Original article

Keywords

Bone loss

Mortality

Pawel Szulc, MD, PhDINSERM 831 ResearchUnit, Universite de Lyon,Hopital Edouard Herriot,Pavillon F, Placed’Arsonval, 69437 Lyon,France

Roland Chapurlat, MD,PhDINSERM 831 Research Unit,Universite de Lyon, HopitalEdouard Herriot, Pavillon F,Place d’Arsonval, 69437Lyon, France

Pierre D. Delmas, MD,PhDINSERM 831 Research Unit,Universite de Lyon, HopitalEdouard Herriot, Pavillon F,Place d’Arsonval, 69437Lyon, France

E-mail:pawel.szulc@inserm.fr

Online 28 September 2010

� 2010 WPMH GmbH. Published

Accelerated bone loss,but not low periostealexpansion, is associatedwith higher all-causemortality in oldermen – prospectiveMINOS study

Pawel Szulc, Roland Chapurlat and Pierre D. Delmas

Abstract

Background: Low bone mineral density (BMD), high bone resorption, fragility fractures and, possibly,

accelerated bone loss are associated with higher mortality. However, it is not known if the higher

mortality is related to lower volumetric BMD or lower bone width, to faster bone loss on endosteal

surfaces (inside bone) or to slower periosteal apposition (formation of bone on the outer bone surface).

Methods: We assessed the association of 10-year mortality with bone width and bone loss in 782 men

aged 50–85 years.

Results: Low bone width and slow periosteal apposition at the femoral neck, distal radius and distal ulna

were not associated with higher mortality. Accelerated apparent bone loss (decrease in BMD), net bone

loss (decrease in bone mineral content) and estimated endosteal bone loss were associated with a higher

10-year all-cause mortality after adjustment for age and other confounders. Accelerated apparent bone

loss at the total hip (lowest quartile) was associated with a two-fold higher mortality (Hazard Ratio

(HR)=1.96, 95% Confidence interval (CI): 1.33, 2.89, p<0.001).

Conclusion: Lack of association between bone size and mortality shows that periosteal expansion is not

an artifact induced by the selective mortality of men with narrow bones. We confirmed that poor bone

status reflects poor health. These data should be interpreted with caution because of the study

limitations, especially the lack of representativity of the cohort and dropout of older and sick men.

However, they suggest that older men with low BMD or accelerated bone loss should obtain detailed

diagnostic assessment to establish general factors that can contribute to their poor bone status. � 2010

WPMH GmbH. Published by Elsevier Ireland Ltd.

Introduction

Recent studies have shown that bone status

reflects general health. Low areal bone mineral

density (aBMD), measured by dual X-ray absorp-

by Elsevier Ireland Ltd.

tiometry (DXA), and high bone resorption are

associated with higher mortality in men and

women, regardless of other confounding fac-

tors [1–4]. Osteoporotic fractures are associated

with higher mortality in both genders, but

Vol. 7, No. 3, pp. 199–210, October 2010 199

Original article

200 Vol. 7, No. 3, p

more so in men [5,6]. This mortality is

increased mainly during the first year after

hip fracture [7,8]. However, vertebral fractures

are also associated with higher mortality,

although they do not induce severe sequelae

[5]. Thus, the higher mortality reflects rather

poor general health status before fracture [9].

Some data have also indicated that accelerated

bone loss is associated with higher mortality

[10,11].

Studies on aBMD and apparent bone loss (a

decrease in aBMD) are influenced by the lim-

itations of DXA. aBMD depends on volumetric

BMD (vBMD: the quantity of bone mineral in

1 cm3) and bone width. People who have nar-

rower bones have a lower aBMD. Thus, the

higher mortality in people with low aBMD

may be related to lower bone width or to lower

vBMD. Bone undergoes two parallel age-related

processes: periosteal apposition (deposition of

new bone on the outer bone surface) and

endosteal bone loss (loss of bone inside on

trabecular, endocortical and intracortical sur-

faces) [12–15]. Periosteal apposition results in

bone widening, which is referred to as perios-

teal expansion. Thus, apparent bone loss

depends on the endosteal bone loss, on peri-

osteal apposition and on bone widening.

As a result, two questions should be asked.

Firstly, is the risk of death higher in men with

low bone width? If yes, then an age-related

increase in bone width in cross-sectional stu-

dies could be partly due to the selective mor-

tality of men with narrow bones [16]. Secondly,

what could be the mechanism underlying the

association between faster apparent bone loss

and higher mortality: lower periosteal apposi-

tion or higher endosteal bone loss?

The aim of this study was to assess the pre-

diction that mortality was a function of the

baseline bone width and of the rate of bone

loss in a cohort of older men followed up for 10

years. The apparent and endosteal bone loss, as

well as periosteal expansion, were estimated

from measurements of aBMD using DXA and

previously published equations [14,17].

Subjects and Methods

Cohort

MINOS is a prospective study of male osteo-

porosis that was initiated in 1995 as a colla-

p. 199–210, October 2010

boration between INSERM and the Societe de

Secours Miniere de Bourgogne (SSMB) in

Montceau les Mines [18]. Letters inviting

participation in the study were sent to a

randomly selected sample of 3400 men aged

50–85 years who were insured by SSMB. From

the 841 men who provided informed consent,

a total of 782 men had a BMD measurement, a

lateral radiograph of the spine, blood sam-

pling and urinary collection at baseline. A

further 60 refused DXA or blood sampling,

or had radiographs of poor quality. The study

was accepted by the local ethics committee

and performed in accordance with the

Helsinki Declaration of 1975 as revised in

1983. For the 182 men who died during the

follow-up period, their dates of death were

provided by the SSMB administration. For two

men, data on their life status after 5 years of

follow-up was not obtained. All other survi-

vors were followed up for 10 years.

At baseline, tobacco smoking was assessed

as current smoker, former smoker of >25

packet-years, former smoker of �25 packet-

years and never-smoker. Alcohol intake was

assessed as the sum of the weekly intake for

wine, beer, and spirits, which was then

divided into quartiles. Current leisure physi-

cal activity was calculated as the overall

amount of time spent walking, gardening

and in leisure sport activity. This was then

divided into four classes of <10, 10–19.99,

20–30, and>30 h/week. Assessment of co-mor-

bidities at baseline comprised ischaemic heart

disease (history of myocardial infarction,

angina pectoris, treatment), diabetes, hyper-

tension, Parkinson’s disease, stroke, lung dis-

eases (chronic obstructive pulmonary disease,

chronic respiratory insufficiency, silicosis),

prostate cancer, gastrointestinal and liver dis-

eases (peptic ulcer, ulcerative colitis, chronic

pancreatitis, cirrhosis, chronic hepatitis). No

patient reported Crohn’s disease or current

cancer of the lung or digestive system. Data on

the medical history was dichotomised as yes

versus no, self-reported, and not ascertained.

Prevalent major osteoporotic fractures were

observed in 74 men (vertebrae, humerus, pel-

vis, distal femur, proximal tibia, multiple rib

fractures) [4]. During the follow-up, major

osteoporotic fractures occurred in 47 men.

The number of medications taken at the time

of recruitment varied from 0 to 15 (median = 2

and interquarile range = 1, 5).

Original article

Clinical tests

Clinical tests were performed as described pre-

viously and included: tests of the strength of

the knee extensors and flexors (standing up

and sitting down from a chair five times), of

the standing balance (standing with the feet in

the side-by-side position for 10 seconds with

eyes open and for 5 seconds with eyes closed),

and of the dynamic balance (10-step tandem

walk forwards then backwards) [19,20]. The

frailty index was scored as 0 if a man accom-

plished all tests correctly and as 1 otherwise,

because the dichotomized frailty index was

strongly associated with mortality.

Assessment of aortic calcifications

Aortic calcifications were assessed on the base-

line lateral radiographs of the lumbar spine

[21]. Calcific deposits in the abdominal aorta

adjacent to the first four lumbar vertebrae were

assessed using the 24-point semi-quantitative

severity scale (aortic calcification score, ACS)

for the posterior and anterior wall of the aorta

using the midpoint of the intervertebral space

above and below the vertebrae as boundaries.

The ACS was a covariate reflecting the cardio-

vascular status [22]. The ACS was dichotomized

(ACS �3 versus 0–2) because this threshold was

associated with higher mortality [21].

Measurements

Areal BMD (aBMD) and bone mineral content

(BMC) were measured at the lumbar spine, hip,

and whole body using pencil-beam DXA

(QDR1500, Hologic Inc. Waltham, MA) and at

the distal forearm using single energy X-ray

absorptiometry (DTX100 Osteometer, Den-

mark) [18]. The region of interest (ROI) for the

femoral neck was positioned perpendicularly

to the axis of the femoral neck so as to cover its

narrowest part. The edges of the femoral neck

were adjusted manually. The QDR1500 device

was calibrated daily using a lumbar spine phan-

tom, yielding a coefficient of variation (CV) for

aBMD of 0.33%. Twice a month, the Hologic hip

phantom was measured (CV of 0.94% for the

femoral neck aBMD and CV of 1.05% for the

femoral neck projected area). Twice a month, a

human lumbar spine embedded in methyl

methacrylate was measured. Its CV was 1.07%

for BMC, 0.62% for aBMD and 1.0% for the

projected area of L2–L4. At the distal forearm,

the distal site included 20 mm of radius situ-

ated proximally to the site where the spacing

between the medial edge of the radius and the

lateral edge of the ulna is 8 mm. Scans with

positioning error were excluded. The DTX100

device was calibrated daily using a standard for

DTX100; its long-term CV was 0.47% for aBMD

and 0.15% for projected area.

Bone width was calculated as the projected

area of the ROI divided by its length. Ageing-

related periosteal apposition (DBMCPA) was esti-

mated as the mass of bone deposited on the

outer bone surface since baseline [14]. The

volume of the ellipsoid cylinder was calculated

assuming that the short axis was 0.75 of the long

axis (width). The deposited bone mass was cal-

culated as the product of the cylinder volume

and the density of bone mineral (1.15 g/cm3)

[23]. We assumed that, during the follow-up,

BMC was determined by baseline BMC, bone

mass deposited on the outer surface (DBMCPA)

and endosteal bone loss (DBMCEBL). DBMCEBL

was calculated using BMC at baseline and dur-

ing the follow-up and the calculated DBMCPA.

The concept of endosteal bone loss does not

make any assumption as to its morphological

basis (cortical thinning, increased cortical por-

osity, trabecular bone loss) nor of the proportion

of cortical to trabecular bone. It reflects the loss

of bone mineral ‘‘inside’’ the bone.

Biochemical measurements

Serum was collected at baseline in the fasting

state at 8 a.m. and stored at�808C until assayed.

Serum 17b-oestradiol and testosterone were

measured using tritiated RIA (radioimmunoas-

say) after diethylether extraction [19,24]. Serum

parathyroid hormone (PTH) and 25-hydroxycho-

lecalciferol (25OHD) levels were measured by

immunochemoluminometric assay (Magic Lite,

Ciba Corning Diagnostic, Medfield, MA) and by

RIA (Incstar Corp. Stillwater, MN), respectively

[25].

Statistical methods

Analyses were performed using SAS8.2 software

(Cary, NC). Bivariate comparisons of continuous

variables were made using a two-sample t-test.

Variables having non-Gaussian distribution

were log-transformed. We compared the survi-

vors versus non-survivors and men who were

followed up versus the 67 men who were lost

to follow-up. As the loss of these men could

Vol. 7, No. 3, pp. 199–210, October 2010 201

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202 Vol. 7, No. 3, p

influence the results, the initial multivariate

models were adjusted for all of the variables

that differed between these two groups. The

predictive variables of interest (bone width,

rate of bone loss and rate of periosteal apposi-

tion) were analysed as quartiles for two rea-

sons. Firstly, many of them had skewed

distributions with outliers that could not be

treated correctly as continuous variables. Sec-

ondly, in the simple survival analyses, most of

the variables showed a threshold, with the

highest mortality for the lowest quartile. A

Cox model was calculated taking the date of

recruitment as the beginning of the follow-up

period in order to calculate the hazard ratio

(HR). The follow-up was censored at the date of

death, the date of last news or 10 years after

recruitment for all others. Backward selection

was used to identify confounders. The initial

model included variables previously associated

with higher mortality [26], and variables which

differed between the men who were followed

up and those who were not. The initial models

included age, body mass index (BMI: <27.7 or

>30.3 versus the reference group who had a

BMI of between 27.7 and 30.3 kg/m2), height,

waist, smoking, alcohol intake (g/week, high-

est versus the 3 lower quartiles), education (>8

versus �8 years at school), leisure physical

activity, occupational physical activity (low

to medium versus high to very high), frailty

index (0 versus 1), prevalent fractures (yes/no),

incident fractures (yes/no), prevalent ischae-

mic heart disease, hypertension, diabetes,

stroke, Parkinson’s disease, ACS (�3 versus

0–2), 17b-oestradiol (highest versus three

lower quartiles), 25OHD level (lowest versus

upper quartiles), concentrations of PTH and

testosterone as well as the aBMD of the ana-

lysed site. For every variable, its strongest form

was used. The final models included variables

that showed p<0.1 or changed the HR value by

�0.05, i.e. age, BMI, height, smoking, educa-

tional level, occupational physical activity,

frailty index, prevalent ischaemic heart dis-

ease, diabetes, ACS, 17b-oestradiol and 25OHD.

Results

Descriptive analysis

The 182 non-survivors were older than the 600

survivors [4]. They were shorter, smoked more,

p. 199–210, October 2010

undertook less physical activity, had poorer

physical performance, more co-morbidity,

higher ACS and took more medications

(Table 1). They had 3.4–6.7% lower BMD and

lower 25OHD concentration but higher 17b-

oestradiol level.

After baseline, 67 men were lost to follow up

[14,27]. On average, they were 5 years older

(p<0.001), undertook less physical activity

(p<0.005), had poorer physical performance

(p<0.001), more co-morbidity (diabetes, Parkin-

son’s disease), higher ACS (p<0.01), and took

more medications (p<0.05). They had 5.0–7.8%

lower BMD (p<0.001), a 12% lower testosterone

level (p< 0.01) and a 23% higher PTH level

(p<0.001).

Among the men who were followed up

for � 18 months, the 137 non-survivors were

compared with the 578 survivors [27]. They

were, on average, 5 years older (p<0.001),

2 cm shorter (p<0.01) and 4 kg lighter

(p<0.01). They smoked more (p<0.02), did less

physical activity (p<0.001), had poor physical

performance (p<0.001), more co-morbidities

(ischaemic heart disease, diabetes, pulmonary

diseases) and took more medications (p<0.001).

On average, they had a 5% higher 17b-oestradiol

level (p<0.05), a 9% higher PTH level and a 19%

lower 25OHD level (p<0.001).

Association between the baseline bonewidth and mortality

The 182 non-survivors did not have lower bone

width of the femoral neck, distal radius and

ulna. The unadjusted survival distribution did

not differ across the quartiles of bone width for

the three sites of measurement (Fig. 1). After

adjustment for the confounding variables, low

bone width was also not associated with

higher mortality (Table 2).

Association between bone loss andmortality in men

The non-survivors had faster apparent bone

loss (decrease in aBMD) and faster net bone

loss (decrease in BMC) at the hip and distal

forearm (Table 3). They also had faster net bone

loss for the whole body and slightly lower bone

gain at the lumbar spine. The unadjusted sur-

vival rate decreased across the quartiles of the

apparent bone loss and was poorest in men in

the lowest quartile (Fig. 2). After adjustment

for confounders, the mortality was signifi-

Original article

Table 1 Bivariate and age-adjusted comparison of men who died during the study and survivors –

baseline data

Parameter Alive (n = 600) Deceased (n = 182) P

Age (years) 64 � 7 70 � 8 <0.001

Body weight (kg) 81 � 13 78 � 12 <0.02

Body height (cm) 169 � 6 168 � 6 <0.01

Body mass index (kg/m2) 28.09 � 3.70 27.64 � 3.77 0.14

Tobacco smoking (n,%) current 65 (8.3) 27 (3.4) 0.005

former >25 packet-years 57 (7.3) 30 (3.8)

former �25 packet-years 275 (35.1) 80 (10.2)

never-smoker 202 (25.8) 48 (6.1)

Leisure physical activity (h/wk) 22.9 � 12.6 18.8 � 13.1 <0.001

Physical activity <10 h/wk (n,%) 65 (10.8) 47 (25.3) <0.001

Physical performance score 12 [9; 14] 10 [7; 13] <0.001

Score <9 (lowest quartile) (n,%) 95 (15.8) 62 (33.7) <0.001

Ischaemic heart disease (n,%) 76 (12.8) 42 (23.2) <0.001

Arterial hypertension (n,%) 136 (22.7) 61 (33.5) <0.002

Diabetes mellitus (n,%) 32 (5.3) 26 (14.0) <0.001

Parkinson’s disease (n,%) 7 (1.2) 8 (4.3) <0.005

Digestive diseases (n,%) 92 (15.4) 41 (22.6) <0.02

Pulmonary disease (n,%) 21 (3.5) 17 (9.2) <0.001

Aortic calcification score (ACS) 2 [0; 5] 5.5 [2; 10] <0.001

ACS � 3 (n, %) 247 (41.5) 128 (72.2) <0.001

Major prevalent fractures (n,%) 46 (7.6) 28 (14.9) <0.002

Major incident fractures (n,%) 33 (5.5) 14 (7.6) 0.30

Number of medications 2 [0; 4] 3 [2; 6] <0.001

Number of medications > 5 (%) 82 (13.7) 49 (27.1) <0.001

Bone mineral density (g/cm2)

Lumbar spine 1.024 � 0.177 1.064 � 0.214 <0.01

Femoral neck 0.848 � 0.116 0.819 � 0.136 <0.005

Trochanter 0.743 � 0.105 0.716 � 0.125 <0.005

Total hip 0.971 � 0.123 0.932 � 0.149 <0.001

Whole body 1.213 � 0.104 1.186 � 0.129 <0.005

Distal forearm 0.528 � 0.053 0.498 � 0.071 <0.001

Distal radius 0.559 � 0.066 0.530 � 0.076 <0.001

Distal ulna 0.480 � 0.064 0.450 � 0.070 <0.001

Ultradistal radius 0.434 � 0.063 0.405 � 0.070 <0.001

Bone width

Femoral neck (cm) 4.07 � 0.31 4.13 � 0.33 <0.05

Distal radius (cm) 2.47 � 0.21 2.48 � 0.21 0.80

Distal ulna (cm) 1.66 � 0.13 1.66 � 0.14 0.87

Hormones

Total testosterone (nmol/l) 17.79 � 6.80 17.58 � 7.43 0.44

17b-oestradiol (pmol/l) 112.3 � 28.1 117.6 � 31.8 <0.05

25OHD (nmol/l) 70.8 � 28.8 57.5 � 27.5 <0.001

PTH (pmol/l) 4.13 � 1.77 4.51 � 2.19 <0.03

25OHD, 25-hydroxycholecalciferol; PTH, parathyroid hormone. Figures in square brackets indicate range of responses.

Vol. 7, No. 3, pp. 199–210, October 2010 203

Original article

[(Figure_1)TD$FIG]

Table 2 Comparison of the mortality in men with the lowest bone width at baseline (1st quartile)versus men in the three higher bone width quartiles (2nd to 4th quartiles)

Skeletal site Unadjusted HR (95% CI) Age-adjusted HR (95% CI) Fully adjusted* HR (95% CI)

Femoral neck 0.81 (0.54, 1.21) 0.81 (0.53, 1.26) 0.79 (0.47, 1.32)

Distal radius 0.98 (0.67, 1.44) 0.94 (0.62, 1.42) 1.04 (0.63, 1.71)

Distal ulna 1.01 (0.69, 1.49) 1.10 (0.72, 1.67) 1.23 (0.74, 2.06)

Comparison was carried out using the Cox model in 782 men aged 50 to 85 years from the MINOS cohort.* Adjusted for age, body mass index (BMI), height, smoking, educational level, occupational physical activity, frailty index,prevalent ischaemic heart disease, diabetes, aortic calcification score (ACS), 17b-oestradiol and 25-hydroxycholecalciferol(25OHD). HR, hazard ratio; CI, confidence interval.

Figure 1 Ten-year mortality for each quartile of the baseline value of the external diameter of the femoral neck (A),

the distal radius (B) and the distal ulna (C).

204 Vol. 7, No. 3, p

cantly higher in men with the fastest apparent

or net bone loss (lowest quartile) in compar-

ison with men in the three upper quartiles,

regardless of the skeletal site (Table 4).

Association of the mortality withperiosteal apposition and endostealbone resorption in men

Unadjusted bone widening rate (increase in

bone width) and periosteal expansion rate

were not lower in the non-survivors and, for

the bones of the distal forearm, they were

higher. In the unadjusted models, survival rate

did not differ across the quartiles for periosteal

expansion at the distal radius or the ulna

p. 199–210, October 2010

(Fig. 3). After adjustment for the confounders,

the slowest periosteal expansion (lowest quar-

tile of bone widening rate and of periosteal

expansion rate) was not associated with higher

mortality when compared with the three

upper quartiles (Table 5).

By contrast, the unadjusted endosteal bone

loss at the distal radius and ulna were twice as

high in the non-survivors in comparison with

the survivors. The unadjusted survival rate was

lower in men in the first quartile for endosteal

bone loss, i.e. in those men who had the fastest

endosteal bone loss. After adjustment for the

confounding variables, the fastest endosteal

bone loss was associated with higher mortality

compared with the three upper quartiles.

Original article

Table 3 Bivariate comparison of the rates of change in areal bone mineral density and in thederived

Table 4 Ten-year risk of death in men with accelerated apparent and net bone loss, defined by the first(lowest) quartile in comparison with men in the three upper quartiles for bone loss (reference group)

Skeletal site Unadjusted Age-adjusted Fully adjusted*

Apparent bone loss (decrease in areal bone mineral density)

Lumbar spine (< �1.5 mg/cm2/year) 1.77 (1.24, 2.55)c 1.56 (1.08, 2.24)a 1.75 (1.16, 2.62)b

Femoral neck (< �6.3 mg/cm2/year) 2.18 (1.52, 3.12)d 1.82 (1.26, 2.62)c 1.60 (1.07, 2.40)a

Trochanter (< �4.7 mg/cm2/year) 2.22 (1.57, 3.15)d 1.77 (1.24, 2.53)c 1.58 (1.06, 2.36)a

Total hip (< �8.5 mg/cm2/year) 3.01 (2.15, 4.22)d 2.23 (1.57, 3.17)d 1.96 (1.33, 2.89)d

Distal forearm (< �4.5 mg/cm2/year) 2.18 (1.55, 3.06)d 1.66 (1.17, 2.35)c 1.49 (1.01, 2.21)a

Ultradistal radius(< �3.3 mg/cm2/year) 1.75 (1.24, 2.48)c 1.50 (1.06, 2.12)a 1.24 (0.83, 1.85)

Net bone loss (decrease in bone mineral content)

L3 (< �58.6 mg/year) 2.30 (1.63, 3.24)d 1.87 (1.31, 2.65)d 1.92 (1.29, 2.81)c

Total hip (< �270 mg/year) 2.99 (2.12, 4.23)d 2.34 (1.64, 3.23)d 2.06 (1.39, 3.06)d

Whole body (< �15.9 g/year) 3.62 (2.60, 5.05)d 2.67 (1.88, 3.79)d 2.24 (1.53, 3.30)d

a p<0.05, b p<0.01, c p<0.005, d p<0.001.* Adjusted for age, body mass index (BMI), height, smoking, educational level, occupational physical activity, frailty index,prevalent ischaemic heart disease, diabetes, aortic calcification score (ACS), 17b-oestradiol and 25-hydroxycholecalciferol(25OHD).

parameters in those men who had at least two DXA measurements

Parameter Survivors (n = 578) Non-survivors (n = 137) p

Apparent bone loss (mg/cm2/year)

Lumbar spine 4.69 � 11.56 2.05 � 22.22 0.06

Femoral neck �2.15 � 6.93 �3.89 � 12.81 <0.05

Trochanter �1.44 � 6.05 �4.20 � 11.95 <0.001

Total hip �4.24 � 6.65 �7.20 � 12.79 <0.001

Distal forearm �2.62 � 3.48 �4.26 � 6.12 <0.001

Distal radius �2.68 � 4.42 �4.24 � 7.97 <0.001

Distal ulna �2.91 � 4.12 �5.14 � 7.65 <0.001

Ultradistal radius �1.47 � 3.83 �2.83 � 8.40 <0.005

Net bone loss

L3 (mg/year) 110.74 � 328.76 53.88 � 616.87 <0.05

Total hip (mg/year) �176.56 � 501.81 �483.33 � 996.86 <0.001

Whole body (g/year) �5.06 � 17.83 �20.15 � 30.06 <0.001

Distal radius (mg/year) �10.19 � 19.92 �18.56 � 33.70 <0.001

Distal ulna (mg/year) �7.50 � 13.96 �13.33 � 24.55 <0.001

Bone widening (mm/year)

Femoral neck 258.9 � 363.9 298.0 � 665.6 0.36

Distal radius 43.7 � 239.6 126.0 � 648.2 <0.05

Distal ulna 47.0 � 127.0 102.1 � 235.8 <0.001

Estimated periosteal apposition (mg/year)

Distal radius 9.43 � 60.54 27.29 � 109.95 <0.01

Distal ulna 7.59 � 18.57 13.38 � 31.82 <0.005

Estimated endosteal bone loss (mg/year)

Distal radius �21.46 � 51.11 �37.13 � 91.36 <0.005

Distal ulna �14.12 � 23.01 �27.93 � 38.16 <0.001

Vol. 7, No. 3, pp. 199–210, October 2010 205

Original article

[(Figure_2)TD$FIG]

[(Figure_3)TD$FIG]

Figure 3 Ten-year mortality for each quartile for the rate of periosteal apposition at the distal radius (A) and at the

distal ulna (B). Ten-year mortality by quartile for the rate of endosteal bone loss at the distal radius (C) and at

the distal ulna (D).

Figure 2 Ten-year mortality, by quartile, for the rate of apparent bone loss at the lumbar spine (A), the total hip (B)

and the distal radius (C).

206 Vol. 7, No. 3, p

Discussion

We have shown that in older men, accelerated

bone loss is associated with higher all-cause

mortality. This association is related to the

accelerated endosteal bone loss. By contrast,

p. 199–210, October 2010

low bone width and low periosteal expansion

are not associated with higher mortality.

The increase in bone resorption, but not of

bone formation, has been shown to be asso-

ciated with higher mortality [3,4]. Higher bone

resorption that is not matched by a parallel

Original article

Table 5 Ten-year mortality in men with accelerated bone loss and low periosteal apposition at the distal radius and the distalulna, defined as a comparison between the lowest quartile of men having normal bone loss and periosteal apposition andthose in the three upper quartiles

Bone parameter Unadjusted Age-adjusted Fully adjusted*

Distal radius

Apparent bone loss – BMD (< �4.5 mg/cm2/year) 1.78 (1.27, 2.50)d 1.41 (1.01, 1.99)a 1.26 (0.85, 1.87)

Net bone loss – decrease in BMC (< �19.5 mg/year) 1.92 (1.37, 2.68)d 1.45 (1.03, 2.04)a 1.40 (0.94, 2.09)

Bone widening – width (< �6.7 mm/year) 1.14 (0.80, 1.65) 1.14 (0.79, 1.64) 1.03 (0.69, 1.54)

Estimated periosteal apposition (< �15.5 mg/year) 1.15 (0.80, 1.65) 1.12 (0.78, 1.62) 1.04 (0.70, 1.54)

Estimated endosteal bone loss (< �44.8 mg/year) 2.15 (1.54, 3.01)d 1.88 (1.34, 2.64)d 1.65 (1.14, 2.41)b

Distal ulna

Apparent bone loss – BMD (< �5.3 mg/cm2/year) 2.59 (1.87, 3.58)d 2.05 (1.47, 2.86)d 1.87 (1.27, 2.73)d

Net bone loss – decrease in BMC (< �14.3 mg/year) 2.16 (1.56, 3.01)d 1.65 (1.18, 2.31)c 1.29 (0.88, 1.90)

Bone widening – width (< �2.5 mm/year) 1.32 (0.93, 1.88) 1.31 (0.94, 1.91) 1.39 (0.89, 2.04)

Estimated periosteal apposition (< �3.5 mg/year) 1.34 (0.88, 1.97) 1.37 (0.86, 1.99) 1.47 (0.90, 2.19)

Estimated endosteal bone loss (< �28.3 mg/year) 2.45 (1.76, 3.41)d 1.98 (1.41, 2.77)d 2.04 (1.40, 2.97)d

a p<0.05, b p<0.01, c p<0.005, d p<0.001.* Adjusted for age, body mass index (BMI), height, smoking, educational level, occupational physical activity, frailty index, prevalent ischaemic heart disease,diabetes, aortic calcification score (ACS), 17b-oestradiol and 25-hydroxycholecalciferol (25OHD).

increase in bone formation may result in faster

bone loss. The association of mortality with

high bone resorption and rapid bone loss was

independent of prevalent and incident frac-

tures, which are themselves associated with

higher mortality. Thus, low aBMD, high bone

resorption and rapid bone loss may reflect

poor health status in older men. The higher

levels of bone markers were also associated

with higher mortality in older patients with

hip fractures and in patients on maintenance

haemodialysis [28,29]. However, the pathophy-

siological mechanisms underlying this associa-

tion are not clear.

Many studies have shown an association

between osteoporosis and cardiovascular dis-

eases [21,30,31]. However, the relationship

between bone loss and mortality was still sig-

nificant even after adjustment for cardiovas-

cular diseases and ACS. The association

between diabetes and osteoporosis is complex

[32]. Areal BMD is decreased in type I diabetes

[33] but increased in type II diabetes [34]. In

diabetic patients, bone resorption and fracture

risk may be increased [35,36]. Diabetes was

associated with faster bone loss in white

women [37]. Diabetes was also associated with

lower life expectancy [26]; however, the asso-

ciation between bone loss and mortality was

still significant after adjustment for diabetes.

Other possible mechanisms should be men-

tioned. Low grade inflammatory syndrome in

men with abdominal obesity is characterised

by higher secretion of proinflammatory cyto-

kines by the visceral adipocytes [38]. These

cytokines stimulate bone resorption and may

induce bone loss, whereas abdominal obesity is

associated with higher mortality [39,40]. Smok-

ing is associated with higher mortality and

faster bone loss [41,42]. Frailty may be asso-

ciated with low aBMD and higher mortality

[43,44]. However, the association between bone

loss and mortality was significant even after

adjustment for BMI, waist, smoking and frailty

as well as for the concentrations of hormones

that are known to be associated with higher

mortality in men [26,45,46]. Thus, our data do

not explain the relationship between bone loss

and mortality. However, they confirm and

expand on the association between poor bone

status and poor health in older men.

Our important finding is the lack of associa-

tion between mortality and bone width or the

rate of periosteal apposition. Many studies

have assessed age-related periosteal expansion

[13–16]. Some, but not all, studies have shown

a greater periosteal expansion in men than in

women [15,47]. The determinants and the phy-

siological role of periosteal apposition remain

speculative. However, the main problem is

whether periosteal expansion really exists. In

cross-sectional studies, periosteal expansion

can be artifactual, if low bone width is asso-

ciated with higher mortality. Periosteal expan-

Vol. 7, No. 3, pp. 199–210, October 2010 207

Original article

208 Vol. 7, No. 3, p

sion may also be artifactual and simply due to

sex-, race- and body segment-specific secular

trends. The periosteal apposition rate found in

prospective studies may be overestimated if

people with a slower periosteal apposition

had a higher risk of death.

Thus, our issue is the beta error, i.e. the risk

that we did not detect an association that was

present. Insufficient statistical power is not

probable. The HR values for both bone width

and periosteal apposition were close to 1 with

variance either side. Confidence intervals lar-

gely overlapped the value of 1. A more relevant

issue is the accuracy of the measurement of

bone width and the estimation of periosteal

apposition. However, DXA devices measure the

projected area with a good reproducibility.

During the follow-up, the ROI was carefully

positioned on the same part of the bone. Bone

edges were adjusted manually and scans with

positioning errors were excluded. Thus, an

effort was made to precisely assess bone size

during the follow-up. DXA is not designed to

measure bone width, however, it is possible to

reduce the noise of estimation for an indivi-

dual slope. For a single line, the measurement

error is high compared with the amount of

average yearly bone widening. However, the

calculation of bone width was based on 15

lines for the femoral neck and 40 lines for

the forearm. Individual slopes were calculated

during a long follow-up and, in most men, they

were based on several measures. Furthermore,

the analysis was carried out on a large cohort.

Thus, despite these limitations, bone width

could be estimated correctly. The estimation

of periosteal apposition and endosteal bone

loss used equations that were based on

assumptions such as elliptical bone shape, a

constant vBMD for newly deposited bone and

homogenous periosteal apposition in all direc-

tions. Only endosteal bone loss predicted

death. This association was significant for both

the distal radius and the ulna after adjustment

for confounding variables. Thus, the data

showing that low bone width and slow peri-

osteal apposition are not related to mortality

in men seem reliable. However, this needs to be

confirmed by using a more direct measure-

ment of bone width.

This study has limitations. The volunteers

were lower-middle class, home-dwelling men.

The cohort was not population-based and may

not be representative of the French population

p. 199–210, October 2010

as a whole. The response rate was 24%, but

responders and non-responders did not differ

[26]. Data on the duration, severity and treat-

ment of diseases were not collected. Diseases

developing after the baseline visit were not

taken into account. Thus, unmeasured resi-

dual confounding is possible. Only all-cause

mortality was assessed, and causes of death

could not be established a posteriori. The SSMB

system was computerised in 2003, and before

that time causes of death were not noted

systematically in the medical records. Only

23% of the cohort died and the analysis may

be underpowered. Men who dropped out of the

study after the baseline visit were older and

sicker, although they represented only 8% of

the cohort. Men who were followed up may

have been healthier, especially in the oldest

group.

DXA has limitations for the evaluation of

bone width. In very old men, subperiosteal

bone mass can be low and may not be recog-

nised by the edge-detection system. The

femoral neck projected area may be overesti-

mated because of calcifications in the fibrous

tissue. The ROI of the radius and ulna is estab-

lished by the DXA device. According to the

anatomy, distally this site is larger and more

trabecular, while proximally it is narrower and

more cortical. The calculation of endosteal

bone loss is based on several assumptions.

The advantage of this concept is that it does

not make any assumption about the morpho-

logical basis underlying any endosteal bone

loss (e.g. cortical thinning or trabecular bone

loss, the proportion of cortical to trabecular

bone, similar rates of trabecular and cortical

bone loss, etc.). Finally, endosteal bone loss was

assessed in the predominantly cortical sites.

Thus, low bone width and low periosteal

apposition do not seem to be associated with

higher mortality. This suggests that periosteal

expansion is a real phenomenon and not an

artifact induced by the selective mortality in

men with narrow bones or slow periosteal

apposition. This study expands on previous

studies that have shown that poor bone status

(low aBMD, high bone turnover, faster bone

loss, fragility fractures) can be a marker of poor

health. Higher mortality was only observed in

those men with the fastest bone loss, suggest-

ing the presence of a threshold effect. Bone is

influenced by many negative factors during

life. Rapid bone loss may be a consequence

Original article

of the simultaneous presence of several nega-

tive factors (lifestyle, severity of any diseases,

treatment). Such a threshold effect shows that

the accumulation of factors that exceed the

organism’s compensatory mechanisms may

induce both rapid bone loss and severe health

deterioration, leading to a higher mortality

rate.

These results should be interpreted with

caution because of the limitations of the study,

mainly the lack of representativeness of the

cohort and the dropout of both older and sick

men. The findings need to be confirmed in

other cohorts and can not be extrapolated to

the general population. However, from a clin-

ical point of view, they suggest that older men

with low aBMD or rapid bone loss should

obtain a detailed assessment of their health

in order to uncover the general factors con-

tributing to their poor bone status.

Acknowledgement

This study has been supported by a contract

between INSERM / Merck Sharp & Dohme Chi-

bret and by the NEMO project (Thematic Net-

work on the Osteoporosis in Men).

[1

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