ORIGINAL ARTICLE JBMR

Concurrent Hypoparathyroidism Is Associated

With Impaired Physical Function and Quality of
Life in Hypothyroidism
Tanja Sikjaer,1 Emil Moser,1 Lars Rolighed,2 Line Underbjerg,1 Lise Sofie Bislev,1 Leif Mosekilde,1
and Lars Rejnmark1
1
Department of Internal Medicine and Endocrinology, Aarhus University Hospital, Aarhus, Denmar
2
Department of Surgery P, Aarhus University Hospital, Aarhus, Denmark

ABSTRACT
Total thyroidectomy causes postsurgical hypothyroidism (HypoT). Besides HypoT, as a complication patients may also develop
hypoparathyroidism (HypoPT). The aim of this study was to assess quality of life (QoL), muscle function, and postural stability in
patients with postsurgical hypothyroidism and hypoparathyroidism (HypoTþPT) as compared to patients with postsurgical HypoT
and healthy controls. Age- and gender-matched patients on treatment for HypoTþPT and HypoT were recruited from our outpatient
clinic. Matched healthy controls were recruited from the general background population. Compared with controls, HypoT was
associated with a significantly lower mental summary score, whereas patients with HypoTþPT had a significantly lower physical
summary score (Short Form 36 Health Survey questionnaire version 2). Moreover, the physical component score was significantly
lower in patients with HypoTþPT compared with HypoT. WHO-5 well-being index was significantly lower in both groups of patients
compared with controls, but did not differ between groups of patients. Compared with controls, muscle strength and maximal force
production was significantly reduced in HypoTþPT, but not in HypoT. In HypoTþPT, the time spent on the Timed Up & Go test and
the Repeated Chair Stands test were significantly longer than in the HypoT group and the control group. Postsurgical HypoTþPT is
associated with a more severe impairment of QoL, in particular regarding physical functioning, than HypoT. HypoTþPT patients are
also hampered by impaired muscle function. Studies on how to improve well-being and muscle function in HypoTþPT patients
are warranted. © 2016 American Society for Bone and Mineral Research.

KEY WORDS: HYPOPARATHYROIDISM; HYPOTHYROIDISM; QUALITY OF LIFE; MUSCLE FUNCTION; POSTURAL STABILITY

Introduction to LT4 therapy, and this seems to be independent of thyroid-

stimulating hormone (TSH), free T4, and free T3 levels.(2–4)

H ypoparathyroidism (HypoPT) is a disease with inadequate

production of parathyroid hormone (PTH) from the parathy-
roid glands leading to hypocalcemia. We have previously shown a
Patients with previous thyroid cancer are often treated with
suppressive LT4 therapy, leaving the patients with subclinical
hyperthyroidism, which has been shown to be associated with
reduced muscle strength and postural stability in patients with a reduced QoL as well as reduced muscle strength in the
HypoPT compared to healthy controls and a reduced quality of life upper extremities.(5)
(QoL) in HypoPT compared to norm-based values on the Short In previous studies, patients with postsurgical HypoPT have
Form questionnaire 36 version 2 (SF36v2) and WHO-5 well-being been shown to have a reduced QoL.(1,6,7) Because most patients
index.(1) One of the issues that arises when comparing HypoPT with postsurgical HypoPT also are suffering from postsurgical
patients with healthy controls is that the patients with postsurgical HypoT, it has been questioned whether the impaired QoL is
HypoPT often have a concurrent thyroid disease such mainly due to disturbances in calcium homeostasis or thyroid
as hypothyroidism (HypoT). Most of the patients have developed function or is attributable to both states of insufficiency in
HypoPT as a complication to total thyroidectomy due to thyroid endogenous synthesis of parathyroid and thyroid hormones.
cancer, atoxic goiter, or toxic goiter. Accordingly, patients with Only one other study has dealt with this problem. Arlt and
postsurgical HypoPT are often also suffering from postsurgical colleagues(6) investigated 50 patients who had undergone
hypothyroidism (HypoTþPT) and are most commonly on subtotal thyroidectomy due to goiter, of which 25 developed
substitution therapy with levothyroxine (LT4) to stay euthyroid. postoperative HypoPT; the remaining 25 patients continued to
In previous studies, patients with postsurgical HypoT have have intact parathyroid function. Twenty of the 25 patients with
been shown to have a reduced QoL despite being euthyroid due postoperative HypoPT, 22 of the 25 patients without HypoPT

Received in original form August 29, 2015; revised form January 15, 2016; accepted February 1, 2016. Accepted manuscript online February 10, 2016.
Address correspondence to: Tanja Sikjaer, MD, PhD, Osteoporosis Clinic, Department of Internal Medicine and Endocrinology (MEA), Aarhus University Hospital,
Tage-Hansensgade 2, 8000 Aarhus, Denmark. E-mail: Tanja.sikjaer@gmail.com
Journal of Bone and Mineral Research, Vol. 31, No. 7, July 2016, pp 1440–1448
DOI: 10.1002/jbmr.2812
© 2016 American Society for Bone and Mineral Research

1440
were on thyroxine replacement therapy, and all of the included within 2 years, and participants hospitalized due to chronic
patients were euthyroid. The patients with HypoPT had higher alcohol or drug abuse. Other exclusion criteria comprised
scores in somatization, depression, anxiety, hostility, phobic sarcoidosis, any previous malignancy (except thyroid cancer),
anxiety, and psychotic tendencies. radiation affecting the skeleton, pregnancy, and untreated
There have to our knowledge not been any previous malabsorption. Finally we excluded participants treated with
investigations on differences in muscle function and postural lithium, amiodarone, and systemic corticosteroids. Moreover,
stability between LT4-treated euthyroid HypoT patients with or controls with a prior history of thyroid disease or a plasma TSH
without HypoPT. outside the reference range were excluded. All participants
In the present study, we aimed to investigate whether the provided written informed consent.
previous shown reduced muscle function, postural stability and We performed the study in accordance with the Declaration
QoL in HypoTþPT is due to lack of endogenous PTH production of Helsinki II and the guidance on Good Clinical Practice (GCP).
or the concomitant lack of endogenous synthesis of thyroid The Danish Data Protection agency was notified about the study.
hormones despite being considered euthyroid due to therapy The Ethical Committee of Central Denmark (no. M-20080040
with LT4. and M-20110260) approved the study.

Biochemistry
Patients and Methods
We measured plasma levels of TSH, creatinine, ionized calcium,
Study subjects albumin, phosphate, magnesium, and creatinine-kinase by stan-
Using a cross-sectional study design, we included 66 subjects dard laboratory methods. eGFR was calculated by the following
divided into three subgroups. Group 1 (HypoTþPT): 22 patients isotope dilution mass spectrometry (IDMS)-traceable Modification
with chronic postsurgical HypoPT and well-substituted hypo- of Diet in Renal Disease (MDRD) Study equation: 175  (standard-
thyroidism; Group 2 (HypoT): 22 patients with postsurgical ized creatinine mmol/L/88.4)–1.154  (age/years)–0.203  (0.742 if the
well-substituted hypothyroidism without HypoPT; and Group 3 patient is a woman).(9)
(controls): 22 healthy controls without abnormalities in their In order to avoid effects of muscle function tests on plasma
thyroid or parathyroid function. The three groups were matched levels of measured indices, we took care that blood samples
on gender and age at time of testing (2 years), and the first two were collected prior to testing muscle function.
groups were also matched on time of thyroid surgery (2 years). To reduce analytical variation, plasma levels of PTH and
Following baseline measurements, the 22 patients with 25-hydroxyvitamin D (25OHD) were analyzed in a single batch.
HypoTþPT were included in a randomized controlled trial on Serum samples were stored at –80°C until analysis. Detailed
replacement therapy with PTH(1-84). The inclusion and exclu- descriptions of the assays used for measuring these indices have
sion criteria for the clinical trial have been described in detail.(8) been reported.(8)
In the present analyses, only baseline measures are used; Creatine kinase (CK) was measured using a NADPH generated
ie, measurement preformed prior to PTH(1-84) therapy. We catalytic reaction on an automated instrument (Cobas 6000;
defined HypoPT as inappropriate low-plasma PTH level in the Roche Diagnostics, GmbH, Mannheim, Germany). The CV% was
setting of hypocalcemia, necessitating continuous treatment 1.25% at 137.57 U/L and 0.99% at 447.02 U/L.
with an active vitamin D analogue (alphacalcidol or calcitriol) or
high doses of ergocalciferol (D2) for at least 12 months. At Muscle strength
inclusion, the participants were required to have stable plasma We used a strain-gauge system in terms of an adjustable
ionized calcium (Ca2þ) levels within or slightly below the lower dynamometer chair connected to a computer (Good Strength;
limit of the reference ranges and there were no recent histories Metitur Ltd., Jyv€askyl€a, Finland).(10,11) We measured the maximal
of hypocalcemia or hypercalcemia. voluntary isometric strength at the upper and lower extremities
The patients with euthyroid hypothyroidism (HypoT) without on the side of the dominant hand. At the upper extremities we
concomitant HypoPT were identified by hospital discharges measured hand grip strength and strength during elbow
codes and recruited from our outpatient clinic. They had extension and flexion with the upper and lower arm at a
undergone thyroid surgery (total/partial thyroidectomy) at neutral position at a 90-degree angle. At the lower extremities,
Aarhus University Hospital, Denmark. knee extension and flexion strengths were measured with the
The HypoT patients were included if they matched the knee positioned at a 60-degree angle and a 90-degree angle
HypoPT patients on age, gender, and time of surgery, and they from the fully extended leg. The extremities were fastened by
were only included if they had received continuous LT4 belts to the strain-gauge system during testing and the trunk
treatment for at least 2 years prior to the inclusion. To identify was fastened with three belts to avoid transferring of strength
controls we used the Danish Civil Registration System, which from other sites to the muscles investigated. All tests were
generated a list providing us with name and address of 100 repeated three times with a rest of 30 s between the tests. The
persons of mixed gender for each birth year between 1932 and best test result was used for analysis. At all seven sites tested,
1982, giving a total of 5000 individuals. These individuals were we measured maximal voluntary force (MF; N) and maximal
selected randomly from the population in and around the city of force production (MFP; N/s).
Aarhus, Denmark. When a HypoTþPT patient and a HypoT were
included, 5 to 10 gender- and age (2 years)-matched controls
Tests of muscle function
were invited by letter to participate on a random basis. Controls
meet the same inclusion and exclusion criteria as patients. We The “repeated chair stands” (RCS) test is the time for 10
excluded participants with severely impaired renal function consecutive chair rises without the use of hands.(12) The best test
(estimated glomerular filtration rate [eGFR] <30 mL/min or out of two was chosen and used for analysis; measured results
plasma creatinine >200 mmol/L), a history of malignant disease are given in seconds.

Journal of Bone and Mineral Research HYPOTþPT ASSOCIATED WITH IMPAIRED PHYSICAL FUNCTION AND QOL IN HYPOT 1441
 In the “Timed Up & Go” (TUG) test,(13) the patient was placed in QoL
a chair with arms crossed in front of the chest. The patient stands
We measured QoL using the Short Form questionnaire 36
up and walks as fast as possible without running 3 m in a straight
version 2 (SF-36v2) and the WHO-Five Well-Being Index survey
line, turns around, and returns to the chair. The best test out
(WHO-5).(19) The SF-36v2 questionnaire consists of 36 questions
of two was recorded. The retest reliability has been measured
that are grouped into eight subscales describing physical
in several studies(13–15) and reported as intraclass correlation
functioning, role-physical, bodily pain, general health, vitality,
coefficient (ICC) ¼ 0.97 to 0.99 and Spearman’s rho ¼ 0.93.
social functioning, role-emotional, and mental health. In
Postural stability addition, a mental component summary score and physical
component summary score was calculated. Both subscales and
We assessed postural stability by measuring body sway using summary scores are expressed in a term called norm-based
a stadiometer (Good Balance Platform System; Metitur Ltd., values, which is a value within the range of 0 to 100; the higher
Jyv€askyl€a, Finland). The stadiometer converts shifts in weight the score, the better.
to digital data to obtain quantitative assessments of mainte- The WHO-5(20) consists of five questions that capture the
nance of balance. The components of the system include an emotional well-being of patients. The answers to the five
equilateral triangular force platform and a computer. The questions of the WHO-5 are scored from 0 (being worst) to
platform records length and speed of sway both mediolaterally 5 (best) and expressed as a percentages of the maximum score.
and anteroposteriorly over a specific duration of time (in our A score of 50% or less suggests poor emotional well-being and a
study 20 s). We measured postural stability under the following score of 28% or below indicates a depression.(20)
four different conditions.
Statistical analysis
1. Normal standing with eyes opens (EO). The patient was
placed with his feet next to each other 20 cm apart and arms We assessed differences between study groups using Fisher’s
in a relaxed position hanging freely at each side and gaze exact test for categorical variables. For continuous variables,
fixed on a marked spot in eye level. between-group differences were tested using a one-way
2. Same position as above, but with eyes closed (EC). analysis of variance (ANOVA). Non-normally distributed data
3. Semi-tandem position with EO. The heel of the nondomi- were either logarithmic transformed or analyzed by Kruskal-
nant hand’s corresponding foot is placed alongside the big Wallis H test, as appropriate. Using a general linear model, we
toe of the dominant hand’s foot. adjusted for between-group differences. Post hoc, groups were
4. Tandem position with EO. The feet are placed in front of each compared using a two-sample t test or Mann-Whitney U test, as
other on a line with the nondominant hand’s foot in the front. appropriate. We report results as mean  SD or median with
interquartile (25% to 75%) range (IQR) unless otherwise stated.
The data are expressed in terms of velocity moment A value of p < 0.05 was considered statistically significant. We
(VM, mm2/s), which is calculated as 90% of the product of the used IBM SPSS Statistics version19 (IBM Corp., Armonk, NY, USA)
actual distance of movement in the mediolateral (ML) and the for the statistical analyses.
anteroposterior (AP) direction from the center of pressure per
second. Accordingly, the velocity moment is a measure of mean
area of movement per second, which reflects postural sway.(16) Results
Ceria-Ulep and colleagues(16) retested normal standing (EO) in
203 patients and found a reliability coefficient (Pearson’s Characteristics of included patients are shown in Table 1. Groups
product-moment coefficient) for VM of 0.37 (p < 0.0001). The were well matched on age and gender. Although BMI did not
effect of body height and vertical location of the center of body differ across groups (p ¼ 0.12), patients with HypoTþPT had a
mass was adjusted by the formula scaled velocity moment higher BMI when compared to the healthy controls (27.7 [IQR,
(SVM) ¼ (VM/(height in cm)2)  1802 (Era and colleagues(17)). 25.1 to 32.6] versus 25.2 [IQR, 22.8 to 28.4] kg/m2, p < 0.05). Nor
Each of the four tests was performed three times. For analyses, was FMI significantly different between groups (p ¼ 0.09), but
we used the best test result; ie, the lowest SVM value indicating showed a higher FMI in the HypoTþPT group compared to the
the best postural stability. controls (9.4 [IQR, 7.5 to 13.8] versus 8.2 [IQR, 5.4 to 10.6] kg/m2,
p < 0.05), whereas there was no difference in total SM or ALMI
between any of the three groups (Table 1).
Dual-energy X-ray absorptiometry
The distribution of diseases necessitating thyroid surgery
Using dual-energy X-ray absorptiometry (DXA), we measured (ie, thyroid cancer, atoxic goiter, or toxic goiter) did not differ
body composition in terms of lean tissue mass (kg) and fat significantly between patients with HypoTþPT and HypoT
mass (kg) using a Hologic Discovery scanner (Hologic Inc., (Table 1). A total of seven patients had a history of thyroid
Marlborough, MA, USA). When measuring by DXA, appendicular cancer. All had been diagnosed and treated between 1966 and
lean mass consists of skeletal muscle, skin, connective tissue, and 2004 and all patients were considered as being cured of their
vasculature in the upper and lower limbs (in kg). We calculated malignant thyroid disease. According to the criteria for inclusion,
the appendicular lean mass index (ALMI) by the equation ALMI all patients in the HypoT and HypoTþPT groups were on
(kg/m2) ¼ total limp lean mass (kg)/height (m)2. treatment with LT4. The median dose of levothyroxine used by
Total body skeletal muscle mass (SM) ¼ ((1.13  ALM) – (0.02  patients in the HypoTþPT group was significantly higher than
age) þ (0.61  gender) þ 0.97), (0 ¼ females and 1 ¼ males) as the dose used by patients in the HypoT group (173 [IQR, 143
described by Kim and colleagues.(18) Fat mass index (FMI) (kg/m2) to 206] versus 133 [IQR, 100 to 159] mg/day, p ¼ 0.01). After
was calculated from subtotal fat mass, which is total body fat mass adjustments for differences in body weight, the daily dose of
without the head. FMI ¼ subtotal fat mass (kg)/height (m)2. levothyroxine did no longer differ significantly between the

1442 SIKJAER ET AL. Journal of Bone and Mineral Research

Table 1. Characteristics of Included Participants in the Control Group and in the Groups of Patients on Treatment for Postsurgical HypoT
and Postsurgical HypoTþPT

Controls (n ¼ 22) HypoT (n ¼ 22) HypoTþPT (n ¼ 22) p

Gender, M/F (n) 18/3 18/3 18/3
Age (years), median (IQR) 55 (45–63) 52 (41–62) 52 (40–60) 0.71
Height (cm), median (IQR) 168 (165–177) 166 (164–174) 170 (164–174) 0.79
Weight (kg), median (IQR) 69.7 (65.9–79.5) 74.4 (65.0–90.1) 80.4 (72.7–96.2) 0.17
BMI (kg/m2), median (IQR) 25.2 (22.8–28.4) 27.4 (23.2–28.5) 27.7 (25.1–32.6) 0.12
ALMI (kg/m2), median (IQR) 7.5 (6.9–8.3) 7.7 (7.2–8.7) 7.9 (7.1–9.1) 0.74
FMI (kg/m2), median (IQR) 8.2 (5.4–10.6) 8.1 (5.7–9.8) 9.4 (7.5–13.8) 0.09
Total SM (kg), median (IQR) 24.3 (21.7–28.5) 24.6 (21.8–29.2) 24.7 (21.9–31.4) 0.94
Diseases necessitating surgery, n (%) 0.16
Thyroid cancer NA 2 (9) 5 (23)
Atoxic goiter NA 7 (32) 10 (45)
Toxic goiter NA 13 (59) 7 (32)
Time since surgery (years) NA 8 (6–14) 5 (4–12) 0.18
Medical treatments
Levothyroxine, n (%) 0 22 (100) 22 (100) NA
Dose (mg/day) 0 133 (100–159) 173 (143–206) 0.01
Alfacalcidol, n (%) 0 0 22 (100) NA
Dose (mg/day) 0 0 2.0 (1.4–3.0) NA
Use of calcium supplements, n (%) 2 (9)b,c 8 (36)a,c 22 (100)a,b <0.01
Dose (users only) (mg/day) 900 (800–900)c 800 (433–1400) 1600 (950–2000)a 0.01
Use of vitamin D3 supplements, n (%) 5 (23)b,c 13 (59)a,c 22 (100)a,b <0.01
Dose (users only) (IU/day) 400 (400–1160) 800 (400–1500) 800 (800–1600) 0.17
Values are n (%) or median (IQR) (25–75 percentile), as indicated. Post hoc tests: p < 0.05 compared with the acontrol group, bHypoT group, and
c
HypoTþPT group. Bold values are significant.
HypoT ¼ postsurgical hypothyroidism; HypoTþPT ¼ hypothyroidism plus hypoparathyroidism; IQR ¼ interquartile range; ALMI ¼ appendicular lean
mass index; FMI ¼ fat mass index; SM ¼ skeletal muscle mass; NA ¼ not applicable.

HypoTþPT and the HypoT group (2.1 [IQR, 1.6 to 2.7] versus 1.7 with HypoTþPT (18%) compared with the controls (0%) and
[IQR, 1.5 to 2.2] mg/kg/day, p ¼ 0.11). the group of patients with HypoT (5%) (p ¼ 0.06).
Table 2 shows biochemical characteristics by study groups.
Compared with the controls, patients with HypoT had lower
Muscle function and postural stability
plasma calcium levels, but did otherwise not differ from the
controls. Most of the biochemical indices differed between the Table 3 shows results on muscle strength by study groups.
HypoTþPT and the control groups. Compared with the controls, Maximal force and maximal force production did not differ
patients with HypoTþPT had lower levels of ionized calcium, between controls and the group of patients with HypoT,
PTH, and TSH, with higher plasma levels of phosphate and whereas patients with HypoTþPT had significantly lower muscle
magnesium. eGFR differed borderline significantly with a lower strength and maximal force production during knee extension
filtration rate in HypoTþPT (p ¼ 0.06). An eGFR <60 mL/min was and flexion compared with the controls. Furthermore, maximal
borderline significantly more prevalent in the group of patients force at knee flexion was significantly lower in the HypoTþPT

Table 2. Biochemistry on Included Participants in the Control Group and in the Groups of Patients on Treatment for Postsurgical HypoT
and Postsurgical HypoTþPT

Controls (n ¼ 22) HypoT (n ¼ 22) HypoTþPT (n ¼ 22) p

Creatine kinase (U/l), median (IQR) 118 (82–175) 99 (78–150) 89 (75–120) 0.29
TSH (mIU/l), median (IQR) 2.10 (1.45–5.57)c 2.59 (1.65–3.56)c 0.64 (0.19–2.08)a,b <0.01
Calcium, ionized (mmol/L), median (IQR) 1.22 (1.18–1.23)b,c 1.18 (1.16–1.21)a,c 1.15 (1.08–1.20)a,b <0.01
Phosphate (mmol/L), median (IQR) 0.95 (0.81–1.11)c 1.00 (0.89–1.09)c 1.09 (1.00–1.22)a,b 0.02
Magnesium (mmol/L), median (IQR) 0.84 (0.82–0.86)c 0.86 (0.84–0.88) 0.89 (0.86–0.92)a <0.01
eGFR (mL/min), median (IQR) 83 (76–95) 84 (73–97) 74 (63–88) 0.06
eGFR <60 mL/min, n (%) 0 1 (5) 4 (18) 0.06
Parathyroid hormone (pmol/L), median (IQR) 4.4 (3.2–4.9)c 3.5 (3.1–4.5)c 1.1 (0.9–2.1)a,b <0.01
25-Hydroxyvitamin D (nmol/L), median (IQR) 66 (55–88) 78 (54–100) 76 (67–94) 0.25
Values are n (%) or median (IQR) (25–75 percentile), as indicated. Post hoc tests: p < 0.05 compared with the acontrol group, bHypoT group, and
c
HypoTþPT group. Bold values are significant.
HypoT ¼ postsurgical hypothyroidism; HypoTþPT ¼ hypothyroidism plus hypoparathyroidism; IQR ¼ interquartile range; TSH ¼ thyroid-stimulating
hormone; eGFR ¼ estimated glomerular filtration rate.

Journal of Bone and Mineral Research HYPOTþPT ASSOCIATED WITH IMPAIRED PHYSICAL FUNCTION AND QOL IN HYPOT 1443
Table 3. Muscle Strength and Postural Stability in Included Participants in the Control Group and in the Groups of Patients on Treatment
for Postsurgical HypoT and Postsurgical HypoTþPT

Controls (n ¼ 22) HypoT (n ¼ 22) HypoTþPT (n ¼ 22)

Muscle strength
Elbow extension
Max force (N) 140 (124–178) 140 (101–187) 144 (115–184)
Max force production (N/s) 431 (278–697) 527 (249–641) 340 (192–522)
Elbow flexion
Max force (N) 221 (182–267) 199 (158–247) 204 (144–253)
Max force production (N/s) 824 (484–1269)c 699 (390–1147)c 364 (244–632)a,b
Hand grip
Max force (N) 338 (272–434) 346 (294–407) 309 (249–410)
Max force production (N/s) 1360 (1138–2704)c 1586 (1229–1930)c 781 (501–1051)a,b
Knee extension 60 degrees
Max force (N) 414 (325–468) 393 (315–447) 350 (270–432)
Max force production (N/s) 1217 (829–1818)c 1130 (757–1681)c 742 (582–982)a,b
Knee flexion 60 degrees
Max force (N) 205 (165–242)c 210 (145–260)c 145 (106–196)a,b
Max force production (N/s) 556 (345–903)c 570 (316–663)c 263 (149–438)a,b
Knee extension 90 degrees
Max force (N) 382 (316–445)c 347 (287–470) 314 (231–377)a
Max force production (N/s) 1341 (869–1815)c 1169 (695–1595)c 776 (560–1039)a,b
Knee flexion 90 degrees
Max force (N) 188 (166–245)c 198 (154–241)c 151 (114–201)a,b
Max force production (N/s) 656 (486–771)c 537 (417–719)c 340 (247–491)a,b
Postural stability
Normal stand eyes open (mm2/s) 3.1 (2.1–4.7) 3.5 (2.3–4.7) 4.0 (2.7–6.2)
Normal stand eyes closed (mm2/s) 5.5 (3.1–10.0) 5.9 (4.0–8.0) 7.9 (5.3–10.9)
Semi-tandem stand (mm2/s) 18.0 (16.0–24.8) 21.3 (13.8–31.0) 25.4 (15.8–34.4)
Tandem stand (mm2/s) 31.3 (23.5–40.9)c 30.8 (22.0–46.9) 40.6 (25.7–71.0)a
Values are median with interquartile (25–75 percentile) range. Post hoc tests: p < 0.05 compared with the acontrol group, bHypoT group, and cHypoTPT group.
HypoT ¼ postsurgical hypothyroidism; HypoTþPT ¼ hypothyroidism plus hypoparathyroidism.

group compared with the HypoT group and maximal Compared with the controls, patients in the HypoTþPT group
force production was significantly reduced at most tested had lower scores in all domains except for the role-emotional
muscle groups in the HypoTþPT group compared with the domain. Moreover, patients with HypoTþPT had significantly
HypoT group. Postural stability did not differ significantly lower scores than the HypoT patients in the physical functioning
between groups, except at tandem standing, during which and the role-physical domains. Figure 3 shows summary
patients in the HypoTþPT group had an impaired balance component scores for the mental and physical domains.
function compared with the controls (Table 3). Compared with controls, patients with HypoT had a significantly
As shown in Fig. 1, patients in the HypoTþPT group spent lower mental summary score, whereas patients with HypoTþPT
significantly more time on performing the TUG test and the RCS had a significantly lower physical summary score. Moreover, the
test compared with the HypoT group and the control group. physical component score was significantly lower among
Adjusting for differences in body weight and plasma levels of patients with HypoTþPT compared with the group of patients
TSH, ionized calcium, phosphate, 25OHD, and eGFR did not with HypoT.
change results to any major degree. However, although the Similar to the results from the SF36v2 questionnaire, the
crude analyses showed no differences between groups in WHO-5 well-being index differed significantly between groups
maximum force production at elbow extension and elbow (p < 0.01) with lower scores in the two groups of patients
flexion, the adjusted data revealed a significantly reduced compared with the control group (Fig. 3). The WHO-5 index did
maximum force production in the HypoTþPT group compared not, however, differ between patients with HypoT and
with the control and the HypoT groups (data not shown). HypoTþPT (p ¼ 0.72).
There were no differences in CK between groups (Table 2) or Results did not change after adjusting for differences in body
in muscle mass as measured by DXA in the form of ALMI and weight or levels of plasma TSH, ionized calcium, 25OHD, and
total SM (Table 1). eGFR (data not shown).

QoL Discussion
Figure 2 shows data on QoL as assessed by the SF36v2
questionnaire. Compared with the controls, patients in the Because postsurgical HypoPT often develops as a complication
HypoT group had significantly lower scores in several domains to thyroid surgery, most patients are also suffering from
including role-physical, bodily pain, vitality, and mental health. postsurgical HypoT. Despite normalization of plasma calcium

1444 SIKJAER ET AL. Journal of Bone and Mineral Research

 and TSH levels in response to replacement therapy with
activated vitamin D analogues, calcium supplements, and
LT4, these patients often have a number of complains
including impaired well-being and musculoskeletal symp-
toms. In the present study, we aimed to assess health-related
QoL and muscle function in patients who had a thyroidectomy
with and without the complication of HypoPT in comparison
with healthy controls. Despite being on relevant medical
treatment, our data suggests that QoL and muscle function
is impaired in patients with HypoTþPT. Muscle strength
and function was not impaired in HypoT, whereas QoL was
reduced in several domains. The mental component score in
patients with only HypoT was lower than both patients also
suffering from HypoPT (nonsignificant [NS]) and healthy
controls (p < 0.05).
Thyroid hormones are known to be of major importance to
general well-being and cognitive functions. In a population-
based survey using questionnaire data, patients on LT4
replacement therapy titrated to a normal TSH level had a
significantly impaired QoL and psychological well-being when
compared to age- and sex-matched controls.(2) It has been
suggested that the addition of liothyronine (T3) to LT4 therapy
may improve mood, cognitive function, and general sense of
well-being, but ambiguous results have been reported in recent
studies.(21) Importantly, none of our patients were on substitu-
tion therapy with liothyronine. Our data supports previous
findings of a reduced QoL in hypothyroidism and hypoparathy-
roidism. The fact that QoL was more severely affected in patients
suffering from both HypoT and HypoPT as compared with
patients only suffering from HypoT suggests that the HypoPT by
itself contributes to an impaired well-being. Moreover, our
findings suggest that the impaired QoL in HypoPT is not fully
Fig. 1. The Timed Up and Go Test and Repeated Chair Stands test in explained by the fact that these patients are suffering from a
patients on treatment for postsurgical HypoT, postsurgical HypoTþPT, and chronic disease, because QoL was impaired compared with
healthy controls. p < 0.01 for both tests (ANOVA). Mean  SD. HypoT ¼ patients suffering from chronic HypoT. Accordingly, the state of
hypothyroidism; HypoTþPT ¼ hypothyroidism and hypoparathyroidism. suffering from a chronic disease does not by itself explain the
reduced QoL in HypoPT. Nevertheless, it is noteworthy that

Fig. 2. Findings on the eight subscales of quality of life as measured by the SF-36v2 in patients on treatment for postsurgical HypoT, postsurgical
HypoTþPT, and healthy controls. Post hoc tests: p < 0.05 for (a) controls versus HypoT, (b) controls versus HypoTþPT, (c) HypoT versus HypoTþPT.
SF-36v2 ¼ Short Form questionnaire 36 version 2; HypoT ¼ hypothyroidism; HypoTþPT ¼ hypothyroidism and hypoparathyroidism.

Journal of Bone and Mineral Research HYPOTþPT ASSOCIATED WITH IMPAIRED PHYSICAL FUNCTION AND QOL IN HYPOT 1445
 In a number of case reports, HypoPT has been associated with
neuromuscular symptoms. In addition to paresthesia, muscular
spasms, and seizures, common complains include muscular
fatigue, pain, and lack of endurance. Cardiac muscle tissue may
be affected as well, because cardiomyopathy has been reported
in severe hypocalcemia due to HypoPT.(22–25) In several of the
case reports and in our own study, elevated plasma levels
of muscle enzymes and cardiac enzymes have been
reported.(22,24,26,27) The pathogenesis causing myopathy in
hypoparathyroidism has not been fully elucidated. In published
case reports, patients affected by myopathy have all had severe
hypocalcemia, which probably is of significance to the
development of myopathy due to the importance of calcium
on muscle contraction. To the best of our knowledge, the
present study is the first to systematically assess muscle strength
and function in a group of patients suffering from treated
chronic HypoPT as compared with healthy controls. Our findings
support an impaired muscle function, because patients with
HypoPT had reduced muscle strength and force production at
most muscle groups tested. Moreover, muscle function was
impaired as assessed by functional tests, but despite these
findings we found no loss of muscle mass as measured by DXA.
The reduced physical functioning found in the QoL question-
naire goes very well along with the findings of impaired muscle
function and strength in the HypoTþPT group. Apparently, this
was not due to concomitant lack of endogenous synthesis of
thyroid hormones, because muscle strength also was reduced
compared with the group of patients on treatment with
levothyroxine due to postsurgical HypoT. Our data do not allow
for conclusions on the mechanism responsible for impaired
muscle function. Normally, plasma calcium levels are tightly
controlled and vary only within a narrow physiological range.(28)
In response to therapy with calcium supplements and activated
vitamin D analogues, plasma calcium levels are normalized,
thereby avoiding severe hypocalcemia. However, the normal
precise physiological minute-to-minute control of calcium
homeostasis is not regained in response to therapy and the
homeostasis of other minerals remains affected, including
relatively high phosphate levels. Accordingly, conventional
calcium and vitamin D therapy only causes an apparent
normalization of calcium homeostasis. Furthermore, as the
PTH receptor is expressed by muscle tissue,(29–31) it may be
speculated whether PTH itself is of importance to muscle
function. In primary hyperparathyroidism (PHPT)patients with
PTH excess there is decreased muscle strength and function
compared with healthy controls(32) and improved muscle
strength and function is seen after parathyroidectomy with
normalization of PTH and Ca2þ levels.(33)
In a recent randomized clinical trial by our group, however, we
found no beneficial effects on muscle function of replacement
therapy with PTH(1-84).(1) The dose of PTH used in our study was
Fig. 3. Box and whisker plots showing the physical component score
too high in some of the patients who developed hypercalcemia
(top) and mental component score (middle) as assessed by the SF-36v2, as
in response to therapy.(8) Because this may have blunted a
well as findings from the WHO-5 well-being index (bottom) in patients on
potential beneficial effect of PTH replacement therapy, further
treatment for postsurgical HypoT, postsurgical HypoTþPT, and healthy
studies on the effects of PTH therapy on muscle function in
controls. SF-36v2 ¼ Short Form questionnaire 36 version 2; HypoT ¼
hypoparathyroidism are warranted.
hypothyroidism; HypoTþPT ¼ hypothyroidism and hypoparathyroidism.
Strength of and limitations to study
A major strength of our study is that we compared well-matched
there are more patients in the HypoTþPT group (23%) than in groups of patients on long-term treatment for HypoT or
the HypoT group (9%) with previous cancer, and having had a HypoTþPT with healthy controls recruited from the general
life-threatening disease might have an impact on QoL even background population. It would have been interesting to
though the cancer was at least 5 years prior to study start. include a group of patients with only HypoPT and not HypoT,

1446 SIKJAER ET AL. Journal of Bone and Mineral Research

but because idiopathic HypoPT is a rare disease it was not Lisbeth Flyvbjerg, Christina Wiegers, Lene Sørensen, and Helle
possible to recruit enough of these patients. At the time of Thøgersen is greatly appreciated.
measurements, all patients were on substitution therapy with Authors’ roles: Study design: TS, EM, LM, and LRe. Study conduct:
LT4 and patients also suffering from hypoparathyroidism TS, EM, and LRo. Data collection: TS, EM, and LRo. Data analysis: TS,
received treatment with active vitamin D and calcium supple- EM, and LRe. Data interpretation: TS, EM, LRo, LM, and LRe. Drafting
ments resulting in (near-) normal plasma levels of TSH and manuscript: TS and LRe. Revising manuscript content: EM, LRo, LB,
calcium. Thus, our study was performed in groups of patients on LU, and LM. Approving final version of manuscript: TS, EM, LRo, LB,
treatment for their hormonal deficiencies according to a gold LU, LM, and LRe. TS takes responsibility for the integrity of the data
standard. Our sample size was, however, relatively small and we analysis.
can therefore not exclude that additional, but more subtle,
differences may also exist between groups. In our sample of
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1448 SIKJAER ET AL. Journal of Bone and Mineral Research