Do studies reporting ‘U’-shaped serum 25-hydroxyvitamin D–health outcome relationships reflect adverse effects?

Figures & data

Table 1. Reports of U-shaped 25(OH)D concentration-PC incidence relations.

Location	Follow-up period (yrs)	Optimal 25(OH)D concentration (nmol/L)	Adverse higher 25(OH)D concentration (nmol/L)	Reference
Finland, Norway and Sweden	Up to 11, 16, or 24,   depending on country	40–59	80	^Citation21
Finland	Up to 20	<16.3	23.8–33.3 and >45	^Citation23
Sweden	Up to 14	<68	85–102	^Citation24
Norway	Up to 25	30–69	>69	^Citation25
USA	Up to 8	58.2–72.9	>72.9	^Citation26
France	13	>62	Not given	^Citation27

Table 2. Results of the 2 observational studies with U-shaped 25(OH)D concentration-CVD risk associations.

Study Location	Outcome examined	Type of Study	25(OH)D (nmol/L)	Fraction of Cases	HR (95% CIs)	Reference
Israel	MACS	Historical prospective	>90–100	0.05?	HR = 1.08 (1.00–1.11)	^Citation43
	MACS	Historical prospective	>100	0.03	HR = 1.13 (1.01–1.21)	^Citation43
Germany	MACCE	Prospective	>100	0.03	OR = 2.34 (1.12–4.89)	^Citation45
Denmark	CVD mortality	Prospective	<75–100	0.12	MR = 1.10	^44
	CVD mortality	Prospective	>100–125	0.04	MR = 1.44	^44
	CVD mortality	Prospective	<125	0.02	MR = 1.51	^44

95% CI, 95% confidence interval; HR, hazard ratio; MACCE, major adverse cardiac and cerebrovascular events during of cardiac surgery or while still at the hospital; MACS, mortality or acute coronary syndrome; MR, mortality rate; OR, odds ratio.

Table 3. Summary of findings.

Outcome of interest	Studies (N) with ‘U’-shaped findings, by topic	Type of study	Reference	Validity	Comments	Possible Non-causal confounders Identified
Allergies				Probable	Common findings	Shift of Th cell balance from Th1 to Th2 cells, increasing inflammatory cytokines
Cancer, of the prostate	6	NCCMeta-analysis	^21,23,24,26,28	Probably not	Confounding by PSA testing possible	Unknown
Pancreatic Cancer	2	NCC	^16,17	No	Not found at lower latitudes	Possible recent high-dose vitamin D supplementation (before blood draw)
CVD	3	Prospective	^43-45,111	Probably not	U-shaped relationship found in 3studies; 1,25(OH)2D measured in one study. Not found in most studies.	Recent vitamin D supplementation, meat consumption, low 1,25(OH)2D production
Cognition	3		^80-82	No	Weak studies, not consistent in outcomes	Recent vitamin D supplementation
Falls, fractures, bolus doses	2		^67,72	Maybe	Repeated
Fractures	1	Prospective	^73	No		Recent vitamin D supplementation
Frailty status	1	Cross-sectional	^50	No	Observed for women but not men	Recent vitamin D supplementation
Mortality rate	3		^40,86,88	Probably not	Observed in some studies; found for some outcomes	CVD, PC.
Pregnancy outcomes	2		^90,92	No	Found in only 2 studies	Not known, but 25(OH)D was measured at <22 weeks' gestation or at term at a single time point Data on dietary intake (vitamins A, C, K; calcium; and magnesium) not available

NCC, nested case–control

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