In cooperation with
Timely Topics in Nutrition
Vitamin D metabolism in canine and feline medicine
Valerie J. Parker dvm From the Department of Veterinary Clinical Sciences, College of Veterinary Medi-
cine, The Ohio State University, Columbus, OH 43210.
Adam J. Rudinsky dvm, ms
Address correspondence to Dr. Parker (parker.888@osu.edu).
Dennis J. Chew dvm
Vitamin D Metabolism
and Hormonal Influences
In many species, the biosynthesis of vitamin
D begins with exposure to UV light, wherein 7-
dehydrocholesterol is transformed to previtamin
D3. Factors that affect synthesis of vitamin D3 in-
clude quantity and quality of the UV light, coat, and
skin pigmentation. Dogs and cats are unique from
humans and many other species in that they lack
the ability to synthesize vitamin D3 in the skin, like-
ly because of high activity of 7-dehydrocholesterol-
∆7-reductase.1,2 For this reason, dogs and cats re-
quire dietary supplementation with vitamin D to
meet nutritional requirements. There are 2 dietary
forms of vitamin D: cholecalciferol (vitamin D3),
which typically comes from animal food sources,
and ergocalciferol (vitamin D2), which typically
comes from plant sources. Cats may not utilize er-
gocalciferol as efficiently as cholecalciferol3 ; how-
ever, dogs have the ability to utilize both dietary
forms equally.4,a
Dietary vitamin D is supplied in commercially
available dog and cat foods in the form of various
ingredients (eg, organ meat or oily fish products)
and supplemental cholecalciferol. Once ingested,
it is transported to the liver via the portal system
and intestinal lymphatics (Figure 1). This process
requires digestive enzymes, chylomicrons, bile ac-
ids, and VDBP or transcalciferon.5,6 After cholecal-
ciferol is transported to the liver, it is hydroxylated
by 25-hydroxylase to form 25(OH)D (also known
ABBREVIATIONS
1,25(OH) 2D 1,25-dihydroxyvitamin D
24,25(OH) 2D 24,25-dihydroxyvitamin D
25(OH)D 25-hydroxyvitamin D
CKD Chronic kidney disease
FGF Fibroblast growth factor
PTH Parathyroid hormone
VDBP Vitamin D binding protein
VDDR Vitamin D–dependent rickets
VitDQAP Vitamin D Metabolites Quality Assurance differentiation of immune cells, reductions in in-
Program
JAVMA • Vol 250 • No. 11 • June 1, 2017 1259
as calcidiol or calcifediol), which binds to VDBP
in the circulation. With a half-life of approximately
2 to 3 weeks, 25(OH)D is thought to be the most
reliable indicator of systemic vitamin D status in
humans.7
Then, 25(OH)D is hydroxylated via 1α-hydroxylase
to form 1,25(OH)2D (the most active naturally occurring
vitamin D metabolite; also known as calcitriol), which
affects many target cells via a vitamin D receptor–medi-
ated mechanism. Calcitriol binds to the vitamin D re-
ceptor much more readily (approx 500 times as read-
ily) than does vitamin D3 or 25(OH)D.8 This activation
of 1,25(OH)2D occurs predominately in the kidneys;
however, it also occurs in other tissues that express
1α-hydroxylase. Although the exact mechanism has not
been completely elucidated, 1α-hydroxylase activity is
tightly regulated by serum concentrations of calcium,
PTH, 1,25(OH)2D, FGF-23, and the Klotho gene.9–12 Within
cells, 1,25(OH)2D can promote or suppress gene transcrip-
tion and expression.13 Both 25(OH)D and 1,25(OH)2D are
inactivated via 24-hydroxylase to form 24,25(OH)2D
and 1,24,25-trihydroxyvitamin D, respectively, and other
metabolites (eg, 25[OH]D-23,23 lactone) that are excret-
ed in the urine and bile.14
A novel vitamin D epimer, which was identified
as a C-3 epimer of 25(OH)D, has recently been dis-
covered in cats by use of high-performance liquid
chromatography.b Serum concentrations ranged from
18 to 30 ng/mL, which represented 29% to 75% of
native 25(OH)D. This epimer has not been identified
in dogs.
Vitamin D Roles
Classically, vitamin D is known for its influence
on calcium-phosphorus homeostasis via the bone-
parathyroid-kidney axis.15,16 However, vitamin D has
been found to have multiple other effects through-
out the body, given the wide variety of cells that
express the vitamin D receptor. Actions induced by
vitamin D receptor activation in humans include
flammation and proteinuria, increases in insulin
Figure 1—Comprehensive overview of vitamin D metabolism, starting with dietary intake and progressing through hepatic and
renal transformation. Also notice the influences of phosphate (Pi), ionized calcium (Ca2+), FGF-23, Klotho, and PTH. CYP =
Cytochrome P450. (Reproduced with permission of The Ohio State University.)

secretion, and improvement of hematopoiesis.17 Measuring Vitamin D Metabolites

In people, vitamin D deficiency (hypovitaminosis
D) has been associated with a multitude of clinical
syndromes, including kidney disease, cancer, obe-
sity, asthma, intestinal disease, diabetes mellitus,
hypertension, and infectious diseases.18–26 Vitamin
D status also affects various disease conditions in
dog and cats.
The VitDQAP27 was established through joint ef-
forts between the National Institute of Standards and
Technology and the National Institutes of Health.
These efforts were initiated because measurement of
vitamin D metabolites was routinely performed (and
results reported) by use of multiple techniques, includ-

1260 JAVMA • Vol 250 • No. 11 • June 1, 2017

ing liquid chromatographic methods, immunoassay
techniques, chemiluminescence immunoassays, and
radioimmunoassays. Furthermore, large variations
in 25(OH)D results attributable to interassay, intra-
assay, and interlaboratory variance make comparisons
among results and defined cutoff points tenuous.28,29
The VitDQAP was able to assist in the development of
standard reference materials and studies to examine
differences among assay performance.
The VitDQAP, which is based on assay performance
characteristics, is an international external quality as-
sessment plan that can be used to evaluate vitamin D
metabolite assays provided by participating laboratories.
That assessment scheme is based, in part, on findings
from studies conducted by the VitDQAP. Liquid chro-
matography methods are currently the most commonly
used methods and remain the criterion-referenced stan-
dard (liquid chromatography with tandem mass spec-
trometric detection) for measurement.30 Importantly,
those studies were performed with human samples,
and the effect of a canine or feline matrix on these
variables and comparability of results is unknown. Re-
gardless, because there is no universally accepted best
method for measurement of vitamin D metabolites, it
is recommended to use a Vitamin D External Quality
Assessment Scheme–certified lab to increase the likeli-
hood of accurate results when measuring vitamin D me-
tabolites. There are age-related differences to consider
as well. The 1,25(OH)2D concentrations of kittens at 3
and 6 months of age are significantly higher than con-
centrations of older kittens and adult cats.31
How Much Vitamin D is Enough?
Defining 25(OH)D sufficiency, insufficiency, and
deficiency is controversial. In humans, vitamin D de-
ficiency is generally defined as < 20 ng/mL and suf-
ficiency is generally > 30 ng/mL. Optimal repletion is
defined by some as > 50 or > 60 ng/mL to achieve the
aforementioned pleiotropic effects on the vitamin D re-
ceptor. Consensus on optimal, adequate, or deficient
vitamin D status in populations of healthy dogs and
cats has not been reached. Multiple variables (includ-
ing signalment, disease, assay technique, and physi-
ologic variation) affect the reference range and the
therapeutic target range.32–34
An inverse relationship exists between circulat-
ing PTH and 25(OH)D concentrations in humans;
therefore, 1 method used to define vitamin D suffi-
ciency in humans has been to determine the lowest
concentration of 25(OH)D associated with suppres-
sion of PTH synthesis.35 On the basis of this meth-
od, 25(OH)D concentrations of 100 to 120 ng/mL
have been recommended by 1 group to represent
sufficiency in healthy dogs because PTH concentra-
tions are most suppressed at these concentrations of
25(OH)D.36 By use of this method, the recommenda-
tion for 25(OH)D sufficiency in dogs36 (100 to 120
ng/mL) differs considerably from that recommended
for humans (> 20 or > 30 ng/mL). In that study36 of ap-
parently healthy dogs, there was an extremely wide
range of circulating 25(OH)D concentrations (9.5 to
249 ng/mL). The reference range for 1 national veteri-
nary endocrine laboratoryc is 24 to 86 ng/mL.
Wide ranges of 25(OH)D concentrations have been
reported for healthy dogs37–50 and cats.51–53 (Table 1). Im-
portantly, assay choice and technique differed among
many of these studies. In general, concentrations of
25(OH)D in healthy dogs and cats are substantially
higher than concentrations in healthy humans. The
higher 25(OH)D concentrations in dogs and cats likely
reflect intake of commercial pet foods that often are

Table 1—Concentrations of vitamin D metabolites in healthy dogs and cats.

25(OH)D 1,25(OH)2D 24,25(OH)2D
Species No. of animals (ng/mL) (pg/mL) (ng/mL) Reference
Dog 282 68.9 (9.5–249.2) — — 36
6 — 26.0 ± 5.0 — 37
33 — 36.0 — 38
24 107.0 ± 38.9* 58.8 ± 19.2* — 39
24 122.8 (19.2–140.2)* 60.6 (23.1–91.9)* — 40
64 40.7 ± 15.6 — — 41
22 — 60.1 (22.5–99.2) — 42
36 30.8* 43.4* — 43

54 48.1 ± 14.0* — — 44
47 40.7 ± 16.5; 37.6 (20.2–105.0) — — 45
24 29.9 (15.0–52.3)* — — 46
51 49.3 ± 17.6* — — 47
8 Day 0: 57.0 ± 13.0 Day 0: 157.0 ± 30.0 Day 0: 54.0 ± 13 48
Day 2: 55.0 ± 11.0 Day 2: 127.0 ± 33.0 Day 2: 54.0 ± 13
Day 8: 57.0 ± 13.0 Day 8: 129.0 ± 32.0 Day 8: 55.0 ± 12
320 69.7 (9.5–249.2) — — 49
10 75.1 (50.4–97.9) 209.6 (168.9–428.0) 38.7 (24.0–89.5) 50

Cat 36 49.0 (22.9–83.1) — — 51

23 45.1 (30.4–61.1) — — 52
20 44.7 (14.9–61.0) — — 53

Values reported are mean, mean ± SD, or median (range).

*Results were originally reported as nmol/L but have been converted.
— = Not reported.

JAVMA • Vol 250 • No. 11 • June 1, 2017 1261

supplemented with vitamin D at concentrations far
above minimal needs, whereas people often eat diets
deficient in vitamin D.54–56
In 1997, adequate intake of vitamin D for an adult
person was 200 U/d, whereas in 2010, adequate in-
take had increased to 600 U/d. According to the As-
sociation of American Feed Control Officials, the
minimum vitamin D recommendation for canine
adult maintenance is to provide 125 U/1,000 kcal.
The Association of American Feed Control Officials
recommends that the maximum amount allowed in
commercial dog foods is 750 U/kcal.55 For example,
a 20-kg (44-lb) dog eating a maintenance energy re-
quirement (1.6 X resting energy requirement) of ap-
proximately 1,000 kcal/d could theoretically ingest a
range of 125 to 750 U of cholecalciferol/d. On the
basis of the 2010 adjustment to adequate intake for
humans, it is possible that optimal dietary intake in
canine and feline subjects might need adjustment in
the future. However, one cannot necessarily predict
a dog’s serum 25(OH)D concentration on the basis of
its cholecalciferol intake.57,d
Vitamin D Metabolite
Status in Various Diseases
The status of vitamin D and vitamin D metabo-
lites can be affected by various diseases and condi-
tions36–40,42–48,50–53,58–62 (Table 2).
Kidney disease
Vitamin D metabolites have been measured in
dogs with several forms of kidney disease, including
acute renal failure,39 CKD,39,40,42,45,50 and proteinuric
kidney disease.e There are several mechanisms by
which vitamin D metabolism can be disrupted with
kidney disease, including decreased dietary intake
of vitamin D, decreased enzymatic conversion from
cholecalciferol to 25(OH)D in the liver,63 decreased
activation via 1α-hydroxylase from 25(OH)D to
1,25(OH) 2D, and increased inactivation of 25(OH)D
and 1,25(OH) 2D.18 With proteinuria, there are addi-
tional potential mechanisms to consider, including
urinary loss of VDBP (with 25[OH]D and 1,25[OH]2D
bound to vitamin D binding protein) and decreased
endocytosis of 25(OH)D into renal cells because of
decreased megalin expression in the proximal renal
tubules.64,65 Furthermore, inflammation may act to
reduce 25(OH)D concentrations.66
In several studies,39,40,42,45,50 it has been report-
ed that dogs with CKD have lower 25(OH)D and
1,25(OH)2D concentrations, compared with concentra-
tions in control dogs. Vitamin D metabolites are corre-
lated with stage of kidney disease (determined via Inter-
national Renal Interest Society criteria), as indicated by
the fact that concentrations of 25(OH)D, 1,25(OH)2D,
and 24,25(OH)2D are significantly decreased in dogs
with stage 3 kidney disease, compared with concentra-
tions in control dogs.42,50 In other studies, many dogs
had 25(OH)D and 1,25(OH)2D concentrations within
1262 JAVMA • Vol 250 • No. 11 • June 1, 2017
reference limits. One possible explanation for this lack
of difference could be the inclusion of dogs with ear-
lier stages of CKD. Alternatively, significant differences
in concentrations of vitamin D metabolites may not
have been detected because of relatively large refer-
ence ranges or the method used to calculate reference
ranges.
One of the consequences of CKD is development
of secondary hyperparathyroidism and CKD-induced
mineral and bone disorders.67–69 Plasma FGF-23 concen-
trations are increased in cats and dogs with CKD.70,71
Concentration of FGF-23 was negatively correlated
with 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D concen-
trations in dogs with CKD50 and with survival dura-
tion in cats with CKD.72 Calcitriol treatment has been
recommended for several decades for dogs and cats
to reduce PTH concentrations and improve quality
of life.73,74,f However, prospective, controlled clinical
studies are needed to determine the manner in which
supplementation with various forms of vitamin D influ-
ences FGF-23 concentrations, Klotho expression, vita-
min D repletion, quality of life, preservation of renal
function, and survival duration.
Finally, dogs with acute renal failure had sig-
nificantly lower 25(OH)D and 1,25(OH)2D concen-
trations, compared with concentrations in control
dogs, but most (7/10) of the dogs with acute renal
failure had concentrations within reference limits.39
These findings possibly could have been attribut-
able to acute inflammation or critical illness66,75 or
could have been spurious results. Proteinuric dogs
have significantly lower 25(OH)D, 1,25(OH)2D, and
24,25(OH)2D concentrations than do control dogs.e
This relationship has been definitively established in
proteinuric people, and vitamin D receptor activators
are frequently prescribed to reduce proteinuria.65,76
Neoplasia
Decreased 25(OH)D concentrations have been
linked to increased risk of numerous neoplasms in
humans, and 1,25(OH)2D has been found to have an-
tineoplastic activity.77,78 Concentrations of circulating
vitamin D metabolites have been measured in dogs with
various neoplasms. Serum 25(OH)D concentrations are
significantly lower for various neoplastic conditions,
including dogs with neoplasia and hemoabdomen,36
cutaneous mast cell tumor,44 and lymphoma.40
Serum 25(OH)D concentrations in dogs and cats
prior to the development of neoplasia have not been
evaluated. Thus, it is not clear whether dogs develop
hypovitaminosis D secondary to neoplasia or wheth-
er hypovitaminosis D is actually a risk factor for de-
velopment of cancer. Dogs with neoplasia are often
ill; this puts them at risk of developing hypovitamino-
sis D as a result of a reduced appetite, which leads to
reduced cholecalciferol intake, and potentially from
decreased intestinal absorption of cholecalciferol.
Serum 1,25(OH)2D concentrations have been
measured in populations of dogs with lymphoma,
both with and without hypercalcemia, with wide
Table 2—Concentrations of vitamin D metabolites in dogs and cats with various diseases or conditions.
No. of 25(OH)D 1,25(OH)2D 24,25(OH)2D
Species animals Disease or condition (ng/mL) (pg/mL) (ng/mL) Reference
Dog 9 Anal sac adenocarcinoma — 23.0 ± 5.0 — 58
and hypercalcemia
6 Solid tumors and — 16.0 ± 4.0 — 58
normocalcemia
18 Lymphoma and hypercalcemia — 6.0 — 37
6 L ymphoma and normocalcemia — 11.0 — 37
25 Lymphoma and hypercalcemia — 43.0 — 38
11 Lymphoma and normocalcemia — 28.0 — 38
8 Anal sac adenocarcinoma — 31.0 — 38
and hypercalcemia
8 Anal sac adenocarcinoma and — 28.5 — 38
normocalcemia
7 Miscellaneous tumors and — 44.0 — 38
hypercalcemia

10 Acute renal failure 52.1 ± 32.9* 28.8 ± 9.6* — 39

21 Chronic renal failure 39.3 ± 24.8* 43.8 ± 29.6* 39
19 Chronic renal failure in acute crisis 27.2 ± 20.8* 26.9 ± 17.7* — 39
12 Lymphoma and hypercalcemia 40.7 (25.6–116.6)* 42.3 (10.0–127.7)* — 40

5 Primary hyperparathyroidism 36.5 (26.4–119.4)* 95.4 (23.5–153.1)* — 40
and hypercalcemia
5 Chronic renal failure 26.8 (14.0–73.7)* 34.0 (10.8–119.2)* — 40
and hypercalcemia
11 CKD–stage 1 — 49.7 (37.4–77.2) — 42
10 CKD–stage 2 — 48.8 (34.9–84.6) — 42
25 CKD–stage 3 — 34.2 (2.4–89.6) — 42
8 CKD–stage 4 — 18.9 (5.0–38.2) — 42

49 Hospitalized non-GI tract illness 26.9* 29.3* — 43
21 Inflammatory bowel disease 28.6* 54.5* — 43
12 Protein-losing enteropathy 5.7* 19.9* — 43
33 Cutaneous mast cell tumor 41.7 ± 12.0* — — 44
19 CKD 19.2 ± 14.1; 14.5 (2.7–53.7) — — 45
26 Neoplastic spirocercosis 12.3 (5.9–24.9)* — — 46
25 Nonneoplastic spirocercosis 21.1 (7.7–52.0)* — — 46
31 Congestive heart failure 40.1 ± 16.8* — — 47
31 Splenic hemangiosarcoma 49.2 (19.4–91.8) — — 36
62 Cancer and hemoabdomen, 49.4 (19.4–151.0) — — 36
including splenic hemangiosarcoma

14 CVHD–stage B1 21.8 (13.4–71.3)* — — 59

17 CVHD–stage B2 14.3 (2.0–68.9)* — — 59
12 CVHD–stage C or D 5.2 (2.0–28.3)* — — 59
12 Racing sled dogs Day 0: 67 ± 9 Day 0: 122 ± 34 Day 0: 66 ± 13 48
Day 2: 72 ± 11 Day 2: 119 ± 26 Day 2: 67 ± 15
Day 8: 87 ± 16 Day 8: 121 ± 22 Day 8: 76 ± 18
26 Chronic enteropathy–survivors 24.9 (15.6–39.5)† — — 60
15 Chronic enteropathy–nonsurvivors 4.3 (1.6–17.0)† — — 60
37 CKD–total 48.2 (3.5–95.8) 120.8 (19.0–286.0) 18.9 (0.3–48.5) 50
10 CKD–stage 1 48.2 (32.6–87.3) 157.6 (94.8–202.4) 24.8 (11.2–48.5) 50
9 CKD–stage 2 55.7 (34.5–93.5) 143.2 (96.4–286.0) 30.3 (14.8–46.8) 50
12 CKD–stage 3 42.7 (3.5–95.8) 104.8 (29.2–228.7) 10.3 (0.3–42.1) 50
6 CKD–stage 4 25.0 (19.0–91.1) 64.7 (19.0–91.1) 7.0 (2.0–16.4) 50

Cat 24 Mycobacteriosis 22.2 (9.7–54.8) — — 51

41 Hospitalized with illness 33.8 (10.6–53.5) — — 51
20 Inflammatory bowel disease (n = 14) 12.7 (2.0–83.1) — — 52
and intestinal lymphoma (6)
39 Hospitalized with illness 30.9 (7.1–82.4) — — 53
59 FIV infection 32.1 (5.0–62.4) — — 53
80 Hospitalized cats–alive 38.5 (1.7–81.6)* — — 61
19 Hospitalized cats–dead 22.9 (8.7–97.1)* — — 61
148 Neutrophil count < 12.8 X 109 cells/L 42.3* — — 62
22 Neutrophil count > 12.8 X 109 cells/L 31.9* — — 62

Values reported are mean, mean ± SD, or median (range).

†Value reported is median (interquartile range).
CVHD = Chronic valvular heart disease. GI = Gastrointestinal.
See Table 1 for remainder of key.

differences in findings.37,38,40 In the earliest study,37
both hypercalcemic and normocalcemic dogs had sig-
nificantly lower 1,25(OH)2D concentrations than did
healthy control dogs. Most of the hypercalcemic dogs
had 1,25(OH)2D concentrations lower than the limit of
detection, which is an appropriate response in the face
of hypercalcemia.37 In a later study,38 hypercalcemic
dogs with lymphoma had a higher mean 1,25(OH)2D
concentration than did control dogs, but the normo-
calcemic dogs with lymphoma had a lower mean
1,25(OH)2D concentration than did control dogs, al-
though these results were not compared with a sta-
tistical assessment. Mean 1,25(OH)2D concentrations
were within reference limits for both hypercalce-
mic and normocalcemic dogs with lymphoma.38 Fi-
nally, in the most recent study,40 median 1,25(OH)2D
concentration was significantly lower in dogs with
lymphoma (110.0 pmol/L) than in control dogs

JAVMA • Vol 250 • No. 11 • June 1, 2017 1263

(157.5 pmol/L); however, there was a wide range of
concentrations that extended below the low end
and above the high end of the reference range.40 The
1,25(OH)2D concentrations in dogs with anal sac
adenocarcinoma (with both hypercalcemia and nor-
mocalcemia) were not significantly different from
1,25(OH)2D concentrations in control dogs.38,58
From an antineoplastic standpoint, calcitriol can
have in vitro activity against osteosarcoma,79 squa-
mous cell carcinoma,80 prostatic epithelial,81 anal sac
adenocarcinoma,82 mammary gland cancer,83 and
mast cell tumor84 canine cell lines.79–84 One in vivo
study83 revealed a synergistic effect of administra-
tion of calcitriol with cisplatin against various tumors
(eg, osteosarcoma and chondrosarcoma) in dogs. In-
vestigators of another in vivo study84 found that cal-
citriol treatment could induce remission of mast cell
tumors; however, the trial was discontinued because
of the high rate of toxic events (ie, hypercalcemia and
azotemia) observed.
Primary hyperparathyroidism
Although primary hyperparathyroidism is tech-
nically a neoplastic condition, it is separated in the
information provided here to avoid confusion with
malignant conditions because most dogs with prima-
ry hyperthyroidism have benign parathyroid gland
adenomas. Compared with concentrations in control
dogs, 5 dogs with primary hyperparathyroidism had
significantly lower serum 25(OH)D concentrations40 ;
however, all values for the dogs with primary hyper-
parathyroidism were within reference limits.40 Serum
1,25(OH)2D concentrations also were significantly
higher in dogs with primary hyperparathyroidism
than concentrations in control dogs, and 1,25(OH)2D
concentrations in 4 of 5 dogs with primary hyper-
parathyroidism were above reference limits.40 Both
findings could possibly be attributed to an upregu-
lating effect of PTH on renal 1α-hydroxylase activity,
which would thus increase 1,25(OH)2D synthesis.
In a studyg of 10 dogs with primary hyperpara-
thyroidism treated by surgical excision of parathyroid
gland adenomas, all had low 25(OH)D concentrations
at the time of diagnosis, compared with concentra-
tions in control dogs, whereas 1,25(OH)2D concentra-
tions were within reference limits. At the time of the
postparathyroidectomy nadir in ionized calcium con-
centration, 25(OH)D concentrations were not differ-
ent from concentrations at the time of initial diagnosis,
but mean 1,25(OH)2D concentrations were lower.g
A diagnosis of primary hyperparathyroidism tra-
ditionally has been made on the basis of an increased
ionized calcium concentration at the time of an inap-
propriately high concentration of PTH. The concen-
tration of circulating 25(OH)D is an important regu-
latory factor for the suppression of PTH synthesis in
people (likely following its conversion to 1,25(OH)2D
within the parathyroid gland). Concentrations of PTH
are higher in humans with concomitant lower circu-
lating 25(OH)D concentrations. It currently is recom-
mended for humans that the diagnosis of primary
1264 JAVMA • Vol 250 • No. 11 • June 1, 2017
hyperparathyroidism only be made when 25(OH)D
concentrations are sufficient or after 25(OH)D has
been repleted following supplementation with vita-
min D.85 The importance of concurrent evaluation of
ionized calcium, PTH, and 25(OH)D concentrations
to make an accurate diagnosis of primary hyperpara-
thyroidism has not yet been investigated in veterinary
medicine.
Gastrointestinal tract disease
Absorption of fat-soluble vitamins depends on
adequate absorption of dietary fat; thus, malabsorp-
tive intestinal diseases can adversely affect vitamin
D absorption and ultimately contribute to hypovi-
taminosis D.86,87 Serum 25(OH)D and 1,25(OH) 2D
concentrations have been evaluated in dogs with in-
flammatory bowel disease and protein-losing enter-
opathy. Both vitamin D metabolite concentrations
were significantly lower in the protein-losing enter-
opathy group than in dogs with inflammatory bowel
disease and healthy dogs.43,88 Additionally, 25(OH)
D concentrations were significantly negatively cor-
related with duodenal inflammation and death.60,88
It is possible that hypoalbuminemia contrib-
utes to hypovitaminosis D through loss of VDBP
via diseased intestines.89 Alternatively, hypovita-
minosis D may contribute to intestinal protein loss
through the effect of vitamin D on the immune
response.90 Results of experiments indicated that
vitamin D receptor–knockout mice are more likely
to develop induced inflammatory bowel disease.91
Additionally, vitamin D–deficient diets predisposed
mice to colitis via dysregulated colonic antimicro-
bial activity and impaired homeostasis of enteric
bacteria.92
Orthopedic disease
Osteoblasts and chondrocytes express 1α-
hydroxylase and vitamin D receptor; however,
it is unknown whether vitamin D plays a direct
or indirect role in bone growth and mineraliza-
tion. Rickets is a metabolic bone disease typically
caused by dietary deficiency of vitamin D or phos-
phorus or by genetic defects affecting vitamin D
or phosphorus metabolism. The most common clini-
cal abnormality is widening of the physeal growth
plates of fast-growing bones (eg, radius and ulna).
Histologically, hypertrophic chondrocytes accu-
mulate, which leads to thickened, irregular growth
plates.93 Dogs and cats fed unbalanced meat-based
diets without vitamin D supplementation are more
likely to develop fibrous osteodystrophy, rather than
rickets, because of the development of nutritional
hyperparathyroidism.93 For an animal with dietary-
induced rickets, treatment entails transitioning the
animal to a complete and balanced diet.
Two autosomal recessive disorders that cause
VDDR in humans have been described. Type I
VDDR is caused by a defect in the gene encoding
1α-hydroxylase, which subsequently leads to inad-
equate activation of 25(OH)D to form 1,25(OH)2D.
This leads to 25(OH)D concentrations within the
reference range but low 1,25(OH)2D concentrations.
Alternatively, type II VDDR is caused by a defect in
the vitamin D receptor gene, which leads to hypo-
calcemia, secondary hyperparathyroidism, and high
1,25(OH)2D concentrations.93 A few cases of both
types of VDDR have been reported in dogs94,95 and
cats.96–99 Treatment of type I VDDR entails providing
supplemental 1,25(OH)2D and typically has a bet-
ter prognosis than does treatment of type II VDDR,
which requires high doses of both 1,25(OH)2D and
calcium.93,100
Cardiovascular disease
Vitamin D plays a role in the pathophysiologic
processes of cardiac disease. Cardiac myocytes ex-
press vitamin D receptor and a calcitriol-dependent
calcium-binding protein.47 In humans, hypovitamino-
sis D is associated with increased rates of myocardial
infarction and cardiovascular events.101 Studies101,102
have revealed an inverse relationship between vita-
min D status and hypertension in people; however,
a meta-analysis of 46 trials revealed that vitamin D
supplementation had no effect on lowering blood
pressure.102 Additionally, both FGF-23 and Klotho
have been linked to cardiovascular disease (eg, ath-
erosclerosis, vascular stiffening, and left ventricular
hypertrophy) in people with CKD.103–105
The association between vitamin D and cardiac
disease has been investigated in dogs. In 1 study47 that
involved evaluation of 31 dogs with congestive heart
failure, mean serum 25(OH)D concentrations were
approximately 20% less than those of healthy control
dogs. Another study59 revealed that serum 25(OH)D
concentrations were significantly lower in dogs with
stage B2, C, or D chronic valvular disease (American
College of Veterinary Internal Medicine criteria),
compared with concentrations in dogs with stage B1
chronic valvular disease (ie, no evidence of cardiac
remodeling). Serum 25(OH)D concentrations were
significantly correlated with left ventricular and atrial
sizes.59 Similar to results for other diseases, decreased
serum 25(OH)D concentrations may be linked to de-
creased dietary intake or increased inflammation. To
the authors’ knowledge, no veterinary studies have
been conducted to evaluate FGF-23 or Klotho values
in relation to cardiovascular disease.
Inflammatory conditions
Vitamin D has been associated with inflamma-
tion and the immune system because most leuko-
cytes express vitamin D receptor.106 Serum 25(OH)
D is a negative acute-phase protein and is typically
inversely related to inflammatory markers (eg, C-
reactive protein) in humans.66,107 Furthermore,
25(OH)D and 1,25(OH) 2D modulate inflammation
by inhibiting production of interleukin-6 and tu-
mor necrosis factor-α.108 In a recent study,48 inves-
tigators evaluated 25(OH)D and C-reactive protein
concentrations in racing sled dogs before and after
JAVMA • Vol 250 • No. 11 • June 1, 2017 1265
strenuous activity. Despite higher C-reactive protein
concentrations, the dogs had higher 25(OH)D con-
centrations after racing.48 Investigators of another
study36 found no correlation between 25(OH)D and
C-reactive protein concentrations in dogs with can-
cer.
Regarding leukocyte counts, serum 25(OH)D
concentrations are significantly negatively corre-
lated with neutrophil count, monocyte count, and
interleukin-2 and -8 concentrations in dogs with
chronic enteropathy.88 Concentrations of 25(OH)D
are significantly lower in hospitalized cats (with a
variety of illnesses) with neutrophilia, compared
with concentrations in hospitalized cats without
neutrophilia.62
Infectious diseases
Serum 25(OH)D concentrations have been in-
vestigated for some infectious diseases of dogs and
cats. Cats with both cutaneous and systemic myco-
bacteriosis had significantly lower 25(OH)D concen-
trations, compared with concentrations in healthy
cats.51 Cats infected with FIV had significantly lower
25(OH)D concentrations, compared with concen-
trations in healthy cats.53 Dogs with both neoplastic
and nonneoplastic spirocercosis had significantly
lower 25(OH)D concentrations than did healthy
dogs.46 Dogs with neoplastic spirocercosis had sig-
nificantly lower 25(OH)D concentrations than did
dogs with nonneoplastic spirocercosis.46
There are several reports in which granuloma-
tous disease induced hypercalcemia in dogs109–113 and
cats.114,115 The major mechanism originally believed to be
the cause of hypercalcemia was dysregulated production
of calcitriol (ie, increased production of 1,25[OH]2D)116;
however, there are granulomatous diseases in humans
and dogs in which hypercalcemia has been attributed to
PTH-related peptide and not to calcitriol.112
Other diseases and conditions
Several diseases and conditions that have been
linked to hypovitaminosis D in humans have not yet
been studied in dogs and cats. These include diabetes
mellitus,23,117,118 obesity,119,120 joint and nerve pain,121,122
gallbladder stasis,123,124 epilepsy,125 acute respiratory
distress syndrome,126 and dry eye syndrome.127
Mortality Rate and Death
Serum 25(OH)D concentrations have been linked
to in-hospital,128 30-day,129 and overall130–132 mortality
rates in people. Serum 25(OH)D status is predictive of
the 30-day mortality rate for hospitalized ill cats, with
those in the lower tertile at higher risk.61 Serum 25(OH)
D concentration at the time of diagnosis is a signifi-
cant predictor of mortality rate for dogs with chronic
enteropathy.60 It remains to be determined whether a
low 25(OH)D concentration specifically influences the
mortality rate or whether it is a consequence of more in-
flammation and a greater severity of underlying disease.
Vitamin D Supplementation
and Toxicosis
Numerous studies have identified decreased con-
centrations of vitamin D metabolites in dogs and cats
with various diseases; however, it has not yet been
determined whether these animals should receive
supplemental vitamin D or vitamin D metabolites and,
if so, the manner for providing them. Potential options
include vitamin D2 (ergocalciferol), vitamin D3 (chole-
calciferol), calcidiol, calcitriol, or other vitamin D re-
ceptor activators (eg, paricalcitol). A modified-release
formulation of 25(OH)Dh was approved by the FDA
in 2016 for treatment of humans with advanced stag-
es of CKD. It was recently reported that providing
supplemental 25(OH)D to dogs rapidly and efficiently
increases serum 25(OH)D concentrations.i Additional
studies are necessary to elucidate appropriate dosing
recommendations.
The goal of supplementation with vitamin D or
25(OH)D should be to increase serum 25(OH)D con-
centrations and improve outcomes specific to the
disease being managed (eg, reducing proteinuria or
improving the survival rate or duration). The form of
supplemental vitamin D administered, half-life of the
product, and potential for toxic effects may differ;
thus, caution must be exercised, and treated animals
must be monitored closely.
Vitamin D toxicosis is most commonly diag-
nosed after the development of hypercalcemia and
is a subsequent risk for acute kidney injury and soft
tissue mineralization. Development of hypercalce-
mia as a result of vitamin D toxicosis is a relatively
late finding. Several factors influence the potential
for vitamin D toxicosis, including lipophilicity, af-
finity of vitamin D metabolites for VDBP, and rates
of metabolite synthesis and degradation. The fact
it is fat soluble is a primary reason that vitamin D
has a long whole-body half-life of approximately 2
months. Half-lives for 25(OH)D and 1,25(OH) 2D
are approximately 2 to 3 weeks and 4 to 6 hours,
respectively.133,134
Vitamin D toxicosis in humans that results in
hypercalcemia is thought to occur when 25(OH)D
concentrations exceed 100 to 150 ng/mL. In vari-
ous animal species (rats, cows, pigs, rabbits, dogs,
and horses), plasma 25(OH)D concentrations asso-
ciated with hypercalcemia have exceeded 150 ng/
mL.133 The most commonly encountered forms of
vitamin D toxicosis in dogs and cats include inges-
tion of cholecalciferol rodenticides and calcitri-
ol- or calcitriol analogue–containing skin creams
(calcipotriol and calcipotriene).135 Occasionally,
misformulation of commercial pet foods may con-
tribute to vitamin D toxicosis.116,135,136 Recently, a
dog was described that had hypercalcemia and azo-
temia secondary to chronic ingestion of maxacal-
citol.137 Iatrogenic toxicosis, typically determined
by measurement of 1,25(OH) 2D concentrations,
may occur secondary to provision of supplemen-
1266 JAVMA • Vol 250 • No. 11 • June 1, 2017
tal calcitriol for management of renal secondary
hyperparathyroidism, primary hypoparathyroidism,
or protein-losing enteropathy or presurgical or post-
surgical treatment of primary hyperparathyroidism.
Hypercalciuria develops during early phases of
vitamin D toxicosis, before hypercalcemia develops.
Hypercalciuria can have negative impacts by increas-
ing the risk of developing calcium-containing uroliths
and renal injury. The urinary calcium-to-creatinine
ratio is used to detect hypercalciuria in humans.138
This concept has received attention in the investiga-
tion of dogs139 and catsj that form calcium-containing
uroliths.
Clinical Summary
Vitamin D homeostasis is characterized by com-
plex interactions between vitamin D metabolites,
ionized calcium, phosphorus, FGF-23, and Klotho,
and regulatory pathways can be disrupted in a vari-
ety of ways. Although reference limits for serum vi-
tamin D metabolites in healthy dogs and cats remain
to be determined, many diseases have been associ-
ated with lower concentrations of vitamin D metabo-
lites, whereas some have been associated with higher
concentrations. The chicken-and-egg conundrum
often applies to these diseases, and it is not defini-
tively clear whether vitamin D deficiency precedes
(causes) or is the result of these diseases. Additional
studies are needed to determine whether vitamin D
supplementation for dogs and cats with various dis-
eases would improve patient outcomes and, if so, the
form and dosing regimen that would best provide
that supplemental vitamin D.
Footnotes
a. Delaney SJ. Serum ionized calcium, 25-hydroxyvitamin D, and
parathyroid hormone in two dogs fed a homemade diet forti-
fied with D2 (abstr). J Anim Physiol Anim Nutr 2015;99:818.
b. Sprinke MC. Previously undescribed vitamin D epimer found
in cats using HPLC method (abstr), in Proceedings. Waltham
Int Nutr Sci Symp 2016;65.
c. Heartland Assays, Ames, Iowa.
d. Middleton R, Nestlé Purina PetCare Research, St Louis: Per-
sonal communication, 2016.
e. Parker VJ, Gilor C, Rudinsky AJ, et al. Association between vi-
tamin D metabolites and proteinuria (abstr), in Proceedings.
Am Coll Vet Intern Med Research Forum 2016;953.
f. Polzin DJ. Clinical benefit of calcitriol in canine chronic kid-
ney disease (abstr). J Vet Intern Med 2005;19:433.
g. Song J. Evaluation of parathyroid hormone and preop-
erative vitamin D as predictive factors for post-operative
hypocalcemia in dogs with primary hyperparathyroidism.
MS thesis, Department of Veterinary Clinical Sciences, Col-
lege of Veterinary Medicine, The Ohio State University, Co-
lumbus, Ohio, 2016.
h. Rayaldee, OPKO Health Inc, Miami, Fla.
i. Young L, Backus RL. Serum 25-hydroxyvitamin D3 and
24R,25-dihydroxyvitamin D3 concentrations in adult dogs
are more substantially increased by oral supplementation
of 25-hydroxyvitmain D3 than by vitamin D3 (abstr), in Pro-
ceedings. Waltham Int Nutr Sci Symp 2016;70–71.
j. Pimenta MM, Reche-Junior A, Freitas MF, et al.
Calcium:creatinine urinary ratio. A predictor of occurrence
of nephrolithiasis in cats? (abstr) J Feline Med Surg 2013;
15:825.
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