This Local Coverage Determination (LCD) identifies the indications and
limitations of Medicare coverage and reimbursement for Vitamin D laboratory
assays in the medical management of patients.

For Medicare beneficiaries, screening tests are governed by statute.
Reimbursement is not allowed for routine screening for vitamin D deficiency in
asymptomatic individuals and/or during general encounters.

Although it is not the active form of the hormone, 25-OH vitamin D is much
more commonly measured because it better reflects the sum total of vitamin D
produced endogenously and absorbed from the diet than does the level of the
active hormone 1,25-dihydroxy vitamin. 25-hydroxyvitamin D [25(OH)D] testing
will be considered medically reasonable and necessary for individuals at risk
for deficiency with the following conditions:

  * Chronic kidney disease (CKD) stage III or greater
  * Cystic Fibrosis (CF)
  * Cirrhosis
  * Crohn's disease
  * Gastric bypass/bariatric surgery
  * Granuloma forming diseases
  * Hyperalimentation
  * Hypocalcemia
  * Hypercalcemia
  * Hypercalciuria
  * Hypervitaminosis D
  * Hypovitaminosis D
  * Inflammatory bowel disease
  * Long term use of medications known to lower vitamin d levels: anticonvulsants, antiretroviral therapy, glucocorticoids, antifungals, and cholestyramine
  * Parathyroid disorders
  * Paget's disease of bone
  * Obesity, if Body Mass Index (BMI)  30 kg/m2
  * Obstructive jaundice
  * Osteomalacia
  * Osteopenia
  * Osteoporosis
  * Osteosclerosis/petrosis
  * Pregnant and lactating women
  * Radiation enteritis
  * Rickets
  * Vitamin D deficiency on replacement therapy related to a condition listed above, to monitor the efficacy of treatment

Deficiency of 1,25-dihydroxy vitamin D, which is present at much lower
concentrations, does not necessarily reflect deficiency of 25-OH vitamin D and
its measurement should be limited to specific clinical situations. It will be
considered reasonable and necessary for patients with the following
conditions:

  * Unexplained hypercalcemia 
  * Unexplained hypercalciuria
  * Suspected genetic childhood rickets
  * Suspected tumor induced osteomalacia
  * Nephrolithiasis 
  * Renal osteodystrophy
  * Sarcoidosis

Once a beneficiary has been shown to be vitamin D deficient with a serum level
of <30 ng/ml, a repeat test after 12 weeks of supplementation will be
considered reasonable and necessary to ensure adequate replacement has been
accomplished. The medical record must reflect that the beneficiary has been
compliant with supplementation. A serum level of 30 ng/ml will be considered
evidence of adequate replacement, and no further testing is necessary.

If, after a 12-week period of supplementation and documentation of compliance
with the prescribed supplementation, the serum level is still <30 ng/ml 1
additional repeat testing within a rolling 12-month period of the initial
test, may be performed.

Thereafter, annual testing may be appropriate depending upon the indication
and other mitigating factors. The documentation must support the need for
annual testing. Annual testing should be rare.

Vitamin D is a fat-soluble vitamin appreciated for its role in calcium
homeostasis and bone health. It consists of 2 bioequivalent forms: Vitamin D2
(D2), also known as ergocalciferol, and Vitamin D3 (D3), also known as
cholecalciferol. D2 is obtained from dietary vegetable sources and oral
supplements. D3 is obtained primarily from skin exposure to ultraviolet
radiation in sunlight, but also ingestion of food sources such as oily fish
and variably fortified foods (milk, juices, margarines, yogurts, cereals, and
soy), and oral supplements. Both D2 and D3 are biologically inert. Once
absorbed from the intestine, they are metabolized in the liver to
25-hydroxyvitamin D [25(OH)D], composed of 25(OH)D2 and 25(OH)D3. 25(OH)D
(also called calcidiol) is then subsequently converted to
1,25-dihydroxyvitamin D [1,25(OH)2D], also known as calcitriol, in the kidney
and select other tissues by the action of the 1-hydroxylase enzyme. This
enzyme in the kidney is regulated by nearly every hormone involved in calcium
homeostasis. Its activity is stimulated by parathyroid hormone (PTH),
estrogen, calcitonin, prolactin, growth hormone, low calcium levels, and low
phosphorus levels and inhibited by calcitriol, thus providing a feedback
loop.1

Lack of vitamin D activity leads to reduced intestinal absorption of calcium
and phosphorus. Early in vitamin D deficiency, hypophosphatemia is more marked
than hypocalcemia. With persistent vitamin D deficiency, hypocalcemia occurs
and causes secondary hyperparathyroidism, which leads to phosphaturia,
demineralization of bones, and, when prolonged and severe, to osteomalacia in
adults and rickets in children. The incidence of osteomalacia in the United
States (U.S.) is rare. Bolland et.al. reviewed over 42,000 25(OH)D
measurements in 32,386 individuals. Only 9 met the criteria for a diagnosis of
osteomalacia (0.02%).2

D3 production in the skin is exceedingly efficient. It is estimated that brief
casual exposure of the arms and face is equivalent to ingestion of 200
international units per day. However, the length of daily exposure required to
obtain the sunlight equivalent of oral vitamin D supplementation is difficult
to predict on an individual basis and varies with the skin type, sunscreen
use, latitude, season, and time of day. At northern latitudes, there is not
enough radiation to produce vitamin D, particularly during the winter.3
Sunlight also induces production of melanin, which reduces production of
vitamin D3 in the skin. Infants, disabled persons, and older adults may have
inadequate sun exposure. The skin of those older than 70 years of age does not
convert vitamin D efficiently. For these reasons, in the U.S., milk, infant
formula, breakfast cereals, and some other foods are fortified with synthetic
vitamin D2 (ergocalciferol), which is derived from radiation of ergosterol
found in plants, the mold ergot, and plankton, or with vitamin D3. In other
parts of the world, cereals and bread products are often fortified with
vitamin D. 4

Vitamin D toxicity, though rare, may cause hypercalciuria, hypercalcemia,
renal stones, and renal calcification with renal failure. Published cases of
vitamin D toxicity with hypercalcemia, for which the 25(OH)D concentration and
vitamin D dose are known, all involve intake of at least 40,000 IU/d with a
serum level of 25 (OH)D of at least 88ng/ml, most being 150- 250 ng/ml.
Vitamin D intoxication generally occurs after inappropriate use of vitamin D
preparations. It may occur in fad dieters who consume "mega doses" of
supplements or in patients who take vitamin D replacement therapy for
malabsorption, renal osteodystrophy, osteoporosis, or psoriasis. Prolonged
exposure of the skin to sunlight does not produce toxic amounts of vitamin D3
(cholecalciferol), due to photoconversion of previtamin D3 and vitamin D3 to
inactive metabolites. The rarity of reports of vitamin D toxicity can be
explained in part by the kidney's ability to limit production of active
calcitriol. Increased calcitriol levels inhibit PTH both directly (through the
vitamin D response element on the PTH gene), and indirectly (by increasing
intestinal calcium absorption), causing calcitriol production in the kidney to
decrease. Renal 24-hydroxylase activity further limits the availability of
calcitriol by creating inert metabolites of both calcitriol
(1,24,25-trihydroxyvitamin D) and calcidiol (24,25-dihydroxyvitamin D). The
24-hydroxylase gene is under the transcriptional control of calcitriol,
thereby providing tight negative feedback.5

The optimal serum 25(OH)D is controversial. The Institute of Medicine has
defined vitamin D deficiency as 25(OH)D less than 12 ng/ml, with levels
greater than 20 ng/ml being considered adequate for bone and overall health.
The National Academy of Medicine supports maintaining a level above 20 ng/ml
while the National Osteoporosis Foundation and the American Geriatric Society
suggest a minimal level of 30 ng/ml. 6 The Endocrine Society has classified
25(OH)D less than 20 ng/ml as deficient and greater than 30 ng/ml as optimal.7
Their goal would be to maintain both children and adults at a level >30 ng/ml
to take full advantage of all the health benefits that vitamin D provides.8

To achieve a serum level of at least 20 ng/ml, the Institute of Medicine (IOM)
has recommended reference values for intake of vitamin D based on available
literature and expert consensus. The IOM report stressed that its
recommendations for vitamin D were based primarily on the intake (and serum
25-hydroxyvitamin D concentration) needed to ensure skeletal health and that,
in the panel's judgment, there was insufficient evidence to make any
recommendations with respect to nonskeletal benefits, such as cardiovascular
disease (CVD), death and quality of life. Recommended daily allowances are 600
IU/d for individuals between 1 and 70 years of age and 800 IU/d for
individuals older than 70 years.9,10

The Endocrine Society disagrees with the IOM recommendations for
supplementation. They state that 600 and 800 IU/d of vitamin D may not be
enough to provide all of the potential nonskeletal health benefits associated
with vitamin D. Their conclusion was that, to raise the blood level of 25(OH)D
above 30 ng/ml, may require at least 1,500-2,000 IU/d of supplemental vitamin
D. They further suggested that obese children and adults who are also on
anticonvulsant medications, glucocorticoids, antifungals, and medications for
AIDS, be given at least 2 to 3 times more vitamin D for their age group to
satisfy their body's vitamin D requirement.11

The maintenance tolerable upper limits (UL) of vitamin D, which is not to be
exceeded without medical supervision, should be 1,000 IU/d for infants up to 6
months, 1,500 IU/d for infants from 6 months to 1 yr., at least 2,500 IU/d for
children aged 1-3yr, 3,000 IU/d for children aged 4-8yr, and 4,000 IU/d for
everyone over 8 yr. However, higher levels of 2,000 IU/d for children 0-1 yr.,
4,000 IU/d for children 1-18 yr., 4,000 IU/d for adults may be needed to
correct vitamin D deficiency.12 Oral vitamin D supplementation between 700 to
800 IU/d appears to reduce the risk of hip and any nonvertebral fractures in
ambulatory or institutionalized elderly persons.13

Vitamin D testing is now the fifth most popular lab test for older adults.
Although a low to moderately priced test ($100-$300 per test), there is a
significant volume of testing performed. In 2015, Medicare spent $337 million
on vitamin D tests for seniors, up from $323 million the year before. Between
25% and 77% of these tests follow a pattern of nonindicated screening rather
than targeted testing of high-risk patients.14 The Choosing Wisely Campaign 15
is an initiative aimed at reducing low value care and highlighting clinical
practices inconsistent with the evidence. Initially founded in 2012 by the
American Board of Internal Medicine (ABIM) Foundation, Choosing Wisely
includes recommendations from over 80 professional medical societies. Medical
societies such as the American Society for Clinical Pathology (ASCP) have
supported the recommendation of "Do not order population-based screening for
vitamin D".

This recommendation aligns with the current United States Preventive Health
Service Task Force (USPSTF) recommendations that consider current medical
evidence insufficient to assess the balance of benefits and harms of screening
for vitamin D deficiency in asymptomatic adults.16 The USPSTF further
concludes that the current evidence is insufficient to assess the balance of
the benefits and harms of vitamin D and calcium supplementation, alone or
combined, for the primary prevention of fractures in community-dwelling,
asymptomatic men and premenopausal women. They also conclude that the current
evidence is insufficient to assess the balance of the benefits and harms of
daily supplementation with doses greater than 400 IU of vitamin D and greater
than 1000 mg of calcium for the primary prevention of fractures in community-
dwelling, postmenopausal women. These recommendations do not apply to persons
with a history of osteoporotic fractures, increased risk for falls, or a
diagnosis of osteoporosis or vitamin D deficiency.17

However, Choosing Wisely does recognize that vitamin D testing may benefit
those at risk for severe deficiency (elderly patients, hospitalized patients,
those with renal insufficiency, malabsorption syndrome, liver failure, etc.)
or those with laboratory or radiographic findings commonly associated with
vitamin D deficiency (low 24-hour urine calcium, elevated parathyroid hormone,
elevated alkaline phosphatase, low serum calcium, osteopenia, osteoporosis). A
pragmatic approach for patients and their physicians was developed by the ABIM
Foundation in its Choosing Wisely initiative. The patient friendly literature
reassures individuals that healthy diet and exercise maintain most persons in
an adequate range of Vitamin D level. It raises the possible justification of
empiric Vitamin D supplementation without testing for those patients without
risk factors but who may be thought to have inadequate sun exposure or dietary
intake, while outlining those clinical risk factors that warrant baseline
diagnostic assays. Given the low risk of toxicity associated with
supplementation, this is a practical approach.

Vitamin D testing is often erroneously used in situations where there is not a
guideline supported diagnosis. An electronic health record (EHR) best practice
alert on vitamin D testing was implemented in the ambulatory clinic sites of
Stanford Health Care on June 28, 2016. When an order for 25(OH) vitamin D was
placed, the EHR queried the patient chart for a history of chronic
kidney/liver disease, malabsorption, granuloma-forming disorders, malignancy,
diabetes mellitus (DM), immunocompromised state, obesity, hyperparathyroidism,
known deficiency, medications that increase risk for deficiency, and previous
falls. If no such comorbidity was documented, an alert explained the low
utility of testing. The provider could then cancel the order or override the
alert with the option of entering a justification. The most common non-
guideline-supported indications from the free-text comments were neurological
symptoms (non-specific tingling, dizziness, headache), preventive care, risk
factors for osteoporosis that were not guideline-supported (e.g., small frame,
family history of osteoporosis), nonspecific pain, and fatigue.18 Other
reasons often cited for Vitamin D testing are the assertion that Vitamin D
deficiency is linked to many chronic diseases such as cancer, CVD, depression,
and chronic pain.19 Observational studies have suggested that low vitamin D
status could be associated with higher mortality from life-threatening
conditions including cancer, CVD, and DM that account for 60% to 70% of total
mortality in high-income countries. Autier et.al. examined the risk of dying
from any cause in subjects who participated in randomized trials testing the
impact of vitamin D supplementation (ergocalciferol [vitamin D2] or
cholecalciferol [vitamin D3]) on any health condition. They identified 18
independent randomized controlled trials, including 57,311 participants. A
total of 4,777 deaths from any cause occurred during a trial size-adjusted
mean of 5.7 years. Daily doses of vitamin D supplements varied from 300 to
2,000 IU. The trial size-adjusted mean daily vitamin D dose was 528 IU. In 9
trials, there was a 1.4 to 5.2-fold difference in serum 25-hydroxyvitamin D
between the intervention and control groups. The summary relative risk for
mortality from any cause was 0.93 (95% confidence interval, 0.87-0.99). Intake
of ordinary doses of vitamin D supplements seemed to be associated with
decreases in total mortality rates.20

It has been postulated that Vitamin D deficiency may be involved in the
development of atherosclerosis and coronary heart disease in humans. Vitamin D
deficiency activates the renin-angiotensin-aldosterone system and can
predispose to hypertension (HTN) and left ventricular hypertrophy.
Additionally, vitamin D deficiency causes an increase in PTH, which increases
insulin resistance and is associated with DM, HTN, inflammation, and increased
cardiovascular risk.21

A nested case-control study was conducted in 18,225 men in the Health
Professionals Follow-up Study; the men were aged 40 to 75 years and were free
of diagnosed CVD at blood collection. The blood samples were returned between
April 1, 1993 and November 30, 1999. During 10 years of follow-up, 454 men
developed nonfatal myocardial infarction (MI) or fatal coronary heart disease.
After adjustment for matched variables, men deficient in 25(OH)D (<or=15
ng/ml) were at increased risk for MI compared with those considered to be
sufficient in 25(OH)D (>or=30 ng/ml) (relative risk [RR], 2.42; 95% confidence
interval [CI], 1.53-3.84; P < .001 for trend). After additional adjustment for
family history of MI, BMI, alcohol consumption, physical activity, history of
DM and HTN, ethnicity, region, marine omega-3 intake, low- and high-density
lipoprotein cholesterol levels, and triglyceride levels, this relationship
remained significant (RR, 2.09; 95% CI, 1.24-3.54; P = .02 for trend). Even
men with intermediate 25(OH)D levels were at elevated risk relative to those
with sufficient 25(OH)D levels (22.6-29.9 ng/ml: RR, 1.60 [95% CI, 1.10-2.32];
and 15.0-22.5 ng/ml: RR, 1.43 [95% CI, 0.96-2.13], respectively). The
conclusion was that low levels of 25(OH)D are associated with higher risk of
MI in a graded manner, even after controlling for factors known to be
associated with coronary artery disease (CAD).22

The Vitamin D and Omega-3 Trial (VITAL) study was a nationwide, randomized,
placebo-controlled, 2x2 factorial trial of marine omega-3 FAs (1 g/d) and
vitamin D3 (2,000 IU/d) in the primary prevention of CVD and cancer among
25,871 US men aged >/=50 and women aged >/=55 years. Median treatment duration
was 5.3 years. A major cardiovascular event occurred in 805 participants (396
in the vitamin D group and 409 in the placebo group). Vitamin D
supplementation did not reduce major CVD events (HR, 0.97 [95% CI, 0.85-1.12])
or other cardiovascular end points. Updated meta-analyses that include VITAL
and other recent trials document coronary risk reduction from supplemental
marine omega-3 FAs but no clear CVD risk reduction from supplemental vitamin
D.23 Supplementation with vitamin D also did not result in a lower incidence
of invasive cancer than placebo.24

Woolcott et al. conducted a case-control study of men and women of multi-
ethnic ancestry with a diagnosis of colorectal carcinoma. Using a direct
competitive chemiluminescence immunoassay, 25(OH)D level was determined in
plasma drawn before diagnosis from 229 cases and 434 controls matched to cases
by sex, ethnicity, birth year, blood draw date and time, and hours fasting. An
inverse trend was observed, odds ratio (OR), per doubling of 25(OH)D, 0.68;
95% confidence interval, 0.51-0.92; P = 0.01), but when examined in
categories, relative to the first quintile (<16.8 ng/ml), the ORs in all other
quintiles were quite similarly reduced between 37% and 46%. In analyses
controlling only for the matching factors, colorectal cancer risk was
significantly reduced among participants with plasma 25(OH)D concentrations in
the highest quintiles (>22 ng/ml relative to the lowest quintile (<16.8
ng/ml). Limitations were that the mean time between blood draw and diagnosis
was short (1.7 years) and 25(OH)D levels further in the past may be more
relevant to colorectal cancer risk. In summary, this study provided evidence
of an association between vitamin D status and reduced risk of colorectal
cancer in an ethnically diverse population.25

The hypothesis that vitamin D reduces the risk of some cancers was studied in
the Harvard cohort studies, including the Nurses' Health Study (NHS), the
Health Professionals Follow-Up Study (HPFS), and the Physicians' Health Study
(PHS). Three approaches have been used, the study of circulating 25(OH)vitamin
D (25(OH)D) level, of dietary and supplementary intake, and of predicted
25(OH)D. These cohorts strongly support an inverse association with colorectal
cancer as this association has been viewed in both the NHS and HPFS cohorts,
for cancers and adenomas, and for plasma, diet, and predicted 25(OH)D
analyses. In the NHS, about a 30% reduction in risk was observed for breast
cancer comparing the highest with lowest quintiles of 25(OH)D levels. Vitamin
D intake was also associated with a lower risk of pancreatic cancer in both
men and women; but studies of plasma or predicted 25(OH)D level or dietary
intake have generally not been supportive of a major role of vitamin D status
in middle-age or elderly men on prostate cancer risk. Results from the HPFS
also suggest that the poor vitamin D status seen in African-Americans
contributes to their higher incidence and mortality from various
malignancies.26

In 2003, the USPSTF reviewed the evidence on the efficacy of multivitamin or
mineral supplements in the general adult population for the prevention of CVD
and cancer. This recommendation applies to healthy adults without special
nutritional needs (typically aged 50 years or older). It does not apply to
children, women who are pregnant or may become pregnant, or persons who are
chronically ill or hospitalized or have a known nutritional deficiency. The
USPSTF concluded that the current evidence is insufficient to assess the
balance of benefits and harms of single- or paired-nutrient supplements
(except beta-carotene and vitamin E) for the prevention of CVD or cancer.27,28

Observational studies also suggest an association between vitamin D deficiency
and chronic pain, most promisingly in fibromyalgia syndrome (FMS). Indeed, it
has been hypothesized that vitamin D has anti-inflammatory properties that
contribute to relieving pain. A systematic literature review of 14 studies
found evidence of vitamin D deficiency among certain patient populations with
FMS; however, there was conflicting evidence regarding supplementation.29
Warner et al. randomized 50 FMS patients with vitamin D levels between 9 and
20 ng/ml in a double-blind fashion to receive either weekly 50,000 IU vitamin
D2 or placebo orally for 3 months. Vitamin D levels were statistically similar
at baseline for both groups (n = 25) and the vitamin D levels of the treatment
group rose significantly higher than that of the placebo group after 3 months;
31.2 ng/ml vs 19.3 ng/ml, p =0.001. This increase was not met by significant
improvements in pain scores in the treated group compared to the placebo group
as assessed using visual analogue scale (VAS), p = 0.12, or functional pain
score (FPS). In fact, a significant difference in FPS after 3 months favored
the placebo group, p =0.05. Thus, while Vitamin D deficiency is common in the
aforementioned groups, few high-quality interventional studies support a
causal relationship between vitamin D deficiency and pain. This deficiency can
instead be a surrogate of poor nutritional status and lack of outdoor activity
associated with chronic illness.30

A correlation between the prevalence of rheumatoid arthritis (RA) and latitude
has been described to hypothesize a potential association between
hypovitaminosis D and the risk of RA. It has been observed in 1 study that
subjects with a higher vitamin D intake have a lower risk of developing RA;
however, this finding has not been confirmed by subsequent studies. Also, no
correlation has been found between levels of 25(OH)D and levels of rheumatoid
factor and anti-cyclic citrullinated peptide antibodies. Some studies have
also described an inverse correlation between disease activity and low levels
of 25(OH)D, although it has not been confirmed by other studies. It is not
actually clear if hypovitaminosis D in patients with active RA is simply a
consequence of the associated disability, leading in particular to reduced sun
exposure, or it directly contributes itself to inflammation and disability.31

The findings on the utility of vitamin D supplementation for depression are
also mixed. In an 8-week, randomized clinical trial of vitamin D
supplementation and placebo in the treatment of depression in 3 psychiatric
clinics, the study sample included 78 older adults aged over 60 years with
moderate to severe depression. Subjects were randomly allocated to receive
50,000 U vitamin D3 pearls weekly for 8 weeks or placebo (39 subjects in each
group). Main outcome measures comprised Geriatric Depression Scale-15 (GDS-15)
questionnaire and 25-hydroxyvitamin D3 [25(OH)D3]. The mean baseline 25(OH)D3
concentration was 22.57 +/- 6.2 ng/ml in vitamin D group and 21.2 +/- 5.8
ng/ml in placebo group (p = 0.16). The Vitamin D increased to 43.48 +/- 9.5
ng/ml in vitamin D group and 25.9 +/- 15.3 ng/ml in placebo group. The
depression score decreased from 9.25 to 7.48 in vitamin D group (p = 0.0001),
while there was a non-significant increase in depression score in placebo
group. The findings seem to indicate that vitamin D supplementation can
improve the depression score in persons aged 60 and over.32

In contrast, the D-Vitaal study primarily aimed to investigate the effect of
vitamin D supplementation on depressive symptoms, functional limitations, and
physical performance in a high-risk older population with low vitamin D
status. This study was a randomized placebo-controlled trial with 155
participants aged 60-80 who had clinically relevant depressive symptoms, >/=1
functional limitations, and serum 25-hydroxyvitamin D [25(OH)D] concentrations
of 15-50/70 nmol/L (depending on season). Participants received 1,200 IU/d
vitamin D3 (n = 77) or placebo tablets (n = 78) for 12 months. Serum 25(OH)D
was measured at baseline, 6 months, and 12 months. The supplementation
increased serum 25(OH)D concentrations in the intervention group to a mean +/-
SD of 85 +/- 16 nmol/L compared with 43 +/- 18 nmol/L in the placebo group
after 6 months (P < 0.001). No relevant differences between the treatment
groups were observed regarding depressive symptoms, functional limitations,
physical performance, or any of the secondary outcomes. Supplementation with
1,200 IU/d vitamin D for 12 months had no effect on depressive symptoms and
physical functioning in older persons with relatively low vitamin D status,
clinically relevant depressive symptoms, and poor physical functioning.33

In an outpatient multicenter study conducted between 2010 and 2013, patients,
18-65 years old, diagnosed with mild to severe depression were randomly
assigned to receive D3 supplementation 70 micrograms (2,800 IU) daily or
placebo on top of standard anti depression treatment. Participants, care
givers and those assessing the outcomes were blinded to group assignment. At
baseline, 23 patients had a normal 25(OH)D level, 39 had insufficiency (< 25
nmol/L). No significant reduction in depression was seen after vitamin D
supplementation compared to placebo utilizing Hamilton D-17 depression score
(18.4-18.0; p = 0.73 at 12 weeks) after 3 and 6 months of supplementation.34

An electronic search was carried out in 4 databases (PubMed, Embase, Web of
Science-Science Citation Index and Scopus) of randomized clinical trials (RCT)
to assess the efficacy of vitamin D, in adults with depression compared to
placebo, from 2013 to date of search (2019). A total of 10 RCTs involving
1.393 participants were included in the study. The result of the meta-analysis
indicates that oral administration of vitamin D did not have a significant
effect on the reduction of post-intervention depression scores.35 Menon et al.
reviewed 61 articles concerning Vitamin D deficiency and depression. Overall
findings were that there is a relationship between vitamin D and depression.
Evidence from supplementation trials suggest a therapeutic effect on subjects
with major depression and concurrent vitamin D deficiency: Serum vitamin D
levels inversely correlate with clinical depression, but the evidence is not
strong enough to recommend universal supplementation in depression.36

A randomized, double-blind trial investigated whether high-dose
cholecalciferol had beneficial effects on depression in pulmonary tuberculosis
(PTB) patients. One hundred twenty-three recurrent PTB patients (aged >/=18
years) meeting Diagnostic and Statistical Manual of Mental Disorders-IV (DSM-
IV) criteria of major depressive disorder from 4 hospitals in Southeast China
were randomly assigned to 8-week oral treatment with 100,000 IU/week
cholecalciferol (Vit D group) or a matching placebo (control group). The
primary outcome was treatment response, defined as a 50% reduction in symptoms
and change in scores of the Beck Depression Inventory (BDI) from baseline to 8
weeks. After 8 weeks, the treatment response or BDI scores did not differ
significantly between groups.37

A longer trial was conducted to examine whether vitamin D (VD) supplementation
would relieve symptoms in patients with depression and anxiety with low serum
25-hydroxy VD [25(OH) D] levels. Subjects with serum 25(OH) D levels 75
nmol/L were randomly assigned to the intervention group (n = 79) and control
group (n = 79). All participants were followed up in the 3rd and 6th months.
The intervention group members were given VD 1,600 mg daily supplementation.
At the endpoint (the 6th month), 62 participants in the intervention group and
44 in the control group completed the study. Serum concentrations of 25(OH) D
were measured using commercial kits. Psychological symptoms were evaluated
with the Hamilton Depression Rating Scale-17 (HAMD-17), Revised Social
Anhedonia Scale (RSAS), Revised Physical Anhedonia scale (RPAS), and Hamilton
Anxiety Rating Scale-14 (HAMA-14). The HAMD-17, RSAS, and RPAS scores did not
change significantly between VD and control groups from baseline to endpoint
(all p > .05); however, there was a significant difference in time effect of
the total HAMA-14 scores between the 2 groups (beta [95% Cl] = -2.235 [-3.818,
-0.653], p = .006 .Vitamin D supplementation was found to improve the anxiety
symptoms but not depressive symptoms in depressive patients with low VD level
after the 6-month intervention.38

In summary, the majority of the findings concerning vitamin D, calcium, or a
combination of both nutrients on the different health outcomes were
inconsistent. Most findings were from observational data and not RCTs, with
much heterogenicity in the RCTs. Synthesizing a dose-response relation between
intake of either vitamin D, calcium, or both nutrients and health outcomes in
this heterogeneous body of literature is challenging and leads to no firm
conclusions.39

The relationship between Vitamin D and bone health is clearer. All cells
comprising the skeleton--chondrocytes, osteoblasts, and osteoclasts--contain
both the vitamin D receptor and the enzyme CYP27B1 required for producing the
active metabolite of vitamin D, 1,25 (OH) D. Direct effects of 25
hydroxyvitamin D and 1,25 (OH)D on these bone cells have been demonstrated.
However, the major skeletal manifestations of vitamin D deficiency or
mutations in the vitamin D receptor and CYP27B1, namely rickets and
osteomalacia, can be corrected by increasing the intestinal absorption of
calcium and phosphate, indicating the importance of indirect effects. On the
other hand, these dietary manipulations do not reverse defects in osteoblast
or osteoclast function that lead to osteopenic bone.40 Osteoporosis is a major
public health problem. The National Osteoporosis Foundation (NOF) estimates
that 10.2 million Americans have osteoporosis and that an additional 43.4
million have low bone mass. More than 2 million osteoporosis-related fractures
occur annually in the U.S., more than 70% of these occur in women. In the
U.S., Medicare currently pays for most of these costs, and as the population
ages, the costs of these fractures are estimated to exceed $25 billion.
Osteoporosis is preventable and treatable, but only a small proportion of
those at increased risk for fracture are evaluated and treated. Age is an
important risk factor for bone loss; by age 60, half of white women have
osteopenia or osteoporosis. The average femoral neck T-score by DXA for a
75-year-old women is -2.5, meaning that more than half of women aged 75 and
older meet the criterion for osteoporosis. More than 20% of postmenopausal
women have prevalent vertebral fractures. Vitamin D deficiency is common in
patients with osteoporosis and hip fracture.40

A meta-analysis pooled 12 RCTs, all using oral cholecalciferol
supplementation. This review of 5 RCTs for hip fracture (n = 9294) and 7 RCTs
for nonvertebral fracture risk (n = 9820) found that a vitamin D dose of 700
to 800 IU/d reduced the relative risk (RR) of hip fracture in ambulatory or
institutionalized patients by 26% (3 RCTs with 5,572 persons; pooled RR, 0.74;
95% confidence interval [CI], 0.61-0.88) and any nonvertebral fracture by 23%
(5 RCTs with 6,098 persons; pooled RR, 0.77; 95% CI, 0.68-0.87) vs calcium or
placebo. No significant benefit was observed for RCTs with 400 IU/d vitamin D
(2 RCTs with 3,722 persons; pooled RR for hip fracture, 1.15; 95% CI,
0.88-1.50; and pooled RR for any nonvertebral fracture, 1.03; 95% CI,
0.86-1.24). 13

A smaller study looked at the effects of 3 years of dietary supplementation
with calcium and vitamin D on bone mineral density (BMD), biochemical measures
of bone metabolism and the incidence of non-vertebral fractures in 176 men and
213 women aged 65 or older who were living at home. They received either 500
mg of calcium plus 700 IU of vitamin D 3(cholecalciferol) per day or placebo.
BMD was measured by dual-energy x-ray absorptiometry, blood and urine were
analyzed every 6 months, and cases of nonvertebral fracture were ascertained
by means of interviews and verified with use of hospital records. The
difference between the calcium-vitamin D and placebo groups was significant at
all skeletal sites after 1 year, but it was significant only for total-body
BMD in the second and third years. Of 37 subjects who had nonvertebral
fractures, 26 were in the placebo group and 11 were in the calcium-vitamin D
group. In men and women 65 years of age or older who are living in the
community, dietary supplementation with calcium and vitamin D moderately
reduced bone loss measured in the femoral neck, spine, and total body over the
3 -year study period and reduced the incidence of nonvertebral fractures. 41

The American Association of Clinical Endocrinologists (AACE) and American
College of Endocrinology (ACE) Clinical Practice Guidelines for the Diagnosis
and Treatment of Postmenopausal Osteoporosis published in 2016,42 recommended
patients who are at risk for vitamin D insufficiency, particularly those with
osteoporosis maintain serum 25-hydroxyvitamin D (25[OH] D) 30 ng/ml.
Typically, 1,000 to 2,000 international units (IU) of daily maintenance
therapy is needed to maintain this optimal serum 25(OH)D level. Higher doses
may be necessary in the presence of certain factors (e.g., obesity,
malabsorption, transplant patients, certain ethnicities, older individuals).

Other studies contradict this benefit. Among asymptomatic, community-dwelling
populations with low vitamin D levels, the evidence suggests that treatment
with vitamin D has no effect on mortality or the incidence of fractures,
falls, depression, DM, CVD, cancer, or adverse events. The evidence is
inconclusive about the effect of treatment on physical functioning.43

The benefits of vitamin D for most of these conditions were reported in
observational studies that compared outcomes for participants with different
serum 25-hydroxyvitamin D levels. Older, frailer individuals who are at risk
of adverse health outcomes have lower 25-hydroxyvitamin D levels, probably
because of decreased sun exposure and decreased efficiency of cutaneous
synthesis of vitamin D.3,4 Therefore, inferring a causal relationship between
low 25-hydroxyvitamin D levels and diseases associated with aging seems
unwise. Numerous large trials have failed to find such effects, and there are
meta-analyses that found no benefits of vitamin D supplementation on falls or
mortality and no reduction in fractures unless combined with calcium, where
the effect was largely restricted to institutionalized older women.44

The results of a recent cross-sectional, observational study conducted at 61
sites across North America showed that 52% of postmenopausal women receiving
therapy for osteoporosis had 25(OH)D levels of less than 30 ng/ml (75 nmol/L).
Some, but not all, observational studies have linked vitamin D inadequacy (or
lower vitamin D intake) to an increased risk of hip and other nonvertebral
fractures. Moreover some, but not all, clinical trials and observational
studies have reported that dietary vitamin D supplementation (often given
together with calcium) lowers fracture risk in the U.S. Glucocorticoids, when
used chronically in high doses, inhibit intestinal vitamin D-dependent calcium
absorption, which is 1 of the mechanisms whereby chronic glucocorticoid excess
leads to osteoporosis and fractures. Decreased BMD is a major risk factor for
fractures, and some studies have linked vitamin D inadequacy or low intake of
vitamin D to low BMD. Many of the vitamin D supplementation studies reported
herein included concurrent calcium supplementation; therefore, the observed
benefits of vitamin D supplementation may be confounded or obscured by the
effects of concurrent calcium supplements and cannot be ascribed to vitamin D
alone.45

Correction of Vitamin D deficiency is relatively straightforward. A common
strategy is to "load" a patient with 50,000 IU of Vitamin D2 or vitamin D3
once per week for 8-12 weeks, or the equivalent of 6,000 IU per day for 8-12
weeks to achieve a level of 25(OH)D above 30ng/ml. Once an optimal range has
been reached, assuming no change in lifestyle or diet, maintenance dosage of
800-2,000 IU will be needed to avoid recurrent deficiency. In obese patients,
patients with malabsorption syndromes, and patients on medications affecting
vitamin D metabolism, it is suggested to give a higher dose of (10,000 IU/d)
vitamin D to treat vitamin D deficiency and to maintain a 25(OH)D level above
30 ng/ml, followed by maintenance therapy of 3,000-6,000 IU/d. High doses of
vitamin D of 10,000 to 50,000 units daily may be necessary to replete vitamin
D in some patients. Patients with mild or moderate hepatic failure or
intestinal fat-malabsorption syndromes, as well as patients who are taking
anticonvulsant medications, glucocorticoids, or other drugs that activate
steroid and xenobiotic receptor, require higher doses of vitamin D 46,47,48
Such patients require careful monitoring to avoid toxicity.

Obesity has been linked to vitamin D deficiency and is thought to be due to
the sequestration of vitamin D in body adipose tissue, leading to reduced
availability.49 Early studies found lower serum vitamin D levels in non-
operative morbidly obese patients, with 62% having deficiencies in serum
25-hydroxyvitamin D (25-OHD) levels.50 A meta-analysis of 23 observational
studies published up to April 2014, demonstrated that the prevalence of
vitamin D deficiency was 35% higher in obese subjects compared to the
eutrophic group (PR: 1.35; 95% CI: 1.21-1.50) and 24% higher than in the
overweight group (PR: 1.24; 95% CI: 1.14-1.34). The vitamin D deficiency was
associated with obesity irrespective of age and latitude.51

For the morbidly obese, taking vitamin and mineral supplements is essential
for appropriate micronutrient repletion both before and after bariatric
surgery. Studies have found that 60-80% of morbidly obese preoperative
candidates have defects in vitamin D. Such defects would reduce dietary
calcium absorption and increase a substance known as calcitriol, which, in
turn, causes metabolic changes that favor adipose tissue accumulation.52 Obese
patients require at least 3,000 international units of vitamin D daily to
titrate to therapeutic 25-hydroxyvitamin D levels >30 ng/ml.53

A prospective cohort study comparing obese to non-obese subjects found serum
25(OH)D and 1,25-dihydroxy vitamin D was negatively correlated with BMI in
Caucasian and African-American adults (p<0.0001 for both groups).54 A large
Canadian cohort with 5,569 individuals reported that a BMI >30 (obese) was
strongly associated with lower levels of serum 25(OH)D (<75nmol/L) in both
males and females. A multivariate regression analysis that included dietary
intake of vitamin D, sunlight exposure, and supplementation showed the impact
of BMI was an independent variable (-11.12 (-14.04;-8.21) females and -8.17
(-13.49; -2.85) males.55 National Health and Nutrition Examination Survey
(NHANES) data reported lower concentrations of 25(OH)D levels among obese
white women compared to leaner counterparts.49 Obese adults also have been
found to have difficulty raising their vitamin D levels by sunlight,
ultraviolet light exposure, or supplementation as compared to nonobese
adults.11,56 The AACE, The Obesity Society and American Society for Metabolic,
and Bariatric Surgery Guidelines recommend vitamin D supplements titrated to
therapeutic 25-hydroxyvitamin D levels >30ng/ml after bariatric surgery (Grade
A recommendation).57

Vitamin D deficiency has been reported in 90% of patients before and 100% of
patients after bariatric surgery. After bariatric surgery, patients should
receive 3,000 IU of D3 daily from all sources to maintain a 25(OH)D level of
>30 ng/ml (75 nmol/L). However, the optimal level of 25(OH)D to prevent
secondary hyperparathyroidism is uncertain. In 1 study of 171 patients who
underwent a Roux-en-Y Gastric Bypass (RYGB) procedure 2 years earlier, PTH
levels and the prevalence of secondary hyperparathyroidism were notably lower
with 25(OH)D 40 ng/ml (100 nmol/L) compared with lower target levels. 58

Baseline and annual postoperative evaluation for vitamin D deficiency is
recommended after RYGB, sleeve gastrectomy, or biliopancreatic diversion
without/with duodenal switch (BPD/DS). Minimal daily nutritional
supplementation for patients with RYGB and Lennox-Gastaut syndrome (LSG) all
in chewable form initially should be at least 3,000 international units of
vitamin D (titrated to therapeutic 25-hydroxyvitamin D levels >30 ng/ml).
Minimal daily nutritional supplementation for patients with Laparoscopic
adjustable gastric banding (LAGB) should include at least 3,000 international
units of vitamin D (titrated to therapeutic 25-dihydroxyvitamin D levels).
Patients with severe vitamin D malabsorption are recommended initial oral
doses of vitamin D2 (50,000 IU 1 to 3 times/weekly) or D3 (minimum of 3,000
IU/day to 6,000 IU/day).53

An increased long-term risk of metabolic bone disease has been documented
after bariatric surgery. One study followed these patients 4 years
postoperatively and found vitamin D deficiency in 63%, hypocalcemia in 48%,
and a corresponding increase in PTH in 69% of patients. Another series found,
at a median follow-up of 32 months, that 25.9% of patients were hypokalemic,
50% had low vitamin D, and 63.1% had elevated PTH, despite taking
multivitamins. The bypass of the duodenum and a shorter common channel in
bariatric surgery patients increases the risk of developing
hyperparathyroidism, related to reduced calcium and 25(OH)D absorption 52 The
American Society of Metabolic and Bariatric Surgery (ASMBS) guidelines require
that a baseline 25-Vitamin D be drawn preoperatively. In patients who have
undergone bariatric surgery, treatment with oral calcium citrate 1,200-1,500
mg/day in divided doses and ergocalciferol or cholecalciferol 3,000 IU/day to
titrate to a level of > 30 ng/ml of 25 (OH)D, is indicated to prevent or
minimize secondary hyperparathyroidism without inducing frank hypercalciuria.
In cases of severe vitamin D malabsorption, oral doses of vitamin D2 or D3 may
need to be as high as 50,000 units 1 to 3 times weekly to daily, and more
recalcitrant cases may require concurrent oral administration of calcitriol
(1,25-dihydroxyvitamin D) (Grade D). 53

Alterations of the endocrine system in patients following RYGB are poorly
described. Prospectively collected data was compiled to determine how RYGB
affects serum calcium, vitamin D, and PTH. Calcium, vitamin D, and PTH levels
were drawn on 243 patients following gastric bypass (GBP). Forty-one patients
had long-limb gastric bypass (LL-GBP), Roux >100 cm, and 202 had short-limb
gastric bypass (SL-GBP), Roux < or =100 cm. When corrected for albumin levels,
mean calcium was 9.3 mg/dL (range, 8.5-10.8 mg/dL), and no difference existed
between LL-GBP and SL-GBP patients. For patients with low vitamin D levels
(<8.9 ng/mL), 88.9% had elevated PTH (>65 pg./mL) and 58.0% of patients with
normal vitamin D levels (> or =8.9 ng/mL) had elevated PTH (P < 0.0001). In
individuals with vitamin D levels <30 ng/mL, 55.1% (n = 103) had elevated PTH,
and of those with vitamin D levels > or =30 ng/mL 28.5% (n = 16) had elevated
PTH (P = 0.0007). Mean vitamin D levels were lower in patients who had
undergone LL-GBP as opposed to those with SL-GBP, 16.8 +/- 10.8 ng/mL versus
22.7 +/- 11.1 ng/mL (P = 0.0022), and PTH was significantly higher in patients
who had a LL-GBP (113.5 +/- 88.0 pg./mL versus 74.5 +/- 52.7 pg./mL, P =
0.0002). There was a linear decrease in vitamin D (P = 0.005) coupled with a
linear increase in PTH (P < 0.0001) the longer patients were followed after
GBP. Alkaline phosphatase levels were elevated in 40.3% of patients and
correlated with PTH levels. Vitamin D deficiency and elevated PTH are common
following GBP and progress over time. There is a significant incidence of
secondary hyperparathyroidism in short-limb GBP patients, even those with
vitamin D levels > or =30 ng/mL, suggesting selective calcium malabsorption.
Thus, calcium malabsorption is inherent to GBP. Careful calcium and vitamin D
supplementation and long-term screening are necessary to prevent deficiencies
and the sequelae of secondary hyperparathyroidism.47

In summary, there are varying studies that proport an association between low
vitamin D levels and CVD, cancer, depression and autoimmune disease, but none
conclusively prove that an intervention of vitamin D supplementation improves
health. The association of low levels of vitamin D and poor bone health is
stronger, but even here, it is unclear as to whether supplementation actually
decreases fracture occurrence. It appears there is an association between
morbid obesity and lower levels of vitamin D, but again there is little
conclusive evidence that supplantation does anything other than improve
vitamin D levels. There is also a very low risk in toxicity of vitamin D. An
equally strong argument could be made for routine supplementation of vitamin D
in standard amounts for the non-obese and in greater amounts for the obese or
those with previous bariatric surgery without testing levels.

Over the past 2 decades, laboratory and epidemiological studies have suggested
that low vitamin D status may be associated with a variety of health risks,
including respiratory illnesses (infections and asthma),depression, RA ,
cancer, adverse pregnancy outcomes, and chronic diseases of adulthood, such as
osteoporosis and CVD . To date, there is limited evidence thus far from RCTs
to support effects on health outcomes other than bone health.

The benefits of treatment of vitamin D supplementation may be modest, and
those benefits are difficult to quantify, due to variation in general health,
exercise, smoking, ethnicity and treatment regimens. It is established that
25-hydroxyvitamin D is more reflective of total body stores of vitamin D than
the shorter lived, active metabolite, 1,25 dihydroxy vitamin D. The 25-OH
vitamin D assay must be used in the evaluation of most patients with
hypovitaminosis D, as outlined in the **_Coverage Indications, Limitations
and/or Medical Necessity_** section above. Measurement of other metabolites is
generally not medically necessary.

The 25-hydroxyvitamin D undergoes additional hydroxylation in the kidney by 1-
alpha hydroxylase under the influence of parathyroid hormone to produce the
active metabolite. The 1,25 dihydroxy vitamin D assay will be considered
reasonable and necessary for those patients where a contributory medical
illness is present as outlined above in the **_Coverage Indications,
Limitations and/or Medical Necessity_** section.

Once a beneficiary has been shown to be Vitamin D deficient, the correctly
chosen assay (25 hydroxyvitamin D, or 1,25 di-hydroxyvitamin D) may be used to
assure correct supplementation to attain the serum levels outlined in the
**_Coverage Indications, Limitations and/or Medical Necessity_** section.
Continued findings outside those parameters (again outlined in the **_Coverage
Indications, Limitations and/or Medical Necessity_** section) may warrant
additional testing.