The prevention and treatment of osteoporosis: a review

Osteoporosis is a disorder characterized by reduced bone strength, diminished bone density, and altered macrogeometry and microscopic architecture. Adult bone mass is the integral measurement of the bone mass level achieved at the peak minus the rate and duration of subsequent bone loss. There is clearly a genetic predisposition to attained peak bone mass, which occurs by a person's mid-20s. Bone loss with age and menopause are universal, but rates vary among individuals. Both peak bone mass and subsequent bone loss can be modified by environmental factors, such as nutrition, physical activity, and concomitant diseases and medications. Osteoporosis prevention requires adequate calcium and vitamin D intake, regular physical activity, and avoiding smoking and excessive alcohol ingestion. Risk of fracture determines whether medication is also warranted. A previous vertebral or hip fracture is the most important predictor of fracture risk. Bone density is the best predictor of fracture risk for those without prior adult fractures. Age, weight, certain medications, and family history also help establish a person's risk for osteoporotic fractures. All women should have a bone density test by the age of 65 or younger (at the time of menopause) if risk factors are present. Guidelines for men are currently in development. Medications include both antiresorptive and anabolic types. Antiresorptive medications--estrogens, selective estrogen receptor modulators (raloxifene), bisphosphonates (alendronate, risedronate, and ibandronate) and calcitonins--work by reducing rates of bone remodeling. Teriparatide (parathyroid hormone) is the only anabolic agent currently approved for osteoporosis in the United States. It stimulates new bone formation, repairing architectural defects and improving bone density. All persons who have had osteoporotic vertebral or hip fractures and those with a bone mineral density diagnostic of osteoporosis should receive treatment. In those with a bone mineral density above the osteoporosis range, treatment may be indicated depending on the number and severity of other risk factors.     

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.     

Estrogens and women's health: interrelation of coronary heart disease, breast cancer and osteoporosis

The determinants of blood levels of estrogen, estrogen metabolites, and relation to receptors and post-transitional effects are the likely primary cause of breast cancer. Very high risk women for breast cancer can now be identified by measuring bone mineral density and hormone levels. These high risk women have rates of breast cancer similar to risk of myocardial infarction. They are candidates for SERM therapies to reduce risk of breast cancer. The completion of the Women's Health Initiative and other such trials will likely provide a definite association of risk and benefit of both estrogen alone and estrogen-progesterone therapy, coronary heart disease, osteoporotic fracture, and breast cancer. The potential intervention of hormone replacement therapy, obesity, or weight gain and increased atherogenic lipoproteinemia may be of concern and confound the results of clinical trials. Estrogens, clearly, are important in the risk of bone loss and osteoporotic fracture. Obesity is the primary determinant of postmenopausal estrogen levels and reduced risk of fracture. Weight reduction may increase rates of bone loss and fracture. Clinical trials that evaluate weight loss should monitor effects on bone. The beneficial addition of increased physical activity, higher dose of calcium or vitamin D, or use of bone reabsorption drugs in coordination with weight loss should be evaluated. Any therapy that raises blood estrogen or metabolite activity and decreases bone loss may increase risk of breast cancer. Future clinical trials must evaluate multiple endpoints such as CHD, osteoporosis, and breast cancer within the study. The use of surrogate markers such as bone mineral density, coronary calcium, carotid intimal medial thickness and plaque, endothelial function, breast density, hormone levels and metabolites could enhance the evaluation of risk factors, genetic-environmental intervention, and new therapies.     

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.     

Osteoporosis,calcium and physical activity.

Sales of calcium supplements have increased dramatically since 1983, as middle-aged women seek to prevent or treat bone loss due to osteoporosis. However, epidemiologic studies have failed to support the hypothesis that larger amounts of calcium are associated with increased bone density or a decreased incidence of fractures. The authors examine the evidence from controlled trials on the effects of calcium supplementation and physical activity on bone loss and find that weight-bearing activity, if undertaken early in life and on a regular basis, can increase the peak bone mass of early adulthood, delay the onset of bone loss and reduce the rate of loss. All of these factors will delay the onset of fractures. Carefully planned and supervised physical activity programs can also provide a safe, effective therapy for people who have osteoporosis.     

Calcium Nutrition and the Aging Process: A Review

Adequate supply of calcium is essential for proper maintenance of the skeletal system. Recent studies suggest that, in the United States, dietary calcium in most women is inadequate to maintain skeletal integrity. Additionally, postmenopausal women will lose bone mass more rapidly because of estrogen deficiency and possibly tack of exercise. Severe loss of bone mass can result in several serious skeletal diseases, the most frequent of which is osteoporosis. This disease is a major contributor (25–30%) to hip fractures and spinal compression fractures in elderly people. Indirect sequelae of these fractures are responsible for 12% to 15% mortality in these patients within three months. Recent research indicates that osteoporitic bone loss may directly affect alveolar bone and may, in fact, exacerbate existing periodontally-induced bone loss. This article will review the literature concerning physiological and biochemical parameters related to the absorption and metabolism of calcium with special emphasis on calcium alterations in the aging process. The following areas will be discussed: Ingestion, Absorption, Factors Effecting Absorption and Bone Maintenance, Calcium/Protein Interactions Affecting the Aging Process, Altered Bone States Associated with the Aging Person, Osteoporosis, Osteomalacia, Paget's Disease, Calcium Affecting Drug Action, and Calcium Affecting Alveolar Bone.     

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, and 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), are considered to be of great importance for anorectic bone quality. The risk of osteoporotic, non-vertebral fractures in AN patients is significantly higher than in healthy women. An 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 of osteoporosis with its consequence of low energy bone fractures. (Pol J Endocrinol 2011; 62 (1): 45-47).     

Clinical problems related to postmenopausal osteoporosis]

Authors discuss current hypotheses related to the causes of osteoporosis and its possible therapy. One of the frequent menopausal disorders is osteoporosis, i.e. decrease in bone density, which may eventually lead to the pathological fractures and marked deformities of the skeleton. Etiology of the postmenopausal osteoporosis is not clearly explained. However, one may assume that hormonal disturbances, especially estrogen deficit, plays an important causative role. The treatment is difficult. It is usually aimed at preventing of bone loss.     

Contribution of bone mineral density and bone turnover markers to the estimation of risk of osteoporotic fracture in postmenopausal women

In osteoporosis, the main cause for concern is the increase in the risk of fractures. The level of bone mineral density (BMD) measured by various techniques has been shown to be a strong predictor of fracture risk in postmenopausal women. However, half of patients with incident fractures have BMD value above the diagnostic threshold of osteoporosis defined as a T-score of -2.5 SD or more below the average value of young healthy women. Clearly there is a need for improvement in the identification of patients at risk for fracture. Several prospective studies have shown that an increased bone resorption evaluated by specific biochemical markers was associated with increased risk of the hip, spine and non-vertebral fractures independently of BMD. The use of bone markers in individual patients may be appropriate in some situations, especially in women who are not detected at risk by BMD measurements. For example, in the OFELY study including 668 postmenopausal women followed prospectively over 9 years, we found that among the 115 incident fractures, 54 (47%) actually occurred in non-osteoporotic women. Among these women, the combination of bone markers and history of previous fracture was highly predictive of fracture risk. Thus, bone markers may be used in the assessment of fracture risk in selected cases in which BMD and clinical risk factors are not enough to take a treatment decision. Advances in our knowledge of bone matrix biochemistry, most notably of post-translational modifications in type I collagen, may allow identification of biochemical markers that reflect changes in the material property of bone, which is an important determinant of bone strength. Preliminary in vitro studies indicate that the extent of post-translational modifications of collagen--which can be reflected in vivo by the measurement of the urinary ratio between native and isomerised type I collagen--play a role in determining the mechanical competence of cortical bone, independently of BMD. Further studies in osteoporosis should explore the changes in these biochemical parameters of bone matrix as they may represent a key component of bone quality.     

Osteoporosis,inflammation and ageing

Osteoporosis is a condition characterized by low bone mass and increased bone fragility, putting patients at risk of fractures, which are major causes of morbidity substantially in older people. Osteoporosis is currently attributed to various endocrine, metabolic and mechanical factors. However, emerging clinical and molecular evidence suggests that inflammation also exerts significant influence on bone turnover, inducing osteoporosis. Numerous proinflammatory cytokines have been implicated in the regulation of osteoblasts and osteoclasts, and a shift towards an activated immune profile has been hypothesized as important risk factor. Chronic inflammation and the immune system remodelling characteristic of ageing, as well as of other pathological conditions commonly associated with osteoporosis, may be determinant pathogenetic factors. The present article will review the current perspectives on the interaction between bone and immune system in the elderly, providing an interpretation of osteoporosis in the light of inflamm-ageing.     

Sex- and age-related response to aromatase deficiency in bone

Deficiency of sex steroids causes osteoporosis, but the relationship between estrogen and androgen is not clear because androgen is converted into estrogen by aromatase. In this study, we characterized bone metabolism in the aromatase-deficient (ArKO) mouse. At 9 weeks old, a marked loss of cancellous bone due to increased bone resorption was observed not only in female ArKO mice but also in males. The degree of bone loss in ArKO males was similar to that in females, and treatment with 17beta-estradiol completely restored the bone mass in both sexes. At 32 weeks old, female ArKO mice showed severe loss of cancellous and cortical bone. Male ArKO mice of this age also showed reduced bone mass, but the degree of bone loss in females was more marked than that in males. Here, we report sex- and age-related responses to aromatase deficiency in bone.     

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.     

Understanding osteoporosis.

Considerable progress has been achieved recently in our understanding of the normal process by which bone mass is regulated. Age-related trabecular bone loss is characterized not simply by a global loss of bone but also by cortical porosity and loss of trabecular connections. Because bone strength depends on architectural as well as material properties, bone quantity alone cannot define fracture risk with precision. Traditional therapies for osteoporosis increase bone mass, and estrogen therapy, in particular, profoundly decreases fracture risk. The pharmacologic restoration of bone quantity and quality, however, remains elusive. Modern biotechnology offers the hope that progress may come about through the development of growth factors and other osteotropic compounds for clinical use.     

Recommendations on the management of fragility fracture risk in women younger than 70 years

The risk for fragility fracture represents a problem of enormous magnitude. It is estimated that only a small fraction of women with this risk take the benefit of preventive measures. The relationship between estrogen and bone mass is well known as they are the other factors related to the risk for fracture. There are precise diagnostic methods, including a tool to diagnose the risk for fracture. Yet there continues to be an under-diagnosis, with the unrecoverable delay in instituting preventive measures. Women under the age of 70 years, being much more numerous than those older, and having risk factors, are a group in which it is essential to avoid that first fragility fracture. Today it is usual not to differentiate between the treatment and the prevention of osteoporosis since the common aim is to prevent fragility fractures. Included in this are women with osteoporosis or with low bone mass and increased risk for fracture, for whom risk factors play a primary role. There is clearly controversy over the type of treatment and its duration, especially given the possible adverse effects of long-term use. This justifies the concept of sequential treatment, even more so in women under the age of 70, since they presumably will need treatment for many years. Bone metabolism is age-dependent. In postmenopausal women under 70 years of age, the increase in bone resorption is clearly predominant, related to a sharp drop in estrogens. Thus a logical treatment is the prevention of fragility fractures by hormone replacement therapy (HRT) and, in asymptomatic women, selective estradiol receptor modulators (SERMs). Afterwards, there is a period of greater resorption, albeit less intense but continuous, when one could utilise anti-resorptive treatments such as bisphosphonates or denosumab or a dual agent like strontium ranelate. Bone formation treatment, such as parathyroid hormone (PTH), in women under 70 years will be uncommon. That is because it should be used in cases where the formation is greatly diminished and there is a high risk for fracture, something found in much older women.     

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。     

Liver and bone

Osteoporosis is a frequent complication in patients with chronic liver disease, especially in end-stages and in cases with chronic cholestasis, hemochromatosis and alcohol abuse. The problem is more critical in transplant patients when bone loss is accelerated during the period immediately after transplantation, leading to a greater incidence of fractures. Advanced age, low body mass index and severity of the liver disease are the main risk factors for bone disease in patients with cholestasis. Mechanisms underlying osteoporosis in chronic liver disease are complex and poorly understood, but osteoporosis mainly results from low bone formation, related to the effects of retained substances of cholestasis, such as bilirubin and bile acids, or to the effects of alcohol on osteoblastic cells. Increased bone resorption has also been described in cholestatic women with advanced disease. Although there is no specific treatment, bisphosphonates associated with supplements of calcium and vitamin D are effective for increasing bone mass in patients with chronic cholestasis and after liver transplantation. The outcome in reducing the incidence of fractures has not been adequately demonstrated essentially because of the low number of patients included in the therapeutic trials. Randomized studies assessing bisphosphonates in larger series of patients, the development of new drugs for osteoporosis and the improvement in the management of liver transplant recipients may change the future.     

Nutritional factors and bone homeostasis: synergistic effect with zinc and genistein in osteogenesis

Bone homeostasis is regulated through osteoclasts and osteoblasts. Osteoporosis, which is induced with its accompanying decrease in bone mass with increasing age, is widely recognized as a major public health problem. Bone loss may be due to decreased osteoblastic bone formation and increased osteoclastic bone resorption. There is growing evidence that nutritional and food factors may play a part in the prevention of bone loss with aging and have been to be worthy of notice in the prevention of osteoporosis. Zinc, an essential trace element, or genistein, which are contained in soybeans, has been shown to have a stimulatory effect on osteoblastic bone formation and an inhibitory effect on osteoclastic bone resorption, thereby increasing bone mass. These factors have an effect on protein synthesis and gene expression, which are related to bone formation in osteoblastic cells and bone resorption in osteoclastic cells. The combination of zinc and genistein is found to reveal the synergistic effect on bone anabolic effect. The oral administration of those factors has been shown to prevent on bone loss in ovariectomized rats, an animal model for osteoporosis, indicating a role in the prevention of osteoporosis. Supplemental intake of ingredient with the combination of zinc and genistein has been shown to have a preventive effect on osteoporosis in human subjects, suggesting a role in the prevention of bone loss.     

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.     

T cells and post menopausal osteoporosis in murine models

Estrogen deficiency is one of the most frequent causes of osteoporosis in women and a possible cause of bone loss in men. But the mechanism involved remains largely unknown. Estrogen deficiency leads to an increase in the immune function, which culminates in an increased production of tumor necrosis factor (TNF) by activated T cells. TNF increases osteoclast formation and bone resorption both directly and by augmenting the sensitivity of maturing osteoclasts to the essential osteoclastogenic factor RANKL (the RANK ligand). Increased T cell production of TNF is induced by estrogen deficiency via a complex mechanism mediated by antigen presenting cells and the cytokines IFNγ, IL-7 and transforming growth factor-β. The experimental evidence that suggests that estrogen prevents bone loss by regulating T cell function and the interactions between immune cells and bone is reviewed here.     

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.