Springer Science and Business Media LLC

Recent developments in biomarkers in many fields of medicine have expanded the array of tools health care providers can use today for disease management. Essentially, biomarkers assist clinicians today in four main ways: screening, diagnosis, assessment of severity or risk, and monitoring of, or deciding on, treatment (1). Surrogate markers known as biochemical markers of bone turnover have been used for decades in the management of diseases of the skeleton. Historically, bone biomarkers required 24-h urine collections, lacked accuracy and reliability, and were cumbersome to use. More recently, they have been shown to be effective surrogates for assessments of treatment response and efficacy in osteoporosis. Although used extensively in research and development and in metabolic bone disease clinics, they are still infrequently used tools for osteoporosis management in clinical practice. Today they have been incorporated into the assessment and management of a variety of diseases of bone including complex metabolic bone disorders, osteoporosis, Paget's disease of bone, and skeletal metastases. Developments in the last decade have greatly enhanced their performance characteristics. A variety of tests and assays are now widely available and significantly more accurate and reliable measures of bone metabolism have been developed. However, techniques and assays vary substantially. In order to maximize their clinical usefulness, an understanding of their strengths and weaknesses, factors that influence them, and knowledge of their unique intricacies is crucial for the ordering physician during the decision-making process. As the field continues to develop, more specific markers and standardization of measurement techniques will enhance reliability, which facilitate their use in practice. The aim of this review is to increase knowledge of the variety of tests available, their potential and limitations, and current best practice for practitioners and researchers, focusing primarily on their use in the management of osteoporosis.

Infection and stones can be associated in two ways. Stone disease can occur due to infection by an organism that expresses the urea-splitting enzyme urease (infection stones). Nephrolithiasis can also be complicated by urinary tract infection that in turn was caused by obstruction of the urinary tract by a stone and/or colonization of a pre-existing stone, in both cases by non-urease producing organisms. Although the incidence of infection stones appears to have declined over recent years in the United States, they remain a cause of significant morbidity and mortality. A strong index of suspicion is necessary to identify infection stones before they become large, damage kidneys, or lead to acute morbidity such as urosepsis. Surgery remains the mainstay of therapy for infection stones, combined with careful attention to antibiotic choice based upon appropriate culture results. Use of medical therapy alone is reserved for those relatively unusual cases in which there is a strong contraindication to surgery. Infection-related stones also require prompt recognition, often via use of non-contrast CT. Any obstruction that is present needs to be promptly relieved in order to decompress the kidney and allow the infection to be cleared by antibiotics chosen based upon culture results.

Several lines of evidence have provided compelling support for low-density lipoprotein receptor-related protein 5 (LRP5) and the canonical Wnt/β-catenin signaling pathway as being important and essential for bone formation. Lrp 5 and its close homolog, Lrp6, are coreceptors with frizzled for Wnt proteins. Binding of Wnt proteins to Lrp5/6 and frizzled activates the Wnt/β-catenin signaling pathway. Mutations in Lrp5 have been shown to give rise to human diseases of low bone mass and loss of vision such as osteoporosis pseudoglioma syndrome (OPPG) and familial exudative vitreoretinopathy (FEVR) as well as several human conditions with increased bone mass and reduced fracture risk, such as the high bone mass (HBM) phenotype. Although it is well established that the Lrp5/6-Wnt canonical pathway is important in embryonic growth and development of the skeleton, its role in the adult skeleton is not clear. Accumulating evidence now supports an important role for Lrp5 in the response of the postnatal skeleton to mechanical load. Transgenic mice carrying the human HBM mutation (LRP5G171V) have increased sensitivity to load, and mice lacking Lrp5 do not respond to mechanical load. In vivo loading of LRP5G171V mice tibia results in increased osteoprotegerin (OPG) gene expression. Mice with either gain-or loss-of-function mutations in protein components of the canonical pathway below the level of Lrp5/6 develop high or low bone mass mainly as a consequence of altered OPG production by osteoblasts, which subsequently alters osteoclastogenesis. Thus, activation of the canonical Wnt signaling pathway apparently has multiple modes of action on bone cells to regulate bone mass. Given the clear importance of LRP5 in regulating bone mass, this gene/protein represents a potentially exciting new target for the development of anabolic agents to treat osteoporosis.

The complexity of cell interactions with their microenvironment and their ability to communicate at the autocrine, paracrine, and endocrine levels has gradually but significantly evolved in the last three decades. The musculoskeletal system has been historically recognized to be governed by a relationship of proximity and function, chiefly dictated by mechanical forces and the work of gravity itself. In this review article, we first provide a historical overview of the biomechanical theory of bone–muscle interactions. Next, we expand to detail the significant evolution in our understanding of the function of bones and muscles as secretory organs. Then, we review and discuss new evidence in support of a biochemical interaction between these two tissues. We then propose that these two models of interaction are complementary and intertwined providing for a new frontier for the investigation of how bone–muscle cross talk could be fully explored for the targeting of new therapies for musculoskeletal diseases, particularly the twin conditions of aging, osteoporosis and sarcopenia. In the last section, we explore the bone–muscle cross talk in the context of their interactions with other tissues and the global impact of these multi-tissue interactions on chronic diseases.

Previous studies on the association between social support and bone health outcomes did not produce consistent results. The main goal of this study was to resolve the inconsistency by systematically examining the studies on the association in the last two decades. In order to do that, we distinguished between two types of social supports: structural supports, which is the pattern of person’s social relationship, and functional support, which is the perceived specific functions from social ties. For fracture, structural social support, especially marital (or cohabitation) status, showed a strong association between both men and women. For osteoporosis, however, only functional social support seemed to have an association, especially only among women. We want to take this conclusion as tentative since there are only 21 research papers on the topic during the period examined. We also ask for more diverse and elaborated measures of social supports developed in social studies.

Cysteine cathepsins are lysosomal proteases with housekeeping as well as tissue-specific functions. One of their specialized functions includes the degradation of extracellular matrix proteins and the regulation of the immune response. In recent years, this protease family received increasing attention as drug targets for bone and cartilage-related diseases. Cathepsin K is identified as the major osteoclast protease with a potent and unique collagenase activity. The protease is responsible for the bulk of collagen degradation in bone remodeling and plays a significant role in the regulation of osteoclast activity. Major efforts in the pharmaceutical industry led to the development of highly potent and specific cathepsin K inhibitors for clinical trials in osteoporosis. Odanacatib, a nitrile-based non-lysosomotropic inhibitor is presently in phase III trials. The compound is well tolerated and showed efficacy regarding the increase of bone mineral density, and reduction of serum and urinary markers of bone resorption. Moreover, cathepsin inhibitors do less or not interfere with the bone formation process. Cathepsin K is also a drug target in arthritic diseases where it is likely involved in type II collagen and glycoprotein degradation. Cathepsin S, which lacks the collagenase activity, is involved in MHC class II antigen presentation in inflammatory and auto-immune related joint diseases and its inhibitors have the potential to represent a new class of anti-inflammatory drugs.

Emerging evidence suggests a stimulating effect of parathyroid hormone (PTH) on the renin–angiotensin–aldosterone system (RAAS). In primary hyperparathyroidism, chronic-elevated PTH levels seem to stimulate the RAAS which may explain the increased risk of cardiovascular disease (CVD). In addition to increased PTH levels, low vitamin D levels may also directly increase risk of CVD, as vitamin D, itself, has been shown to inhibit the RAAS. Angiotensin II, aldosterone and cortisol all negatively impact bone health. Hyperaldosteronism is associated with a reversible secondary hyperparathyroidism due to increased renal calcium excretion. Moreover, the angiotensin II receptor is expressed by human parathyroid tissue, and angiotensin may therefore directly stimulates PTH secretion. An increased bone loss is found in patients with hyperaldosteronism. The angiotensin II receptor seems main responsible for the RAAS-initiated bone loss due to a receptor activator of NF-κB ligand-mediated activation of the osteoclasts. Available data suggest a reduced fracture rate and increased bone mineral density in patients treated with angiotensin II receptor blockers, whereas treatment with angiotensin-converting enzyme inhibitors causes the opposite effects. Mineralocorticoid receptor antagonists seem to be beneficial to bone in patients with hyperaldosteronism, but it is unknown whether this also applies to other individuals. Further long-term studies are needed to clarify the effect of RAAS inhibitors on bone health. RAAS inhibitors, are widely prescribed worldwide and beneficial as well as harmful effects may have large impact on bone health in the general population.

Despite its abundant sunshine the Middle East, a region spanning latitudes from 12°N to 42°N allowing vitamin D synthesis year round, registers some of the lowest levels of vitamin D and the highest rates of hypovitaminosis D worldwide. This major public health problem affects individuals across all life stages including pregnant women, neonates, infants, children and adolescents, adults, and the elderly. Furthermore, while rickets is almost eradicated from developed countries, it is still reported in several countries in the Middle East. These observations can be explained by limited sun exposure due to cultural practices, dark skin color, and very hot climate in several countries in the gulf area, along with prolonged breast feeding without vitamin D supplementation, decreased calcium content of diets and outdoor activity, obesity, and lack of government regulation for vitamin D fortification of food, in several if not in all countries. The lack of population based studies renders estimates for the prevalence and incidence of rickets in the Middle East difficult, but several series from the region illustrate its dire consequences on growth and development. Furthermore, it is reported that 20–80% of apparently healthy individuals from several countries in this region have suboptimal vitamin D levels, depending on the cut-off used for defining hypovitaminosis D, the country, season, age group, and gender studied. Suboptimal levels have been associated with compromised skeletal health across age groups, and with poor muscular function and increased fall risk and osteoporotic fractures in the elderly. Studies detailing associations between low vitamin D levels and musculoskeletal health in the Middle East, and the impact of various treatment regimens are reviewed. Current recommendations for vitamin D derived from data in western subjects may not be sufficient for subjects from the Middle East, therefore suggestions for vitamin D replacement doses based on evidence available to-date are provided. Hypovitaminosis D is a major public health problem across all life stages in the Middle East with deleterious immediate and latent manifestations. Long term strategies to address this often silent disease should include public education, national health policies for screening and prevention through food fortification, and treatment through vitamin D supplementation.

Calcitonin is a 32-amino acid polypeptide secreted by the parafollicular cells of the thyroid. Effects on bone include inhibition of osteoclasts, thus preventing bone resorption, as well as increased renal calcium excretion. Salmon calcitonin is often used therapeutically because it is more potent and has a longer duration of action compared with human calcitonin. Calcitonin also possesses analgesic properties. The mechanism of its analgesic effect is unknown but is thought to involve inhibition of prostaglandins and stimulation of β-endorphins. Most of the clinical data in postmenopausal osteoporosis involves the use of salmon calciton in nasal spray. Clinical trials have demonstrated a reduction in the risk of vertebral fractures and increased bone mineral density. Studies examining nonvertebral fractures have shown mixed results, some indicating a nonsignificant risk In general, calcitonin is inferior to bisphosphonates (BPs) in reducing fracture risk. Calcitonin is effective in the treatment of osteopathic pain. It has also been used in glucocorticoid-induced osteoporosis. Parenteral calcitonin is generally associated with more frequent side effects compared with intranasal calcitonin. Injectable administration can cause flushing, tingling, nausea, and injection site and allergic reactions. Side effects with intranasal use are usually limited to local effects (nasal congestion and irritation). Recent phase I trials with a new oral dosage form show promise in terms of efficacy and tolerability for treating patients who prefer this route of administration. This review of pertinent literature on calcitonin indicates that this remains a viable, though second-or third-line, agent for osteoporotic patients who refuse or cannot tolerate other treatments (e.g., BPs, raloxifene, and estrogen).