Population-Based Osteoporosis Primary Prevention and Screening for Quality of Care in Osteoporosis, Current Osteoporosis Reports Abstract Purpose of Review Despite the high prevalence and impact of osteoporosis, screening and treatment rates remain low, with few women age 65 years and older utilizing osteoporosis screening for primary prevention. Recent Findings This review examines opportunities and challenges related to primary prevention and screening for osteoporosis at the population level. Strategies on how to identify individuals at high fracture risk and target them for treatment have lagged far behind other developments in the osteoporosis field. Most osteoporosis quality improvement strategies have focused on patients with recent or prior fracture (secondary prevention), with limited attention to individuals without prior fracture. For populations without prior fracture, the only quality improvement strategy for which meta-analysis demonstrated significant improvement in osteoporosis care was patient self-scheduling of DXA plus education Summary Much more work is needed to develop and validate effective primary screening and prevention strategies and translate these into high-quality guidelines.

Complex Phenotypes: Mechanisms Underlying Variation in Human Stature Abstract Purpose of Review The goal of the review is to provide a comprehensive overview of the current understanding of the mechanisms underlying variation in human stature. Recent Findings Human height is an anthropometric trait that varies considerably within human populations as well as across the globe. Historically, much research focus was placed on understanding the biology of growth plate chondrocytes and how modifications to core chondrocyte proliferation and differentiation pathways potentially shaped height attainment in normal as well as pathological contexts. Recently, much progress has been made to improve our understanding regarding the mechanisms underlying the normal and pathological range of height variation within as well as between human populations, and today, it is understood to reflect complex interactions among a myriad of genetic, environmental, and evolutionary factors. Indeed, recent improvements in genetics (e.g., GWAS) and breakthroughs in functional genomics (e.g., whole exome sequencing, DNA methylation analysis, ATAC-sequencing, and CRISPR) have shed light on previously unknown pathways/mechanisms governing pathological and common height variation. Additionally, the use of an evolutionary perspective has also revealed important mechanisms that have shaped height variation across the planet. Summary This review provides an overview of the current knowledge of the biological mechanisms underlying height variation by highlighting new research findings on skeletal growth control with an emphasis on previously unknown pathways/mechanisms influencing pathological and common height variation. In this context, this review also discusses how evolutionary forces likely shaped the genomic architecture of height across the globe.

The Role of Lower-Limb Geometry in the Pathophysiology of Atypical Femoral Fracture Abstract Purposeof Review The etiology of atypical femoral fracture (AFF) is likely multifactorial. In this review, we examined the recent literature investigating the role of lower-limb geometry in the pathophysiology of AFF. Recent Findings Increased femoral bowing was associated with prevalent AFF and a greater likelihood of a diaphyseal versus a subtrochanteric AFF location. Femoral neck geometry or hip alignment may also be related to AFF, but findings remain equivocal. Differences in femoral geometry may, in part, be responsible for the high rate of AFF in Asian compared with Caucasian populations. Finally, simulation studies suggest that lower-limb geometry influences AFF risk via its effects on mechanical strain of the lateral femoral cortex. Summary Femoral geometry, and bowing in particular, is related to prevalent AFF, but more prospective investigation is needed to determine whether measurements of geometry can be used for clinical risk stratification.

Breast Cancer Dormancy in Bone Abstract Purpose of Review The goal of this review is to summarize recent experimental and clinical evidence for metastatic latency and the molecular mechanisms that regulate tumor dormancy in the bone. Recent Findings Tumor dormancy contributes to the progression of metastasis and thus has significant clinical implications for prognosis and treatment. Tumor-intrinsic signaling and specialized bone marrow niches play a pivotal role in determining the dormancy status of bone disseminated tumor cells. Experimental models have provided significant insight into the effects of the bone microenvironment on tumor cells; however, these models remain limited in their ability to study dormancy. Summary Despite recent advances in the mechanistic understanding of how tumor cells remain dormant in the bone for prolonged periods of time, the signals that trigger spontaneous dormancy escape remain unclear. This review highlights the need for further investigation of mechanisms underlying tumor dormancy using clinically relevant models.

Osteoglycin and Bone—a Systematic Review Abstract Purpose of Review Bone turnover is a regulated process. Osteoglycin is suggested to have an important impact on bone function but may also affect cardiovascular and metabolic functions. This review investigates the action of osteoglycin in bone as well as its potential endocrine effects. Recent Findings Osteoglycin is expressed by several tissues including bone and muscle. Some studies suggest that osteoglycin increases osteoblast differentiation whereas others suggest that osteoglycin decreases osteoblast differentiation. Thus, findings on the influence of osteoglycin in bone are conflicting. A recent study found increased bone mass in osteoglycin deficient mice. Another study reported that osteoglycin is a marker of low bone mineral density and vertebral fractures in women with type 2 diabetes. Furthermore, clinical studies link osteoglycin to insulin resistance and cardiovascular disease. Summary Osteoglycin may be a novel marker of a muscle, pancreatic, and bone axis. However, current evidence is limited and further research investigating osteoglycin in both a pre-clinical and a clinical setting is needed.

Peripheral Neuropathy as a Component of Skeletal Disease in Diabetes Abstract Purpose of Review The goal of this review is to explore clinical associations between peripheral neuropathy and diabetic bone disease and to discuss how nerve dysfunction may contribute to dysregulation of bone metabolism, reduced bone quality, and fracture risk. Recent Findings Diabetic neuropathy can decrease peripheral sensation (sensory neuropathy), impair motor coordination (motor neuropathy), and increase postural hypotension (autonomic neuropathy). Together, this can impair overall balance and increase the risk for falls and fractures. In addition, the peripheral nervous system has the potential to regulate bone metabolism directly through the action of local neurotransmitters on bone cells and indirectly through neuroregulation of the skeletal vascular supply. Summary This review critically evaluates existing evidence for diabetic peripheral neuropathy as a risk factor or direct actor on bone disease. In addition, we address therapeutic and experimental considerations to guide patient care and future research evaluating the emerging relationship between diabetic neuropathy and bone health.

The Effect of Type 2 Diabetes on Bone Biomechanics Abstract Purpose of Review There is ample evidence that patients with type 2 diabetes (T2D) have increased risk of fracture even though they have normal or high bone mineral density. As a result, poor bone quality is suggested to contribute to skeletal fragility in this population. Thus, our goal was to conduct a comprehensive literature review to understand how bone quality components are altered in T2D and their effects on bone biomechanics and fracture risk. Recent Findings T2D does affect bone quality via alterations in bone microarchitecture, organic matrix, and cellular behavior. Further, studies indicate that bone biomechanical properties are generally deteriorated in T2D, but there are few reports in patients. Summary Additional work is needed to better understand molecular and cellular mechanisms that contribute to skeletal fragility in T2D. This knowledge can contribute to the development of improved diagnostic tools and drug targets to for improved quality of life for those with T2D.

Controversies in the Management of Secondary Hyperparathyroidism in Chronic Kidney Disease Abstract Secondary hyperparathyroidism is a frequent complication of chronic kidney disease that begins early in the course of renal insufficiency as an adaptive response to maintain mineral homeostasis. This complex disorder affects the bone, leading to an increase in fracture risk and is associated with increased risks of vascular calcification and mortality. Purpose of Review In this review, we examine the different strategies available to manage secondary hyperparathyroidism. Particularly, we focus on the adequate control of serum phosphorus by restricting intake and the use of phosphate binders, correction of hypocalcemia while minimizing calcium burden, and reduction in PTH levels through the use of vitamin D sterols and calcimimetics. Recent Findings It was observed that although numerous agents directed at the correction of these abnormalities have demonstrated effectiveness on biochemical markers, there is still a relative scarcity of studies demonstrating treatment effectiveness as measured by hard clinical outcomes. In addition, most agents have side effects that may limit their use, even in patients in which the treatment has demonstrated efficacy in controlling these parameters. Summary There is still controversy as to what therapeutic regimens to choose for a particular patient and what parameter should be used to follow their effects, including outcomes, side effects, pill burden, and costs, among others. In the present article, we analyze controversial aspects of the different therapeutic agents available. Although many tools and regimens are available, no one by itself is enough for an adequate management of the patient. But rather, combined therapy and individualization of approaches are recommended for better results. We suggest that new studies analyzing the effectiveness of therapeutic approaches to the management of secondary hyperparathyroidism should be directed not only to controlling parathyroid hormone levels but also to the evaluation of long-term outcomes, based on modification of morbidity, mortality, and end organ impact, while reducing side effects and controlling costs, among others.

Cellular Processes by Which Osteoblasts and Osteocytes Control Bone Mineral Deposition and Maturation Revealed by Stage-Specific EphrinB2 Knockdown Abstract Purpose of Review We outline the diverse processes contributing to bone mineralization and bone matrix maturation by describing two mouse models with bone strength defects caused by restricted deletion of the receptor tyrosine kinase ligand EphrinB2. Recent Findings Stage-specific EphrinB2 deletion differs in its effects on skeletal strength. Early-stage deletion in osteoblasts leads to osteoblast apoptosis, delayed initiation of mineralization, and increased bone flexibility. Deletion later in the lineage targeted to osteocytes leads to a brittle bone phenotype and increased osteocyte autophagy. In these latter mice, although mineralization is initiated normally, all processes involved in matrix maturation, including mineral accrual, carbonate substitution, and collagen compaction, progress more rapidly. Summary Osteoblasts and osteocytes control the many processes involved in bone mineralization; defining the contributing signaling activities may lead to new ways to understand and treat human skeletal fragilities.

When Low Bone Mineral Density and Fractures Is Not Osteoporosis Abstract Purpose of Review To review the differential diagnosis of low bone mineral density (BMD). Recent Findings Osteoporosis is the most common cause of low BMD in adults; however, non-osteoporotic causes of low BMD should be considered in the differential diagnosis of patients with low BMD. Mild osteogenesis imperfecta, osteomalacia, and mineral and bone disorder of chronic kidney disease as well as several other rare diseases can be characterized by low BMD. Summary This review summarizes the differential diagnosis of low BMD. It is important to differentiate osteoporosis from other causes of low BMD since treatment regimens can vary tremendously between these different disease processes. In fact, some treatments for osteoporosis could worsen or exacerbate the mineral abnormalities in other causes of low BMD.