Drake, Matthew T.

ABSTRACT Although the role of ERα in regulating bone metabolism has been extensively studied, ERβ has been largely dismissed as a relevant modulator of bone mass. Previous studies examining ERβ utilized a germline knockout mouse expressing transcript variants of ERβ and displaying systemic hormonal changes that confounded interpretation of the skeletal phenotype. Thus, we used a conditional ERβ mouse model to achieve deletion of ERβ specifically in early osteoprogenitor cells using the Prx1-Cre driver. We observed marked increases in the trabecular bone volume fraction (of 58% [p < 0.003] and 93% [p < 0.0003] in 6- and 12-week-old female ERβPrx1–CKO mice, respectively) but no changes in cortical bone. Serum estradiol and IGF-I levels were unaltered in ERβPrx1–CKO mice. Bone formation and resorption indices by histomorphometry and serum assays were unchanged in these mice, suggesting that alterations in bone turnover may have occurred early in development. However, the ratio of colony-forming unit-osteoblasts (CFU-OBs) to CFU-fibroblasts (CFU-Fs) was increased in bone marrow cultures from ERβPrx1–CKO compared with control mice, indicating increased differentiation of osteoblast precursor cells into osteoblasts in ERβPrx1–CKO mice. Detailed quantitative polymerase chain reaction analyses of 128 genes in 16 prespecified pathways revealed significant downregulation of 11 pathways in ERβPrx1–CKO mice. Thus, deletion of ERβ specifically in osteoblast lineage cells, in the absence of all splice variants, increases trabecular bone mass and modulates multiple pathways related to bone metabolism. These findings suggest that pharmacological inhibition of ERβ in bone may provide a novel approach to treat osteoporosis. © 2015 American Society for Bone and Mineral Research.

ABSTRACT Bisphosphonates (BPs) are the most commonly used medications for osteoporosis. This ASBMR report provides guidance on BP therapy duration with a risk-benefit perspective. Two trials provided evidence for long-term BP use. In the Fracture Intervention Trial Long-term Extension (FLEX), postmenopausal women receiving alendronate for 10 years had fewer clinical vertebral fractures than those switched to placebo after 5 years. In the HORIZON extension, women who received 6 annual infusions of zoledronic acid had fewer morphometric vertebral fractures compared with those switched to placebo after 3 years. Low hip T-score, between –2 and –2.5 in FLEX and below –2.5 in HORIZON extension, predicted a beneficial response to continued therapy. Hence, the Task Force suggests that after 5 years of oral BP or 3 years of intravenous BP, reassessment of risk should be considered. In women at high risk, for example, older women, those with a low hip T-score or high fracture risk score, those with previous major osteoporotic fracture, or who fracture on therapy, continuation of treatment for up to 10 years (oral) or 6 years (intravenous), with periodic evaluation, should be considered. The risk of atypical femoral fracture, but not osteonecrosis of the jaw, clearly increases with BP therapy duration, but such rare events are outweighed by vertebral fracture risk reduction in high-risk patients. For women not at high fracture risk after 3 to 5 years of BP treatment, a drug holiday of 2 to 3 years can be considered. The suggested approach for long-term BP use is based on limited evidence, only for vertebral fracture reduction, in mostly white postmenopausal women, and does not replace the need for clinical judgment. It may be applicable to men and patients with glucocorticoid-induced osteoporosis, with some adaptations. It is unlikely that future trials will provide data for formulating definitive recommendations. © 2015 American Society for Bone and Mineral Research.

Abstract Background: The health benefits associated with maintaining adequate circulating levels of vitamin D are well known. More recently, data have emerged supporting an inverse association between vitamin D levels and risk of several human cancers. Related to this, African Americans (AAs) are at increased risk of hypovitaminosis D due to elevated levels of melanin in the skin that reduce the conversion of cholesterol to vitamin D3 (cholecalciferol). Herein, we simultaneously assess levels of awareness regarding the health benefits of vitamin D and the prevalence of hypovitaminosis D in a metropolitan African American community. Methods: From January 2012 through August 2013, we partnered with African American churches and community organizations in the metropolitan Jacksonville, FL area to provide nine education programs focused on vitamin D and the evidence linking poor vitamin D levels with increased risk of chronic disease, including cancer. Participants were offered free vitamin D testing to estimate the prevalence of vitamin D insufficiency (<25 ng/mL) and deficiency (< 15 ng/mL) in this population. Moreover, participants also completed surveys prior to the events to assess their awareness of issues related to vitamin D, including the emerging link with cancer risk. Results: Out of 305 attendees, 285 agreed to provide blood samples for vitamin D screening. Of these, 262 (92%) self-identified as African American (75% female, 25% male). The median age of the AA participants was 59 years. Laboratory testing for 25(OH) vit D revealed 43% of the AA participants had normal levels of vitamin D (>25 ng/mL), 35% had insufficient levels (15-24 ng/mL) and 22% had deficient levels (< 15 ng/mL). Of interest, despite the high level of hypovitaminosis D (insufficient + deficient) in this population, participants reported high levels of awareness regarding vitamin D prior to the education program. For example, 82% of AA respondents correctly answered that the main source of vitamin D came from sunlight and 76% correctly answered that AAs are at risk of lower levels of vitamin D because of the amount of melanin in the skin. Moreover, 83% of AA respondents answered that maintaining proper vitamin D levels could potentially decrease risk for various chronic health conditions, including certain cancers. Finally, 75% of the AA participants reported never having had a vitamin D test discussed with them by their doctor. Conclusions: We report a high prevalence of hypovitaminosis D in a large AA community in Jacksonville, FL. Moreover, we report that despite this high prevalence, awareness of the health benefits of vitamin D are high, yet regular vitamin D testing levels appear to be very low. These data provide the foundation for developing targeted interventions to raise vitamin D levels in this community. Citation Format: Alexander Parker, Monica Albertie, Nancy Diehl, Matthew Drake. Evaluation of the prevalence of hypovitaminosis D and vitamin D awareness in African Americans living in a metropolitan southern community. [abstract]. In: Proceedings of the Sixth AACR Conference: The Science of Cancer Health Disparities; Dec 6–9, 2013; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2014;23(11 Suppl):Abstract nr B61. doi:10.1158/1538-7755.DISP13-B61

Key PointsMGUS patients have significantly increased cortical bone porosity and reduced bone strength relative to matched controls.

Context: Studies in postmenopausal women have shown that estrogen reduces circulating sclerostin levels, but effects of estrogen on skeletal sclerostin mRNA levels are unknown. Objective: The objective of the study was to evaluate the effects of short-term estrogen treatment on bone mRNA levels of sclerostin and other genes relevant to bone metabolism. Design, Setting, and Patients: Needle bone biopsies were obtained from 20 postmenopausal women treated with transdermal estrogen for 3 weeks and 20 untreated controls. Quantitative PCR analyses were used to examine the expression of sclerostin and other genes related to bone metabolism, including 71 additional genes linked to bone density/fracture from genome-wide association studies. Results: Estrogen treatment was associated with lower bone sclerostin mRNA levels (by 48%, P < .05) and with lower (by 54%, P < .01) mRNA levels of the sclerostin-related protein, sclerostin domain-containing protein 1 (SOSTDC1), which is also a Wnt/bone morphogenetic protein inhibitor. Consistent with studies in mice showing that ovariectomy increased nuclear factor-κB (NF-κB) activation, we found that estrogen treatment was associated with a significant reduction in inflammatory genes as a group (P = .028), with bone mRNA levels of NFKB2 and RELB (both encoding proteins in the NF-κB transcription factor complex) being significantly reduced individual genes. Eight of the 71 genome-wide association study-related genes examined were modulated by estrogen (P < .05, false discovery rate < 0.10). Conclusion: In humans, estrogen-induced decreases in two key inhibitors of Wnt/bone morphogenetic protein signaling, sclerostin and SOSTDC1, along with reductions in NF-κB signaling, may be responsible for at least part of the protective effects of estrogen on bone.

ABSTRACT Although patients with type 2 diabetes (T2D) are at significant risk for well-recognized diabetic complications, including macrovascular disease, retinopathy, nephropathy, and neuropathy, it is also clear that T2D patients are at increased risk for fragility fractures. Furthermore, fragility fractures in patients with T2D occur at higher bone mineral density (BMD) values compared to nondiabetic controls, suggesting abnormalities in bone material strength (BMS) and/or bone microarchitecture (bone “quality”). Thus, we performed in vivo microindentation testing of the tibia to directly measure BMS in 60 postmenopausal women (age range, 50–80 years) including 30 patients diagnosed with T2D for >10 years and 30 age-matched, nondiabetic controls. Regional BMD was measured by dual-energy X-ray absorptiometry (DXA); cortical and trabecular bone microarchitecture was assessed from high-resolution peripheral quantitative computed tomography (HRpQCT) images of the distal radius and tibia. Compared to controls, T2D patients had significantly lower BMS: unadjusted (−11.7%; p < 0.001); following adjustment for body mass index (BMI) (−10.5%; p < 0.001); and following additional adjustment for age, hypertension, nephropathy, neuropathy, retinopathy, and vascular disease (−9.2%; p = 0.022). By contrast, after adjustment for confounding by BMI, T2D patients had bone microarchitecture and BMD that were not significantly different than controls; however, radial cortical porosity tended to be higher in the T2D patients. In addition, patients with T2D had significantly reduced serum markers of bone turnover (all p < 0.001) compared to controls. Of note, in patients with T2D, the average glycated hemoglobin level over the previous 10 years was negatively correlated with BMS (r = −0.41; p = 0.026). In conclusion, these findings represent the first demonstration of compromised BMS in patients with T2D. Furthermore, our results confirm previous studies demonstrating low bone turnover in patients with T2D and highlight the potential detrimental effects of prolonged hyperglycemia on bone quality. Thus, the skeleton needs to be recognized as another important target tissue subject to diabetic complications. © 2014 American Society for Bone and Mineral Research.