Obesity, Type 2 Diabetes and Bone in Adults

Abstract

In an increasingly obese and ageing population, type 2 diabetes (T2DM) and osteoporotic fracture are major public health concerns. Understanding how obesity and type 2 diabetes modulate fracture risk is important to identify and treat people at risk of fracture. Additionally, the study of the mechanisms of action of obesity and T2DM on bone has already offered insights that may be applicable to osteoporosis in the general population. Most available evidence indicates lower risk of proximal femur and vertebral fracture in obese adults. However the risk of some fractures (proximal humerus, femur and ankle) is higher, and a significant number fractures occur in obese people. BMI is positively associated with BMD and the mechanisms of this association in vivo may include increased loading, adipokines such as leptin, and higher aromatase activity. However, some fat depots could have negative effects on bone; cytokines from visceral fat are pro-resorptive and high intramuscular fat content is associated with poorer muscle function, attenuating loading effects and increasing falls risk. T2DM is also associated with higher bone mineral density (BMD), but increased overall and hip fracture risk. There are some similarities between bone in obesity and T2DM, but T2DM seems to have additional harmful effects and emerging evidence suggests that glycation of collagen may be an important factor. Higher BMD but higher fracture risk presents challenges in fracture prediction in obesity and T2DM. Dual energy X-ray absorptiometry underestimates risk, standard clinical risk factors may not capture all relevant information, and risk is under-recognised by clinicians. However, the limited available evidence suggests that osteoporosis treatment does reduce fracture risk in obesity and T2DM with generally similar efficacy to other patients.

Full text

Vol:.(1234567890)
Calcif Tissue Int (2017) 100:528–535
DOI 10.1007/s00223-016-0229-0
1 3
REVIEW
Obesity, Type 2 Diabetes andBone inAdults
JenniferS.Walsh1· TatianeVilaca1
Received: 27 June 2016 / Accepted: 26 December 2016 / Published online: 9 March 2017
© The Author(s) 2017. This article is published with open access at Springerlink.com
clinicians. However, the limited available evidence sug-
gests that osteoporosis treatment does reduce fracture risk
in obesity and T2DM with generally similar efficacy to
other patients.
Keywords Bone· Obesity· Diabetes· Fat· Fracture
Obesity, Type 2 Diabetes andBone
Obesity is a major and growing public health problem; for
example, in the UK, 40% of adults will be obese by 2025
[1]. Obesity is the most important risk factor for type 2 dia-
betes (T2DM), and the global prevalence of T2DM is likely
to be 592million by 2035 [2]. As the population ages, the
burden of osteoporosis and fragility fracture also increases.
Obesity and T2DM have effects on fracture risk, and frac-
tures in T2DM are associated with greater morbidity than
in the general population. Understanding how to assess and
treat fracture risk in these groups is important for health
care planning and individual patients. Additionally, the
study of the mechanisms of action of obesity and T2DM on
bone has already offered insights that may be applicable in
the broader study of osteoporosis, such as the effects of adi-
pokines on bone cells and the effects of collagen glycation
on material properties of bone. There are some similari-
ties in the effect of obesity and T2DM on bone, but some
important differences such as cortical porosity and collagen
glycation.
In this review, we describe the effects of obesity and
T2DM on fracture risk and discuss possible mechanisms of
their effects. We also consider the validity of existing frac-
ture risk prediction tools and efficacy of osteoporosis treat-
ment in these patient groups.
Abstract In an increasingly obese and ageing population,
type 2 diabetes (T2DM) and osteoporotic fracture are major
public health concerns. Understanding how obesity and
type 2 diabetes modulate fracture risk is important to iden-
tify and treat people at risk of fracture. Additionally, the
study of the mechanisms of action of obesity and T2DM on
bone has already offered insights that may be applicable to
osteoporosis in the general population. Most available evi-
dence indicates lower risk of proximal femur and vertebral
fracture in obese adults. However the risk of some frac-
tures (proximal humerus, femur and ankle) is higher, and
a significant number fractures occur in obese people. BMI
is positively associated with BMD and the mechanisms of
this association invivo may include increased loading, adi-
pokines such as leptin, and higher aromatase activity. How-
ever, some fat depots could have negative effects on bone;
cytokines from visceral fat are pro-resorptive and high
intramuscular fat content is associated with poorer muscle
function, attenuating loading effects and increasing falls
risk. T2DM is also associated with higher bone mineral
density (BMD), but increased overall and hip fracture risk.
There are some similarities between bone in obesity and
T2DM, but T2DM seems to have additional harmful effects
and emerging evidence suggests that glycation of collagen
may be an important factor. Higher BMD but higher frac-
ture risk presents challenges in fracture prediction in obe-
sity and T2DM. Dual energy X-ray absorptiometry under-
estimates risk, standard clinical risk factors may not capture
all relevant information, and risk is under-recognised by
* Jennifer S. Walsh
j.walsh@sheffield.ac.uk
1 Academic Unit ofBone Metabolism, Mellanby Centre
forBone Research, University ofSheffield, Sheffield, UK
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529Obesity, Type 2 Diabetes andBone inAdults
1 3
Obesity, Fracture andBMD
Most of the available evidence supports a lower risk of
proximal femur and vertebral fracture in obese adults
[3]. However, fracture risk in obesity is not lower at all
skeletal sites; the risk of some non-spine fractures includ-
ing proximal humerus (RR 1.28), upper leg (OR 1.7) and
ankle fracture (OR 1.5) is higher [4, 5]. A large number
of low-trauma fractures occur in overweight and obese
men and women, and the prevalence of low-trauma
fractures is similar in obese and non-obese women [6].
Therefore, obesity is not entirely protective against frac-
ture, and there are some site-specific effects on fracture.
There is a positive association between body mass
index (BMI) and bone mineral density (BMD) [7]. BMD
by dual-energy X-ray absorptiometry (DXA) is higher in
obese people, but higher BMI and soft tissue thickness
cause error in DXA measurement [8] through assump-
tions about abdominal thickness and beam hardening
effects. However, other quantitative imaging methods
(CT and ultrasound) also support higher BMD by DXA
(although other methods are also subject to some influ-
ence from surrounding soft tissue). Calcaneus bone stiff-
ness by ultrasound is greater in obesity [9] and by high-
resolution peripheral quantitative computed tomography
(HR-pQCT), obese adults have higher BMD, higher cor-
tical BMD, higher trabecular BMD and greater trabecu-
lar number at the distal radius and distal tibia [10, 11].
Radius and tibia strength estimated by finite element
analysisfrom HR-pQCT is greater in obesity than in nor-
mal weight controls [10]. Therefore, BMD probably is
truly higher in obesity, and there is no site-specific BMD
deficit to explain the site-specific fracture risk.
It is possible that even if BMD increases in response to
obesity, the capacity for increase is limited and eventually
the load-to-strength ratio rises far enough to cause frac-
ture in low-trauma injuries. The increase in radius and tibia
strength by HR-pQCT in obesity is proportionally less than
the increase in BMI [11]. At the hip, by QCT and DXA,
obese people have favourable features for bone strength,
but the load-to-strength ratio is greater than normal weight
controls [12, 13]. Greater soft-tissue thickness over the
lateral hip dissipates fall impact, and so may continue to
protect against hip fracture at high body weight even when
load-to-strength ratio is exceeded [12, 14]. Intramuscular
fat content is increased in obesity, and may be associated
with poorer muscle function and increased fracture risk
(‘dynapenic obesity’) [15, 16]. Poorer muscle function
could increase falls and injury when falling, and there are
data showing an excess of falls in obese people [17].
Thus, although BMD is higher in obesity, it may not
be increased sufficiently to resist the greater forces acting
when obese people fall. Non-bone factors such as muscle
function and soft tissue thickness should also be considered
as contributory and protective factors.
Mechanisms ofAction ofObesity onBone
Some insight into how obesity may exert effects on bone
can be obtained from biochemical markers of bone turno-
ver. Biochemical markers are lower in obesity than in nor-
mal weight [18], but the difference in resorption markers
may be greater than the difference in formation markers.
This results in a higher uncoupling index in obesity, sug-
gesting positive bone balance which helps to maintain bone
mass in adulthood and with ageing [10]. Menopause causes
a rapid increase in bone turnover, with net higher bone
resorption and negative bone balance leading to bone loss.
Higher body weight is associated with slower menopausal
bone loss [19] consistent with a tendency towards positive
bone balance in obesity.
One possible mechanism for higher BMD in obesity
is increased mechanical loading and strain. Obese adults
have increased body fat mass, but also increased lean mass,
so passive loading and muscle-induced strain may have
effects on bone modelling, density and geometry. However,
impaired muscle function due to intramuscular fat accu-
mulation could attenuate the positive effects of increased
muscle mass on bone. If the dominant mechanism acting to
increase BMD were physical loading, an increase in bone
size by periosteal apposition might be expected. Hip cross-
sectional area by DXA and QCT is increased in obesity
[12, 13], but bone size at the radius and tibia by HR-pQCT
does not differ between obese and normal weight controls
[10]. Therefore, loading probably does not explain all of
the action of obesity on bone.
Obesity has effects on a number of hormones known
to act on bone, and so may act on bone through endocrine
pathways. Adipocytes produce endocrine factors shown to
influence bone cell number and activity. Leptin is produced
by adipocytes, and circulating leptin levels reflect body fat
mass with a primary role to regulate long-term energy bal-
ance by signalling satiety in the hypothalamus and reducing
food intake. Circulating leptin acts on bone cells directly
to increase bone formation [20], but when acting through
the hypothalamus, it may inhibit bone formation through
increased activation of the sympathetic nervous system
[21]. The evidence from clinical human studies suggests
that the dominant effect invivo is probably the peripheral
action to increase BMD [22]. Adiponectin is secreted in
inverse proportion to fat mass, and has roles in the regula-
tion of glucose and lipid metabolism. In humans, circulat-
ing adiponectin levels are inversely related to BMD [23].
Osteoclasts and osteoblasts express adiponectin receptors,
and there is some experimental evidence that adiponectin
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530 J.S.Walsh, T.Vilaca
1 3
could modulate RANK/RANK-ligand/OPG signalling [24].
Similarly to leptin, mouse studies suggest that adiponec-
tin may also signal through the central nervous system to
regulate bone turnover through autonomic innervation [25].
However, the dominant mechanism through which it acts
on the skeleton in obese humans in vivo is not yet clear.
Adipocytes express aromatase, and aromatisation of andro-
gens is the main source of oestrogen in postmenopausal
women and men. High fat mass is associated with higher
circulating estradiol, and so aromatase activity is likely to
contribute to positive effects of fat on bone, particularly in
postmenopausal women [26].
Pancreatic and gut hormone secretion is altered in obe-
sity and may influence bone metabolism. Insulin, amylin
and preptin are increased in obesity, and may have direct
effects on bone cells to increase bone formation and
decrease resorption. Insulin may also have indirect posi-
tive effects on bone by decreasing hepatic sex-hormone
binding globulin production, increasing bioavailability of
oestrogen and androgens. Ghrelin, gastric inhibitory pol-
ypeptide (GIP) and glucagon-like peptide 2 (GLP-2) have
direct and indirect effects on bone metabolism, driven
by the acute response to food intake and more long-term
energy balance [27].
Serum 25-hydroxy vitamin D (25OHD) is lower in
obesity than normal weight controls, but this is likely to
reflect greater volume of distribution (into fat, muscle
and extracellular fluid). Therefore, serum 25OHD may
not indicate low whole-body vitamin D status in obesity,
and it does not seem to be associated with lower BMD or
higher bone turnover. It is possible that the lower vita-
min D in obesity would adversely affect BMD, but that
the other positive effects of obesity on BMD are domi-
nant [28].
Not all fat is the same, and some fat depots could have
negative effects on bone (Fig. 1). Subcutaneous and vis-
ceral fat have different metabolic profiles, and pro-inflam-
matory cytokines from visceral fat such as interleukin-6
(IL-6) and tumour necrosis factor alpha (TNF-α) increase
bone resorption, so may have harmful effects on BMD [29].
In support of adverse actions, greater central and visceral
adiposity is associated with lower BMD and some adverse
microstructural features from bone biopsy and HR-pQCT
but the relationship may vary with age and gender [30–32].
Fig. 1 Fat depot actions on bone in obesity
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531Obesity, Type 2 Diabetes andBone inAdults
1 3
Fracture Risk Assessment andOsteoporosis
Treatment inObesity
Fracture risk assessment in clinical practice uses bone
densitometry by DXA and clinical risk factors. This offers
some challenges in obesity—the precision of DXA meas-
urements is reduced in obesity due to effects of soft tis-
sue thickness [8]. Also, because fracture pattern differs
between obese and normal weight groups, and we do not
yet fully understand the cause of fractures in obesity, the
usual fracture prediction tools might not be expected to
perform so well. However, FRAX (with and without BMD)
predicted hip and major osteoporotic fracture with similar
accuracy in obese and non-obese postmenopausal women
in the Study of Osteoporotic Fractures [33].
Most currently used drugs for osteoporosis are anti-
resorptive. Because bone turnover and bone resorption are
already reduced in obesity, the question has been raised
whether anti-resorptive treatment is effective for fracture
prevention in obesity. The key clinical trials of bisphospho-
nates did not include large numbers of obese people, but
there are some available data. In the Horizon trial, 3years
of zoledronic acid decreased vertebral fracture more in
postmenopausal women with BMI above 25 kg/m2 than
women with BMI below 25kg/m2 [34]. Non-vertebral frac-
ture reduction did not differ by BMI. In the Freedom trial,
with 3 years of denosumab, vertebral fracture risk reduc-
tion was independent of BMI, but non-vertebral fracture
reduction was not significant in women with BMI above
25kg/m2 [35].
Type 2 Diabetes, Fracture andBMD
A number of meta-analyses have reported an increase in
the risk of fractures in type 2 diabetes (T2DM) [36–40].
There is a 1.3- to 2.1-fold increased risk of hip fracture
[36, 37, 39, 40] and 1.2-fold increased risk of other frac-
tures [36, 37], but vertebral fracture risk does not seem to
be increased [37, 40] (Table 1). The size of the fracture
risk increase may be modest, but it is important to recog-
nise that after fracture, patients with diabetes have greater
mortality, develop more complications (such as renal
impairment and cardiac problems) and recover less well
than non-diabetic patients [41, 42].
Although fracture risk is higher, BMD is increased
in T2DM (lumbar spine Z-score + 0.41, total hip
Z-score + 0.27) [37]. Nearly all people with T2DM are
obese, and so the higher BMD in T2DM is probably due to
similar mechanisms as those acting in non-diabetic obese
people. In addition, high circulating insulin could increase
osteoblast activity and bone formation [43]. The increase in
foot and ankle fractures is consistent with the pattern seen
in obesity, but the increase in hip fracture risk is discrepant
between T2DM and non-diabetic obese, so additional fac-
tors may be acting to increase bone fragility in T2DM.
Microarchitecture studies with HR-pQCT suggest a cor-
tical strength deficit in T2DM. There is decreased cortical
thickness and volumetric BMD (vBMD), with increased
cortical porosity and pore size in T2DM [44] patients with
microvascular disease (retinopathy, neuropathy or nephrop-
athy). These changes are associated with decreased bone
strength by finite element analysis [44, 45] and are greater
in T2DM patients with previous fractures [46], suggesting
that they may be clinically significant contributors to frac-
ture risk.
Mechanisms ofAction ofT2DM onBone
Bone turnover markers studies in diabetes have had some
conflicting results, but the most consistent finding is that
markers of resorption (C-terminal cross-linking telopeptide
of type I collagen (CTX), N-terminal cross-linking telopep-
tide of type I collagen (NTX)) and formation (procollagen
type I N propeptide (P1NP), osteocalcin) are reduced [47,
48]. Methodological studies have excluded a direct effect
of glucose in the measurements [48], so the bone turnover
markers probably do reflect a true biological effect. Histo-
morphometry in T2D shows decrease in bone volume,
osteoid volume, thickness and osteoblast surface, and poor
uptake of label indicating reduced bone formation [49, 50]
consistent with lower turnover from biochemical markers.
One important factor which may contribute to bone
fragility in T2DM is post-translational glycation of colla-
gen in bone matrix. Enzymatic cross-linking of collagen
maintains the strength of normal bone matrix because the
Table 1 Risk of hip, spine and
other any fractures in T2DM
according to meta-analyses
*Statistically significant increase in the risk
Study Hip fractures Spine fractures Other fractures
Janghorbani [32] 1.7 (1.3–2.2)* 1.2 (0.7–2.2) Any fracture 1.2 (1.01–1.5)*
Vestergaard [33] 1.38 (1.25–1.53)* 0.93 (0.63–1.37) Any fractures 1.19 (1.11–1.27)*
Fan [35] 2.07 (1.83–2.33)* – –
Dytfeld [36] 1.26 (1.07–1.57)* 1.13 (0.94–1.37) –
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532 J.S.Walsh, T.Vilaca
1 3
collagen matrix confers toughness, allowing the bone to
endure plastic strain without breaking. Increasing numbers
of cross-links reduces the plasticity of the matrix, and the
bone breaks at lower strain. Older collagen has more cross-
links and less plasticity. Exposure to high glucose levels
promotes glycation of proteins [advanced glycation end
products (AGEs)]. In collagen, AGEs lead to non-enzy-
matic cross-linking [51], and so could decrease plasticity
and bone material strength [52]. Higher urine pentosidine
(a marker of AGEs) is associated with higher vertebral
fracture risk in post-menopausal non-diabetic women [53].
Bone material strength can be evaluated invivo by ref-
erence point indentation (Osteoprobe). By this method,
material strength is 10% lower in T2DM than matched con-
trols. The difference persists after correction for BMI and
is correlated with average HbA1c [54]. Indirect measure-
ment of AGEs using skin auto fluorescence explains 26%
of the reduced bone strength by indentation, and is asso-
ciated with lower P1NP in patients with T2D [55]. There-
fore, there is some evidence for an association of glucose
exposure with poor bone material quality in T2DM, and
collagen glycation is a plausible contributor to increased
fracture risk.
Particularly for foot and ankle fracture, it is possible that
neuropathy and vasculopathy in T2DM could have effects
on bone cell function or bone material properties. Symp-
thetic tone contributes to the regulation of bone turnover,
and the extreme example of Charcot foot demonstrates the
potential for bone to dysfunction when normal sensory
and autonomic innervation is lost. However, these factors
have not yet been investigated in the context of diabetes
and fracture. Besides the intrinsic bone properties, other
factors could increase the risk of fractures in T2DM. Poor
metabolic control, hypoglycaemia and neuropathy increase
falls risk [56, 57], and in meta-analysis, hypoglycaemia
was associated with fracture (OR 1.92) [58]. However,
increased fracture risk persists after correction for falls
[59].
Diabetes treatment may also modulate fracture risk [60].
Metformin and sulfonylureas have neutral or slightly pro-
tective associations with fracture risk [60, 61]. It is possible
that metformin increases osteoblast activity through Runt-
related transcription factor 2 (Runx2) signalling. Thiazoli-
dinediones (TZDs, glitazones) activate peroxisome prolif-
erator-activated receptor gamma (PPARγ) which decreases
insulin resistance. Activation of PPARγ suppresses IGF-1
expression in bone and drives differentiation of mesenchy-
mal stem cells to adipocytes rather than to osteoblasts [62].
TZD use is associated with increased fracture risk—the
ADOPT study reported cumulative incidence of fractures of
15.1% with rosiglitazone versus 7.3% with metformin [63].
Sodium–glucose cotransporter-2 (SGLT2) inhibitors have
been associated with increased fracture risk [64], possibly
through increased renal phosphate reabsorption leading to
increased parathyroid hormone (PTH) and increased bone
resorption [65]. Gut peptides such as GLP-2 decrease turn-
over in response to feeding, and there has been interest in
the possible bone effects of GLP-1 analogues and dipepti-
dyl peptidase 4 (DPP-4) inhibitors in diabetes treatment. So
far, there is no clear evidence of an effect on fracture risk
[66]. Fracture risk is higher in people treated with insulin
than with oral agents, but this may reflect insulin use as a
marker of longer duration of disease, poorer control and
more microvascular complications rather than a direct bio-
logical effect.
Fracture Risk Assessment andOsteoporosis
Treatment inT2DM
Because BMD is increased in T2DM, and there are dis-
ease-specific risk factors such as microvascular disease and
collagen glycation, standard fracture risk assessments using
DXA and clinical risk factors (including FRAX) underesti-
mate fracture risk in T2DM [67]. Inadequate or inaccurate
risk assessment is reflected in the observation that people
with diabetes are less likely to be prescribed bisphospho-
nates than those without diabetes [68]. This may be partly
due to underestimation of risk by assessment tools, but also
because clinicians do not recognise that people with diabe-
tes are at risk of fracture, so do not assess their risk or treat.
Although the pathophysiology of fracture in T2DM dif-
fers from postmenopausal osteoporosis, (particularly in that
bone turnover is low in T2DM), osteoporosis treatments do
reduce fracture in T2DM. In post hoc analysis of the FIT
alendronate and HORIZON zoledronic acid trial, fracture
reduction was similar in participants with and without dia-
betes [69]. Teriparatide and sclerostin antibodies increase
BMD in Zucker diabetic rats, but the rats’ bone phenotype
is different from human T2DM, and there is not yet avail-
able information on these drugs in humans with T2DM [70,
71].
Summary andDiscussion
Obesity in adults is protective against some fractures, par-
ticularly hip fractures. However, some fractures, such as
ankle and humerus are more common in obesity, and the
prevalence of low-trauma fractures is similar in obese and
non-obese women. BMD in obese people is higher at all
sites, bone turnover is lower, and bone strength measures
suggest that obesity is favourable for bone strength, but
bone strength does not seem sufficiently increased to pro-
tect against all fractures. Therefore, explanations for the
fracture pattern in obesity need to consider other factors
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533Obesity, Type 2 Diabetes andBone inAdults
1 3
such as load-to-strength ratio, soft tissue padding, muscle
function and falls. Finite element models incorporating
patient-specific factors such as height, weight, soft tissue
thickness and quantitative gait assessment with bone physi-
cal measurements may offer a route of investigation for
these potential contributors.
There are many possible mechanisms acting on bone
metabolism in obesity, such as adipokines and gut hor-
mones. Some of these are potential therapeutic targets
for the treatment of osteoporosis in obese and non-obese
people.
Type 2 diabetes is associated with increased BMD and
lower bone turnover but increased overall risk of frac-
ture and hip fracture. Some of the mechanisms acting to
increase BMD in obesity are likely to be relevant in T2DM,
but the pathophysiology of bone fragility in T2DM is not
yet clearly understood. Additional influence of AGEs on
bone matrix and complications of diabetes are likely to
contribute to the increased fracture risk, and AGE markers
might be of value in further research and clinical assess-
ment. If glucose exposure and diabetes complications are
major contributors, the most effective strategy to reduce
fracture risk may be to improve glycaemic control. Fracture
risk in T2DM is under-recognised, under-estimated and
undertreated, but anti-resorptives do seem to be effective in
fracture prevention. If diabetes bone disease is a low-turno-
ver state, it would be interesting to see whether it responds
well to anabolic bone agents or whether the underlying
pathology impairs the anabolic response.
As our populations become older and more obese,
understanding the interactions of obesity, T2DM and frac-
ture is becoming a pressing need to reduce the societal and
individual costsof fracture.
Open Access This article is distributed under the terms of the
Creative Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted
use, distribution, and reproduction in any medium, provided you give
appropriate credit to the original author(s) and the source, provide a
link to the Creative Commons license, and indicate if changes were
made.
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