Key Points

Abstract

Introduction

Vitamin D supplementation has been considered beneficial for prevention and treatment of osteoporosis. Clinical trial data support skeletal benefits of vitamin D supplementation in persons with circulating 25-hydroxyvitamin D (25[OH]D) levels of less than 30 nmol/L.^1,2 However, recent meta-analyses do not support a major treatment benefit of vitamin D for osteoporosis^3,4 or preventing falls⁴ or fractures.^4,5 Most vitamin D supplementation recommendations range from 400 to 2000 IU daily^6,7 with a tolerable upper intake level of 4000 IU to 10000 IU^6,8. Between 2013 and 2014, three percent of US adults consumed daily doses of at least 4000 IU of vitamin D⁹; one study assessed the effects of daily doses of greater than 4000 IU for at least 12 months, finding 6500 IU no different than 800 IU for changes in bone mineral density (BMD).¹⁰

The clinical diagnosis of osteoporosis and prediction of fracture risk relies on dual x-ray absorptiometry (DXA) scans measuring areal BMD at different skeletal sites. However, bone strength, an important component of fracture risk, is determined by a combination of bone mass, morphology, and microarchitecture.¹¹ High-resolution peripheral quantitative computed tomography (HR-pQCT) has higher resolution and sensitivity than DXA and assesses compartmental volumetric bone density, microarchitecture, and estimates of bone strength. In a prospective study with 7254 participants, HR-pQCT parameters were associated with fracture risk independently of DXA-measured areal BMD.¹¹ Vitamin D effects on the skeleton have not been prospectively assessed using HR-pQCT.

Motivated by the prevalence of high-dose vitamin D supplementation among healthy adults, this study explored the dose-response effects of daily vitamin D supplementation (400, 4000, 10000 IU) on total volumetric BMD and bone strength in healthy community-dwelling adults over 3 years, while ensuring adequate calcium intake. It was hypothesized that a higher dose of vitamin D has a positive effect on HR-pQCT measures of volumetric density and strength, perhaps via suppression of parathyroid hormone (PTH)–mediated bone turnover.

Methods

Results

The flow of participants is presented in Figure 1. A total of 542 participants were screened, 311 met inclusion criteria and were randomized, and 287 (92%) completed all aspects of the 3-year trial. The primary analyses included 303 participants. Baseline demographic information is shown in Table 1. The cohort was 53% men, and predominantly white (95%). Classified by DXA T score, participants had normal (81%) or low (19%) total hip areal BMD.

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Figure 1.

Flow Diagram of Participants Through the Study

Participants who received at least 1 dose of study drug and underwent at least 1 follow-up measurement were included in the primary analyses.

Table 1.

Baseline Demographic, Health Characteristics, and Laboratory Values

Variable	No. (%)
	10000 IU	4000 IU	400 IU
No. of participants	101	97	105
Demographics
Sex
Men	53 (52.5)	50 (51.5)	60 (57.1)
Women	48 (47.5)	47 (48.5)	45 (42.9)
Age, mean (SD). y	61.9 (4.1)	62.6 (4.3)	62.2 (4.2)
Years since menopause, mean (SD), y	12.5 (5.6)	11.7 (7.3)	12.6 (5.9)
BMI, mean (SD)a	27.1 (4.1)	28.1 (5.0)	27.7 (4.3)
Body fat, mean (SD), %	32.2 (8.4)	34.0 (8.9)	33.3 (9.0)
Race/ethnicity
Non-Hispanic white	98 (97.0)	94 (96.9)	98 (93.3)
Non-Hispanic black	0	1 (1.0)	1 (1.0)
Asian	2 (2.0)	2 (2.1)	5 (4.7)
Hispanic	1 (1.0)	0	1 (1.0)
Health characteristics, mean (SD)
Systolic blood pressure, mm Hg	125.6 (16.0)	131.6 (16.7)	128.5 (15.4)
Diastolic blood pressure, mm Hg	80.4 (10.5)	80.8 (8.3)	81.1 (7.7)
Vitamin D supplementationb	34 (34)	38 (39)	32 (30)
Medical history
Skin cancerc	15 (14.9)	7 (7.2)	12 (11.4)
Other cancer	10 (9.9)	7 (7.2)	5 (4.8)
Cardiovascular-related diagnoses	13 (12.9)	10 (10.3)	21 (20.0)
Type 2 diabetes	3(3.0)	4 (4.1)	2 (1.9)
Rheumatoid arthritis	1 (1.0)	2 (2.1)	1 (1.0)
Asthma	9 (8.9)	6 (6.2)	5 (4.8)
Smoker	4 (4.0)	0	2 (1.9)
Fallsd	18 (17.8)	20 (20.6)	22 (21.0)
Fracture after age 50 y	17 (16.8)	13 (13.4)	17 (16.2)
Lumbar spine T scoree	0.1 (1.5)	0.2 (1.3)	0.0 (1.5)
Total hip T scoref	0.0 (1.1)	0.2 (1.1)	0.1 (1.1)
Laboratory values
Serum
25(OH)D, nmol/L	78.4 (18.4)	81.3 (20.1)	76.7 (21.0)
PTH, ng/L	22.1 (7.4)	21.5 (6.6)	22.2 (7.7)
Calcium, mmol/L	2.4 (0.1)	2.4 (0.1)	2.4 (0.1)
Phosphate, mmol/L	1.0 (0.1)	1.0 (0.2)	1.0 (0.2)
Creatinine, μmol/L	80.1 (14.4)	79.7 (15.1)	80.7 (13.9)
Alkaline phosphatase, U/L	70.1 (17.1)	65.8 (15.3)	69.1 (18.1)
Estimated GFR, mL/min/1.73m2	80.2 (11.4)	80.3 (12.0)	80.7 (11.2)
24-h Urine calcium, mmol/d	4.2 (2.0)	4.8 (2.1)	4.2 (2.0)
Plasma CTx (β-crosslaps), ng/Lg	344.9 (126.6)	339.4 (130.7)	335.5 (118.8)
Fasting blood glucose, mg/dL	102.6 (12.6)	102.6 (5.4)	102.6 (5.4)
Hemoglobin A1C, %	5.2 (1.6)	5.1 (0.6)	5.1 (0.8)

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Abbreviations: BMI, body mass index; CTx, C-telopeptide of type 1 collagen (β-crosslaps); GFR, glomerular filtration rate; PTH, parathyroid hormone; 25(OH)D, 25-hydroxyvitamin D.

^a Calculated as weight in kilograms divided by height in meters squared.

^b Supplementation between 1000 and 2000 IU daily at screening.

^c Includes melanoma.

^d Number of falls in the last year.

^e Lumbar spine T scores range from 4.7 to −2.4 meaning participants were not osteoporotic (osteoporosis is defined as a T score below −2.5).

^f Total hip T scores range from 3.8 to −2.3 meaning participants were not osteoporotic (osteoporosis is defined as a T score below −2.5).

^g A marker of bone resorption.

Eleven participants discontinued the study supplement but continued follow-up (400 IU, 2; 4000 IU, 3; 10000 IU, 6). Reasons for discontinuing included starting or stopping hormone therapy, concerns with kidney function or stones, decision to take other vitamin D supplementation, and possible hyperparathyroidism. The mean vitamin D supplementation adherence was 99% (range, 81%-100%) for participants who completed the trial on study supplement. There were no significant differences in adherence between treatment groups. Mean serum 25(OH)D measurements did not change for the 400-IU group from baseline through 36 months (76.3-77.4 nmol/L). A significant increase in mean serum 25(OH)D from baseline was seen in the 4000-IU group at 3 months (81.3-115.3 nmol/L) with a further increase to 132.2 nmol/L by month 36. The baseline to 3 month increase in the 10000-IU group (78.4-188.0 nmol/L), increased to 200.4 nmol/L at 18 months but fell to 144.4 nmol/L at 36 months (Figure 2; eTable 1 and eFigure 1 in Supplement 3). In addition, many study participants (76%) received calcium supplements throughout the study; more than half (65%) took a single 300 mg tablet per day.

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Figure 2.

Data Distribution for Serum 25-Hydroxyvitamin D, Parathyroid Hormone, and C-Telopeptide of Type 1 Collagen Throughout the 3-Year Study

The horizontal line in the middle of each box indicates the median, the top and bottom borders of the box mark the 75th and 25th percentiles, the whiskers above and bolow the box indicate the 90th and 10th percentiles, and the points beyond the whiskers are outliers beyond the 90th or 10th percentiles.

Some participants had missing HR-pQCT data due to motion artifact (12 participants had at least 1 radius scan removed) or inadequate (<75%) overlap in scan region across all study visits (13 participants had radius scans at one time point removed). One participant had all radius scans removed due to motion and inadequate scan region overlap.

Primary Outcomes

Data distribution and changes in volumetric bone density and strength are displayed in Figure 3. Group×time interactions were significant in total volumetric BMD at the tibia (P<.001) and radius (P<.001). At both sites, total volumetric BMD displayed a negative dose-response relationship (Figure 3; eTable 2 in Supplement 3)—greater losses associated with higher dose of vitamin D supplementation. At trial end, the difference between the 4000 and 400 IU group was −3.9 mg hydroxyapatite (HA)/cm³ (95% CI, −6.5 to −1.3) and between the 10000 and 400 IU group was −7.5 mg HA/cm³ (95% CI, −10.1 to −5.0) for total volumetric BMD at the radius, based on mixed-model analysis. This is equivalent to changes from the mean baseline values of −1.2% (400-IU group), −2.4% (4000-IU group) and −3.5% (10000-IU group) at the radius. For mixed-model analysis of total volumetric BMD at the tibia, the equivalent differences between groups were −1.8 mg HA/cm³ (95% CI, −3.7 to 0.1; not statistically significant) in the 4000-IU group and −4.1 mg HA/cm³ (95% CI, −6.0 to −2.2) in the 10000-IU group; equivalent mean changes from baseline were −0.4% (400 IU-group), −1.0% (4000 IU-group) and −1.7% (10000 IU-group). Bone strength decreased over trial duration; however, group×time interactions were not significant (radius, P=.06; tibia, P=.12).

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Figure 3.

Data Distribution and Change in Total Bone Mineral Density (BMD) and Failure Load During 3 Years of Vitamin D Supplementation

The horizontal line in the middle of each box (left column) indicates the median, the top and bottom borders of the box mark the 75th and 25th percentiles, the whiskers above and bolow the box indicate the 90th and 10th percentiles, and the points beyond the whiskers are outliers beyond the 90th or 10th percentiles. The modeled data (right column) show the mean 95% CIs for the predicted values using the random-effects model. P values indicate the group×time interaction effect.

Secondary Outcomes

For secondary outcomes, the point estimates represent the difference for 4000 or 10000 IU compared with the 400 IU at 36 months. There were significant group×time interactions for cortical volumetric BMD of the radius (P=.001; −6.3 [95% CI, −11.1 to −1.5] for 4000 IU and −8.6 [95% CI, −13.3 to −3.8] for 10000 IU) and tibia (P=.004; −4.2 [95% CI, −9.8 to 1.2] for 4000 IU and −9.8 [95% CI, −14.8 to −4.0] for 10000 IU), for trabecular volumetric BMD of the radius (P=.01; −0.95 [95% CI, −2.6 to 0.7] for 4000 IU and −2.71 [95% CI, −4.3 to −1.1] for 10000 IU; eFigure 2 and eFigure 3 in Supplement 3), and for trabecular number for the radius (P=.01; 0.003 [95% CI, −0.013 to 0.018] for 4000 IU and −0.019 [95% CI, −0.035 to −0.004] for 10000 IU; eTable 3, eFigure 4, and eFigure 5 in Supplement 3). As observed with total volumetric BMD, cortical BMD results also demonstrated larger losses in bone density associated with higher dose of vitamin D at both sites. Trabecular volumetric BMD increased over trial duration with the 10000-IU group gaining the least amount of bone density at the radius.

Group×time interactions were not statistically significant for trabecular volumetric BMD of the tibia (P=.13; 0.20 [95% CI, −0.1 to 1.5] for 4000 IU and −1.1 [95% CI, −2.4 to 0.2] for 10000 IU), cortical porosity of the radius (P=.37; 0.06 [95% CI, −0.025 to 0.15] for 4000 IU and 0.04 [95% CI, −0.043 to 0.13] for 10000 IU) and tibia (P=.89; 0.01 [95% CI, −0.17 to 0.19] for 4000 IU and 0.04 [95% CI, −0.13 to 0.22] for 10000 IU), and trabecular number for the tibia (P=.20; −0.01 [95% CI, −0.03 to 0.01] for 4000 IU and −0.02 [95% CI, −0.04 to 0.004] for 10000 IU).

DXA total hip areal BMD remained stable over the duration of the trial with no significant differences between groups (P=.87; 0.0007 [95% CI, −0.0064 to 0.0078] for 4000 IU and 0.0019 [95% CI, −0.0052 to 0.0090] for 10000 IU; eTable 3 and eTable 4 in Supplement 3). Differences between all 3 treatment groups at 3 years were less than 0.2%. There were no significant changes in balance (P=.12; −0.005 [95% CI, −0.09 to 0.08] for 4000 IU and −0.08 [95% CI, −0.17 to 0.004] for 10000 IU), grip strength (P=.92; −0.12 [95% CI, −1.4 to 1.1] for 4000 IU and −0.26 [95% CI, −1.5 to 1.0] for 10000 IU), timed up-and-go (P=.27; 0.38 [95% CI, −0.11 to 0.86] for 4000 IU and 0.31 [95% CI, −0.18 to 0.79] for 10000 IU), or quality of life (P=.57 for the mental component summary; 0.70 [95% CI, −0.8 to 2.2] for 4000 IU and 0.71 [95% CI, −0.8 to 2.2] for 10000 IU).

PTH decreased between baseline and month 18 and was lowest in the 10000-IU group (eFigure 1 in Supplement 3). CTx increased throughout the study, being highest in the 10000-IU group (eFigure 1 in Supplement 3).

After study completion and removal of blinding, a decline in 25(OH)D was detected in the 10000-IU group at the 24-month assessment. Upon investigation, it was determined that without the knowledge of investigators, Ddrops changed its manufacturing laboratory source, and the long-term stability of the 2000 IU per drop solution was reduced. This change began affecting the 10000-IU group between 18 and 24 months (depending on participant progress through the study). With independent third-party testing and information from Ddrops, participants began receiving a dose estimated to vary between 2000 and 10000 IU per day. Despite reduced supplementation, mean 25(OH)D levels remained higher than the 4000-IU group throughout the study.

Prespecified safety outcomes are shown in Table 2. In total, 44 serious adverse events occurred in 38 (12.2%) participants. One death (presumed myocardial infarction) occurred in a participant in the 400-IU group. Among the prespecified adverse events, only hypercalcemia (P=.005) and hypercalciuria (P=.006) demonstrated a significant dose-response effect. All episodes of hypercalcemia were mild (2.56-2.64 mmol/L) and resolved on follow-up testing. One participant in the 10000-IU group experienced 2 episodes of transient hypercalcemia (months 6 and 30). There was no significant difference in falls detected among the 3 groups.

Table 2.

Summary of Prespecified Adverse Events in Healthy Adults Taking Vitamin D Supplementation 400 IU, 4000 IU, or 10000 IU Daily for 3 Years^a

	10000 IU (n=102)		4000 IU (n=100)		400 IU (n=109)
	Total Events, No.	Participants With Events, No. (%)	Total Events, No.	Participants With Events, No. (%)	Total Events, No.	Participants With Events, No. (%)
Serious adverse eventsb	14	14 (14)	10	8 (8)	20	16 (15)
Hypercalcemiac	10	9 (9)	4	4 (4)	0	0
Hypercalciuriad	54	34 (33)	34	22 (22)	25	19 (17)
Renal dysfunctione	4	2 (2)	2	2 (2)	1	1 (1)
Nephrolithiasis	2	1 (1)	1	1 (1)	0	0
Hepatic dysfunctionf	3	3 (3)	3	3 (3)	8	5 (5)
Falls	6	5 (5)	11	10 (10)	4	4 (4)
Low-trauma fracturesg	5	5 (5)	3	3 (2)	4	4 (4)
Cancerh	5	5 (5)	3	3 (3)	1	1 (1)

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Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; ULN, upper limit of normal.

SI units: to convert ALT and AST to μkat/L, multiply by 0.0167.

^a Any participant who was randomized and received at least 1 dose of study drug was included in this table.

^b Serious adverse events were determined using the standard International Conference on Harmonization Good Clinical Practice definition.

^c Hypercalcemia indicates a serum calcium level greater than 2.55 mmol/L.

^d Hypercalciuria indicates 24-hour urine calcium excretion exceeding 7.5 mmol per day for participants of less than 75 kg body weight or greater than 0.1 mmol/kg per day for those with body weight of 75 kg or greater.

^e Renal dysfunction indicates a serum creatinine level of greater than 133 μmol/L.

^f Hepatic dysfunction indicates AST or ALT greater than 1.5×ULN. AST ULN is indicated by 32 U/L for women and 40 U/L for men. ALT ULN is indicated by 40 U/L for women and 60 U/L for men.

^g Low-trauma (fragility) fractures were defined as resulting from low trauma (eg, a fall from ≤standing height).

^h Cancer includes all nonskin cancers and melanoma.

Discussion

This 3-year randomized clinical trial examined the effect of 3 daily doses of vitamin D: 400 IU, 4000 IU (the National Academy of Medicine [formerly the Institute of Medicine {IOM}] tolerable upper intake level), and 10000 IU in healthy adults aged 55 to 70 years and failed to find a positive effect of vitamin D on volumetric BMD and estimated bone strength, as measured by HR-pQCT at the radius and tibia.

Instead of the hypothesized increase, a negative dose-response relationship was observed for volumetric BMD. Using the 400-IU group as a reference point, high-dose vitamin D supplementation (10000 IU/d) was associated with a significantly greater loss of bone. Because these results are in the opposite direction of the research hypothesis, this evidence of high-dose vitamin D having a negative effect on bone should be regarded as hypothesis generating, requiring confirmation with further research. Therefore, the appropriate interpretation of this study is that for maintenance of bone quality in healthy vitamin D–sufficient adults, these results do not support a skeletal benefit of vitamin D doses well above the recommended dietary allowance.⁶

If the observed vitamin D dose-dependent loss of volumetric BMD seen in this trial represents a real effect, it might be related to the observed combination of an increased plasma marker of bone resorption (CTx) and suppression of PTH seen in the 10000-IU group. High-dose vitamin D without extra calcium supplementation has been associated with increased levels of the active vitamin D metabolite 1, 25(OH)₂ vitamin D (calcitriol), and an increase in CTx.²⁷ Calcitriol stimulates osteoclastogenesis and differentiation, either through action on osteoblasts²⁸ or by direct action on osteoclast precursors.²⁹ High-dose vitamin D may also suppress PTH by direct action on parathyroid cells or indirectly by enhancing intestinal calcium absorption. This might reduce PTH-mediated bone formation, which when combined with a vitamin D–mediated direct effect on osteoclast activity (as supported by the trend to higher CTx in the 10000-IU group), could result in the dose-related accelerated decline in observed volumetric BMD. The observation of an increased trabecular volumetric BMD while cortical volumetric BMD declined may reflect this increase in resorption, leading to trabecularization of the endocortical surface of the cortex.

DXA findings in this study align with others showing nonsignificant changes in areal BMD at the total hip following high-dose vitamin D supplementation^10,30,31,32 and no additional benefit for high compared with low-dose supplementation.^10,31,32,33 These results are supported by a recent meta-analysis that did not support a public health recommendation for vitamin D supplementation for the prevention of falls, fractures, or beneficial effects on bone density.⁴

There is growing evidence that for bone, the benefit of vitamin D supplementation is only seen in the treatment of vitamin D deficiency.^1,2 There is also evidence that very high intermittent (monthly or annual) doses of vitamin D may be harmful, with increased risk of falls or fracture^34,35; but not all such studies report increased risk of falls or fractures.³⁶ There was no effect on fall rates in this study and no evidence of a relationship between changes in volumetric BMD and fracture risk, which may reflect the healthy status of the population that was studied. However, if high-dose vitamin D does stimulate an increased rate of bone loss, this could have greater clinical significance in older individuals with osteoporosis.

Most of the prespecified safety outcomes occurred in all 3 vitamin D treatment groups. However, episodes of hypercalcemia and hypercalciuria were more common with increasing vitamin D dose, consistent with previous reports,³⁷ and the risk of hypercalcemia and hypercalciuria is higher in individuals taking calcium supplementation,³⁸ suggesting that supplemental calcium intake may be a significant driver of hypercalcemia in individuals taking vitamin D. The dose-dependent increase in incidence of hypercalciuria and mild hypercalcemia suggests that for individuals taking high-dose vitamin D, it may be prudent to assess calcium intake and evaluate biochemical measures of calcium metabolism. However, in the 400-IU group that was following the National Academy of Medicine–recommended dietary allowance of calcium and vitamin D₃, 17% had hypercalciuria on at least 1 occasion over the study duration.

Conclusions

Among healthy adults, treatment with vitamin D for 3 years at a dose of 4000 IU per day or 10000 IU per day, compared with 400 IU per day, resulted in statistically significant lower radial BMD; tibial BMD was significantly lower only with the daily dose of 10000 IU. There were no significant differences in bone strength at either the radius or tibia. These findings do not support a benefit of high-dose vitamin D supplementation for bone health; further research would be needed to determine whether it is harmful.

Notes

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