2010_olmos_bone turnover markers and bone mineral density in hypertensive
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Maturitas 65 (2010) 396402
Contents lists available at ScienceDirect
Maturitas
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / m a t u r i t a s
Bone turnover markers and bone mineral density in hypertensivepostmenopausal women on treatment
Jos M. Olmos a,, Jos L. Hernndez a, Josefina Martnez a, Jess Castillo b, Carmen Valero a,Isabel Prez Pajares b, Daniel Nan a, Jess Gonzlez-Macas a
a Department of Internal Medicine, Hospital Universitario Marqus de Valdecilla, University of Cantabria, RETICEF, Santander, Spainb Centro de Salud Jos Barros, Camargo, University of Cantabria, Santander, Spain
a r t i c l e i n f o
Article history:
Received 30 August 2009
Received in revised form 7 January 2010
Accepted 8 January 2010
Keywords:
Hypertension
Thiazides
Bone mineral density
Quantitative ultrasound
Parathyroid hormone
Bone turnover markers
a b s t r a c t
Objective: To evaluate bonemineral density (BMD)and bonemetabolismin hypertensive postmenopausal
women, and to differentiate the effect of thiazides from that of other antihypertensive agents.
Subjects and methods: A community-based population of 636 postmenopausal women, 293 with hyper-
tension (160 receiving thiazides, and 133 receiving other antihypertensive treatments), and 343 control
women, were evaluated.Serum levels of aminoterminalpropeptide of type I collagen (P1NP), C-terminal
telopeptide of type I collagen (-CTX), 25-hydroxivitamin D, and intact parathyroid hormone were mea-sured by electrochemiluminiscence. BMD was determined by DXA, and heel quantitative ultrasound
measurements (QUS) with a gel-coupled device.
Results: BMD expressed as Z-score was higher in both groups of hypertensive women at all locations.
Expressed as g/cm2, it was also higher in patients on thiazides at femoral neck and lumbar spine. Only
in the latter site, differences remained significant after adjusting for potential confounding variables,
including BMI. Bone turnover markers were lower in both groups of hypertensive women, although
the difference was greater in those on thiazides. After adjusting for potential confounders, differences
remained significant only in the thiazide group.
Conclusions: Our results add evidence to the idea that thiazides are beneficial to prevent bone loss.
2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction
Osteoporosis is a disease characterized by an increase in bone
fragility, resulting in fractures induced by low-energy trauma or
even of a spontaneous nature. It is estimated that more than one-
third of all Caucasian women over the age of 50 will suffer a
fracture of the spine, hip or wrist in their life-time [1,2]. Dual X-
ray absorptiometry (DXA) is recognized as the reference method
for measuring bone mineral density (BMD), and for each standard
deviation decrease in BMD, fracture risk approximately doubles
[2]. In recent years, quantitative ultrasound (QUS) measurements
Abbreviations: BMD, bone mineral density; BMI, body mass index; BMT, bone
turnover markers; BUA, broadband ultrasound attenuation; -CTX, C-terminal
telopeptide of type I collagen; cCa, albumin-corrected serum total calcium; CV,
coefficients of variation; DXA, dual X-ray absorptiometry; eBMD, estimated bone
mineral density; FN, femoral neck; iPTH, intact parathyroid hormone; LS, lumbar
spine; NHANES III, Third National Health and Nutrition Examination Survey; P1NP,
aminoterminal propeptide of type I collagen; QUI, quantitative ultrasound index;
QUS, quantitative ultrasound measurements; SD, standard deviation; SOS, speed of
sound; TCa, serum total calcium; TH, total hip; 25OHD, 25-hydroxivitamin D. Corresponding author. Tel.: +34 942202513; fax: +34 942201695.
E-mail address: [email protected] (J.M. Olmos).
have been proposed as an alternative method for the non-invasive
assessment of skeletal status, as they reflect not only the BMD but
also qualitative aspects of bone such as elasticity, structure and
geometry [3].
On the other hand, hypertension is a chronic disease charac-
terized by progressive damage to target organs, such as the heart,
kidney and brain. Its prevalence increases with age, as osteoporo-
sis does [4]. However, the relationship between both disorders has
not been clearly established. Thus, in several studies, hyperten-
sion has been shown to be inversely correlated with bone mineral
content [5], whereas a direct relation [6] or no significant associ-
ation [7] with BMD has also been described in others. Moreover,information about the long-term effects of antihypertensive treat-
ment on BMD is scarce, except in the case of thiazides. It has been
suggested that thiazide diuretics, which are commonly used to
treat hypertension, may be of benefit in the prevention of osteo-
porosis. As a matter of fact, large epidemiologic studies, either
prospective or case-control designs, have consistently shown that
thiazides are associated with a risk reduction in osteoporotic frac-
tures [812]. In addition, in most, but not all, studies, the use
of thiazides has been associated with higher BMD in both sexes
[1317]. Moreover, a decrease in bone turnover markers has also
beenreported[13,14,1618]. However, no significant changeshave
0378-5122/$ see front matter 2010 Elsevier Ireland Ltd. All rights reserved.
doi:10.1016/j.maturitas.2010.01.007
http://www.sciencedirect.com/science/journal/03785122http://www.elsevier.com/locate/maturitasmailto:[email protected]://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.maturitas.2010.01.007http://localhost/var/www/apps/conversion/tmp/scratch_3/dx.doi.org/10.1016/j.maturitas.2010.01.007mailto:[email protected]://www.elsevier.com/locate/maturitashttp://www.sciencedirect.com/science/journal/03785122 -
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J.M. Olmos et al. / Maturitas 65 (2010) 396402 397
been described in QUS parameters in postmenopausal women
treated with thiazides [19].
A number of mechanisms have been proposed to explain the
positive effects of thiazides on osteoporosis. These diuretics reduce
renal calcium excretion and may cause a positive calcium balance,
decreasing plasma levels of parathyroid hormone (PTH) and thus,
reducing bone turnover [13,14,16,20]. Nevertheless, experimental
data do not fully support this hypothesis, since conflicting results
have been reported on the effect of thiazides on calciotropic hor-
mones. Both 1,25(OH)2D and PTH levels have been reported as
being decreased, unchanged, and evenincreasedin response to thi-
azide treatment [17,18,2126], suggesting that these agents might
have a direct action on bone [17,26].
The aim of the present study was to evaluate bone turnover
markers and BMD, estimated by DXA and QUS, in a population-
basedstudy of hypertensivepostmenopausal women on treatment,
andto determine the effectof thiazides andotherantihypertensive
drugs on calcium homeostasis and bone mass.
2. Subjects and methods
2.1. Study design and participants
The study population was set up with postmenopausal women
included in the Camargo Cohort Study. The Camargo Cohort is a
community-based study established to evaluate the prevalence of
metabolic bone diseases as well as the prevalence of risk factors
for osteoporosis and fragility fractures in postmenopausal women
and men older than 50 in our region. Blood analysis, including
parameters related to bone metabolism (PTH, 25OHD, and bone
turnovermarkers), DXAand QUS measurements, as wellas thoracic
and lumbar spine radiographs, were performed in each participant.
A questionnaire including diseases, treatments and risk factors
related to bone and mineral metabolism (see below) was filled out
foreveryone of them. Additionally, advantage wastakenof the fact
that the cohort was also being set up to analyze aspects related to
vascular diseases, and information on this subject (e.g., history ofdyslipidemia or hypertension, or treatment for bothdisorders) was
also collected. Participants were recruited at a Primary Care Centre
in Northern Spain, while attending for medical reasons or for their
regular health examination, whichever happened first. Because of
this routine check up, all postmenopausal women are expected to
attend the centre annually.
In the current study we have included the first 794 consecu-
tive postmenopausal women attending the clinic. Because of the
goal of the study, women whose baseline assessment revealed
the presence of diseases or treatments (other than antihyperten-
sive drugs) known to affect bone metabolism, such as primary
hyperparathyroidism, hyperthyroidism, osteoporosis, serum crea-
tinine> 151mol/l, or treatment withbisphosphonates, oestrogen,
raloxifene, strontium ranelate, teriparatide, l-thyroxinor glucocor-ticoids, were excluded. All participants were white, as more than
95%of people in our region(Cantabria). Thestudywas approved by
the local Ethics Committee, and all subjects gave written informed
consent.
At the baseline visit, women were interviewed by investiga-
tors and all participants provided data regarding the risk factors
for osteoporosis and fractures using a structured questionnaire
which included age, race, weight, height, body mass index (BMI),
age of menarcheand menopause, personal antecedents of fractures
in adulthood (>40 years), history of osteoporotic fractures among
first-degree relatives, tobacco use, dairy calcium intake, alcohol
consumption, physical exercise, number of falls in the previous
year, presence of chronic diseases (hypertension, dyslipidemia,
diabetes mellitus, urolithiasis, hyperthyroidism, hyperparathy-
roidism, etc.); and present or past use of medications, including
diuretics and antihypertensive agents. BMI was defined as weight
(kg)dividedby squared height (m2). Tobaccosmokingwas assessed
as current smoker, former smoker or never smoker. Dairy calcium
consumption was assessed by a food frequency questionnaire [3].
Regarding alcohol consumption, participants were asked for how
much they had consumed during the past 30 days and how many
times they had consumed three or more drinks per day during this
period. Habitual physical activity was classified as high (moving,
walking and working energetically and participating in vigorous
exercise), moderate (walks reasonable distances, does light house-
work shopping or equivalent, normal activities of day-to-day living
but no appreciable exercise), and sedentary (little walking outside
home, or sits in a chair or lies in bed most of the time). Hyperten-
sion was defined according to the Joint National Committee (JNC
VII) criteria. The presence of subclinical thyroid dysfunction was
excluded by determination of serum T4 and TSH levels.
2.2. Biochemical tests
Blood samples were obtained in a fasting state between 09:00
and 10:30h. Serum was divided into 0.5-ml aliquots and stored at
40 C. Serum total calcium (TCa), phosphate, glucose, creatinine,
total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides,albumin, and total alkaline phosphatase measurements were
determined by standard automated methods in a Technicon Dax
autoanalyser (Technicon Instruments, CO, USA). TCa measure-
ments were corrected for albumin concentration (cCa) following
a previously published formula [27]. Serum concentrations of
aminoterminal propeptide of type I collagen (P1NP), C-terminal
telopeptide of type I collagen (-CTX), 25-hydroxyvitamin D3(25OHD), and intact parathyroid hormone (iPTH) were determined
by a fully automated electrochemiluminiscence system (Elecsys
2010, Roche Diagnostics, GmbH, Mannheim, Germany). The P1NP
limit of detection was 5 ng/ml (reference range between 20 and
76 ng/ml), with an intraassay and interassay coefficients of vari-
ation (CV) of 3.1% and 3.5%, respectively [28]. Intraassay and
interassay CV for-CTX were 4.2% and 4.7%, andits reference rangeof 0.1081.033ng/ml, respectively [29]. The detection limit of
serum25 OHDwas4 ng/ml, itsintraassayCV was5%,andits interas-
say CV was 8.5%. Regarding iPTH, the detection limit was 6 pg/ml,
with a normal range of 1565 pg/ml. Intraassay and interassay CV
were 5.4% and 5.9%, respectively.
2.3. DXA measurements
BMD was measured by DXA (Hologic QDR 4500, Bedford, MA,
USA) at the lumbar spine (L2L4), and proximal right femur
(femoral neck [FN], and total hip [TH]). BMD (g/cm2) for each sub-
ject was calculated by dividing the amount of bone mineral content
by the projected area of the region of interest. In vivo precision
was 0.41.5% at the different measurement sites. Results were alsoexpressed as T-score (defined as the number of standard devia-
tions [SDs] below the mean value of young women) and as Z-score
(defined as the number of SDs below the mean for women of the
same age). Only one measurement was obtained from each par-
ticipant. Quality control was performed according to the usual
standards [30].
2.4. Quantitative ultrasound measurements
Calcaneal QUS measurements were performed using the Sahara
ClinicalSonometer (Hologic,Walthman,MA, USA), which measures
bothbroadband ultrasoundattenuation (BUA) (dB/MHz) and speed
of sound (SOS) (m/s) at a fixed region of interest in the right mid-
calcaneus. The BUA and SOS results are combined to provide the
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Table 1
Baseline characteristics of the study population (mean SD).
On thiazides On other anti-hypertensives Control group
Age (years) 679*** 659*** 608
Weight (kg) 7314*** 7212*** 6711
Height (cm) 1556 1556 1566
BMI (kg/m2) 30.25.2*** 30.34.9*** 27.74.5
Waists circumference (cm) 10012*** 10313*** 9212
Age of menarche (years) 132 132 132
Age of menopause (years) 49
5 49
4 49
5History of falls (last year) (%) 32* 26 22
Any fracture >40 years (%) 20 18 15
Family history of fractures (%) 12 18 16
Physical activity
Sedentary (%) 6 3 3
Moderate (%) 41 48 42
High (%) 53 49 55
Current smoking (%) 11* 8* 17
Current alcohol consumption [> 2 units/day] (%) 8 10 9
Dairy calcium consumption (mg/day) 684400 663327 665314
Calcium supplements (%) 10 11 11
Vitamin D supplements (%) 8 12 9
Dyslipidemia (%) 36** 44*** 24
Diabetes mellitus (%) 15*** 20*** 3
Urolithiasis (%) 11 11 10
BMI: body mass index.* p < 0.05 (differences with control group).
** p < 0.01 (differences with control group).
*** p < 0.001 (differences with control group).
quantitative ultrasound index (QUI),and theestimatedbone min-
eral density (eBMD) of the calcaneus in g/cm2. Moreover, eBMD is
also reported based on its T-score. The European reference popu-
lation used for its calculation [31] yields results similar to those
obtained with the application of values from Spanish women, as
has been previously published [32]. Only one measurement was
also performed in each patient. In vivo short-term precision was
4.9% for BUA, 0.4 for SOS, 3.4% for QUI, and 4.1% for eBMD.
Quality controls were performed daily by scanning
manufacturer-provided phantoms.
2.5. Statistical analyses
Results were expressed as meanSD for quantitative variables
and percentages for qualitative variables. Data were analyzed for
normality, and,as appropriate, underwent logarithmic transforma-
tion. Chi-squared test or Fishers exact test was performed in order
to identify differences in categorical variables between groups.
Students t-testor MannWhitneyU-testwas used tocompare non-
categorical variables between the overall group of hypertensive
women and controls. One-way ANOVA with Bonferroni post hoc
test or KruskallWallis test were performed to analyze differences
among the threegroups of subjects included in the study hyperten-
sive women on thiazides, on other antihypertensive agents, andcontrols. Multiple stepwise linear regression models were con-
structed to adjust site-specific BMD and bone markers for age,
BMI, smoking habits, alcohol consumption, physical activity, dairy
calcium intake, history of falls in the previous year, diabetes, dys-
lipidemia, current -blockers and statin use, serum calcium, iPTH,25OHD, PINP and -CTX levels. All p-values 151mol/l), or because they wereon drugs known to affect bone metabolism. Of the remaining
636 women, 160 were receiving thiazide diuretics (hydrochloroth-
iazide: 12.550mg/day) for more than 1 year, due to hypertension,
whether alone (32 women) or in combination with other anti-
hypertensive agents (128 women), and 133 were only on
antihypertensive drugs other than thiazides (-blockers [25.6%],calcium channel blockers [15%], angiotensin converting enzyme
inhibitors or angiotensin receptor antagonists [66.2%], and loop
diuretics [37%]). Normotensive women who were not on thiazideor on other antihypertensive drugs were considered as the control
group(n = 343). The baseline characteristics of the study population
are listed in Table 1.
Hypertensive women on thiazides or on other antihypertensive
treatments were older than controls, and also had greater body
weight, BMI, and waist circumference values. Moreover, hyper-
tensive postmenopausal women had higher prevalence of diabetes
mellitus and dyslipidemia thancontrols. Conversely, current smok-
ing was less frequent in these patients. On the other hand, women
on thiazides reported a greater number of falls during the previ-
ous year, and both groups of hypertensive women showed a slight
non-significant higher number of fractures after 40 years of age
than controls. No differences in other risk factors for osteoporosis
or fractures were observed between either group of hypertensivewomen and controls (Table 1).
As previously indicated, most of hypertensive women treated
with thiazides were not on these agents alone, but received a com-
bination of several drugs. The percentage of patients treated with-blockers or calcium channel blockers, was similar in hyperten-sive women receiving thiazides and in those not receiving these
drugs (16.9%vs. 25.6% [p = 0.08] and 14.4% vs. 15% [p = 0.87], respec-
tively). However, current use of angiotensin converting enzyme
inhibitors or angiotensin receptorantagonistswas lower in patients
treated with thiazides (50.6% vs. 66.2%, p = 0.01).
The percentage of current statin users was also similar in both
groups of hypertensive patients (27.7% vs. 34.6%, p = 0.20); how-
ever, it was higher than in controls (13%, p < 0.0001 in both cases).
Serum glucose was higher in both groups of hypertensive women
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Table 2
Biochemical parameters in postmenopausal women on thiazides, on other antihypertensive agents, and in controls (mean SD).
Hypertensive women (N= 293) On t hiazides (N=160) On other anti-hypertensives (N= 133) Con tr ol group (N=343)
Glucose (mmol/l) 5.38 1.49*** 5.44 1.60*** 5.33 1.44** 4.94 0.72
Creatinine (mol/l) 88 14 88 14 88 27 85 20
Total cholesterol (mmol/l) 5.74 1.00* 5.71 1.00* 5.84 0.96 5.92 0.96
HDL-cholesterol (mmol/l) 1.45 0.36** 1.45 0.39* 1.47 0.39 1.53 0.39
LDL-cholesterol (mmol/l) 3.67 0.88** 3.65 0.88* 3.72 0.85 3.85 0.82
Triglycerides (mmol/l) 1.4 2 0.83** 1.39 0.82* 1.44 0.76* 1.21 0.64
Calcium (mmol/l) 2.43
0.10**
2.44
0.10**
2.43
0.10 2.41
0.09Phosphate (mmol/l) 1.16 0.11 1.13 0.11* 1.16 0.13 1.16 0.13
Albumin (g/l) 45 3 45 3 45 2 45 3
cCa (mmol/l) 2.31 0.09** 2.31 0.09** 2.30 0.09 2.28 0.08
Alkaline phosphatase (U/l) 72 20 70 17 75 22 71 19
25OHD (ng/ml) 23 8** 23 8* 23 9* 25 9
iPTH (pg/ml) 54 20* 55 21* 55 32* 51 23
P1NP (ng/ml) 43.0 21.3*** 41.9 20.8*** 44.6 21.3** 50.5 17.9
-CTX (ng/ml) 0.329 0.186*** 0.308 0.188*** 0.361 0.176* 0.411 0.184
cCa: albumin-corrected serum total calcium; 25OHD: 25-hydroxyvitamin D; iPTH intact parathyroid hormone; P1NP: aminoterminal propeptide of type I collagen; -CTX:
C-terminal telopeptide of type I collagen.* p < 0.05 (differences with control group).
** p < 0.01 (differences with control group).*** p < 0.001 (differences with control group).
comparedtothecontrolgroup(p < 0.01). Totalalkaline phosphatase
and creatinine levels were similar in women on thiazides or onother antihypertensive drugs as well as in the control group. Total
and albumin-corrected serum calcium were significantly higher
(p < 0.01) in the thiazide group than in controls. In the non-thiazide
hypertensive group, serum calcium levels were also higher than in
controls, but not significantly so. Serum iPTH was increased and
serum 25OD slightly, but significantly, decreased in both groups of
hypertensive women compared to controls (Table 2).
As expected, iPTH was negatively related with 25OHD levels
in each group (women on thiazides: r=0.215, p < 0.01; on other
antihypertensive drugs: r=0.368, p < 0.001; controls: r=0.314,
p < 0.001).
Regarding biochemical markers of bone remodeling, serum
P1NP and -CTX were significantly lower in hypertensive women
than in controls (Table 2). The decrease was more pronouncedamong thiazide users, in which a 17% and 25% decrease in serum
P1NP and -CTX levels, were observed, respectively (p < 0.001).Women on other antihypertensive drugs also have significantly
lower levels of both markers compared with controls, although in
this case changes were less pronounced (11% and 12%, respec-
tively; p < 0.05).
As shown in Table 3, BMD at the lumbar spine and hip
was higher in hypertensive women than in controls. Women
on thiazides had higher BMD at the lumbar spine (+3.8%;
p < 0.05) and at the femoral neck (+3.4%; p < 0.05) than con-
trols (Table 3). No significant differences were observed at the
total hip (+2.4%). However, when BMD was expressed as Z-score,
implying an age-adjustment, its values were higher at all levels
(Table 3). Women on antihypertensive agents other than thiazides
tended to show higher BMD values (expressed as g/cm2) at the
three sites, although differences did not reach statistical signif-
icance. When results were expressed as Z-score, BMD was also
higher at all bone locations (Table 3). Regarding QUS parame-
ters, no differences were found between patients on thiazides
(BUA: 64.818.9dB/mHz; SOS: 154032 m/sg; QUI: 87.919.7;
eBMD: 0.4790.125 g/cm2), other anti-hypertensives (BUA:
63.721.1 dB/mHz; SOS: 153934m/sg; QUI: 86.522.1; eBMD:
0.4720.140 g/cm2), and controls (BUA: 64.119.4dB/mHz; SOS:
154331m/sg; QUI: 87.419.9; eBMD: 0.4760.126 g/cm2).
Nevertheless, QUS and DXA measurements were significantly
related at any paired combination. The higher r values were
seen when total hip was one of the elements of the pair
(Table 4).
A stepwise multiple regression analysis was performed with
lumbar spine, femoral neck BMD and bone turnover markers asdependent variables, and age, BMI, smoking habits, alcohol con-
sumption, physical activity, dairy calcium intake, history of falls in
the previous year, diabetes, dyslipidemia, current -blockers andstatin use, serum calcium, iPTH, 25OHD, PINP and -CTX as inde-pendent variables, as previously stated. After adjustment, lumbar
spine BMDwas related with age, BMI, and thiazide use, butnot with
antihypertensive agents other than thiazides (Table 5). Thiazides
explainedabout 1%of the variabilityin lumbarspine BMD. Noinflu-
ence of thiazide use was noted regarding femoral neck or total hip
BMD. On the other hand, bone turnover markers were lower in
hypertensive women on treatment, although the difference was
greater in those on thiazides. After adjusting for confounders, dif-
ferences remained significant only in the thiazide group (data not
shown).
4. Discussion
In thepresent study we have compared BMDand bone turnover
markers in women with essential hypertension with those of
a control group, in the setting of a cohort of postmenopausal
women established to assess the prevalence of bone and calcium
metabolism disorders. Treated hypertensive women were divided
into two groups according to whether they were (or were not) on
thiazide treatment, irrespective of whether theywere also on other
antihypertensive drugs. The percentage of women on angiotensin
converting enzyme inhibitors or angiotensin receptor antagonists
was somewhat lower in women on thiazides than in those without
(50.6% vs. 66.2%), but no significant differences were found relatingto -blockers or calcium channel blockers. As expected, hyperten-sive womenwere older,had greater BMIandsuffered from diabetes
or dyslipidemia more frequently than those without hypertension.
BMD expressed as Z-score (which implies an adjustment for age)
was higher in both groups of hypertensive women at the three
measured levels (lumbar spine, femoral neck and total hip). BMD
expressed in absolute terms (g/cm2) was also higher in patients
on thiazides at the femoral neck and lumbar spine. Only the latter
difference remained significant after adjusting for potential con-
founding variables, including BMI. Bone turnover markers (both
P1NP and -CTX) were lower in the two groups of hypertensivewomen, although the difference was greater in those on thiazides.
Afteradjusting for potentialconfounders,differences remainedsig-
nificantonly in thethiazide group. Other differences found between
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Table 3
Comparisons of the BMD measured by DXA in the two study groups (mean SD).
Hypertensive women On thiazides On other anti-hypertensives Control group
LS (g/cm2) 0.926 0.132* 0.934 0.142* 0.922 0.123 0.898 0.132
T-score 1.38 1.20* 1.32 1.30* 1.43 1.12 1.62 1.20
Z-score 0.49 1.26*** 0.62 1.33** 0.38 1.17** 0.11 1.23
FN (g/cm2) 0.730 0.105 0.738 0.111* 0.727 0.109 0.713 0.115
T-score 1.65 1.05 1.57 1.10 1.68 1.09 1.80 1.16
Z-score 0.37 1.03*** 0.49 1.07** 0.30 1.04** 0.13 1.12
TH (g/cm2
) 0.874
0.114 0.871
0.122 0.874
0.112 0.850
0.126T-score 0.85 0.94* 0.87 1.01 0.85 0.93 1.04 1.05
Z-score 0.61 0.96*** 0.64 0.97** 0.57 0.97** 0.11 1.04
BMD: bone mineral density; LS: bone mineral density at the lumbar spine; FN: bone mineral density at the femoral neck; TH: bone mineral density at the total hip.* p < 0.05 (differences with control group).
** p < 0.01 (differences with control group).*** p < 0.001 (differences with control group).
Table 4
Relationship between QUS and BMD parameters in the whole population.
LS (g/cm2) FN (g/cm2) TH (g/cm2)
BUA (dB/mHz) 0.310* 0.287* 0.349*
SOS (m/sg) 0.312* 0.293* 0.353*
QUI 0.329* 0.316* 0.376*
eBMD (g/cm2) 0.331* 0.317* 0.375*
QUS:quantitative ultrasound; BMD:bone mineral density;LS: bonemineraldensityat the lumbar spine; FN: bone mineral density at the femoral neck, TH: bone min-
eral density at the total hip; BUA: broadband ultrasound attenuation. SOS: speed of
sound; QUI: quantitative ultrasound index; eBMD: estimated bone mineral density
of the calcaneus.* p < 0.0001.
patients on thiazides and controls were higher serum levels of cal-
cium and iPTH, and lower levels of 25OHD. Hypertensive women
on non-thiazide treatment also showed lower concentrations of
25OHD; serum levels of calcium and iPTH were higher than in
controls, but not significantly so.
Differences in bone and calcium metabolism between the non-
thiazide group and the control group are cancelled out after
adjusting for factors associated with both BMD and hypertension,
such as age or BMI. However, the differences between the thiazide
andcontrolgroup, besides beingmore pronounced than inthe non-
thiazide group, remain after adjustment, indicating that the drug
itself plays a role in this case. The possibility could also be enter-
tained that patients selected for treatment with the diuretic were
somehow different in nature from other hypertensive women, but
such a possibility seems very unlikely, since no important differ-
ences between them were observed regarding age, weight, glucose
and creatinine levels, statin treatment, etc. (see Tables 1 and 2).
The relationship between hypertension and bonemass has been
widely studied, although data have been inconclusive. In a cross-
sectional study, Hanley et al. [6] found that hypertension was
associated with higherBMD in womenand men, particularly at the
lumbar spine. However, Tsuda et al.[5] found that high blood pres-
sure was associated with reduced BMD in women, and Cappuccio
Table 5
Multivariate linear regression analysis (lumbar spine BMD [g/cm2] as a dependent
variable).a .
-Coefficient p
On thiazides 0.142 0.001
On other antihypertensive agent 0.062 0.15
BMI (kg/m2) 0.229
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decrease in bone turnover markers, in spite of higher serum PTH
levels, supporting the idea of a direct effect of thiazides on bone
[42,43].
No statistical significant changes were found in QUS measure-
ments in hypertensive women. To our knowledge, the relationship
between hypertension and QUS has not been previously studied.
Nevertheless, in a population-based study, van Daele et al. [19] did
not observe that treatment with thiazides affects ultrasound mea-
surements, an observation which is in agreement with our results.
Interestingly, a trend to a higher number of falls was seen in
hypertensive women, which reached a significant difference in the
case of women on thiazides. In addition, both groups of hyperten-
sive women showed a slightly higher number of fractures after 40
yearsof age,although thedifference wasnot significant.This coinci-
dence raises the possibility thatboth findingsare related, fallsbeing
a contributory factor for fracture development. There is no clear
reasonfor the increase infallsin hypertensive women,butthereare
a number of possible explanations that may be entertained, such
as episodes of hypotension in the case of drug overdose, or even
transient ischemic attacks. Diabetes is commoner in hypertensive
patients than in controls, and polyneuritis could also be consid-
ered. On the other hand, the greater number of fractures in patients
on thiazides is at contradiction with the supposed beneficial effect
of these drugs on bone mass. In dealing with this contradictionwe should take into account that the difference we have found,
although suggestive, is not significant. But if we accept that such
a difference may indeed be real, we have to consider, along with
the falls previously commented on, the possibility of bone quality
changes. For instance, coming backto the greater prevalence of dia-
betesin hypertensive patients,it has beenpointed out thatcollagen
glycosylation, through the pentosidine cross-links, may result in a
deterioration of bone quality and the corresponding fractures [44].
Our study has several limitations. As an observational study, it
is therefore subject to some possible bias due to confounding fac-
tors. However, adjustment for many potential confounding factors
such as age or weight has been carried out. In addition, obser-
vational studies often lack information on some details that may
be of some interest. In our case, we did not have precise infor-mation on the length of thiazide treatment. It could have been of
interest to relate this length with the effect of the drug on bone
metabolism. However, in real life, patients tend to follow treat-
ments somewhat irregularly, and therefore no precise therapeutic
periods may be defined. Therefore, we decided to ask for a year
of well followed treatment. By the same token, in everyday prac-
tice, some measurements are difficult to carry out, as it is the case
with 24h urine collections. Consequently, we do not have 24h uri-
nary calcium excretion values, which could have been interesting,
as they usually are when bone and mineral metabolism is studied.
Nevertheless, it is well known that thiazides interfere with urinary
calcium excretion. In our study, therefore, this parameter may not
be as important as in others.
In summary, we have found that hypertensive women on treat-ment with thiazides show higher BMD and lower bone turnover
markers than controls. Hypertensive women on treatments other
than thiazides show similar changes, although to a lesser extent.
Adjustingfor possible confounders, such as BMI, cancels out differ-
ences in non-thiazidetreatedpatients, but notin those on thiazides.
This suggests that,in thefirst group, such differences areaccounted
for by factors related to hypertension, of which overweight maybe
an example. However, the findings reported for the second group
seem to indicate that thiazides themselves are responsible for the
changes described in bone and calcium metabolism. Therefore, our
results add evidence to the idea that thiazides are beneficial to pre-
vent bone loss. This may be a factor to take into account when
choosing treatment among the several antihypertensive drugs,
especially in postmenopausal women at risk of osteoporosis.
Conflict of interest
No conflict of interest was declared.
Funding
This study was supported by grants from the Fondo de Inves-
tigacin Sanitaria, Ministerio de Sanidad y Consumo, Spain (FIS:
PI05 0125 and FIS: PI08 0183) and Instituto de Formacin eInvestigacin Marqus de Valdecilla, Santander, Spain (IFIMAV:
API/07/13).
Contributors
Jos M. Olmos: Conception, design, interpretation, and coor-
dination of the work, as well as to write the manuscript. Jos L.
Hernndez, Execution of the statistical analysis and interpreta-
tion of the study. Revision of the manuscript. Josefina Martnez:
Execution of biochemical studies and interpretation of the results.
Jess Castillo: Recruitment of subjects, interpretation of the study.
Carmen Valero: Execution of BMD and ultrasound studies and
interpretation of the results of the study. Isabel Prez Pajares:
Recruitment of subjects, interpretation of the study. Daniel Nan:Participation in recruitment o f subjects, and execution of BMD
studies. JessGonzlez-Macas: Conception, design, interpretation,
and revision of the manuscript.
Ethical approval
The study protocolwas approvedby thelocal EthicalCommittee.
References
[1] WHOStudyGroup. Assessment of fracture risk andits applicationto screeningfor postmenopausal osteoporosis. Technical report series 843. Geneva: WHO;1994.
[2] Melton III LJ, Chrischilles EA, Cooper C, Lane AW, Riggs BL. How many women
have osteoporosis? J Bone Miner Res 1992;7:100510.[3] Dez A, Gonzlez-Macas J, Marn F, et al. Prediction of absolute risk of non-
spinal fractures using clinical risk factors and heel quantitative ultrasound.Osteoporos Int 2007;18:62939.
[4] Prez-CastrillnJL, JustoI, Sanz-CantalapiedraA, Pueyo C,Hernndez G,DuenasA. Effect of the antihypertensive treatment on the bone mineral density andosteoporotic fracture. Curr Hypertens Rev 2005;1:616.
[5] Tsuda K, Nistui I, Masuyama Y. Bone mineral density in women with essentialhypertension. Am J Hypertens 2001;14:7047.
[6] Hanley DA, Brown JP, Tenenhause A, et al. Associations between disease con-ditions, bone mineral density, and prevalent vertebral deformities in men andwomen 50 years of age and older: cross-sectional results of the Canadian Mul-ticentre Osteoporosis Study. J Bone Miner Res 2003;18:78490.
[7] Mussolino ME,GillumRF. Bonemineral densityand hypertensionprevalence inpostmenopausal women: results fromthe ThirdNational Health and NutritionExamination Survey. Ann Epidemiol 2006;16:3959.
[8] Renjmark L, Vestergaard P, Mosekilde L. Reduced fracture risk in users of thi-azide diuretics. Calcif Tissue Int 2005;76:16775.
[9] CauleyJA, CummingsSR, SeeleyDG, etal. Effects ofthiazidediuretic therapy on
bone mass, fractures, and falls. The Study of Osteoporotic Fractures ResearchGroup. Ann Intern Med 1993;118:66673.
[10] Feskanisch D, Willet WC, Stampfer JM, Golditz GA. A prospective study of thi-azide use and fractures in women. Osteoporos Int 1997;7:7984.
[11] Schoofs MW, van der Klift M, Hofman A, et al. Thiazide diuretics and the riskfor hip fracture. Ann Intern Med 2000;139:47682.
[12] La Croix AZ, Wienpahl J, White LR, et al. Thiazide diuretic agents and the inci-dence of hip fracture. N Engl J Med 1990;322:28690.
[13] LaCroix AZ,Ott SM,IchikawaL, Scholes D, BarlowWE. Low-dosehydrocloroth-iazide and preservation of bone mineral density in older adults A randomized,double-blind, placebo-controlled trial. Ann Intern Med 2000;133:51626.
[14] Bolland MJ,AmesRW,HorneAM,Orr-WalkerBJ, GambleGD,Reid IR.Theeffectof treatment with a thiazide diuretic for 4 years on bone density in normalpostmenopausal women. Osteoporos Int 2007;18:47986.
[15] Wasnick RD, Davis J, Ross P, Vogel J. Effect of thiazide on rates of bone mineralloss: a longitudinal study. Br Med J 1990;301:13035.
[16] SigurdsonG, Franzson L. Increasedbone mineral density in a population-basedgroupof 70-year-old women on thiazide diuretics,independentof parathyroid
hormone levels. J Intern Med 2001;250:516.
-
7/27/2019 2010_Olmos_Bone Turnover Markers and Bone Mineral Density in Hypertensive
7/7
402 J.M. Olmos et al. / Maturitas 65 (2010) 396402
[17] Rejnmark L, Vestergaard P, Heickendorff L, Adreansen F, Mosekilde L. Effectsof thiazide- and loop-diuretics, alone or in combination, on calciotropic horm-mones and biochemical bonemarkers:a randomizedcontrolled study. J InternMed 2001;250:14453.
[18] Reid IR, Ames RW, Orr-Walker BJ, et al. Hydrochlorothiazide reduces loss ofcorticalbone innormalpostmenopausalwomen:a randomizedcontrolledtrial.Am J Med 2000;109:36270.
[19] van Daele PL, Burguer H, Algra D, et al. Age-associated changes in ultrasoundmeasurements of the calcaneus in men and women: the Rotterdam Study. JBone Miner Res 1994;9:17517.
[20] Transbol I, Christensen MS, Jensen GF, Christiansen C, McNair P. Thiazide for
the postponement of postmenopausal bone loss. Metabolism 1982;31:3836.[21] Bauer DC, Browner WS, Cauley JA, et al. Factors associated with appendicu-
lar bone mass in older women. The Study of Osteoporotic Fractures ResearchGroup. Ann Intern Med 1993;118:65765.
[22] Reusz GS, Dobos M, Vasarhely B, et al. Sodium transport and bone mineraldensity in hypercalciuria with thiazide treatment. Pediatr Nephrol 1998;12:304.
[23] Middler S, Pack CY, Murad F, Bartter FC. Thiazide diuretics and calciummetabolism. Metabolism 1973;22:13946.
[24] Nowack R, Hofner MC, Reichel H, Schmidt Gayk H, Ritz E. Subacute effects ofthiazide administrationon renalhemodynamicsand calcium metabolism. ClinInvest 1992;70:68991.
[25] Lemann JJ, Gray RW, Malerhofer WJ, Cheung HS. Hydrochlorothiazideinhibits bone resorption in men despite experimentally elevated serum 1,25-dihydroxyvitamin D concentrations. Kidney Int 1985;28:9518.
[26] Lalande A, Roux S, Denne MA, et al. Indapamide, a thiazide diuretic decreasebone resorption in vitro. J Bone Miner Res 2001;16:36170.
[27] Berry EM, Gupta MM, Turner SJ, Burns RR. Variations in plasma calcium withinduced changes in plasma specific gravity, total protein, and albumin. Br Med
J 1973;IV:6403.[28] GarneroP, VergnaudP, Hoyle N. Evaluationof a fullyautomated serumassayfor
totalN-terminal propeptideof typeI collagen in postmenopausalosteoporosis.Clin Chem 2008;54:18896.
[29] Garnero P, Borel O, Delmas PD. Evaluation of a fully automated serum assayfor C-terminal cross-linking telopeptide of type I collagen in osteoporosis. ClinChem 2001;47:694702.
[30] Riancho JA, Valero C, Hernndez JL, et al. Biomechanical indices of the femoralneck estimated from the Standard DXA output: age- and sex-related differ-ences. J Clin Densitomet 2007;10:3945.
[31] Alenfeld FM, Engelke K, Schmidt T, Bredzger M, Diessel E, Felsenberg D.Diagnostic agreement of two calcaneal ultrasound devices: the Sahara bonesonometer and the Achilles+. Br J Radiol 2002;75:895902.
[32] Sosa M, Saavedra P, Munoz M, et al. Quantitative ultrasound calcaneusmeasurements:normativedata andprecision inthe Spanishpopulation. Osteo-poros Int 2002;13:48792.
[33] Cappuccio FP, Meihlan E, Zmuda JM, Cauley JA. High blood pressure andbone mineral loss in elderly white women: a prospective study. Lancet1999;354:9715.
[34] Kamel HK. Low-dose thiazide and bone density. Lancet 2002;136:2523.[35] OttSM, La Croix AZ,Scholles D, IchikawaLE, WuK. Effects ofthreeyears oflow-
dose thiazides on mineral metabolism in healthy elderly persons. OsteoporosInt 2008;19:131522.
[36] Wasnick RD, Davis JW, He YF, Petrovic H, Ross PD. A randomized, double-masked, placebo-controlled trial of chlortalidone and bone loss in elderlywomen. Osteoporos Int 1995;5:24751.
[37] Peh CA, Horowitz M, Wishart JM, Need AG, Morris HA, Nordin BE. Theeffect of chlorothiazide on bone-related biochemical variables in normal post-menopausal women. J Am Geriatr Soc 1993;41:5136.
[38] Sun J, Elwood W, Barnes PJ, Chung KF. Effect of thiazide diuretics against neu-rally mediated contraction of guinea pig airways: contribution of carbonicanhydrase. Am Rev Respir Dis 1993;148:9028.
[39] Pierce WM, Nardin GF, Fuqua MF, Sabah-Maren E, Stern SH. Effect of chroniccarbonic anhydraseinhibitortherapyon bonemineraldensity inwhite women.
J Bone Miner Res 1991 ;6:34754.[40] Steiniche T, Mosekilde L, Christensen MS, Melsen F. Histomorphometric analy-
sisof bonein idiopatichypercalciuriabeforeand aftertreatmentwith thiazides.APMIS 1989;97:3028.
[41] Prez Castrilln JL, Justo I, Silva J, et al. Bone mass and bone modelling mark-ers in hypertensive postmenopausal women. J Hum Hypertens 2003;17:107
10.[42] Barry EL, Gesek FA, Kaplan MR, Herbert SC, Friedman PA. Expression of the
sodium-chloridecotransporterin osteoblast-likecells:effectof thiazidediuret-ics. Am J Physiol 1997;272:C10916.
[43] Lajeunesse D, Menard P, Morceau R, Hamel L. Direct effects of thiazides on thehuman osteosarcoma cell line MG-63. J Bone Miner Res 1994;9:S355.
[44] Yamamoto M, Yamaguchi T, Yamauchi M, Yano S, Sugimoto T. Serum pentosi-dine levels are positively associated with the presence of vertebral fractureson postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab2008;93:10139.