Correction to: Weaker bones and white skin as adaptions to improve anthropological "fitness" for northern environments.

The original version of this article, published on 06 November 2019 unfortunately contained a mistake.

Weaker bones and white skin as adaptions to improve anthropological "fitness" for northern environments.

The vitamin D paradox relates to the lower risk of osteoporosis in people of sub-Saharan African ancestry (Blacks) compared with people of European ancestry (Whites). The paradox implies that for bone health, Blacks require less vitamin D and calcium than Whites do. Why should populations that migrated northward out of Africa have ended up needing more vitamin D than tropical Blacks? Human skin color became lighter away from the tropics to permit greater skin penetration of the UVB light that generates vitamin D. Lack of vitamin D impairs intestinal calcium absorption and limits the amount of calcium that can deposit into the protein matrix of bone, causing rickets or osteomalacia. These can cause cephalopelvic disproportion and death in childbirth. Whiter skin was more fit for reproduction in UV-light restricted environments, but natural selection was also driven by the phenotype of bone per se. Bone formation starts with the deposition of bone-matrix proteins. Mineralization of the matrix happens more slowly, and it stiffens bone. If vitamin D and/or calcium supplies are marginal, larger bones will not be as fully mineralized as smaller bones. For the same amount of mineral, unmineralized or partially mineralized bone is more easily deformed than fully mineralized bone. The evidence leads to the hypothesis that to minimize the soft bone that causes pelvic deformation, a decrease in amount of bone, along with more rapid mineralization of osteoid improved reproductive fitness in Whites. Adaptation of bone biology for reproductive fitness in response to the environmental stress of limited availability of vitamin D and calcium came at the cost of greater risk of osteoporosis later in life.

Greater seasonal cycling of 25-hydroxyvitamin D is associated with increased parathyroid hormone and bone resorption.

SUMMARY: This analysis assessed whether seasonal change in 25-hydroxyvitamin D concentration was associated with bone resorption, as evidenced by serum parathyroid hormone and C-terminal telopeptide concentrations. The main finding was that increased seasonal fluctuation in 25-hydroxyvitamin D was associated with increased levels of parathyroid hormone and C-terminal telopeptide. INTRODUCTION: It is established that adequate 25-hydroxyvitamin D (25(OH)D, vitamin D) concentration is required for healthy bone mineralisation. It is unknown whether seasonal fluctuations in 25(OH)D also impact on bone health. If large seasonal fluctuations in 25(OH)D were associated with increased bone resorption, this would suggest a detriment to bone health. Therefore, this analysis assessed whether there is an association between seasonal variation in 25(OH)D and bone resorption. METHODS: The participants were (n = 279) Caucasian and (n = 88) South Asian women (mean (±SD); age 48.2 years (14.4)) who participated in the longitudinal Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England study (2006-2007). The main outcomes were serum 25(OH)D, serum parathyroid hormone (sPTH) and serum C-terminal telopeptide of collagen (sCTX), sampled once per season for each participant. RESULTS: Non-linear mixed modelling showed the (amplitude/mesor) ratio for seasonal change in log 25(OH)D to be predictive of log sPTH (estimate = 0.057, 95 % CI (0.051, 0.063), p < 0.0001). Therefore, individuals with a higher seasonal change in log 25(OH)D, adjusted for overall log 25(OH)D concentration, showed increased levels of log sPTH. There was a corresponding significant ability to predict the range of seasonal change in log 25(OH)D through the level of sCTX. Here, the corresponding parameter statistics were estimate = 0.528, 95 % CI (0.418, 0.638) and p ≤ 0.0001. CONCLUSIONS: These findings suggest a possible detriment to bone health via increased levels of sPTH and sCTX in individuals with a larger seasonal change in 25(OH)D concentration. Further larger cohort studies are required to further investigate these preliminary findings.

Association between serum 25-hydroxyvitamin D in early pregnancy and risk of gestational diabetes mellitus.

AIMS: There is emerging evidence of a relationship between vitamin D insufficiency and glucose intolerance. The aim of this study was to determine whether low serum 25-hydroxyvitamin D in early pregnancy is associated with an increased risk of gestational diabetes mellitus. METHODS: This nested case-control study examined the association between serum 25-hydroxyvitamin D and risk of gestational diabetes within a cohort of pregnant women from March 2008 to December 2009, who had undergone antenatal screening between 15 and 18 weeks gestation and subsequent glucose tolerance testing. Cases were women diagnosed with gestational diabetes and each case was matched to up to two controls without gestational diabetes on age, race and date of blood collection. Serum 25-hydroxyvitamin D was measured from stored antenatal screening samples and compared between cases and controls. RESULTS: Of the 116 women with gestational diabetes and 219 control subjects studied, the average age was 34.3 years and 41% were of non-Caucasian race. Women with gestational diabetes had significantly lower serum 25-hydroxyvitamin D compared with control subjects (56.3 vs. 62.0 nmol/l, P = 0.018). After adjusting for gestational age and maternal weight, serum 25-hydroxyvitamin D below the top quartile (< 73.5 nmol/l) was associated with a twofold greater likelihood of gestational diabetes (adjusted odds ratio 2.21, 95% confidence interval 1.19-4.13). CONCLUSIONS: Lower vitamin D status in early pregnancy was associated with a significantly increased risk of subsequent gestational diabetes that was independent of race, age, season and maternal weight. This study suggests that vitamin D may influence glucose tolerance during pregnancy and provides support for studies of vitamin D as a potential intervention to prevent gestational diabetes.

Proceedings of the Rank Forum on Vitamin D.

The Rank Forum on Vitamin D was held on 2nd and 3rd July 2009 at the University of Surrey, Guildford, UK. The workshop consisted of a series of scene-setting presentations to address the current issues and challenges concerning vitamin D and health, and included an open discussion focusing on the identification of the concentrations of serum 25-hydroxyvitamin D (25(OH)D) (a marker of vitamin D status) that may be regarded as optimal, and the implications this process may have in the setting of future dietary reference values for vitamin D in the UK. The Forum was in agreement with the fact that it is desirable for all of the population to have a serum 25(OH)D concentration above 25 nmol/l, but it discussed some uncertainty about the strength of evidence for the need to aim for substantially higher concentrations (25(OH)D concentrations>75 nmol/l). Any discussion of 'optimal' concentration of serum 25(OH)D needs to define 'optimal' with care since it is important to consider the normal distribution of requirements and the vitamin D needs for a wide range of outcomes. Current UK reference values concentrate on the requirements of particular subgroups of the population; this differs from the approaches used in other European countries where a wider range of age groups tend to be covered. With the re-emergence of rickets and the public health burden of low vitamin D status being already apparent, there is a need for urgent action from policy makers and risk managers. The Forum highlighted concerns regarding the failure of implementation of existing strategies in the UK for achieving current vitamin D recommendations.

Change in urinary markers of osteoclast activity following palliative radiotherapy for bone metastases.

AIMS: To examine the effect of radiotherapy for bone metastases on urinary markers of osteoclast activity. MATERIALS AND METHODS: Patients with radiological evidence of bone metastases planned for palliative radiotherapy were eligible for the study. A urine specimen was collected before and 1 month after radiotherapy to assess levels of calcium, creatinine, magnesium, phosphate, N-telopeptide and pyridinoline. The Brief Pain Inventory was completed in person at baseline and by telephone follow-up at 1 month after radiotherapy. Patients were classified as responders (complete or partial pain response) or non-responders (stable or progressive pain) to radiotherapy based on the International Bone Metastases Consensus Criteria for end point measurements. Absolute values of urine markers were compared between responders and non-responders, or between responders and patients with progression. RESULTS: Our study population consisted of 74 men and 51 women. A single 8 Gy or 20 Gy in five daily fractions were commonly employed. At the 1 month follow-up, all Brief Pain Inventory functional interference scores showed a highly significant decrease from baseline (P<0.01). From our study population, 58 (64%) were classified as responders and 57 (46%) as non-responders to radiotherapy. We compared the urinary markers between the responders and the non-responders. There were no statistically significant differences between the two groups either in terms of baseline markers or in terms of month 1 follow-up markers. There was no significant change from baseline to the 1 month follow-up in responders or in non-responders to radiotherapy. CONCLUSION: Baseline levels of urinary markers could not predict which patient would benefit from palliative radiotherapy.

Higher bone resorption excretion in South Asian women vs. White Caucasians and increased bone loss with higher seasonal cycling of vitamin D: Results from the D-FINES cohort study.

Few data exist on bone turnover in South Asian women and it is not well elucidated as to whether Western dwelling South Asian women have different bone resorption levels to that of women from European ethnic backgrounds. This study assessed bone resorption levels in UK dwelling South Asian and Caucasian women as well as evaluating whether seasonal variation in 25-hydroxyvitamin D [25(OH)D] is associated with bone resorption in either ethnic group. Data for seasonal measures of urinary N-telopeptide of collagen (uNTX) and serum 25(OH)D were analysed from n=373 women (four groups; South Asian postmenopausal n=44, South Asian premenopausal n=50, Caucasian postmenopausal n=144, Caucasian premenopausal n=135) (mean (±SD) age 48 (14) years; age range 18-79years) who participated in the longitudinal D-FINES (Diet, Food Intake, Nutrition and Exposure to the Sun in Southern England) cohort study (2006-2007). A mixed between-within subjects ANOVA (n=192) showed a between subjects effect of the four groups (P<0.001) on uNTX concentration, but no significant main effect of season (P=0.163). Bonferroni adjusted Post hoc tests (P≤0.008) suggested that there was no significant difference between the postmenopausal Asian and premenopausal Asian groups. Season specific age-matched-pairs analyses showed that in winter (P=0.04) and spring (P=0.007), premenopausal Asian women had a 16 to 20nmolBCE/mmol Cr higher uNTX than premenopausal Caucasian women. The (amplitude/mesor) ratio (i.e. seasonal change) for 25(OH)D was predictive of uNTX, with estimate (SD)=0.213 (0.015) and 95% CI (0.182, 0.245; P<0.001) in a non-linear mixed model (n=154). This showed that individuals with a higher seasonal change in 25(OH)D, adjusted for overall 25(OH)D concentration, showed increased levels of uNTX. Although the effect size was smaller than for the amplitude/mesor ratio, the mesor for 25(OH)D concentration was also predictive of uNTX, with estimate (SD)=-0.035 (0.004), and 95% CI (-0.043, -0.028; P<0.001). This study demonstrates higher levels of uNTX in premenopausal South Asian women than would be expected for their age, being greater than same-age Caucasian women, and similar to postmenopausal Asian women. This highlights potentially higher than expected bone resorption levels in premenopausal South Asian women which, if not offset by concurrent increased bone formation, may have future clinical and public health implications which warrant further investigation. Individuals with a larger seasonal change in 25(OH)D concentration showed an increased bone resorption, an association which was larger than that of the 25(OH)D yearly average, suggesting it may be as important clinically to ensure a stable and steady 25(OH)D concentration, as well as one that is high enough to be optimal for bone health.

The genetic influence on bone susceptibility to fluoride.

INTRODUCTION: The influence of genetic background on bone architecture and mechanical properties is well established. Nevertheless, to date, only few animal studies explore an underlying genetic basis for extrinsic factors effect such as fluoride effect on bone metabolism. MATERIALS AND METHODS: This study assessed the effect of increasing fluoride doses (0 ppm, 25 ppm, 50 ppm, 100 ppm) on the bone properties in 3 inbred mouse strains that demonstrate different susceptibilities to developing enamel fluorosis (A/J a "susceptible" strain, 129P3/J a "resistant" strain and SWR/J an "intermediate" strain). Fluoride concentrations were determined in femora and vertebral bodies. Bone mineral density was evaluating through DEXA. Finally, three-point bend testing of femora, compression testing of vertebral bodies and femoral neck-fracture testing were performed to evaluate mechanical properties. RESULTS: Concordant with increasing fluoride dose were significant increases of fluoride concentration in femora and vertebral bodies from all 3 strains. Fluoride treatment had little effect on the bone mineral densities (BMD) in the 3 strains. Mechanical testing showed significant alterations in "bone quality" in the A/J strain, whereas moderate alterations in "bone quality" in the SWR/J strain and no effects in the 129P3/J strain were observed. CONCLUSION: The results suggest that genetic factors may contribute to the variation in bone response to fluoride exposure and that fluoride might affect bone properties without altering BMD.

Presystemic 24-hydroxylation of oral 25-hydroxyvitamin D3 in rats.

The metabolism of 25-hydroxyvitamin D3 (25-OHD3) was compared following its intracardial or gastric administration. The rats were deprived of calcium and vitamin D. A mixture of radiolabeled (0.3 microCi) and stable (2 micrograms) 25-OHD3 was given as a single dose. After 24 h the rats given the dose by gastric tube had significantly lower serum concentrations of 25-OHD3 and 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3] than those injected intracardially. In contrast, serum 24,25-dihydroxyvitamin D3 [24,25-(OH)2D3] was much higher in the rats given the 25-OHD3 dose by gastric tube (6.2 nmol/liter +/- 1.3 SD, n = 7) compared to the intracardial group (0.9 nmol/liter +/- 0.5, p less than 0.001). The preceding results were based on specific radioactivity of metabolites. The same findings were obtained by reanalyzing the samples using conventional competitive binding assays for 25-OHD3, 1,25-(OH)2D3, and 24,25-(OH)2D3. The results show that orally administered 25-OHD3 is partly metabolized to 24,25-(OH)2D3 presystemically.

Alleles of the estrogen receptor alpha-gene and an estrogen receptor cotranscriptional activator gene, amplified in breast cancer-1 (AIB1), are associated with quantitative calcaneal ultrasound.

Quantitative bone ultrasound (QUS) has a significant heritable component. Because estrogen is required for attainment of peak bone mass, we studied alleles of two genes, estrogen receptor alpha (ER1) and amplified in breast cancer-1 (AIB1), for their association with QUS. In a volunteer sample of 663 white women aged 18-35 years, bone ultrasound attenuation (BUA), speed of sound (SOS), and heel stiffness index (SI), the latter consisting of the component measures of BUA and SOS, were measured at the right calcaneus by QUS. Subjects were genotyped for the ER1 polymorphisms Xba I and Pvu II and for the AIB1 polyglutamine tract polymorphism. In a multiple regression analysis, ER1 genotype was an independent predictor of QUS-SI (p = 0.03). Because AIB1 and ER1 enhance gene expression in a coordinate manner, we also searched for interactions. A gene-by-gene interaction effect was seen for QUS-SI (p = 0.009), QUS-BUA (p = 0.03), and QUS-SOS (p = 0.004). These remained significant after the inclusion of clinically relevant variables into the final regression model. Overall, these clinical and genetic factors accounted for up to 16% of the variance in peak QUS; the genetic markers alone accounted for 4-7%. This is the first demonstration of specific genetic effects on calcaneal QUS encoded by alleles of genes directly involved in mediating estrogen effects on bone.

The long-term treatment of steroid osteoporosis with fluoride.

Twenty-two patients with steroid-induced osteoporosis were studied retrospectively to assess the effects on bone mass of fluoride therapy over 4 years. Thirteen of 19 patients with miscellaneous disorders and 2 with Cushing's syndrome received 1 g calcium/day, 50,000 IU vitamin D (D) weekly, and 40-60 mg/day sodium fluoride (F). Six patients with miscellaneous disorders and one with Cushing's syndrome received only Ca and vitamin D. The mean (+/- SD) cumulative dose of prednisone for fluoride-treated patients at the beginning of the study was 42 +/- 25 g, and for those patients treated with only Ca and vitamin D, 45 +/- 47 g, and during the study the cumulative dose was comparable in both groups. The bone mineral mass of the central skeleton was measured by neutron activation analysis and the results expressed as the calcium bone index (CaBI) which normalizes the results to that of young adults of the same body size (normal range 0.75-1.2). In the 13 patients with miscellaneous disorders treated with fluoride, the mean +/- SD CaBI rose from 0.65 +/- .03 to 0.75 +/- .03 after 3 years p less than 0.001) and to 0.81 +/- .11 at 4 years. Patients without fluoride had an initial mean CaBI of 0.70 +/- .08 and it was not significantly changed over 3 years, 0.68 +/- .09 and 4 years, 0.71 +/- .09. The rise in CaBI in fluoride-treated patients with steroid-induced osteoporosis including Cushing's syndrome was comparable to that of 61 patients with postmenopausal osteoporosis treated with fluoride.(ABSTRACT TRUNCATED AT 250 WORDS)

Fluoride-induced fractures: relation to osteogenic effect.

The possible effects of fluoride in inducing fractures were studied in 61 patients treated with sodium fluoride (NaF), 40-60 mg daily in combination with calcium and vitamin D. Nine patients developed the fluoride-(F) related lower extremity pain syndrome. Four other patients had stress fractures associated with trauma. Seven of the 61 patients had 10 upper femur fractures of which 5 were stress fractures. The bone mineral mass of the central skeleton including the hips was measured by neutron activation and the results expressed as a calcium bone index (CaBI) which normalizes the results to that of young adults of the same body size (normal range 0.75-1.2). At the time of hip fracture, 4 patients with a minimal increase in bone mass (mean delta CaBI 0.01) had 4 femur fractures and 3 patients with a marked increase (mean delta CaBI 0.24) had 6. The 7 patients with upper femur fractures at 4 years had a significantly higher bone fluoride retention, 30 mg/g Ca compared with 23.9 mg/g Ca for the other 54 (p less than 0.02) and were older, 73.1 versus 64.2 years (p less than 0.01). Using all 61 fluoride-treated patients, femur fractures/patient were significantly correlated to bone fluoride (p less than 0.05) and to age (p less than 0.05). By partial correlation, only the correlation between hip fractures/patient and bone fluoride remained significant after controlling for the effect of age (p less than 0.05). These results suggest that fluoride therapy may be implicated in the pathogenesis of hip fractures which may occur in treated patients despite a rapid, marked increase in bone mass. The lower extremity pain syndrome is not frequently associated with stress fractures in this study.

The effect of fluoride on bone histology in postmenopausal osteoporosis depends on adequate fluoride absorption and retention.

Forty-one women with idiopathic postmenopausal osteoporosis have been followed for 2 years after initiation of sodium fluoride at 40-50 mg/day, given together with a daily calcium supplement of 1 gram and vitamin D2, at 50,000 IU weekly. Histological and histomorphometric analyses were done on bone biopsies taken prior to and after 1 year of treatment (mean 1.25 +/- 0.35 years). Thirty patients (74%) developed the histological fluoride effect of hyperosteoidosis, while the remaining 11 patients (26%) had no change from pretreatment biopsies. Hyperosteoidosis was based on increased values for osteoid volume and/or thickened osteoid with greater than 3 lamellar bands. Based on previously reported findings, this histological evidence of hypersoteoidosis within 12-18 months of initiation of therapy provides a useful predictor of ultimate satisfactory fluoride response in terms of bone mineral accretion. No increases in bone mass (measured by neutron activation analysis) were observed at the time of the posttreatment biopsy but, according to this previous work, increases are anticipated over a further 2-3 years of treatment. Factors affecting the development of hyperosteoidosis were analyzed. Hyperosteoidosis was associated with a significantly higher dose of sodium fluoride and a significantly higher level of bone fluoride retention but without significant increase in fasting serum fluoride. Results suggest that fluoride retention depends not only on fluoride dose but also on body size, renal function, and intestinal absorptions of calcium and fluoride. There were no differences in the initial investigations between patients with and without hyperosteoidosis, with respect to age, years of postmenopause, estrogen use, initial biochemistry, or initial bone histology.(ABSTRACT TRUNCATED AT 250 WORDS)

Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety.

For adults, the 5-microg (200 IU) vitamin D recommended dietary allowance may prevent osteomalacia in the absence of sunlight, but more is needed to help prevent osteoporosis and secondary hyperparathyroidism. Other benefits of vitamin D supplementation are implicated epidemiologically: prevention of some cancers, osteoarthritis progression, multiple sclerosis, and hypertension. Total-body sun exposure easily provides the equivalent of 250 microg (10000 IU) vitamin D/d, suggesting that this is a physiologic limit. Sailors in US submarines are deprived of environmentally acquired vitamin D equivalent to 20-50 microg (800-2000 IU)/d. The assembled data from many vitamin D supplementation studies reveal a curve for vitamin D dose versus serum 25-hydroxyvitamin D [25(OH)D] response that is surprisingly flat up to 250 microg (10000 IU) vitamin D/d. To ensure that serum 25(OH)D concentrations exceed 100 nmol/L, a total vitamin D supply of 100 microg (4000 IU)/d is required. Except in those with conditions causing hypersensitivity, there is no evidence of adverse effects with serum 25(OH)D concentrations <140 nmol/L, which require a total vitamin D supply of 250 microg (10000 IU)/d to attain. Published cases of vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and vitamin D dose are known, all involve intake of > or = 1000 microg (40000 IU)/d. Because vitamin D is potentially toxic, intake of >25 microg (1000 IU)/d has been avoided even though the weight of evidence shows that the currently accepted, no observed adverse effect limit of 50 microg (2000 IU)/d is too low by at least 5-fold.

Efficacy and safety of vitamin D3 intake exceeding the lowest observed adverse effect level.

BACKGROUND: The Food and Nutrition Board of the National Academy of Sciences states that 95 microg vitamin D/d is the lowest observed adverse effect level (LOAEL). OBJECTIVE: Our objective was to assess the efficacy and safety of prolonged vitamin D3 intakes of 25 and 100 microg (1000 and 4000 IU)/d. Efficacy was based on the lowest serum 25-hydroxyvitamin D [25(OH)D] concentration achieved by subjects taking vitamin D3; potential toxicity was monitored by measuring serum calcium concentrations and by calculating urinary calcium-creatinine ratios. DESIGN: Healthy men and women (n = 61) aged 41 +/- 9 y (mean +/- SD) were randomly assigned to receive either 25 or 100 microg vitamin D3/d for 2-5 mo, starting between January and February. Serum 25(OH)D was measured by radioimmunoassay. RESULTS: Baseline serum 25(OH)D was 40.7 +/- 15.4 nmol/L (mean +/- SD). From 3 mo on, serum 25(OH)D plateaued at 68.7 +/- 16.9 nmol/L in the 25-microg/d group and at 96.4 +/- 14.6 nmol/L in the 100-microg/d group. Summertime serum 25(OH)D concentrations in 25 comparable subjects not taking vitamin D3 were 46.7 +/- 17.8 nmol/L. The minimum and maximum plateau serum 25(OH)D concentrations in subjects taking 25 and 100 microg vitamin D3/d were 40 and 100 nmol/L and 69 and 125 nmol/L, respectively. Serum calcium and urinary calcium excretion did not change significantly at either dosage during the study. CONCLUSIONS: The 100-microg/d dosage of vitamin D3 effectively increased 25(OH)D to high-normal concentrations in practically all adults and serum 25(OH)D remained within the physiologic range; therefore, we consider 100 microg vitamin D3/d to be a safe intake.

Evidence that vitamin D3 increases serum 25-hydroxyvitamin D more efficiently than does vitamin D2.

In all species tested, except humans, biological differences between vitamins D2 and D3 are accepted as fact. To test the presumption of equivalence in humans, we compared the ability of equal molar quantities of vitamin D2 or D3 to increase serum 25-hydroxyvitamin D [25(OH)D], the measure of vitamin D nutrition. Subjects took 260 nmol (approximately 4000 IU) vitamin D2 (n=17) or vitamin D3 (n=55) daily for 14 d. 25(OH)D was assayed with a method that detects both the vitamin D2 and D3 forms. With vitamin D3, mean (+/-SD) serum 25(OH)D increased from 41.3+/-17.7 nmol/L before to 64.6+/-17.2 nmol/L after treatment. With vitamin D2, the 25(OH)D concentration went from 43.7+/-17.7 nmol/L before to 57.4+/-13.0 nmol/L after. The increase in 25(OH)D with vitamin D3 was 23.3+/-15.7 nmol/L, or 1.7 times the increase obtained with vitamin D2 (13.7+/-11.4 nmol/L; P=0.03). There was an inverse relation between the increase in 25(OH)D and the initial 25(OH)D concentration. The lowest 2 tertiles for basal 25(OH)D showed larger increases in 25(OH)D: 30.6 and 25.5 nmol/L, respectively, for the first and second tertiles. In the highest tertile [25(OH)D >49 nmol/L] the mean increase in 25(OH)D was 13.3 nmol/L (P < 0.03 for comparison with each lower tertile). Although the 1.7-times greater efficacy for vitamin D3 shown here may seem small, it is more than what others have shown for 25(OH)D increases when comparing 2-fold differences in vitamin D3 dose. The assumption that vitamins D2 and D3 have equal nutritional value is probably wrong and should be reconsidered.

Estrogen dose required to maintain parathyroid hormone mediated bone gain in osteopenic ovariectomized rats is probably higher than in preventive treatment with estrogen.

Successful prevention of bone loss in ovariectomized rats with 17 beta-estradiol (E2) at 10 micrograms/kg/d has been reported. Here we show that E2 dose twice that much is not enough to maintain PTH(1-34) mediated bone gain. Three-month-old female Wistar rats were ovariectomized and fed with regular rodent chow and water ad libitum. Three months later they were divided into 9 groups (5-8 per group) and treated cyclically with PTH(1-34) (20 micrograms/kg/d sc, 5d/w for 3w) and E2 (20 micrograms/kg/d sc, 5d/w for 4w). There were also a baseline group and five vehicle control groups. Cancellous bone volume (Cn.BV/TV) of distal femoral metaphyses was measured by computer-aided histomorphometry on trichrome stained thin sections, and 24-hour fasted urine was analyzed for pyridinoline/creatinine (PYR/CREA) by immunoassay. Histomorphometric results showed that PTH(1-34) progressively increased Cn.BV/TV but E2 failed to maintain them. Urinary PYR/CREA results showed that E2-treated groups had lower values. We conclude that E2 dose > 20 micrograms/kg/d is required to maintain the PTH mediated bone gain.

Pamidronate content and turnover in sternum, vertebral body, and iliac bones of dogs.

Therapeutic efficacy of bisphosphonates depends on how much drug is present in bone. Therefore, it is important to measure the amount of bone bisphosphonate in toxicological and pharmacological studies. We analyzed pamidronate content of bone samples from two previously published long-term dose studies. In the first study, mature beagle dogs were given oral pamidronate at doses of 0, 2.5, 12.5 and 25 mg/kg per day for 1 year. The dogs in the second study received the same dosages for 1 year followed by 1 year without drug. In both studies, the amount of pamidronate measured was dependent upon dose in bone samples of ilium, sternum, and vertebral body. After 1 year of treatment, vertebral bone had more pamidronate than sternum or iliac bone on a permilligram basis. After 2 years, there was significantly less pamidronate in the vertebral body, sternum, and ilium than there had been at 1 year. The fall in pamidronate content was largest in vertebral body and least in the ilium. The higher uptake of pamidronate by the vertebral body during the 1 year study, and its greater loss of pamidronate after a year without drug treatment, would reflect the higher turnover of trabecular bone in the vertebral body vs. cortical bone in the ilium. The percent difference in bone pamidronate content between the 1 and 2 year dogs varied with dose. The largest percent loss occurred in the intermediate-dose group. These data suggest that, after 1 year without the drug, bone turnover rates in dogs treated with the highest dose of pamidronate were lower than at the intermediate dose. Thus, the time required for bone turnover rates to return to pretreatment levels is probably dose-dependent.

Seasonal prevalence of vitamin D deficiency in institutionalized older adults.

OBJECTIVE: To determine the prevalence and seasonal variation of vitamin D deficiency among older residents of long-term care facilities. DESIGN: Cross-sectional survey with 6-month follow-up. SETTING: Three long-term care facilities in Toronto. PATIENTS: Persons more than 65 years old, medically stable, who had resided in the facility for at least 6 months and had no conditions known to interfere with vitamin D metabolism. MEASUREMENTS: Information regarding demographics, past health, and medication use was collected. Mental and functional status were assessed by questionnaire. Venous blood samples were analyzed for alkaline phosphatase, calcium profile, albumin, intact parathyroid hormone, 25 hydroxyvitamin D (25OHD), and vitamin D binding protein in September 1994 and March 1995. In a subgroup of patients, bone specific alkaline phosphatase was measured, and dietary intake of vitamin D was assessed. RESULTS: A total of 155 subjects completed the study. The mean age of the subjects was 83.2 years (SD 7.1), and 47% were female. The mean 25OHD level in the March sample (39.9 nmol/L, SD 19.7) was significantly lower than the mean 25OHD level in the September sample (44.9 nmol/L, SD 16.9) (P = .001). The prevalence of vitamin D deficiency in the osteomalacic range (25OHD < 25 nmol/L) increased from 9% in the fall sample to 18% after the winter (chi 2 = 4.65, P = .03). The prevalence of borderline deficiency or hypovitaminosis D (25OHD < 40 nmol/L) increased from 38% in the fall sample to 60% in the spring sample (chi 2 = 14.9, P < .001). Dependence in transfers was associated with an increased risk of hypovitaminosis D, odds ratio 2.08 (95% confidence interval 1.08-4.01), dependence in ambulation 2.57 (1.26-5.23), and regular use of a wheelchair 2.17 (1.09-4.31). When entered into a forward conditional logistic regression model, only dependence in ambulation remained significant, with an adjusted odds ratio of 2.57 (95% CI: 1.26-5.18). CONCLUSIONS: Vitamin D deficiency and borderline vitamin D status are common among older residents of long-term care facilities in Canada. Even though this population has limited outdoor exposure, seasonal variation in the prevalence of deficiency remains significant. Evaluation of interventions to improve the status of vitamin D nutrition in this population is needed.

Relevance of vitamin D metabolite concentrations in supporting the diagnosis of primary hyperparathyroidism.

We compared the relationships between 25-hydroxyvitamin D [25(OH)D] and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in patients with primary hyperparathyroidism (PHPT) and 38 volunteer blood donors. There was no significant difference in mean 25(OH)D levels between patients with PHPT (34 +/- 21 nmol/L; n = 21) and the donor samples (41 +/- 19 nmol/L; n = 38). Serum 1,25(OH)2D levels were higher in the patients with PHPT compared with the donors (122 +/- 61 pmol/L vs 56 +/- 41 pmol/L; p less than 0.001). The 95th percentile 1,25(OH)2D value for the donors was exceeded in 65% of the patients with PHPT. There was a significant correlation between serum 1,25(OH)2D versus 25(OH)D in the patients with PHPT (r = 0.50; p less than 0.05) but not in the donors (r = 0.02). We conclude from the distinct elevation in 1,25(OH)2D levels in the majority of our patients with PHPT that the concentration of this parathyroid hormone-dependent hormone can be of critical value in corroborating the diagnosis of PHPT.