In a 5-yr randomized prospective study we examined the treatment effect of estrogen replacement therapy/hormone replacement therapy (ERT/HRT), calcitriol, ERT/HRT and calcitriol, or placebo for 3 yr ...and the effect of discontinuation of therapy for 2 more yr on bone mineral density (BMD), calciotropic hormones, markers of bone remodeling, and calcium absorption in 489 elderly women. The treatment phase of the study was double-blinded. After discontinuing therapy for 2 yr, there was rapid bone loss in all 3 treatment groups, and most of the decrease in BMD occurred in the first year.
In the ERT/HRT group, spine BMD increased 5.5% in yr 3, decreased 3.2% in yr 4, and decreased 0.7% in yr 5; femoral neck BMD increased 3.7% in yr 3, decreased 2.5% in yr 4, and decreased 0.4% in yr 5; total body BMD increased 2.1% in yr 3, decreased 1.4% in yr 4, and decreased 0.6% in yr 5. In the combination group, spine BMD increased 7.1% in yr 3, decreased 4.3% in yr 4, and decreased 0.3% in yr 5; femoral neck BMD increased 4.5% in yr 3, decreased 3.0% in yr 4, and decreased 0.01% in yr 5; total body BMD increased 2.2% in yr 3, decreased 1.5% in yr 4, and decreased 0.6% in yr 5. In the calcitriol group, spine BMD increased 1.8% in yr 3, decreased 1.8% in yr 4, and showed no change in yr 5; femoral neck BMD increased 0.2% in yr 3, decreased 0.2% in yr 4, and decreased 0.6% in yr 5; total body BMD decreased 0.4% in yr 3, decreased 0.6% in yr 4, and decreased 0.4% in yr 5.
Compared with placebo, all treated groups at yr 5 had significantly higher total body BMD; only the combination group had significantly higher spine BMD (3.4%; P < 0.001) and total hip BMD (2.4%; P < 0.01.) compared with the placebo group. Compared with baseline, only spine BMD in the combination group was significantly higher (2.6%; P < 0.001) at yr 5.
The increase in calcium absorption and the decrease in serum PTH levels in the calcitriol groups were reversed after discontinuation of treatment, and the decrease in bone markers was reversed in the hormone-treated groups. These results suggest that discontinuation of ERT/HRT and/or calcitriol therapy in elderly women leads to a decrease in much of the BMD gained on treatment; however, in the combination group there was a statistically significant residual effect on spine BMD.
Establishing and maintaining the complex network of connections required for neuronal communication requires the transport and in situ translation of large groups of mRNAs to create local proteomes. ...In this Review, we discuss the regulation of local mRNA translation in neurons and the RNA‐binding proteins that recognise RNA zipcode elements and connect the mRNAs to the cellular transport networks, as well as regulate their translation control. However, mRNA recognition by the regulatory proteins is mediated by the combinatorial action of multiple RNA‐binding domains. This increases the specificity and affinity of the interaction, while allowing the protein to recognise a diverse set of targets and mediate a range of mechanisms for translational regulation. The structural and molecular understanding of the interactions can be used together with novel microscopy and transcriptome‐wide data to build a mechanistic framework for the regulation of local mRNA translation.
This double-blind, 15-month pilot study was designed to investigate the effect of soy protein isolate with varying concentrations of isoflavones on early postmenopausal bone loss and lipids.
A total ...of 65 women, with a mean age of 55 years and 7.5 years since menopause, were randomized to one of three groups; soy protein with 96 mg isoflavones/day, soy with 52 mg isoflavones/day, or soy without isoflavones (< 4 mg isoflavones/day). Soy was given for 9 months and then discontinued; participants were followed for an additional 6 months. Bone mineral density (BMD) and blood lipids were measured during this time.
Measurement of serum isoflavones at 3 months showed dose-related increases in the three groups. There was no significant effect of the soy supplements on BMD of the spine or femoral neck in any of the three groups. BMD increased significantly in the trochanter at 9 months (P = 0.0219) and at 15 months (P < 0.05) in the group given isoflavone-free soy compared with the other two groups. There was no significant effect of soy on lipid metabolism at the end of the intervention.
The present study did not find a significant positive effect of soy protein isolate supplemented with isoflavones on BMD and the serum lipid profile in early postmenopausal women.
Context:
The discovery of hypercalcemic diseases due to loss-of-function mutations in 25-hydroxyvitamin D-24-hydroxylase has placed a new demand for sensitive and precise assays for ...24,25-dihydroxyvitamin D 24,25-(OH)2D.
Objective:
We describe a novel liquid chromatography and tandem mass spectrometry-based method involving derivatization with DMEQ-TAD {4-2-(6,7-dimethoxy-4-methyl-3,4-dihydroquinoxalinyl)ethyl-1,2,4-triazoline-3,5-dione} to simultaneously assay multiple vitamin D metabolites including 25-hydroxyvitamin D (25-OH-D) and 24,25-(OH)2D using 100 μL of serum with a 5-minute run time.
Design:
The assay uses a newly synthesized internal standard d6-24,25-(OH)2D3 enabling the quantitation of 24,25-(OH)2D3 as well as the determination of the ratio of 25-OH-D3 to 24,25-(OH)2D3, a physiologically useful parameter.
Setting:
We report data on more than 1000 normal and disease samples involving vitamin D deficiency or hypercalcemia in addition to studies involving knockout mouse models.
Results:
The assay showed good correlation with samples from quality assurance schemes for 25-OH-D (25-OH-D2 and 25-OH-D3) determination (−2% to −5% bias) and exhibited low inter- and intraassay coefficients of variation (4%–7%) and lower limits of quantitation of 0.25–0.45 nmol/L. In clinical studies, we found a strong correlation between serum levels of 25-OH-D3 and 24,25-(OH)2D3 (r2 = 0.80) in subjects over a broad range of 25-OH-D3 values and a marked lack of production of 24,25-(OH)2D3 below 25 nmol/L of 25-OH-D. The ratio of 25-OH-D3 to 24,25-(OH)2D3, which remained less than 25 in vitamin D-sufficient subjects (serum 25-OH-D < 50 nmol/L) but was greatly elevated (80–100) in patients with idiopathic infantile hypercalcemia.
Conclusions:
The new method showed good utility in clinical settings involving vitamin D deficiency; supplementation with vitamin D and idiopathic infantile hypercalcemia, as well as in animal models with ablation of selected cytochrome P450-containing enzymes involved in vitamin D metabolism.
Stringent enrollment criteria can limit the diversity of patient populations in clinical trials and, consequently, the generalizability of clinical trial data to real-world clinical practice. In this ...podcast, we discuss how real-world data in heterogeneous patient populations can complement clinical trial data in informing treatment decision making for patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) metastatic breast cancer. Specifically, our focus is on P-REALITY X, an observational retrospective analysis that was recently published in
npj Breast Cancer.
P-REALITY X used real-world data from the Flatiron database to compare the effectiveness of palbociclib plus an aromatase inhibitor versus an aromatase inhibitor alone as first-line treatment for patients with HR+/HER2− metastatic breast cancer. After stabilized inverse probability treatment weighting to control for observed confounders, both overall survival and real-world progression-free survival were significantly prolonged with palbociclib plus an aromatase inhibitor versus an aromatase inhibitor alone. Furthermore, overall survival and real-world progression-free survival benefits were observed across most subgroups examined. We discuss the clinical implications of P-REALITY X data, including how these results add to data from prior randomized clinical trials and real-world studies in supporting the use of first-line palbociclib plus an aromatase inhibitor as a standard-of-care treatment for patients with HR+/HER2− metastatic breast cancer. We also provide an example of how to integrate and describe key information about the P-REALITY X study in plain language when discussing palbociclib as a therapeutic option with patients.
The aim of this study was to examine the effect of hormone therapy and calcitriol on depression in older postmenopausal women and to determine whether the response was associated with polymorphisms ...of estrogen receptor α and vitamin D receptor.
In a double-blind placebo-controlled prospective trial involving 489 postmenopausal older women, a secondary analysis of depression was done. The Geriatric Depression Scale was used to screen for depression. We used binary logistic regression to examine the effect of treatment on depression and one-way analysis of variance to find a relationship between gene polymorphisms and depression.
There was no effect of hormone therapy (odds ratio OR, 1.65; 95% CI, 0.66-4.12; P = 0.277), calcitriol (OR, 1.15; 95% CI, 0.43-3.11; P = 0.772), or hormone therapy with calcitriol (OR, 1.01; 95% CI, 0.36-2.80; P = 0.979) on depression. Neither the polymorphisms of estrogen receptor α (XbaI-β = 0.093; CI, -0.337 to 1.350; P = 0.239 and PvuII-β = -0.064; CI, -1.171 to 0.491, P = 0.421) nor those of vitamin D receptor (BsmI-β = 0.044, CI -2.546 to 3.030, P = 0.865 and TaqI-β = -0.015, CI -2.900 to 2.738, P = 0.955) were associated with depression.
In older postmenopausal women, there was no effect of hormone therapy and calcitriol either individually or in combination with depression. Estrogen receptor α and vitamin D receptor polymorphisms are not associated with depression or the response to intervention in older postmenopausal women. Additional trials are required to confirm these findings.
This study aims to prospectively assess the incidence of hypercalciuria and hypercalcemia with different doses of vitamin D and with a calcium intake of approximately 1,200 mg/day.
This was a 1-year ...randomized placebo-controlled study of vitamin D (400-4,800 IU/d) in 163 white women aged 57 to 90 years. Calcium citrate tablets (200 mg) were added to the diet to achieve a total calcium intake of approximately 1,200 mg/day in all groups. All women had vitamin D insufficiency at baseline, with serum 25-hydroxyvitaminD levels lower than 20 ng/mL (50 nmol/L). Serum and 24-hour urine calcium were collected every 3 months on supplementation, any test result above the upper reference range represented an episode of hypercalcemia or hypercalciuria. Mixed-effects models and multivariate logistic regression were used in the analysis.
Hypercalcemia (>10.2 mg/dL 2.55 mmol/L) occurred in 8.8% of white women. Hypercalciuria (>300 mg/d 7.5 mmol) occurred in 30.6% of white women. Episodes of hypercalciuria were transient in half of the group and recurrent in the other half. No relationship between hypercalcemia or hypercalciuria and vitamin D dose was found, and hypercalciuria was equally common in the placebo group.
Hypercalciuria and hypercalcemia commonly occur with vitamin D and calcium supplements. Whether hypercalciuria and hypercalcemia are caused by calcium, vitamin D, or both is unclear. These findings may have relevance to the reported increase in kidney stones in the Women's Health Initiative trial. Because calcium 1,200 mg and vitamin D 800 IU/day are widely recommended in postmenopausal women, systematic evaluation of the safety of supplements is warranted in clinical management and in future studies.
: To update for both clinicians and the lay public the evidence-based position statement published by The North American Menopause Society (NAMS) in March 2007 regarding its recommendations for ...menopausal hormone therapy (HT) for postmenopausal women, with consideration for the therapeutic benefit-risk ratio at various times through menopause and beyond.
: An Advisory Panel of clinicians and researchers expert in the field of women's health was enlisted to review the March 2007 NAMS position statement, evaluate new evidence through an evidence-based analysis, and reach consensus on recommendations. The Panel's recommendations were reviewed and approved by the NAMS Board of Trustees as an official NAMS position statement. The document was provided to other interested organizations to seek their endorsement.
: Current evidence supports a consensus regarding the role of HT in postmenopausal women, when potential therapeutic benefits and risks around the time of menopause are considered. This paper lists all these areas along with explanatory comments. Conclusions that vary from the 2007 position statement are highlighted. Addenda include a discussion of risk concepts, a new component not included in the 2007 paper, and a recommended list of areas for future HT research. A suggested reading list of key references is also provided.
: Recent data support the initiation of HT around the time of menopause to treat menopause-related symptoms; to treat or reduce the risk of certain disorders, such as osteoporosis or fractures in select postmenopausal women; or both. The benefit-risk ratio for menopausal HT is favorable close to menopause but decreases with aging and with time since menopause in previously untreated women.
Background: The role of dietary protein in bone metabolism is controversial. Objective: We investigated the associations of dietary protein intake with baseline bone mineral density (BMD) and the ...rate of bone loss over 3 y in postmenopausal elderly women. Design: Women aged 65-77 y (n = 489) were enrolled in an osteoporosis intervention trial. We studied the associations of protein intake as a percentage of energy with baseline BMD and the rate of bone loss in 96 women in the placebo group (n = 96). We also examined the effect of the interaction of dietary calcium intake with protein intake on BMD. Results: In the cross-sectional study, a higher intake of protein was associated with higher BMD. BMD was significantly higher (P < 0.05) in the spine (7%), midradius (6%), and total body (5%) in subjects in the highest quartile of protein intake than in those in the lower 2 quartiles. This positive association was seen in women with calcium intakes > 408 mg/d. There was no significant effect of protein intake on hip BMD. In the longitudinal study of the placebo group, there was no association between protein intake and the rate of bone loss. Conclusions: The highest quartile of protein intake (x̄: 72 g/d) was associated with higher BMD in elderly women at baseline only when the calcium intake exceeded 408 mg/d. In the longitudinal study, no association was seen between protein intake and the rate of bone loss, perhaps because the sample size was too small or the follow-up period of 3 y was not long enough to detect changes.
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