A Predictive Equation to Guide Vitamin D Replacement Dose in Patients

Gurmukh Singh; Aaron J. Bonham

doi:10.3122/jabfm.2014.04.130306

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Figure 1.
Annual volume of 25-hydroxyvitamin D testing and mean serum concentrations of 25-hydroxyvitamin D in each year. The year-to-year changes in the mean concentrations (inset) of 25-hydroxyvitamin D are statistically significantly different (P < .05). The testing volume increased from <300 to >12,000 per year without any improvement in the outcome of average serum concentrations of 25-hydroxyvitamin D, despite the providers' prescription being in keeping with recommended doses of vitamin D, suggesting that the recommended doses were inadequate.
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Figure 2.
Dose response in a patient. The graph displays the starting concentration (black), end concentration (white), and change (diagonal lines) in 25-hydroxyvitamin D concentration in one patient given the recommended doses of 600 to 800 IU/day interspersed with treatment with higher doses. Doses administered are given below each episode of treatment. In this purposely selected nursing home patient, each episode of treatment with the Geriatric Society–recommend dose resulted in decline in serum 25-hydroxyvitamin D concentration, and each episode of treatment with a higher dose increased the serum concentration of 25-hydroxyvitamin D, suggesting that the Geriatric Society–recommended dose was inadequate. The patient was admitted to the nursing home at the age of 47 with a 10-year history of multiple sclerosis and had paraplegia, urinary retention with repeated infections, fecal incontinence, pressure ulcers, gastroesophageal reflux, type 2 diabetes mellitus, body mass index of 29.8 kg/m², rheumatoid arthritis, lactose intolerance, hypertension, hyperlipidemia, history of vitamin B₁₂ and folate deficiency, depression, degenerative joint disease, and dysphagia with risk of aspiration. She made multiple attempts to live at home but was readmitted and developed heart failure and experienced episodes of renal and respiratory failure often associated with sepsis. She died at the age of 54 due to progressive heart failure.

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Table 1. Number of Tests for Serum 25-Hydroxyvitamin D and Serum Concentrations of 25-Hydroxyvitamin D

Year	Serum 25-Hydroxyvitamin D Concentration (ng/mL)				Total Tests (n)
Year	<12	<20	<30	>150	Total Tests (n)
2007	17.24	48.62	71.38	0.34	290
2008	21.04	47.4	75.77	0	846
2009	16.65	39.01	69.19	0	2,889
2010	15.53	35.55	63.27	0.04	5,358
2011	16.81	38.15	65.14	0.02	8,910
2012	33.11	60.83	82.22	0.07	12,194

Data are percentages unless otherwise indicated. The number of serum 25-hydroxyvitamin D tests done increased from 290 in 2007 to 12194 in 2012. The percentage of patients with serum concentrations of 25-hydroxyvitamin D <12, 20, 30 or >150 ng/mL did not change appreciably. If anything the serum25-hydroxyvitamin D concentrations decreased during the period of observation, again attesting that patients were undertreated.

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Table 2. Average (Median) Daily Doses of Vitamin D (IU/day) and Changes in Serum 25-Hydroxyvitamin D Concentrations after Treatment

Population	Average Dose ± Standard Deviation (Median)
Population	Decrease or No Increase	Any Increase	Increase ≥10 ng/mL
All	1907 ± 1771 (1000)	4707 ± 3856 (4000)	5682 ± 4323 (4800)
Ambulatory	2154 ± 1716 (2000)	4229 ± 3637 (3976)	5092 ± 4092 (4000)
Nursing home	1427 ± 1709 (800)	6103 ± 4131 (5448)	7574 ± 4505 (6597)

An average daily dose of about 2000 IU/day did not register a positive change in serum concentrations of 25-hydroxyvitamin D. Doses of about 4000 to 7000 IU/day were needed for meaningful increases in serum concentrations of 25-hydroxyvitamin D. The observed doses that resulted in positive changes in serum concentrations of 25-hydroxyvitamin D are far greater than the doses recommended by national agencies.

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Table 3. Average Responses of Various Subsets of Patients to Average Daily Doses of Vitamin D Treatment

Population	Patients (n)	Observations (n)	Average Dose (IU/day)	Average Concentration (ng/mL)		Concentration <30 ng/mL (%)
Population	Patients (n)	Observations (n)	Average Dose (IU/day)	Before Treatment	After Treatment	Before Treatment	After Treatment
Total	1327	3885	3588	25.2	30.5	68.5	55.3
Ambulatory	1183	2763	3460	22.4	29.1	75.7	61.1
Women	839	1947	3494	22.5	29.1	76	62.0
Men	344	816	3375	22.4	29.2	74.9	59.1
Nursing Home	144	1122	3907	32.2	34.1	47.1	41.0
Women	104	820	2902	32	33.9	48.8	42.4
Men	40	302	3918	32.5	34.4	42.7	37.1

The average increase in serum concentrations of 25-hydroxyvitamin D, with an average dose of 3588 IU/day, for the whole population (total observations = 3885) was 5.3 ng/mL.

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Table 4. Regression Coefficients Predicting Change in Serum 25-Hydroxyvitamin D Concentration: Full and Reduced Models for All Patients and All 3885 Observations

	B	P Value	95% Confidence Interval
	B	P Value	Lower	Upper
Full model
Age	0.092	<.001^*	0.05	0.13
Sex	0.647	.269	−0.50	1.8
BMI	−0.200	<.001^*	−0.26	−0.14
Nursing Home	1.390	.057	−0.04	2.82
Albumin	1.457	.013^*	0.28	2.44
Creatinine	−0.462	.209	−1.18	0.26
Dose of vitamin D	0.002	<.001^*	0.002	0.002
Starting vitamin D	−0.615	<.001^*	−0.65	−0.58
Constant	7.838	.008^*	2.02	13.66
Reduced model
Age	0.074	<.001^*	0.04	0.11
BMI	−0.202	<.001^*	−0.26	−0.14
Albumin	1.739	.001^*	0.73	2.75
Dose of vitamin D	0.002	<.001^*	0.002	0.002
Starting vitamin D	−0.622	<.001^*	−0.66	−0.59
Constant	8.521	.003^*	2.86	14.18

↵* Statistically significant (P < .05).
BMI, body mass index.

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Table 5. Regression Coefficients Predicting End (after Treatment) Serum 25-Hydroxyvitamin D Concentration

	B	P Value	95% Confidence Interval
	B	P Value	Lower	Upper
Full model
Age	0.092	<.001^*	0.05	0.13
Sex	0.616	.293	−0.53	1.77
BMI	−0.201	<.001^*	−0.26	−0.14
Nursing home	1.349	.065	−0.08	2.78
Albumin	1.378	.012^*	0.30	2.46
Creatinine	−0.467	.205	−1.19	0.26
Dose of vitamin D	0.002	<.001^*	0.002	0.002
Starting vitamin D	0.384	<.001^*	0.35	0.42
Constant	7.853	.008^*	2.03	13.68
Reduced model
Age	0.074	<.001^*	0.04	0.11
BMI	−0.203	<.001^*	−0.26	−0.15
Albumin	1.749	.001^*	0.74	2.76
Dose of vitamin D	0.002	<.001^*	0.002	0.002
Starting vitamin D	0.074	<.001^*	0.04	0.11
Constant	−0.203	<.001^*	−0.26	−0.15

Full and reduced models for all patients and all 3885 observations are included.
↵* Statistically significant (P < .05).
BMI, body mass index.

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Table 6. Bivariate Comparisons of Nursing Home and Ambulatory Patient Encounters

	Ambulatory		Nursing Home		P Value
	No.	Mean (SD)	No.	Mean (SD)	P Value
Age^*	2763	56.0 (12.8)	1122	73.1 (14.1)	<.001^{^†}
BMI	2763	33.4 (8.9)	1122	30.4 (9.1)	<.001^{^†}
Vitamin D concentration
Start^*	2763	22.4 (15.1)	1122	32.2 (13.8)	<.001^{^†}
End^*	2763	29.1 (19.8)	1122	34.1 (13.8)	<.001^{^†}
Change	2763	6.7 (21.5)	1122	1.9 (19.8)	<.001^{^†}
Dose^*	2763	3458.2 (3228.7)	1122	3906.6 (3997.8)	.018^{^†}
Creatinine^*	2754	1.17 (0.77)	1122	1.00 (0.62)	<.001^{^†}
Albumin^*	2735	3.8 (0.5)	1118	3.3 (0.5)	<.001^{^†}
Sex^{^‡}
Female	1947 (70.5)		820 (73.1)		.113
Male	813 (29.5)		302 (26.9)

↵* Statistically significant (P < .05).
↵† Comparisons fail to meet the assumption of equal variances.
↵‡ Data for Sex are n (%).
BMI, body mass index; SD, standard deviation.

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Table 7. Comparison of Starting Serum Levels of 25-Hydroxyvitamin D and Average Doses Resulting in Decrease or No Increase, Any Increase, or Increase of ≥10 ng/mL between Races

	White	Black	Other
Patients (n)	710	521	96
Episodes (n)	2227	1385	273
Results of average dose (mean ± SD)
Decrease or no change	1995 ± 1830	1774 ± 1689	1868 ± 1646
Any increase	4827 ± 3865	4540 ± 3781	4554 ± 4107
Increase of ≥10 ng/mL	5760 ± 4362	5539 ± 4216	5744 ± 4536
25-hydroxyvitamin D serum concentration (ng/mL) at start of treatment episode	25.5 ± 15.0	25.3 ± 15.9	23.0 ± 14.8