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OBJECTIVE Describe the secretion and profile of adrenal steroids in patients with adrenal incidentalomas compared to control subjects. DESIGN, SETTING AND PARTICIPANTS A prospective study, 73 patients with adrenal incidentalomas, 21 bilateral and 52 unilateral and 34 matched controls in University Hospital. METHODS Collect fasting blood sample before and 60 min after ACTH test (250 µg IV). One week later, perform overnight 1 mg dexamethasone test. The following steroids were measured by liquid chromatography-mass spectrometry (LC-MS): pregnenolone, 17-OH pregnenolone, 17-OH progesterone, 11-deoxycorticosterone, 11-deoxyortisol, 21-deoxycortisol, corticosterone, cortisol, androstenedione and aldosterone. RESULTS Mean baseline serum cortisol was higher in incidentalomas, bilateral 361 ± 124, (range 143-665) nmol/L,(p

Context and purpose There is an urgent need to develop vitamin D dietary recommendations for dark-skinned populations resident at high latitude. Using data from randomised controlled trials (RCTs) with vitamin D3-supplements/fortified foods, we undertook an individual participant data-level meta-regression (IPD) analysis of the response of wintertime serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among dark-skinned children and adults residing at ≥ 40° N and derived dietary requirement values for vitamin D. Methods IPD analysis using data from 677 dark-skinned participants (of Black or South Asian descent; ages 5-86 years) in 10 RCTs with vitamin D supplements/fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D intake estimates across a range of 25(OH)D thresholds. Results To maintain serum 25(OH)D concentrations ≥ 25 and 30 nmol/L in 97.5% of individuals, 23.9 and 27.3 µg/day of vitamin D, respectively, were required among South Asian and 24.1 and 33.2 µg/day, respectively, among Black participants. Overall, our age-stratified intake estimates did not exceed age-specific Tolerable Upper Intake Levels for vitamin D. The vitamin D intake required by dark-skinned individuals to maintain 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L was 66.8 µg/day. This intake predicted that the upper 2.5% of individuals could potentially achieve serum 25(OH)D concentrations ≥ 158 nmol/L, which has been linked to potential adverse effects in older adults in supplementation studies. Conclusions Our IPD-derived vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25, 30 and 50 nmol/L are substantially higher than the equivalent estimates for White individuals. These requirement estimates are also higher than those currently recommended internationally by several agencies, which are based predominantly on data from Whites and derived from standard meta-regression based on aggregate data. Much more work is needed in dark-skinned populations both in the dose-response relationship and risk characterisation for health outcomes. Trail registration PROSPERO International Prospective Register of Systematic Reviews (Registration Number: CRD42018097260).

Vitamin D insufficiency and deficiency can be diagnosed with measurements of serum 25-hydroxyvitamin D (25OHD). Most vitamin D is derived from sunlight (80%), so serum 25OHD levels are lowest in late winter and early spring. Dietary vitamin D in North America is small, about 100 to 200 IU daily. A recent review of the literature shows many association studies relating vitamin D deficiency and insufficiency to several diseases. Large randomized trials of vitamin D are underway and soon there may be answers as to whether vitamin D is clinically effective and what level of serum 25OHD is necessary.

CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid-chromatography tandem mass spectrometry (LC-MS/MS)-based blood test enabling measurement of the 25-OH-D3 :24,25-(OH)2 D3 ratio (R) can identify IIH patients on the basis of reduced C24-hydroxylation of 25-OH-D3 by CYP24A1 in vivo. Although values of this ratio are significantly elevated in IIH, somewhat surprisingly, serum 24,25-(OH)2 D3 remains detectable. The current study explores possible explanations for this including: residual CYP24A1 enzyme activity in individuals with certain CYP24A1 genotypes, expression of alternative C24-hydroxylases, and the possibility of isobaric contamination of the 24,25-(OH)2 D3 peak on LC-MS/MS. We employed an extended 20-min run time on LC-MS/MS to study serum vitamin D metabolites in patients with IIH due to mutations of CYP24A1 or SLC34A1; in unaffected heterozygotes and dialysis patients; in patients with vitamin D deficiency; as well as in normal subjects exhibiting a broad range of 25-OH-D levels. We identified 25,26-(OH)2 D3 as a contaminant of the 24,25-(OH)2 D3 peak. In normals, the concentration of 24,25-(OH)2 D3 greatly exceeds 25,26-(OH)2 D3 ; however, 25,26-(OH)2 D3 becomes more significant in IIH with CYP24A1 mutations and in dialysis patients, where 24,25-(OH)2 D3 levels are low when CYP24A1 function is compromised. Mean R in 30 IIH-CYP24A1 patients was 700 (range, 166 to 2168; cutoff = 140) as compared with 31 in 163 controls. Furthermore, patients possessing CYP24A1 L409S alleles exhibited higher 24,25-(OH)2 D3 levels and lower R (mean R = 268; n = 8) than patients with other mutations. We conclude that a chromatographic approach which resolves 24,25-(OH)2 D3 from 25,26-(OH)2 D3 produces a more accurate R that can be used to differentiate pathological states where CYP24A1 activity is altered. The origin of the residual serum 24,25-(OH)2 D3 in IIH patients appears to be multifactorial. © 2017 American Society for Bone and Mineral Research.

Conjugated estrogens/bazedoxifene reduces vasomotor symptoms and prevents postmenopausal bone loss without stimulating the breast and endometrium. We analyzed changes in bone mineral density (BMD) and bone markers using pooled data from two phase-3 trials.Selective Estrogens, Menopause, and Response to Therapy (SMART)-1 and SMART-5 were randomized, double-blind, placebo- and active-controlled studies conducted in postmenopausal nonhysterectomized women. BMD and turnover marker data were pooled for women given conjugated estrogens (0.45 or 0.625 mg) plus bazedoxifene 20 mg or placebo over 12 months. Sensitivity analyses were conducted using baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, race, and geographic region.There were 1,172 women, mean age 54.9 years, mean 6.21 years since menopause, mean lumbar spine, and total hip T scores -1.05 and -0.58; 58.8% had a Fracture Risk Assessment Tool score less than 5% indicating low fracture risk. At 12 months, adjusted differences (vs placebo) in BMD change in the groups taking conjugated estrogens 0.45 or 0.625 mg plus bazedoxifene 20 mg were 2.3% and 2.4% for lumbar spine, 1.4% and 1.5% for total hip, and 1.1% and 1.5% for femoral neck (all P 0.001 vs placebo). These increases were unrelated to baseline Fracture Risk Assessment Tool score, age, years since menopause, body mass index, or geographic region. Both doses reduced bone turnover markers (P 0.001).Conjugated estrogens/bazedoxifene significantly improved BMD and turnover in a large population of younger postmenopausal women at low fracture risk and is a promising therapy for preventing postmenopausal bone loss.

Falls are a major health problem in elderly individuals. Although intensive physical therapy and management of hazards in the home can reduce falls by 25%, long-term practicality limits their use. Interest in vitamin D as a medical therapy has led to many trials; however, results using daily oral doses of vitamin D have been inconsistent. In the past 5 years, studies on the effect of bolus doses of vitamin D have produced surprising results. Bolus doses of vitamin D, given annually (at a dose of 300,000 IU or 500,000 IU) or monthly (at a dose of 24,000 IU or 60,000 IU) - equivalent to approximate daily doses of 800 IU, 1400 IU and 2,000 IU - result in a significant increase in the number of falls and fractures associated with serum levels of 25-hydroxyvitamin D greater than 40-45 ng/ml (equivalent to 100-112 nmol/l). These unexpected results show increased falls and fractures are adverse events related to vitamin D administration. Until further safety data is available, bolus dosing or daily doses should not exceed 3,000 IU and serum levels of 25-hydroxyvitamin D should not exceed 40-45 ng/ml (equivalent to 100-112 nmol/l) in elderly individuals.

ContextThe optimal measure of vitamin D status is unknown.ObjectiveTo directly measure circulating free 25-hydroxyvitamin D[25(OH)D] concentrations and relationships to total 25(OH)D in a clinically diverse sample of humans.DesignCross-sectional analysis.SettingSeven academic sites.PatientsA total of 1661 adults: healthy (n = 279), prediabetic (n = 479), outpatients (n = 714), cirrhotic (n = 90), pregnant (n = 20), nursing home resident (n = 79).InterventionsMerge research data on circulating free 25(OH)D (directly-measured immunoassay), total 25(OH)D (liquid chromatography/tandem mass spectrometry), D-binding protein [DBP; by radial (polyclonal) immunodiffusion assay], albumin, creatinine, intact parathyroid hormone, and DBP haplotype.Main outcome measuresDistribution of free 25(OH)D (ANOVA with Bonferroni correction for post hoc comparisons) and relationships between free and total 25(OH)D (mixed-effects modeling incorporating clinical condition, DBP haplotype with sex, race, estimated glomerular filtration rate (eGFR), body mass index (BMI), and other covariates).ResultsFree 25(OH)D was 4.7 ± 1.8 pg/mL (mean ± SD) in healthy persons and 4.3 ± 1.9 pg/mL in outpatients, with levels of 0.5 to 8.1 pg/mL and 0.9 to 8.1 pg/mL encompassing 95% of healthy persons and outpatients, respectively. Free 25(OH)D was higher in patients with cirrhosis (7.1 ± 3.0 pg/mL; P < 0.0033) and nursing home residents (7.9 ± 2.1 pg/mL; P < 0.0033) than in other groups and differed between whites and blacks (P < 0.0033) and between DBP haplotypes (P < 0.0001). Mixed-effects modeling of relationships between free and total 25(OH)D identified clinical conditions (patients with cirrhosis > nursing home residents > patients with prediabetes > outpatients > pregnant women) and BMI (lesser effect) as covariates affecting relationships but not eGFR, sex, race, or DBP haplotype.ConclusionsTotal 25(OH)D, health condition, race, and DBP haplotype affected free 25(OH)D, but only health conditions and BMI affected relationships between total and free 25(OH)D. Clinical importance of free 25(OH)D needs to be established in studies assessing outcomes.

Osteoporosis is a skeletal disease associated with an imbalance between formation and resorption, leading to net loss of bone mass, loss of bone microarchitecture, and development of fractures. Bone resorption is primarily due to an activation of osteoclastogenesis and an increase in receptor activator of nuclear factor kappa-B ligand (RANKL) expression, a cytokine involved in the final pathway of the osteoclast cycle.Recent studies of genetic diseases led to the discovery of the wingless-type (Wnt) signaling pathway that plays a major role in bone formation. Further work showed that sclerostin produced by osteocytes and the Dickkopf (DKK1) protein secreted in bone were negative regulators of the Wnt signaling bone formation pathway that act directly by binding to the co-receptors LRP5 and LRP6 of WnT and thereby inhibiting the anabolic Wnt pathway. This understanding of the bone remodeling led to the discovery of new biological drugs that target these pathways and have been evaluated in clinical trials.The current article discusses the role of these newer "biological" agents in management of osteoporosis. Denosumab, a human monoclonal antibody that specifically binds RANKL, blocks the binding of RANK to its ligand markedly reducing bone resorption, increases bone density, and reduces fractures and is approved for osteoporosis. Parathyroid hormone PTH 1-34 (teriparatide) stimulates bone formation through inhibition of sclerostin, DKK1, and frizzled protein; increases BMD; improves microarchitecture; and decreases fractures and is approved for osteoporosis. The anti-sclerostin antibodies (romosozumab, blosozumab) increase bone mass by neutralizing the negative effects of sclerostin on the Wnt signaling pathway. These biologics are being evaluated now in a clinical trial and early data looks promising. Cathepsin K is a proteolytic enzyme that degrades bone matrix and inhibitors such as odanacatib show increasing bone density and perhaps decreased fractures. The potential power of combining these newer antiresorptives with the newer anabolic agents could theoretically increase bone mass rapidly to normal within 1 year and reduce fractures. These newer treatments are revolutionizing the management of osteoporosis.

In the beginning, that is from the 1960's, when a link between menopause and osteoporosis was first identified; estrogen treatment was the standard for preventing bone loss, however there was no fracture data, even though it was thought to be effective. This continued until the Women's Health Initiative (WHI) study in 2001 that published data on 6 years of treatment with hormone therapy that showed an increase in heart attacks and breast cancer. Even though the risks were small, 1 per 1500 users annually, patients were worried and there was a large drop off in estrogen use. In later analyses the WHI study showed that estrogen reduced fractures and actually prevented heart attacks in the 50-60 year age group. Estrogen alone appeared to be safer to use than estrogen+the progestin medroxyprogesterone acetate and actually reduced breast cancer. At the same time other drugs were being developed for bone that belong to the bisphosphonate group and the first generation of compounds showed moderate potency on bone resorption. The second and third generation compounds were much more potent and in a series of large trials were shown to reduce fractures. For the last 15 years the treatment of osteoporosis belonged to the bisphosphonate compounds, most of which reduce fracture rates by 50 percent. With the exception of gastrointestinal irritation the drugs are well tolerated and highly effective. The sophistication of the delivery systems now allow treatment that can be given daily, weekly, monthly and annually either orally or intravenously. Bone remodeling is a dynamic process that repairs microfractures and replaces old bone with new bone. In the last 10 years there has been a remarkable understanding of bone biology so that new therapies can be specifically designed on a biological basis. The realization that RANKL was the final cytokine involved in the resorption process and that marrow cells produced a natural antagonist called Osteoprotegerin (OPG) quickly led to two lines of therapy. First OPG was used as a therapy to block RANKL was initially successful but later antibodies against OPG developed and this line of treatment had to be discontinued. The next step was to develop a monoclonal antibody against RANKL and this proved to be highly effective in blocking bone resorption. It led to development of a drug Denosumab that successfully reduces fractures and is now one of the therapeutic options for osteoporosis treatment. On the anabolic side bone biology research showed that osteocytes produces sclerostin an inhibitor of the anabolic WNT signaling pathway. Recent development of a monoclonal antibody against sclerostin has shown remarkable anabolic activity in bone showing large increases in bone density and fracture trials are now underway. The newer treatments for osteoporosis are likely to be based on our understanding of bone biology and the design of new highly specific compounds with fewer side effects. This review summarizes the diagnosis of postmenopausal osteoporosis and various available non-pharmacological and pharmacological therapies available for its management. This article is part of a Special Issue entitled 'Menopause'.

It is commonly said that vitamin D should be used to increase calcium absorption. We tested this statement in a dose-response study of vitamin D on calcium absorption. A total of 198 white and African American women, aged 25 to 45 years, with vitamin D insufficiency, serum 25-hydroxyvitamin D (25OHD)

There is limited information on the effects of vitamin D on serum 25 hydroxyvitamin D (25OHD) in young people and none on African Americans. The main objective of this trial was to measure the effect of different doses of vitamin D3 on serum 25OHD and serum parathyroid hormone (PTH) in young women with vitamin D insufficiency (serum 25OHD ≤ 20 ng/mL (50 nmol/L). A randomized double-blind placebo-controlled trial of vitamin D3 was conducted in young white and African American women, age 25 to 45 years. A total of 198 healthy white (60%) and African American (40%) women were randomly assigned to placebo, or to 400, 800, 1600, or 2400 IU of vitamin D3 daily. Calcium supplements were added to maintain a total calcium intake of 1000 to 1200 mg daily. The primary outcomes of the study were the final serum 25OHD and PTH levels at 12 months. The absolute increase in serum 25OHD with 400, 800, 1600, and 2400 IU of vitamin D daily was slightly greater in African American women than in white women. On the highest dose of 2400 IU/d, the mixed model predicted that mean 25OHD increased from baseline 12.4 ng/mL (95% confidence interval [CI], 9.2–15.7) to 43.2 ng/mL (95% CI, 38.2–48.1) in African American women and from 15.0 ng/mL (95% CI, 12.3–17.6) to 39.1 ng/mL (95% CI, 36.2–42.0) in white women. There was no significant effect of vitamin D dose on serum PTH in either race but there was a significant inverse relationship between final serum PTH and serum 25OHD. Serum 25OHD exceeded 20 ng/mL in 97.5% of whites on the 400 IU/d dose and between 800 and 1600 IU/d for African Americans. The recommended dietary allowance (RDA) suggested by the Institute of Medicine for young people is 600 IU daily. The increase in serum 25OHD after vitamin D supplementation was similar in young and old, and in white and African American women. © 2014 American Society for Bone and Mineral Research.

Women who have significant bone loss or a new fracture on monotherapy are considered for combination therapy. Combination therapies increase bone density more than monotherapy by targeting different parts of the osteoclast pathway.In early postmenopausal women who are symptomatic, the use of combination antiresorptives should include hormone therapy with a bisphosphonate or with bazodoxifene. In women who initially receive a weaker antiresorptive such as the SERM raloxifene, a combination with bisphosphonates and calcium supplementation is necessary to prevent bone loss. In older women over 65 years of age who often have impaired calcium absorption, the combination of calcitriol with bisphosphonates has been shown to increase bone density more than monotherapy.

Obese people are known to have lower serum 25OHD levels compared to non-obese people. It is not known whether it is due to storage of vitamin D in fat, inadequate input from sunlight, diet or other unknown factors. We examined the relationship at study baseline of serum 25OHD, PTH, 1,25(OH)2D with body composition measurements using dual energy X-ray absorptiometry. The results showed a significant inverse relation between total body fat mass and serum 25OHD (p0.0001) and serum 1,25(OH2)D (p=034) and an independent positive correlation between serum PTH and total body fat mass (p0.0001). In a randomized controlled study of seven doses of vitamin D (400-4800IU/d) the increase in serum 25OHD levels was compared in women with a normal body mass index to obese women. The response to the low doses of vitamin D (400-800IU/d) was significantly less than that of the medium (1600-2400IU/d) and high doses groups (3200-4800IU) (p0.0001) in all BMI categories. The increase in serum 25OHD in the medium and high dose groups was not significantly different with increasing level of obesity. But thinner women with a normal BMI (25kg/m(2)) showed a much higher response to vitamin D at any dose level compared to other BMI groups. There was no significant change in total body fat mass after treatment with vitamin D or calcitriol in our randomized trials. In summary, the response to vitamin D is dependent on body weight. Women with BMI25kg/m(2) develop much higher levels of serum 25OHD after vitamin D supplementation compared to those with BMI of25kg/m(2). The differences in serum 25OHD levels between normal and obese women may be due to differences in volume dilution. After vitamin D supplementation, all obese women reach adequate levels of serum 25OHD but normal women (BMI25kg/m(2)) reach much higher levels of 25OHD and in this group smaller doses of vitamin D used should be used. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Aging affects the formation of 1,25-dihydroxyvitamin D (1,25[OH]2D; calcitriol), the active form of vitamin D. Production of 1,25(OH)2D is reduced by 50% as a result of an age-related decline in renal function, although serum 1,25(OH)2D levels are maintained in part by secondary hyperparathyroidism. Aging also causes a decrease in calcium absorption that precedes the decrease in 1,25(OH)2D by 10 to 15 years. Because 1,25(OH)2D is dependent on an adequate supply of the substrate vitamin D, the development of vitamin D deficiency leads to further reduction in the formation of 1,25(OH)2D. Measurement of the metabolite 25OHD provides the most widely used assessment of vitamin D deficiency. A serum 25OHD level lower than 10 ng/mL (25 nmol/L) represents vitamin D deficiency and leads to a reduction in serum 1,25(OH)2D. Vitamin D deficiency, is uncommon in North America, probably because of supplementation of dairy products and other foods with vitamin D. Sunlight exposure increases serum 25OHD levels by about 10 ng/mL during the months of April through September, resulting in low serum 25OHD for about 3 to 4 months in winter, with 2 additional months of low levels in more northern latitudes, such as Canada, and 2 fewer months in the southern states. Vitamin D supplementation in the winter can prevent vitamin D deficiency. Vitamin D insufficiency has been defined by the Institute of Medicine as a serum 25OHD level lower than 20 ng/mL (and >10 ng/mL). A serum 25OHD level lower than 20 ng/mL is associated with an increased fracture rate and increased rate of bone loss and treatment. Although other diseases have been associated with low serum 25OHD levels, the evidence for a causative role has not yet been established. Treatment of elderly people with vitamin D 800 IU daily will increase serum 25OHD levels to higher than 20 ng/mL and reduce fractures; this is particularly important in institutionalized people.

Serum 25-hydroxyvitamin D (25OHD) is lower in women with darker skin color. Is it due to lower skin production, lower absorption, or different metabolism of vitamin D?The objective of the study was to measure the effect of vitamin D3 on serum 25OHD and serum PTH in older African American women with vitamin D insufficiency and the serum 25OHD 20 ng/mL or less (50 nmol/L). The results can be used to estimate the Recommended Dietary Allowance (RDA).This was a randomized, double-blind placebo trial at Creighton University Medical Center and Indiana University Medical Center.Participants were 110 healthy older African American women.The intervention consisted of participants randomly assigned to placebo, vitamin D3 400, 800, 1600, 2400, 3200, 4000, or 4800 IU daily; calcium supplements were given to maintain total calcium intake of 1200-1400 mg/d.Change in serum 25OHD and serum PTH levels at 12 months was measured.Mean baseline serum 25OHD was 13 ng/mL (33 nmol/L). On 4800 IU, serum 25OHD averaged 50 ng/mL (125 nmol/L) compared with 47 ng/mL (117 nmol/L) in Caucasian women. Serum PTH at 12 months decreased significantly (P = .008) when related to serum 25OHD but not dose. Hypercalcemia occurred in 7% and hypercalciuria in 15%. Events were unrelated to vitamin D dose.Vitamin D3 800 IU increased serum 25OHD greater than 20 ng/mL (50 nmol/L) in 97.5% of the African American women just as it did in the Caucasian women, and therefore, the RDA is the same for both groups. Because absorption and metabolism of oral vitamin D absorption is similar in both groups, lower levels of serum 25OHD in African Americans must be due to lower production of vitamin D in skin.

CYP24A1 mutations are now accepted as a cause of idiopathic infantile hypercalcemia (IIH). A rapid liquid-chromatography tandem mass spectrometry (LC-MS/MS)-based blood test enabling measurement of the 25-OH-D

Falls are a serious health problem in the aging population. Because low levels of vitamin D have been associated with increased fall rates, many trials have been performed with vitamin D; two meta-analyses showed either a small effect or no effect of vitamin D on falls. We conducted a study of the effect of vitamin D on serum 25 hydroxyvitamin D (25OHD) and data on falls was collected as a secondary outcome. In a 12-month double blind randomized placebo trial, elderly women, mean age 66 years, were randomized to one of seven daily oral doses of vitamin D or placebo. The main inclusion criterion for study was a baseline serum 25OHD< 20ng/ml(50nmol/L). A history of falls was collected at baseline and fall events were collected every 3 months. Results showed that the effect of vitamin D on falls followed a U-shaped curve whether analyzed by dose or serum 25OHD levels. There was no decrease in falls on low vitamin D doses 400, 800 IU, a significant decrease on medium doses 1600, 2400,3200 IU (p=0.020) and no decrease on high doses 4000, 4800 IU compared to placebo(p=0.55). When compared to 12-month serum 25OHD quintiles, the faller rate was 60% in the lowest quintile < 25ng/ml(

Randomized control trials (RCT) of the effect of vitamin D/calcium supplementation on skeletal muscle strength have not shown promising effect in the elderly.Our objective was to assess the effect of vitamin D and/or calcium on muscle strength in young adults with vitamin D deficiency.We conducted a RCT using a factorial design at a tertiary-care center from September 2010 to April 2011.A total of 173 healthy females with mean age, body mass index, and 25-hydroxyvitamin D [25(OH)D] of 21.7 ± 4.4 yr, 20.8 ± 2.96 kg/m(2), and 9.3 ± 3.37 ng/ml, respectively, were block randomized to 1) double placebo, 2) calcium/placebo, 3) cholecalciferol/placebo, and 4) cholecalciferol/calcium for 6 months. Cholecalciferol was given at 60,000 IU/wk for 8 wk followed by 60,000 IU/fortnight. Elemental calcium was given in doses of 500 mg twice per day for 6 months.Assessment included hand grip (primary outcome) and pinch grip strength, distance walked in 6 min, dyspnea score, quality of life by Short Form (36) Health Survey (SP-36), serum 25(OH)D, 1,25-dihydroxyvitamin D, and intact PTH.The serum 25(OH)D increased significantly to 29.9 ± 8.35 and 27.0 ± 9.54 ng/ml in two groups on cholecalciferol. The mean hand grip strength (19.4 ± 3.92, 21.1 ± 3.31, 20.6 ± 3.92, and 20.1 ± 4.00 kg) and its increase from baseline (0.3 ± 2.25, 0.3 ± 2.64, -0.3 ± 2.41, and 0.6 ± 2.30 kg) were comparable in four groups at 6 months. Quality of life, urinary calcium/creatinine ratio, and adverse effects were also comparable in groups.Oral cholecalciferol/calcium supplementation in the dose/schedule used is effective and safe in increasing and maintaining serum 25(OH)D. However, this does not lead to improved skeletal muscle strength in young females.

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.

In early 2011, a committee convened by the Institute of Medicine issued a report on the Dietary Reference Intakes for calcium and vitamin D. The Endocrine Society Task Force in July 2011 published a guideline for the evaluation, treatment, and prevention of vitamin D deficiency. Although these reports are intended for different purposes, the disagreements concerning the nature of the available data and the resulting conclusions have caused confusion for clinicians, researchers, and the public. In this commentary, members of the Institute of Medicine committee respond to aspects of The Endocrine Society guideline that are not well supported and in need of reconsideration. These concerns focus on target serum 25-hydroxyvitamin D levels, the definition of vitamin D deficiency, and the question of who constitutes a population at risk vs. the general population.

The Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D comprehensively reviewed the evidence for both skeletal and nonskeletal health outcomes and concluded that a causal role of calcium and vitamin D in skeletal health provided the necessary basis for the 2011 Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for ages older than 1 year. For nonskeletal outcomes, including cancer, cardiovascular disease, diabetes, infections, and autoimmune disorders, randomized clinical trials were sparse, and evidence was inconsistent, inconclusive as to causality, and insufficient for Dietary Reference Intake (DRI) development. The EAR and RDA for calcium range from 500 to 1,100 and 700 to 1,300 mg daily, respectively, for ages 1 year and older. For vitamin D (assuming minimal sun exposure), the EAR is 400 IU/day for ages older than 1 year and the RDA is 600 IU/day for ages 1 to 70 years and 800 IU/day for 71 years and older, corresponding to serum 25-hydroxyvitamin D (25OHD) levels of 16 ng/mL (40 nmol/L) for EARs and 20 ng/mL (50 nmol/L) or more for RDAs. Prevalence of vitamin D inadequacy in North America has been overestimated based on serum 25OHD levels corresponding to the EAR and RDA. Higher serum 25OHD levels were not consistently associated with greater benefit, and for some outcomes U-shaped associations with risks at both low and high levels were observed. The Tolerable Upper Intake Level for calcium ranges from 1,000 to 3,000 mg daily, based on calcium excretion or kidney stone formation, and from 1,000 to 4,000 IU daily for vitamin D, based on hypercalcemia adjusted for uncertainty resulting from emerging risk relationships. Urgently needed are evidence-based guidelines to interpret serum 25OHD levels relative to vitamin D status and intervention.

Context Denosumab treatment for 24 months increased bone mineral density (BMD) and reduced bone turnover markers (BTM) in postmenopausal women. Objective The aim was to determine the effects of prior denosumab or placebo injections on BMD, BTM, and safety over 24 months after treatment discontinuation. Design We conducted an off-treatment extension of a phase 3, randomized, double-blind, parallel-group study. Participants A total of 256 postmenopausal women with a mean age of 59 yr and a mean lumbar spine T-score of -1.61 at randomization participated in the study. Interventions Participants received placebo or 60 mg denosumab every 6 months for 24 months, followed by 24 months off treatment. Main outcome measures We measured the percentage changes in BMD and BTM, and evaluated safety. Results Of the 256 participants enrolled in the posttreatment phase, 87% completed the study. During 24 months of denosumab treatment, BMD increased (lumbar spine, 6.4%; total hip, 3.6%; 1/3 radius, 1.4%), and BTM decreased (serum C-terminal telopeptide of type 1 collagen, 63%; and N-terminal propeptide of type 1 procollagen, 47%), compared with placebo. After discontinuation, BMD declined, but the previously treated denosumab group maintained higher BMD than the previously treated placebo group at these sites (P ≤ 0.05). Final BMD at month 48 strongly correlated with month 0 BMD. After denosumab discontinuation, BTM increased above baseline within 3 months (serum C-terminal telopeptide of type 1 collagen) or 6 months (N-terminal propeptide of type 1 procollagen) and returned to baseline by month 48. Adverse event rates during the off-treatment phase were similar between groups. Conclusions In postmenopausal women with low BMD, the effects of 60 mg denosumab treatment for 24 months on BMD and BTM are reversible upon discontinuation, reflecting its biological mechanism of action. Residual BMD measurements remained above those of the group previously treated with placebo.

This article summarizes the new 2011 report on dietary requirements for calcium and vitamin D from the Institute of Medicine (IOM). An IOM Committee charged with determining the population needs for these nutrients in North America conducted a comprehensive review of the evidence for both skeletal and extraskeletal outcomes. The Committee concluded that available scientific evidence supports a key role of calcium and vitamin D in skeletal health, consistent with a cause-and-effect relationship and providing a sound basis for determination of intake requirements. For extraskeletal outcomes, including cancer, cardiovascular disease, diabetes, and autoimmune disorders, the evidence was inconsistent, inconclusive as to causality, and insufficient to inform nutritional requirements. Randomized clinical trial evidence for extraskeletal outcomes was limited and generally uninformative. Based on bone health, Recommended Dietary Allowances (RDAs; covering requirements of ≥97.5% of the population) for calcium range from 700 to 1300 mg/d for life-stage groups at least 1 yr of age. For vitamin D, RDAs of 600 IU/d for ages 1–70 yr and 800 IU/d for ages 71 yr and older, corresponding to a serum 25-hydroxyvitamin D level of at least 20 ng/ml (50 nmol/liter), meet the requirements of at least 97.5% of the population. RDAs for vitamin D were derived based on conditions of minimal sun exposure due to wide variability in vitamin D synthesis from ultraviolet light and the risks of skin cancer. Higher values were not consistently associated with greater benefit, and for some outcomes U-shaped associations were observed, with risks at both low and high levels. The Committee concluded that the prevalence of vitamin D inadequacy in North America has been overestimated. Urgent research and clinical priorities were identified, including reassessment of laboratory ranges for 25-hydroxyvitamin D, to avoid problems of both undertreatment and overtreatment., There is an urgent clinical and public health need for consensus cut-points for serum 25OHD inadequacy to avoid problems of both under- and overtreatment.

Calcium absorption declines with age. Because 1,25-dihydroxyvitamin D (1,25(OH)2D) is the major hormone controlling calcium absorption, changes in vitamin D metabolism may account for the malabsorption of aging. Serum levels of 1,25(OH)2D have been reported to either decrease or remain unchanged with age. To assess the effect of aging on renal production of 1,25(OH)2D, we evaluated the response of renal 25OHD 1 alpha hydroxylase to human parathyroid hormone (hPTH(1-34) stimulation in 119 women ages 25-83 years. In this population, baseline serum 25OHD and 1,25(OH)2D values did not significantly change with age, but serum iPTH (r = 0.44; p < 0.001) and serum creatinine (r = 0.31; p < 0.01) increased with age. However, the stimulatory activity of hPTH(1-34) on the renal production of 1,25(OH)2D declined with age (r3 = -0.36; p < 0.001) and was most apparent after age 75, being 50% less than that of younger women. Besides age, the production of 1,25(OH)2D was found to be dependent on baseline serum iPTH (r = -0.31; p < 0.0001). Administration of hPTH(1-34) led to suppression of endogenous PTH, and suppressibility of endogenous PTH declined with age (r = 0.53; p < 0.0001). The increase in serum PTH and decreased suppressibility of PTH with age could be due to mild secondary hyperparathyroidism. The increase in PTH with age is probably responsible for maintaining normal serum 1,25(OH)2D levels in elderly subjects; however, decreased metabolism of 1,25(OH)2D in the elderly could also maintain normal serum 1,25(OH)2D levels.

Vitamin D enters the body as a nutrient from dietary sources and as a pre-vitamin that is activated by sunlight in skin. Circulating vitamin D undergoes further activation in the liver to 25 hydroxyvitamin D (25OHD) and then in the kidney to the active metabolite 1,25 dihydroxyvitamin D (1,25(OH)2D or calcitriol) that functions as a hormone. There is positive stimulation of 1,25 dihydroxyvitamin D secretion by parathyroid hormone (PTH) mediated by changes in serum calcium [1] and negative feedback on 1,25 dihydroxyvitamin D secretion by Fibroblast growth factor 23 (FGF23) a hormone derived mainly from osteocytes that is stimulated by and regulates changes in serum phosphorus [2]. 1,25 dihydroxyvitamin D (1,25(OH)2D) binds to the vitamin D receptor (VDR) in the intestine and controls the efficiency of calcium absorption by determining the amount of calcium absorbed from the diet [3]. When calcium intake is low there is increased PTH secretion, increased 1,25 dihydroxyvitamin D and increased calcium absorption and when calcium intake is high the mechanism is reversed [4]. This adaptive process was first described by Nicolaysen in 1953 long before the discovery of 1,25 dihydroxyvitamin D [5].

Decreased calcitriol production due to impaired renal function may be a significant risk factor for falls in normal aging population.The objective of the study was to examine the association between creatinine clearance (CrCl) and the incidence of falls and fallers in groups treated with placebo, calcitriol, estrogen therapy (ET)/estrogen + progestin therapy (HT), and calcitriol + ET/HT.This was a 3-yr, double-blind, placebo-controlled study designed to test the efficacy of calcitriol and ET/HT on bone loss and falls with analysis by intention to treat and post hoc.The study was conducted at an academic outpatient center.Four hundred eighty-nine normal elderly women aged 65-77 yr; 415 women completed the study.Subjects were randomized to placebo, calcitriol 0.25 mug twice a day, ET daily (conjugated equine estrogens 0.625 mg), HT (conjugated equine estrogen 0.625 mg + medroxyprogesterone acetate 2.5 mg) and calcitriol + ET/HT.Cumulative number of falls and fallers were compared between groups with 24-h urine CrCl less than 60 and 60 ml/min or greater.Calcitriol treatment decreased the number of fallers and falls. Low CrCl less than 60 ml/min was a predictor of the number of falls per person but not fallers in the placebo group (P = 0.007). In the low CrCl group (60 ml/min), the rate of falls decreased on calcitriol by 53% [95% confidence interval (CI) -71% to -22%; P = 0.003], calcitriol + ET/HT by 61% (95% CI -76% to -37%; P = 0.001), and ET/HT by 25% (95% CI: -55% to +24%; not significant). Calcitriol reduced the rate of falls by 30% (95% CI -49% to -4%; P = 0.027) in the CrCl 60 ml/min or greater group.Calcitriol treatment decreases falls in all subjects but especially in elderly women with decreased renal function (60 ml/min) and frequent fallers.

Transiliac bone biopsies were obtained from 55 women treated with teriparatide or placebo for 12–24 months. We report direct evidence that modeling bone formation at quiescent surfaces was present only in teriparatide-treated patients and bone formation at remodeling sites was higher with teriparatide than placebo. Introduction: Recombinant teriparatide [human PTH(1-34)], a bone formation agent for the treatment of osteoporosis when given once daily subcutaneously, increases biochemical markers of bone turnover and activation frequency in histomorphometry studies. Materials and Methods: We studied the mechanisms underlying this bone-forming action of teriparatide at the basic multicellular unit by the appearance of cement lines, a method used to directly classify surfaces as modeling or remodeling osteons, and by the immunolocalization of IGF-I and IGF-II. Transiliac bone biopsies were obtained from 55 postmenopausal women treated with teriparatide 20 or 40 μg or placebo for 12–24 months (median, 19.8 months) in the Fracture Prevention Trial. Results: A dose-dependent relationship was observed in modeling and mixed remodeling/modeling trabecular hemiosteons. Trabecular and endosteal hemiosteon mean wall thicknesses were significantly higher in both teriparatide groups than in placebo. There was a dose-dependent relationship in IGF-II immunoreactive staining at all bone envelopes studied. The greater local IGF-II presence after treatment with teriparatide may play a key role in stimulating bone formation. Conclusions: Direct evidence is presented that 12–24 months of teriparatide treatment induced modeling bone formation at quiescent surfaces and resulted in greater bone formation at remodeling sites, relative to placebo.

The relationship between prior fractures and risk of new fractures was evaluated in 931 postmenopausal women with prevalent vertebral fractures randomized to daily placebo or teriparatide (20 mug) in the Fracture Prevention Trial. The median observation time was 21 months. Among placebo patients with one, two, or three or more prevalent vertebral fractures, 7%, 16%, and 23%, respectively, developed vertebral fractures (by Cochran-Armitage trend test, P0.001), and 3%, 9%, and 17% developed moderate or severe vertebral fractures (P0.001). Among placebo patients with mild, moderate, or severe prevalent vertebral fractures, 10%, 13%, and 28%, respectively, developed vertebral fractures (P0.001), and 4%, 8%, and 23% developed moderate or severe vertebral fractures (P0.001). Among placebo patients with zero, one, or two or more prior nonvertebral fragility fractures, 4%, 8%, and 18%, respectively, developed nonvertebral fragility fractures (P0.001). In the teriparatide-treated group, there was no significant increase in vertebral or nonvertebral fracture risk in these subgroups. In summary, the number and severity of prevalent vertebral fractures independently predicted the risk for new vertebral fractures, and the number of prior nonvertebral fractures predicted the risk for new nonvertebral fractures in placebo patients. However, in teriparatide-treated patients, the increased fracture risk associated with prior number and severity of fracture was not observed.

Lower doses of conjugated estrogens (CE) alone or combined with lower doses of medroxyprogesterone acetate (MPA) increase mean bone mineral density (BMD) from baseline at the spine and hip in early postmenopausal women. However, not all women on therapy gain BMD. The incidence of continued bone loss (defined as a loss of BMD of2% from baseline) among women using lower doses of CE and CE/MPA is unknown. This randomized, double-blind, placebo-controlled, multicenter substudy of the Women's Health, Osteoporosis, Progestin, Estrogen (Women's HOPE) trial investigated the incidence of continued bone loss with lower-dose CE and CE/MPA. Eight hundred twenty-two healthy postmenopausal women with intact uteri received CE 0.625, CE 0.625/MPA 2.5, CE 0.45, CE 0.45/MPA 2.5, CE 0.45/MPA 1.5, CE 0.3, CE 0.3/MPA 1.5 (all doses in mg/day), or placebo for 2 years along with 600 mg/day of calcium. Changes from baseline in spine and total hip BMD were compared among treatment groups in an intent-to-treat analysis. At 12 months,10% of women on active treatment lost2% of spinal BMD (except CE 0.3/MPA 1.5 [15.6%]), compared with 41.2% of women on placebo. At 24 months, the percentages of women on active treatment who lost2% of spine BMD ranged from 4.5% with CE 0.45/MPA 1.5-15.6% with CE 0.3/MPA 1.5, compared with 55.2% of women taking placebo. More than 85% of women on active treatment did not experience continued BMD loss at the hip at 12 months and 24 months, in contrast to 30.6% of women on placebo at 12 months and 36.5% at 24 months. Women receiving active treatment who lost2% of spine or hip BMD also had a lesser reduction in biochemical markers of bone turnover. In summary, continued bone loss among early postmenopausal women treated with lower doses of CE or CE/MPA is uncommon.

Vitamin D is often recommended for use with calcium supplements to increase absorption. There are no systematic studies of vitamin D on calcium absorption that indicate what dose should be recommended.Our objective was to study the effect of increasing doses of vitamin D3 on calcium absorption.We conducted a randomized double-blind placebo-controlled trial at Creighton University Medical Center, Omaha, NE.Participants included 163 postmenopausal Caucasian women with vitamin D insufficiency, defined as a serum 25-hydroxyvitamin D (25OHD) below 20 ng/ml (50 nmol/liter).Participants were randomized to receive one of the vitamin D3 doses, 400, 800, 1600, 2400, 3200, 4000, or 4800 IU/d, or placebo for 1 yr. Calcium intake was increased to 1200-1400 mg daily by giving daily calcium citrate.We evaluated the change in calcium absorption on vitamin D.Mean serum 25OHD increased from baseline 15.6 ng/ml (39 nmol/liter) to 46.5 ng/ml (112 nmol/liter) in subjects randomized to the highest dose of vitamin D (4800 IU). Calcium absorption was more significantly related to serum 25OHD (R2=0.50; P=0.001) than dose (R2=0.47; P=0.033). Calcium absorption of a 100-mg dose increased from 52-58% (6 mg) over a serum 25OHD range of 20-66 ng/ml (50-165 nmol/liter).There was no evidence of a threshold for reduced calcium absorption in the serum 25OHD range of 10-66 ng/ml (25-165 nmol/liter). The increase in absorbed calcium of 6% on high doses of vitamin D is so small that the same amount could be obtained from half a glass of milk (100 ml) or 100 mg elemental calcium. The results challenge assumptions about the value of adding vitamin D to increase calcium absorption except when serum 25OHD is very low that is less than 10 ng/ml (25 nmol/liter).

Seasonal variation of serum vitamin D metabolites, PTH, bone turnover markers, and bone mineral density (BMD), adjusted for confounding variables, was studied in a cross-sectional population of 251 ambulatory elderly women aged 65-77 yr. A significant (P < 0.05) seasonal change was observed in serum 25 hydroxyvitamin D (25OHD), bone resorption marker (urine N-telopeptide), and BMD of the spine, total body, and mid-radius. Serum 25OHD was significantly lower (P < 0.05) in winter (December, January, February, March) compared with summer (June, July, August, September), with the nadir in February (68.4 +/- 6.74 nmol/liter) and the zenith in August (85.6 +/- 5.12 nmol/liter). Mean serum PTH levels were higher in winter when serum 25OHD was low, and mean serum PTH was lower in summer when serum 25OHD was high, although the seasonal change in serum PTH was not significant. The change in serum 1,25-dihydroxy vitamin D(3) paralleled that of serum 25OHD levels, but the seasonal effect was not significant. Mean 24-h urine N-telopeptide showed a significant seasonal change (P < 0.05); it was about 24% higher in February (zenith) compared with that in August (nadir). The zenith month of urine N-telopeptide levels corresponded to the nadir month of serum 25OHD levels and vice versa. A significant (P < 0.05) inverse correlation was observed between 24-h urine N-telopeptides and serum 25OHD levels. There was a significant (P < 0.05) seasonal change in mean BMD of spine, total body, and mid-radius. These changes paralleled those in serum 25OHD levels. Spine BMD was 8.4% higher in August (zenith) compared with that in February (nadir), whereas total body BMD and mid-radius BMD were 6.1 and 7.6% higher, respectively, in July (zenith) compared with that in January (nadir). There was a nonsignificant increase of 3.6% in total hip BMD. In summary (see Fig. 5), the seasonal changes in vitamin D metabolism in elderly women are closely associated with small changes in serum PTH, changes in bone resorption, and BMD.

Several large placebo-controlled trials have demonstrated that conjugated estrogens with or without progestins significantly reduce the risk of vertebral and nonvertebral fractures and increase bone mineral density in postmenopausal women. The occurrence of endometrial stimulation and other unwanted hormonal-related side-effects with hormone therapy led to combined use with selective estrogen receptor modulators (SERMs) such as raloxifene, in an attempt to prevent bone loss while sparing the endometrium. Because raloxifene failed to reduce important vasomotor symptoms such as hot flashes and night sweats, other more selective SERMS were investigated. In animal studies and clinical studies, a new SERM, bazedoxifene (BZA), was shown to have effects on bone metabolism similar to raloxifene but showed no evidence of vasomotor symptoms. The present trial was part of a multicenter, randomized, double-blind, placebo- and active-controlled, phase 3 trial (Selective estrogen Menopause And Response to Therapy-1). The Selective estrogen Menopause And Response to Therapy-1 trial was designed to evaluate the effectiveness of treatment with a combination of a CE with BZA in a tissue-selective estrogen complex in preventing postmenopausal bone loss, relieving menopausal hot flashes, and treating vaginal and vulvar atrophy. The present study assessed the efficacy of BZ/CE to prevent bone loss in postmenopausal women. The study subjects in the Osteoporosis Prevention I and II substudies were 3397 women who were >5 years postmenopausal and 1 to 5 years postmenopausal, respectively. All participants were randomly assigned to receive once daily doses for up to 2 years of one of 8 regimens: BZA and CE (BZA: 10, 20, or 40 mg) each with CE, 0.625 or 0.45 mg), raloxifene (60 mg), or placebo. The primary study outcome was change in bone mineral density of the lumbar spine. Secondary outcomes included changes in BMD measured at the hip. Compared with placebo, the increase in BMD of the lumbar spine and total hip for all BZA/CE doses was significantly greater in both substudies (P < 0.001). The percent increase in lumbar spine BMD was significantly higher compared to raloxifene for most BZA/CE treatment groups (P < 0.05). In addition, serum concentrations of the bone turnover markers osteocalcin and C-telopeptide were significantly greater with all BZA/CE doses than with placebo (P < 0.001) and for most doses compared to raloxifene. These findings demonstrate that treatment of postmenopausal women at increased risk for osteoporosis with tissue-selective estrogen complex containing various BZA/CE combinations was associated with decreased bone turnover and bone loss.

There is a lack of substantial data on changes in calciotropic hormones and bone markers in elderly subjects living in North America. Parathyroid hormone (PTH), serum 25-hydroxyvitamin D (25(OH)D) and bone markers (serum osteocalcin and urine N-telopeptide), were measured in 735 Caucasian subjects (235 men and 500 women) aged 65-87 years. There was a significant increase in serum osteocalcin and urine N-telopeptide with age in men, and a significant increase in serum osteocalcin with age in women. Serum PTH and 25(OH)D showed no significant change with age in men or women. After adjusting for age, calcium intake, serum creatinine, season, and weight, mean serum PTH (p = 0.01), serum osteocalcin (p = 0.0001) and 24 h urine N-telopeptide (p = 0.0001) were higher in women than men, and mean serum 25(OH)D (p = 0.0001) and 24 h urine calcium (p = 0.0001) were higher in men than women. Serum PTH was correlated with serum osteocalcin in men and women, r = 0.24, r = 0.17, p < 0.001, but not with urine N-telopeptide. Serum PTH was inversely correlated with serum 25(OH)D (r = -0.25, r = -034,p < 0.001), and positively correlated with serum creatinine (r = 0.14, r = 0.17,p < 0.01) in men and women. The prevalence of serum 25(OH)D levels below 12 ng/ml was only 33% in females and 0.4% in men. Thus vitamin D deficiency was very uncommon in the U.S.A. compared with Europe. Although mean serum PTH was increased in the elderly, only 4-6% had PTH levels above the normal range. In summary, the increase in serum PTH in the elderly can be explained more by changes in vitamin D status than by declining renal function. These data also show significantly higher (p = 0.001) bone remodeling markers in women.

The exact mechanism for the decrease in intestinal calcium absorption with age is not yet understood. A decrease with age in serum 1,25-dihydroxyvitamin D (1,25(OH)2D) or a decrease in the intestinal vitamin D receptor (VDR) protein concentration are possible causes. The objective of this study was to examine the effect of age on these factors. Fifty-nine young women age 25–35 years were compared with 41 elderly women age 65–83 years who underwent measurements of VDR, calcium absorption using a 20 mg and 100 mg calcium carrier, and calciotropic hormones. Calcium absorption by both tests was lower in the elderly women compared with the young women (p < 0.05). Serum 1,25(OH)2D and duodenal VDR protein concentration were not significantly different between the two age groups. Serum 1,25(OH)2D correlated with the 20 mg calcium absorption test in both young (r = 0.35, p < 0.007) and elderly women (r = 0.58, p < 0.0001) and with the 100 mg calcium absorption in the elderly (r = 0.32; p < 0.05). VDR did not correlate with calcium absorption in young women or elderly women, nor did VDR correlate with serum 1,25(OH)2D and serum 25-hydroxyvitamin D. In summary, the decrease in calcium absorption cannot be explained by a decrease in intestinal VDR. The correlation between serum 1,25(OH)2D and both calcium absorption tests only accounts for 12–30% of the variance in the age-related change in the calcium absorption tests. Other factors, not yet understood, are responsible for the decline in calcium absorption with age.

It is commonly said that vitamin D should be used to increase calcium absorption. We tested this statement in a dose-response study of vitamin D on calcium absorption. A total of 198 white and African American women, aged 25 to 45 years, with vitamin D insufficiency, serum 25-hydroxyvitamin D (25OHD)20 ng/mL, were randomized in a double-blind study to vitamin D3 400, 800, 1600, 2400 IU, or placebo. A calcium supplement was given to increase mean calcium intake at baseline from 706 mg/d to 1031 mg/d. Calcium absorption was measured at baseline and after 12 months using a single isotope method with radiocalcium45 and 100 mg of calcium. Mean baseline serum 25OHD was 13.4 ng/mL (33.5 nmol/L) and increased to 40 ng/mL (100 nmol/L) on the highest dose of 2400 IU. Using a multivariate regression analysis with significant predictors, baseline absorption, calcium intake, and weight, there was no increase in 12-month calcium absorption compared with baseline on any dose of vitamin D in either whites or African Americans. There was no significant relationship between 12-month calcium absorption and final serum 25OHD. In an analysis of calcium absorption and serum 25OHD at baseline, serum 25OHD levels were divided into groups: 0 to 5, 6 to 10, 11 to 15, or 16 to 20 ng/mL. There was no evidence of a threshold decrease in calcium absorption or serum 1,25 dihydroxyvitamin D (1,25(OH)2 D) amongst the lowest groups. Vitamin D doses up to 2400 IU daily did not increase calcium absorption. No threshold level of serum 25OHD for calcium absorption was found at baseline or in the longitudinal study, suggesting that active transport of calcium is saturated at very low serum 25OHD levels5 ng/mL. There is no need to recommend vitamin D for increasing calcium absorption in normal subjects. Very efficient calcium absorption at very low levels of serum 25OHD explains why people do not develop osteomalacia provided that dietary intakes of calcium and phosphorus are adequate.

There is limited information on the effects of vitamin D on serum 25 hydroxyvitamin D (25OHD) in young people and none on African Americans. The main objective of this trial was to measure the effect of different doses of vitamin D3 on serum 25OHD and serum parathyroid hormone (PTH) in young women with vitamin D insufficiency (serum 25OHD ≤ 20 ng/mL (50 nmol/L). A randomized double-blind placebo-controlled trial of vitamin D3 was conducted in young white and African American women, age 25 to 45 years. A total of 198 healthy white (60%) and African American (40%) women were randomly assigned to placebo, or to 400, 800, 1600, or 2400 IU of vitamin D3 daily. Calcium supplements were added to maintain a total calcium intake of 1000 to 1200 mg daily. The primary outcomes of the study were the final serum 25OHD and PTH levels at 12 months. The absolute increase in serum 25OHD with 400, 800, 1600, and 2400 IU of vitamin D daily was slightly greater in African American women than in white women. On the highest dose of 2400 IU/d, the mixed model predicted that mean 25OHD increased from baseline 12.4 ng/mL (95% confidence interval [CI], 9.2-15.7) to 43.2 ng/mL (95% CI, 38.2-48.1) in African American women and from 15.0 ng/mL (95% CI, 12.3-17.6) to 39.1 ng/mL (95% CI, 36.2-42.0) in white women. There was no significant effect of vitamin D dose on serum PTH in either race but there was a significant inverse relationship between final serum PTH and serum 25OHD. Serum 25OHD exceeded 20 ng/mL in 97.5% of whites on the 400 IU/d dose and between 800 and 1600 IU/d for African Americans. The recommended dietary allowance (RDA) suggested by the Institute of Medicine for young people is 600 IU daily. The increase in serum 25OHD after vitamin D supplementation was similar in young and old, and in white and African American women.

A high intake of soy is thought to be responsible for a lower incidence of osteoporosis in Asian countries compared to the Western countries. A review of randomized control trials that studied the effect of soy isoflavones on bone density reported no significant difference from placebo at the spine and hip in 11 out of 14 trials involving 2,971 postmenopausal women. The amount of isoflavones studied ranged from 40 to 300 mg/day and the proportion of genistein and daidzein varied amongst studies. Meta-analyses reported inconsistent results probably because the included studies varied in each meta-analysis. Despite these facts their use in bone health has generally been promoted by nutritional and holistic sources that do not follow the concept of evidence-based studies.

Millions of women in the United States and across the globe abruptly discontinued postmenopausal hormone therapy (HT) after the initial Women's Health Initiative trial publication. Few data describing the effects of HT cessation on hip fracture incidence in the general population are available. We evaluated the impact of HT cessation on hip fracture incidence in a large cohort from the Southern California Kaiser Permanente health management organization.In this longitudinal observational study, 80,955 postmenopausal women using HT as of July 2002 were followed up through December 2008. Data on HT use after July 2002, antiosteoporotic medication use, and occurrence of hip fracture were collected from the electronic medical record system. Bone mineral density (BMD) was assessed in 54,209 women once during the study period using the dual-energy x-ray absorptiometry scan.After 6.5 years of follow-up, age- and race-adjusted Cox proportional hazard models showed that women who discontinued HT were at 55% greater risk of hip fracture compared with those who continued using HT (hazard ratio, 1.55; 95% CI, 1.36-1.77). Hip fracture risk increased as early as 2 years after cessation of HT (hazard ratio, 1.52; 95% CI, 1.26-1.84), and the risk incrementally increased with longer duration of cessation (P for trend0.0001). Longer duration of HT cessation was linearly correlated with lower BMD (β estimate [SE]) = -0.13 [0.003] T-score SD unit per year of HT cessation; P0.0001).Women who discontinued postmenopausal HT had significantly increased risk of hip fracture and lower BMD compared with women who continued taking HT. The protective association of HT with hip fracture disappeared within 2 years of cessation of HT. These results have public health implications with regard to morbidity and mortality from hip fracture.

Vitamin D is an essential nutrient for skeletal mineralization and maintenance of bone mass. Most healthy individuals can meet their vitamin D requirements through dietary means, modest supplementation and solar exposure for short periods of time. The serum level of 25OHD that determines adequacy is 20 ng/ml, which corresponds with consumption of 6-800 IU of vitamin D per day, according to the Institute of Medicine review. There is still debate about whether higher doses of vitamin D are required for treating patients with osteoporosis.

The Institute of Medicine Committee to Review Dietary Reference Intakes for Calcium and Vitamin D comprehensively reviewed the evidence for both skeletal and nonskeletal health outcomes and concluded that a causal role of calcium and vitamin D in skeletal health provided the necessary basis for the 2011 Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA) for ages older than 1 year. For nonskeletal outcomes, including cancer, cardiovascular disease, diabetes, infections, and autoimmune disorders, randomized clinical trials were sparse, and evidence was inconsistent, inconclusive as to causality, and insufficient for Dietary Reference Intake (DRI) development. The EAR and RDA for calcium range from 500 to 1,100 and 700 to 1,300 mg daily, respectively, for ages 1 year and older. For vitamin D (assuming minimal sun exposure), the EAR is 400 IU/day for ages older than 1 year and the RDA is 600 IU/day for ages 1 to 70 years and 800 IU/day for 71 years and older, corresponding to serum 25-hydroxyvitamin D (25OHD) levels of 16 ng/mL (40 nmol/L) for EARs and 20 ng/mL (50 nmol/L) or more for RDAs. Prevalence of vitamin D inadequacy in North America has been overestimated based on serum 25OHD levels corresponding to the EAR and RDA. Higher serum 25OHD levels were not consistently associated with greater benefit, and for some outcomes U-shaped associations with risks at both low and high levels were observed. The Tolerable Upper Intake Level for calcium ranges from 1,000 to 3,000 mg daily, based on calcium excretion or kidney stone formation, and from 1,000 to 4,000 IU daily for vitamin D, based on hypercalcemia adjusted for uncertainty resulting from emerging risk relationships. Urgently needed are evidence-based guidelines to interpret serum 25OHD levels relative to vitamin D status and intervention.

As background information, the reader should appreciate that at he 13th Vitamin DWorkshop in 2006 it was agreed that about half f elderly North Americans and Western Europeans and probably lso two thirds of the rest of the world are vitamin D deficient as udgedby their inability tomaintain a healthy bonedensity [1–3]. It as also generally agreed that the serum concentration of 25(OH)D n normal subjects is the best indicator for judging the vitamin D tatus in patients with vitamin D-related disease states [4]. The14thWorkshoponVitaminD,held inBrugge, Belgium,Octoer 4–8, 2009wasattendedby419 scientists from35countrieswho ere privileged to listen and participate in a Vitamin D Roundtable hat was held in order to allow presentation and broad discusion of two distinct views of and approaches to worldwide vitamin nutritional status. One Roundtable position is that an absolute inimum 25(OH)D level of 20ng/ml (50nmol/l) is necessary in all ndividuals in order to support and maintain all the classic actions f vitamin D on bone andmineral health and that, according to this riterion, a large proportion of the world’s population is vitamin D eficient. Thosewhohold this position further believe that thehuge ffort needed to ameliorate this deficiency must be undertaken as oon and actively as possible and that the target 25(OH)D levels of 20ng/ml should be obtained in the majority of the target populaion. The second Roundtable position is that newer data showing ssociations between vitamin D status and prevalence of several iseases such as cardiovascular disease, hypertension, colon and reast cancer, multiple sclerosis as well as the involvement of vitain D in muscle strength and immune functions [5], indicates that arget levels of 25(OH)D should be 30–40ng/ml (75–100nmol/l) t the minimum. As a basis for policy decision making, these two ositions are incompatible with one another. However, through onsideration of the aspects of vitamin D nutrition upon which the roponents of the two views agree, as well as acknowledging diferences in opinion, consensus on how to proceed in the near term an emerge. This was the goal of the Vitamin D Roundtable. TheRoundtable, chaired byAnthonyNorman (USA) andChristoher Gallagher (USA), began with 15-min presentations from obert Heaney (USA) and Reinhold Vieth (Canada), both propoents of 25(OH)D>40ng/ml, followed by presentations by Roger ouillon (Belgium) and Paul Lips (Netherlands),who advocateminmum25(OH)D levels of 20ng/ml. A selected group of experts from round theworld, Bess Dawson-Hughes (USA), John Pettifor (South frica), Peter Ebeling (Australia), and Christine Lamberg-Allardt

Objective: To review the data on the effect of early menopause on bone. Do women undergoing early menopause develop lower bone mineral density at an earlier age and do they have a higher incidence of osteoporotic fractures? Is there a difference on bone between women who undergo early natural menopause compared to women who have early menopause after oophorectomy? Results: The earlier in life that menopause occurs, the lower the bone density will be later in life. Low bone density is associated with a higher fracture rate, and several studies show a relationship between early menopause, oophorectomy, and an increase in osteoporotic fractures. Conclusions: Early menopause is a risk factor for osteoporosis. Women with an early menopause should have bone density testing performed within 10 years of menopause so that osteopenia or osteoporosis will be diagnosed early and appropriate antiresorptive therapy initiated.