Showing papers in "Current Osteoporosis Reports in 2012"

Vitamin D and Bone

Abstract: All cells comprising the skeleton—chondrocytes, osteoblasts, and osteoclasts—contain both the vitamin D receptor and the enzyme CYP27B1 required for producing the active metabolite of vitamin D, 1,25 dihydroxyvitamin D Direct effects of 25 hydroxyvitamin D and 1,25 dihydroxyvitamin D on these bone cells have been demonstrated However, the major skeletal manifestations of vitamin D deficiency or mutations in the vitamin D receptor and CYP27B1, namely rickets and osteomalacia, can be corrected by increasing the intestinal absorption of calcium and phosphate, indicating the importance of indirect effects On the other hand, these dietary manipulations do not reverse defects in osteoblast or osteoclast function that lead to osteopenic bone This review discusses the relative importance of the direct versus indirect actions of vitamin D on bone, and provides guidelines for the clinical use of vitamin D to prevent/treat bone loss and fractures

Effects of Bone Matrix Proteins on Fracture and Fragility in Osteoporosis

Abstract: Bone mineral density alone cannot reliably predict fracture risk in humans and laboratory animals. Therefore, other factors including the quality of organic bone matrix components and their interactions may be of crucial importance to understanding of fragility fractures. Emerging research evidence shows, that in addition to collagen, certain noncollagenous proteins (NCPs) play a significant role in the structural organization of bone and influence its mechanical properties. However, their contribution to bone strength still remains largely undefined. Collagen and NCPs undergo different post-translational modifications, which alter the quality of the extracellular matrix and the response of bone to mechanical load. The primary focus of this overview is on NCPs that, together with collagen, contribute to structural and mechanical properties of bone. Current information on several mechanisms through which some NCPs influence bone’s resistance to fracture, including the role of nonenzymatic glycation, is also presented.

Osteocyte Signaling in Bone

Abstract: Osteocytes, the cells residing within the bone matrix and comprising 90% to 95% of the all bone cells, have long been considered quiescent bystander cells compared to the osteoblasts and osteoclasts whose activities cause bone gain and loss, and whose dysfunction lead to growth defects and osteoporosis. However, recent studies show that osteocytes play a crucial, central role in regulating the dynamic nature of bone in all its diverse functions. Osteocytes are now known to be the principal sensors for mechanical loading of bone. They produce the soluble factors that regulate the onset of both bone formation and resorption. Osteocytes regulate local mineral deposition and chemistry at the bone matrix level, and they also function as endocrine cells producing factors that target distant organs such as the kidney to regulate phosphate transport. Osteocytes appear to be the major local orchestrator of many of bone's functions.

Pathways for Bone Loss in Inflammatory Disease

Abstract: Chronic inflammation including autoimmune disease is an important risk factor for the development of osteoporosis. Receptor activator of nuclear factor-κB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play a central role in osteoclast differentiation and function, and the molecular pathways by which M-CSF and RANKL induce osteoclast differentiation have been analyzed in detail. Proinflammatory cytokines directly or indirectly regulate osteoclastogenesis and bone resorption providing a link between inflammation and osteoporosis. Tumor necrosis factor-α, interleukin (IL)-1, IL-6, and IL-17 are the most important proinflammatory cytokines triggering inflammatory bone loss. Inhibition of these cytokines has provided potent therapeutic effects in the treatment of diseases such as rheumatoid arthritis. Further investigation is needed to understand the pathophysiology and to develop new strategies to treat inflammatory bone loss. This review summarizes new data on inflammatory bone loss obtained in 2011.

Intercellular cross-talk among bone cells: new factors and pathways.

Abstract: Intercellular communication within the bone microenvironment is critical for the maintenance of normal bone structure. Osteoblast-lineage cells at all stages of differentiation, from pluripotent precursors to matrix-embedded osteocytes, produce regulatory factors that modulate the differentiation and activity of both bone-forming osteoblasts and bone-resorbing osteoclasts. Osteoclasts can also release factors that feed back to regulate osteoblast activity. Intercellular cross-talk within the bone microenvironment is not restricted only to these bone cells. Other cells within the bone marrow microenvironment, including adipocytes, T cells, and macrophages, play key roles that influence the processes of bone formation and resorption. This review discusses recent work that provides new insights into some of these communication networks and the factors involved, including osteocytic production of receptor activator of nuclear factor-κB ligand (RANKL) and sclerostin, osteoblastic production of interleukin-33, osteoclast-derived Semaphorin 4D, ephrin signaling, and signals from T helper cells and resident osteal macrophages (osteomacs).

Inhibition of cathepsin K for treatment of osteoporosis.

Abstract: Cathepsin K is the protease that is primarily responsible for the degradation of bone matrix by osteoclasts. Inhibitors of cathepsin K are in development for treatment of osteoporosis. Currently available antiresorptive drugs interfere with osteoclast function. They inhibit both bone resorption and formation, due to the coupling between these processes. Cathepsin K inhibitors, conversely, target the resorption process itself and may not interfere with osteoclast stimulation of bone formation. In fact, when cathepsin K is absent or inhibited in mice, rabbits, or monkeys, bone formation is maintained or increased. In humans, inhibition of cathepsin K is associated with sustained reductions in bone resorption markers but with smaller and transient reductions in bone formation markers. The usefulness of cathepsin K inhibitors in osteoporosis is now being examined in phase 2 and phase 3 clinical trials of postmenopausal osteoporotic women.

Spinal Cord Injury-Induced Osteoporosis: Pathogenesis and Emerging Therapies

Abstract: Spinal cord injury causes rapid, severe osteoporosis with increased fracture risk. Mechanical unloading after paralysis results in increased osteocyte expression of sclerostin, suppressed bone formation, and indirect stimulation of bone resorption. At this time, there are no clinical guidelines to prevent bone loss after SCI, and fractures are common. More research is required to define the pathophysiology and epidemiology of SCI-induced osteoporosis. This review summarizes emerging therapeutics including anti-sclerostin antibodies, mechanical loading of the lower extremity with electrical stimulation, and mechanical stimulation via vibration therapy.

Osteoporosis in Asia: a call to action

Abstract: Asia is witnessing a rapid growth in its aging population. Yet osteoporosis in this region has received relatively little attention. Hip fracture rates have increased by 2- to 3-fold in most Asian countries during the past 30 years. Lack of quality epidemiologic data, widespread vitamin D deficiency, low dietary calcium intakes, and uneven access to diagnostic and therapeutic facilities are some of the major challenges faced in this region. Osteoporotic fractures constitute a huge medical, social, and economic burden in Asia. There is an urgent need to promote research, spread awareness, and build national health programs to check this growing problem.

Vitamin D in the new millennium.

Abstract: The incidence of vitamin D deficiency is rising worldwide, yet in the vast majority of patients, the condition remains undiagnosed and untreated. Current evidence overwhelmingly indicates that supplemental doses greater than 800 IU/day have beneficial effects on the musculoskeletal system, improving skeletal homeostasis, thus leading to fewer falls and fractures. Evidence is also accumulating on the beneficial effects of vitamin D on extraskeletal systems, such as improving immune health, autoimmune disorders, cancer, neuromodulation, diabetes, and metabolic syndrome. The cause-effect relationship of vitamin D deficiency with increasing incidences of nonskeletal disorders is being investigated. Published reports support the definition of sufficiency, serum levels of 25-hydroxyvitamin D [25(OH)D] greater than 30 ng/mL (75 nmol/L). To achieve this, most people need vitamin D supplementation ranging from 600 to 2000 IU/day; consumption up to of 5000 international units (IU) per day of vitamin D is reported as safe. Although light-skinned individuals need 1000 IU/day of vitamin D, elderly and dark-skinned individuals are likely to need approximately 2000 IU/day to maintain serum 25(OH)D levels greater than 30 ng/mL. Other vulnerable patients, such as the obese, those who have undergone bariatric surgery, and those with gastrointestinal malabsorption syndromes, may require higher doses of vitamin D to maintain normal serum levels and be healthy.

Signaling Pathways Affecting Skeletal Health

Abstract: Skeletal health is dependent on the balance between bone resorption and formation during bone remodeling. Multiple signaling pathways play essential roles in the maintenance of skeletal integrity by positively or negatively regulating bone cells. During the last years, significant advances have been made in our understanding of the essential signaling pathways that regulate bone cell commitment, differentiation and survival. New signaling anabolic pathways triggered by parathyroid hormone, local growth factors, Wnt signaling, and calcium sensing receptor have been identified. Novel signals induced by interactions between bone cells-matrix (integrins), osteoblasts/osteocytes (cadherins, connexins), and osteoblasts/osteoclast (ephrins, Wnt-RhoA, semaphorins) have been discovered. Recent studies revealed the key pathways (MAPK, PI3K/Akt) that critically control bone cells and skeletal mass. This review summarizes the most recent knowledge on the major signaling pathways that control bone cells, and their potential impact on the development of therapeutic strategies to improve human bone health.

Sclerostin: Therapeutic Horizons Based Upon Its Actions

Abstract: Inactivating mutations of the SOST gene cause a reduction in sclerostin levels and are associated with high bone mass. The clinical phenotypes, sclerosteosis and van Buchem’s disease, were described in 1950s. Much later, it was learned that both diseases are due to loss-of-function mutations in the SOST gene. As a regulator of an important osteoanabolic pathway, Wnt, inactivation of SOST leads to a stimulation of the pathway it regulates. The high bone mass in patients with either sclerosteosis or van Buchem’s disease is associated with unusual skeletal strength; they do not fracture. Knowledge of this molecule and its actions led rather quickly to the development of anti-sclerostin antibodies that lead to marked increases in bone mass in both animals and human subjects. Blocking sclerostin action with anti-sclerostin antibodies is a promising new therapeutic approach to osteoanabolic therapy of osteoporosis.

Osteoporosis after transplantation.

Abstract: Transplantation is an established therapy for end-stage diseases of kidney, lung, liver, and heart among others. Osteoporosis and fragility fractures are serious complications of organ transplantation, particularly in the first post-transplant year. Many factors contribute to the pathogenesis of osteoporosis following organ transplantation. This review addresses the mechanisms of bone loss that occurs both in the early and late post-transplant periods, including the contribution of the immunosuppressive agents as well as the specific features to bone loss after kidney, lung, liver, cardiac, and bone marrow transplantation. Prevention and treatment for osteoporosis in the transplant recipient are also discussed.

Assessment of Fracture Risk

Abstract: Osteoporosis-related fractures (low-trauma, fragility fractures) are associated with significant morbidity, mortality, and health care expenditure worldwide. In the absence of a defining fracture, the diagnosis of osteoporosis is based on the World Health Organization's T-score criteria using central dual-energy x-ray absorptiometry (DXA). Paradoxically, the majority of those patients who will sustain a low-trauma fracture do not meet the T-score definition of osteoporosis. Conversely, younger individuals with bone density in the osteoporotic range but no other risk factors have relatively low fracture rates and yet are frequently considered candidates for osteoporosis therapies. The limited accuracy of bone density testing alone to predict fractures has led to the development of a variety of fracture assessment tools that utilize the combination of bone density and clinical risk factors to improve the prediction of low-trauma fractures. These fracture assessment tools quantitatively predict the 10-year fracture probability of hip and major osteoporosis-related fractures, and can be used to define cost-effective intervention strategies for primary and secondary fracture prevention.

Fracture Risk Assessment: State of the Art, Methodologically Unsound, or Poorly Reported?

Abstract: Osteoporotic fractures, including hip fractures, are a global health concern associated with significant morbidity and mortality as well as a major economic burden. Identifying individuals who are at an increased risk of osteoporotic fracture is an important challenge to be resolved. Recently, multivariable prediction tools have been developed to assist clinicians in the management of their patients by calculating their 10-year risk of fracture (FRAX, QFracture, Garvan) using a combination of known risk factors. These prediction models have revolutionized the way clinicians assess the risk of fracture. Studies evaluating the performance of prediction models in this and other areas of medicine have, however, been characterized by poor design, methodological conduct, and reporting. We examine recently developed fracture prediction models and critically discuss issues in their design, validation, and transparency.

The role of diet in osteoporosis prevention and management.

Abstract: Diet, a modifiable osteoporosis risk factor, plays an important role in the acquisition and maintenance of bone mass. The influence of diet on bone begins in childhood; even maternal diet can influence bone mass in the offspring. A good general nutritional status and adequate dietary protein, calcium, vitamin D, fruits, and vegetables have a positive influence on bone health, while a high caloric diet and heavy alcohol consumption have been associated with lower bone mass and higher rates of fracture. The evidence for a role of other minerals and vitamins in skeletal health is not as strong, but recent evidence suggests that vitamins C and K might also have an effect on bone.

Role of insulin-like growth factor-1 in the regulation of skeletal growth

Abstract: The importance of the insulin-like growth factor (IGF)-I axis in the regulation of bone size and bone mineral density, two important determinants of bone strength, has been well established from clinical studies involving patients with growth hormone deficiency and IGF-I gene disruption. Data from transgenic animal studies involving disruption and overexpression of components of the IGF-I axis also provide support for a key role for IGF-I in bone metabolism. IGF-I actions in bone are subject to regulation by systemic hormones, local growth factors, as well as mechanical stress. In this review we describe findings from various genetic mouse models that pertain to the role of endocrine and local sources of IGF-I in the regulation of skeletal growth.

Heart failure as a risk factor for osteoporosis and fractures.

Abstract: Although heart failure (HF) and osteoporosis are common diseases, particularly in elderly populations, patients with HF have an increased risk for osteoporosis. The relationship of HF with osteoporosis is modified by gender and the severity of HF. In addition, shared risk factors, medication use, and common pathogenic mechanisms affect both HF and osteoporosis. Shared risk factors for these 2 conditions include advanced age, hypovitaminosis D, renal disease, and diabetes mellitus. Medications used to treat HF, including spironolactone, thiazide diuretics, nitric oxide donors, and aspirin, may protect against osteoporosis. In contrast, loop diuretics may make osteoporosis worse. HF and osteoporosis appear to share common pathogenic mechanisms, including activation of the renin-angiotensin-aldosterone system, increased parathyroid hormone levels, and/or oxidative/nitrosative stress. HF is a major risk factor for mortality following fractures. Thus, in HF patients, it is important to carefully assess osteoporosis and take measures to reduce the risk of osteoporotic fractures.

Body composition and skeletal health: too heavy? Too thin?

Abstract: The relationship between body composition and skeletal metabolism has received growing recognition. Low body weight is an established risk factor for fracture. The effect of obesity on skeletal health is less well defined. Extensive studies in patients with anorexia nervosa and obesity have illuminated many of the underlying biologic mechanisms by which body composition modulates bone mass. This review examines the relationship between body composition and bone mass through data from recent research studies throughout the weight spectrum ranging from anorexia nervosa to obesity.

The Contribution of the Extracellular Matrix to the Fracture Resistance of Bone

Abstract: The likelihood of suffering a bone fracture is not solely predicated on areal bone mineral density. As people age, there are numerous changes to the skeleton occurring at multiple length scales (from millimeters to submicron scales) that reduce the ability of bone to resist fracture. Herein is a review of the current knowledge about the role of the extracellular matrix (ECM) in this resistance, with emphasis on engineering principles that characterize fracture resistance beyond bone strength to include bone toughness and fracture toughness. These measurements of the capacity to dissipate energy and to resist crack propagation during failure precipitously decline with age. An age-related loss in collagen integrity is strongly associated with decreases in these mechanical properties. One potential cause for this deleterious change in the ECM is an increase in advanced glycation end products, which accumulate with aging through nonenzymatic collagen crosslinking. Potential regulators and diagnostic tools of the ECM with respect to fracture resistance are also discussed.

Potential Role for Therapies Targeting DKK1, LRP5, and Serotonin in the Treatment of Osteoporosis

Abstract: Osteoporosis is a common disorder in which diminished bone mass leads to progressive microarchitectural skeletal deterioration and increased fracture risk. Our understanding of both normal and pathologic bone biology continues to evolve, and with it our grasp of the highly coordinated relationships between primary bone cells (osteoblasts, osteoclasts, and osteocytes) and the complex molecular signals bone cells use to integrate signals derived from other organ systems, including the immune, hematopoietic, gastrointestinal, and central nervous systems. It is now clear that the Wnt signaling pathway is central to regulation of both skeletal modeling and remodeling. Herein, we discuss components of the Wnt signaling pathway (DKK1, an endogenous soluble inhibitor of Wnt signaling) and LRP5 (a plasma membrane-localized Wnt co-receptor) as potential future targets for osteoporosis therapy. Finally, we discuss the current controversial role for serotonin in skeletal metabolism, and the potential role of future therapies targeting serotonin for osteoporosis treatment.

The Interaction of Biological Factors with Mechanical Signals in Bone Adaptation: Recent Developments

Abstract: Mechanotransduction in bone is fundamental to proper skeletal development. Deficiencies in signaling mechanisms that transduce physical forces to effector cells can have severe consequences for skeletal integrity. Therefore, a solid understanding of the cellular and molecular components of mechanotransduction is crucial for correcting skeletal modeling and remodeling errors and designing effective therapies. In recent years, progress has been made on many fronts regarding our understanding of bone cell mechanotransduction, including subcellular localization of mechanosensitive components in bone cells, the discovery of mechanosensitive G-protein-coupled receptors, identification of new ion channels and larger pores (eg, hemichannels) involved in physical signal transduction, and cell adhesion proteins, among others. These and other recent mechanisms are reviewed to provide a synthesis of recent experimental findings, in the larger context of whole bone adaptation.

HIV Infection and Osteoporosis: Pathophysiology, Diagnosis, and Treatment Options

Abstract: As the population with HIV continues to age, specialists in HIV care are increasingly encountering chronic health conditions, which now include osteoporosis, osteopenia, and fragility fractures. The pathophysiology of the bone effects of HIV infection is complex and includes traditional risk factors for bone loss as well as specific effects due to the virus itself, chronic inflammation, and HAART. Examining risk factors for low bone density and screening of certain patients is suggested, and consideration should be given to treatment for those considered high risk for fracture.

The NPY system and its neural and neuroendocrine regulation of bone.

Abstract: The past decade has seen a significant expansion of our understanding of the interaction between the neural system and bone. While innervation of bone was long appreciated, the discovery of central relays from the hypothalamus to the cells of bone has seen the identification of a number of efferent neural pathways to bone. The neuropeptide Y (NPY) system has proven to represent a major central pathway, regulating the activity of osteoblasts and osteoclasts, through signaling of central and peripheral ligands, through specific receptors within the hypothalamus and the osteoblast. Moreover, this pathway is now recognized as acting to coordinate both skeletal and energy homeostasis. This review examines the mechanism and actions of the NPY pathway to regulate bone mass and bone cell activity.

Trabecular Architecture and Vertebral Fragility in Osteoporosis

Abstract: Osteoporosis heightens vertebral fragility owing to the biomechanical effects of diminished bone structure and composition. These biomechanical effects are only partially explained by loss in bone mass, so additional factors that are independent of bone mass are also thought to play an important role in vertebral fragility. Recent advances in imaging equipment, imaging-processing methods, and computational capacity allow researchers to quantify trabecular architecture in the vertebra at the level of the individual trabecular elements and to derive biomechanics-based measures of architecture that are independent of bone mass and density. These advances have shed light on the role of architecture in vertebral fragility. In addition to the adverse biomechanical consequences associated with trabecular thinning and loss of connectivity, a reduction in the number of vertical trabecular plates appears to be particularly harmful to vertebral strength. In the clinic, detailed architecture analysis is primarily applied to peripheral sites such as the distal radius and tibia. Analysis of trabecular architecture at these peripheral sites has shown mixed results for discriminating between patients with and without a vertebral fracture independent of bone mass, but has the potential to provide unique insight into the effects of therapeutic treatments. Overall, it does appear that trabecular architecture has an independent role on vertebral strength. Additional research is required to determine how and where architecture should be measured in vivo and whether assessment of trabecular architecture in a clinical setting improves prospective fracture risk assessment for the vertebra.

Nitric Oxide Donors for the Treatment of Osteoporosis

Abstract: The number of osteoporotic fractures is increasing worldwide as populations age. An inexpensive and widely available treatment is necessary to alleviate this increase in fractures. Current treatments decrease fractures at trabecular bone sites (spine) but have limited effects at cortical sites (hip, legs, forearm, and upper arm)—the most common sites of osteoporotic fracture. Treatments are also limited by costs, side effects, and lack of availability. Nitric oxide is a novel agent that has the potential to influence cortical bone, is inexpensive, is widely available, and has limited side effects. In this review we evaluate the in vitro and in vivo data which support the concept that nitric oxide is important in bone cell function, review the observational and case–control studies reporting on subjects taking organic nitrates that act as nitric oxide donors, and review the effects of nitrates on bone mineral density measurements and fracture risk.

Idiopathic hypercalciuria and bone health

Abstract: Calcium is an important participant in many physiologic processes including coagulation, cell membrane transfer, hormone release, neuromuscular activation, and myocardial contraction. The body cooperates in a sophisticated web of hormonally mediated interactions to maintain stable extracellular calcium levels. Calcium is vital for skeletal mineralization, and perturbations in extracellular calcium may be corrected at the expense of bone strength and integrity. The aim of this review is to delineate our current understanding of idiopathic hypercalciuria in the context of bone health, specifically its definition, etiology, epidemiology, laboratory evaluation, and potential therapeutic management.

Systems Genetics: A Novel Approach to Dissect the Genetic Basis of Osteoporosis

Abstract: From the early 1990s to the middle of the last decade, the search for genes influencing osteoporosis proved difficult with few successes. However, over the last 5 years this has begun to change with the introduction of genome-wide association (GWA) studies. In this short period of time, GWA studies have significantly accelerated the pace of gene discovery, leading to the identification of nearly 100 independent associations for osteoporosis-related traits. However, GWA does not specifically pinpoint causal genes or provide functional context for associations. Thus, there is a need for approaches that provide systems-level insight on how associated variants influence cellular function, downstream gene networks, and ultimately disease. In this review we discuss the emerging field of “systems genetics” and how it is being used in combination with and independent of GWA to improve our understanding of the molecular mechanisms involved in bone fragility.

Primary Arthroplasty for Management of Osteoporotic Fractures about the Knee

Abstract: Primary cemented arthroplasty of the knee is a viable alternative to open reduction and internal fixation (ORIF) for treatment of osteoporotic fractures about the knee. This permits early return of knee function and weight bearing activity. Stemmed revision total knee arthroplasty implants and techniques are needed, which can be associated with complications of late loosening and periprosthetic fracture. However, for elderly sedentary patients who would not be expected to outlive the durability of the arthroplasty and with fracture patterns in which ORIF may be associated with poor outcomes, primary arthroplasty can be a favorable treatment option.

Brains, Bones, and Aging: Psychotropic Medications and Bone Health Among Older Adults

Abstract: Psychotropic drugs are a crucial element of treatment for psychiatric disorders; however there is an established association between many classes of psychotropic medications and fracture risk among older adults, and growing evidence that some classes of medications may also impact bone mineral density (BMD) In this paper we review recent epidemiologic research on the association between psychotropic medications and osteoporosis, and discuss current controversies and unresolved issues surrounding this relationship Key areas in need of focused inquiry include resolving whether the apparent association between psychotropic medications and BMD is due to confounding by indication, whether this relationship differs for men and women, and whether the implications of these medications for bone health vary over the life course Clinical research to delineate the risk/benefit ratio of psychotropic medications for older adults, particularly those who are at high risk for fracture, is also needed to facilitate prescribing decisions between patients and physicians

Clinical Use of Bone Turnover Markers to Monitor Pharmacologic Fracture Prevention Therapy

Abstract: Monitoring of drug therapies to prevent fractures is controversial. Measurement of bone turnover markers has the potential to identify those with a suboptimal response to fracture prevention medication within a few months of its commencement. However, given the imprecision of currently commercially available assays of bone turnover markers, many individual persons who are “suboptimal medication responders” are likely to be misclassified as “adequate responders” or vice versa, depending on the cut point chosen to define suboptimal and adequate response. Before bone turnover markers can be recommended for routine use in clinical practice to monitor fracture prevention therapies, three advances are needed: 1) bone marker assays with better precision; 2) research establishing optimal cut points of bone marker levels to distinguish “suboptimal responders” from “adequate responders”; and 3) research establishing the incremental fracture reduction benefit from clinical interventions for “suboptimal responders” identified from bone marker measurements.