Osteoporos Int (2013) 24:69–76

DOI 10.1007/s00198-012-2209-1

ORIGINAL ARTICLE

Overweight/obesity and underweight are both risk factors

for osteoporotic fractures at different sites in Japanese
postmenopausal women
S. Tanaka & T. Kuroda & M. Saito & M. Shiraki

Received: 28 March 2012 / Accepted: 11 October 2012 / Published online: 15 November 2012
# International Osteoporosis Foundation and National Osteoporosis Foundation 2012

Abstract and normal weight women were significantly lower than

Summary This cohort study of 1,614 postmenopausal Japa- overweight or obese women by 0.45 (95 % confidence inter-
nese women followed for 6.7 years showed that overweight/ val: 0.32 to 0.63) and 0.61 (0.50 to 0.74), respectively, if BMD
obesity and underweight are both risk factors for fractures at and other risk factors were adjusted, and by 0.66 (0.48 to 0.90)
different sites. Fracture risk assessment may be improved if and 0.70 (0.58 to 0.84) if only BMD was not adjusted.
fracture sites are taken into account and BMI is categorized. Incidence rates of femoral neck and long-bone fractures in
Introduction The effect of body mass index (BMI) on frac- the underweight group were higher than the overweight/obese
ture at a given level of bone mineral density (BMD) is group by 2.15 (0.73 to 6.34) and 1.51 (0.82 to 2.77) and were
controversial, since varying associations between BMI and similar between normal weight and overweight/obesity.
fracture sites have been reported. Conclusions Overweight/obesity and underweight are both
Methods A total of 1,614 postmenopausal Japanese women risk factors for fractures at different sites. Fracture risk
were followed for 6.7 years in a hospital-based cohort study. assessment may be improved if fracture sites are taken into
Endpoints included incident vertebral, femoral neck, and account and BMI is categorized.
long-bone fractures. Rate ratios were estimated by Poisson
regression models adjusted for age, diabetes mellitus, BMD, Keywords Body composition . Cohort study .
prior fracture, back pain, and treatment by estrogen. Epidemiology . Obesity . Osteoporosis
Results Over a mean follow-up period of 6.7 years, a total of
254 clinical and 335 morphometric vertebral fractures, 48 Abbreviations
femoral neck fractures, and 159 long-bone fractures were BAP Bone alkaline phosphatase
observed. Incidence rates of vertebral fracture in underweight BMD Bone mineral density
BMI Body mass index
S. Tanaka (*)
CART Cocaine and amphetamine-regulated transcript
Division of Clinical Trial Design and Management,
Translational Research Center, Kyoto University, eGFR Estimated glomerular filtration rate
54 Shogoin Kawahara-Cho, Sakyo-ku, DXA Dual energy x-ray absorptiometry
Kyoto 606-8507, Japan DM Diabetes mellitus
e-mail: shiro@kuhp.kyoto-u.ac.jp
FRAX Fracture risk assessment tool
T. Kuroda FRISC Fracture and immobilization score
Public Health Research Foundation, NTX N-terminal telopeptide of type I collagen
Tokyo, Japan SBP Systolic blood pressure
SD Standard deviation
M. Saito
Department of Orthopaedic Surgery, SERM Selective estrogen receptor modulator
Jikei University School of Medicine, ucOC Undercarboxylated osteocalcin
Tokyo, Japan VD3 Active vitamin D3
25(OH)D 25-Hydroxy-cholecalciferol
M. Shiraki
Research Institute and Practice for Involutional Diseases, VK2 Vitamin K2
Nagano, Japan YAM Young adult mean
70
Introduction
Osteoporotic fractures are an increasing problem in our
aging society, and the associated medical costs are a serious
concern [1]. As an adjunct to the development of bisphosph-
onates and selective estrogen receptor modulators (SERMs),
early identification of high-risk populations is regarded as
an effective strategy to alleviate this burden [2]. In this
context, substantial efforts have been devoted to identifying
clinical risk factors beyond bone mineral density (BMD)
and integrating them into a risk assessment tool or predic-
tion model, such as the World Health Organization (WHO)
fracture risk assessment tool (FRAX) [3] or the fracture and
immobilization score (FRISC) [4]. Many clinical guidelines
on osteoporosis recommend the use of such tools [5–8].
Key factors in fracture risk assessment are body mass
index (BMI) and body weight. The general consensus is that
obese people tend to have high BMD levels, making frac-
tures less likely. In fact, the FRAX includes BMI based on a
meta-analysis of 12 cohorts, which showed a negative cor-
relation between BMI and incident hip, osteoporotic, and all
fractures, when the models did not include BMD [9]. This
finding has been recently confirmed by the Million Women
Study [10]. A large-scale observational study found that
women with higher BMI have not only increased BMD but
also robust femur geometry assessed by hip structure analy-
sis, and the negative BMI–fracture association is specific to
hip and central body fractures [11].
The effect of BMI on fracture at a given level of BMD,
however, remains controversial, partly due to its differential
effects on different fracture sites. For example, increased
BMI was a protective factor of hip fracture in the meta-
analysis above-mentioned, while obesity was a risk factor of
ankle and upper leg fractures in the Global Longitudinal
Study of Osteoporosis in Women [12]. In our cohort of
Japanese postmenopausal women, an increase in body
weight was a significant risk factor for major osteoporotic
fracture [4]. Obesity accompanies a variety of metabolic
disorders and accelerated senescence, which can contribute
to increased risk of fracture. For example, type 2 diabetes
[13–15], metabolic syndrome [16], peripheral artery disease
[17], increased homocysteine [18], and pentosidine levels
[19–22], and high propensity of falls [11] are established for
potential risk factors for fracture. Further, it is postulated
that excessive fat mass may have adverse effects on bone,
such as secretion of adipocyte-derived hormones and in-
flammatory cytokines that affect bone metabolism [23]. In
other words, osteoporosis and obesity may share the same
pathophysiology of bone cell metabolism. These lines of
evidence prompted us to determine the association between
BMI and related indices, and incidence rates of vertebral,
femoral neck, and long-bone fractures in Japanese postmen-
opausal women.
Osteoporos Int (2013) 24:69–76
Methods
Subjects
The Nagano Cohort study is an ongoing cohort study of out-
patients at a medical institute in Nagano Prefecture, Japan [24].
Study participants were postmenopausal ambulatory volunteers
over 50 years of age who were recruited from patients visiting
this institute and were assessed for eligibility by two practi-
tioners. Between April 1993 and August 2011, 3,212 postmen-
opausal women were enrolled. The exclusion criteria for the
current analysis are secondary osteoporosis (e.g., osteopenia
with hyperparathyroidism, hyperthyroidism, chronic kidney
disease, or osteomalacia); treatment with osteoporosis medica-
tions, such as bisphosphonates, SERMs or teriparatide; and
current or previous treatment with glucocorticoids. Women with
premature menopause were not excluded. A total of 1,614
subjects were included in this analysis after exclusion of 303
cases of secondary osteoporosis, 356 cases treated by bone
resorption inhibitors, and 976 subjects not followed for more
than 1 year. The protocol was approved by the ethics committee
of the Research Institute and Practice for Involutional Diseases
and we obtained written informed consent from all subjects.
Baseline data collection
At baseline, anthropometric indices including body weight,
body height, and waist circumference were measured. Body
fat mass and lean mass were measured by a dual energy x-
ray absorptiometry (DXA) total body scan. Subjects were
also interviewed about lifestyle factors (smoking habit, al-
cohol consumption, and past and present occupation) and
medical history (age at menopause and presence of pain and
comorbidity such as diabetes mellitus).
The diagnosis of osteoporosis was made in accordance
with the 2000 version of the Japanese diagnostic criteria by
the Japanese Society for Bone and Mineral Research [25], in
which osteoporosis is defined as the presence of fragility
fractures in any bone in a person with a BMD of less than
80 % (−1.63 SD) of the young adult mean (YAM). Osteopo-
rosis was also diagnosed when the lumbar BMD was less than
70 % (−2.45 SD) of the YAM, even in those without any
prevalent fragility fracture. Osteopenia is defined by lumbar
BMD of less than 80 % (−1.63 SD) of the YAM without
osteoporosis. The BMD of the lumbar spine was measured
at baseline using dual-energy X-ray absorptiometry (Lunar
DPX-L or DPX-IQ or Prodigy; GE Lunar Corporation, Mad-
ison, WI, USA) and a quality assurance test was carried out on
every measurement to detect machine drift. The interassay
variance of the lumbar BMD measurement in our laboratory
was 0.5±0.5 % (CV±SD) [26]. A major osteoporotic fracture
was defined as a clinical vertebral fracture or fractures at hip,
forearm, and humerus.
Osteoporos Int (2013) 24:69–76
Underweight, overweight, and obesity are defined by a BMI
of less than 18.5 kg/m2, between 25 and 29 kg/m2, or 30 kg/m2
or more, respectively. Hypertension was defined by systolic
blood pressure (SBP) of 140 mmHg or more, diastolic blood
pressure (DBP) of 90 mmHg or more, or patients under
treatment. Hyperlipidemia was defined by fasting triglycer-
ides of 150 mg/dL or more, high density lipoprotein choles-
terol less than 40 mg/dL, or patients under treatment. Type 2
diabetes was defined by HbA1c of 6.5 % or more, or
patients under treatment. Estimated glomerular filtration
rate (eGFR) was calculated by the Modification of Diet


in Renal Disease formula: eGFR mL=min 1:73 m2 ¼
186:3  Cr1:154  Age0:203  0:742  0:881 . Back pain
was defined as any symptom of pain in the back trunk area,
regardless of the degree or consistency of the pain [27].
Endpoints
Endpoints were incidence of vertebral fracture, incidence of
femoral neck fracture, and incidence of long-bone fracture
analyzed by the person-year method. Incident vertebral
fractures include both new clinical and morphometric frac-
tures. Morphometric vertebral fractures were evaluated
based on radiographs by the semiquantitative visual method
[28]. A validation analysis of our semiquantitative method
for analyzing incident vertebral fracture has been reported
elsewhere [29]. Radiographs were taken at baseline and
during the follow-up period annually and when a patient
complained fracture-related symptoms. Femoral neck and
long-bone fractures were identified from medical records or
confirmed by radiographs. The accumulation of person-
years at risk began at registration of each patient and ended
at date of death, date of lost to follow-up, or date of last visit
before August, 2011. During follow-up, we asked patients to
visit the institute regularly and we attempted to contact the
participant by telephone or letter in case of lost to follow-up.
Statistical analysis
Baseline characteristics and laboratory measurements were
described by mean ± SD or as a percentage and were com-
pared between groups by analysis of variance type tests using
general linear models, logistic regression models, or polyto-
mous logistic regression models adjusted for age. To estimate
rate ratios for BMI, body weight, lean mass, % fat mass, and
waist circumference at each endpoint, we fitted multivariate
Poisson regression models. The following adjustment varia-
bles were forced into the models throughout: age, diabetes
mellitus, lumbar or femoral neck BMD, prior fracture, pres-
ence of back pain, and treatment by conjugated estrogen or
estradiol. Missing data were treated by the multiple imputation
method using the adjustment variables. All reported p values
71
are two-tailed and p<0.05 was taken to indicate statistical
significance. All statistical analyses were performed using
SAS version 9.2 (SAS Institute, Cary, NC, USA).
Results
Baseline characteristics
Baseline characteristics of the 1,614 Japanese postmenopausal
women according to BMI levels are summarized in Table 1.
Overall, 21.6 % of the subjects were overweight and 2.0 %
had a BMI of 30 kg/m2 or more, while 8.4 % were under-
weight. As expected, subjects with higher BMI had a higher
prevalence of metabolic disorders, such as type 2 diabetes
mellitus, hypertension, and hyperlipidemia, as well as higher
BMD levels of the lumbar spine and femur.
Types of incident fractures according to body mass index
Over a mean follow-up period of 6.7 years, a total of 254
clinical and 335 morphometric vertebral fractures and 159
long-bone fractures (48 femoral neck, 47 forearm, four hu-
merus, ten rib, and 50 other sites) were observed, over a total
of 10,737.9 person-years. We observed no incidences of ankle
fracture. Multiple vertebral fractures occurred in 138 subjects.
Table 2 lists the types of incident fractures according to BMI.
Crude incidence rates of vertebral fractures, femoral neck
fracture, and long-bone fractures per 1,000 person-year were
54.9 (95 %CI: 50.6 to 59.5), 4.5 (95 %CI: 3.4 to 5.9), and 14.8
(95 %CI: 12.7 to 17.3), respectively.
Body mass index and incidence rate of fracture
Figure 1 presents crude incidence rates per person-year of
vertebral, long-bone, and femoral neck fractures. In the whole
cohort, incidence rates of long-bone and femoral neck fractures
decreased as BMI levels increased (trend p00.04 and p00.01,
respectively), while there was a weak increasing trend for
vertebral fracture (trend p00.055). However, the increasing
trends in incidence rates of vertebral fracture were substantial
when subjects were stratified according to osteoporosis status
and the gradients of BMI–fracture associations were different
across osteoporosis strata (interaction p<0.01). The effect
modification by osteoporosis status were not significant for
long-bone and femoral neck fractures (interaction p00.49 and
p00.42, respectively).
Table 3 shows rate ratios for each fracture type according
to the BMD groups in the multivariate Poisson regression
analysis. Incidence rates of clinical and morphometric ver-
tebral fractures in underweight and normal weight women
were significantly lower than overweight or obese women
by 0.45 (95 %CI: 0.32 to 0.63) and 0.61 (0.50 to 0.74),
72 Osteoporos Int (2013) 24:69–76

Table 1 Baseline characteristics of the 1,614 postmenopausal women according to body mass index

Underweight (N0135)b Normal weight (N01,131) Overweight/obese (N0348)b

Mean SD Mean SD Mean SD pc

Age (year) 65.5 14.3 62.5 11.2 63.2 10.1 –

BMI (kg/m2) 17.2 1.2 21.9 1.7 27.2 2.4 –
Weight (kg) 39.4 4.8 50.4 5.8 61.4 7.8 <0.01
Lean mass (kg) 31.6 3.2 34.1 3.4 36.1 3.5 <0.01
Fat mass (%) 19.8 6.5 31.4 5.8 40.0 4.6 <0.01
Waist circumference (cm) 74.8 7.7 83.9 7.5 93.0 10.5 <0.01
DM (%) 3.7 % 6.1 % 16.1 % <0.01
Hypertension (%) 58.5 % 66.0 % 79.9 % <0.01
Hyperlipidemia (%) 30.4 % 50.5 % 64.4 % <0.01
Smoker (%) 2.3 % 2.6 % 3.8 % 0.17
Treated by conjugated estrogen or estradiol 7.4 % 6.9 % 2.9 % 0.01
eGFR (mL/min/1.73 m2) 62.2 19.5 63.9 20.2 66.4 62.2 0.04
Osteoporosis (%)a 57.8 % 31.3 % 21.0/15.3 % <0.01
Osteopenia (%)a 19.3 % 22.1 % 21.0/15.3 % 0.06
Prior fracture (%) 23.7 % 42.7 % 17.4 % 37.9 % 15.8 % 23.7 % 0.65
Lumbar BMD (g/cm2) 0.821 0.220 0.955 0.197 1.037 0.199/0.144 <0.01
Femur BMD (g/cm2) 0.661 0.121 0.774 0.131 0.844 0.199/0.144 <0.01
Back pain (%) 34.1 % 29.3 % 26.4 % 0.19
BAP (IU) 30.8 10.9 30.6 11.8 31.4 11.4 0.45
NTX (nM/mMCr) 56.0 29.8 51.3 27.2 50.3 26.9 0.20
Osteocalcin (ng/mL) 8.6 4.2 7.8 3.5 7.4 7.2 0.02
ucOC (ng/mL) 5.2 2.4 4.6 3.1 4.7 3.2 0.87
25(OH)D (nmol/L) 36.1 13.9 34.1 12.1 33.8 12.5 0.29

SD standard deviation, BMI body mass index, DM diabetes mellitus, eGFR estimated glomerular filtration rate, BMD bone mineral density, BAP
bone alkaline phosphatase, NTX N-terminal telopeptide, ucOC undercarboxylated osteocalcin, 25(OH)D 25-hydroxy-cholecalciferol
a
Osteoporosis is defined as lumbar BMD<YAM80% (−1.63 SD) with fragility fractures or lumbar BMD<YAM70% (−2.45 SD) without fragility
fractures. Osteopenia is defined as lumbar BMD<YAM80% (−1.63 SD) without osteoporosis
b
Underweight, overweight, and obesity are defined by a BMI of less than 18.5 kg/m2 , between 25 and 29 kg/m2 , or 30 kg/m2 or more, respectively
c
Trend test adjusted for age

respectively, if BMD and other risk factors were adjusted BMD was not adjusted. These rate ratios were essentially
and by 0.66 (0.48 to 0.90) and 0.70 (0.58 to 0.84) if only similar if we analyzed clinical vertebral fracture (0.44

Table 2 Types of incident fractures in the 1,614 postmenopausal women according to body mass index

Underweight (N0135)a Normal weight (N01,131) Overweight/obese (N0348)a

Frequency Proportion Frequency Proportion Frequency Proportion

Vertebral fracture 53 39.3 % 387 34.2 % 149 42.8 %

Clinical vertebral fracture 21 15.6 % 167 14.8 % 66 19.0 %
Major osteoporotic fracture 36 26.7 % 236 20.9 % 80 23.0 %
Long-bone fracture 21 15.6 % 111 9.8 % 27 7.8 %
Femoral neck fracture 10 7.4 % 31 2.7 % 7 2.0 %
Forearm fracture 5 3.7 % 38 3.4 % 4 1.1 %
Humerus fracture 0 0.0 % 1 0.1 % 3 0.9 %
Rib fracture 1 0.7 % 8 0.7 % 1 0.3 %
a
Underweight, overweight, and obesity are defined by a BMI of less than 18.5 kg/m2 , between 25 and 29 kg/m2 , or 30 kg/m2 or more, respectively
Osteoporos Int (2013) 24:69–76 73

a obese group by 2.15 (95 % CI: 0.73 to 6.34) and 1.51

Annual rate of vertebral fracture (95 % CI: 0.82 to 2.77), respectively, in the analysis adjust-
0.14
ed for lumber BMD (Table 3). Further, incidence rates of
0.12 Underweight femoral neck and long-bone fractures were similar between
Normal weight the normal weight and overweight/obese groups (Table 3).
0.10
Overweight
Similar trends were observed if we adjusted for femoral
0.08
neck BMD (data not shown).
0.06
Comparison of body mass index and related indices
0.04

0.02 Table 4 compares rate ratios per a 1−SD increment of BMI

0.00 and related indices in Poisson regression models adjusted
Normal Osteopenia Osteoporosis Whole cohort for BMD and other risk factors. Rate ratios of BMI, weight,
(N=779) (N=329) (N=505) (N=1614)
% fat mass, and waist circumference ranged between 1.16
b and 1.28 for vertebral fracture, suggesting that these indices
Annual rate of femoral neck fracture are useful predictors in risk assessment tools that use BMD
0.14 for vertebral fracture but not for long-bone and femoral neck
0.12 Underweight fracture. In contrast, lean mass was not related to incidence
Normal weight rates of vertebral, femoral neck, or long-bone fractures.
0.10
Overweight
0.08

0.06
Discussion

0.04
This 6-year follow-up study of 1,614 postmenopausal wom-
0.02 en found paradoxical associations of BMI; overweight/obe-
0.00
sity was associated with an increased incidence rate of
Normal Osteopenia Osteoporosis Whole cohort vertebral fracture, while underweight correlated with an
(N=779) (N=329) (N=505) (N=1614)
increased risks of femoral neck and long-bone fracture in
c analyses adjusted for BMD. A qualitatively similar finding
Annual rate of long-bone fracture was obtained when BMI was treated as a continuous vari-
0.14 able, but the BMI–fracture associations appeared to be non-
0.12 Underweight linear. The rate ratios per a 1−SD increment of BMI and
Normal weight related indices were similar except for lean mass.
0.10
Overweight Obesity is widely believed to be protective against frac-
0.08 ture, but varying associations between BMI and fracture
0.06 sites have been reported. Increased BMI and obesity were
consistently associated with decrease in hip fracture [9]. The
0.04
negative BMI–fracture association was specific to hip and
0.02 central body fractures in the Women's Health Initiative [11].
0.00
The Osteoporotic Fractures in Men Study found that obesity
Normal Osteopenia Osteoporosis Whole cohort as compared to subjects with normal weight was associated
(N=779) (N=329) (N=505) (N=1614)
with an increased risk of nonspine, hip, and upper and lower
Fig. 1 Crude incidence rates per 1,000 person-years of vertebral extremity fractures for a given level of BMD [30]. On the
fracture (left), femoral neck fracture (middle), and long-bone fracture other hand, obese women in the Global Longitudinal Study
(right) according to body mass index and osteoporosis status in the
of Osteoporosis in Women had increased risk of ankle and
1,614 postmenopausal women. Osteoporosis is defined as lumbar
BMD<YAM80% (−1.63 SD) with fragility fractures or lumbar BMD upper leg fractures [12]. In an analysis of medical records in
<YAM70% (−2.45 SD) without fragility fractures. Osteopenia is de- Spain, obesity was associated with an almost 30 % increase
fined as lumbar BMD<YAM80% (−1.63 SD) without osteoporosis in risk for proximal humerus fractures [31]. In a cross-
sectional study of 2,235 postmenopausal women, increased
[95 %CI: 0.26 to 0.74], 0.60 (0.45 to 0.81), 0.58 [0.35 to BMI was associated with a significantly higher risk of
0.95], and 0.67 [0.50 to 0.89], respectively). In contrast, the humerus fracture and a lower risk of hip fracture, but no
incidence rates of femoral neck and long-bone fractures in relationship was seen between BMI and either wrist or ankle
the underweight group were higher than the overweight/ fractures [32]. The association between BMI and vertebral
74 Osteoporos Int (2013) 24:69–76

Table 3 Rate ratios with 95 % confidence intervals for body mass index groups with and without adjustment for bone mineral density

Vertebral fracture Femoral neck fracture Long-bone fracture

RR 95 % CI p RR 95 % CI p RR 95 % CI P

Unadjusted for BMDa

Underweightb 0.66 (0.48 to 0.90) 0.01 2.06 (0.76 to 5.57) 0.16 1.73 (0.97 to 3.08) 0.06
Normal weight 0.70 (0.58 to 0.84) <0.01 1.16 (0.51 to 2.67) 0.72 1.21 (0.79 to 1.85) 0.38
Overweight/obeseb Ref. – – Ref. – – Ref. – –
Further adjusted for BMD
Underweightb 0.45 (0.32 to 0.63) <0.01 2.15 (0.73 to 6.34) 0.16 1.51 (0.82 to 2.77) 0.18
Normal weight 0.61 (0.50 to 0.74) <0.01 1.18 (0.51 to 2.74) 0.70 1.15 (0.75 to 1.77) 0.52
Overweight/obeseb Ref – – Ref – – Ref – –

RR rate ratio, CI confidence interval, BMD bone mineral density

a
Adjusted for age, diabetes mellitus, prior fracture, back pain, and treatment by conjugated estrogen or estradiol
b
Underweight, overweight, and obesity are defined by a BMI of less than 18.5 kg/m2 , between 25 and 29 kg/m2 , or 30 kg/m2 or more, respectively

fracture risk remain controversial. Increased BMI was a
protective factor of vertebral fracture in the Study of Oste-
oporotic Fractures [33] but was associated with increase in
number of vertebral fractures in small-scale cross-sectional
studies [34, 35]. In the Malmö Preventive Project, increase
in BMI was associated with decrease in incident vertebral
fracture in men, but not in women [36].
Compared to the previous studies, subjects in this cohort
had markedly lower BMI, with 8.4 % of underweight and
2.0 % of obesity, and a higher incidence rate of vertebral
fracture. This is attributable to ethnic difference between Asian
and Caucasians. In fact, the prevalence rates of overweight and
obese in this cohort were similar to estimates in general
Japanese women (17.4 % for overweight and 3.2 % for obe-
sity) [37], and the prevalent rates of diabetes mellitus, hyper-
tension, and hyperlipidemia were also comparable to general
populations (13.2 % and 42.1 %, 50.6 %, respectively) [37].
The low prevalence of obesity in Asian is well-known, and a
recent multiethnic study reported that clinical vertebral-to-hip
fracture ratios in cohorts in Hong Kong and Japan are higher
than that in Swedish Caucasian population [38]. Subjects in
the underweight group had lower BMD and higher incidence
rates of long-bone and femoral neck fractures. These findings
are consistent with the previous studies [9–12, 30, 32]. In
contrast, the increased incidence rate of vertebral fracture in
overweight women have not been reported.
The mechanisms whereby overweight affects incident ver-
tebral fracture are not entirely clear. Increase in BMI accom-
panies a variety of metabolic disorders and accelerated
senescence, which can contribute to increased risk of fracture,
such as type 2 diabetes [13–15], metabolic syndrome [16],
peripheral artery disease [17], increased homocysteine [18],
and pentosidine levels, [19–22], high sensitive C-reactive
protein [39], and high propensity of falls [11]. It is also well-
known that obese postmenopausal women tend to have high
estrogenecity because in fat tissue, androstenedione and tes-
tosterone are converted to estrone and estradiole [40], leading
to high BMD and low bone turnover, which can contribute to
a decreased fracture risk. On the other hand, obesity leads to
generation of reactive oxygen species (ROS) through chronic
inflammatory process. ROS mainly deteriorates the prolifera-
tion and survival of osteoclast, osteoblasts, and osteocytes

Table 4 Comparison of body mass index and related indices in terms of rate ratios per a 1−SD increment

Vertebral fracture Femoral neck fracture Long-bone fracture

RRa 95 % CI p RRa 95 % CI p RRa 95 % CI P

BMI, +1 SD 1.28 (1.17 to 1.40) <0.01 0.81 (0.58 to 1.12) 0.21 0.95 (0.80 to 1.13) 0.56
Weight, +1 SD 1.25 (1.14 to 1.38) <0.01 0.97 (0.68 to 1.38) 0.85 1.03 (0.86 to 1.25) 0.73
Lean mass, +1 SD 1.06 (0.96 to 1.18) 0.26 1.16 (0.79 to 1.72) 0.45 1.05 (0.85 to 1.30) 0.63
% Fat mass, +1 SD 1.19 (1.10 to 1.30) <0.01 0.81 (0.61 to 1.07) 0.14 0.98 (0.83 to 1.15) 0.78
Waist circumference, +1 SD 1.15 (1.03 to 1.29) 0.01 0.89 (0.62 to 1.27) 0.52 0.97 (0.77 to 1.23) 0.64

RR rate ratio per a 1−SD increment, CI confidence interval, BMI body mass index
a
Estimated by separate Poisson regression models, adjusted for age, diabetes mellitus, prior fracture, bone mineral density, back pain, and treatment
by conjugated estrogen or estradiol
Osteoporos Int (2013) 24:69–76
[41]. Obesity or excess generation of ROS may induce exces-
sive tissue oxidation if the defense system against ROS works
insufficiently, including abnormal cross-links of collagen [15].
Higher BMI induces higher levels of adipocytokines or proin-
flammatory cytokines in visceral fat [42, 43]. Vitamin D status
is inversely related to BMI and to insulin resistance, providing
other mechanisms of fracture [44, 45]. In this study, there were
no significant differences in serum level of 25(OH)D and
urinary NTX across the BMI groups. On the other hand,
serum level of osteocalcin was significantly lower in the high
overweight/obese group than that in the other groups, suggest-
ing that low bone formation by osteoblasts may account for
high susceptibility of vertebral fracture in overweight or obese
women. High BMD and high adiposity in overweight or obese
women, on the other hand, may protect long-bone fractures,
which can mainly be induced by fall [11].
These findings must be interpreted in the context of the
limitations of the study. First, our analysis is likely to be
influenced by several other sources of bias, such as selection
bias, informative censoring, and bias caused by treatment
for osteoporosis initiated during follow-up. Second, our
results may not be generally applicable to populations with
different genetic or lifestyle factors, given that the preva-
lence of obesity is quite low in Japanese women. Confirma-
tion of our findings in studies in different ethnic populations
is, therefore, necessary. Third, some data that would provide
more insights into the BMI–fracture associations, such as
weight change or estrogen levels, were not measured in this
study. Finally, we used conventional criteria to define under-
and overweight but whether these criteria are optimal for
prediction of osteoporotic fracture remains unknown.
These limitations notwithstanding, we conclude that over-
weight and underweight are both risk factors for osteoporotic
fracture at different sites. BMI, body weight, % fat mass, and
waist circumference are useful, readily available predictors of
fracture, but fracture risk assessment may be improved if
fracture sites are taken into account and BMI is categorized.
Acknowledgments S.T. performed statistical analysis and drafted the
manuscript. M. Shiraki is the principal investigator of the Nagano cohort
study. S.T., T.K., M. Saito, and M. Shiraki contributed to the interpretation
of the data and the writing of the manuscript. This work was partly
supported by a grant-in-aid from the Japan Osteoporosis Foundation.
Conflicts of interest None.
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