Wintertime Vitamin D Deficiency in Male Adolescents: Effect on Parathyroid Function and Response to Vitamin D3 Supplements

The first part of this study consisted of an 18 month follow-up of the vitamin D status and parathyroid function in a group of 54 French male adolescents, aged from 13 to 16 years old and all pupils of a jockey training school. During the 18 month period four samplings were made, one every 6 months. The first was during September of the first year, the second and third during March and October of the second year, and the last in March of the third year. Therefore we had two main periods: summer and winter. The summer 25-hydroxyvitamin D (25(OH)D) concentrations were higher (71.6 ± 19.9 and 52.4 ± 16.5 nmol/l) than the winter ones (20.4 ± 6.9 and 21.4 ± 6.1 nmol/l). Conversely, the winter intact parathyroid hormone (iPTH) serum levels (4.18 ± 1.18 and 4.11 ± 1.35 pmol/l) were higher than the summer ones (2.44 ± 0.82 and 2.71 ± 0.71 pmol/l). At the two winter time points the 25(OH)D concentrations were lower than 25 nmol/l (10 ng/ml) in 72% (2nd year) and 68% (3rd year) of the adolescents. In the second part of the study we tried a vitamin D₃ supplementation procedure designed to maintain the 25(OH)D and iPTH postsummer serum levels throughout the winter. Pairs of male adolescents matched for height, weight and Tanner pubertal stage were randomly assigned to either vitamin D₃ supplementation (2.5 mg, i.e., 100 000 IU) administered orally at three specific periods (end of September, November and January) or no vitamin D₃ treatment (control subjects). Blood was collected just before the first intake of vitamin D₃ and 2 months after the last intake (March). The control subjects had blood drawn at the same time points. In the vitamin D₃-treated subjects, the concentrations of 25 (OH)D (55.3 ± 11.5 nmol/l) and of iPTH (3.09 ± 1.16 pmol/l) in March and September (53.8 ± 12.3 nmol/l and 2.75 ± 1.26 pmol/l) were not significantly different. In the control subjects, March 25(OH)D levels (21.0 ± nmol/l were low, with values below 25 nmol/l in 78% of subjects, and iPTH concentrations (3.97 ± 1.08 pmol/l) were significantly (p<0.001) higher than in September (2.91 ± 0.81 pmol/l). The constant vitamin D wintertime deficiency and wintertime rise in iPTH in adolescent French males throughout puberty has been demonstrated. In adolescents with low dairy calcium intakes, the vitamin D₃ treatment was sufficient to maintain 25(OH)D concentrations at their summer levels throughout winter and to prevent an excessive wintertime rise in iPTH levels. Received: 6 February 2001 / Accepted: 9 May 2001     

Vitamin D for skeletal and non-skeletal health: What we should know

Vitamin D plays an essential role in regulating calcium and phosphate metabolism and maintaining a healthy mineralized skeleton. Humans obtain vitamin D from sunlight exposure, dietary foods and supplements. There are two forms of vitamin D: vitamin D₃ and vitamin D₂. Vitamin D₃ is synthesized endogenously in the skin and found naturally in oily fish and cod liver oil. Vitamin D₂ is synthesized from ergosterol and found in yeast and mushrooms. Once vitamin D enters the circulation it is converted by 25-hydroxylase in the liver to 25-hydroxyvitamin D [25(OH)D], which is further converted by the 25-hydroxyvitamin D-1α-hydroxylase in the kidneys to the active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D]. 1,25(OH)₂D binds to its nuclear vitamin D receptor to exert its physiologic functions. These functions include: promotion of intestinal calcium and phosphate absorption, renal tubular calcium reabsorption, and calcium mobilization from bone. The Endocrine Society's Clinical Practice Guideline defines vitamin D deficiency, insufficiency, and sufficiency as serum concentrations of 25(OH)D of <20 ng/mL, 21–29 ng/mL, and 30–100 ng/mL, respectively. Vitamin D deficiency is a major global public health problem in all age groups. It is estimated that 1 billion people worldwide have vitamin D deficiency or insufficiency. This pandemic of vitamin D deficiency and insufficiency is attributed to a modern lifestyle and environmental factors that restrict sunlight exposure, which is essential for endogenous synthesis of vitamin D in the skin. Vitamin D deficiency is the most common cause of rickets and osteomalacia, and can exacerbate osteoporosis. It is also associated with chronic musculoskeletal pain, muscle weakness, and an increased risk of falling. In addition, several observational studies observed the association between robust levels of serum 25(OH)D in the range of 40–60 ng/mL with decreased mortality and risk of development of several types of chronic diseases. Therefore, vitamin D-deficient patients should be treated with vitamin D₂ or vitamin D₃ supplementation to achieve an optimal level of serum 25(OH)D. Screening of vitamin D deficiency by measuring serum 25(OH)D is recommended in individuals at risk such as patients with diseases affecting vitamin D metabolism and absorption, osteoporosis, and older adults with a history of falls or nontraumatic fracture. It is important to know if a laboratory assay measures total 25(OH)D or only 25(OH)D₃. Using assays that measure only 25(OH)D₃ could underestimate total levels of 25(OH)D and may mislead physicians who treat patients with vitamin D₂ supplementation.     

Standard multivitamin supplementation does not improve vitamin D insufficiency after burns

Children suffering severe burns develop progressive vitamin D deficiency because of inability of burned skin to produce normal quantities of vitamin D₃ and lack of vitamin D supplementation on discharge. Our study was designed to determine whether a daily supplement of a standard multivitamin tablet containing vitamin D₂ 400 IU (10 μg) for 6 months would raise serum levels of 25-hydroxyvitamin D [25(OH)D] to normal. We recruited eight burned children, ages 5–18, whose families were deemed reliable by the research staff. These children were given a daily multivitamin tablet in the hospital for 3 months in the presence of a member of the research staff and then given the remainder at home. At 6 months, the subjects returned for measurements of serum levels of 25(OH)D,1,25-dihydroxyvitamin D [1,25(OH)₂D], intact parathyroid hormone (iPTH), Ca, P, albumin, and total protein as well as bone mass by dual energy X-ray absorptiometry. Serum 25(OH)D levels were compared to a group of seven age-matched burned children studied at an earlier date without the vitamin supplement but with the same method of determination of 25(OH)D at 6 months post-burn. In addition, the chewable vitamins were analyzed for vitamin D₂ content by high performance liquid chromatography. Serum concentration of 25(OH)D was 21 ± 11(SD) ng/ml (sufficient range 30–100) with only one of the eight children having a value in the sufficient range. In comparison, the unsupplemented burn patients had mean serum 25(OH)D level of 16 ± 7, P = 0.33 versus supplemented. Serum levels of 1,25(OH)₂D, iPTH, Ca, P, albumin, and total protein were all normal in the supplemented group. Vitamin D₂ content of the chewable tablets after being saponified and extracted was 460 ± 20 IU. Bone mineral content of the total body and lumbar spine, as well as lumbar spine bone density, failed to increase as expected in the supplemented group. No correlations were found between serum 25(OH)D levels and age, length of stay, percent body surface area burn or third-degree burn. Supplementation of burned children with a standard multivitamin tablet stated to contain 400 IU of vitamin D₂ failed to correct the vitamin D insufficiency.     

Vitamin D insufficiency defined by serum 25-hydroxyvitamin D and parathyroid hormone before and after oral vitamin D3 load in Japanese subjects

Vitamin D insufficiency is a risk for both skeletal and nonskeletal health. However, some ambiguity remains about threshold serum 25(OH)D for vitamin D insufficiency. To determine the threshold serum 25(OH)D to maintain normal calcium availability without elevation in serum parathyroid hormone (PTH) among Japanese subjects with various calcium intakes, we conducted a multicenter prospective open-labeled study. We recruited 107 ambulatory subjects without disorders affecting vitamin D metabolism to whom oral vitamin D₃ 800?IU/day for 4?weeks or 1,200?IU/day for 8?weeks was given. Serum 25(OH)D, PTH, calcium, phosphate, and magnesium were measured before and after vitamin D₃ supplementation. Calcium intake was assessed by questionnaires. When all the data were combined, serum 25(OH)D was negatively correlated with PTH. The cubic spline curve between serum 25(OH)D and PTH indicated PTH reached its plateau between 35 and 40?pg/ml at 25(OH)D between 25 and 30?ng/ml. Vitamin D₃ supplementation increased serum 25(OH)D and decreased PTH. Change in PTH correlated positively with baseline serum 25(OH)D. From the regression analyses, baseline serum 25(OH)D above 28?ng/ml corresponded to the threshold level without reduction in PTH after vitamin D₃ supplementation. In multivariate regression analyses, age but not calcium intake was a significant determinant of PTH. We concluded that a serum 25(OH)D level of 28?ng/ml was identified as a threshold for vitamin D insufficiency necessary to stabilize PTH to optimal levels.     

The renal metabolism of 25-hydroxyvitamin D3 in the rat: Regulation by 1,25-dihydroxyvitamin D3

Summary To determine the effects of 1α,25-dihydroxyvitamin D₃ [1,25(OH)₂D₃] on the renal metabolism of 25-hydroxyvitamin D₃ [25(OH)D₃], the influence of 1,25(OH)₂D₃ and 24,25-dihydroxyvitamin D₃ [24,25(OH)₂D₃] was compared in vitamin D-deficient rats. Serum calcium (Ca), serum immunoreactive parathyroid hormone (iPTH) and the specific activities (SA) of renal 25(OH)D₃: 24-hydroxylase (24-hydroxylase) and 25(OH)D₃: 1α-hydroxylase (1-hydroxylase) were measured. In vitamin D-deficient rats, mean serum Ca was low, serum iPTH was increased, renal 1-hydroxylase was increased, and renal 24-hydroxylase was below the limit of detection. Treatment with either 1,25(OH)₂D₃ or 24,25(OH)₂D₃, 50 ng/d for 2 days, significantly increased mean serum Ca but did not change serum iPTH, renal 1-hydroxylase SA, or renal 24-hydroxylase SA. 1,25(OH)₂D₃, 50 ng/d for 7 days, returned serum Ca and iPTH to normal, lowered renal 1-hydroxylase SA, and induced renal 24-hydroxylase activity. In contrast, 24,25(OH)₂D₃, 50 ng/d for 7 days, similarly lowered renal 1-hydroxylase SA but did not induce renal 24-hydroxylase activity. Thyroparathyroidectomy of vitamin D-deficient rats resulted in a rapid decline in 1-hydroxylase SA. The results indicate that in vitamin D-deficient rats a) 1,25(OH)₂D₃ reduces renal 1-hydroxylase SA and increases renal 24-hydroxylase SA and b) 24,25(OH)₂D₃ reduces renal 1-hydroxylase SA and does not alter renal 24-hydroxylase SA. Inhibition of renal 1-hydroxylase by the two metabolites is apparently mediated through changes in serum Ca and circulating iPTH, whereas stimulation by 1,25(OH)₂D₃ of renal 24-hydroxylase activity is direct.     

Rapid correction of low vitamin D status in nursing home residents

Summary  This prospective study finds that ergocalciferol 50,000 IU three times weekly for four weeks effectively and safely corrects vitamin D inadequacy in nursing home residents. Introduction  Low vitamin D status is common among nursing home residents and contributes to bone loss, falls and fractures. The objective of this study was to evaluate the efficacy and safety of short course, high dose, oral vitamin D₂ (ergocalciferol) treatment. Methods  This prospective study included 63 nursing home residents. The 25 with low vitamin D status (serum 25(OH)D ≤ 25 ng/ml) received oral ergocalciferol 50,000 IU three times weekly for four weeks; the others received no change to their routine care. Serum total 25(OH)D, 25(OH)D₂, 25(OH)D₃, calcium, parathyroid hormone (PTH), bone turnover markers and neuro-cognitive assessments were obtained at baseline and four weeks. Results  Mean total 25(OH)D concentration increased (p < 0.0001) from 17.3 to 63.8 ng/ml in the treated group and remained unchanged in the comparison group. Serum 25(OH)D₃ remained stable in the comparison group, but declined (p < 0.0001) with D₂ treatment from 15.4 to 9.1 ng/ml. Serum PTH trended down in the treatment group (p = 0.06). No treatment-induced improvement in ambulation, cognition or behavior was observed. No hypercalcemia or other adverse effects were observed with ergocalciferol treatment. Conclusion  Four weeks of oral vitamin D₂ supplementation effectively and safely normalizes serum 25(OH)D in nursing home residents.     

Vitamin D status and its relationship with bone mineral density in healthy Asian Indians

Synthesis of vitamin D takes place in the skin under the effect of sunlight. The Indian subcontinent is situated between 8.4° N and 37.6° N latitudes and has adequate sunshine throughout the year. Thus, it has been presumed that Indians are vitamin D sufficient. We measured serum 25-hydroxy vitamin D [25(OH)D] (n=92) and 1,25-dihydroxy vitamin D [1, 25(OH)₂D] (n=65) levels in healthy hospital staff, using ¹²⁵I radioimmunoassay. Serum intact parathyroid hormone (PTH) concentration was estimated by immunoradiometric assay. Bone mineral density was estimated using a dual energy X-ray absorptiometer (Hologic^R QDR 4500A). Using a serum 25(OH)D level of 15 ng/ml as a cutoff, 66.3% (61/92) of the subjects were found to be vitamin D deficient. Of these, 20.6% (19/92) subjects had severe vitamin D deficiency (<5 ng/ml), 27.2% (25/92) had moderate vitamin D deficiency (5–9.9 ng/ml), while 18.5% (17/92) had mild vitamin D deficiency (10–14.9 ng/ml). When a serum 25(OH)D level of 20 ng/ml was used as a cutoff, 78.3% subjects were diagnosed to be vitamin D deficient/insufficient. The serum 1,25(OH)₂D level was within the normal range (40.6±20.1 pg/ml; mean ± SD). Mean (±SD) serum intact PTH, estimated in a limited number of subjects (n=15), was 72.3 (±21.0) pg/ml (range 36–100 pg/ml). There was a significant correlation between daily sun exposure and 25(OH)D levels (r=0.731, P<0.001). The serum 25(OH)D level correlated with BMD at the femoral neck and Ward's triangle (r=0.50, P=0.020 and r=0.46, P=0.037, respectively). Our findings show that vitamin D deficiency is common in urban north Indian hospital staff. The possible reasons include inadequate sunlight exposure and skin pigmentation in Indians. The serum 1,25(OH)₂D level is not a good indicator of vitamin D deficiency. A low serum 25(OH)D level is possibly one of the reasons for lower bone mineral density among Indians.     

Relative effectiveness of vitamin D metabolites in increasing bone mineral solubility

Summary Weanling rats were given a vitamin D-deficient diet containing 1.4% calcium and 1.0% phosphorus. After 4 weeks these deficient animals were injected for 7 days with selected doses of one of the following vitamin D metabolites: 25(OH)D₃, 1,25(OH)₂D₃, 24,25(OH)₂D₃, 25,26(OH)₂D₃ or the ethanol vehicle. A vitamin D-replete group was placed on the same diet but injected with 50 IU of vitamin D₃ once a week for the entire 5-week period. By the use of a modified Ussing chamber [1], the measurements of calcium fluxes into and from the rat calvaria were possible. These data enabled the apparent mineral solubilities to be derived. After 5 weeks on this diet the vitamin D-deficient rats had low levels of serum calcium (1.41 mM) and decreased mineral solubility when compared to the vitamin D-replete group. The apparent solubility of the bone mineral increased toward the vitamin D-replete level in calvaria from vitamin D metabolite-treated rats. However, these changes did not directly reflect the alterations in the level of serum calcium. At any given dose level, 1,25(OH)₂D₃ was the most effective metabolite in increasing serum calcium. In fact, the high dose (250 pmoles/day) was hypercalcemic. Next in effectiveness was 25(OH)D₃. These two metabolites were equally effective in increasing mineral solubility. At a 10 times higher dose, the 24,25(OH)₂D₃ metabolite was able to normalize serum calcium and improve but not normalize mineral solubility. At the high dose (260 pmoles/day), the 25,26(OH)₂D₃ metabolite caused no effect on mineral solubility and minimal increases in serum calcium.     

Comparison of metabolism of vitamins D2 and D3 in children with nutritional rickets

Children with calcium‐deficiency rickets may have increased vitamin D requirements and respond differently to vitamin D₂ and vitamin D₃. Our objective was to compare the metabolism of vitamins D₂ and D₃ in rachitic and control children. We administered an oral single dose of vitamin D₂ or D₃ of 1.25 mg to 49 Nigerian children—28 with active rickets and 21 healthy controls. The primary outcome measure was the incremental change in vitamin D metabolites. Baseline serum 25‐hydroxyvitamin D [25(OH)D] concentrations ranged from 7 to 24 and 15 to 34 ng/mL in rachitic and control children, respectively (p < .001), whereas baseline 1,25‐dihydroxyvitamin D [1,25(OH)₂D] values (mean ± SD) were 224 ± 72 and 121 ± 34 pg/mL, respectively (p < .001), and baseline 24,25‐dihydroxyvitamin D [24,25(OH)₂D] values were 1.13 ± 0.59 and 4.03 ± 1.33 ng/mL, respectively (p < .001). The peak increment in 25(OH)D was on day 3 and was similar with vitamins D₂ and D₃ in children with rickets (29 ± 17 and 25 ± 11 ng/mL, respectively) and in control children (33 ± 13 and 31 ± 16 ng/mL, respectively). 1,25(OH)₂D rose significantly (p < .001) and similarly (p = .18) on day 3 by 166 ± 80 and 209 ± 83 pg/mL after vitamin D₂ and D₃ administration, respectively, in children with rickets. By contrast, control children had no significant increase in 1,25(OH)₂D (19 ± 28 and 16 ± 38 pg/mL after vitamin D₂ and D₃ administration, respectively). We conclude that in the short term, vitamins D₂ and D₃ similarly increase serum 25(OH)D concentrations in rachitic and healthy children. A marked increase in 1,25(OH)₂D in response to vitamin D distinguishes children with putative dietary calcium‐deficiency rickets from healthy children, consistent with increased vitamin D requirements in children with calcium‐deficiency rickets. © 2010 American Society for Bone and Mineral Research     

Action of vitamin D metabolites on PTH secretion in man

Summary We have examined the effects of metabolites of vitamin D [25OHD₃, 1,25(OH)₂D₃, 24,25(OH)₂D₃, and 25,26(OH)₂D₃] on serum calcium and iPTH in human deficient-D osteomalacia. The four metabolites decreased iPTH, but only for 1,25(OH)₂D₃ was a significant correlation between increase of serum calcium and decrease of iPTH observed. The 24,25(OH)₂D₃ and 25,26(OH)₂D₃ decreased iPTH despite a decrease of serum calcium at the beginning of treatment. The 25OHD decreased iPTH before increased serum calcium. These results could be interpreted as a direct effect of metabolites of vitamin D on PTH secretion. However, the conversion of other metabolites and the calcium concentration in parathyroid cells must be determined before this hypothesis can be accepted.     

Anticonvulsant drug-induced osteomalacia: Alterations in mineral metabolism and response to vitamin D3 administration

Summary Parameters of mineral metabolism were examined in 6 patients with moderately severe anticonvulsant drug-induced osteomalacia. Compared to 15 matched controls, the patients exhibited significantly reduced serum calcium, inorganic phosphate, and 25-hydroxyvitamin D concentration, elevated serum alkaline phosphatase and immunoreactive parathyroid hormone (iPTH) concentration, reduced intestinal⁴⁷Ca absorption, reduced urinary calcium and increased urinary hydroxyproline excretion, and reduced forearm bone mass. Intestinal absorption of vitamin D₃ was normal. Following 4 months of treatment with vitamin D₃ (4000 units/day), serum 25-OHD concentration was increased to 3 times mean normal values and all parameters except serum iPTH, urinary calcium excretion, and forearm bone mass were returned to levels not significantly different from normal. Serum iPTH concentration was reduced by 39% (P<0.05); 24-h urinary calcium excretion rose by 98% (P<0.001), and forearm bone mass increased by 5.6% (P<0.05). It is concluded that moderate-dose vitamin D₃ supplementation is effective in normalizing parameters of mineral metabolism in this disorder, despite evidence of resistance to the biologic effects of vitamin D.     

Higher 1,25-dihydroxyvitamin D3 concentrations associated with lower fall rates in older community-dwelling women

Introduction The purpose of this study was to examine the relationships of vitamin D supplementation and serum concentrations of vitamin D metabolites and parathyroid hormone (PTH) with neuromuscular function and falls in older community-dwelling women.Methods We examined these relationships using a 4-year prospective multi-center study among 9,526 community-dwelling women enrolled in the Study of Osteoporotic Fractures (median age: 70 years; interquartile range: 67–75) and a subset of 389 women (97%) out of 400 who were randomly selected from the entire cohort for serum measures. Measurements included: vitamin D supplementation, serum 25-hydroxyvitamin D₃ [25(OH)D₃], serum 1,25-dihydroxyvitamin D₃ [1,25(OH) ₂D₃], and serum intact parathyroid hormone (iPTH); grip and quadriceps strength, chair-stand time, walking speed, reaction time, and balance-walk time (including changes in grip strength, chair-stand time, walking speed and balance-walk time over approximately 3.7 years); and incident fall rates (number of falls/woman-years).Results In 9,526 women, vitamin D supplementation was not associated with any measures of neuromuscular function, change in neuromuscular function, or fall rates (p>0.01 for all). In a subgroup of 389 women, there was a trend of higher 25(OH)D₃ concentration with slightly weaker grip strength (p=0.007), and women in the fourth quartile of 1,25(OH)₂D₃ had a faster chair-stand time (p=0.017) than women in the first quartile; still, in general, concentrations of 25(OH)D₃, 1,25(OH)₂D₃, and iPTH were not associated with either neuromuscular function or changes in neuromuscular function (p>0.05 for all). However, higher 1,25(OH)₂D₃ concentration was associated with lower fall rates (p=0.039).Conclusions Higher 1,25(OH)₂D₃ concentration is associated with a lower fall risk in older community-dwelling women, but vitamin D supplementation, and 25(OH)D₃ and iPTH concentrations are not associated with either neuromuscular function or falls.     

Vitamin D Insufficiency in Internal Medicine Residents

Medical residents may be vulnerable to low vitamin D status because of long work hours and lack of sun exposure. We conducted a prospective cohort study to measure serum 25-hydroxyvitamin D concentrations among internal medicine residents, document seasonal variation in vitamin D status, and assess risk factors for inadequate vitamin D stores. Dietary intake of calcium and vitamin D, lifestyle characteristics, and serum concentrations of 25(OH)-vitamin D and intact parathyroid hormone (iPTH) were measured in 35 resident volunteers before and after the winter season. A total of 63–69% of medical residents consumed <400 IU/day of vitamin D; 61–67% consumed <1000 mg/day of calcium. Twenty-five (74%) had lower serum 25(OH)-vitamin D concentrations and 23 (68%) had higher serum iPTH in the spring than in the fall. Nine (26%) residents had serum concentrations of 25(OH)-vitamin D of <20 ng/mL in the fall; and sixteen (47%) in the spring. Seven residents (20%) had serum concentrations of 25(OH)-vitamin D of <20 ng/mL at both time-periods; Eighteen residents (51.4%) had 25(OH)-vitamin D levels of <20 ng/mL for at least one of the time-periods. Medical residents are at risk for hypovitaminosis D, particularly during the winter months and should be aware of the need to supplement their vitamin D stores. Insufficient vitamin D status and inadequate vitamin D intake may have long-term implications for bone health in these individuals. Increased educational efforts to promote healthy dietary and lifestyle choices that allow attainment and maintenance of skeletal health are appropriate in this population.Presented in part at the National Meeting of the Society of General Internal Medicine, (Vancouver, BC, May, 2003).     

Vitamin D and its Major Metabolites: Serum Levels after Graded Oral Dosing in Healthy Men

We determined the quantitative relationships between graded oral dosing with vitamin D₃, 25(OH)D₃, and 1,25(OH)₂D₃ for short treatment periods and changes in circulating levels of these substances. The subjects were 116 healthy men (mean age, 28 + 4 years, with usual milk consumption of 40.47 l/day and mean serum 25(OH)D of 67 + 25 nmol/l). They were distributed among nine open-label treatment groups: vitamin D₃ (25, 250 or 1250 mg/day for 8 weeks), 25(OH)D₃ (10, 20 or 50 mg/day for 4 weeks) and 1,25(OH)₂D₃ (0.5, 1.0 or 1.0 mg/day for 2 weeks). All treatment occurred between January 3 and April 3. We measured fasting serum calcium, parathyroid hormone, vitamin D₃, 25(OH)D and 1,25(OH)₂D immediately before and after treatment. In the three groups treated with vitamin D₃, mean values for circulating vitamin D₃ increased by 13, 137 and 883 nmol/l and serum 25(OH)D increased by 29, 146 and 643 nmol/l for the three dosage groups, respectively. Treatment with 25(OH)D₃ increased circulating 25(OH)D by 40, 76 and 206 nmol/l, respectively. Neither compound changed serum 1,25(OH)₂D levels. However, treatment with 1,25(OH)₂D₃ increased circulating 1,25(OH)₂D by 10, 46 and 60 pmol/l, respectively. Slopes calculated from these data allow the following estimates of mean treatment effects for typical dosage units in healthy 70-kg adults: an 8-week course of vitamin D₃ at 10 mg/day (400 IU/day) would raise serum vitamin D by 9 nmol/l and serum 25(OH)D by 11 nmol/l; a 4-week course of 25(OH)D₃ at 20 mg/day would raise serum 25(OH)D by 94 nmol/l; and a 2-week course of 1,25(OH)₂D₃ at 0.5 mg/day would raise serum 1,25(OH)₂D by 17 pmol/l. Received: 4 August 1997 / Accepted: 14 October 1997     

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 ≤−1.0 SD (low range normal value) had 25(OH)D levels <15 ng/ml. Low 25(OH)D levels were inversely related to high iPTH values (r = 0.30, P < 0.0001). Hypercalciuria was present in 15% of our patients, elevations of PTH levels (>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. Received: 9 February 1998 / Accepted: 1 October 1998     

Vitamin D metabolism in pregnant and pseudopregnant rats: Identification of 25-hydroxycholecalciferol-1-hydroxylase in decidual tissue

Summary Elevated levels of 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) are found in late pregnancy but the factors responsible for this are not known. To determine if the maternal-fetal calcium flux or the presence of a previously described extrarenal 25-hydroxycholecalciferol-1-hydroxylase (25(OH)-D₃-1-hydroxylase) play a role, serum calcium and 1,25(OH)₂D₃ were measured in pregnant, nonpregnant, and decidua-bearing pseudopregnant rats. Serum calcium was 8.74± 0.26 mg/dl (mean±SEM) in nonpregnant rats. In pregnant rats, serum calcium was not significantly different from nonpregnant controls on day 12 and only slightly higher on day 15. Pseudopregnant rats were significantly hypercalcemic on days 12 (11.93±0.19 mg/dl) and 15 (11.45±0.23 mg/dl) compared with nonpregnant rats (P<0.001). In nonpregnant controls the serum level of 1,25(OH)₂D₃ was 44.6±6.3 pg/ml. Levels in pregnant rats were not significantly different on days 12 or 15 but tended to be higher by day 15 (75.2±19.7 pg/ml). Pseudopregnant rats had levels of 72.6±13.5 pg/ml on day 12 and 102.8±10.9 pg/ml on day 15, the latter of which was significantly higher than nonpregnant values (P<0.05). 25(OH)D₃-1-hydroxylase activity was determined in whole tissue homogenates of placenta and decidua. Placenta from pregnant rats and decidua from pregnant and pseudopregnant rats both formed putative 1,25(OH)₂D₃ in short-term incubation with 25(OH)D₃ as identified by comigration with authentic 1,25(OH)₂D₃ on high pressure liquid chromatography (HPLC). The results suggest that hypercalcemia during pseudopregnancy is due to unregulated production of 1,25(OH)₂D₃ by decidual tissue. Pregnant rats may not become hypercalcemic because the fetus acts as a calcium sink or the 25(OH)D₃-1-hydroxylase is under regulation in the pregnant state.     

Sequential changes in mineral metabolism and serum vitamin D metabolite concentrations produced by phenobarbital administration in the rat

Summary We examined the effect of daily phenobarbital administration on serum vitamin D metabolite levels and indices of vitamin D biologic activity in 7-week-old male rats maintained on parenteral vitamin D supplementation (125 ng/day). Treatment with phenobarbital (75 mg/kg/day) produced a biphasic response in parameters of vitamin D biologic effect, including serum calcium concentration, serum inorganic phosphate concentration, and intestinal⁴⁵Ca calcium absorption. An initial increase in these values, maximal after 3–5 days of treatment, was followed by a subsequent decline to subnormal levels by day 21. A parallel biphasic pattern was observed for serum 25-hydroxyvitamin D (25OHD) concentration. Serum 25OHD reached a peak increase of 87% above control levels (P<0.01), observed after 5 days of treatment, and subsequently declined to 62% of control animal values (P<0.01) by 21 days. Serum 24,25(OH)₂D concentration followed a similar course and exhibited a strong positive correlation with serum 25OHD concentrations (r=0.74,P<0.01). In contrast, serum 1,25(OH)₂D concentration was not significantly different from control values after 5 days but was increased 80% over control values (P<0.05) by day 21. Serum vitamin D concentration declined progressively in treated animals, falling to 50% of control levels (P<0.05) by day 5 and to 27% of control levels (P<0.001) by day 21. At the point of maximal increase in serum 25OHD concentration, hepatic microsomal vitamin D₃-25-hydroxylase activity was not increased in the treated animals whereas hepatic mitochondrial vitamin D₃-25-hydroxylase activity was increased by 2.4-fold. Increased hepatic mitochondrial vitamin D₃-25-hydroxylase activity persisted through 21 days of phenobarbital treatment. It is concluded that phenobarbital administration in the rat produces an initial increase in vitamin D biologic effect which correlates temporally with increased circulating levels of 25OHD, the latter possibly resulting from increased hepatic mitochondrial vitamin D-25-hydroxylase activity. A subsequent decline in serum 250HD concentration may be the result of decreased availability of vitamin D as substrate. This sequence of alterations in vitamin D metabolism bears potentially important implications for the timing of prophylactic vitamin D supplementation in patients treated with anticonvulsant drugs.     

Correlation of vitamin D,bone mineral density and parathyroid hormone levels in adults with low bone density

Background:

Bone mineral densiy (BMD) is known to be affected by serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels. Indian data pertinent to above observation is scant. Our study aimed to investigate the relationships between serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels and bone mineral density (BMD) in a cohort of Indian patients.

Materials and Methods:

Adults with or without fragility fractures with low BMD at the hip or lumbar spine were evaluated clinically along with laboratory investigations. T-scores of the hip and spine were derived from BMD-DEXA (dual-energy X-ray absorptiometry). Multivariate regression models were used to investigate the relationships between serum 25(OH) D, iPTH and BMD.

Results:

Total of 102 patients (male:female = 38:64) with a mean age of 62.5 ± 6.4 years were included in the study. Forty-four patients had osteopenia. Osteoporosis was present in 58 patients. The mean values for serum 25(OH) D and iPTH levels were 21.3 ± 0.5 ng/ml and 53.1 ± 22.3 pg/ml, respectively. In 84.3% of patients, serum 25(OH) D levels were below 30 ng/ml (Normal = 30-74 ng/ml), confirming vitamin D deficiency. There was no association between 25(OH) D levels and BMD at the hip or lumbar spine (P = 0.473 and 0.353, respectively). Both at the hip and lumbar spine; iPTH levels, male gender, body mass index (BMI) and age were found to be significant predictors of BMD. Patients with higher BMI had significantly lower BMD and T-score. At levels <30 ng/ml, 25(OH) D was negatively associated with iPTH (P = 0.041).

Conclusion:

Among our cohort of patients with low BMD, no direct relationship between serum 25(OH) D levels and BMD was observed. However, a negative correlation between iPTH and 25(OH) D at serum 25(OH) D concentrations <30 ng/ml. Serum iPTH levels showed a significant negative association with BMD at the hip and lumbar spine. Our findings underscore the critical role of parathyroid hormone in bone metabolism and health.     

Prevalence of Vitamin D Insufficiency in an Adult Normal Population

The vitamin D status of a general adult urban population was estimated between November and April in 1569 subjects selected from 20 French cities grouped in nine geographical regions (between latitude 43° and 51° N). Major differences in 25-hydroxyvitamin D (25(OH)D) concentration were found between regions, the lowest values being seen in the North and the greatest in the South, with a significant ‘sun’ effect (r = 0.72; p = 0.03) and latitude effect (r = -0.79; p = 0.01). In this healthy adult population, 14% of subjects exhibited 25(OH)D values ≤ 30 nmol/l (12 ng/ml), which represents the lower limit (< 2 SD) for a normal adult population measured in winter with the same method (RIA Incstar). A significant negative correlation was found between serum intact parathyroid hormone (iPTH) and serum 25(OH)D values (p < 0.01). Serum iPTH held a stable plateau level at 36 pg/ml as long as serum 25(OH)D values were higher than 78 nmol/l (31 ng/ml), but increased when the serum 25(OH)D value fell below this. When the 25(OH)D concentration became equal to or lower than 11.3 nmol/l (4.6 ng/ml), the PTH values reached the upper limit of normal values (55 pg/ml) found in vitamin D replete subjects. These results showed that in French normal adults living in an urban environment with a lack of direct exposure to sunshine, diet failed to provide an adequate amount of vitamin D. It is important to pay attention to this rather high prevalence of vitamin D insufficiency in the general adult population and to discuss the clinical utility of winter supplementation with low doses of vitamin D.