Where Wnts Went: The Exploding Field of Lrp5 and Lrp6 Signaling in Bone

Wnt signaling has emerged as a central regulator of skeletal modeling and remodeling. Loss- or gain-of-function mutations in two Wnt co-receptors, Lrp5 and (more recently) Lrp6, have drawn attention to the importance of the Wnt pathway in bone biology. This review summarizes our current understanding of how the Wnt pathway operates on bone and the implications this has for skeletal physiology and drug discovery. Over the past 9 yr, rapid advances have been made in our understanding of the cellular targets for Wnt signaling and of the important regulatory molecules in this metabolic pathway. Both canonical and noncanonical signaling pathways seem to be important for mediating the effects of Wnt in bone. A rapidly expanding catalog of genetically engineered mice has been used to establish the importance of downstream effector molecules (such as β-catenin) in the Wnt pathway, as well as the critical role of endogenous inhibitors of Wnt signaling (such as Dkk1 and sclerostin) in bone metabolism. Indeed, regulation of sclerostin in osteocytes is emerging as an important final pathway for regulating bone anabolism in response to diverse trophic stimuli, from mechnotransduction to the anabolic actions of PTH. From the outset, it had been assumed that the effects of Wnt signaling in bone were caused by direct actions in osteoblast precursors, osteoblasts, and osteocytes. However, startling recent findings have challenged this view and suggest that a key target, at least in mice, is the duodenal enterochromaffin cell. There, Wnt signaling transduced by Lrp5 regulates serotonin synthesis, which acts in an endocrine fashion to regulate bone cell metabolism. It will take time to reconcile this new information with the considerable body of information we already have regarding the actions of Wnt in bone. The Wnt pathway has rapidly emerged as a therapeutic target for drug discovery. Neutralizing antibodies and small-molecule inhibitors of endogenous Wnt inhibitors have shown early promise as bone anabolic agents. However, given the central role of the Wnt pathway in regulating growth and development in extraskeletal tissues, as well as our still rudimentary understanding of how this signaling cascade actually affects bone metabolism, considerable work will be needed to ensure the safety of these new therapies

Torus Palatinus: A New Anatomical Correlation with Bone Density in Postmenopausal Women

The observation that subjects who have a striking oral exostosis, called torus palatinus, also tended to have normal or high bone densities prompted us to examine an unselected population referred for bone density assessment for a possible correlation with torus palatinus. Subjects referred from community physicians had a visual examination of the open mouth to estimate the size of any torus palatinus (0 for none/ trace to 5 for very large) before undergoing a bone density measurement by dual energy x-ray absortiometry. Bone density T- and z-scores were correlated with the size of each subject’s torus palatinus. Torus size groups were also correlated with other variables affecting bone density. About 20% of 370 postmenopausal female subjects,\u3e90% Caucasian, had a moderate to large torus palatinus. Regression correlations for torus size were modest, but significantly related to T- and z-scores of lumbar vertebrae and left hip (P \u3c 0.01 for each). Differences due to medication, body mass index, smoking, parity, and several other factors that affect bone density did not diminish the relation to torus size. This study shows a small, but significant, positive relation for postmenopausal, Caucasian women between bone mineral density and torus size after controlling for several variables known to affect bone density were examined. Torus prominence, in association with other factors, can be considered in decisions for testing bone density in otherwise normal postmenopausal women

Vertebral fractures among breast cancer survivors in China: a cross-sectional study of prevalence and health services gaps

Abstract Background Breast cancer survivors are at high risk for fracture due to cancer treatment-induced bone loss, however, data is scarce regarding the scope of this problem from an epidemiologic and health services perspective among Chinese women with breast cancer. Methods We designed a cross-sectional study comparing prevalence of vertebral fractures among age- and BMI-matched women from two cohorts. Women in the Breast Cancer Survivors cohort were enrolled from a large cancer hospital in Beijing. Eligibility criteria included age 50–70 years, initiation of treatment for breast cancer at least 5 years prior to enrollment, and no history of metabolic bone disease or bone metastases. Data collected included sociodemographic characteristics; fracture-related risk factors, screening and preventive measures; breast cancer history; and thoracolumbar x-ray. The matched comparator group was selected from participants enrolled in the Peking Vertebral Fracture Study, an independent cohort of healthy community-dwelling postmenopausal women from Beijing. Results Two hundred breast cancer survivors were enrolled (mean age 57.5 ± 4.9 years), and compared with 200 matched healthy women. Twenty-two (11%) vertebral fractures were identified among breast cancer survivors compared with 7 (3.5%) vertebral fractures in the comparison group, yielding an adjusted odds ratio for vertebral fracture of 4.16 (95%CI 1.69–10.21, p < 0.01). The majority had early stage (85.3%) and estrogen and/or progesterone receptor positive (84.6%) breast cancer. Approximately half of breast cancer survivors reported taking calcium supplements, 6.1% reported taking vitamin D supplements, and only 27% reported having a bone density scan since being diagnosed with breast cancer. Conclusions Despite a four-fold increased odds of prevalent vertebral fracture among Chinese breast cancer survivors in our study, rates of screening for osteoporosis and fracture risk were low reflecting a lack of standardization of care regarding cancer-treatment induced bone loss

Animal versus plant protein and adult bone health: A systematic review and meta-analysis from the National Osteoporosis Foundation

Background: Protein may have both beneficial and detrimental effects on bone health depending on a variety of factors, including protein source. Objective: The aim was to conduct a systematic review and meta-analysis evaluating the effects of animal versus plant protein intake on bone mineral density (BMD), bone mineral content (BMC) and select bone biomarkers in healthy adults. Methods: Searches across five databases were conducted through 10/31/16 for randomized controlled trials (RCTs) and prospective cohort studies in healthy adults that examined the effects of animal versus plant protein intake on 1) total body (TB), total hip (TH), lumbar spine (LS) or femoral neck (FN) BMD or TB BMC for at least one year, or 2) select bone formation and resorption biomarkers for at least six months. Strength of evidence (SOE) was assessed and random effect meta-analyses were performed. Results: Seven RCTs examining animal vs. isoflavone-rich soy (Soy+) protein intake in 633 healthy peri-menopausal (n = 1) and post-menopausal (n = 6) women were included. Overall risk of bias was medium. Limited SOE suggests no significant difference between Soy+ vs. animal protein on LS, TH, FN and TB BMD, TB BMC, and bone turnover markers BSAP and NTX. Meta-analysis results showed on average, the differences between Soy+ and animal protein groups were close to zero and not significant for BMD outcomes (LS: n = 4, pooled net % change: 0.24%, 95% CI: -0.80%, 1.28%; TB: n = 3, -0.24%, 95% CI: -0.81%, 0.33%; FN: n = 3, 0.13%, 95% CI: -0.94%, 1.21%). All meta-analyses had no statistical heterogeneity. Conclusions: These results do not support soy protein consumption as more advantageous than animal protein, or vice versa. Future studies are needed examining the effects of different protein sources in different populations on BMD, BMC, and fracture

Orthopaedic management improves the rate of early osteoporosis treatment after hip fracture a randomized clinical trial

Background: Although osteoporosis is strongly associated with hip fractures, the initiation of osteoporosis treatment following hip fractures occurs at surprisingly low rates of between 5% and 30%. Currently, most patients receiving treatment have been referred back to their primary care physician for osteoporosis management. The purpose of this study was to compare the effect of osteoporosis management initiated by the orthopaedic team and osteoporosis management initiated by the primary care physician on the rates of treatment at six months. Methods: A prospective randomized trial was conducted to assess the difference in the rate of osteoporosis treatment when an in-house assessment of osteoporosis was initiated by the orthopaedic surgeon and follow-up was conducted in a specialized orthopaedic osteoporosis clinic compared with osteoporosis education and usual care. Results: Sixty-two patients were enrolled in the study. Thirty-one patients each were in the control and intervention groups. The percentage of patients who were on pharmacologic treatment for osteoporosis at six months after the fracture was significantly greater when the evaluation was initiated by the orthopaedic surgeon and was managed in a specialized orthopaedic osteoporosis clinic (58%) than when treatment was managed by a primary care physician (29%) (p = 0.04). Conclusions: An active role by orthopaedic surgeons in the management of osteoporosis improves the rate of treatment at six months following a hip fracture. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence. Copyright © 2008 by The Journal of Bone and Joint Surgery, Incorporated

Calcium Intake in the United States from Dietary and Supplemental Sources across Adult Age Groups: New Estimates from the National Health and Nutrition Examination Survey 2003–2006

Background Adequate lifelong calcium intake is essential in optimizing bone health. Recent National Health and Nutrition Examination Survey data were used to quantify variation in calcium intake across adult age groups and to relate age-associated changes in calcium intake with energy intake. Additional goals were to assess differences in dietary calcium intake between supplemental calcium users and nonusers and to evaluate associations between age and calcium density in the diet. Design This cross-sectional analysis determined calcium and energy intake for National Health and Nutrition Examination Survey respondents during 2003–2006. Diet was assessed with 24-hour recall and supplement use via questionnaire. Trends in median intakes for dietary calcium, total calcium, and energy across age categories were assessed using survey analysis methods. Nutrient density was represented using calcium to energy intake ratios. Results The analyses included data from 9,475 adults. When compared to the 19- to 30-year age group, median dietary calcium intake was lower in the ≥81-year age group by 23% in men (P\u3c0.001) and by 14% in women (P=0.003). These reductions coincided with 35% and 28% decreases, respectively, in median energy intake (P\u3c0.001 for each sex). In contrast, the frequency of calcium supplement use increased (P\u3c0.001) with age in both men and women. Yet, among female supplement users, the decline in median dietary calcium intake was greater than in nonusers (P=0.02). Calcium density in the diet significantly increased relative to age in men and women (P\u3c0.001 for each sex); however, dietary and total calcium to energy ratios were insufficient to meet target ratios inferred by adequate intake standards after age 50 years. Conclusions Although supplemental calcium use and calcium density were highest in older age groups, they were not sufficient in meeting recommended levels. New approaches to increasing the frequency and level of calcium supplement use to enhance calcium density in diets may be necessary to reduce osteoporosis risk among older Americans

AgRP Neurons Regulate Bone Mass

The hypothalamus has been implicated in skeletal metabolism. Whether hunger-promoting neurons of the arcuate nucleus impact the bone is not known. We generated multiple lines of mice to affect AgRP neuronal circuit integrity. We found that mice with Ucp2 gene deletion, in which AgRP neuronal function was impaired, were osteopenic. This phenotype was rescued by cell-selective reactivation of Ucp2 in AgRP neurons. When the AgRP circuitry was impaired by early postnatal deletion of AgRP neurons or by cell autonomous deletion of Sirt1 (AgRP-Sirt1−/−), mice also developed reduced bone mass. No impact of leptin receptor deletion in AgRP neurons was found on bone homeostasis. Suppression of sympathetic tone in AgRP-Sirt1−/− mice reversed osteopenia in transgenic animals. Taken together, these observations establish a significant regulatory role for AgRP neurons in skeletal bone metabolism independent of leptin action