To review current evidence regarding the vertebral fracture prevalence, the accuracy of vertebral fracture identification on current imaging technologies, and the potential impact of vertebral fracture identification on fracture risk.Important new studies have clarified the features of prevalent vertebral fracture that most strongly predict incident fractures. Age- and sex-stratified estimates of vertebral fracture prevalence on densitometric lateral spine images in the US population are now available. The accuracy of densitometric vertebral fracture assessment, how computed tomography scans and other spinal images obtained for indications other than vertebral fracture assessment can be leveraged to detect prevalent vertebral fractures, and the potential impact of vertebral fracture assessment on patient and provider fracture risk management behavior have been clarified. Substantial progress has been made regarding screening strategies using lateral spine imaging to detect prevalent vertebral fracture in the older population. Further research regarding implementation of these strategies in clinical practice and their impact on clinical outcomes is needed.

Alzheimer's disease is the most frequent cause of dementia in older patients. The prevalence is higher in women than in men. This may be the result of both the higher life expectancy of women and the loss of neuroprotective estrogen after menopause. Earlier age at menopause (spontaneous or surgical) is associated with an enhanced risk of developing Alzheimer's disease. Therefore, it is postulated that estrogen could be protective against it. If so, increasing exposure to estrogen through the use of postmenopausal hormone replacement could also be protective against Alzheimer's disease. The results of the clinical studies that have examined this hypothesis are inconclusive, however. One explanation for this is that estrogen treatment is protective only if it is initiated in the years immediately after menopause. Another possibility is that the neuroprotective effects of estrogen are negated by a particular genotype of apolipoprotein E. This protein plays an important role in cholesterol transport to the neurons. Studies that have examined the link between estrogen replacement therapy, Alzheimer's disease and the E4 allele of ApoE are inconclusive. This article reviews the literature on the influence of hormone replacement therapy on the incidence and progression of Alzheimer's disease.Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Studies suggest a link between bone loss and Alzheimer's disease. To examine bone mineral density (BMD) in early Alzheimer's disease (AD) and its relationship to brain structure and cognition, we evaluated 71 patients with early stage AD (Clinical Dementia Rating (CDR) 0.5 and 1) and 69 non-demented elderly control participants (CDR 0). Measures included whole body BMD by dual energy x-ray absorptiometry (DXA) and normalized whole brain volumes computed from structural MRI scans. Cognition was assessed with a standard neuropsychological test battery. Mean BMD was lower in the early AD group (1.11 +/- 0.13) compared to the non-demented control group (1.16 +/- 0.12, p = 0.02), independent of age, gender, habitual physical activity, smoking, depression, estrogen replacement, and apolipoprotein E4 carrier status. In the early AD group, BMD was related to whole brain volume (b = 0.18, p = 0.03). BMD was also associated with cognitive performance, primarily in tests of memory (logical memory [b = 0.15, p = 0.04], delayed logical memory [b = 0.16, p = 0.02], and the selective reminding task - free recall [b = 0.18, p = 0.009]). BMD is reduced in the earliest clinical stages of AD and associated with brain atrophy and memory decline, suggesting that central mechanisms may contribute to bone loss in early AD.

Accelerated bone loss is associated with Alzheimer's disease (AD). Although the central nervous system plays a direct role in regulating bone mass, primarily through the actions of the hypothalamus, there is little work investigating the possible role of neurodegeneration in bone loss. In this cross-sectional study, we examined the association between bone mineral density (BMD) and neuroimaging markers of neurodegeneration (i.e., global and regional measures of brain volume) in early AD and non-demented aging. Fifty-five non-demented and 63 early AD participants underwent standard neurological and neuropsychological assessment, structural MRI scanning, and dual energy x-ray absorptiometry. In early AD, voxel-based morphometry analyses demonstrated that low BMD was associated with low volume in limbic grey matter (GM) including the hypothalamus, cingulate, and parahippocampal gyri and in the left superior temporal gyrus and left inferior parietal cortex. No relationship between BMD and regional GM volume was found in non-demented controls. The hypothesis-driven region of interest analysis further isolating the hypothalamus demonstrated a positive relationship between BMD and hypothalamic volume after controlling for age and gender in the early AD group but not in non-demented controls. These results demonstrate that lower BMD is associated with lower hypothalamic volume in early AD, suggesting that central mechanisms of bone remodeling may be disrupted by neurodegeneration.

Osteoporotic fractures are common and result in extensive morbidity and mortality. It is possible to decrease the risk of fracture in postmenopausal, male, and glucocorticoid-induced osteoporosis with appropriate screening and treatment. The assessment of fracture risk, for which bone densitometry is only 1 component, should be the main focus of patient evaluation. Epidemiologically derived risk-assessment tools such as World Health Organization Fracture Risk Assessment Tool (FRAX) provide physicians with a way to determine the 10-year risk of osteoporotic fracture and effectively choose candidates for therapy. A number of potent skeletal antiresorptive and anabolic drugs have become available to treat osteoporosis and prevent up to 70% of fractures. Here, we provide a detailed update on clinical osteoporosis, the contribution of bone densitometry, and the approach to patients using risk assessment in the consideration of treatments. Progress in osteoporosis is an example of successful bench-to-bedside research benefitting populations worldwide.

Bone, the major structural scaffold of the human body, has recently been demonstrated to interact with several other organ systems through the actions of bone-derived cells and bone-derived cell secretory proteins. Interestingly, the brain is one organ that appears to fall into this interconnected network. Furthermore, the fact that osteoporosis and Alzheimer's disease are two common age-related disorders raises the possibility that these two organ systems are interconnected in terms of disease pathogenesis. This review focuses on the latest evidence demonstrating the impact of bone-derived cells and bone-derived proteins on the central nervous system, and on how this may be relevant in the progression of Alzheimer's disease and for the identification of novel therapeutic approaches to treat this neurodegenerative disorder.

Vitamin D has been investigated in association with cognitive function in older adults. It is unclear whether hypovitaminosis D could be associated with Alzheimer's disease (AD). Our objective was to systematically review and quantitatively synthesize the association of low serum 25-hydroxyvitamin D (25OHD) concentrations with AD in adults. A Medline and PsycINFO® search was conducted on May 2012, with no limit of date, using the MeSH terms "Vitamin D" OR "Hydroxycholecalciferols" combined with the MeSH terms "Alzheimer disease" OR "Dementia" OR "Cognition" OR "Cognition disorders" OR "Memory" OR "Memory Disorders" OR "Executive Function" OR "Attention" OR "Neuropsychological Tests". Of the 284 selected studies, 10 observational studies (including 9 case-controls and 1 cohort study) met the selection criteria. All were of good quality. The number of AD cases ranged from 20 to 211 (40%-100% female). Finally, 7 case-control studies were eligible for fixed and random-effects meta-analyses of bias-corrected effect size of the difference in serum 25OHD concentrations between AD cases and controls using an inverse-variance method. The pooled effect size in random-effects meta-analysis was 1.40 (95% CI: 0.26;2.54), a 'large' effect size that indicates that serum 25OHD concentrations were 1.4 standard deviation units lower in AD cases compared to cognitively healthy controls (p = 0.016). In conclusion, AD cases had lower serum vitamin D concentrations than matched controls. This reinforces the conceptualization of vitamin D as a 'neurosteroid hormone' and as a potential biomarker of AD.

To determine whether low vitamin D concentrations are associated with an increased risk of incident all-cause dementia and Alzheimer disease.One thousand six hundred fifty-eight elderly ambulatory adults free from dementia, cardiovascular disease, and stroke who participated in the US population-based Cardiovascular Health Study between 1992-1993 and 1999 were included. Serum 25-hydroxyvitamin D (25(OH)D) concentrations were determined by liquid chromatography-tandem mass spectrometry from blood samples collected in 1992-1993. Incident all-cause dementia and Alzheimer disease status were assessed during follow-up using National Institute of Neurological and Communicative Disorders and Stroke/Alzheimer's Disease and Related Disorders Association criteria.During a mean follow-up of 5.6 years, 171 participants developed all-cause dementia, including 102 cases of Alzheimer disease. Using Cox proportional hazards models, the multivariate adjusted hazard ratios (95% confidence interval [CI]) for incident all-cause dementia in participants who were severely 25(OH)D deficient (<25 nmol/L) and deficient (≥25 to <50 nmol/L) were 2.25 (95% CI: 1.23-4.13) and 1.53 (95% CI: 1.06-2.21) compared to participants with sufficient concentrations (≥50 nmol/L). The multivariate adjusted hazard ratios for incident Alzheimer disease in participants who were severely 25(OH)D deficient and deficient compared to participants with sufficient concentrations were 2.22 (95% CI: 1.02-4.83) and 1.69 (95% CI: 1.06-2.69). In multivariate adjusted penalized smoothing spline plots, the risk of all-cause dementia and Alzheimer disease markedly increased below a threshold of 50 nmol/L.Our results confirm that vitamin D deficiency is associated with a substantially increased risk of all-cause dementia and Alzheimer disease. This adds to the ongoing debate about the role of vitamin D in nonskeletal conditions.© 2014 American Academy of Neurology.

The level of vitamin D-binding protein (DBP) is increased in the cerebrospinal fluid of patients with Alzheimer's disease (AD), suggesting a relationship with its pathogenesis. In this study, we investigated whether and how DBP is related to AD using several different approaches. A pull-down assay and a surface plasmon resonance binding assay indicated direct interactions between purified DBP and amyloid beta (Aβ), which was confirmed in the brain of AD patients and transgenic AD model mice by immunoprecipitation assay and immunohistochemical double-staining method. Moreover, atomic force microscopic examination revealed that DBP reduced Aβ aggregation in vitro. DBP also prevented Aβ-mediated death in cultured mouse hippocampal HT22 cell line. Finally, DBP decreased Aβ-induced synaptic loss in the hippocampus and rescued memory deficits in mice after injection of Aβ into the lateral ventricle. These results provide converging evidence that DBP attenuates the harmful effects of Aβ by a direct interaction, and suggest that DBP is a promising therapeutic agent for the treatment of AD.

Major advances in understanding basic bone biology and the cellular and molecular mechanisms responsible for the development of osteoporosis, over the last 20 years, have dramatically altered the management of this disease. The purpose of this mini-review is to highlight the seminal role of Wnt signaling in bone homeostasis and disease and the emergence of novel osteoporosis therapies by targeting Wnt signaling with drugs. Published by Elsevier Ireland Ltd.

WNT-3A is a secreted lipoglycoprotein that engages Class Frizzled receptors and LDL receptor related protein 5/6 (LRP5/6) for cellular communication. Generally, WNT-3A mediates WNT/β-catenin signaling to regulate TCF/LEF-dependent gene expression. We have previously shown that β-catenin levels are elevated in proinflammatory microglia of Alzheimer's disease patients and that WNT-3A can evoke a strong proinflammatory response in primary microglia. In order to investigate the underlying mechanisms, we focus here on the pharmacological dissection of WNT-3A-induced signaling to β-catenin and to the extracellular signal-regulated kinases 1/2 (ERK1/2) in mouse primary microglia. Both pathways are induced by WNT-3A with slightly different kinetics, suggesting that they might be pharmacologically separable. Inhibition of heterotrimeric Gαi/o proteins by pertussis toxin blocks WNT-3A-induced LRP6 phosphorylation, disheveled shift, β-catenin stabilization and phosphorylation of ERK1/2. On the other hand LRP6 blockade by Dickkopf 1 treatment abrogated the WNT/β-catenin pathway without affecting WNT/ERK1/2 signaling. In the opposite way, inhibition of βγ subunits, phospholipase C (PLC), intracellular calcium and MEK1/2, the upstream kinase of ERK1/2, blocked ERK1/2 phosphorylation but not β-catenin stabilization. In summary, the data suggest a central role of Gαi/o for both β-catenin-dependent and -independent pathways. WNT-3A-induced ERK1/2 phosphorylation is mediated by βγ subunits, PLC, intracellular calcium and MEK1/2. Furthermore, we show that cyclooxygenase 2 (COX2), a generic proinflammatory marker of microglia, is induced by WNT-3A through ERK1/2-dependent pathways arguing that β-catenin-independent signaling downstream of WNT-3A is of physiological importance for the proinflammatory regulation of microglia.Copyright © 2012 Elsevier Inc. All rights reserved.

17β-estradiol (E2 or estrogen) is an endogenous steroid hormone that is well known to exert neuroprotection. Along these lines, one mechanism through which E2 protects the hippocampus from cerebral ischemia is by preventing the post-ischemic elevation of Dkk1, a neurodegenerative factor that serves as an antagonist of the canonical Wnt signaling pathway, and simultaneously inducing pro-survival Wnt/β-Catenin signaling in hippocampal neurons. Intriguingly, while expression of Dkk1 is required for proper neural development, overexpression of Dkk1 is characteristic of many neurodegenerative diseases, such as stroke, Alzheimer's disease, Parkinson's disease, and temporal lobe epilepsy. In this review, we will briefly summarize the canonical Wnt signaling pathway, highlight the current literature linking alterations of Dkk1 and Wnt/β-Catenin signaling with neurological disease, and discuss E2's role in maintaining the delicate balance of Dkk1 and Wnt/β-Catenin signaling in the adult brain. Finally, we will consider the implications of long-term E2 deprivation and hormone therapy on this crucial neural pathway. This article is part of a Special Issue entitled Hormone Therapy.Copyright © 2013 Elsevier B.V. All rights reserved.

Dickkopf-1 (DKK1), a soluble inhibitor of Wnt signaling secreted by multiple myeloma (MM) cells contributes to osteolytic bone disease by inhibiting the differentiation of osteoblasts. In this study, we tested the effect of anti-DKK1 therapy on bone metabolism and tumor growth in a SCID-rab system. SCID-rab mice were engrafted with primary MM cells expressing varying levels of DKK1 from 11 patients and treated with control and DKK1-neutralizing antibodies for 4 to 6 weeks. Whereas bone mineral density (BMD) of the implanted myelomatous bone in control mice was reduced during the experimental period, the BMD in mice treated with anti-DKK1 increased from pretreatment levels (P <.001). Histologic examination revealed that myelomatous bones of anti-DKK1-treated mice had increased numbers of osteocalcin-expressing osteoblasts and reduced number of multinucleated TRAP-expressing osteoclasts. The bone anabolic effect of anti-DKK1 was associated with reduced MM burden (P <.04). Anti-DKK1 also significantly increased BMD of the implanted bone and murine femur in nonmyelomatous SCID-rab mice, suggesting that DKK1 is physiologically an important regulator of bone remodeling in adults. We conclude that DKK1 is a key player in MM bone disease and that blocking DKK1 activity in myelomatous bones reduces osteolytic bone resorption, increases bone formation, and helps control MM growth.