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CLINCAL STUDY
Hypercalciuria is a common and important finding
in postmenopausal women with osteoporosis
Sandro Giannini
1,2
, Martino Nobile
1
, Luca Dalle Carbonare
1
, Maria Giuseppina Lodetti
1
, Stefania Sella
1
,
Gabriele Vittadello
1
, Nadia Minicuci
2
and Gaetano Crepaldi
1,2
1
Department of Medical and Surgical Sciences, Clinica Medica 1, University of Padua, Padua, Italy and
2
National Research Council,
Institute of Neurosciences, Aging Unit of Padua, Padua, Italy
(Correspondence should be addressed to S Giannini, Department of Medical and Surgical Sciences, Clinica Medica I, University of Padua, Via Giustiniani,
2, 35128 Padua, Italy; Email: sandro.giannini@unipd.it)
Abstract
Objective and design: The prevalence and the effects of hypercalciuria on bone in patients with primary
osteoporosis are poorly defined. We therefore retrospectively analyzed the data of 241 otherwise
healthy women. They were 45–88 years of age and had been referred for their first visit to our
Unit for Metabolic Bone Diseases over a 2-year period because of primary osteoporosis (bone density
T-score ,22.5).
Methods: The main parameters of calcium and skeletal metabolism had been analyzed in all subjects.
This population was then divided into two groups, according to the presence (HCþ ) or absence
(HC2 ) of hypercalciuria.
Results: Elevated urinary calcium was present in 19% of the subjects. Due to the selection criteria,
spinal and femoral bone loss was similar in the two groups. Urinary calcium, phosphate and frac-
tional calcium excretion were higher in hypercalciuric patients. In a logistic regression model, the
higher the Tm of phosphate, the lower the risk of hypercalciuria (odds ratio 0.33, confidence interval
0.18– 0.62). On the contrary, hypercalciuria was the most important predictor of low bone mass in
HCþ (accounting for more than 50% of the variance in spinal bone density).
Conclusions: Hypercalciuria is a common feature in postmenopausal bone loss. Since increased urin-
ary calcium excretion and low bone mass appear to be linked, hypercalciuria seems to be an import-
ant determinant of reduced bone density in this setting as well.
European Journal of Endocrinology 149 209–213
Introduction
Osteoporosis is a common disease which affects both
women and men with a ratio of approximately 3:1
(1). It is characterized by low bone mass and micro-
architectural deterioration of bone tissue that lead to
an increase in bone fragility and consequent risk of
fracture (2).
While in most patients with reduced bone mass there
are no obvious factors that can be associated with the
appearance of the disease, it is well known that many
conditions can induce a secondary form of osteoporosis.
These include a number of pharmacological treatments
as well as some clinical disorders, such as hyperpara-
thyroidism, hyperthyroidism, exogenous or endogenous
hypercorticism, several intestinal disorders and many
others (3).
The effect of idiopathic hypercalciuria on bone
(defined as increased calcium excretion in the absence
of secondary causes) has been widely evaluated in
patients with calcium nephrolithiasis. Many authors
have reported that the increase in urinary calcium
excretion is associated with decreased bone mass and
increased bone turnover in patients with kidney
stones (4–6). Melton et al. (7) also reported an
increased vertebral fracture risk in patients with
urolithiasis.
It is generally agreed that hypercalciuria may be
involved in the pathogenesis of low bone mass in
patients referring for osteoporosis. However, the fre-
quency and the pathogenetic relevance of this meta-
bolic defect in osteoporotic patients have not been
clearly described as yet. In a very recent paper focusing
on the use of laboratory testing in revealing hidden
alterations that can induce secondary osteoporosis,
Tannenbaum and co-workers (8) found that hypercal-
ciuria was the most common defect, being present
in approximately 10% of their otherwise healthy
European Journal of Endocrinology (2003) 149 209–213 ISSN 0804-4643
q 2003 Society of the European Journal of Endocrinology Online version via http://www.eje.org
osteoporotic women. However, in that study no attempt
was made to correlate increased calcium excretion with
low bone density.
The purposes of our study, therefore, were to
evaluate the prevalence of hypercalciuria in a popu-
lation of patients referring for the first time to our out-
patient Unit for Metabolic Bone Diseases, and to assess
the possible associations between hypercalciuria and
bone density in this setting.
Subjects and methods
Patients
In a chart-review study we retrospectively examined the
clinical records of 914 female outpatients consecutively
referred to our Unit between 1 January 2000 and 31
December 2001 for a possible metabolic bone disease.
Inclusion criteria were postmenopausal status and the
presence of spinal or femoral osteoporosis (bone density
T-score of ,22.5 standard deviations as compared
with normal young adults). Pre- or perimenopausal
women with spinal or femoral bone density higher
than 2 2.5 standard deviations below the mean levels
observed in normal young adults were excluded.
Subjects with diseases (primary and secondary hyper-
parathyroidism, hyperthyroidism, renal tubular
acidosis, medullary sponge kidney disease, multiple
myeloma, sarcoidosis, hypercortisolism, liver or kidney
failure, diabetes mellitus, severe gastrointestinal
disorders, Paget’s disease of bone) or taking drugs (cor-
ticosteroids, anti-convulsants,
L-thyroxine, cyclosporin
A, diuretics) known to influence bone and calcium
metabolism were also excluded. From the remaining
302 postmenopausal women, aged 45 – 88 years
(mean^
S.D. age 64^7 years, body mass index (BMI)
24^3 kg/m
2
, daily calcium intake 685^202 mg and
time since menopause 15^8 years), we further
excluded 61 patients who were already taking medi-
cation for the treatment of bone loss (bisphosphonates,
raloxifene, oestrogens, vitamin D, fluoride and calcium
supplements). The study was then carried out on a
population of 241 postmenopausal women with osteo-
porosis, aged 45– 88 years.
Assay methods
All patients had undergone a clinical history and physi-
cal examination. Fasting blood and 24-h urine samples
had been obtained in all subjects and analyzed for cal-
cium, phosphate and creatinine (Automatic Analyzer;
Technicon Instruments Corporation, Tarrytown, NY,
USA). Serum bone alkaline phosphatase (b-ALP) iso-
enzyme in catalytic activity was determined by lectin
from wheat germ precipitation (Iso-ALP; Boehringer
Mannheim, Milan, Italy). After the total ALP activity
had been determined (according to IFCC; Roche
Diagnostics, Milan, Italy), b-ALP was precipitated
using lectin from wheat germ as precipitant and the
remaining ALP activity in the supernatant was
measured (normal range: 5–56 U/l). This method
has intra- and interassay coefficients of variation , 4
and , 10% respectively, and it has a good correlation
with an immunoradiometric assay measuring bone
ALP mass concentration (9). Intact parathyroid hor-
mone (PTH) was evaluated by a commercial immuno-
radiometric assay (Biorad Laboratories, Milan, Italy;
normal range 10 – 60 pg/ml), with intra- and interas-
say coefficients of variation of 6 and 8% respectively.
Daily dietary calcium intake was assessed by a vali-
dated questionnaire (10). The presence of hypercal-
ciuria was first defined as urinary calcium excretion
higher than 250 mg/day or 4 mg/kg body weight per
day on a free diet. (4). In order to exclude dietetic
sources of increased urinary calcium excretion, hyper-
calciuric patients underwent a further 24-h urine col-
lection after a 10-day normocaloric diet containing
1000 mg calcium, 100 mmol sodium, 60 mmol potass-
ium and 1 g protein/kg body weight.
Fractional calcium excretion and the Tm values of
phosphate were calculated according to standard
formulas.
Bone densitometry
Dual X-ray absorptiometry (DXA) evaluation of the
lumbar spine (L
2
–L
4
) was performed by Hologic QDR
4500 (Hologic Corporation, Waltham, MA, USA) in
all patients. DXA scans of the proximal femur were
also obtained. The results are expressed as bone min-
eral density (BMD; g/cm
2
) T- and Z-score (number of
standard deviations of difference between the patient’s
BMD value and the BMD level of normal young adults
or sex- and age-matched normal controls respectively).
The T- and Z-scores were calculated using the manufac-
turer’s normal values. The in vivo coefficient of vari-
ation, calculated as described in detail elsewhere (11),
was 1.06% for the spine, 1.16% for the total femur
and 1.63% for the femoral neck.
Statistical analysis
The results are expressed as means^S.D. Two-sample
Student’s t-test was performed to determine statistical
differences between means. Logistic regression and step-
wise multiple regression analyses were used to evaluate
the relationships between the variables. P values less
than 0.05 were considered to be statistically significant.
An SPSS package 10.1 version was used.
Results
The main clinical and metabolic parameters of the 241
patients enrolled are summarized in Table 1. The
T-scores of the lumbar spine, total hip and femoral
210
S Giannini and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 149
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neck were 2 3.3^0.7, 2 2.2^0.7 and 2 2.4^0.6
respectively.
According to the 24-h urinary calcium excretion,
this population was then divided into two groups: 46
patients (19.1%) with a hypercalciuria of undetermined
origin (HCþ ) and 195 without (HC2 ). The main clini-
cal and metabolic parameters of the two groups are
summarized in Table 2. The groups did not differ as
to the main serum variables, apart from 24-h urinary
calcium which, by definition, was higher in HCþ
(312^51 mg) as compared with HC2 patients
(136^56 mg), and 24-h urinary phosphate, Tm phos-
phate and fractional calcium excretion, which were
higher in patients classified as hypercalciuric (Table 2).
Bone density T-scores of the spine and femur did
not differ between the two groups (Table 3). When
the small difference in age was taken into account
(Z-scores), bone density was still similar between
patients with or without hypercalciuria.
To adjust correlation analysis for possible confoun-
ders, two different regression analysis models were
devised. The first one was a logistic regression, using
urinary calcium excretion (as a dummy for the absence
or presence of hypercalciuria, HC2 ¼ 0 and HCþ¼1)
as a dependent variable, and age, BMI, Tm phosphate,
dietary calcium intake, PTH and b-ALP as the predic-
tive values. Only Tm phosphate was maintained by
the model as a significant predictor (odds ratio (OR)
0.33, 95% confidence interval (C.I.) 0.18–0.62).
The second multiple regression analysis model
included the spinal T-score as a dependent variable,
and age, BMI, time since menopause, dietary calcium
intake, b-ALP, PTH, urinary calcium and phosphate
excretions, and a dummy coded 0 for the absence
(HC2 ) and 1 for the presence (HCþ ) of hypercalciuria,
as the predictive values. When this model was applied
to the whole population only BMI, years since meno-
pause and urinary calcium excretion were left signifi-
cantly associated with the outcome (Table 4). Because
of the different and specific meaning of urinary calcium
in hypercalciuric patients, we also wanted to evaluate
the predictive value of the same variables (with the
exclusion of the dummy) on bone density in this specific
population (Table 5). In this model, only age and urin-
ary calcium remained as significant predictors, with
hypercalciuria explaining, by itself, more than 50% of
spinal bone mass.
When patients with a more severe degree of spinal
osteoporosis were considered (T-score #23.0), only
urinary calcium and time since menopause entered in
the model as predictive variables in HCþ patients
(R
2
¼ 0.61, P ¼ 0.015), with calciuria explaining
38% of the variance in spinal bone density.
When hypercalciuric patients were divided according
to total hip T-score (,23.0 vs $23.0), urinary cal-
cium excretion was significantly higher in patients with
Table 1 Clinical and biochemical parameters in the whole patient
population (n ¼ 241).
Patients Normal values
Age (years) 64^7
Years since menopause 15^8
BMI (kg/m
2
)24^3
Dietary Ca intake (mg/day) 685^202
Serum creatinine (mg/dl) 0.84^0.15 0.7–1.2
Serum calcium (mg/dl) 9.4^0.5 8.6–10.5
Serum phosphate (mg/dl) 3.5^0.5 2.5–4.2
PTH (pg/ml) 47^22 10–55
b-ALP (U/l) 34^19 5–50
Urinary calcium (mg/day) 174^91 60–250
Urinary phosphate (mg/day) 703^273 400–1250
Table 2 Clinical and biochemical parameters in patients with
(HCþ ) or without (HC2 ) hypercalciuria.
HC2
(n 5 195)
HC1
(n 5 46) P
Age (years) 64^763^7ns
Years since menopause 16^814^9ns
BMI (kg/m
2
)24^324^3ns
Dietary Ca intake (mg/day) 678^195 709^227 ns
Serum creatinine (mg/dl) 0.85^0.15 0.82^0.14 ns
Serum calcium (mg/dl) 9.4^0.5 9.3^0.5 ns
Serum phosphate (mg/dl) 3.5^0.5 3.5^0.6 ns
PTH (pg/ml) 47^22 45^24 ns
b-ALP (U/l) 35^18 34^23 ns
Urinary phosphate (mg/day) 632^217 964^301 ,0.001
FECa 1.5^1.7 3.5^2.9 , 0.0001
Tm Pi (mg/dl) 2.8^0.6 2.3^0.8 , 0.0001
ns, not significant. FECa, fractional excretion of calcium.
Table 3 Bone densitometry data in patients with (HCþ )or
without (HC2 ) hypercalciuria.
HC2 (n 5 195) HC1 (n 5 46) P
T-score
Lumbar spine 2 3.2^0.7 2 3.1^0.6 ns
Total hip 2 2.2^0.7 2 2.0^0.6 ns
Femoral neck 2 2.4^0.6 2 2.3^0.8 ns
Z-score
Lumbar spine 2 1.7^0.8 2 1.7^0.7 ns
Total hip 2 1.0^0.7 2 0.9^0.8 ns
Femoral neck 2 1.0^0.6 2 0.8^0.6 ns
ns, not significant.
Table 4 Multiple regression analysis in the whole population of
patients, with spinal T-score as a dependent variable (R
2
¼ 13%).
b P
BMI 0.19 0.005
Years since menopause 2 0.28 , 0.0001
Urinary Ca 2 0.38 0.008
HC2 /HCþ
a
0.21 0.06
a
Dummy variable with non-hypercalciuric (HC2 ) ¼ 0 and hypercalciuric
patients (HCþ ) ¼ 1.
Hypercalciuria and primary bone loss 211EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 149
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the worst degree of osteoporosis (359^44 vs 308^50,
P , 0.05).
Discussion
No clear-cut indications for the inclusion or exclusion
of urinary calcium excretion measurement as a first-
line diagnostic tool in patients with osteoporosis are
currently available. This probably occurs because
there are no comprehensive data on the prevalence
and the role of this defect in postmenopausal women
with low bone density.
Our study demonstrates that an apparently primary
form of hypercalciuria is present in up to 19% of post-
menopausal women with osteoporosis. The only data
concerning this issue have been recently published by
Tannenbaum and co-workers (8), who conducted a
chart-review study on otherwise healthy women with
osteoporosis. By means of laboratory testing, they
observed that a cumulative proportion of 32% of their
patients had a secondary form (unexpected on a clinical
basis) of decreased bone mass, with 10% of these sub-
jects showing hypercalciuria. This alteration was by
far the most frequent that they found in these patients.
In our study, the prevalence of hypercalciuria was
much higher than that in the paper by Tannenbaum
et al. (8). However, while we used a classical definition
of hypercalciuria (4), they referred to a different (and
higher) normal range for urinary calcium (12), having
enrolled oestrogen-deprived or -replete patients and on
very different dietary calcium intakes. Even taking into
account these differences, the two studies share the
finding that hypercalciuria is surprisingly common in
patients with a ‘primary’ form of osteoporosis.
Even fewer data exist on the meaning of hypercal-
ciuria in postmenopausal osteoporosis. The relation-
ships between bone metabolism and idiopathic
hypercalciuria have been extensively studied in patients
with calcium nephrolithiasis. In these subjects, the pre-
sence of reduced bone density has been clearly found to
be related to the increased urinary calcium excretion
(13). Our study may only partially help in addressing
the issue of a possible cause–effect relationship
between hypercalciuria and osteoporosis in those
women carrying this defect. However, our data show
that spinal bone mass is largely influenced by the
increased calcium excretion in hypercalciuric patients.
Accordingly, urinary calcium excretion was higher in
hypercalciuric patients with the worst degree of femoral
osteoporosis. These observations suggest that hypercal-
ciuria is a specific and important landmark of this form
of osteoporosis. The absence of differences in bone den-
sity between patients with and without hypercalciuria
does not argue against this hypothesis. Indeed, because
of the selection criteria, only patients with osteoporosis
have been recruited and this has made differentiation of
patients in terms of severity of bone loss rather unlikely.
Several considerations may strengthen the import-
ance and the specificity of the relationship between
osteoporosis and hypercalciuria. An increased risk of
fractures has been reported in patients with urolithiasis
(7). Although the reason for this remains unclear, hyper-
calciuria, which is present in up to 60 –70% of these
patients (14), may be one of the factors involved. Accord-
ingly, low bone density has been reported by most
authors in nephrolithiasic patients with hypercalciuria,
but not in those without (6, 15–17). Furthermore,
several retrospective and prospective studies have
shown that thiazide use is associated with a reduction
in fracture incidence (18–22) and an increase in bone
density (23 –25). In addition, although thiazides may
act directly on bone resorption (24, 25), the reduction
of renal calcium excretion remains the most important
contributing factor to the improvement in bone
density detected in thiazide-treated subjects (23–25).
This study has some limitations. Its design was retro-
spective and thus it was impossible to define the patho-
genesis and type of hypercalciuria (diet dependent or
independent). For the same reason, intestinal calcium
absorption and dietary protein intake were not
measured in these patients. However, subjects with sec-
ondary causes of hypercalciuria were not included. In
addition, it seems rather unlikely that a diet-dependent
form of hypercalciuria may have predominantly
occurred in our patients, because dietary calcium
intake was generally low. This also suggests that the
majority of our patients might suffer from a diet-inde-
pendent form of hypercalciuria, similar to that seen in
patients with kidney stones and low bone density
(6, 16, 17, 26). In addition, hypercalciuric patients
showed increased fractional calcium excretion, which
seems to indicate that at least part of the increase in
urinary calcium may not depend upon intestinal
calcium absorption. The reduced Tm phosphate
values in these patients further strengthen this hypoth-
esis. Finally, elevated urinary calcium excretion was
confirmed after a diet with a normal amount of dietary
proteins, and an excessive protein intake seems rather
unlikely to be common in patients at this age.
In conclusion, hypercalciuria is a very frequent
feature in women with reduced bone density. Increased
urinary calcium excretion and bone loss appear to be
linked, and these subjects seem to suffer from a peculiar
form of osteoporosis. Consequently, urinary calcium
excretion should be measured in osteoporotic patients
in order to identify those patients reporting this specific
alteration.
Table 5 Multiple regression analysis in patients with
hypercalciuria (HCþ ), with spinal T-score as a dependent
variable (R
2
¼ 61%).
b P
Age 2 0.35 0.03
Urinary Ca 2 0.72 , 0.0001
212 S Giannini and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 149
www.eje.org
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Received 31 January 2003
Accepted 5 June 2003
Hypercalciuria and primary bone loss 213EUROPEAN JOURNAL OF ENDOCRINOLOGY (2003) 149
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