Menopausal bone changes and incident fractures in diabetic women: A cohort study

Abstract

The purpose of this study was to evaluate the rate of bone loss and incident fractures in women with diabetes mellitus (DM) across menopause. During menopause, DM women experienced bone mineral density (BMD) loss that was faster at hip and slower at spine and had a higher risk of fractures, perhaps because of their earlier menopause. The increasing DM epidemic will contribute to higher fracture burden.
Women with DM have a higher risk of fractures independent of age, body mass index (BMI), and BMD. Our objective is to evaluate if women with DM experience greater bone loss and more fractures across menopause.
Two thousand one hundred seventy one women, aged 42 to 52 years at baseline (1996), enrolled in the Study of Women's Health Across the Nation (SWAN), a prospective study, with 8 years of annual follow up. One thousand three hundred forty six (62%) completed annual visit 7 (2004). Women with baseline fasting blood glucose level of ≥126 mg/dl and those being treated for diabetes were designated as DM. Annual assessment of menopausal stage, BMD, and urinary N-telopeptide (NTx) were carried out. Rate of change in BMD across menopause and annual self-report data for risk of incident fractures by DM status were determined.
Despite higher baseline BMD at hip (p = <0.001), and lumbar spine (p = <0.001), rate of decline in BMD was faster at hip (β = -0.45 vs. -0.11 gm/cm(2)/year, p = <0.001) for DM women, compared to non-DM. However, lumbar spine bone loss was slower in women with DM as compared to non-DM women (β = 0.04 vs. -0.25 gm/cm(2)/year, p = 0.004). DM women experienced menopause 3 years earlier than non-DM women (p = 0.002), and age adjusted incident fractures were two fold higher in women with DM compared to non-DM (RR = 2.20, 95% CI: 1.26-3.85, p = <0.006).
BMD loss is greater in hip and slower at spine in DM women during menopausal transition. Women with DM have a higher risk of fractures, perhaps because of their earlier menopause.

Full text

Menopausal bone changes and incident fractures in diabetic
women: a cohort study
N. Khalil,
Department of Community Health, Boonshoft School of Medicine, Wright State University,
Dayton, OH, USA
Assistant Professor Environmental Health, Center for Global Health Systems, Management, and
Policy, Boonshoft School of Medicine, Wright State University, 3123 Research Blvd., Suite 200,
Kettering, OH 45420, USA
K. Sutton-Tyrrell,
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, PA, USA
E. S. Strotmeyer,
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, PA, USA
G. A. Greendale,
Division of Geriatrics, David Geffen School of Medicine, University of California at Los Angeles,
Los Angeles, CA, USA
M. Vuga,
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, PA, USA
F. Selzer,
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, PA, USA
C. J. Crandall, and
Division of General Internal Medicine, David Geffen School of Medicine, University of California at
Los Angeles, Los Angeles, CA, USA
J. A. Cauley
Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh,
Pittsburgh, PA, USA
N. Khalil: naila.khalil@wright.edu
Summary
The purpose of this study was to evaluate the rate of bone loss and incident fractures in women
with diabetes mellitus (DM) across menopause. During menopause, DM women experienced bone
mineral density (BMD) loss that was faster at hip and slower at spine and had a higher risk of
fractures, perhaps because of their earlier menopause. The increasing DM epidemic will contribute
to higher fracture burden.
© International Osteoporosis Foundation and National Osteoporosis Foundation 2010
Correspondence to: N. Khalil, naila.khalil@wright.edu.
Conflicts of interest None.
NIH Public Access
Author Manuscript
Osteoporos Int. Author manuscript; available in PMC 2011 May 1.
Published in final edited form as:
Osteoporos Int
. 2011 May ; 22(5): 1367–1376. doi:10.1007/s00198-010-1357-4.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript

Introduction—Women with DM have a higher risk of fractures independent of age, body mass
index (BMI), and BMD. Our objective is to evaluate if women with DM experience greater bone
loss and more fractures across menopause.
Methods—Two thousand one hundred seventy one women, aged 42 to 52 years at baseline
(1996), enrolled in the Study of Women's Health Across the Nation (SWAN), a prospective study,
with 8 years of annual follow up. One thousand three hundred forty six (62%) completed annual
visit 7 (2004). Women with baseline fasting blood glucose level of ≥126 mg/dl and those being
treated for diabetes were designated as DM. Annual assessment of menopausal stage, BMD, and
urinary N-telopeptide (NTx) were carried out. Rate of change in BMD across menopause and
annual self-report data for risk of incident fractures by DM status were determined.
Results—Despite higher baseline BMD at hip (p=<0.001), and lumbar spine (p=<0.001), rate of
decline in BMD was faster at hip (β=−0.45 vs. −0.11 gm/cm2/year, p=<0.001) for DM women,
compared to non-DM. However, lumbar spine bone loss was slower in women with DM as
compared to non-DM women (β=0.04 vs. −0.25 gm/cm2/year, p=0.004). DM women experienced
menopause 3 years earlier than non-DM women (p=0.002), and age adjusted incident fractures
were two fold higher in women with DM compared to non-DM (RR=2.20, 95% CI: 1.26–3.85,
p=<0.006).
Conclusions—BMD loss is greater in hip and slower at spine in DM women during menopausal
transition. Women with DM have a higher risk of fractures, perhaps because of their earlier
menopause.
Keywords
Bone; Density; Diabetes; Menopause; Women
Introduction
Osteoporosis and diabetes mellitus (DM), two of the most common chronic conditions, are
public health concerns. In the USA, two million osteoporotic fractures occur every year [1].
Incident DM affects 7.8% of the US population [2]. With global demographic trends of
aging and obesity, the prevalence of diabetes is projected to double in the next 20 years [3].
Menopause is the most significant period for bone loss in women, when rapid metabolic and
endocrine changes occur. Bone loss initiates before the last menstrual period [4]. The
percent decrease in bone mineral density (BMD) in the first 5 years post-menopause can be
as high as 9–13% [5]. Although menopause has a greater effect on bone loss than
chronological age [6], age is also an independent risk for osteoporotic fractures [7].
DM affects bone metabolism; the relationship between DM and osteoporosis is complex,
and the mechanisms underlying this association remain controversial. While low BMD is
consistently observed in type 1 DM, the association is less clear in type 2 DM; both type 1
and type 2 DM have been associated with a higher risk of fractures [8]. New bone formation
and bone quality (micro-architectural bone composition and characteristics of bone strength)
may be impaired in DM, leading to lower mechanical strength and a propensity to fracture.
The majority of published studies involving DM and skeletal outcomes have been conducted
in postmenopausal older women who were predominantly Caucasian. Prospective studies of
BMD change in DM women of diverse ethnicity, across menopause, that concurrently
evaluate bone biomarkers and fracture risk are lacking. The Study of Women’s Health
Across the Nation (SWAN) is uniquely positioned to address BMD changes across
menopause. Women of Caucasian, African American, Chinese, and Japanese ethnicity have
been followed annually up to 8 years in SWAN. In this analysis, we report BMD changes
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and fracture risk across menopause in women with DM compared to women without DM.
We tested the following hypotheses: (1) women with DM experience greater bone loss and
more fractures across the menopausal transition and (2) this association may be mediated by
menopause status.
Subjects and methods
Study population
SWAN began in 1996–1997 to study the health changes during mid-life in a multi-ethnic
community-based cohort of 3,302 women. Eligibility criteria have been detailed elsewhere
[9]. Briefly, women eligible for SWAN were aged between 42 and 52 years at baseline, had
an intact uterus, had at least one intact ovary, were not currently taking hormone therapy or
oral contraceptives, were not pregnant or lactating, and had ≥1 menstrual period in the
previous 3 months.
The SWAN bone study aims to describe skeletal changes as women transition menopause
and to compare associated factors across different ethnic backgrounds. In addition to
recruiting Caucasian women, each of the five bone-study sites enrolled women of another
ethnic group: African American (Boston, MA; Pittsburgh, PA; Detroit, MI), Chinese
(Oakland, CA), and Japanese (Los Angeles, CA). Japanese women formed the referent
group in the current analyses. Though the overall rate of BMD loss as previously shown in
SWAN was similar among ethnic groups across menopause, Japanese women had the most
rapid lumbar spine bone loss [10]. The rate of hip fracture in Japanese women is 50% lower
than in Caucasian women, as revealed in another study [11]. Each clinical center and the
data coordinating center received institutional review board approval, and all women
provided written informed consent.
This analysis included data from baseline (1996) through annual visit 7 (2004) from
participants who had baseline assessment of blood glucose and underwent at least one BMD
measurement during the observation period. At baseline, observations from women who
reported anorexia (n=28), reported bulimia (n=16), were missing information for diabetes
(n=175), or were missing information for BMD at the total hip or lumbar spine (n=27) were
excluded, leaving an analytic baseline sample of 2,155 women. During follow up, 386
observations from women who reported use of medication that influence bone turnover
(hormone preparations, GnRH agonist therapy, or antiresorptive therapy including
bisphophonates, calcitonin, tamoxifen, raloxifene) at any visit, or reported use of steroid
preparations on two consecutive visits, were censored from further analysis [10].
Observations from women who developed incident diabetes at any annual follow up visit
after baseline in this cohort were censored from subsequent analysis: n=98(6%) women
developed DM at visit 1 and none at visit 2 because created diabetes variable was not
available at visit 2 (blood glucose concentrations were not obtainable at this visit), n=91
(6%) at visit 3, n=97 (7%) at visit 4, n=111 (8%) at visit 5, n=112 (8%) at visit 6, and n=112
(8%) at visit 7 (1,929 total incident DM observations censored from longitudinal analysis)].
One thousand three hundred forty six women completed visit 7 (62% of the baseline cohort).
Bone mineral density measurements
BMD at the total hip and the lumbar spine were measured at baseline and annually with dual
X-ray absorptiometry (DXA). Hologic QDR 2000 densitometers (Hologic, Waltham, MA,
USA) were used in Pittsburgh and Oakland sites and 4500A in Boston, Detroit, and Los
Angeles. Reproducibility of hip measurements was improved by using Osteodyne (Research
Triangle Park, NC, USA) positioning devices [12]. Quality control protocol comprised of
daily scans of anthropomorphic spine phantoms, cross-site and cross-time calibration with a
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Hologic spine phantom, and an on-site review. Scans with potential problems, and 5% of all
scans, were reviewed by Synarc (Waltham, MA, USA). Short-term in vivo measurement
standard deviations were 0.014 g/cm2 for the lumbar spine and 0.016 g/cm2 (2.2 %) for the
lumbar spine and femoral neck (hip), respectively [10].
Urinary N-telopeptide
Urinary N-telopeptide of type 1 collagen (NTx) was measured in singlicate using an
automated immunoassay (Vitros ECi; Ortho Clinical., Rochester, NT, USA). The assay was
based on competition between urinary peptide and synthetic NTx peptide coating the wells,
for binding by an anti-NTx monoclonal antibody conjugated to horse radish peroxidase. The
bound conjugate was measured by chemiluminescence. NTx was expressed as nanomoles of
bone collagen equivalents per liter per millimole creatinine per liter (nM BCE/mM
creatinine). The lower limit of detection was 10 nM BCE and intra- and inter-assay
coefficients of variation were 2.75% and 4.8%, respectively, over the assay range. Samples
>3,000 nM BCE were diluted 1/20 prior to measurement. Creatinine was measured on the
Cobas Mira (Horiba ABX, Montpellier, France) based on the Jaffé reaction (to calculate
NTx/Cr ratio). The lower limit of detection was 0.014 mM and the intra- and inter-assay
coefficients of variation were 0.62% and 4.12%, respectively, across the assay range.
Ascertainment of baseline diabetes
DM was defined as [1] fasting baseline glucose level ≥126 mg/dl or [2] self-report of
current hypoglycemic medications or insulin.
Questionnaire-based and anthropometric measurements
At baseline and at each annual visit, women underwent an interview that included
menopause status checklist and socio demographic and lifestyle characteristics. Ethnicity
was self-identified. Smoking was coded as never (referent), past, or current. Alcohol
consumption was categorized as none vs. any alcoholic beverages per day (referent). Self-
reported daily use of vitamin D and calcium supplement was ascertained as none (referent)
vs. any use. Physical activity was categorized as moderate to more activity vs. less or much
less (referent). Self-reported baseline health status was coded as good/fair (referent) vs.
poor/unchanged, and economic status as difficulty in paying for basic necessities vs. no
difficulty (referent). At baseline and annual visits, weight (kg) was measured with a balance
beam scale. Medication use was ascertained and verified through an interviewer-
administered questionnaire. A complete inventory was taken at baseline and subsequent
annual visits that included but was not limited to use of hormone preparations, steroids,
GnRH agonist therapy, and antiresorptive therapy (including bisphophonates, calcitonin,
tamoxifen, raloxifene) [10].
Assessment of fractures
At baseline, participants reported fracture and their age at the time of fracture since age 20,
as ascertained by a physician. During follow-up annual visits, participants self-reported
incident fractures, including the site and number of fractures since their last study visit. The
reliability of self-reported fractures with medical records confirmation has been documented
in several studies. In 161,809 post-menopausal women enrolled in Women Health Initiative
study, the overall fracture confirmation rate between self report and medical records was
71% [13]. Nevitt et al. described that 78% of fractures were confirmed when self-reported
non-spine fractures were compared with radiographs and medical reports in 9,704 elderly
women [14].
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Menopausal status
Menopausal status was based on self-reported menstrual cycle characteristics recalled over
the past year: premenopausal (menstruation in the past 3 months with no change in
menstrual regularity in past year), early peri-menopausal (menstruation in past 3 months
with decreased regularity in past year), late peri-menopausal (no menstruation for 3–11
months), and post-menopausal (no menstruation for past 12 months) [15].
Role of the funding source
The sponsors had no role in the design and conduct of the study; collection, management,
analysis, and interpretation of the data; and preparation, review, or approval of the
manuscript.
Statistical analysis
Separate linear mixed models with random intercept were run using SAS PROC MIXED to
ascertain rate of change in BMD at lumbar spine, and total hip, as repeated-measure
analysis. Baseline age and weight were centered at their means, percentage change in weight
since baseline was computed for all follow-up visits. Statistical model building comprised of
the sequential addition of one covariate to the preceeding model starting with DM, followed
by the addition of age, baseline weight, percentage change in weight from baseline,
smoking, lifestyle (alcoholic beverages consumed/day, physical activity, study site, health
and economic status), daily supplement use (calcium and vitamin D) baseline BMD at
respective bone site, ethnicity, and NTx/Cr.
DM has been associated with an earlier menopause [16,17]; thus, in the final model, we
adjusted for menopausal status. We hypothesized that, if the association between DM and
fracture was modified when menopause was added to the model, this would suggest that a
higher fracture risk among DM women would reflect their earlier menopause. SAS PROC
GLM was used to ascertain difference in age at menopause across DM status in unadjusted
and multivariate adjusted models. An interaction term for DM and time, to test if change in
BMD differed between DM and non-DM over time, was also included. In secondary
analyses, the same modeling strategy was repeated to test if the interaction of time, DM, and
menopause status predicted BMD change across menopause over time.
The relative risk of fractures by DM status was estimated using SAS PROC GENMOD as
repeated measures analysis sequentially adjusting for the same covariates listed above.
Analyses were performed using SAS 9.2 (SAS Institute, Cary, NC, USA).
Results
Characteristics of the participants
The prevalence of DM at baseline was 5%, mean age was 46, and approximately half of
participants were non-Caucasian (Table 1). Although all women at baseline were
premenopausal (54%) or early peri-menopausal (46%), a significantly higher proportion of
DM women had transitioned to early peri-menopausal as compared to those without DM
(58% vs. 45%, respectively, p<0.001). Mean weight for DM women was higher than for
non-DM women (95 vs. 72 kg, p<0.001). DM women were less likely to consume alcohol,
to be economically better-off, or to be physically active (p<0.001 for all). Smoking status
and overall health status did not differ by DM. Women with DM reported significantly less
use of calcium supplements (p=0.001); however, use of vitamin D was similar. DM women
had higher mean baseline total hip and lumbar spine BMD (p<0.001 for both) as compared
to non-DM women. DM women were also more likely to report a history of fracture than
non-DM women (26% vs. 19%, respectively, p=0.065).
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DM and change in BMD
Over a maximum follow up of 8 years (median 3.1, interquartile range 4.1), the magnitude
of decline in adjusted BMD was about fourfold higher in women with DM compared to non-
DM women at the total hip (β=−0.45 vs. −0.11 gm/cm2/year, p=<0.001) (Table 2). However
adjusted lumbar spine bone loss was significantly slower in women with DM as compared to
non-DM women (β=0.04 vs. −0.25 gm/cm2/year, p=<0.01). Addition of menopausal status
to the models attenuated the effect slightly, but the rate of bone loss remained significantly
different in DM vs. non-DM women. Mean BMD in the final models was significantly
lower in DM women compared with non-DM women at the total hip (Table 2); however,
adjusted mean lumbar spine BMD was significantly higher in women with DM as compared
to non-DM women (p=<0.01 for both).
DM, menopause stage, and change in BMD
DM women reached menopause at a mean age of 49 years, compared to 52 years in non-DM
women, an average of 3 years earlier in unadjusted (p=0.0015) and risk-factor-adjusted
models (p=0.0046) (Table 3).
Rate of BMD change in women with DM vs. those without DM at various stages of
menopause were compared. In adjusted models, the interaction between menopause status
and DM was significant in both bone sites, implying a different rate of BMD change across
the menopause by DM status (total hip p=0.016, lumbar spine p=<0.001) (Table 3; Fig. 1).
At the total hip, a trend towards higher rate of BMD change over post-menopause was
observed in women with DM (p=0.058). However, at the lumbar spine, DM women
experienced a significantly slower rate of BMD loss, compared to non-DM participants both
during late peri-menopause and post-menopause (p<0.001 for both).
Fractures
Baseline self-reported fractures (n=415) since age 20 were significantly higher in women
with DM compared to women without DM [30 (26%) vs. 385 (19%), p=0.065], respectively.
The percentage of baseline fractures at all bone sites was higher in DM women, although
this difference reached statistical significance only for fractures of the lower arm (Table 1).
During 8 years of follow up, 260 incident fractures were reported overall; 232 women
reported a single fracture, 12 women reported fractures on more than one visit (nine reported
fractures on two different visits, two reported fractures on three visits, and one reported
fracture on four separate visits). A total of 245 women reported any fracture; percentage of
fractures was significantly higher in DM women compared to non-DM participants [26 (5%)
vs. 219 (2%), respectively (p<0.0001)]. The relative risk of incident fractures was
approximately twofold higher in women with DM compared to non-DM women in age
(RR=2.16, 95% CI: 1.26–3.72, p=<0.006), and multivariate adjusted (RR=1.85; 95%
CI=1.06, 3.22, p=0.036) models. However, the addition of menopausal status to the models
attenuated the effect of DM on fractures (RR=1.53; 95% CI=0.76, 3.14, p=0.292) [Fig. 2 (p
values are not shown in the figure)].
Secondary analysis
To explore if insulin use influenced BMD loss and fracture outcomes in DM participants, we
carried out a secondary analysis by excluding women who were using insulin at baseline.
After insulin exclusion, rate of hip BMD loss was significantly faster in adjusted models in
DM women, relative to non-DM participants (p=0.016). However, in lumbar spine, women
with DM experienced slower bone loss (p=0.040). The relative risk of fracture in DM,
compared to non-DM women, was not significant in adjusted models (RR=0.78; 95%
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CI=0.27, 2.24). Even after excluding insulin users, a higher proportion of DM women
suffered a fracture compared to non-DM women [10 (2.9%) vs. 266 (2.2%), respectively
(p=0.374)], although results were not statistically significant
Discussion
The results of this study suggest that, during menopause, women with DM experience a
higher risk of fracture and a rate of bone loss that is faster at the hip and slower at the spine.
An earlier age of menopause in DM women was observed, which, in conjunction with their
fourfold faster rate of bone loss, may contribute to a higher risk of having any fracture. The
SWAN study provides further evidence that, despite their higher baseline BMD, women
with DM are at greater risk of fracture. To our knowledge, this is the first longitudinal study
to report a more rapid rate of hip bone loss and a higher risk of fractures in a relatively
young cohort of DM women.
The observation of a higher baseline BMD supports the findings of previous studies in
which a higher BMD has been observed in women with DM compared with age-matched
subjects without DM, in femoral neck, lumbar spine [18], and calcaneus [19].While low
BMD is observed in type 1 DM, the relationship is less definitive in type 2 DM, with recent
reviews reporting modestly higher or unchanged BMD [8]. Despite discrepancies between
BMD, recent research underscores that bone formation, micro-architecture, and bone quality
are affected in both types of DM [20].
Recent meta-analyses also reported a higher hip fracture risk with both type 1 and type 2
DM (RR=1.4–1.7) [8,21], although the mechanism is not well understood. DM women,
regardless of the type, had significantly elevated hip fracture risk from studies in Europe
[22], Canada [23], and USA [24]. The SWAN findings extend these observations to a much
younger group of women.
Even though, in adults, type 2 accounts for 90–95% of all diagnosed cases of DM,
information related to longitudinal changes in BMD in type 2 DM in women is sparse [25].
A faster rate of hip bone loss has been reported in one longitudinal study of older adults (age
at least 65), in which Caucasian women with type 2 DM lost bone more rapidly at the hip
relative to those without DM [26]. In a prospective evaluation of type 2 DM men and
women (age 70–79) in the Health, Aging, and Body Composition Study (Health ABC),
women lost more hip BMD over 4 years of follow up, despite having higher baseline BMD
[27]. In another analysis from the same cohort, type 2 DM participants with fractures had
lower hip BMD when compared to those without fractures [18].
These epidemiologic observations are supported by animal data, which showed that, in
rodent models (diabetic mouse model, MKR), although bone density is greater in DM, bone
structure is more fragile, with fractures occurring under a smaller mechanical load [28]. In
other spontaneous diabetic rat models, despite having normal BMD, decreased femoral bone
strength against torsion, bending, and energy absorption was noted [29]. Specifically, in type
2 DM, skeletal fragility may arise from reduced transverse bone accumulation and increased
resorption, as explained in a recent study of MKR mice [28]; type 2 diabetic mice had thin
long bones with 20% decreased strength (p<0.05) relative to controls. Micro-computed
tomography and histomorphometry revealed that, although BMD was not affected,
periosteal increase was impaired, cortical bone resorption was 250% faster, and bone
formation was 40% reduced as compared to normal mice (p<0.05) [28]. Similar structural
and mechanical change could play a role in DM-induced fragility in human bone.
DM could also affect bone remodeling by various mechanisms, including insulin deficiency
and microangiopathy; higher circulating glucose levels may predispose to accumulation of
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advanced glycation end products (AGE) in bone, which lead to impaired bone quality and
biomechanics as studied in diabetic rats [28] and human cadaver femurs [30]. The
combination of poor bone quality and microstructure and an accelerated bone loss would
reduce bone strength. As observed in our study, bone fragility due to rapid bone loss cannot
be calculated from DXA measure of BMD. However, newer technology, peripheral
quantitative computed tomography (p-QCT), can measure volumetric density (v BMD) and
skeletal properties. In a recent publication, Petit and colleagues compared tibial and radial v
BMD using p-QCT in type 2 DM men 65 years, relative to those without DM [31]. There
was lower bone bending strength at both tibia and radius in DM men, despite no difference
in cortical vBMD at both sites.
Adjusting for menopause status attenuated the higher risk of fracture in DM women, which
implies that menopause status is an intermediary in the association between DM and fracture
risk. A significant difference in age at menopause was seen; DM women reached menopause
on average 3 years earlier as compared to non-DM women. While premature menopause has
been linked with type 1 DM [17], its association is less defined with type 2 DM [32]. Earlier
menopause is an independent risk factor for fractures [7]. In a cross sectional eligibility
survey of about 16,000 women for SWAN, DM was associated with premature ovarian
failure, defined as menses cessation before age 40 [16]. More research is clearly needed to
explore the impact of DM on age at menopause and its clinical consequences.
We found a relatively higher lumbar spine BMD and a lower rate of vertebral bone loss over
time in DM women as compared to women without DM. This finding is consistent with
other studies that evaluated spine BMD with DXA in female DM patients [33].
Measurements of spinal BMD with DXA are inaccurately high (radiological artifact) as
extra-osseous calcification in adjacent aorta and degenerative osteo-arthritic changes are
incorporated in the radiograph [34]. Moreover, individuals with DM have a higher
propensity of calcification in the aorta [35], the mechanism for which is not completely
understood, though AGE is proposed as a trigger [36].
We did not observe a difference in NTx/Cr, a bone resorption biomarker in DM vs. non-DM
women. Previous studies have not revealed a consistent association between DM status and
rates of bone change as assessed by bone turnover markers [37]. Clearly, the mechanism(s)
involved in bone turnover in DM is complex, and more research is needed.
Newer hypoglycemic medications (TZD), rosiglitazone (Avandia), and pioglitazone (Actos)
are associated with elevated fracture risk in white women and, for rosiglitazone, more rapid
bone loss [38]. Information on the use of these drugs was not ascertained for this analysis, as
they were introduced in USA in 1999 [39] after the baseline SWAN visit (1996).
Our study has several strengths, including longitudinal design. We collected comprehensive
health and lifestyle data across a diverse cohort of women undergoing menopause. With
almost 2,200 participants, this was the largest study with information on bone biomarker;
eight annual BMD examinations at two anatomical sites. There are, however, limitations to
our results; the fractures were self reported and were not confirmed radiologically, which
could lead to misclassification. However, self-reported fractures have good reliability [40];
frequencies of self-reported fractures are found to be similar to those verified using
radiographs. One additional limitation of this analysis is the small number of fracture events,
especially in DM women. A fracture is a relatively rare endpoint; individual studies often
lack power, as accrual of events takes time, more so in younger subjects. The SWAN
participants are relatively young (42–52 years at baseline in 1996–1997) and are now
reaching an age when incidence of osteoporotic fractures begins to increase markedly.
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The current analysis was also limited by our inability to differentiate between type 1 and 2
DM. In the US, type 1 accounts for 5–10% of DM cases [25]. It is reasonable to assume that
the proportions of type 1 and 2 diabetes in the SWAN are similar to the US figures.
Diagnosis of DM has distinct criteria, which can be clearly conveyed to participants, which,
in turn, make it easier to ascertain the validity of a self report for the diagnosis [41]. For
instance, in 87,253 women 34–59 years old, enrolled in Nurses’ Health Study, validation of
diabetes self report with medical records was 98.4% [42]. Other researchers have also shown
relatively high agreement (96.4%) between diabetes self reports and medical records [43]. In
one validation study, Kaye et al. reported 64% confirmation rate between self-report of DM
and participants' physicians [44].
In secondary analysis, insulin use did not explain the faster bone loss at hip in DM women.
The risk persisted even when insulin users were excluded. This result is similar to
observation by Levin et al., who reported that loss in bone density was seen in patients
within 5 years of diagnosis of DM [45] but it did not correlate with duration of DM. This
supports the hypothesis that the loss of skeletal tissue in DM reflects the underlying disease
since it occurs early and is not related to severity of disease, as evidenced by the need for
insulin.
In conclusion, loss in BMD is significantly greater in the hip and slower in the spine in
women with DM during the menopausal transition. DM women had a higher risk of
fractures than non-DM women, perhaps because of their earlier menopause. The increasing
epidemic of DM may contribute to an increasing fracture burden.
Acknowledgments
The SWAN has grant support from the National Institutes of Health (NIH), DHHS, through the National Institute
on Aging (NIA), the National Institute of Nursing Research (NINR), and the NIH Office of Research on Women's
Health (ORWH) (grants NR004061; AG012505, AG012535, AG012531, AG012539, AG012546, AG012553,
AG012554, and AG012495). The content of this manuscript is solely the responsibility of the authors and does not
necessarily represent the official views of the NIA, NINR, ORWH, or the NIH.
Clinical Centers: University of Michigan, Ann Arbor, MaryFran Sowers, PI; Massachusetts General Hospital,
Boston, MA, Robert Neer, PI 1994–1999; Joel Finkelstein, PI 1999– present; Rush University, Rush University
Medical Center, Chicago, IL, Lynda Powell, PI 1994–2009; Howard Kravitz, PI 2009; University of California,
Davis/Kaiser, Ellen Gold, PI; University of California, Los Angeles, Gail Greendale, PI; University of Medicine
and Dentistry, New Jersey Medical School, Newark, Gerson Weiss, PI 1994–2004; Nanette Santoro, PI 2004–
present; and the University of Pittsburgh, Pittsburgh, PA, Karen Matthews, PI.
NIH Program Office: National Institute on Aging, Bethesda, MD, Marcia Ory 1994–2001; Sherry Sherman 1994–
present; National Institute of Nursing Research, Bethesda, MD, Program Officers.
Central Laboratory: University of Michigan, Ann Arbor, Daniel McConnell (Central Ligand Assay Satellite
Services).
Coordinating Center: New England Research Institutes, Watertown, MA, Sonja McKinlay, PI 1995–2001;
University of Pittsburgh, Pittsburgh, PA, Kim Sutton-Tyrrell, PI 2001–present.
Steering Committee: Chris Gallagher, Chair; Susan Johnson, Chair
We thank the study staff at each site and all the women who participated in SWAN.
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Fig. 1.
Rate of change in adjusted BMD by DM status across menopause stages. Pre pre-
menopause, Early peri early peri-menopause, Late peri late peri-menopause, Post post-
menopause. *p value significant at <0.05 for comparison of BMD between DM and non-DM
in respective menopause status. Data were adjusted for same variables as in Table 3. DM
diabetes, Non-DM no-diabetes
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Fig. 2.
Adjusted relative risk (RR) and 95% confidence intervals (CI) for incident fractures
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Table 1
Baseline characteristics of women in SWAN across DM status
Characteristic (N=2,171) DM (n=117) Non-DM (n=2054) p value
Age, mean (SD), year 47 (3) 46 (3) 0.329
Ethnicity, n (%)
African American 61.7 (53) 542.6 (27)
Caucasian 48.6 (42) 1,024.7 (50) <0.001
Chinese 4.9 (4) 217.8 (11)
Japanese 0.9 (1) 254.2 (12)
Baseline menopause status, n (%)
Pre-menopause 49.3 (42) 1,115.6 (55) 0.007
Early peri-menopause 67.4 (58) 910.5 (45)
Difficult to pay for basics (yes), n (%) 18.7 (17) 141.4 (7) <0.001
Weight, mean (SD), kg 95.4 (20) 71.6 (19) <0.001
BMI, mean (SD), kg/m236.2 (7) 26.7 (7) <0.001
Alcoholic beverages/day (any vs. none), n (%) 81.8 (70) 1,021.3 (50) <0.001
Smoking, n (%)
Never 58.1 (50) 1177.8 (57)
Past 30.6 (27) 534.9 (26) 0.161
Current 25.3 (21) 314.8 (15)
Physically active, n (col %)
Less active 45.7 (39) 374.6 (18) <0.001
More active 66.7 (57) 1,612.2 (78)
Health status compared to a year ago, n (%) 0.178
Better 30.1 (26) 426.3 (21)
Same, poor, or worse 83.5 (74) 1,601.7 (79)
Vitamin D supplement use, n (%) 36.7 (32) 800.2 (39) 0.113
Calcium supplement use, n (%) 40.2 (34) 935.7 (46) 0.016
NTx/Cr, mean (SD), nM BCE/mM creatininea33.6 (17) 34.6 (16) 0.610
Baseline BMD, mean (SD), g/cm2
Total hip 1.09 (0.16) 0.95 (0.14) <0.001
Lumbar spine 1.17 (0.16) 1.07 (0.14) <0.001
Baseline history of fractures, n (%)
All fractures 30.3 (26) 385.4 (19) 0.065
Spinal fractures 2.9 (3) 18.1 (1) 0.070
Foot fractures 4.1 (3) 55.6 (3) 0.657
Lower arm fractures 7.3 (6) 52.6 (3) 0.029
Upper arm fractures 1.8 (2) 15.6 (1) 0.280
Hip fracture 0.0 (0) 6.7 (0.3) 0.527
Lower leg fractures 7.8 (7) 96.4 (5) 0.286
Reference group for categorical variables: smoking (referent = none), alcoholic beverages/day (referent=> = 1 drink/day), physical activity
(referent = less or much less), health (referent = better), and economic status (referent = not hard to pay), supplement use (referent = none), study
site (referent = Pittsburgh), and ethnicity (referent = Japanese), menopause status (referent = pre-menopause)
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DM diabetes, Non-DM no diabetes
aNTx/Cr is expressed as nanomoles of bone collagen equivalents per liter per millimole creatinine per liter (nM BCE/mM creatinine, corrected for
creatinine level)
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Table 2
Adjusted rate of BMD change/year across diabetes status between baseline and visit 7
Model BMD (g/cm2/yr)
Total hip Lumbar spine
DM Non-DM PaDM Non-DM Pa
Unadjusted −0.58 −0.24 <0.001 −0.27 −0.54 0.014
Ageb−0.58 −0.24 <0.001 −0.27 −0.54 0.014
Weightb−0.58 −0.24 <0.001 −0.27 −0.53 0.012
% Wt changeb−0.58 −0.32 <0.001 −0.26 −0.58 0.004
Smokingb−0.60 −0.32 <0.001 −0.25 −0.58 0.003
Lifestyleb, c−0.60 −0.32 <0.001 −0.26 −0.58 0.004
Supplement useb, d−0.60 −0.32 <0.001 −0.26 −0.58 0.004
Respective baseline BMDb−0.60 −0.32 <0.001 −0.26 −0.58 0.004
Ethnicityb−0.60 −0.32 <0.001 −0.25 −0.59 0.003
NTxb−0.60 −0.33 <0.001 −0.25 −0.59 0.003
Menopause statusb−0.45 −0.11 <0.001 0.04 −0.25 0.004
Least square means 0.928 0.938 <0.001e1.050 1.039 0.002e
Standard error 0.003 0.002 – 0.004 0.002 –
Reference group for categorical variables: smoking (referent = none), alcoholic beverages/day (referent=> = 1 drink/day), physical activity (referent = less or much less), health (referent = better), and
economic status (referent = not hard to pay), supplement use (referent = none), study site (referent = Pittsburgh), ethnicity (referent = Japanese), menopause status (referent = pre-menopause)
DM diabetes, Non-DM no-diabetes
aP = All p values for interaction between DM status and time
bAll models adjusted for variable that sequentially appear above
cAdjusted for alcoholic beverages consumed/day, physical activity, study site, health and economic status
dVitamin D, calcium
eP = p values for difference of least squares means
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Table 3
Adjusted rate of change in BMD across DM status over menopause stages
Mean age at menopause (year) DM Non-DM p value
Unadjusted 49.1 52.4 0.002
Multivariate adjusteda48.9 51.7 0.005
Adjusted rate of change in BMD across DM status
Total hip % Rate of BMD change/yearb
Menopause statusaDM Non-DM p value
Pre-menopause referent referent referent
Early peri-menopause 0.10 0.15 0.684
Late peri-menopause −0.37 −0.96 0.069
Post menopause −3.16 −2.33 0.058
Lumbar spine
Pre-menopause Referent Referent Referent
Early peri-menopause 0.20 0.16 0.630
Late peri-menopause 0.45 −1.94 <0.001
Post menopause −1.59 −3.94 <0.001
DM diabetes, Non-DM no-diabetes
aAll models adjusted for baseline age and weight, percent weight change, smoking (referent = none, alcoholic beverages/day (referent=> = 1 drink/
day), physical activity (referent = less or much less), health (referent = better), and economic status (referent = not hard to pay), supplement use
(referent = none), study site (referent = Pittsburgh), and ethnicity (referent = Japanese), menopause status (referent = pre-menopause)
bOverall interaction between and menopause status and rate of change in BMD p value: total hip p=0.016, lumbar spine p=<0.001
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