature and also provide skill in balancing oneself to prevent fails. The difference in fracture incidence should be analyzed from various angles to obtain a firm ground for the future prevention of hip fracture due to osteoporosis. Although osteoporosis universally affects all races and nationalities, conspicuous differences may be encountered in the severity of its manifestations and complications.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relevance of bone mineral density, bone quality and falls in reduction of vertebral and non-vertebral fractures

All epidemiological studies conclude that without prompt, concerted and well-designed prevention programs, the increasing cost related to osteoporotic fractures will become an unbearable burden for the community within the next fifteen years. However, the most effective way of setting up such preventive strategies is not yet unequivocally defined. Low bone mass and microarchitectural damage of bone tissue may account for a large part of the epidemiology of vertebral fractures. Extraskeletal determinants, including low muscle strength, poor balance and gait, all resulting in an increased propensity to fall, also play a major role in the occurrence of hip fracture. Depending on the localization of the fractures, the relative importance of skeletal and extraskeletal risk factors can significantly differ. For prevention of vertebral fractures, drugs affecting bone mass and skeletal architecture may provide a substantial benefit while hip fracture prevention will be more successfully targeted by multi-faceted strategies concentrating not only on the skeletal dimension of the fracture but also aiming, either pharmacologically or through multi-intervention programs, at a reduction in the incidence and in the consequences of falls in the elderly.     

Osteoporosis in Men

ObjectiveTo review information pertinent to bone health and osteoporosis in men.MethodsA review of pertinent literature was conducted.ResultsOsteoporosis affects approximately 2 million men in the US and accounts for an estimated 600,000 fractures each year. There are significant differences in skeletal size and structure between men and women that account for differences in fracture incidence, location, and outcomes. Bone density testing is appropriate for men age 70 and older and younger men (50-69) who have risk factors for osteoporosis. Lifestyle management, including adequate calcium and vitamin D intake, appropriate physical activity, and avoidance of tobacco and heavy alcohol use, is appropriate for all men. Pharmacologic therapy to reduce fracture risk is advisable for men with a clinical diagnosis of osteoporosis (a spine or hip fracture) or a T-score of −2.5 or below in the spine, femoral neck, total hip or 1/3 radius; however, the majority of men at high risk will only be identified using a fracture risk assessment tool, such as FRAX. Alendronate, risedronate, zoledronic acid, denosumab, and teriparatide are Food and Drug Administration (FDA)-approved therapeutic options.ConclusionOsteoporosis in men presents an important public health problem with significant morbidity and mortality. There are recommended strategies for identifying men at high risk of fracture, and effective agents are available for treatment. (Endocr Pract. 2013;19:834-838)     

The role of anorexia nervosa in secondary osteoporosis development with the risk for low energy fractures

Anorexia nervosa (AN) has in recent years become considerably more common. The disease primarily affects girls and young women, also boys and young men. AN is a risk factor for secondary osteoporosis. AN-related metabolic disturbances lead to diminished bone quality and increased risk of fractures. The consequences of low energy fractures are the main causes of death in women with AN. Hormonal disturbances (e.g. hypoestrogenism, increased levels of ghrelin and Y peptide, changes in leptin and endocannabinoid levels), as well as the mechanisms involved in bone resorption (RANK/RANKL/OPG system), are considered to be of great importance for anorectic bone quality. The risk for osteoporotic, non-vertebral fractures in AN patients is significantly higher than in healthy women. Improvement of bone mineral density is possible after substantial body mass increase. Weight loss, in conjunction with a well-balanced, controlled diet, is the key to correct peak bone mass levels, and diminishes the risk for osteoporosis with its consequence of low energy bone fractures.     

Genetics of osteoporosis from genome-wide association studies: advances and challenges

Osteoporosis is among the most common and costly diseases and is increasing in prevalence owing to the ageing of our global population. Clinically defined largely through bone mineral density, osteoporosis and osteoporotic fractures have reasonably high heritabilities, prompting much effort to identify the genetic determinants of this disease. Genome-wide association studies have recently provided rapid insights into the allelic architecture of this condition, identifying 62 genome-wide-significant loci. Here, we review how these new loci provide an opportunity to explore how the genetics of osteoporosis can elucidate its pathophysiology, provide drug targets and allow for prediction of future fracture risk.     

The determinants of fracture in men

Osteoporosis represents an increasingly important clinical and public health problem among older men. Estimates indicated that 1-2 million (3-6%) men aged 50 years and over in the United States have osteoporosis and 8-13 million (28- 47%) have osteopenia. The lifetime risk of suffering a hip, spine or forearm fracture for a 50-year-old man is 13%, similar to the risk for prostate cancer. The number of osteoporotic fractures in men is expected to increase dramatically due to aging of the population and secular increases in fracture rates. Identification of men who are at greatest risk of osteoporosis and the risk factors, which predispose men to fracture, are essential so that preventive steps can be taken. Data on risk factors are emerging but many questions remain. Men may fracture at a higher bone mineral density (BMD) level than women. However, estimates of volumetric BMD, which correct in part for gender differences in bone size, and risk of fracture, may actually show similar relationships in men and women. Fracture rates are similar in older African American women and Caucasian men. Improved understanding of ethnic differences in fracture could identify potential reasons for gender differences. Family history and genetic factors are also important risk factors for fractures but the specific candidate genes are not known and whether gender modifies the effects of these genetic polymorphisms on BMD and the risk of fracture is also not known. In general, lifestyle factors and anthropometric measurements show similar relationships with fractures in men and women although few comprehensive prospective studies have been conducted. Current data will be reviewed on the relationships between markers of skeletal health, genetic polymorphisms, lifestyle and anthropometric factors and fracture.