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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.

Background/methods: We examined 21 clinical trials (16 articles and 5 abstracts) that compared intravenous (i.v.) and oral vitamin D analogs for the treatment of secondary hyperparathyroidism in hemodialysis patients. Nearly all the studies had severe limitations, especially study size. Only 2 studies utilized more than 25 patients per treatment arm; 11 of the 16 articles and 4 of the 5 abstracts had less than 15 patients per arm. Calcitriol and/or alpha-calcidol were studied in 20 trials of the 21 studies (15 of the 16 articles) while 1 article examined doxercalciferol., Results: No difference of efficacy between i.v. and oral dosing was found in 10 of the 15 articles in which efficacy was assessed. The i.v. route provided significantly faster suppression of elevated parathyroid hormone (PTH) and/or a greater degree of suppression in 5 of 15 applicable articles, but in 2 of these 5 studies the i.v. dose was substantially greater than the oral dose. Side effects, chiefly hypercalcemia, were noted in half of the articles. Six of 9 articles with detailed results found no significant difference; only 2 found significantly increased hypercalcemia with oral dosing, and 1 found significantly increased hypercalcemia with i.v. dosing. Only 3 articles reported on hyperphosphatemia and no difference was found for mode of administration. One factor influencing 19 of the 21 comparisons was the use of oral doses that were therapeutically equivalent to about half or less the i.v. dose given the lower bioavailability of oral D hormones. One larger study (70 patients) that compared equipotent dosing of the 2 administration routes found 4 times more hypercalcemia using oral than i.v. dosing (p < 0.001). Another factor complicating interpretation is that the treatment periods were short, with half being 16 weeks or less and only 2 lasting 36 weeks., Conclusion: Conclusions about the comparative efficacy and safety of the 2 administration routes require larger studies of longer duration that utilize therapeutically equivalent doses.

Most reports on the effectiveness and side effects of oral versus parenteral calcitriol or alfacalcidol in hemodialysis patients with secondary hyperparathyroidism show no advantage of parenteral treatment. The efficacy and safety of intravenous doxercalciferol (1alphaD(2)) were studied in hemodialysis patients with secondary hyperparathyroidism (plasma intact parathyroid hormone [iPTH]: range, 266 to 3,644 pg/mL; median, 707 pg/mL). These results were compared with those of a previous trial using intermittent oral 1alphaD(2); the same 70 patients were entered onto both trials, and 64 patients completed both trials per protocol. Twelve weeks of open-label treatment in both trials were preceded by identical 8-week washout periods. Degrees of iPTH suppression from baseline were similar in the two trials, with iPTH level reductions less than 50% in 89% and 78% of patients during oral and intravenous treatment, respectively. Grouping patients according to entry iPTH levels (<750 and >/=750 pg/mL) showed similar but more rapid iPTH suppression in the low-iPTH groups, whereas longer treatment and larger doses were required by the high-iPTH groups. Highest serum calcium levels averaged 9.82 +/- 0.14 and 9.67 +/- 0.11 mg/dL during oral and intravenous 1alphaD(2) treatment, respectively (P: = not significant [NS]). Prevalences of serum calcium levels greater than 11.2 mg/dL during oral and intravenous treatment were 3.62% and 0.86% of calcium measurements, respectively (P: < 0.001). Highest serum phosphorus levels during oral and intravenous treatment averaged 5.82 +/- 0.21 and 5.60 +/- 0.21 mg/dL, respectively (P: = NS). The percentage of increments in serum phosphorus levels during oral treatment exceeded that during intravenous treatment during 5 of 12 treatment weeks. Thus, intermittent oral and intravenous therapy with 1alphaD(2) reduced iPTH levels effectively and similarly, hypercalcemia was less frequent, and serum phosphorus levels increased less during intravenous than oral 1alphaD(2) therapy, suggesting that intravenous 1alphaD(2) therapy may be advantageous in patients prone to hypercalcemia or hyperphosphatemia.

We compared the bone and body composition results in vivo on two bone densitometers using fan-beam geometry (EXPERT and PRODIGY) with those using pencil-beam geometry (DPX). Measurements were made on large groups of adults ranging in weight from about 50 to 120 kg. Both spine and femur neck BMD on the fan-beam densitometers averaged within 1% of the pencil-beam results, and there was no magnitude dependence of the results by Bland-Altman analysis. Total body BMC and BMD on the PRODIGY and DPX were congruent, but on the EXPERT, BMC was about 2% lower and BMD 2% higher than corresponding values on the DPX. Soft-tissue composition was closely congruent for the PRODIGY and DPX; the comparable EXPERT-DPX differences showed greater scatter but no significant magnitude dependence. The smaller fan-angle of the PRODIGY (4 degrees ) probably contributed to its better congruence to pencil-beam results compared with the EXPERT (12 degrees ).

Hypercalcemia and hyperphosphatemia frequently necessitate vitamin D withdrawal in hemodialysis patients with secondary hyperparathyroidism. In short-term trials, doxercalciferol (1alpha-hydroxyvitamin D(2) [1alphaD(2)]) suppressed intact parathyroid hormone (iPTH) effectively with minimal increases in serum calcium and phosphorus (P) levels. This modified, double-blinded, controlled trial examined the efficacy and safety of 1alphaD(2) use in 138 hemodialysis patients with moderate to severe secondary hyperparathyroidism by using novel dose titration; 99 patients completed the study. Hemodialysis patients with secondary hyperparathyroidism were enrolled onto this study, consisting of washout (8 weeks), open-label 1alphaD(2) treatment (16 weeks), and randomized, double-blinded treatment with 1alphaD(2) or placebo (8 weeks). Oral 1alphaD(2) was administered at each hemodialysis session, with doses titrated to achieve target iPTH levels of 150 to 300 pg/mL. Baseline iPTH levels (897 +/- 52 [SE] pg/mL) decreased by 20% +/- 3.4% by week 1 (P: < 0.001) and by 55% +/- 2.9% at week 16; iPTH levels returned to baseline during placebo treatment but remained suppressed with 1alphaD(2) treatment. In 80% of the patients, iPTH level decreased by 70%, reaching the target level in 83% of the patients. Grouping patients by entry iPTH level (<600, 600 to 1,200, and >1,200 pg/mL) showed rapid iPTH suppression in the group with the lowest level; greater doses and longer treatment were required in the group with the highest level. During open-label treatment, serum calcium and P levels were 9.2 +/- 0.84 (SD) to 9.7 +/- 1.05 mg/dL and 5.4 +/- 1.10 to 5.9 +/- 1.55 mg/dL, respectively. During double-blinded treatment, serum calcium levels were slightly greater with 1alphaD(2) than placebo, but P levels did not differ. During double-blinded treatment, 3.26% and 0.46% of serum calcium measurements exceeded 11.2 mg/dL with 1alphaD(2) and placebo, respectively (P: < 0.01); median level was 11.6 mg/dL during hypercalcemia. Intermittent oral 1alphaD(2) therapy effectively suppresses iPTH in hemodialysis patients with secondary hyperparathyroidism, with acceptable mild hypercalcemia and hyperphosphatemia.

Both femora were measured on 61 normal adults using dual X-ray absorptiometry (DXA). In a subset of 31 subjects, each femur was scanned once using the conventional leg-positioning device supplied with the densitometer, and once using a new positioning device and software that allowed both legs to be measured simultaneously. In another subgroup (n = 30), subjects were measured three times using the new dual-femur approach to better assess precision error. The data were analyzed for differences owing to the different positioning devices and for differences between right and left sides. The correlation between results with the old and new positioners was high (r > 0.99, standard error of the estimate [SEE] = 0.01-0.02 g/cm(2)). There was no significant difference in the average bone mineral density (BMD) values between the old and new positioner. The precision errors for each femur alone with the dual-femur approach were similar to those reported for the single-femur scans (1 to 2%), but the precision errors for the combined femora were reduced by 30% as expected. The correlation between right and left sides was high (r = 0.94-0.96), and the SEE in predicting one side from the other was moderate for total, trochanteric, and femoral neck BMD (0.05, 0. 05, and 0.06 g/cm(2), respectively). These SEE equate to about 0.5 standard deviation in terms of T-score. Differences in many individual cases between the right and left sides were significantly greater than the precision error. The new dual-femur software and leg positioner allows rapid measurement and analysis of both femora, thereby eliminating the uncertainty between sides.

We assessed a new dual-energy bone densitometer, the PRODIGY, that uses a narrow-angle fan-beam (4.5 degrees) oriented parallel to the longitudinal axis of the body (i.e., perpendicular to the usual orientation). High-resolution scans across the body can be stepped at 17 mm intervals. The energy-sensitive array detector uses cadmium zinc telluride, which allowed rapid photon counting. Spine and femur scans required 30 s, and total-body scans required 4-5 min; the dose was only 3.7 mrem and 0.04 mrem respectively, or about 5 to 10 times lower than conventional fan-beam densitometry. We found only a small influence of soft-tissue thickness on bone mineral density (BMD) results. There was also a small (+/- 1%) influence of height above the tabletop on BMD results. A software correction for object height allowed a first-order correction for the large magnification effects of position on bone mineral content (BMC) and area. Consequently, the results for BMC and area, as well as BMD, with PRODIGY corresponded closely to those obtained using the predecessor DPX densitometer, both in vitro and in vivo; there was a generally high correlation (r = 0.98-0.99) for BMD values. Spine and femur values for BMC, area and BMD averaged within 0.5% in vivo (n = 122), as did total-body BMC and BMD (n = 46). PRODIGY values for total-body lean tissue and fat also corresponded within 1% to DPX values. Regional and total-body BMD were measured with 0.5% precision in vitro and 1% precision in vivo. The new PRODIGY densitometer appears to combine the low dose and high accuracy of pencil-beam densitometry with the speed of fan-beam densitometers.

We measured bone mineral density (BMD in g/cm(2)) of the spine (L2-L4) and femur (four regions) in 1472 and 1487 cases, respectively, of ambulatory white women ages 20-79 years in the USA. A DPX densitometer was used in a mobile setting. The BMD values for women up to 69 years corresponded closely with published values for the USA, the UK, and northern Europe; our values were somewhat lower than those from other studies only in women over 70 years. The USA data were combined with data from Europe to give reference curves on about 12,000 subjects. Decreases of BMD with age in women below 50 years were much smaller than in older women (0.2% versus 0.6-1.0% per year). Femoral bone decreased from the neck region, but not the trochanter with age; the decrease of total femur BMD with age was due to loss from the former region. Loss of bone mineral content (BMC in g) from the femur neck and total femur region did not accelerate until after age 50 years, much like the spine. The apparent decrease of BMD in these regions that begins about age 40 actually is due to an increase of bone area. About 20% of USA women aged 50-79 years had BMD levels for the lumbar spine, or for the femur neck, more than -2.5 SD below the average values in young adult women 20-39 years old. Body weight had several times more impact on BMD than height, and in fact, a change of 1 kg in postmenopausal women was commensurate with the effect of a 1-year change in age. Subjects in the lowest quartile of body weight had T-scores that were 1 SD below those in the highest quartile.

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.