Bone mineralization defects and vitamin D deficiency: Histomorphometric analysis of iliac crest bone biopsies and circulating 25‐hydroxyvitamin D in 675 patients

Parathyroid hormone (PTH) is only one measurable index of skeletal health, and we reasoned that a histomorphometric analysis of iliac crest biopsies would be another and even more direct approach to assess bone health and address the required minimum 25‐Hydroxyvitamin D [25(OH)D] level. A cohort from the northern European population with its known high prevalence of vitamin D deficiency therefore would be ideal to answer the latter question. We examined 675 iliac crest biopsies from male and female individuals, excluding all patients who showed any signs of secondary bone diseases at autopsy. Structural histomorphometric parameters, including osteoid indices, were quantified using the Osteomeasure System according to ASBMR standards, and serum 25(OH)D levels were measured for all patients. Statistical analysis was performed by Student's t test. The histologic results demonstrate an unexpected high prevalence of mineralization defects, that is, a pathologic increase in osteoid. Indeed, 36.15% of the analyzed patients presented with an osteoid surface per bone surface (OS/BS) of more than 20%. Based on the most conservative threshold that defines osteomalacia at the histomorphometric level with a pathologic increase in osteoid volume per bone volume (OV/BV) greater than 2% manifest mineralization defects were present in 25.63% of the patients. The latter were found independent of bone volume per trabecular volume (BV/TV) throughout all ages and affected both sexes equally. While we could not establish a minimum 25(OH)D level that was inevitably associated with mineralization defects, we did not find pathologic accumulation of osteoid in any patient with circulating 25(OH)D above 75 nmol/L. Our data demonstrate that pathologic mineralization defects of bone occur in patients with a serum 25(OH)D below 75 nmol/L and strongly argue that in conjunction with a sufficient calcium intake, the dose of vitamin D supplementation should ensure that circulating levels of 25(OH)D reach this minimum threshold (75 nmol/L or 30 ng/mL) to maintain skeletal health. © 2010 American Society for Bone and Mineral Research     

Seasonal change in osteoid thickness and mineralization lag time in ambulant patients.

Low vitamin D levels are common. Bone biopsies taken from 121 ambulant patients were therefore reviewed. Seasonal changes in mineralization correlated inversely with serum 25-hydroxyvitamin D but not the more active metabolite, 1,25-dihydroxyvitamin D. This implies that the latter is produced in bone. INTRODUCTION: It has been 30 yr since a seasonal variation in osteoid surfaces and calcification fronts was noted in bone biopsies from hip fracture patients in Leeds and attributed to vitamin D status. It was suggested at that time that mild vitamin D deficiency might cause osteoporosis from malabsorption of calcium and more severe deficiency osteomalacia, but little has been published on this subject since. MATERIALS AND METHODS: We examined bone biopsies, calcium absorption data, and serum vitamin D metabolites in 121 patients attending our osteoporosis clinics in Adelaide. Biopsies were collected from the anterior iliac crest with a Jamshidi needle after two stat oral doses of 1 g of tetracycline 10 days apart, processed into plastic without demineralization, and all parameters were measured by point counting using a Weibel II graticule. Calcium absorption was measured after an oral dose of 5 microCi of (45)Ca in 250 ml of water with 20 mg of calcium carrier. Serum 25-hydroxyvitamin D [25(OH)D] was measured by radioimmunoassay and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] by radioimmunoassay after high-performance liquid chromatography (HPLC). RESULTS: 25(OH)D levels were lower from late autumn to early spring (April to September) than from late spring to early autumn (October to March) (51 +/- 23 versus 61 +/- 27 [SD] nM; p=0.040). None of the biopsies yielded a diagnosis of osteomalacia, but osteoid thickness (O.Th.) was greater in the winter than the summer months (8.5 +/- 3.6 versus 7.1 +/- 2.8 microm; p=0.015) as was mineralization lag time (MLT; 11.9 +/- 5.2 versus 9.5 +/- 3.6; p=0.005). O.Th and log MLT were both inversely related to serum 25(OH)D (p=0.014 and 0.036) but not serum 1,25(OH)(2)D. Calcium absorption was related to serum 1,25(OH)(2)D but not serum 25(OH)D. CONCLUSIONS: We conclude that circulating 25(OH)D affects the mineralization process, whereas circulating 1,25(OH)(2)D affects bone indirectly through its effect on calcium absorption.     

Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: Analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV‐3, 2009 and KNHANES V‐1, 2010)

The relative contributions of calcium and vitamin D to calcium metabolism and bone mineral density (BMD) have been examined previously, but not in a population with very low calcium intake. To determine the relative importance of dietary calcium intake and serum 25‐hydroxyvitamin D [25(OH)D] concentration to calcium metabolism and bone mass in a population with low calcium intake, a total of 4662 adults (2567 men and 2095 women) ≥50 years of age from the 2009–2010 Korea National Health and Nutrition Examination Survey (KNHANES) were divided into groups according to dietary calcium intakes (quintiles means: 154, 278, 400, 557, and 951 mg/d) and serum 25(OH)D concentrations (<50, 50–75, and >75 nmol/L). Serum intact parathyroid hormone (PTH) and femoral neck and lumbar spine BMD were evaluated according to dietary calcium intake and serum 25(OH)D. Mean calcium intake was 485 mg/d; mean serum 25(OH)D concentration was 48.1 nmol/L; PTH was 68.4 pg/mL; femoral neck BMD was 0.692 g/cm²; and lumbar spine BMD was 0.881 g/cm². Lower dietary calcium intakes were significantly associated with higher serum PTH concentrations and lower femoral neck BMD, not only at lower (<50 nmol/L) but also at higher (>75 nmol/L) serum 25(OH)D concentrations. Serum PTH was highest and femoral neck BMD was lowest in the group, with a serum 25(OH)D less than 50 nmol/L. In this low‐intake population, calcium intake is a significant determinant of serum PTH and BMD at higher as well as lower 25(OH)D levels. This finding indicates that low calcium intake cannot be compensated for with higher 25(OH)D levels alone. As expected, serum 25(OH)D levels were inversely associated with serum PTH and BMD. A calcium intake of at least 668 mg/d and a serum 25(OH)D level of at least 50 nmol/L may be needed to maintain bone mass in this calcium deficient population. © 2013 American Society for Bone and Mineral Research.     

Bone histomorphometry in celiac disease.

BACKGROUND AND AIMS: Bone metabolism in celiac patients is not well understood and there are no previous histomorphometric studies on bone of patients with celiac disease. The aim of the study was to investigate bone metabolism in celiac patients using bone histomorphometry, measurement of bone mineral density (BMD) and biochemical parameters. MATERIAL AND METHODS: The patient groups included 19 men and 23 women with previously diagnosed celiac disease in remission (group I), 7 women not in remission (group II) and 19 women and 9 men with newly diagnosed celiac disease (group III). Static and dynamic parameters of bone structure, formation and resorption were measured using undecalcified sections. The following parameters were obtained: bone volume (BV/TV; %), osteoid volume (OV/BV; %), osteoid surface (OS/BS; %), resoprtion surface (ES/BS; %), osteoid thickness(Oth; microm), mineral apposition rate (MAR; microm/day), and mineralization lag time (MinLag; day). BMD was measured at the spine (L2-4) and left femoral neck, trochanter and Ward's triangle. Serum calcium (S-Ca; mmol/L), alkaline phosphatase (AP; U/L), intact parathyroid hormone (S-PTH; ng/L), 25-hydroxyvitamin D (S-25(OH)D; nmol/L), cross-linked carboxyterminal telopeptide of human type I collagen (S-ICTP; microg/L) and C-terminal extension peptide of type I procollagen (S-PICP; microg/L) were analysed. RESULTS: In the histomorphometric analysis there were no significant differences in static or dynamic parameters between the groups. Very low bone mass (< 10%) was found in one patient in every group. OV/BV was increased (> 3.5%) in all groups (31% in group I, 13% in group II and 29% in group III). OS/BS was increased (> 36.5%) in groups I and III (17% and 29% respectively). In group II OS/BS was normal in all patients. Mineralization defect was found in four patients in group I and in two patients in group III with otherwise normal histomorphometric results. ES/BS was increased in three patients in group I and III and in one patient in group II. One female patient in group III had increased osteoid parameters, resorption surface, S-PTH and low concentration of vitamin D reflecting hyperparathyroid changes in bone. S-PTH was increased (66-87 ng/L) in four patients in group III and one of these patients had hyperparathyroid histological changes in bone. CONCLUSIONS: Static and dynamic histomorphometry of iliac crest bone biopsy are useful tools to evaluate bone metabolism in celiac disease especially if hyperparathyroidism or mineralization defect are suspected. Hyperparathyroidism may be a problem in the patients before introducing gluten-free diet. Mineralization defect and osteomalacic changes are common later on irrespective of whether the patients are in remission or not.     

Adverse interaction of low‐calcium diet and low 25(OH)D levels on lumbar spine mineralization in late‐pubertal girls

No consensus has been reached on the serum 25‐hydroxyvitamin D [25(OH)D] levels required to ensure optimal bone health around menarche. We searched for a possible interaction of 25(OH)D levels and calcium intake on lumbar spine mineralization and on biologic features of bone metabolism in healthy late‐pubertal girls. Lumbar spine parameters (ie, area, mineral content, and density) and calcium intake were evaluated in 211 healthy white adolescent girls at pubertal stages IV–V (11 to 16.9 years), together with biologic markers of calcium and bone metabolism and with International External Quality Assessment Scheme for Vitamin D Metabolite (DEQAS)–validated serum 25(OH)D levels. A high prevalence of 25(OH)D levels ≤ 30 nmol/L (41%), ≤40 nmol/L (61%), and ≤50 nmol/L (70%) was found during winter–spring. Parathyroid hormone (PTH) levels were inversely associated with 25(OH)D levels (p = .0021). In contrast, lumbar spine mineral content and density were not associated with 25(OH)D, excepted when calcium intake was below 600 mg/day (p = .0081). Girls with such low calcium intake and 25(OH)D levels of 40 nmol/L or less (9% of the cohort) had a 0.4 to 0.7 SD lower mean areal bone mineral density Z‐score than girls with higher calcium intake and/or higher 25(OH)D status. The adverse association between lumbar spine mineralization and combined calcium deficiency–low 25(OH)D levels remained significant in the 91 girls who could be followed over 4 years after their initial evaluation. We conclude that low 25(OH)D levels (≤40 nmol/L) are observed frequently during winter–spring in late‐pubertal European girls, which may exacerbate the negative impact of calcium deficiency on lumbar spine mineralization. © 2010 American Society for Bone and Mineral Research.     

Hip bone loss is attenuated with 1000 IU but not 400 IU daily vitamin D3: A 1‐year double‐blind RCT in postmenopausal women

Few year‐long vitamin D supplementation trials exist that match seasonal changes. The aim of this study was to determine whether daily oral vitamin D₃ at 400 IU or 1000 IU compared with placebo affects annual bone mineral density (BMD) change in postmenopausal women in a 1‐year double‐blind placebo controlled trial in Scotland. White women aged 60 to 70 years (n = 305) were randomized to one of two doses of vitamin D or placebo. All participants started simultaneously in January/February 2009, attending visits at bimonthly intervals with 265 (87%) women attending the final visit and an additional visit 1 month after treatment cessation. BMD (Lunar iDXA) and 1,25‐dihydroxyvitamin D[1,25(OH)₂D], N‐terminal propeptide of type 1 collagen [P1NP], C‐terminal telopeptide of type I collagen [CTX], and fibroblast growth factor‐23 [FGF23] were measured by immunoassay at the start and end of treatment. Circulating PTH, serum Ca, and total 25‐hydroxyvitamin D [25(OH)D] (latter by tandem mass spectrometry) were measured at each visit. Mean BMD loss at the hip was significantly less for the 1000 IU vitamin D group (0.05% ± 1.46%) compared with the 400 IU vitamin D or placebo groups (0.57% ± 1.33% and 0.60% ± 1.67%, respectively) (p < 0.05). Mean (± SD) baseline 25(OH)D was 33.8 ± 14.6 nmol/L; comparative 25(OH)D change for the placebo, 400 IU, and 1000 IU vitamin D groups was ?4.1 ± 11.5 nmol/L, +31.6 ± 19.8 nmol/L, and +42.6 ± 18.9 nmol/L, respectively. Treatment did not change markers of bone metabolism, except for a small reduction in PTH and an increase in serum calcium (latter with 1000 IU dose only). The discordance between the incremental increase in 25(OH)D between the 400 IU and 1000 IU vitamin D and effect on BMD suggests that 25(OH)D may not accurately reflect clinical outcome, nor how much vitamin D is being stored. © 2013 American Society for Bone and Mineral Research.     

Bone histology in patients with nephrotic syndrome and normal renal function

BACKGROUND: The prevalence of metabolic bone disease in patients with nephrotic syndrome (NS) at normal level of renal function remains uncertain. METHODS: To address this issue, we studied 30 patients (20 men and 10 women, mean age 27.3 +/- 11.7 years) with NS who had normal renal function (mean creatinine clearance 103 +/- 4 ml/min). We evaluated their serum calcium, phosphorus, alkaline phosphatase, immunoreactive parathyroid hormone (iPTH), vitamin D metabolites, urinary calcium, and skeletal survey. The extent of bone mineralization was analyzed by histomorphometric analysis of iliac crest bone biopsy specimens in all patients. The findings on bone histology were correlated with biochemical parameters. RESULTS: The mean duration of NS was 35.5 +/- 26.9 months, with a protein excretion of 7.3 +/- 3.2 g/24 hr and a serum albumin of 2.2 +/- 0.8 g/dl. Total serum calcium was 7.8 +/- 0.8 mg/dl, whereas ionized calcium was 5.7 +/- 0.7 mg/dl, phosphorus 3.2 +/- 1.2 mg/dl, and alkaline phosphatase 149 +/- 48.6 U/liter. Serum iPTH levels were normal in all except two patients. The mean serum 25-hydroxyvitamin D [25(OH)D] level was 3.9 +/- 1.2 ng/ml (normal 15 to 30 ng/ml), whereas 1,25-dihydroxyvitamin D was 24 +/- 4.7 pg/ml (normal 16 to 65). There was an inverse correlation between serum levels of 25(OH)D and the magnitude of proteinuria (r = -0.42, P < 0.05). The mean 24-hour urinary calcium excretion was 82 +/- 21 mg/day. The skeletal survey was normal in all patients. Bone histology was normal in 33.3% of the patients, whereas 56.7% had isolated osteomalacia (OSM), and 10% had an increased bone resorption in association with defective mineralization. The severity of OSM measured by mineralization lag time correlated linearly with the duration (r = 0.94, P < 0.0001) and the amount (r = 0.97, P < 0.0001) of proteinuria. All patients with NS for more than three years had histological changes. Patients with OSM had lower 25(OH)D and serum albumin as compared with those with normal histology (P < 0.005). Bone mineralization had no significant correlation with serum iPTH, divalent ions, or vitamin D levels. CONCLUSIONS: OSM is a frequent finding in adult patients with NS, even at a normal level of renal function. Its severity correlates with the amount and duration of proteinuria.     

Vitamin D status, bone mass, and bone metabolism in home-dwelling postmenopausal Japanese women: Yokogoshi Study

Little has been understood about vitamin D status in relation to bone health in Asian women. The purpose of this study was to identify how the serum 25-hydroxyvitamin D (25[OH]D) concentration is associated with bone mass and bone metabolism. This cross-sectional, community-based epidemiologic study was conducted among 600 ambulatory postmenopausal women. The serum 25(OH)D concentration was measured with radioimmunoassay. Other blood biochemical measurements were intact parathyroid hormone and markers of bone turnover, including osteocalcin and type I collagen cross-linked N-telopeptides. Bone mineral density (BMD) of the lumbar spine and right femoral neck were measured with the dual-energy X-ray absorptiometry method using a QDR4500a. The mean serum 25(OH)D concentration was 55.6 nmol/L (SD 14.6). Serum 25(OH)D concentration was linearly associated with BMD of the femoral neck (R(2)=0.020, P=0.003), but not with BMD of the lumbar spine. Odds ratios (ORs) for low BMD (defined as t score < or =-2.5 SD) were calculated for strata defined by 25(OH)D concentration. The prevalence of low BMD of the lumbar spine was significantly higher in the 40- to 50-nmol/L 25(OH)D group (adjusted OR=3.0, 95% CI: 1.3-7.0) compared to the reference group (> or =70 nmol/L). Prevalence of low BMD for the femoral neck was significantly higher in the 30- to 40-nmol/L (adjusted OR=3.6, 95% CI: 1.1-12.1) and the 40- to 50-nmol/L (adjusted OR=7.6, 95% CI: 2.5-23.2) groups compared to the reference group (> or =70 nmol/L). The mean serum concentration of intact PTH was significantly higher in subjects with serum 25(OH)D <50 nmol/L compared to those with serum 25(OH)D > or =50 nmol/L. The present study suggests that higher serum 25(OH)D concentrations are associated with increased BMD of the femoral neck, and that a serum 25(OH)D concentration of at least 70 nmol/L is needed to obtain high BMD of the femoral neck, and that of at least 50 nmol/L is needed to achieve normal PTH levels and prevent low BMD in home-dwelling postmenopausal Japanese women.     

Correction of preoperative vitamin D deficiency after Roux-en-Y gastric bypass surgery

BACKGROUND: To evaluate the adequacy of supplementation to correct preoperative vitamin D deficiency in adult patients during the year after Roux-en-Y gastric bypass (RYGB) surgery. METHODS: The medical records were reviewed and the preoperative and 12-month postoperative serum 25-hydroxyvitamin D [25(OH)D] levels were compared in patients who underwent RYGB from 2002 to 2004. The serum 25(OH)D levels were defined as being optimal (> or = 80 nmol/L), suboptimal (50-79 nmol/L), or deficient (<50 nmol/L). Patients with deficient 25(OH)D levels were prescribed 50,000 IU ergocalciferol weekly. The remaining patients averaged 710 IU supplemental vitamin D intake daily. RESULTS: The mean patient age was 43.8 +/- 10.7 years, and the mean preoperative body mass index was 51.8 +/- 9.8 kg/m2. Of the 95 patients with baseline and 12-month 25(OH)D levels, 89% were women. The mean preoperative 25(OH)D level was 49.7 +/- 26.5 nmol/L; 34% had suboptimal 25(OH)D levels and 54% had deficient levels before surgery. Twelve months after surgery, those receiving 50,000 IU weekly (n = 40) had a mean 25(OH)D level of 69.2 +/- 22.2 nmol/L; 63% had suboptimal and 8% deficient levels. Those taking 710 IU daily (n = 55) had a mean 25(OH)D level of 85.5 +/- 33.0 nmol/L; 44% had suboptimal and 6% deficient levels. CONCLUSION: Vitamin D deficiency is prevalent in RYGB patients before surgery. The vitamin D status improved markedly after RYGB surgery with either 710 IU vitamin D daily or 50,000 IU weekly. Current supplementation practices do not appear to optimize the serum 25(OH)D levels and need to be more closely examined.     

Temporal trends and determinants of longitudinal change in 25-hydroxyvitamin D and parathyroid hormone levels

Vitamin D is essential for facilitating calcium absorption and preventing increases in parathyroid hormone (PTH), which can augment bone resorption. Our objectives were to examine serum levels of 25-hydroxyvitamin D [25(OH)D] and PTH, and factors related to longitudinal change in a population-based cohort. This is the first longitudinal population-based study looking at PTH and 25(OH)D levels. We analyzed 3896 blood samples from 1896 women and 829 men in the Canadian Multicentre Osteoporosis Study over a 10-year period starting in 1995 to 1997. We fit hierarchical models with all available data and adjusted for season. Over 10 years, vitamin D supplement intake increased by 317 (95% confidence interval [CI] 277 to 359) IU/day in women and by 193 (135 to 252) IU/day in men. Serum 25(OH)D (without adjustment) increased by 9.3 (7.3 to 11.4) nmol/L in women and by 3.5 (0.6 to 6.4) nmol/L in men but increased by 4.7 (2.4 to 7.0) nmol/L in women and by 2.7 (-0.6 to 6.2) nmol/L in men after adjustment for vitamin D supplements. The percentage of participants with 25(OH)D levels <50 nmol/L was 29.7% (26.2 to 33.2) at baseline and 19.8% (18.0 to 21.6) at year 10 follow-up. PTH decreased over 10 years by 7.9 (5.4 to 11.3) pg/mL in women and by 4.6 (0.2 to 9.0) pg/mL in men. Higher 25(OH)D levels were associated with summer, younger age, lower body mass index (BMI), regular physical activity, sun exposure, and higher total calcium intake. Lower PTH levels were associated with younger age and higher 25(OH)D levels in both women and men and with lower BMI and participation in regular physical activity in women only. We have observed concurrent increasing 25(OH)D levels and decreasing PTH levels over 10 years. Secular increases in supplemental vitamin D intake influenced both changes in serum 25(OH)D and PTH levels.     

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.     

Predictive risk factors for postoperative tetany in female patients with Graves' disease

BACKGROUND: Postoperative tetany occurs in patients with secondary hyperparathyroidism caused by a deficiency in calcium and vitamin D concomitant with transient hypoparathyroidism induced by surgery. In the present study, we further clarified the risk factors by referring to serum 25-hydroxyvitamin D [25(OH)D] and alkaline phosphatase. STUDY DESIGN: The serum levels of intact parathyroid hormone, calcium and other electrolytes, and 25-hydroxyvitamin D [25(OH)D] were measured preoperatively in 178 female patients with Graves' disease who underwent subtotal thyroidectomy. RESULTS: Of the 178 female patients, 15 (8.4%) developed tetany. Univariate analysis of 16 possible risk factors showed that 2 were statistically significant: serum 25(OH)D and alkaline phosphatase levels. The incidence of tetany according to the serum levels of 25(OH)D and alkaline phosphatase was 19.1% (9/47) in patients with 25(OH)D < or = 25 nmol/L and alkaline phosphatase > 155, 11.8% (4/34) in those with 25(OH)D < or = 25 nmol/L and alkaline phosphatase < or = 155, 6.7% (2/30) in those with 25(OH)D > 25 nmol/L and alkaline phosphatase > 155, and 0% (0/50) in those with 25(OH)D > 25 nmol/L and alkaline phosphatase < or = 155. CONCLUSIONS: Patients with Graves' disease who have vitamin D deficiency with high serum alkaline phosphatase levels are the highest-risk group for postoperative tetany. Serum 25(OH)D and alkaline phosphatase should be monitored in patients with Graves' disease.     

Serum 25(OH)-vitamin D levels and bone metabolism in patients on maintenance hemodialysis

AIMS: An increasing amount of evidence suggests that 25-hydroxy vitamin D3 (25(OH)D3) may contribute to the bone health of patients with chronic kidney disease (CKD). The underlying vitamin D status of these patients, however, has often been neglected. In a cross-sectional study we assessed the association between vitamin D status and parathyroid function, bone turnover, bone mass and structure in patients on maintenance hemodialysis. METHODS: 69 patients on maintenance hemodialysis were assessed by bone densitometry (DEXA) and quantitative bone ultrasound (QUS). Serum 25-hydroxy vitamin D3 levels, serum markers of bone turnover and clinical data were tabulated. RESULTS: A high prevalence of potentially significant vitamin D3 deficiency was found in this patient group: 59% of the patients had a 25(OH)D3 level below 20 nmol/l. There was a significant negative correlation between serum 25(OH)D3 levels and serum intact parathyroid hormone (iPTH) (r = -0.231, p < 0.05), and this association remained significant after controlling for potential covariables. Furthermore, we show here that serum 25(OH)D3 concentration is positively correlated with bone mineral density (BMD) measured at the radius (r = 0.424, p < 0.01). Finally, we show for the first time that 25(OH)D3 levels are significantly and independently correlated with broadband ultrasound attenuation (beta = 0.262, p < 0.05) measured with calcaneal quantitative bone ultrasound (QUS) in patients with chronic renal failure. CONCLUSION: Vitamin D3 deficiency may contribute to the impaired bone health of patients on maintenance dialysis.     

Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues?

The vitamin D endocrine system is critical for the maintenance of circulating calcium concentrations, but recently, there has been advocacy for the widespread use of vitamin D supplements to improve skeletal and nonskeletal health. Recent studies of tissue-selective vitamin D receptor knockout mice indicate that the principal action of vitamin D responsible for the maintenance of calcium homoeostasis is the regulation of intestinal calcium absorption. High levels of vitamin D can increase bone resorption and impair mineralization, consistent with its role in maintaining circulating calcium concentrations. These findings suggest that circumspection is appropriate in its clinical use. There is now substantial clinical trial data with vitamin D supplements, which fails to establish their efficacy on bone density or the prevention of falls or fractures. However, some trials in frail and/or vitamin D-deficient populations have produced positive outcomes. Where there are positive effects of vitamin D supplementation on skeletal outcomes, these are mainly seen in cohorts with baseline circulating 25-hydroxyvitamin D (25(OH)D) levels in the range 25–40 nmol/L or lower. A great diversity of nonskeletal conditions have been associated with low 25(OH)D, but there is little evidence for efficacy of vitamin D supplementation for such end-points. At present, supplements should be advised for populations with risk factors (e.g., lifestyle, skin color, and frailty) for having serum 25(OH)D levels in the 25- to 40-nmol/L range or below. A dose of ≤800 IU/day is adequate. This approach will maintain 25(OH)D levels well above the threshold for osteomalacia and makes allowance for the poor accuracy and precision of some 25(OH)D assays.     

Correction of preoperative vitamin D deficiency after Roux-en-Y gastric bypass surgery

BackgroundTo evaluate the adequacy of supplementation to correct preoperative vitamin D deficiency in adult patients during the year after Roux-en-Y gastric bypass (RYGB) surgery.MethodsThe medical records were reviewed and the preoperative and 12-month postoperative serum 25-hydroxyvitamin D [25(OH)D] levels were compared in patients who underwent RYGB from 2002 to 2004. The serum 25(OH)D levels were defined as being optimal (≥80 nmol/L), suboptimal (50–79 nmol/L), or deficient (<50 nmol/L). Patients with deficient 25(OH)D levels were prescribed 50,000 IU ergocalciferol weekly. The remaining patients averaged 710 IU supplemental vitamin D intake daily.ResultsThe mean patient age was 43.8 ± 10.7 years, and the mean preoperative body mass index was 51.8 ± 9.8 kg/m². Of the 95 patients with baseline and 12-month 25(OH)D levels, 89% were women. The mean preoperative 25(OH)D level was 49.7 ± 26.5 nmol/L; 34% had suboptimal 25(OH)D levels and 54% had deficient levels before surgery. Twelve months after surgery, those receiving 50,000 IU weekly (n = 40) had a mean 25(OH)D level of 69.2 ± 22.2 nmol/L; 63% had suboptimal and 8% deficient levels. Those taking 710 IU daily (n = 55) had a mean 25(OH)D level of 85.5 ± 33.0 nmol/L; 44% had suboptimal and 6% deficient levels.ConclusionVitamin D deficiency is prevalent in RYGB patients before surgery. The vitamin D status improved markedly after RYGB surgery with either 710 IU vitamin D daily or 50,000 IU weekly. Current supplementation practices do not appear to optimize the serum 25(OH)D levels and need to be more closely examined.     

Lack of osteomalacia in chronic cholestatic liver disease

Assessment of osteomalacia using rigorous histologic definition was carried out in 36 unselected patients with chronic cholestatic liver disease, 33 with primary biliary cirrhosis, and 3 with primary sclerosing cholangitis. Disease duration varied from 1 to 11 years. The mean values for total trabecular bone volume, osteoid volume, osteoid surface, and mineralization appositional rate were all decreased when compared to age-matched and sex-matched controls. There was a highly significant decrease in the mean osteoid seam width in both females (P = 0.001) and males (P = 0.02), and a significant prolongation of the mineralization lag time was found in females (P = 0.05), but failed to reach significance in males. These results excluded osteomalacia but were more indicative of osteoporosis. Biochemical evidence of osteomalacia was also absent, with serum calcium, serum phosphorus, and mean 25-hydroxyvitamin D levels not significantly different from control values, although there was a nonsignificant decrease in the mean value of 25-hydroxyvitamin D in patients with elevated serum bilirubin levels, and all patients with levels below 20 nmol/L had avoided sunlight exposure. The present results suggest that osteoporosis is the major type of metabolic bone disease in patients with chronic cholestatic liver disease.     

Impaired bone mineralization accompanied by low vitamin D and secondary hyperparathyroidism in patients with femoral neck fracture

Summary

Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal bone mineral density (BMD) is rather low. Here, we have identified bone mineralization defects together with low serum 25-hydroxyvitamin D (25-(OH) D) levels as additional factors associated with femoral neck fractures.

Introduction

Osteoporotic fractures of the femoral neck are associated with increased morbidity and mortality. Although it is well established that a decrease in bone mass increases the risk of osteoporotic fractures, the proportion of fractures attributable to areal BMD is rather low. To identify possible additional factors influencing femur neck fragility, we analyzed patients with femoral neck fracture.

Methods

We performed a detailed clinical and histomorphometrical evaluation on 103 patients with femoral neck fracture including dual-energy X-ray absorptiometry, laboratory parameters, and histomorphometric and bone mineral density distribution (BMDD) analyses of undecalcified processed biopsies of the femoral head and set them in direct comparison to skeletal healthy control individuals.

Results

Patients with femoral neck fracture displayed significantly lower serum 25-(OH) D levels and increased serum parathyroid hormone (PTH) compared to controls. Histomorphometric analysis revealed not only a decreased bone volume and trabecular thickness in the biopsies of the patients, but also a significant increase of osteoid indices. BMDD analysis showed increased heterogeneity of mineralization in patients with femoral neck fracture. Moreover, patients with femoral neck fracture and serum 25-(OH) D levels below 12 μg/l displayed significantly thinner trabecular bone.

Conclusion

Taken together, our data suggest that impaired bone mineralization accompanied by low serum 25-(OH) D levels is of major importance in the etiology of femoral neck fractures. Therefore, balancing serum 25-(OH) D levels and thereby normalizing PTH serum levels may counteract pronounced mineralization defects and might decrease the incidence of femoral neck fractures.     

Osteogenesis imperfecta type VI: a form of brittle bone disease with a mineralization defect.

Osteogenesis imperfecta (OI) is a heritable disease of bone in which the hallmark is bone fragility. Usually, the disorder is divided into four groups on clinical grounds. We previously described a group of patients initially classified with OI type IV who had a discrete phenotype including hyperplastic callus formation without evidence of mutations in type I collagen. We called that disease entity OI type V. In this study, we describe another group of 8 patients initially diagnosed with OI type IV who share unique, common characteristics. We propose to name this disorder "OI type VI." Fractures were first documented between 4 and 18 months of age. Patients with OI type VI sustained more frequent fractures than patients with OI type IV. Sclerae were white or faintly blue and dentinogenesis imperfecta was uniformly absent. All patients had vertebral compression fractures. No patients showed radiological signs of rickets. Lumbar spine areal bone mineral density (aBMD) was low and similar to age-matched patients with OI type IV. Serum alkaline phosphatase levels were elevated compared with age-matched patients with type IV OI (409 +/- 145 U/liter vs. 295 +/- 95 U/liter; p < 0.03 by t-test). Other biochemical parameters of bone and mineral metabolism were within the reference range. Mutation screening of the coding regions and exon/intron boundaries of both collagen type I genes did not reveal any mutations, and type I collagen protein analyses were normal. Qualitative histology of iliac crest bone biopsy specimens showed an absence of the birefringent pattern of normal lamellar bone under polarized light, often with a "fish-scale" pattern. Quantitative histomorphometry revealed thin cortices, hyperosteoidosis, and a prolonged mineralization lag time in the presence of a decreased mineral apposition rate. We conclude that type VI OI is a moderate to severe form of brittle bone disease with accumulation of osteoid due to a mineralization defect, in the absence of a disturbance of mineral metabolism. The underlying genetic defect remains to be elucidated.     

Relationship between serum 25-hydroxyvitamin D and bone resorption markers in vitamin D insufficiency

It is known that nursing-home patients with vitamin D insufficiency have elevated serum parathyroid hormone (PTH) as well as raised serum alkaline phosphatase (ALP). Although it is well known that vitamin D insufficiency and secondary hyperparathyroidism are common among the elderly in western countries, there is continuing controversy over the level of serum 25-hydroxyvitamin D [25(OH)D] necessary for bone health. We approached this issue by examining the relationships between serum 25(OH)D, ionized calcium, PTH, and ALP and the urinary bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline, corrected for creatinine (OHPr/Cr, Pyd/Cr, and Dpd/Cr, respectively), in 486 postmenopausal women of mean age 63 (SD 9.5) years, who were referred to our osteoporosis and menopause clinics for investigation. When the patients were divided into two groups with 25(OH)D above and below 20 nmol/L, 30 nmol/L, 40 nmol/L, 50 nmol/L, 60 nmol/L, or 70 nmol/L, the most significant differences between the two groups thus derived was found at a serum 25(OH)D level of 60 nmol/L (P < 0.001 for all markers). The most significant difference between groups for serum PTH was found when the patients were divided at a serum 25(OH)D of 50 nmol/L. PTH, OHPr/Cr, Pyd/Cr, and ALP were inversely related to serum 25(OH)D. PTH was inversely related to serum ionized calcium. There was a trend for ionized calcium to be positively related to 25(OH)D, but this did not reach statistical significance. We conclude that rises in three bone resorption markers and ALP can be detected in postmenopausal women when the serum 25(OH)D level falls below 60 nmol/L. Levels above this may be required for optimal bone health.     

Optimal Use of Vitamin D When Treating Osteoporosis

Inadequate serum 25-hydroxyvitamin D (25[OH]D) concentrations are associated with muscle weakness, decreased physical performance, and increased propensity in falls and fractures. This paper discusses several aspects with regard to vitamin D status and supplementation when treating patients with osteoporosis in relation to risks and prevention of falls and fractures. Based on evidence from literature, adequate supplementation with at least 700 IU of vitamin D, preferably cholecalciferol, is required for improving physical function and prevention of falls and fractures. Additional calcium supplementation may be considered when dietary calcium intake is below 700 mg/day. For optimal bone mineral density response in patients treated with antiresorptive or anabolic therapy, adequate vitamin D and calcium supplementation is also necessary. Monitoring of 25(OH)D levels during follow-up and adjustment of vitamin D supplementation should be considered to reach and maintain adequate serum 25(OH)D levels of at least 50 nmol/L, preferably greater than 75 nmol/L in all patients.