Associations of serum 25-hydroxyvitamin D with circulating PTH, phosphate and calcium in patients with primary hyperparathyroidism

O R I G I N A L A R T I C L E

Associations of serum 25-hydroxyvitamin D with circulating PTH,phosphate and calcium in patients with primaryhyperparathyroidism

Channa N. Jayasena*, Manish Modi*, Fausto Palazzo†, Akila De Silva*, Mandy Donaldson‡, Karim Meeran* and

Waljit S. Dhillo*

*Section of Investigative Medicine, Imperial College London, Hammersmith Hospital, †Department of Endocrine Surgery, Imperial

College London, Hammersmith Hospital and ‡Department of Clinical Chemistry, Imperial College Healthcare NHS Trust, Charing

Cross Hospital, London, UK

Abstract

Background Despite NIH clinical recommendations, many cli-

nicians are reluctant to replace vitamin D in patients with hyper-

calcaemia with primary hyperparathyroidism (PHP) due to

concerns over aggravating hypercalcaemia. Furthermore, the opti-

mum level of vitamin D replacement in PHP remains unclear.

Methods We performed a large retrospective study to deter-

mine whether a relationship exists between serum 25-hydroxyvi-

tamin D levels, calcium and other important biochemical

markers in patients with PHP. Serum, plasma and urinary bio-

chemical measurements were collected from 251 patients with

hypercalcaemia diagnosed with PHP.

Results When examining overall mean circulating levels during

clinical follow-up, serum 25-hydroxyvitamin D correlated highly

significantly with plasma parathyroid hormone (PTH)

(r = �0�23, P = 0�0003) and serum phosphate (r = 0�16,P = 0�0119). No significant relationship was observed between

serum calcium and 25-hydroxyvitamin D (r = 0�002, P = 0�98).Mean plasma PTH during clinical follow-up was 51% lower in

patients with serum 25-hydroxyvitamin D > 60 nM when com-

pared with patients who had 25-hydroxyvitamin D < 20 nM

(P < 0�01).Conclusions Patients with PHP who have 25-hydroxyvitamin

D levels > 60 nM have significantly reduced PTH hypersecretion

when compared with patients with deficient vitamin D levels,

without exhibiting worse hypercalcaemia.

(Received 23 April 2012; returned for revision 14 May 2012; finally

revised 26 September 2012; accepted 26 September 2012)

Introduction

Primary hyperparathyroidism (PHP) is the most common cause

of hypercalcaemia in asymptomatic patients, affecting 0�3% of

the population.1 It arises from neoplastic (generally benign) or

hyperplastic growth of one or more parathyroid glands. Autono-

mous elevation of circulating parathyroid hormone (PTH)

increases serum levels of calcium and may cause end-organ

damage such as osteoporosis and nephrolithiasis.

Vitamin D is a regulatory hormone that promotes bone

mineralization and gut calcium absorption. Vitamin D defi-

ciency is common in Northern Europe and the USA2 and has

a higher prevalence in patients with PHP when compared with

healthy controls,3 thought to be due to increased vitamin D

metabolism.4 Previous studies suggest that vitamin D defi-

ciency is associated with worsened PTH hypersecretion and

increased parathyroid adenoma mass, in addition to greater

end-organ damage such as nephrolithiasis, cortical bone thin-

ning5 and increased risk of fractures.6–8 Low preoperative levels

of vitamin D also increase the risk of developing hypocalca-

emia due to hungry bone syndrome in the postoperative

period.9,10

NIH clinical guidelines recommend that vitamin D replace-

ment therapy should be given to asymptomatic patients with

hypercalcaemia with vitamin D deficiency.11 However, amongst

clinicians, there is apprehension in implementing this practice

due to concerns over the safety of vitamin D replacement in

patients with PHP. Early case reports suggested that vitamin D

replacement aggravates the hypercalcaemia of PHP,12,13

although a number of small subsequent studies have failed to

validate these findings14–16 and further demonstrated that vita-

min D replacement ameliorates markers of bone turnover.6,15,17

Furthermore, the optimum level of vitamin D replacement in

PHP remains unclear. Therefore, many clinicians remain reluc-

tant to replace vitamin D in patients with hypercalcaemia due

to concerns over aggravating hypercalcaemia and uncertainty

over the extent to which vitamin D deficiency should be

treated.

Correspondence: Prof. Waljit S. Dhillo, Section of Investigative Medicine,Imperial College London, 6th Floor, Commonwealth Building, Hammer-smith Hospital, Du Cane Road, London W12 ONN, UK.Tel.: +44 208 383 2820; Fax: +44 208 383 3142;E-mail: [email protected]

838 © 2012 John Wiley & Sons Ltd

Clinical Endocrinology (2013) 78, 838–843 doi: 10.1111/cen.12062

We performed a large retrospective study to examine the rela-

tionship between serum vitamin D levels, calcium and other

important biochemical markers in patients with PHP.

Methods

Subjects

Serum, plasma and 24-h urine biochemical measurements from

251 patients with hypercalcaemia diagnosed with PHP present-

ing to a single specialist endocrine unit were analysed retrospec-

tively. Patients were further divided into four groups according

to vitamin D status: 86 patients with serum 25-hydroxyvitamin

D < 20 nM; 97 patients with serum 25-hydroxyvitamin D

20–40 nM; 39 patients with serum 25-hydroxyvitamin D 40–

60 nM; 29 patients with serum 25-hydroxyvitamin D > 60 nM.

One hundred and forty-four patients had a parathyroidectomy

with histological features of PHP and normocalcaemia postsur-

gery. The remaining 107 patients had an elevated serum PTH,

hypophosphatemia, and ultrasound or 99mtechnetium-sestamibi

localization of a parathyroid adenoma. The mean age was

60 years (range 14–94 years). Fifty-nine patients were male.

Only patients presenting with hypercalcaemia, defined as an

albumin-adjusted serum calcium concentration greater than

2�6 mM, were included in the study. Patients on lithium or thia-

zide medication, or with an estimated glomerular filtration rate

below 30 ml/min/1�73 m2, were excluded. Patient data were col-

lected in anonymized fashion, covered by the UK National

Research Ethics Service category of service evaluation.

Biochemical measurements

Hypercalcaemia was defined as albumin-adjusted serum calcium

above 2�6 mM. The range of serum albumin observed in patients

with PHP was 25–48 g/l. Serum 25-hydroxyvitamin D was mea-

sured between 2000–2006 using Advantage Automated Immuno-

assay (Nichols Institute Diagnostics, San Clemente, CA, USA),

between 2006–2007 using an extraction radioimmunoassay

(Immunodiagnostics Systems Ltd, Boldon, UK), between 2007–

2009 using Diasorin Liaison Automated Immunoassay (Diasorin

S.p.A, Crescentino, Italy) and from 2009 onwards using in-house

liquid chromatography tandem mass spectrometry. Plasma PTH

was measured between 2000–2006 using Advantage Automated

Immunoassay (Nichols Institute Diagnostics), between 2006–

2009 using Siemens Immulite immunoassay (Siemens Healthcare

Diagnostics, Deerfield, IL, USA) and from 2009 onwards using

Abbott Architect Automated Immunoassay (Abbott Laboratories,

North Chicago, IL, USA).

Data analysis

Data are presented as mean ± standard error of mean (SEM).

Statistical significance was defined by a P value < 0�05. Prism

5�0 software (GraphPad Inc., La Jolla, CA, USA) was used to

calculate Pearson’s correlation coefficient, to compare mean val-

ues of serum calcium, serum phosphate, plasma PTH and total

24-h urine calcium using one-way ANOVA with post hoc Tukey’s

tests. Pairs of means were compared using unpaired two-tailed

t-test.

Results

Relationships between initial serum 25-hydroxyvitamin

D with initial circulating PTH, phosphate and calcium

We initially examined the first recorded set of measurements of

circulating 25-hydroxyvitamin D, PTH, phosphate and calcium

in each patient with PHP.

There was a significant negative correlation between serum

25-hydroxyvitamin D and plasma PTH concentrations

(r = �0�20, P = 0�0019) (Fig. 1a). To further examine the rela-

tionship between 25-hydroxyvitamin D and PTH, patients were

subdivided into four groups according to vitamin D status

(Fig. 1b). Patients with serum 25-hydroxyvitamin D < 20 nM

had the highest levels of plasma PTH, and these levels were sig-

nificantly higher when compared with patients with serum

25-hydroxyvitamin D > 60 nM (plasma PTH in pM: 20�2 ± 1�3,25-hydroxyvitamin D < 20 nM; 12�6 ± 1�4, 25-hydroxyvitamin

D > 60 nM; P < 0�05 vs 25-hydroxyvitamin D < 20 nM).

There was no significant correlation between 25-hydroxyvita-

min D levels and serum phosphate (r = 0�02, P = 0�81)(Fig. 1c). Levels of serum phosphate were not significantly dif-

ferent between patients with serum 25-hydroxyvitamin D < 20,

20–40, 40–60 and >60 nM (Fig. 1d). No significant correlation

was observed between plasma PTH and serum phosphate levels

(r = �0�026, P = 0�69, data not shown). No significant relation-

ship was observed between serum calcium and serum

25-hydroxyvitamin D (r = 0�002, P = 0�98) (Fig. 1e). There wereno significant differences in serum calcium concentrations when


(Fig. 1f).

Relationships between mean serum 25-hydroxyvitamin

D with mean circulating PTH, phosphate and calcium

To further examine the relationships between 25-hydroxyvita-

min D, PTH, phosphate and calcium, we calculated a mean cir-

culating level for each biochemical factor during the entire

pretreatment period of each patient with PHP.

There was a highly significant negative correlation between

serum 25-hydroxyvitamin D and plasma PTH concentrations

(r = �0�23, P = 0�0003) (Fig. 2a). Patients were subsequently


(Fig. 2b); mean levels of plasma PTH were significantly higher

in patients with mean serum levels of 25-hydroxyvitamin

D < 20 nM when compared with patients with mean serum lev-

els of 25-hydroxyvitamin D > 60 nM (plasma PTH in pM:

24�7 ± 4�2, 25-hydroxyvitamin D < 20 nM; 12�2 ± 0�9, 25-

hydroxyvitamin D > 60 nM; P < 0�01 vs 25-hydroxyvitamin

D < 20 nM).

There was a significant positive correlation between 25-

hydroxyvitamin D levels and serum phosphate (r = 0�16,

© 2012 John Wiley & Sons Ltd

Clinical Endocrinology (2013), 78, 838–843

Primary hyperparathyroidism and vitamin D deficiency 839

P = 0�0119) (Fig. 2c). Mean levels of serum phosphate were sig-

nificantly higher in patients with mean levels of 25-hydroxyvita-

min D > 60 nM when compared with patients with mean serum

levels of 25-hydroxyvitamin D < 20 nM (serum phosphate in

mM: 0�83 ± 0�024, 25-hydroxyvitamin D < 20 nM; 0�91 ± 0�025,25-hydroxyvitamin D > 60 nM; P < 0�05 vs 25-hydroxyvitamin

D < 20 nM) (Fig. 2d). There was a highly significant negative

correlation between plasma PTH and serum phosphate levels

(r = �0�33, P < 0�0001) (Fig. S1). No significant relationship

was observed between mean serum calcium and mean

25-hydroxyvitamin D (r = �0�11, P = 0�11) (Fig. 2e). There

were no significant differences in mean serum calcium concen-

trations when subdivided into four groups according to vitamin

D status (Fig. 2f).

Relationship between serum 25-hydroxyvitamin D and

urine calcium excretion

We finally compared the first recorded set of measurement of

circulating 25-hydroxyvitamin D with 24-h total urine calcium

in each patient with PHP. There was a nonsignificant positive

correlation between 24-h total urine calcium levels and serum

25-hydroxyvitamin D (r = 0�14, P = 0�0533) (Fig. 3a). Results

were then classified into four groups according to vitamin D sta-

tus. Patients with serum 25-hydroxyvitamin D levels <20 nM did

not have significantly lower 24-h total urine calcium levels when

compared with patients with serum 25-hydroxyvitamin D levels

of 20–40, 40–60 or >60 nM (Fig. 3b). However, patients with

serum 25-hydroxyvitamin D levels <20 nM had significantly

lower 24-h total urine calcium levels when compared with all

other patients, that is, those with serum 25-hydroxyvitamin D

levels >20 nM (mean 24-h total urine calcium in mmol/24 h:

6�49 ± 0�64 when serum 25(OH) vitamin D <20 nM; 7�80 ± 0�36when serum 25(OH) Vitamin D > 20 nM; P = 0�0116).

Discussion

Current guidelines recommend vitamin D replacement in all

asymptomatic patients with vitamin D deficiency11; however,

many clinicians remain concerned about the risk of aggravating

hypercalcaemia and are uncertain to what extent vitamin D defi-

ciency should be treated. Early case reports suggested that vita-

min D replacement aggravates the hypercalcaemia of PHP,12,13

but a number of small studies have recently suggested that

0 50 100 1500

20

40

60

80

100

Serum 25(OH) Vitamin D (nM)

Plas

ma

PTH

(pM

)

0 50 100 1500·4

0·8

1·2

1·6


Seru

m P

hosp

hate

(mM

)

0 50 100 1502·0

2·5

3·0

3·5

4·0


Seru

m C

alci

um (m

M)

<20 20–40 40–60 >600

5

10

15

20

25**

*


Plas

ma

PTH

(pM

)

<20 20–40 40–60 >600·0

0·2

0·4

0·6

0·8

1·0


Seru

m P

hosp

hate

(mM

)

<20 20–40 40–60 >600

1

2

3


Seru

m C

alci

um (m

M)

r = –0·20, P = 0·0019 r = 0·02, P = 0·81 r = 0·002, P = 0·98(a) (c) (e)

(b) (d) (f)

Fig. 1 Relationships between the first recorded set of measurements of circulating 25-OH vitamin D, parathyroid hormone (PTH), phosphate and

calcium in each patient with primary hyperparathyroidism. There was a significant negative correlation between serum 25-OH vitamin D levels and

plasma PTH levels (a), no significant correlation between serum 25-OH vitamin D levels and serum phosphate levels (c) and no significant correlation

between serum 25-OH vitamin D levels and serum calcium levels (e). Subdivision of 25-OH vitamin D levels into four groups further revealed a

negative association with plasma PTH levels (b) and no association with serum phosphate levels (d) or calcium levels (f). *P < 0�05, **P < 0�01.



840 C. N. Jayasena et al.

0 50 100 1500

20

40

60

80

100


Plas

ma

PTH

(pM

)

0 50 100 150

0·5

1·0

1·5


Seru

m P

hosp

hate

(mM

)

0 50 100 1502·0

2·5

3·0

3·5

4·0


Seru

m C

alci

um (m

M)

<20 20–40 40–60 >600

10

20

30**

**


Plas

ma

PTH

(pM

)

<20 20–40 40–60 >600·0

0·2

0·4

0·6

0·8

1·0*


Seru

m P

hosp

hate

(mM

)

<20 20–40 40–60 >600

1

2

3


Seru

m C

alci

um (m

M)

r = –0·23, P = 0·0003 r = 0·16, P = 0·0119 r = –0·11, P = 0·11(a) (c) (e)

(b) (d) (f)

Fig. 2 Relationships between the mean circulating levels of circulating 25-OH vitamin D, parathyroid hormone (PTH), phosphate and calcium during

the entire pretreatment period in each patient with primary hyperparathyroidism. There was a significant negative correlation between serum 25-OH

vitamin D levels and plasma PTH levels (a), a significant positive correlation between serum 25-OH vitamin D levels and serum phosphate levels (c),

but no significant correlation between serum 25-OH vitamin D levels and serum calcium levels. (e). Subdivision of 25-OH vitamin D levels into four

groups further revealed a negative association with plasma PTH levels (b), a positive association with serum phosphate levels (d), but no association

with serum calcium levels (f). *P < 0�05, **P < 0�01.

r = 0·14, P = 0·0533 (a) (b)

Fig. 3 Relationships between measurements of circulating 25-OH vitamin D and total urinary calcium excretion in each patient with primary

hyperparathyroidism (PHP). In patients with PHP, there was a nonsignificant positive correlation between serum 25-OH vitamin D levels and 24-h

total urine calcium levels (a). 24-h total urine calcium levels are presented for patients with serum 25-OH vitamin D levels <20, 20–40, 40–60 >60 and

>20 nM (b). Data represent the first recorded set of measurement of circulating 25-hydroxyvitamin D with 24-h total urine calcium in each patient

with PHP. *P < 0�05.




vitamin D replacement does not worsen hypercalcaemia14–16 and

ameliorates markers of bone turnover.6,15,17 Furthermore, the

optimum level of vitamin D replacement in PHP remains unde-

fined in the literature. We have performed the largest retrospec-

tive study of patients with PHP, to determine whether

significant relationships exist between serum vitamin D levels,

calcium and other important biochemical markers in patients

with PHP. Although our observational study does not address

the safety of vitamin D replacement, it suggests that in agree-

ment with current guidelines,11 vitamin D status is not related

to increasing mean serum levels of calcium in patients with

PHP. Furthermore, in patients with PHP, vitamin D status is

associated with increased urinary calcium excretion, increased

serum phosphate levels and reduced PTH secretion.

Parathyroid hormone hypersecretion leads to bone demineral-

ization and osteoporosis. Furthermore, vitamin D deficiency is

known to stimulate secondary hyperparathyroidism. However, a

recent review18 noted that only two of five studies found a sta-

tistically significant reduction in the level of PTH secretion with

vitamin D replacement in PHP.6,14–17 We observed a highly

significant inverse correlation between 25-hydroxyvitamin D and

PTH secretion. In patients with PHP, serum 25-hydroxyvitamin

D levels <20 nM were associated with approximately double

plasma PTH levels when compared with serum 25-hydroxyvita-

min D levels >60 nM; furthermore, even modest serum

25-hydroxyvitamin D levels of 20–40 nM were associated with

significantly reduced PTH hypersecretion compared with serum

25-hydroxyvitamin D levels <20 nM. Our data therefore suggest

that even modest levels of 25-hydroxyvitamin D (above 20 nM)

are sufficient to reduce the PTH hypersecretion. Further studies

are required to determine conclusively whether vitamin D

replacement reduces PTH hypersecretion and associated end-

organ damage such as osteoporosis and nephrocalcinosis.

Hypophosphatemia may cause weakness, altered mental status

and abnormal bone mineralization, resulting in severe bone pain

and fractures.19 Our data suggest that in patients with PHP,

serum 25-hydroxyvitamin D levels >60 nM were associated with

approximately 10% higher serum phosphate levels when com-

pared with serum 25-hydroxyvitamin D levels <20 nM. Coexistent

vitamin D deficiency may therefore aggravate the hypophosphat-

emia associated with PHP, possibly through increased PTH

hypersecretion. It would be interesting to confirm prospectively

whether vitamin D replacement alleviates hypophosphataemia,

and its associated symptoms and end-organ damage.

Twenty-four-hour total urine calcium was approximately 10%

higher in PHP patients without vitamin D deficiency when com-

pared with patients with vitamin D deficiency. The increased

urine calcium excretion observed with higher vitamin D levels

may be a consequence of reduced PTH hypersecretion.15 It is

therefore possible that higher 25-hydroxyvitamin D levels are

not associated with worsened hypercalcaemia in patients with

PHP because of increased urinary calcium excretion.

Four recent prospective studies suggest that vitamin D

replacement in deficient patients with PHP is safe from the

viewpoint of not worsening hypercalcaemia.14–17 Both Tucci

et al. and Grubbs et al. followed up patients for only 4–8 weeks

during vitamin D replacement; it is therefore possible that

adverse effects of vitamin D replacement might have occurred

after this follow-up period. Isidro & Ruano and Grey et al. used

vitamin D replacement to increase serum levels to sufficient lev-

els (72 and 77 nM respectively) during a 12-month follow-up

period; however, the collective number of patients in these stud-

ies was relatively small (48 patients). Furthermore, none of these

studies examined the relationship between serum 25-OH vitamin

D and hypophosphataemia. Our study adds to these previous

studies, by investigating in a large cohort of patients with PHP,

levels of circulating calcium, PTH and phosphate within specific

categories of vitamin D status. It is important to recognize that

this was an observational retrospective study, so we are unable

to conclude whether or not the observed correlations are attrib-

utable primarily to vitamin D status. Twenty-four-hour urine

collections were not available for all corresponding biochemical

measurements, particularly if patients were infirm or elderly.

Furthermore, multiple assays for plasma PTH and serum

25-hydroxyvitamin D were used between 2000 and 2011.

To comprehensively analyse our circulating vitamin D and

PTH and phosphate data, we examined both the first set of

measurements and the calculated mean measurements during

clinical follow-up in all patients with PHP. Stronger correla-

tions between circulating vitamin D and PTH and phosphate

were observed when comparing calculated mean measurements

yielded rather than the first set of measurements. However,

the lack of correlation between serum 25-hydroxyvitamin D

levels and serum calcium, along with the strong negative cor-

relation between serum 25-hydroxyvitamin D levels and

plasma PTH levels, was preserved regardless of the method of

analysis.

In summary, this study suggests that serum 25-hydroxyvita-

min D levels >20 nM are sufficient to reduce parathyroid hor-

mone hypersecretion and hypophosphataemia significantly in

patients with primary hyperparathyroidism; furthermore,

25-hydroxyvitamin D levels >60 nM are associated with maximal

improvement in these biochemical abnormalities. Significantly,

vitamin D status was not associated with mean serum calcium

levels in patients with primary hyperparathyroidism. Our study

therefore suggests that although modest increases in vitamin D

status may be beneficial and safe in asymptomatic patients with

primary hyperparathyroidism, achieving serum 25-hydroxyvita-

min D levels >60 nM is optimal.

Conflict of interests

Nothing to declare.

Funding

NIHR Clinical Lectureship (C.N.J); AMS/Wellcome Starter

Grant (C.N.J); SFE Early Career Grant (C.N.J); Society for Endo-

crinology Summer Studentship (M.M.); Wellcome/GSK Fellow-

ship (A.D.S); NIHR Career Development Fellowship (W.S.D).

This work was supported by the NIHR Imperial Biomedical

Research Centre Funding Scheme.



842 C. N. Jayasena et al.

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Supporting Information

Additional Supporting Information may be found in the online

version of this article:

Fig S1. In patients with PHP, there was a significant negative

correlation between plasma PTH and serum phosphate levels

(r = �0�33, P < 0�0001). Data represent the mean circulating

levels of PTH and phosphate during the entire pre-treatment

period in each patient with PHP.




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Associations of serum 25-hydroxyvitamin D with circulating PTH, phosphate and calcium in patients with primary hyperparathyroidism