Showing papers in "Current Osteoporosis Reports in 2009"

Proinflammatory cytokines and osteoporosis

Abstract: Experimental studies indicate that the proinflammatory cytokines interleukin-1, interleukin-6, and tumor necrosis factor-α are important regulators of bone resorption and may play an important role in age- and estrogen deficiency-related bone loss. Although the observation of accelerated bone loss in patients with inflammatory disorders supports this mechanism, the role of cytokines in the etiology of osteoporosis has yet to be determined. Elucidation of this potential relationship could not only provide clinicians with an additional tool to identify patients at risk for osteoporosis, but may also inform the development of cytokine-blocking therapies as potential interventions to curb bone loss. Although some epidemiologic studies suggest increases in proinflammatory cytokines are associated with decreased bone mass and greater fracture risk, the totality of evidence is limited and provides no clear indication of which cytokines may be most important for bone health. Additional studies are required to establish if inflammation is an important risk factor for osteoporosis.

Osteoporosis prevention and nutrition

Abstract: Although calcium and vitamin D have been the primary focus of nutritional prevention of osteoporosis, recent research has clarified the importance of several additional nutrients and food constituents. Further, results of calcium and vitamin D supplementation trials have been inconsistent, suggesting that reliance on this intervention may be inadequate. In addition to dairy, fruit and vegetable intake has emerged as an important modifiable protective factor for bone health. Several nutrients, including magnesium, potassium, vitamin C, vitamin K, several B vitamins, and carotenoids, have been shown to be more important than previously realized. Rather than having a negative effect on bone, protein intake appears to benefit bone status, particularly in older adults. Regular intake of cola beverages shows negative effects and moderate alcohol intake shows positive effects on bone, particularly in older women. Current research on diet and bone status supports encouragement of balanced diets with plenty of fruit and vegetables, adequate dairy and other protein foods, and limitation of foods with low nutrient density.

Vitamin D and immune function: Understanding common pathways

Abstract: Vitamin D, acting through its active metabolite 1,25(OH)2D3, exerts its influence on many physiologic processes in addition to the regulation of calcium and phosphate homeostasis. These processes include the immune system. Both the adaptive and innate immune systems are affected by 1,25(OH)2D3 and its receptor, and the cells involved express not only the vitamin D receptor but also, in most cases, the enzyme CYP27B1, which produces 1,25(OH)2D3. Both the vitamin D receptor and CYP27B1 can be constitutive or induced by the ligands that activate the immune processes in these cells, providing feedback loops that help regulate the immune response. In general, 1,25(OH)2D3 suppresses most elements of the adaptive immune system while inducing most elements of the innate immune system. Thus 1,25(OH)2D3 may be protective against various autoimmune diseases and may limit graft rejection by suppressing adaptive immunity while enhancing the first line of defense against invading microorganisms via upregulation of innate immunity.

Denosumab: anti-RANKL antibody.

Abstract: Denosumab (anti-receptor activator of nuclear factorκB ligand [RANKL] antibody) is a novel agent, a fully human monoclonal antibody that inhibits osteoclastic-medicated bone resorption by binding to osteoblast-produced RANKL. By reducing RANKL binding to the osteoclast receptor RANK, bone resorption and turnover decrease. In phase 2 dose-ranging studies, denosumab had a rapid onset and offset effect. Also, in patients who had received 2 years of denosumab and were discontinued for the third year, rechallenge with denosumab during the fourth year demonstrated a return of responsiveness to denosumab that mimicked the initial treatment. Phase 3 pivotal fracture data were recently presented with positive outcome data; denosumab (60 mg subcutaneously every 6 months) significantly reduced vertebral, nonvertebral, and hip fracture risk compared with placebo, and had an excellent safety profile through 3 years of use. Denosumab will offer a novel approach to managing postmenopausal osteoporosis, one that should be associated with a high adherence rate and global fracture risk reduction.

Wnt signaling during fracture repair.

Abstract: Bone is one of the few tissues in the body with the capacity to regenerate and repair itself. Fractures usually are completely repaired in a relatively short time, but in a small percentage of cases, healing never occurs and nonunion is the result. Fracture repair and bone regeneration require the localized reactivation of signaling cascades that are crucial for skeletal development. The Wnt/β-catenin signaling pathway is one such developmental pathway whose role in bone formation and regeneration recently has been appreciated. During the past decade, much has been learned about how Wnt pathways regulate bone mass. Small molecules and biologics aimed at this pathway are now being tested as potential new anabolic agents. This article reviews recent data demonstrating that Wnt pathways are active during fracture repair and that increasing the activities of Wnt pathway components accelerates bone regeneration.

From relative risk to absolute fracture risk calculation: The FRAX algorithm

Abstract: FRAX is a computer-based algorithm that provides models for the assessment of fracture probability in men and women (http://www.shef.ac.uk/FRAX). The approach uses easily obtained clinical risk factors to estimate 10-year fracture probability, with or without femoral neck bone mineral density (BMD), to enhance fracture risk prediction. It has been constructed using primary data from population-based cohorts around the world. The gradients of fracture risk have been validated in independent cohorts with a similar geographic distribution. The FRAX tool should not be considered as a gold standard, but rather as a platform technology on which to build as new validated risk indicators become available. Notwithstanding, the present models provide an aid to enhance patient assessment by the integration of clinical risk factors alone and/or in combination with BMD. This article describes the steps undertaken in the development of FRAX.

Bone markers in osteoporosis

Abstract: Current biological markers of bone turnover have proven useful in improving fracture risk assessment and monitoring treatment efficacy in postmenopausal osteoporosis. Recent developments in the field of bone markers include 1) identification of new biochemical markers providing additional information on the complex pathways leading to bone fragility; 2) application of novel technologies such as proteomics for the discovery of novel markers; 3) automation and multiplexing for improving analytical performance and convenience; and 4) refinement of the clinical interpretation of markers. Currently, however, for the management of individual patients, their most established application is to monitor treatment efficacy and possibly to improve fracture risk assessment. The role of bone markers for improving adherence to therapy will need to be investigated in further studies. This brief review discusses these novel technological developments and the recent clinical data on the use of established and new markers in postmenopausal osteoporosis.

Bone loss or lost bone: Rationale and recommendations for the diagnosis and treatment of early postmenopausal bone loss

Abstract: Recent reports suggest that bone loss begins during late perimenopause at a dramatic rate, even before estrogen levels plummet. During the ensuing 5 years, there is evidence of the beginnings of microarchitectural deterioration, which impacts bone strength and ultimately enhances its propensity to fracture. The diagnosis of osteoporosis based on T-scores alone, or through stratification for a high fracture risk by FRAX, excludes these women who are rapidly losing bone. Because all antiosteoporosis therapies, in particular bisphosphonates, reduce bone loss, we propose aggressive, likely short-term therapy with a goal to reduce bone loss, stabilize bone density, and prevent microarchitectural deterioration.

Glucocorticoid-induced osteoporosis.

Abstract: Glucocorticoid treatment can alter bone metabolism, reduce bone strength, and increase the risk for osteoporotic fractures. Risk factors for glucocorticoid-induced osteoporosis (GIO) include older age, high doses, and longer duration of glucocorticoid use. The bone loss that accompanies glucocorticoid use is rapid, and early treatment with bone-sparing agents can prevent bone loss and reduce fracture risk. Several randomized controlled clinical trials have found prevention and treatment of GIO with bisphosphonates, and recently the treatment of GIO with teriparatide, to be effective. This article reviews current information on the epidemiology, pathophysiology, and clinical studies that support using bone-active agents to prevent and treat GIO.

Variation in risk factors for fractures at different sites

Abstract: Fractures in older people are important medical problems. Knowledge of risk factors is essential for successful preventive measures, but when fracture sites of diverse etiology are combined, risk factors for any one site are difficult to identify and may be missed entirely. Among older people, incidence rates of hip, proximal humerus, and vertebral fractures increase with age, but not rates of distal forearm and foot fractures. Low bone mineral density is strongly associated with hip, distal forearm, vertebral, and proximal humerus fractures, but not foot fracture. Most fractures of the hip, distal forearm, and proximal humerus result from a fall, whereas smaller proportions of fractures of the foot and vertebrae follow a fall. Frail people are likely to fracture their hip or proximal humerus, while healthy, active people tend to fracture their distal forearm. We strongly recommend that studies identify risk factors on a site-specific basis.

Early life factors in the pathogenesis of osteoporosis

Abstract: Osteoporosis is a major public health burden through associated fragility fractures. Bone mass, a composite of bone size and volumetric density, increases through early life and childhood to a peak in early adulthood. The peak bone mass attained is a strong predictor of future risk of osteoporosis. Evidence is accruing that environmental factors in utero and in early infancy may permanently modify the postnatal pattern of skeletal growth to peak and thus influence risk of osteoporosis in later life. This article describes the latest data in this exciting area of research, including novel epigenetic and translation work, which should help to elucidate the underlying mechanisms and give rise to potential public health interventions to reduce the burden of osteoporotic fracture in future generations.

Bisphosphonates for postmenopausal osteoporosis: determining duration of treatment.

Abstract: Doctors who treat patients with osteoporosis are increasingly confronted with the question of how long to continue treatment with bisphosphonates (BPs), which have the unique characteristic of accumulating in the skeleton. Limited available long-term data suggest that such decisions should be made on a case-by-case approach and guided by an individual re-evaluation of clinical fracture risks and bone mineral density, efficacy, and safety issues. In patients who still have a high fracture risk after 5 years of treatment with BPs, continuing treatment could be considered, but stopping BPs could be appropriate in those with a low fracture risk after 5 years of treatment. Switching to recombinant human parathyroid hormone 1–34 or 1–84 is indicated when recurrent incident vertebral fractures occur despite adequate antiresorptive therapy for more than 1 year. However, the usefulness of more than 5 years of treatment with BPs needs to be proved with higher levels of evidence-based medicine.

Thyroid-stimulating hormone, thyroid hormones, and bone loss

Abstract: It has become accepted by virtue of rich anecdotal experience and clinical research that thyrotoxicosis is associated with high-turnover osteoporosis. The bone loss, primarily due to accelerated resorption that is not compensated by a coupled increase in bone formation, has been attributed solely to elevated thyroid hormone levels. Evidence using mice lacking the thyroid hormone receptors α and β establishes a role for thyroid hormones in regulating bone remodeling but does not exclude an independent action of thyroid-stimulating hormone (TSH), levels of which are low in hyperthyroid states, even when thyroid hormones are normal, as after thyroxine supplementation and in subclinical hyperthyroidism. We show that TSH directly suppresses bone remodeling and that TSH receptor null mice have profound bone loss, suggesting that reduced TSH signaling contributes to hyperthyroid osteoporosis. TSH and its receptor could become valuable drug targets in treating bone loss.

Mechanisms linking osteoporosis with cardiovascular calcification

Abstract: Cardiovascular calcium deposition is associated with osteoporosis through various potential mechanisms involving molecular regulatory factors at the nanoscale level that govern skeletal bone and cardiovascular tissues. In this article, several possible mechanisms linking cardiovascular calcification and osteoporosis are discussed, including aging, tissue-specific responses to chronic inflammation, flow-limiting atherosclerosis of skeletal end arteries causing ischemic abnormalities in metabolism, shared endogenous regulatory factors that affect the two tissues in a reciprocal manner, and changes in a cysteine protease inhibitor, fetuin. Any or all of these factors and phenomena may contribute to the association.

Quality health care gaps in osteoporosis: how can patients, providers, and the health system do a better job?

Abstract: A significant gap exists between evidence-based advances and real-world clinical practice in the diagnosis and prevention of osteoporosis. The goal of osteoporosis care is to prevent fractures and improve health-related quality of life, and ideally lower mortality. Despite recent advances in osteoporosis detection and treatment options, studies suggest underdiagnosis and undertreatment of osteoporosis, even among those who have already sustained fractures. The challenges in translating knowledge into practice are multifaceted, with efforts directed at the patient, provider, and health care system levels achieving variable success at the population level. Methods to improve quality of care in osteoporosis need to be multipronged, with emphasis on clinical process improvement and reliance on interdisciplinary teams. We review the growing literature on quality of care for osteoporosis.

Clinical relevance of diagnosing vertebral fractures by vertebral fracture assessment

Abstract: Low bone mineral density and the presence of vertebral fractures are independent predictors for future vertebral and non-vertebral fractures. Combining the conventional measurement of bone mineral density of spine and hips with the morphometry of the thoracal and lumbar vertebrae on lateral images using dual energy x-ray absorptiometry scanners, a technique called vertebral fracture assessment, facilitates detection of vertebral fractures in those patients at older age and with clinical risk factors for osteoporosis. Particularly, the finding of one or more vertebral deformities in patients with osteopenia is clinically important, because this might prompt the start of anti-osteoporotic treatment.

New therapies for osteoporosis: zoledronic acid, bazedoxifene, and denosumab.

Abstract: Intravenous (IV) zoledronic acid, a new once-yearly bisphosphonate therapy, is approved by the US Food and Drug Administration for treatment of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and osteoporosis in men. IV zoledronic acid significantly reduced the risk of vertebral, nonvertebral, and hip fractures in postmenopausal women and decreased risk of clinical fracture and clinical vertebral fracture in men and women with hip fracture. Two promising new therapies are in late clinical development. Denosumab is a monoclonal receptor activator of nuclear factor-κB ligand (RANKL) antibody given by subcutaneous injection every 6 months that has been shown to significantly reduce risk of vertebral-, nonvertebral-, and hip fracture in postmenopausal women. Bazedoxifene, an estrogen agonist/antagonist, has significantly reduced the risk of vertebral fracture in postmenopausal women; a post hoc analysis showed reduction in risk of nonvertebral fracture in high-risk women.

Strontium ranelate: new data on fracture prevention and mechanisms of action.

Abstract: Osteoporosis treatments need to combine an unequivocally demonstrated reduction of fractures, at various skeletal sites, long-term safety, and a user-friendly profile that optimizes therapeutic adherence. Strontium ranelate is the first compound to simultaneously decrease bone resorption and stimulate bone formation. Its anti-fracture efficacy at various skeletal sites has been established for as long as 5 years through studies of the highest methodological standards. Increases in bone mineral density observed after 1 year of treatment are predictive of the long-term fracture efficacy, suggesting for the first time in osteoporosis that bone densitometry can be used as a monitoring tool. Due to a positive risk/benefit ratio, strontium ranelate is now considered as a first-line treatment in the management of osteoporosis.

The influence of parathyroid hormone on the adult hematopoietic stem cell niche.

Abstract: Adult hematopoietic stem cells (HSCs) reside in the bone marrow in stable microenvironments known as the stem cell niche. One key component of the stem cell niche is cells of the osteoblastic lineage. Factors that are known to affect osteoblast activity, such as parathyroid hormone (PTH), have also been shown to affect the HSCs. Treatment of mice with PTH has led to beneficial effects on the HSC pool, which have led to clinical trials of PTH treatment to enhance HSC-based therapies.

Nutritional therapies (including fosteum)

Abstract: Nutrition is important in promoting bone health and in managing an individual with low bone mass or osteoporosis. In adult women and men, known losses of bone mass and microarchitecture occur, and nutrition can help minimize these losses. In every patient, a healthy diet with adequate protein, fruits, vegetables, calcium, and vitamin D is required to maintain bone health. Recent reports on nutritional remedies for osteoporosis have highlighted the importance of calcium in youth and continued importance in conjunction with vitamin D as the population ages. It is likely that a calcium intake of 1200 mg/d is ideal, and there are some concerns about excessive calcium intakes. However, vitamin D intake needs to be increased in most populations. The ability of soy products, particularly genistein aglycone, to provide skeletal benefit has been recently studied, including some data that support a new medical food marketed as Fosteum (Primus Pharmaceuticals, Scottsdale, AZ).

Assessment of Material, Structural, and Functional Properties of the Human Skeleton by pQCT Systems

Abstract: Peripheral quantitative computed tomography (pQCT) systems measure bone parameters noninvasively using low radiation doses. This limits image resolution but is practical for the diagnosis and quantitative monitoring of the properties of the peripheral human skeleton. pQCT determines volumetric bone mineral density separately in trabecular and cortical bone. It may combine densitometry determinations with geometric estimates and use strain-stress indexes, and it may be used to analyze muscle variables in some areas, allowing the study of regional fragility. Experimental and clinical ex vivo studies show that pQCT variables correlate with biomechanical predictors of fragility and/or fractures. Since pQCT was approved by the US Food and Drug Administration in 1997, new skeletal regions (human femur and mandible) have been considered in the development of the system. Basically, pQCT explores intraindividual and interindividual variations in greater detail and compares the impact of skeletal diseases, risk factors, and anabolic and catabolic treatments within a given bone cross section.

Glucocorticoid-induced osteoporosis: an indication for anabolic therapy.

Abstract: Introduction: Glucocorticoid (GC) use is associated with disturbed calcium homeostasis and an increased risk of osteoporosis, muscle weakness, and fractures; these changes occur dose-dependently from the initiation of GCs [1]. Bone remodeling includes disturbed suppression of bone formation, stimulation of bone resorption, and osteocyte death [2,3]. The increase of bone resorption has often been related to increased parathyroid hormone (PTH) secretion secondary to decreased calcium absorption from the gut, but a review of the literature could not confi rm this [4], except for changes in spontaneous pulsatile secretion of PTH [5]. Increased bone resorption during GC treatment is related to an increase in the ratio of the receptor activator of the nuclear factorκB ligand over osteoprotegerin (RANKL/OPG) [2]. Catabolic effects of GCs on muscle result in muscle weakness [6,7], which contributes to an increased risk of falls. In case-fi nding algorithms such as FRAX (the World Health Organization risk assessment tool), any pre vious use of GCs is considered to be a clinical risk factor for fractures, but the dose of GCs and fall risk are not included [8]. Other algorithms, such as the fracture incidence in GC users (FIGS), include the dose of GCs and fall risk [9]. Using FIGS, a history of falls contributed as much to fracture risk as a high dose of GCs. Clearly, the etiology of GC-induced osteoporosis (GIOP) is multifactorial and related to skeletal and non-skeletal factors. The current standard of care for the prevention and treatment of GIOP is to provide suffi cient calcium and vitamin D [10]. In addition, in high-risk patients, bisphosphonate therapy has been shown to increase bone mineral density (BMD), decrease bone remodeling, and decrease the risk of fractures in post-hoc analyses [10]. From a pathophysiologic standpoint, one would expect that anabolic bone-directed therapy would have a positive impact on GIOP. In a study of postmenopausal women with GIOP, treatment with synthetic teriparatide and estrogen signifi cantly increased BMD at the lumbar spine, as compared with estrogen alone [11].