Optimisation of vitamin D status in global populations.

Vitamin D is important for musculoskeletal health. Concentrations of 25-hydroxyvitamin D, the most commonly measured metabolite, vary markedly around the world and are influenced by many factors including sun exposure, skin pigmentation, covering, season and supplement use. Whilst overt vitamin D deficiency with biochemical consequences presents an increased risk of severe sequelae such as rickets, osteomalacia or cardiomyopathy and usually warrants prompt replacement treatment, the role of vitamin D supplementation in the population presents a different set of considerations. Here the issue is to keep, on average, the population at a level whereby the risk of adverse health outcomes in the population is minimised. This position paper, which complements recently published work from the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, addresses key considerations regarding vitamin D assessment and intervention from the population perspective. This position paper, on behalf of the International Osteoporosis Foundation Vitamin D Working Group, summarises the burden and possible amelioration of vitamin D deficiency in global populations. It addresses key issues including screening, supplementation and food fortification.

IOF position statement: vitamin D recommendations for older adults.

This position paper of the International Osteoporosis Foundation makes recommendations for vitamin D nutrition in elderly men and women from an evidence-based perspective.

Impact of maternal veiling during pregnancy and socioeconomic status on offspring's musculoskeletal health.

UNLABELLED: The impact of maternal veiling during pregnancy and of socioeconomic status on offspring's bone mass was investigated in 326 healthy adolescents. Veiling during pregnancy was associated with decreased musculoskeletal parameters in the offspring boys, but not girls. SES was a significant predictor of bone mass in both genders. INTRODUCTION: This study investigates the effects of maternal veiling during pregnancy, a surrogate for low vitamin D level, and socioeconomic status (SES), a surrogate of nutritional status, on their offspring's bone mass at adolescence. METHODS: Three hundred and twenty-six healthy adolescents aged 13.1(2.0) years and their mothers were studied. The impact of maternal veiling on offspring's bone mass was evaluated through regression analyses. Outcome variables were bone mineral density (BMD) and content (BMC) at the spine, hip, and total body of the children. Predictors were maternal veiling during pregnancy and SES. Covariates were height, body composition, Tanner staging, calcium intake, vitamin D and exercise in children. RESULTS: In boys, adjusted analyses revealed that both maternal veiling during pregnancy and SES were significant predictors of bone mass, at multiple skeletal sites. In girls, SES but not maternal veiling during pregnancy was a significant predictor of bone mass at multiple sites. CONCLUSION: Maternal veiling during pregnancy was associated with decreased musculoskeletal parameters of boys, but not girls. SES was a significant predictor of bone mass in both genders. These findings may have profound implications on children's bone health.

Alendronate in early postmenopausal women: effects on bone mass during long-term treatment and after withdrawal. Alendronate Osteoporosis Prevention Study Group.

We studied the effect on bone mass of alendronate treatment for 5 yr and its withdrawal. Four hundred and forty-seven postmenopausal women with normal bone mass entered a 3-yr randomized trial followed by a 2-yr open label extension. Three hundred and eleven women completed the first 3 yr, and 263 consented to continue and completed the extension. We are reporting data from groups using the dose of alendronate currently approved for osteoporosis prevention (5 mg) or from the group in which alendronate treatment was withdrawn: 52 women received alendronate (5 mg) for 5 yr (group I), 56 received 3 yr of placebo followed by alendronate (5 mg) for 2 yr (group II), and 52 received alendronate (20 mg) for 2 yr followed by 3 yr off therapy (group III). In group I, alendronate (5 mg) increased bone mineral density (BMD) at the spine and trochanter by 2.5-3.2% (P < 0.001 vs. baseline) and stabilized total body and femoral neck BMD (change vs. baseline, P = NS) over 5 yr. By the end of 5 yr, BMD was comparable at the spine, hip, and total body in groups I and III. The 3-yr decrease in BMD after withdrawal of alendronate (20 mg) in group III was 1.8-5.7% (P < 0.01 vs. baseline) and similar to the 3-yr decrease in BMD in group II during the initial 3 yr. In conclusion, alendronate (5 mg) for 5 yr or alendronate (20 mg) for 2 yr followed by 3 yr off therapy prevented postmenopausal bone loss. After withdrawal of alendronate (20 mg), bone loss resumed at the normal early postmenopausal rate.

Nutritional osteomalacia: substantial clinical improvement and gain in bone density posttherapy.

A 52-yr-old white female presented with worsening low back and hip pain, associated with lower limb proximal muscle weakness and a waddling gait. Her laboratory evaluation revealed hypocalcemia, hypophosphatemia, a very low 25-hydroxyvitamin D level of less than 5 ng/mL, and a bone mineral density in the osteoporotic range. Her laboratory studies were consistent with osteomalacia, although this diagnosis was not established by histomorphometry. She avoided dairy products, spent little time outdoors, and when she went out, she covered her face, arms, and legs. She was on no medication. Her workup for malabsorption including sprue was negative. She was treated with calcium plus high-dose vitamin D 600,000 IU intramuscularly twice witihin 2 mo and had an impressive clinical improvement. Her difficulty with ambulation improved within 1 wk of start of therapy. Her bone mineral density increased by 40% at the spine and 35% at the hip at 4 mo of therapy, by 63% and 39% at 10 mo, and by 62% and 52% at 15 mo at these sites, respectively. Treatment of osteomalacia is extremely rewarding, with dramtic clinical improvement and normalization of bone mineral density.

Calcidiol and PTH levels in women attending an osteoporosis program.

We performed a retrospective study of 237 patients attending a specialty osteoporosis practice. Secondary causes for reduced bone mineral density (BMD) were evaluated in 196 postmenopausal women and 41 premenopausal women; mean age was 56 +/- 13.8 years (mean +/- SD). BMD was measured by dual-energy X-ray absorptiometry (DXA) (QDR 1000W/2000 Hologic). Levels of intact parathyroid hormone (iPTH), calcidiol [25(OH)D], thyroid-stimulating hormone, and 24-hour urinary calcium were measured, and serum and urine protein (SPEP and UPEP) electrophoresis were performed. Overall, 16% of our patients had 25(OH)D levels <15 ng/ml, the lowest acceptable vitamin D level without a concomitant rise in iPTH levels. Among the osteoporotic patients (T score <-2.5 SD), 17% had 25(OH)D levels <15 ng/ml and 7% <10 ng/ml. Among the osteopenic patients (-2.5 < T < -1.0 SD), 11% had 25(OH)D levels <15 ng/ml. Seventeen percent of patients with Z score 65 pg/ml, upper normal limit of assay) were present in 11.5%, and hyperthyroidism in 4%. A 25(OH)D level of <25 ng/ml in women (n = 86) with no known secondary causes of low BMD was associated with an iPTH level above 49 pg/ml. The measurement of 25(OH)D levels is recommended in the evaluation of secondary causes for reduced BMD. Supplementation with vitamin D appears needed to keep 25(OH)D above 25 ng/ml, the level required to prevent increments in iPTH levels.

The effect of lithium on calcium-induced changes in adrenocorticotrophin levels.

The calcium receptor (CaR) plays a central role in calcium (Ca) sensing by the parathyroid gland and other organs, including the brain. Chronic lithium (Li) therapy causes a significant alteration in Ca-sensing by the CaR-expressing parathyroid chief cells through an unknown mechanism, shifting the PTH set-point (the level of Ca that half-maximally suppresses PTH secretion) to the right. Ca is known to stimulate ACTH levels in normal subjects, and baseline ACTH levels are increased in patients with bipolar disorder. Because the stimulation of ACTH secretion by Ca likely involves the CaR, the aim of this study was to investigate the effects of Li on Ca-induced changes in ACTH levels, using Ca and citrate infusions in seven Li-treated patients and seven controls. During the Ca infusion, increments in serum-ionized Ca concentration (Ca(i)) were accompanied by increments in ACTH levels that were significantly greater in the Li-treated group, P = 0.014, by ANOVA. Also, cortisol levels increased significantly in the Li-treated, but not the control group, during the Ca infusion, P < 0.0001. There was a statistically significant shift in the midpoint of the Ca(i)/ACTH curve, to the right, in the Li-treated group, compared with the controls (P = 0.042), that was largely caused by an effect of Li on Ca(i). However, for comparable levels of Ca(i), there were no significant differences in the levels of ACTH between the two groups. Therefore, within the physiological range of Ca, there was no effect of Li on Ca(i)-induced change in ACTH levels.

Calcium modulation of adrenocorticotropin levels in women--a clinical research center study.

In vitro calcium modulation of anterior pituitary hormone secretion has been well described. In addition, several investigations performed in human subjects have documented modulation of the circulating levels of pituitary hormones by supraphysiological calcium concentrations. Recent data from our laboratory document the existence of an extracellular calcium-sensing receptor that is thought to mediate the effects of variations in extracellular calcium on the secretion of PTH and calcitonin. We have also demonstrated the presence of this receptor in pituitary-derived, ACTH-secreting AtT-20 cells as well as in the anterior pituitary of rats and mice. In the present study we investigated the effect on anterior pituitary hormone levels of variations in serum calcium within the physiological range. We serially measured serum levels of ionized calcium (Cai), ACTH, cortisol, TSH, and PRL during 90-min iv infusions (on separate days) of calcium, citrate, and dextrose in 10 healthy women with a mean age of 55 +/- 5 yr. During the calcium infusion, the serum Cai level increased significantly from 4.32 +/- 0.10 mg/dL at baseline to 4.86 +/- 0.08 mg/dL at completion (P = 0.002), and this change was accompanied by a significant increment in the serum ACTH level from 9.87 +/- 1.32 to 16.31 +/- 2.84 pg/mL (P = 0.0008). There was no change in the serum ACTH level during the citrate infusion despite significant decrements in serum Cai, nor were there changes in either Cai or ACTH during the dextrose infusion. Finally, changes in Cai did not alter TSH or PRL levels. In summary, our dynamic studies are the first to demonstrate an increase in baseline serum ACTH levels in response to physiological increments in Cai (i.e. increments within the normal range). This effect was specific for increments and not decrements in serum Cai and was selective for ACTH, as TSH and PRL levels did not change with any of the infusions.

Intact parathyroid hormone levels are not elevated in glucocorticoid-treated subjects.

To assess whether chronic glucocorticoid therapy results in a compensatory increase in parathyroid hormone (PTH), we measured intact PTH levels and other indices of mineral metabolism in 13 postmenopausal glucocorticoid-treated women and 16 normal age-matched controls. The glucocorticoid-treated women received a mean prednisone dose of 15.8 +/- 3.1 mg/day for 12.9 +/- 3.1 years. A linear regression analysis between intact PTH levels and a wide range of prednisone doses in these 13 glucocorticoid-treated women and 26 additional male and female subjects receiving chronic glucocorticoid therapy for a variety of rheumatic and pulmonary disorders (n = 39) was also performed. Intact PTH levels using the sensitive immunoradiometric assay (IRMA, Nichols Institute, San Juan Capistrano, CA) were comparable in the glucocorticoid-treated and normal control women (35.3 +/- 4.4 vs 31.3 +/- 3.2 ng/l, respectively) as wee the total calcium concentrations (9.67 +/- 0.12 vs 9.52 +/- 0.11 mg/dl). In the glucocorticoid-treated women, the 25-hydroxyvitamin D levels, measured by competitive protein assay were similar to those of the control subjects (29.2 +/- 2.8 vs 29.1 +/- 2.3 mg/ml), and no patient was treated with vitamin D in excess of 400 IU daily. In the combined 39 male and female patients, there were also no significant regression relationships between daily prednisone dose and intact PTH levels. Thus, secondary hyperparathyroidism does not accompany chronic oral glucocorticoid therapy in women on low to moderate doses of oral glucocorticoids. The lack of an elevation in intact PTH levels in the presence of chronic glucocorticoid therapy may represent an increased sensitivity of bone to PTH, or an alteration in the relationship between calcium and PTH, or both.

Reproducibility of DXA absorptiometry: a model for bone loss estimates.

The enhanced precision of dual-energy X-ray absorptiometry (DXA) allows the detection of very small changes in bone mineral density (BMD). True clinical changes in BMD in patients must be evaluated with the appropriate error of variance. We evaluated the responsiveness of our measures to true bone loss using a statistical variance components model that characterizes the variability associated with error introduced by the machine, operator, and subjects. Our techniques were applied to data from a prospective study of BMD measurements on spine phantoms and on pre- and postmenopausal women performed on the same day or up to 4 weeks apart with DXA (QDR 1000W, Hologic). Our model determined that most of the error in measurements was introduced by operators' and subjects' variability rather than machine performance. The false-positive rates for true bone change are significantly reduced when the appropriate CV% is used to estimate the significance of bone loss over time. Our study underscores the need to use the appropriate precision error to evaluate the clinical significance of changes in bone mass in individual subjects over time.

Racial differences in parathyroid hormone dynamics.

Elevations in PTH levels have been reported in black subjects. Such observations have not been consistent, however, and seem paradoxical in view of the known bone-resorptive action of this hormone and the fact that black subjects have a higher bone mineral density and fewer fractures than their white counterparts. In this study, we used dynamic stimulation of the calcium-PTH axis to fully characterize potential racial differences in PTH dynamics. We, therefore, defined the inverse sigmoidal curve that describes the relationship between serum ionized calcium concentration and intact PTH levels in six normal white and six normal black volunteers and determined the four parameters that characterize this relationship. An elevation in any one of these parameters can result in hyperparathyroidism. Black subjects had higher maximal and minimal PTH responses to hypo- and hypercalcemia (mean intact PTH levels of 9.2 +/- 13 and 0.7 +/- 0.1 pmol/L respectively) than white subjects (6.9 +/- 0.6 and 0.3 +/- 0.1 pmol/L, respectively). There were no differences in the set-points or slopes of the curves. Despite the higher baseline and stimulated endogenous PTH levels in black subjects, their baseline and stimulated osteocalcin levels were lower. Our dynamic studies, therefore, document mild hyperparathyroidism in black subjects and suggest mild skeletal resistance to PTH.

The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families.

Familial hypocalciuric hypercalcemia (FHH) is an autosomal dominant syndrome of unknown aetiology characterized by lifelong elevation in serum calcium concentration and low urinary calcium excretion. These features suggest that the causal gene is important for maintenance of extracellular calcium homeostasis by the parathyroid gland and kidney. To identify the chromosomal location of FHH gene(s), we clinically evaluated 114 individuals in four unrelated affected families and performed linkage analyses. The disease gene mapped to the long arm of chromosome 3 in each family (combined maximum multipoint lod score = 20.67). We suggest that this is the predominant FHH locus and anticipate that identification of the FHH gene will improve our understanding of the molecular basis for physiologic and pathologic regulation of calcium.

Dual-energy x-ray absorptiometry of the forearm: reproducibility and correlation with single-photon absorptiometry.

Although single-photon absorptiometry (SPA) has been the predominant tool used to assess bone mineral density (BMD) in the forearm, the development of dual-energy x-ray absorptiometry (DEXA) provides the benefits of greater source stability, reduced scanning time, and improved image resolution compared to SPA. In the present study we used the DEXA bone densitometer (Hologic, Inc., Waltham, MA) to (1) measure BMD in the one-third radius and ultradistal radius; (2) examine the reproducibility of these BMD measurements; and (3) compare the BMD at the one-third radius with SPA (SP2, Lunar Corp., Madison, WI). In 65 normal women (ages 22-74 years) we examined changes in the forearm DEXA BMD with age, revealing significant quadratic regression equations. The reproducibility of DEXA BMD (mean +/- SEM) in 7 normal subjects aged 22-50 years is 0.85 +/- 0.16% for the predominantly cortical one-third radius site and 0.97 +/- 0.15% for the more trabecular ultradistal site. The regression relationship between DEXA and SPA of the one-third radius in 26 subjects (ages 22-68 years) is DEXA BMD = 0.105 + 0.826 (SPA BMD); R = 0.97, R2 = 0.94, p less than 0.0001. Bone densitometry of the forearm using DEXA may be performed relatively rapidly, providing reproducibility and image resolution that are generally superior to those observed with SPA.

A comparison of the effects of concanavalin-A and tetradecanoylphorbol acetate on the modulation of parathyroid function by extracellular calcium and neomycin in dispersed bovine parathyroid cells.

Ca2+ and other polyvalent cations as well as polycations, such as neomycin, produce similar effects on intracellular second messengers and PTH release in dispersed bovine parathyroid cells, but it is unclear whether all of these agents share the same mechanism of action. The lectin Concanavalin-A (Con-A) and the activator of protein kinase-C tetradecanoylphorbol acetate (TPA) blunt the effects of elevated extracellular calcium (Ca2+) concentrations on several aspects of parathyroid function, including PTH release, the cytosolic calcium concentration, and the accumulation of cAMP and inositol phosphates. In the present studies we used these two agents as well as pertussis toxin as probes to investigate further whether neomycin acts on parathyroid cells through the same receptor-like mechanism used by extracellular Ca2+ to regulate parathyroid function. Con-A and TPA both enhanced PTH release by about 2-fold at 0.5-1 x 10(-4) M neomycin, concentrations that inhibited PTH release to an extent (40-50%) similar to that seen with high (1.5-2 mM) Ca2+. Con-A also reduced the inhibition of agonist-stimulated cAMP accumulation by the same concentrations of neomycin. Conversely, Con-A and TPA produced 70-80% decreases in the cytosolic calcium concentration transient and the accumulation of inositol phosphates stimulated by neomycin. The effects of these two agents on neomycin-regulated parathyroid function were similar in magnitude to their actions on the modulation of these same parameters by extracellular Ca2+. Pertussis toxin, however, which we have previously shown to block the inhibitory effects of high Ca2+ and neomycin on cAMP accumulation, had no effect on the inhibition of PTH release by these two agents. These results provide further indirect evidence that polyvalent cations and polycations act on the parathyroid cell through related pathways, which probably involve cell surface moieties containing carbohydrate(s).

Hypervitaminosis D associated with drinking milk.

BACKGROUND: Vitamin D has been added to milk in the United States since the 1930s to prevent rickets. We report the unusual occurrence of eight cases of vitamin D intoxication that appear to have been caused by excessive vitamin D fortification of dairy milk. METHODS: Medical records were reviewed and a dietary questionnaire was sent to eight patients who had unexplained hypervitaminosis D. Vitamin D analyses with high-performance liquid chromatography were performed on samples of the patients' serum, the dairy milk they drank, and the vitamin D concentrate added to the milk. RESULTS: All eight patients drank milk produced by a local dairy in amounts ranging from 1/2 to 3 cups (118 to 710 ml) daily. All had elevated serum 25-hydroxyvitamin D concentrations (mean [+/- SD], 731 +/- 434 nmol per liter [293 +/- 174 ng per milliliter]). Six of the eight patients had elevated serum vitamin D3 concentrations. Of the eight patients, seven had hypercalcemia and one had hypercalciuria but normocalcemia (mean serum calcium, 3.14 +/- 0.51 mmol per liter [12.6 +/- 2.1 mg per deciliter]). Analysis of the dairy's vitamin D-fortified milk revealed concentrations of vitamin D3 (cholecalciferol) that ranged from undetectable to as high as 232,565 IU per quart (245,840 IU per liter). An analysis of the concentrate that was used to fortify the milk, labeled as containing vitamin D2 (ergocalciferol), revealed that it contained vitamin D3. CONCLUSIONS: Hypervitaminosis D may result from drinking milk that is incorrectly and excessively fortified with vitamin D. Milk that is fortified with vitamin D must be carefully monitored.