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Competing Interests: All authors state that they have no conflicts of interest.

In this review we summarize the impact of bolus versus daily dosing of vitamin D on 25(OH)D and 1,25(OH) 2 D levels, as well as on key countervailing factors that block vitamin D functions at the cellular level. Further, we discuss the role of bolus versus daily dosing of vitamin D for several health outcomes, including respiratory infections and coronavirus disease 2019 (COVID-19), rickets, falls and fractures, any cancer, and cancer-related mortality. This discussion appears timely because bolus doses continue to be tested for various disease outcomes despite a growing amount of evidence suggesting lack of efficacy or even detrimental effects of bolus dosing of vitamin D for outcomes where daily dosing at modest levels was effective in the vitamin D deficient. As a result, these discordant results may bias health recommendations for vitamin D if the recommendations are based on meta-analyses combining both daily and bolus dosing trials. © 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., (© 2021 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Background: 1,24-Dihydroxyvitamin D2 (1,24(OH)2D2) is a naturally occurring metabolite of vitamin D2 with low calcemic activity and potent antiproliferative activity. We evaluated the activity of 1,24(OH)2D2 in breast cancer models., Materials and Methods: The antiproliferative activity of 1,24(OH)2D2 was quantitated against human and murine breast cancer cell lines. The antitumor activity of 1,24(OH)2D2 was quantitated using MCF-7 xenografts in nude mice., Results: 1,24(OH)2D2 inhibited growth of vitamin D receptor (VDR)-positive, but not VDR-negative, breast cancer cells. 1,24(OH)2D2 (10 microg/kg or 50 microg/kg) reduced MCF-7 xenograft growth by 50% after five weeks. Tumor morphology in treated animals was consistent with replacement of epithelial cells by stromal tissue. Mice treated with 1,24(OH)2D2 showed no loss of body weight, hypercalcemia or kidney calcification., Conclusion: 1,24(OH)2D2 inhibits growth of breast cancer cells via VDR-dependent mechanisms; its complete lack of toxicity and significant antitumor activity supports further development for chemotherapeutic applications.

Calcitriol, as used for treating secondary hyperparathyroidism, has a low therapeutic index. The safety and efficacy of the vitamin D analog, 1 alpha (OH)-vitamin D2, (1 alpha D2), which has less toxicity in animals than 1 alpha (OH)-vitamin D3, was tested in a multicenter study of 24 hemodialysis patients with secondary hyperparathyroidism [serum intact (i) PTH > 400 pg/ml]. Calcium-based phosphate binders alone were used to maintain serum phosphorus < or = 6.9 mg/dl. After eight weeks without calcitriol (washout), oral 1 alpha D2, 4 micrograms/day or 4 micrograms thrice weekly, was started, with the dose adjusted over 12 weeks to maintain serum iPTH between 130 and 250 pg/ml. Pre-treatment serum iPTH fell from 672 +/- 70 pg/ml (SEM) to 289 +/- 36 after treatment (P < 0.05). The maximal decrease in serum iPTH was 48 to 96%, with 87.5% of patients reaching target iPTH levels. The final dose of 1 alpha D2 average 14.2 micrograms/week. Pre-treatment serum calcium rose modestly from 8.8 +/- 0.2 mg/dl to 9.5 +/0 0.2 after treatment (P < 0.001). Only once did modest hypercalcemia (serum Ca > 11.2 mg/dl) necessitate stopping treatment. Neither the average serum P level, the incidence of hyperphosphatemia, nor the dose of phosphate binders changed from washout to treatment. Thus, oral 1 alpha D2 is highly efficacious in suppressing secondary hyperparathyroidism in hemodialysis patients and is safe despite exclusive use of calcium-based phosphate-binders. Future studies should clarify the optimal dosage regimen.

Calcitriol is effective in suppressing PTH levels in haemodialysis patients with hyperparathyroidism but has a low therapeutic index. There is a search for other vitamin D sterols that suppress PTH but cause less hypercalcaemia. We review evidence that 1 alpha-hydroxy-vitamin D2 (1 alpha-D2) may be an effective and safer alternative to calcitriol. In vitamin D-deficient rats, 1 alpha-D2 is equipotent to 1 alpha-D3, which is converted to calcitriol before it acts; but, in normal rats, 1 alpha-D2 is much less toxic at high doses. In osteopenia models, either steroid-induced or following ovariectomy, 1 alpha-D2 is equal to or more effective than 1 alpha-D3 in preventing bone loss but causes less hypercalciuria. Studies in osteoporotic women reveal minimal hypercalciuria with 1 alpha-D2 at doses up to 4 micrograms/day, data suggesting greater safety than reported with calcitriol or 1 alpha-D3. Preliminary data in haemodialysis patients with secondary hyperparathyroidism demonstrate the efficacy of 1 alpha-D2 in suppressing PTH levels with minimal untoward effects on serum Ca and no effects on serum P. Taken together, these observations suggest that 1 alpha-D2 deserves strong consideration as a therapeutic agent for secondary hyperparathyroidism associated with end-stage renal disease.

This study is the first reported administration of 1 alpha-hydroxyvitamin D2 (1 alpha-OHD2) to human subjects. A total of 15 postmenopausal osteopenic women were given increasing oral doses of 1 alpha-OHD2, beginning with a low dose of 0.5 microgram/day. In 15 subjects, the doses were raised at weekly intervals to 1.0, 2.0, 4.0, and 5.0 micrograms/day, and in 5 of these subjects, the dose was further increased to 8.0 or 10.0 micrograms/day. Mean urine calcium +/- SEM showed a dose-related increase from 134 +/- 17 mg/24 h on 0.5 microgram/day to 198 +/- 21 mg/24 h on 4.0 micrograms/day (p < 0.05) and to 241 +/- 35 mg/24 h on 5.0 micrograms/day (p < 0.05). No subjects had hypercalciuria (> 350 mg/24 h, the upper limit of the laboratory normal range) at doses less than 5.0 micrograms/day; 5 subjects had hypercalciuria at or above 5.0 micrograms/day (3 at 5.0 micrograms/day, 1 at 8.0 micrograms/day, and 1 at 10.0 micrograms/day). Mean serum calcium increased slightly on the 4.0 micrograms dose only (p < 0.05) but remained well within the normal range. Mean creatinine clearance and BUN, used as measures of renal function, showed no significant changes. Routine blood and urine assays also showed no significant changes.(ABSTRACT TRUNCATED AT 250 WORDS)

We investigated several transformations of bone mineral content (BMC) and area density (BMD), in particular volumetric density (BMAD), to ascertain the influence on (1) body size dependence, (2) diagnostic sensitivity, and (3) precision. These transformations were examined in a group of 657 normal postmenopausal women and 327 women with osteoporotic fracture. First, expression of results as BMAD removed some of the slight dependence on body size; 21% of the variation in BMC and 15% of the variation i BMD were associated with body weight, but only 8% with BMAD. Second, the Z scores compared with those for age-matched controls for BMD and BMC were -1.85 and -1.71, respectively; the Z score for BMAD was -1.64. Third, the precision error for BMC was reduced by expressing results as BMD (1.1 versus 0.5%); BMAD degraded precision slightly (0.7%). BMD appeared to be the optimal expression for bone densitometry because it provided the best diagnostic sensitivity and lowest precision error; there was a minimal influence of body size on BMD results. This study also showed that osteoporotic women, even in the first postmenopausal decade, had low spine BMD, small vertebral area, and low body weight. Such women may be particularly at risk of crush fracture.

Bone mineral content (BMC, g) using DEXA (Lunar DPX) was measured on known hydroxyapatite samples in a water bath in the presence of uniform and nonuniform covering of fat-equivalent materials. Selective placement of paraffin over bone had a greater effect than lard in reducing apparent BMC, and polycarbonate plastic had a lesser effect. Measured BMC was 100.1 +/- 1.1% of actual hydroxyapatite weight when (1) fat over bone was about twice the mass of hydroxyapatite, and (2) the surrounding soft tissue was 15-30% fat. There was a linear relationship between observed and expected BMC, area (cm2), and bone mineral density (BMD, g/cm2) measured on an aluminum phantom using either the Lunar DPX or the Hologic QDR-1000. The measured area with the two densitometers was identical, but BMC differed. For both an anthropomorphic phantom and human subjects, use of a constant-threshold (0.2 g/cm2) edge-detection algorithm excluded less low-density bone from the transverse processes than the standard DPX edge-detection algorithm. Differences in edge detection could influence the results obtained with phantoms and in vivo and make system intercomparison difficult.

Bone mineral density (BMD) was measured in normal white males using 153 Gd dual-photon absorptiometry. Measurements were made on the lumbar spine (n = 315) and on the proximal femur (n = 282) utilizing three regions of interest. There was a small but significant age-related decrease in spinal BMD (r = -0.11; -0.001 g/cm2 per year) and trochanteric BMD (r = 0.27; -0.002 g/cm2 per year). The BMD of the other femoral sites decreased more rapidly; the femoral neck (r = -0.58; -0.005 g/cm2 per year) and Ward's triangle (r = -0.69; -0.007 g/cm2 per year) declined by about 21 and 34%, respectively, from age 20 to age 70. These femoral BMD decreases were three to four times greater than those usually seen in the peripheral skeleton in males but less than the decreases of 25-30 and 40% in the femoral neck and Ward's triangle of white females. This pattern of aging bone loss may partially explain the paucity of spine fractures and the lower incidence of hip fractures in males versus females.

Density of the radius (by single-photon absorptiometry) and the spine (by dual-photon absorptiometry) was measured in 281 normal young women and in a large heterogeneous group of 1,622 consecutive female patients. Both spinal and radial density were useful measurements when performed on patients with medical indications; spine and radius densities in these patients averaged 10-20% below those of age-matched controls. However, patients younger than 60 years of age had deficits of spine density that were twice as large as those in the radius, and twice as many of these patients had spinal osteopenia, compared with those with radial osteopenia. After age 70, loss of density in the radius approximated that in the spine and the prevalence of osteopenia was similar at both sites. The poorer sensitivity of the radius measurement reflected the fact that it did not predict spine density. The standard error of the estimate was 0.12 gm/cm2 in normal subjects and 0.15 gm/cm2 in patients. At any given radial density, the spinal density of patients averaged 0.18 gm/cm2 (15-20%) below that in normal subjects. Predictions of spinal density from body weight were as accurate as predictions from radial density. Preferential spinal osteopenia occurring without radial osteopenia precluded radial densitometry as a screening method for individuals with osteoporosis before age 60. However, measurement of the radius was more effective than body weight for defining groups at risk, even though the radius did not reliably predict individual spine density. A radius shaft density less than 0.55 gm/cm2 occurring with a body weight less than 55 kg was associated with a high prevalence of spinal osteopenia.

Patterns of bone loss in the axial and the appendicular skeleton were studied in 185 normal volunteers (105 women and 82 men; age range, 20--89 yr) and in 76 women and 9 men with vertebral fractures due to osteoporosis. Bone mineral density was measured in vivo at the lumbar spine (predominantly trabecular bone) by dual photon absorptiometry and at the midradius (greater than 95% cortical bone) and distal radius (75% cortical and 25% trabecular bone) by single photon absorptiometry. In normal women, bone diminution from the vertebrae began in young adulthood and was linear. In the appendicular skeleton, bone diminution did not occur until age 50 yr, was accelerated from aged 51 to 65 yr, and then decelerated somewhat after age 65 yr. Overall bone diminution throughout life was 47% for the vertebrae, 30% for the midradius, and 39% for the distal radius. In normal men, vertebral and appendicular bone diminution with aging was minimal or insignificant. Mean bone mineral density was lower in patients with osteoporosis than in age- and sex-matched normal subjects at all three scanning sites, although spinal measurements discriminated best; however, there was considerable overlap. By age 65 yr, half of the normal women (and by age 85 yr, virtually all of them) had vertebral bone mineral density values below the 90th percentile of women with vertebral fractures and, thus, might be considered to have asymptomatic osteoporosis. For men, the degree of overlap was less. The data suggest that disproportionate loss of trabecular bone from the axial skeleton is a distinguishing characteristic of spinal osteoporosis.

Single-photon (I-125) absorptiometry was used to measure bone mineral content (BMC) of the distal third of the radius, and dual-photon absorptiometry (Gd-153) was used to measure total-body bone mineral (TBBM), as well as the BMC of major skeletal regions. Measurements were done in normal females, normal males, osteoporotic females, osteoporotic males, and renal patients. The BMC of the radius predicted TBBM well in normal subjects, but was less satisfactory in the patient groups. The spinal BMC was predicted with even lower accuracy from radius measurement. The error in predicting areal density (bone mass per unit projected skeletal area) of the lumbar and thoracic spine from the radius BMC divided by its width was smaller, but the regressions differed significantly among normals, osteoporotics, and renal patients. There was a preferential spinal osteopenia in the osteoporotic group and in about half of the renal patients. Bone measurements on the radius can indicate overall skeletal status in normal subjects and to a lesser degree in patients, but these radius measurements are inaccurate, even on the average, as an indicator of spinal state.

At the Bone Mineral Laboratory of the University of Wisconsin a microcomputer-based digital read-out system was designed specifically for determining bone mineral content (BMC) and bone width (BW) in newborn infants with the following features: (1) high accuracy and precision; (2) high reproducibility in vivo; (3) direct read-out of BMC and BW; (4) automatic data calibration; and (5) use of a low activity [125I] source (less than 50 mCi). BMC and BW were determined on the left radius on a series of 114 newborn infants of all gestational ages and a curve for intrauterine bone mineral content extrapolated from the data. Accuracy of the photon absorptiometric system was assessed by measuring BMC on a series of nine small bone sections (29-212 mg/cm) and confirmed by subsequent ashing of these bone sections (r = 0.99). Short-term precision (weekly, coefficient of variation 1.7%) and long-term precision (monthly, coefficient of variation 2.1%) for measuring BMC were determined by multiple determinations on a four-chambered bone phantom calibrated with the bone sections. Immediate reproducibility (without repositioning the arm) for the 4-6 scans performed for each determination of BMC and BW was good with a mean coefficient of variation of 3.9% for BMC and 3.6% for BW. In 84 infants, repositioning error was determined by repeating the measurement of BMC and BW after repositioning the arm. The correlation coefficients between measurements before and after repositioning the arm were 0.97 for BMC and 0.95 for BW. BMC correlated well with gestational age (r = 0.92), birth weight (r = 0.89) and bone width (r = 0.92). BW also correlated with gestational age (r = 0.84) and birth weight (r = 0.85). A multiple linear regression analysis of BMC versus BW, gestational age, and birth weight was done. The correlation coefficient between the predicted BMC from these variables and measured BMC was 0.95. Photon absorptiometry can be used with high accuracy, precision, and reproducibility in vivo in newborn infants. BMC correlates with gestational age, birth weight, and bone width.

Vitamin D metabolites were measured in children, untreated with glucocorticoids, who had renal disease. Two groups were defined in relation to endogenous creatinine clearance values: those with impaired clearance , 0 to 48 ml/min per 1.73 m2; and those with unimpaired clearance, 75 to 150 ml/min per 1.73 m2. Serum 1.25(OH)2D was 16 +/- (SD) 12 pg/ml in impaired patients (N=24) and 48 +/- 16 pg/ml in unimpaired patients (N=18). The latter level is not different from healthy childhood controls (43 +/- 12 pg/ml; N=194). Serum samples of 25(OH)D2 and D3 were comparable in each group and not different from control values of 33.2 +/- 10.3 ng/ml. Serum 24,25(OH)2D was 0.6 +/- (SD) 0.14 ng/ml in patients with a clearance of less than 13 ml/min per 1.73 m2, 1.39 +/- 0.54 ng/ml in those with a clearance of 18 to 48 ml/min per 1.73 m2, and 152 +/- 0.91 ng/ml in patients without an impairment of clearance. Only patients with the lowest clearance had values different from control values of 1.70 +/- 0.57 ng/ml. In our study we suggest that a significant reduction in 24,25(OH)2D and 1,25(OH)2D are found at low clearance values in children with tubulointerstitial disease. Our study further suggests that a reduction in renal tubular mass is important in accounting for these changes in vitamin D metabolite values.

Bone mineral density (BMD) was measured in 140 normal young women (aged 20 to 39 years) and in 423 consecutive women over age 40 referred for evaluation of osteoporosis. Lumbar spine and proximal femur BMD was measured using dual-photon absorptiometry (153Gd), whereas the radius shaft measurement used single-photon absorptiometry (125I). There were 324 older women with no fractures, of which 278 aged 60 to 80 years served as age-matched controls. There were 99 women with fractures including 32 with vertebral and 22 with hip fractures. Subsequently, another 25 women with hip fractures had BMD measured in another laboratory; their mean BMD was within 2% of that of the original series. The mean age in both the nonfracture and fracture groups was 70 +/- 5 years. The BMD in the age-matched controls was 20% to 25% below that of normal young women for the radius, spine, and femur, but the Ward's triangle region of the femur showed even greater loss (35%). The mean BMD at all sites in the crush fracture cases was about 10% to 15% below that of age-matched controls. Spinal abnormality was best discriminated by spine and femoral measurements (Z score about 0.9). In women with hip fractures, the BMD was 10% below that of age-matched controls for the radius and the spine, and the BMD for the femoral sites was about 25% to 30% below that of age-matched control (Z score about 1.6). Femoral densities gave the best discrimination of hip fracture cases and even reflected spinal osteopenia. In contrast, neither the spine nor the radius reflected the full extent of femoral osteopenia in hip fracture.

We measured bone mineral density (BMD) of the proximal femur, lumbar spine, or both by dual photon absorptiometry in 205 normal volunteers (123 women and 82 men; age range 20 to 92 yr) and in 31 patients with hip fractures (26 women and 5 men; mean age, 78 yr). For normal women, the regression of BMD on age was negative and linear at each site; overall decrease during life was 58% in the femoral neck, 53% in the intertrochanteric region of the femur, and 42% in the lumbar spine. For normal men, the age regression was linear also; the rate of decrease in BMD was two-thirds of that in women for femoral neck and intertrochanteric femur but was only one-fourth of that in women for lumbar spine. This difference may explain why the female/male ratio is 2:1 for hip fractures but 8:1 for vertebral fractures. The standard deviation (Z-score) from the sex-specific age-adjusted normal mean in 26 women with hip fracture averaged -0.31 (P < 0.05) for the femoral neck, -0.53 (P < 0.01) for the intertrochanteric femur, and +0.24 (NS) for the lumbar spine; results were similar for 5 men with hip fractures. By contrast, for 27 additional women, ages 51-65 yr, with only nontraumatic vertebral fractures, the Z-score was -1.92 (P < 0.001) for the lumbar spine. Thus, contrary to the view that osteoporosis is a single age-related entity, our data suggest the existence of two distinct syndromes. One form, "postmenopausal osteoporosis," is characterized by excessive and disproportionate trabecular bone loss, involves a small subset of women in the early postmenopausal period, and is associated mainly with vertebral fractures. The other form, "senile osteoporosis," is characterized by proportionate loss of both cortical and trabecular bone, involves essentially the entire population of aging women and, to a lesser extent, aging men, and is associated with hip fractures or vertebral fractures or both.

Bone density measurements are currently being performed throughout the world in the diagnosis and management of osteoporosis as well as in research into this major health problem. However, it is not clear to what extent bone mineral density (BMD) values determined by dual-photon absorptiometry at one center can be applied to another. This is particularly relevant for the quantitative comparison of results from studies carried out in different laboratories. Furthermore, many centers now acquiring densitometers may not have the resources to determine their own normal range, relying instead on a "normal" range provided by the manufacturer. The question of the comparability of BMD data obtained in different centers was examined by comparing the normal range for the lumbar spine and proximal femur in 203 normal white Australian women and 892 normal white U.S. women, obtained using the same model densitometer. The two populations were compared according to decade. From superimposition of the Australian individual values on the North American normal ranges, only minor differences between the two populations were seen at any of the sites measured at any decade. None of these minor differences were statistically significant. This study shows a close similarity between BMD values in both the proximal femur and lumbar spine in normal white women in Australia and North America, provided the same model densitometer is used. Thus data obtained from different centers in populations with similar ethnic composition may be compared directly. These findings provide for the first time a sound basis for the quantitative comparison of the at times conflicting studies carried out in widely differing settings around the world.

A dietary survey conducted in the southern highlands of Peru revealed two important sources of dietary calcium not previously reported. Mineral and ash calcium ingested as a food spice, and along with coca, raises the calcium intake from the low figures recorded by standard nutritional surveys to a more substantial level.

For pottery sherds from an arid region, the ratio of natural thermoluminescence to thermoluminescence induced by a standard dose of radiation corresponds closely to the independently assessed archeologic age. Difficulties in age determination, because of variations among sherds, are reduced by averaging results for samples from the same time period.

The use of nearly monochromatic radiation (l(125)) for the direct determination of bone mineral absorption in cadaver materials indicates that underlying bone components can be measured accurately on the flesh-covered forearm. The correlation of the bone mass, determined by this scanning technique, with actual bone weight is 0.96. The method is the most accurate yet demonstrated for bone with overlying tissue, and may prove suitable for these studies in vivo where it has not been possible to use previous roentgenologic techniques.