Health risks and benefits from calcium and vitamin D supplementation: Women's Health Initiative clinical trial and cohort study

Summary

The Women's Health Initiative (WHI) double-blind, placebo-controlled clinical trial randomly assigned 36,282 postmenopausal women in the U.S. to 1,000 mg elemental calcium carbonate plus 400 IU of vitamin D₃ daily or placebo, with average intervention period of 7.0 years. The trial was designed to test whether calcium plus vitamin D supplementation in a population in which the use of these supplements was widespread would reduce hip fracture, and secondarily, total fracture and colorectal cancer.

Introduction

This study further examines the health benefits and risks of calcium and vitamin D supplementation using WHI data, with emphasis on fractures, cardiovascular disease, cancer, and total mortality.

Methods

WHI calcium and vitamin D randomized clinical trial (CT) data through the end of the intervention period were further analyzed with emphasis on treatment effects in relation to duration of supplementation, and these data were contrasted and combined with corresponding data from the WHI prospective observational study (OS).

Results

Among women not taking personal calcium or vitamin D supplements at baseline, the hazard ratio [HR] for hip fracture occurrence in the CT following 5 or more years of calcium and vitamin D supplementation versus placebo was 0.62 (95 % confidence interval (CI), 0.38–1.00). In combined analyses of CT and OS data, the corresponding HR was 0.65 (95 % CI, 0.44–0.98). Supplementation effects were not apparent on the risks of myocardial infarction, coronary heart disease, total heart disease, stroke, overall cardiovascular disease, colorectal cancer, or total mortality, while evidence for a reduction in breast cancer risk and total invasive cancer risk among calcium plus vitamin D users was only suggestive.

Conclusion

Though based primarily on a subset analysis, long-term use of calcium and vitamin D appears to confer a reduction that may be substantial in the risk of hip fracture among postmenopausal women. Other health benefits and risks of supplementation at doses considered, including an elevation in urinary tract stone formation, appear to be modest and approximately balanced.     

Vitamin D status in relation to obesity, bone mineral density, bone turnover markers and vitamin D receptor genotypes in healthy Saudi pre- and postmenopausal women

Summary

The various factors that may contribute to vitamin D deficiency or insufficiency were examined among healthy Saudi pre- and postmenopausal women. Vitamin D deficiency was highly prevalent among studied Saudi women with obesity, poor sunlight exposure, poor dietary vitamin D supplementation and age as the main risk factors.

Introduction

The various factors that may contribute to vitamin D deficiency or insufficiency in relation to bone health among Saudi women are not known. The main objectives of the present study were to determine the factors influencing vitamin D status in relation to serum 25-hydroxyvitamin D (25(OH)D), intact parathyroid hormone (PTH), bone turnover markers (BTMs), bone mineral density (BMD), and vitamin D receptor genotype (VDR) in healthy Saudi pre- and postmenopausal women.

Methods

A total number of 1,172 healthy Saudi women living in the Jeddah area were randomly selected and studied. Anthropometric parameters, socioeconomic status, sun exposure index together with serum levels of 25(OH)D, calcitriol, intact PTH, Ca, PO4, Mg, creatinine, albumin, and biochemical BTMs were measured. BMD was measured by a dual energy X-ray absorptiometry and VDR genotypes were also determined.

Results

About 80.0% of Saudi women studied exhibited vitamin D deficiency (serum 25(OH)D?<?50.0?nmol/L) with only 11.8% of all women were considered with adequate vitamin D status (serum 25(OH)D?>?75?nmol/L). Secondary hyperparathyroidism was evident in 18.5% and 24.6% in pre- and postmenopausal women with 25(OH)D?<?50?nmol/L. Serum 25(OH)D was lower (P?<?0.001) and intact PTH higher (P?<?0.001) in the upper quintiles of body mass index (BMI) and waist-to-hip ratio (WHR). Multiple linear regression analysis showed that BMI, sun exposure index, poor dietary vitamin D supplementation, WHR, and age were independent positive predictors of serum 25(OH)D values.

Conclusions

Vitamin D deficiency is highly prevalent among healthy Saudi pre-and postmenopausal women and largely attributed to obesity, poor exposure to sunlight, poor dietary vitamin D supplementation, and age.     

Serum osteocalcin levels are inversely associated with abdominal aortic calcification in men with type 2 diabetes mellitus

Summary

We found that serum osteocalcin (OC) and undercarboxylated OC (ucOC) levels were negatively associated with abdominal aortic calcification in type 2 diabetes mellitus (T2DM) men. This finding suggests that circulating OC and ucOC are not only related to glucose or fat metabolism but also to arteriosclerosis.

Introduction

Recent studies revealed that serum osteocalcin levels were associated with not only bone metabolism but also glucose and fat metabolism. However, the relationship between serum OC levels and arteriosclerosis remains controversial. We examined whether or not bone metabolic markers including OC are associated with abdominal aortic calcification in patients with type 2 diabetes mellitus.

Methods

We recruited 118 men and 100 postmenopausal women with T2DM. We evaluated the abdominal aortic calcification score (ACS) on a lateral lumbar radiograph and examined the association between serum OC or undercarboxylated OC levels and ACS.

Results

The ACS of 3 and greater, which corresponded well to the highest quartile, was significantly and negatively associated with serum OC and ucOC levels in men by logistic regression analyses after adjusting for age, BMI, serum levels of creatinine and LDL cholesterol, radial bone mineral density, smoking, duration of DM, hemoglobin A1c, and the index of insulin resistance [odds ratio (OR) 0.36, 95 % confidence interval (CI) 0.19–0.70, P?<?0.005, and OR 0.28, 95 % CI 0.12–0.69, P?<?0.01, per standard deviation increase in OC and ucOC, respectively]. These observations were still significant after an additional adjustment for other bone markers. In contrast, there were no significant relationships with serum OC or ucOC levels and ACS in women.

Conclusions

These findings suggest that serum OC and ucOC levels are associated with not only bone metabolism but also arteriosclerosis in men, but not in women with type 2 diabetes mellitus.     

Vitamin K supplementation for the primary prevention of osteoporotic fractures: is it cost-effective and is future research warranted?

Summary

Lifetime supplementation with vitamin K, vitamin D₃, and calcium is likely to reduce fractures and increase survival in postmenopausal women. It would be a cost-effective intervention at commonly used thresholds, but high uncertainty around the cost-effectiveness estimates persists. Further research on the effect of vitamin K on fractures is warranted.

Introduction

Vitamin K might have a role in the primary prevention of fractures, but uncertainties about its effectiveness and cost-effectiveness persist.

Methods

We developed a state-transition probabilistic microsimulation model to quantify the cost-effectiveness of various interventions to prevent fractures in 50-year-old postmenopausal women without osteoporosis. We compared no supplementation, vitamin D₃ (800?IU/day) with calcium (1,200?mg/day), and vitamin K₂ (45?mg/day) with vitamin D₃ and calcium (at the same doses). An additional analysis explored replacing vitamin K₂ with vitamin K₁ (5?mg/day).

Results

Adding vitamin K₂ to vitamin D₃ with calcium reduced the lifetime probability of at least one fracture by 25%, increased discounted survival by 0.7 quality-adjusted life-years (QALYs) (95% credible interval (CrI) 0.2; 1.3) and discounted costs by $8,956, yielding an incremental cost-effectiveness ratio (ICER) of $12,268/QALY. At a $50,000/QALY threshold, the probability of cost-effectiveness was 95% and the population expected value of perfect information (EVPI) was $28.9 billion. Adding vitamin K₁ to vitamin D and calcium reduced the lifetime probability of at least one fracture by 20%, increased discounted survival by 0.4 QALYs (95% CrI ?1.9; 1.4) and discounted costs by $4,014, yielding an ICER of $9,557/QALY. At a $50,000/QALY threshold, the probability of cost-effectiveness was 80% while the EVPI was $414.9 billion. The efficacy of vitamin K was the most important parameter in sensitivity analyses.

Conclusions

Lifetime supplementation with vitamin K, vitamin D₃, and calcium is likely to reduce fractures and increase survival in postmenopausal women. Given high uncertainty around the cost-effectiveness estimates, further research on the efficacy of vitamin K on fractures is warranted.     

Vitamin D deficiency in HIV-infected postmenopausal Hispanic and African-American women

Summary

We evaluated vitamin D status in HIV+ and HIV? postmenopausal African-American (AA) and Hispanic women. Most women (74-78%) had insufficient 25-hydroxyvitamin D (25OHD) levels, regardless of HIV status. 25OHD was lower in AA women and women lacking supplement use, providing support for screening and supplementation. Among HIV+ women, 25OHD was associated with current CD4 but not type of antiretroviral therapy.

Introduction

To evaluate vitamin D status and factors associated with vitamin D deficiency and insufficiency in HIV-infected (HIV+) postmenopausal minority women.

Methods

In this cross-sectional study, 89 HIV+ and 95 HIV? postmenopausal women (33% AA and 67% Hispanic) underwent assessment of 25OHD, 1,25-dihydroxyvitamin D, parathyroid hormone, markers of bone turnover and bone mineral density by dual energy X-ray absorptiometry.

Results

The prevalence of low 25OHD did not differ by HIV status; the majority of both HIV+ and HIV? women (74-78%) had insufficient levels (<30?ng/ml). Regardless of HIV status, 25OHD was significantly lower in AA subjects, and higher in subjects who used both calcium and multivitamins. In HIV+ women on antiretroviral therapy (ART), 25OHD was directly associated with current CD4 count (r?=?0.32; p?<?0.01) independent of age, ethnicity, BMI, or history of AIDS-defining illness. No association was observed between 1,25(OH)₂D and CD4 count or between serum 25OHD, 1,25(OH)₂D or PTH and type of ART.

Conclusions

In postmenopausal minority women, vitamin D deficiency was highly prevalent and associated with AA race and lack of supplement use, as well as lower current CD4 cell count. These results provide support for screening and repletion of vitamin D in HIV+ patients.     

More radial shortening after low-energy Colles’ fractures is associated with type 2 diabetes mellitus among postmenopausal women, irrespective of bone mineral density

Background

Recent meta-analysis data reveal that patients with type 2 diabetes mellitus (DM) have a higher risk of fracture, despite higher bone mineral density (BMD), than patients without type 2 DM. The purpose of this study was to compare BMD and distal radial shortening after low-energy Colles’ fractures among Japanese postmenopausal women aged ≥50 years with type 2 DM with those in women without it (non-DM).

Methods

One-hundred and ten postmenopausal women aged ≥50 years with distal radius fractures resulting from a fall were enrolled in this study. Twelve patients had DM. BMD, type I collagen cross-linked N-telopeptide (NTX), undercarboxylated osteocalcin (ucOC), estimated glomerular filtration rate (eGFR), grip strength of the unfractured hand, unipedal standing time, and the degree of radial shortening were measured.

Results

There were no significant differences in age and body height between the two groups. The DM group had significantly greater body weight and body mass index than the non-DM group. BMDs of the lumbar spine and proximal hip were significantly higher in the DM group than in the non-DM group. NTX, ucOC, grip strength, and the percentage of women with unipedal standing time <15 s did not differ between the two groups. Stepwise regression analysis identified DM and shorter unipedal standing time as significant factors associated with more radial shortening, and identified more radial shortening and lower eGFR as significant factors associated with DM.

Conclusions

More radial shortening after low-energy Colles’ fractures was significantly associated with type 2 DM among postmenopausal women aged ≥50 years, irrespective of BMD.     

The impact of dietary calcium intake and vitamin D status on the effects of zoledronate

Summary

We investigated whether baseline dietary calcium intake or vitamin D status modified the effects of zoledronate. Neither variable influenced the effect of zoledronate on bone mineral density, bone turnover, or risk of acute phase reaction, suggesting that co-administration of calcium and vitamin D supplements with zoledronate may not always be necessary.

Introduction

Calcium and vitamin D supplements are often co-administered with bisphosphonates, but it is unclear whether they are necessary for therapeutic efficacy or minimizing side effects of bisphosphonates. We investigated whether baseline dietary calcium intake or vitamin D status modified the effect of zoledronate on bone mineral density (BMD) or bone turnover at 1 year, or the risk of acute phase reactions (APR).

Methods

Data were pooled from two trials of zoledronate in postmenopausal women without vitamin D deficiency in which calcium and vitamin D were not routinely administered. The cohort (zoledronate n?=?154, placebo n?=?68) was divided into subgroups by baseline dietary calcium intake (<800 vs. ≥800 mg/day) and vitamin D status [25-hydroxyvitamin D (25OHD) <50 vs. ≥50 nmol/L, and <75 nmol/L vs. ≥75 nmol/L] and treatment?×?subgroup interactions tested.

Results

There were 52, 86, and 36 % of the zoledronate group and 64, 94, and 46 % of the placebo group that had dietary calcium intake ≥800 mg/day, 25OHD ≥50 nmol/L, and 25OHD ≥75 nmol/L, respectively. There were no significant interactions between treatment and either baseline dietary calcium or baseline vitamin D status for lumbar spine BMD, total hip BMD, the bone turnover markers P1NP and β-CTx, or the risk of an APR. There was also no three-way interaction between baseline dietary calcium intake, baseline vitamin D status, and treatment for any of these variables.

Conclusions

Baseline dietary calcium intake and vitamin D status did not alter the effects of zoledronate, suggesting that co-administration of calcium and vitamin D with zoledronate may not be necessary for individuals not at risk of marked vitamin D deficiency.     

Teriparatide increases the maturation of circulating osteoblast precursors

Summary

This study shows that teriparatide promotes the circulating osteoblast (OB) precursor degree of maturation in patients affected by postmenopausal osteoporosis.

Introduction

Anabolic treatment with teriparatide has proven effective for the therapy of postmenopausal osteoporosis and significantly reduces the risk of non-vertebral fragility fractures. The aim of this study was to investigate the effect of teriparatide on circulating OB precursors.

Methods

We evaluated by flow cytometry and real-time PCR the expression of OBs typical markers in peripheral blood mononuclear cells during treatment with teriparatide plus calcium and vitamin D, raloxifene plus calcium and vitamin D or calcium and vitamin D alone at various time points. Serum bone alkaline phosphatase and osteocalcin (OC) were measured as markers of bone turnover.

Results

Our results show that circulating OB precursors are more numerous and more immature in patients affected by fragility fractures than in osteoporotic patients without fractures. We also show that teriparatide treatment increases the expression of alkaline phosphatase and of OC in OB precursors; thus, it increases their degree of maturation.

Conclusions

We suggest that teriparatide acts as anabolic agents also by promoting the maturation of OB precursors.     

Significant inverse relationship between serum undercarboxylated osteocalcin and glycemic control in maintenance hemodialysis patients

Summary

Increased levels of serum undercarboxylated osteocalcin, which were associated with bone metabolism markers, correlated inversely with indices of glucose metabolism (plasma glucose, hemoglobin A1C, and glycated albumin) in hemodialysis patients with abnormalities of bone metabolism.

Introduction

Undercarboxylated osteocalcin (ucOC), a possible marker of bone metabolism and one of the osteoblast-specific secreted proteins, has recently been reported to be associated with glucose metabolism. We tested the hypothesis that ucOC levels are associated with indices of glucose metabolism in chronic hemodialysis patients with abnormalities of bone metabolism.

Methods

Serum ucOC, bone alkaline phosphatase (BAP, a bone formation marker), and tartrate-resistant acid phosphatase-5b (TRACP-5b, a bone resorption marker) were measured in 189 maintenance hemodialysis patients (96 diabetics and 93 non-diabetics), and their relationships with glucose metabolism were examined.

Results

ucOC correlated positively with BAP (ρ?=?0.489, p?<?0.0001), TRACP-5b (ρ?=?0.585, p?<?0.0001) and intact parathyroid hormone (iPTH; ρ?=?0.621, p?<?0.0001). Serum ucOC levels in the diabetic patients were lower than those of non-diabetic patients (p?<?0.001), although there were no significant differences in serum BAP or TRACP-5b between diabetic and non-diabetic patients. Serum ucOC correlated negatively with plasma glucose (ρ?=??0.303, p?<?0.0001), hemoglobin A1C (ρ?=??0.214, p?<?0.01), and glycated albumin (ρ?=??0.271, p?<?0.001), although serum BAP or TRACP-5b did not. In multiple linear regression analysis, log [plasma glucose], log [hemoglobin A1C], and log [glycated albumin] were associated significantly with log [ucOC] after adjustment for age, gender, hemodialysis duration, and body mass index but were not associated with log [BAP], log [TRACP-5b], or log [intact PTH].

Conclusion

Increased levels of serum ucOC, which were associated with bone metabolism markers, were inversely associated with indices of glucose metabolism in hemodialysis patients.     

Vitamin D: do we get enough?

Summary

On September 29, 2011, acknowledged experts in the field of vitamin D, mainly European, were brought together in order to discuss the recent scientific advances in relation to vitamin D: the current requirements and associations with various health outcomes. In this article, the discussions resulting from the meeting are summarized.

Introduction

Several groups at risk for developing vitamin D insufficiency have been identified. Accordingly, reviews indicate that a significant percentage of the population worldwide have serum 25-hydroxyvitamin D levels below 50 nmol/l. In addition to the role of vitamin D in bone health, recent studies suggest that it may play a pivotal role in other systems, e.g., the cardiovascular system, pancreas, muscle, immune system and brain. Most evidence, however, is obtained from observational studies and yet inconclusive.

Methods

To exchange and broaden knowledge on the requirements for vitamin D and its effect on various health outcomes, a workshop entitled “Vitamin D Expert Meeting: Do we get enough?”, was organized.

Results

Despite low vitamin D levels worldwide, consensus on the definition of deficiency is not yet reached. In order to define cut-off points for vitamin D whilst taking into account extraskeletal health effects, randomized controlled trials in these fields are warranted. The experts do emphasize that there is evidence to suggest an important role for vitamin D in the maintenance of optimal bone health at all ages and that vitamin D supplementation, in most studies co-administered with calcium, reduces fracture risk in the senior population.

Conclusion

To reach a serum 25-hydroxyvitamin D level of 50 nmol/l older adults aged ≥65 years are therefore recommended to meet a mean daily vitamin D intake of 20 μg (800 IU), which is best achieved with a supplement.     

Vitamin D supplementation in breastfed infants from Montréal,Canada: 25-hydroxyvitamin D and bone health effects from a follow-up study at 3 years of age

Summary

Whether infant vitamin D supplementation may have long-term bone benefits is unclear. In this study, breastfed infants who received vitamin dosages greater than 400 IU/day did not have higher bone mineralization at 3 years. This study provides important data to inform pediatric public health recommendations for vitamin D.

Introduction

North American health agencies recommend breastfed infants should be supplemented with 400 IU of vitamin D/day to support bone health. Few studies examined the long-term benefits of early life vitamin D supplementation on bone mineralization. The objective of this study was to determine if a dose-response relationship exists between infant vitamin D supplementation, vitamin D status, and bone outcomes at 3 years of age.

Methods

This was a double-blind randomized trial of 132, 1-month-old healthy, breastfed infants from Montréal, Canada, between 2007 and 2010. In this longitudinal analysis, 87 infants (66 %) returned for follow-up at 3 years of age, between 2010 and 2013. At 1 month of age, participants were randomly assigned to receive oral cholecalciferol (vitamin D₃) supplements of 400, 800, 1200, or 1600 IU/day until 12 months of age. Lumbar spine vertebrae 1–4 (LS) bone mineral density (BMD), LS and whole body bone mineral content (BMC), and mineral accretion were measured by dual-energy x-ray absorptiometry at 3 years.

Results

At follow-up, the treatment groups were similar in terms of diet, sun exposure, and demographics. There were no significant differences among the groups in LS or whole body BMC, BMD, or accretion. Although, 25(OH)D concentrations were not different among the groups, higher doses (1200 and 1600 IU/day) achieved higher 25(OH)D area under the curve from 1 to 36 months vs. 400 IU/day.

Conclusions

This is the first longitudinal follow-up of an infant vitamin D dose-response study which examines bone mineralization at 3 years of age. Dosages higher than 400 IU/day do not appear to provide additional benefits to the bone at follow-up. Larger studies with more ethnically diverse groups are needed to confirm these results.

     

Factors associated with bisphosphonate treatment failure in postmenopausal women with primary osteoporosis

Summary

Among 97 postmenopausal women with primary osteoporosis, adequate calcium and vitamin D supplementation, and good compliance to a 36-month bisphosphonate treatment, the 25.8 % of patients are inadequate responders. Current smoking and a bone turnover in the upper part of the normal range increase the risk of treatment failure.

Introduction

To evaluate the prevalence of the bisphosphonate treatment failure and its possible associated factors in women with primary osteoporosis (PO).

Methods

We studied 97 previously untreated postmenopausal women with PO and fragility fractures and/or a FRAX® 10-year probability of a major osteoporotic fracture ≥7.5 %, before and after a 36-month treatment with alendronate or risedronate and adequate vitamin D supplementation with good compliance. At baseline and after 36 months, lumbar spine (LS) and femoral bone mineral density (BMD) were assessed by Dual X-ray absorptiometry and vertebral fractures by spinal radiographs. Spinal deformity index (SDI) was calculated. Treatment failure was defined by the presence of ≥2 incident fragility fractures and/or a BMD decrease greater than the least significant change.

Results

Bisphosphonate treatment failure was observed in 25.8 % of patients. Age, body mass index, years since menopause, familiar history of hip fracture, number of falls, type of bisphosphonate used, 25-hydroxyvitamin D levels (25OHVitD), BMD, SDI, and FRAX® score at baseline were not different between responders and inadequate responders. Treatment failure was associated with current smoking (OR 3.22, 95 % CI 1.10–9.50, P?=?0.034) and baseline alkaline phosphatase total activity levels ≥66.5 U/L (OR 4.22, 95 % CI 1.48–12.01, P?=?0.007), regardless of age, number of falls, LS BMD, and baseline SDI.

Conclusions

The 25.8 % of PO postmenopausal women inadequately responds to bisphosphonates, despite a good compliance to therapy and normal 25OHVitD levels. The current smoking and bone turnover in the upper part of the normal range are associated with the inadequate response to bisphosphonates.     

Comparison of the effect of 18-month daily teriparatide administration on patients with rheumatoid arthritis and postmenopausal osteoporosis patients

Summary

Patients with rheumatoid arthritis showed greater response to 18-month administration of daily teriparatide especially in the increase of bone formation markers at 1 month and femoral neck bone mineral density at 18 months compared to postmenopausal osteoporosis patients.

Introduction

The aim of this study was to evaluate the effects of 18-month administration of daily teriparatide (TPTD) in osteoporosis patients with rheumatoid arthritis (RA) by comparing that of postmenopausal osteoporosis patients (Porosis).

Methods

The effects of TPTD were examined between RA (n?=?70; age 68.4 years; disease activity score assessing 28 joints with CRP [DAS28-CRP] 2.8; rheumatoid factor [RF] positivity 75.5 %) with 77.1 % of prior bisphosphonate (BP), 84.3 % of oral prednisolone (PSL) (4.4 mg/day at baseline), 25.7 % of biologics, and Porosis (n?=?62; age 71.3 years) with 77.4 % of prior BP.

Results

Femoral neck (FN) bone mineral density (BMD) increase at 18 months was significantly greater in RA compared to Porosis (4.7 vs. 0.7 %, P?=?0.038), whereas it was 9.7 versus 7.9 % (P?=?0.736) in the lumbar spine (LS). The increase of bone formation markers (bone alkaline phosphatase [bone ALP] and N-terminal type I procollagen propeptide [PINP]) at 1 month were all significantly greater in RA compared to Porosis. A multivariate logistic regression analysis revealed that the significant indicator of 18-month BMD increase in RA was a 3-month increase of under-carboxylated osteocalcin (ucOC) for LS (β?=?0.446, P?=?0.005) and baseline ucOC for FN (β?=?0.554, P?=?0.001), in which both showed significant negative correlation with baseline PSL dose.

Conclusions

RA showed greater response to daily TPTD administration, especially in the increase of bone formation markers at 1 month and FN BMD increase at 18 months compared to Porosis.     

Undercarboxylated osteocalcin is positively associated with free testosterone in male patients with type 2 diabetes mellitus

Summary

Although a recent study showed that undercarboxylated osteocalcin (ucOC) is important for male fertility and testosterone production by testes, little is known about the relationship between ucOC and testosterone in humans. We found for the first time that ucOC is positively associated with free testosterone in men with type 2 diabetes.

Introduction

The ucOC has been shown to play a key role in energy metabolism as an endocrine hormone. Although a recent animal study demonstrated that ucOC is also important for male fertility and testosterone production by the testes, association between serum osteocalcin and testosterone levels has not been understood in humans.

Methods

Sixty-nine male patients with type 2 diabetes were recruited and chemical bone markers [total osteocalcin (TOC), ucOC, bone-specific alkaline phosphatase (BAP), and urinary N-terminal cross-linked telopeptide of type I collagen (uNTX)], gonadotropic hormones [luteinizing hormone (LH) and follicle-stimulating hormone (FSH)], and free testosterone (FT) were measured.

Results

Multiple regression analysis showed that ucOC and ucOC/TOC ratio were associated positively with FT and negatively with LH (for ucOC, β?=?0.30, p?=?0.042 and β?=??0.52, p?=?0.048; for ucOC/TOC ratio, β?=?0.31, p?=?0.031 and β?=??0.54, p?=?0.036, respectively) independently of age, duration of diabetes, body mass index, and hemoglobin A1c. ucOC and ucOC/TOC ratio were significantly associated with FT even after adjusting for LH and FSH (β?=?0.24, p?=?0.042 and β?=?0.25, p?=?0.031, respectively). However, neither TOC, BAP, nor uNTX was associated with the gonadotropic hormones or FT levels.

Conclusions

The present study indicates for the first time that ucOC is associated positively with FT and negatively with LH in type 2 diabetes. These findings support the recent evidence that ucOC is involved in testosterone production in male subjects.     

Serum undercarboxylated osteocalcin levels are inversely associated with glycemic status and insulin resistance in an elderly Japanese male population: Fujiwara-kyo Osteoporosis Risk in Men (FORMEN) Study

Summary

Recent animal studies have demonstrated that undercarboxylated osteocalcin upregulates insulin secretion via osteoblast-insulin signaling. However, it remains unclear whether such a pathway exists in humans. This study showed that serum undercarboxylated osteocalcin levels were inversely associated with fasting plasma glucose, hemoglobin A_1c, and homeostasis model assessment of insulin resistance (HOMA-IR) levels in community-dwelling elderly Japanese men.

Introduction

Undercarboxylated osteocalcin (ucOC) was reported to increase insulin secretion and improve glucose tolerance via osteoblast-insulin signaling in animal-based studies. Whether this pathway also exists in humans is unknown. We aimed to clarify whether serum ucOC levels are associated with glycemic status and insulin resistance in the general Japanese population.

Methods

We included 2,174 Japanese men (??65?years) who were able to walk without aid from others and lived at home in four cities of Nara Prefecture. We excluded participants with a history of diseases or medications that affect bone metabolism, other than type 2 diabetes mellitus (T2DM). Fasting plasma glucose, glycated hemoglobin A_1c, and HOMA-IR levels were determined as outcome measures.

Results

Of the 1,597 participants included in the analysis, both intact OC (iOC) and ucOC levels showed significant inverse correlations with all outcome measures, even after adjusting for potential confounders. Mean values of outcome measures showed a significant decreasing trend with higher quintiles of iOC or ucOC after adjusting for confounders. This trend remained significant for ucOC quintiles after further adjustment for iOC levels, but was not significant for iOC quintiles after adjusting for ucOC levels. These results were attenuated, but still apparent, after excluding participants receiving drug therapy for T2DM.

Conclusions

Levels of ucOC, but not iOC, were inversely associated with glycemic index and insulin resistance in a population of Japanese men. These findings will need to be confirmed with longitudinal studies.     

High prevalence of vitamin K and D deficiency and decreased BMD in inflammatory bowel disease

Summary  Vitamin K and D deficiency and decreased bone mineral density (BMD) were highly prevalent in patients with inflammatory bowel disease (IBD), especially Crohn’s disease (CD). Dietary intakes of these vitamins, however, were above the Japanese adequate intakes in IBD patients, suggesting that malabsorption is the basis for hypovitaminosis K and D and decreased BMD. Introduction  We have studied the possible involvement of vitamin K and D deficiency in the pathogenesis of decreased BMD in IBD. Methods  Seventy patients with IBD were evaluated for their BMD; plasma levels of vitamin K; phylloquinone (PK), menaquinone-7 (MK-7), and 25OH-D; serum PTH, protein induced by vitamin K absence (PIVKA-II), and undercarboxylated osteocalcin (ucOC) levels; and their food intake. Results  Compared with ulcerative colitis (UC) patients, CD patients had significantly lower plasma vitamin K and 25OH-D concentrations; significantly higher serum levels of PTH, PIVKA-II, and ucOC; and significantly lower BMD scores at almost all measurement sites. More IBD patients were vitamin K deficient in bone than in liver. Multiple regression analyses revealed that low plasma concentrations of vitamin K and 25OH-D were independent risk factors for low BMD and that they were associated with the patients’ fat intake, but not with their intake of these vitamins. Conclusion  IBD patients have high prevalence of decreased BMD and vitamin K and D deficiency probably caused by malabsorption of these vitamins.     

Calcium and vitamin-D supplementation on bone structural properties in peripubertal female identical twins: a randomised controlled trial

Summary

A randomised controlled trial was used in assessing the impact of 6?months of daily calcium and vitamin-D supplementation on trabecular and cortical bone acquisition at distal tibial and radial sites using peripheral quantitative computed tomography (pQCT). Daily supplementation was associated with increased bone density and bone strength at the distal tibia and radius.

Introduction

pQCT has not been used to assess bone responses to calcium and vitamin-D supplementation on peripubertal children. This randomised controlled trial aimed to assess the impact of a 6-month daily calcium and vitamin-D supplementation on trabecular and cortical bone acquisition at distal tibial and radial sites using pQCT.

Methods

Twenty pairs of peripubertal female identical twins, aged 9 to 13?years, were randomly assigned to receive either 800?mg of calcium and 400?IU of vitamin D3, or a matched placebo. Bone structural properties at the distal tibia and distal radius were acquired at baseline and 6?months.

Results

The calcium-supplemented group showed greater gains in trabecular density, trabecular area and strength strain index at the 4% of distal tibial and radial sites compared with the placebo group (p?=?0.001). Greater gains in cortical area at the 38% and 66% of tibial sites were also found in twins receiving the calcium supplement (p?=?0.001).

Conclusions

Daily supplementation for a period of 6?months was associated with increased trabecular area, trabecular density and strength strain index at the ultra-distal tibia and radius and increased cortical area at tibial mid-shaft.     

Dose-related effect of urinary cotinine levels on bone mineral density among Korean females

Summary

To evaluate the dose-dependent relationship between smoking and bone mineral density (BMD), the present study used the BMD dataset of the Korean National Health and Nutrition Examination Survey IV (KNHANES IV). The linearity of BMD for urinary cotinine levels was demonstrated with statistical significance in postmenopausal females.

Introduction

It is well established that smoking is an important lifestyle risk factor for bone health (bone loss, osteoporosis, and fracture). However, several studies demonstrated conflicting evidence for a dose-dependent relationship between smoking and bone health. To evaluate the dose-dependent relationship between smoking and BMD, the present study estimated dose-related effects of smoking (urinary cotinine level) on BMD at various sites (femur neck, total femur, and lumbar spine) in females with controlling menopausal status.

Methods

The present study used the BMD dataset of the KNHANES IV, which was performed in 2008 and 2009. A total of 4,260 pre- and postmenopausal females were included in the present study. Dose–response relationships between BMD and urinary cotinine levels were estimated using analysis of covariance in pre-menopausal females and postmenopausal females, respectively.

Results

In postmenopausal females, the regression coefficients for BMD with urinary cotinine levels were ?0.006, ?0.006, and ?0.008 (g/cm² per ng/ml) at femur neck, total femur, and lumbar spine, respectively (p value?<?0.05). Thus, the linearity of BMD for urinary cotinine levels was demonstrated with statistical significance in postmenopausal females.

Conclusion

Our findings suggested a significant dose-related effect of urinary cotinine level with BMD at femur neck, total femur, and lumbar spine among postmenopausal females.     

The Value of Postoperative Parathyroid Hormone Levels in Predicting the Need for Long-Term Vitamin D Supplementation after Total Thyroidectomy

Background

Few studies have examined the need for vitamin D supplementation after total thyroidectomy. This study examines the role of postoperative day (POD) 1 serum calcium and parathyroid hormone (PTH) levels in predicting the need for long-term vitamin D supplementation after total thyroidectomy.

Methods

A retrospective, single institutional study of patients who underwent total thyroidectomy between January 2007 and December 2008 was performed. Data collected included extent of surgery, final pathology, postoperative calcium (mg/dl) and PTH (pg/ml) values, and duration of vitamin D supplementation. Patients were divided into 4 groups based on POD1 PTH values: group 1 (<5.0); group 2 (5.0–10); group 3 (10.1–20); and group 4 (>20).

Results

Of the 104 patients, 26 were in group 1, 12 in group 2, 18 in group 3, and 48 in group 4, with median PTH values of <2.5, 8.2, 14.1, and 30 pg/ml, respectively. All 7 (7%) patients who required vitamin D supplementation >1 month were in group 1. The positive predictive value of POD1 PTH <5.0 in predicting supplementation >1 month was 27% (sensitivity 100%, specificity 80%). Seventy-eight patients had a POD1 PTH level ≥5, and none required vitamin D supplementation >1 month (100% negative predictive value). The positive predictive value of various POD1 calcium thresholds (<7.5, <8.0, and <8.5 mg/dl) was 17, 14, and 15%, respectively.

Conclusions

Postoperative PTH levels better predict long-term hypocalcemia requiring vitamin D supplementation than serum calcium levels. A PTH level ≥5.0 may identify patients who can be safely discharged without routine vitamin D supplementation.