Diagnosis and management of primary hyperparathyroidism
B.L. LANGDAHL1and S.H. RALSTON2
From the1Department of Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000
Aarhus C, Denmark and2Head of the School of Molecular and Clinical Medicine & ARC Professor of
Rheumatology, Molecular Medicine Centre, Western General Hospital, Edinburgh, EH4 2XU, UK
Address correspondence to B.L. Langdahl, PhD, DMSc, Consultant Asst. Professor, Department of
Endocrinology and Internal Medicine, Aarhus University Hospital, DK-8000 Aarhus C, Denmark.
Received 29 March 2011 and in revised form 21 October 2011
Background: There is continued debate as to the
optimal strategy for diagnosis and management of
primary hyperparathyroidism (PHPT).
Aim: To compare the strategies used for the diagno-
sis and management of PHPT by physicians in
five European countries.
Design: Questionnaire-based survey.
Methods: Physicians in France, Germany, the UK,
Italy and Spain were invited to participate in the
survey which was conducted using a web-based
interface and were included in the evaluation if
they had treated a minimum of four patients suffer-
ing from PHPT in the past year.
Results: A total of 421 physicians completed the
survey. The majority of respondents were endo-
crinologists (68%) but other specialities included
rheumatologists (10.9%), internists (11.8%) and
urologists (9.2%). Diagnostic methods were similar
across different countries and specialities but there
were significant differences in the proportion of
physicians who recommended parathyroidectomy
in asymptomatic patients with indications for
surgery according to the 2002 National Institutes
of Health (NIH) consensus conference statement
(?2=26.1, P<0.001). The proportion of patients
referred for surgery ranged from 32% in Italy to
66%in Spain with
Germany (64%), France (55%) and the UK (53%).
Conversely, pharmacological therapy was used
most frequently for these patients in Italy (32%)
and least frequently in Spain (14%).
Conclusion: Significant differences exist in the
management of patients with asymptomatic PHPT
in countries across Europe who have accepted indi-
cations for surgery according to the NIH consensus
statement. Further research will be required to ex-
plore the reasons for this and to determine if these
differences affect the clinical outcome of PHPT.
intermediate values in
Primary hyperparathyroidism (PHPT) is a common
disease which affects 0.1–2% of populations,
with a 3:1 female preponderance.1The clinical
presentation of PHPT has changed dramatically
over the past 30 years from a symptomatic disorder
associated with severe hypercalcaemia, renal stones
and bone disease to a condition that is often
! The Author 2012. Published by Oxford University Press on behalf of the Association of Physicians.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0), which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Q J Med 2012; 105:519–525
doi:10.1093/qjmed/hcr225 Advance Access Publication 7 May 2012
asymptomatic, which is picked up as an ‘incidental’
finding on biochemical screening. Nonetheless, pa-
tients with mild PHPT can progress to develop
symptoms and complications, and epidemiological
studies have suggested that untreated PHPT may be
associated with an increased risk of cardiovascular
The optimal strategy for the diagnosis and man-
agement of PHPT has been the subject of several
position statements, including those which emerged
from National Institutes of Health (NIH) Consensus
Development Conferences in 20023and the third
thyroidism in 20094–8and that published by the
American Association of Clinical Endocrinologists
and Endocrine Surgeons in 2005.9Although these
statements have been endorsed by some European
organizations, including the European Calcified
Tissues Society (www.ectsoc.org), it is unclear to
what extent European physicians adhere to these
recommendations for the diagnosis and manage-
ment of PHPT. In view of this, the aim of the present
study was to evaluate to what extent physicians in
Europe who regularly manage PHPT follow these
guidelines and to determine if there is variation
across Europe in the management of this disease.
To achieve this aim we conducted a web-based
survey of the clinical strategies used by endocrinolo-
gists, rheumatologists, internists and urologists to
diagnose and manage PHPT in France, Germany,
the UK, Italy and Spain in 2009.
on primary hyperpara-
Potential participants in this study were recruited to
a panel by various methods including telephone,
face-to-face and referral recruitment processes.
Panel members were then verified as registered
physicians. For the purposes of this study, specific-
ally endocrinologists, rheumatologists, internist or
urologists in the countries of interest (France,
Germany, the UK, Italy and Spain) were invited by
an email to participate in a survey on the diagnosis
and management of PHPT. Respondents were only
included in the evaluation if they had been practis-
ing for53 years, had treated a minimum of four
PHPT patients a year, and had spent >50% of their
time treating patients. Respondents were excluded if
they had taken part in any market research of a simi-
lar topic in the last 3 months. The survey was con-
ducted online between 12 and 30 June 2009. The
aim was to collect data from 80 clinicians per coun-
try to provide a reasonable sample size for analysis
although we did not perform any specific power
calculations before deciding upon the sample size.
The survey topics and the available answer options
are summarized in Supplementary Table 1. They
included questions regarding the methods used for
the diagnosis of PHPT, the respondents’ preferred
management strategy for symptomatic and asymp-
tomatic PHPT, and if diagnosis and management
strategieswere in accordance
Additional questions were aimed
at excluding ineligible participants according to
the criteria mentioned previously (data not shown).
Differences in management strategies employed
by respondents in different groups were analysed
by chi-square test.
Demographics of respondents
A total of 1269 physicians initially responded to an
email invitation to participate. Responses to the
questionnaire were obtained from 421 eligible phys-
icians from five European countries as summarized
in Table 1. The main reasons for this difference were
that the physicians did not fulfil the inclusion criteria
(82%) or did not complete the questionnaire (9%).
The majority of respondents were endocrinologists
Table 1 Respondents by speciality and country
TotalFrance GermanyUK Italy Spain
Values shown are number (%) of respondents.
520B.L. Langdahl and S.H. Ralston
and the distribution of specialities represented in the
survey was similar across all countries. The average
number of patients seen per year varied across
countries, with the lowest number in France
(Q1, Q3), 20 (10, 30)] and the highest in the UK
Diagnosis of PHPT
The diagnostic tests used in patients suspected to
have PHPT were similar across Europe. The vast
majorityof respondents(98%) reported that
parathyroid hormone (PTH) was measured as part
of the diagnostic work up with no significant differ-
ence between countries. Other tests used frequently
were serum calcium (85%), serum creatinine (96%)
and 24-h urinary excretion of calcium (85%).
Adherence to guidelines
Approximately a third of respondents in each coun-
try (34–44%) reported that they adhered to the NIH
2002 guidelines3when treating PHPT (Table 2),
with no significant difference between countries.
The majority of the remaining respondents followed
other guidelines and only a very limited number
Figure 1. Preferred management strategies for symptomatic PHPT. Values (%) are respondents’ answers to the multi-choice
Question 11 ‘When a PHPT patient is symptomatic do you...?’ Respondents chose a single answer from a multi-choice list.
Table 2 Do your treatment decisions always follow guidelines?
France Germany UKItalySpain
3rd Int. Workshop
Values are numbers (%) of respondents who followed guidelines. AACE/AAES, American Society of Clinical
Endocrinologists/American Society of Endocrine Surgeons.
Diagnosis and management of PHPT in Europe521
of respondents in each country did not always
follow any guidelines when making treatment
Management of symptomatic PHPT
The preferred management strategies for symp-
Parathyroidectomy was the preferred treatment
option for 72% of UK respondents and 73.8% of
favoured by Italian respondents: only 42% recom-
mended parathyroidectomy as first-line treatment.
Intermediate values were found for France (63.8%)
and Spain (60.0%) and the differences between
countries was statistically significant (?2=23.8,
P<0.001). In keeping with these observations,
pharmacologic treatment for symptomatic patients
was the most favoured first-line option for Italian
respondents (44.3%), but this was less favoured by
German respondents (16.3%), UK respondents
(22.6%), French respondents (25.0%) and Spanish
respondents (30.0%) (?2=19.4, P=0.001).
Management of asymptomatic PHPT
The preferred management strategies for a patient
with asymptomatic PHPT in different countries are
summarized in Figure 2. Asymptomatic PHPT is
defined as elevated serum levels of PTH in combin-
ation with high or normal serum levels of calcium,
all causes of secondary hyperparathyroidism being
ruled out, in a patient without symptoms that have
been related to this condition.3–9Few respondents
selected parathyroidectomy as the first-line option,
but this was more favoured in an asymptomatic
patient who had complications such as signifi-
cant hypercalcaemia [serum calcium >1.0mg/dl
function or osteoporosis. Between 48.0% and
66.0% of respondents in most countries favoured
Figure 2. Preferred management strategies for asymptomatic PHPT. Values (%) are respondents’ answers to the multi-choice
Question 12 ‘When a PHPT patient is asymptomatic do you...?’
aRecommendation based on 2002 NIH Consensus
522 B.L. Langdahl and S.H. Ralston
parathyroidectomy in these patients with the excep-
tion of Italy where only 32% would have considered
parathyroidectomy as first line. The difference
P<0.001). Follow-up with monitoring of serum
calcium values, with and without pharmacological
treatment, were reasonably popular options for
these patients in the UK and Italy, but were less
popular in Germany, France and Spain.
Pharmacologic therapies used in the
medical management of PHPT
Respondents were asked about their preferred
medical management options when used as an
alternative to surgery. Treatment options include
bisphosphonate therapy, calcimimetics, diuretics
and hormone-replacement therapy (HRT) which
includes both oestrogen and oestrogen receptor
Respondents from all countries selected bispho-
sphonate therapy as the first-line option they found
most suitable (mean ranking) followed by calcimi-
metics as the second option and the diuretic
furosemide as the third. Combination therapy,
oestrogen treatment and oestrogen receptor agonists
were found to be the less suitable options [in varying
order of preference depending on country (Table 3)].
As reflected by the mean rankings, it was apparent
that most respondents tried three to four individual
treatments before trying combination therapy; how-
ever, those individual respondents who recorded
combination therapy as ranking from 1–3 were
required to state the most common combination
drug treatments used in the medical management
of PHPT along with the percentage of patients that
received this combination. These percentages are
shown in Figure 3. The three most commonly used
therapy with either HRT, calcimimetic or diuretic
Differences between specialities
There were no differences between specialities in
the approaches to the diagnosis and management
of PHPT with one exception: the management of
patients with asymptomatic PHPT. For this group
of patients, parathyroidectomy was favoured as the
first choice treatment by 204/286 endocrinologists
(71.3%), compared with 20/51 internists (39.2%),
21/48 rheumatologists (43.7%) and 17/36 urologists
(47.2%), a difference that was significant (?2=31.9,
The optimal strategy for the management of PHPT
continues to be a subject of considerable debate,
probably reflecting the fact that there have been
no large-scale randomized studies addressing the
long-term effects of surgical versus conservative
management for this condition. In the absence of
these studies, several reviews, clinical guidelines
and position statements have been published by
expert groups to help physicians decide upon how
best to manage the individual patient.3–9In the pre-
sent survey, we did not ask physicians if they were
aware of guidelines but only if they managed
patients with PHPT according to specific guidelines
(Supplementary Table 1). However, most respond-
ents in each country reported that they adhered to a
guideline when treating PHPT. The majority of the
physicians across the five countries used the 2002
NIH guideline and not the updated 2009 guideline
that was the result of the third international work-
shop on primary hyperparathyroidism. This may, at
least in part, be explained by the fact that the present
survey was conducted in 2009 at the time of publi-
cation of the updated 2009 guideline.
It is generally agreed that parathyroidectomy
should be the treatment of first choice for patients
Table 3 Preferred pharmacological treatment for PHPT
Ranking, 1–6 (mean)
France Germany UK Italy Spain
Oestrogen receptor agonists
Values are rankings (1 representing the most frequently preferred treatment and 6 the least preferred treatment) based on the
median ranking of each treatment modality by country. The mean ranking is provided in parentheses.
Diagnosis and management of PHPT in Europe523
with symptomatic PHPT and this was the option
favoured by physicians in most European countries,
with the notable exception of Italy where only 42%
of physicians favoured parathyroidectomy as the
treatment of first choice for symptomatic patients.
The lack of enthusiasm for surgery in Italy was coun-
terbalanced by a relatively increased preference for
pharmacological options: 44% of physicians fa-
voured medical treatment with follow-up.
Few physicians favoured surgery as the first
choice treatment option for asymptomatic PHPT
without complications, but this was the most popu-
lar option in most countries where patients with
PHPT had complications such as impaired renal
function, hypercalciuria, low bone mineral density
(BMD) and more severe hypercalcaemia. A notable
exception was Italy, however, where the proportion
of physicians who favoured surgery for such patients
was only 32.0%.
Medical management of symptomatic PHPT with
follow-up was considered to be the treatment of
choice by between 16.3% and 44.3% of respond-
ents with the lowest proportion in Germany and the
highest in Italy. This approach was favoured less for
asymptomatic patients in all countries, with values
ranging from 13.0% in Germany to 32.0% in Italy.
Relatively few randomized trials have been
conducted to determine how surgery compares
with conservative management of patients with
PHPT. It has been reported that many patients with
asymptomatic PHPT actually suffer from undiag-
nosed neurocognitive symptoms,10and a small
randomized controlled trial showed that some of
these symptoms improved following surgery.11
In an epidemiological study it was reported that
mortality is increased in patients with mild hypercal-
caemia,12but this could not be confirmed in another
epidemiological study where mortality only was
increased among the quartile of patients with the
highest serum levels of calcium.13It has been
suggested that conservative treatment should be
abandoned for the management of PHPT14although
there is no evidence to suggest that lowering
calcium values in these patients, either medically
or by parathyroidectomy, is effective in reducing
the increased mortality of these subjects.
At the present time several medical therapies are
used for the treatment of osteoporosis associated
with PHPT, including HRT, raloxifene and bispho-
sphonates. These drugs have been shown to be
effective in increasing BMD values in patients with
PHPT but they do not reduce serum calcium values
Figure 3. Patients receiving preferred combination pharmacological therapies for the treatment of PHPT. Values are
estimate percentages of the number of patients with PHPT receiving combination therapy given by those physicians ranking
combination therapy from 1–3 (1, most suitable; 6, least suitable).
524 B.L. Langdahl and S.H. Ralston
significantly. The calcimimetic cinacalcet has also Download full-text
become available for the treatment of PHPT. This
lowers PTH and serum calcium levels significantly
but does not increase BMD values.15In the present
survey, bisphosphonates were the most widely used
treatments for PHPT and when used in combination
were generally combined with HRT, diuretics or
cinacalcet. Although diuretics were quite commonly
used in this survey, presumably in an attempt to
lower serum calcium values in PHPT because of
their calciuric effect, we are not aware of any
evidence from randomized trials to suggest that
they are actually effective in this condition.
There are limitations associated with the use of
survey data. Perhaps most significantly, there is the
inherent potential for bias in responding, such as
giving an affirmative answer to a question because
it is the perceived ‘correct answer’. The format of the
questionnaire, designed to maximize response rate,
led to a relatively closed selection choice possibly
In summary, the present survey has shown that
substantial variation exists in clinicians’ approach
to the management of PHPT in different European
countries. This emphasizes the need for further
research to fully explore the long-term efficacy of
different management strategies.
Dataare available at QJMED
Editorial assistance was provided by ApotheCom
ScopeMedical Ltd funded by Amgen (Europe)
GmbH and by Dr Caterina Hatzifoti of Amgen
This study was funded by Amgen (Europe) GmbH.
Conflict of interest: B. L. L. has spoken at a speakers’
bureau supported by Amgen and has consulted for
Amgen, Eli Lilly, MSD, Novartis, Nycomed and
Servier. She has also received research grants from
Amgen, Eli Lilly, MSD, Novartis, Nycomed and
Pfizer. S. H. R. has received research grants from
Eli Lilly and has consulted for MSD, Novartis and
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