Calcif Tissue Int (2017) 100:528535

DOI 10.1007/s00223-016-0229-0

REVIEW

Obesity, Type 2 Diabetes andBone inAdults

JenniferS.Walsh1 TatianeVilaca1

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

Abstract In an increasingly obese and ageing population, clinicians. However, the limited available evidence sug-
type 2 diabetes (T2DM) and osteoporotic fracture are major gests that osteoporosis treatment does reduce fracture risk
public health concerns. Understanding how obesity and in obesity and T2DM with generally similar efficacy to
type 2 diabetes modulate fracture risk is important to iden- other patients.
tify and treat people at risk of fracture. Additionally, the
study of the mechanisms of action of obesity and T2DM on Keywords Bone Obesity Diabetes Fat Fracture
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 Obesity, Type 2 Diabetes andBone
fracture in obese adults. However the risk of some frac-
tures (proximal humerus, femur and ankle) is higher, and Obesity is a major and growing public health problem; for
a significant number fractures occur in obese people. BMI example, in the UK, 40% of adults will be obese by 2025
is positively associated with BMD and the mechanisms of [1]. Obesity is the most important risk factor for type 2 dia-
this association invivo may include increased loading, adi- betes (T2DM), and the global prevalence of T2DM is likely
pokines such as leptin, and higher aromatase activity. How- to be 592million by 2035 [2]. As the population ages, the
ever, some fat depots could have negative effects on bone; burden of osteoporosis and fragility fracture also increases.
cytokines from visceral fat are pro-resorptive and high Obesity and T2DM have effects on fracture risk, and frac-
intramuscular fat content is associated with poorer muscle tures in T2DM are associated with greater morbidity than
function, attenuating loading effects and increasing falls in the general population. Understanding how to assess and
risk. T2DM is also associated with higher bone mineral treat fracture risk in these groups is important for health
density (BMD), but increased overall and hip fracture risk. care planning and individual patients. Additionally, the
There are some similarities between bone in obesity and study of the mechanisms of action of obesity and T2DM on
T2DM, but T2DM seems to have additional harmful effects bone has already offered insights that may be applicable in
and emerging evidence suggests that glycation of collagen the broader study of osteoporosis, such as the effects of adi-
may be an important factor. Higher BMD but higher frac- pokines on bone cells and the effects of collagen glycation
ture risk presents challenges in fracture prediction in obe- on material properties of bone. There are some similari-
sity and T2DM. Dual energy X-ray absorptiometry under- ties in the effect of obesity and T2DM on bone, but some
estimates risk, standard clinical risk factors may not capture important differences such as cortical porosity and collagen
all relevant information, and risk is under-recognised by glycation.
In this review, we describe the effects of obesity and
T2DM on fracture risk and discuss possible mechanisms of
* Jennifer S. Walsh their effects. We also consider the validity of existing frac-
[email protected]
ture risk prediction tools and efficacy of osteoporosis treat-
1
Academic Unit ofBone Metabolism, Mellanby Centre ment in these patient groups.
forBone Research, University ofSheffield, Sheffield, UK

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Obesity, Type 2 Diabetes andBone inAdults 529

Obesity, Fracture andBMD function and soft tissue thickness should also be considered
as contributory and protective factors.
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 Mechanisms ofAction ofObesity onBone
skeletal sites; the risk of some non-spine fractures includ-
ing proximal humerus (RR 1.28), upper leg (OR 1.7) and Some insight into how obesity may exert effects on bone
ankle fracture (OR 1.5) is higher [4, 5]. A large number can be obtained from biochemical markers of bone turno-
of low-trauma fractures occur in overweight and obese ver. Biochemical markers are lower in obesity than in nor-
men and women, and the prevalence of low-trauma mal weight [18], but the difference in resorption markers
fractures is similar in obese and non-obese women [6]. may be greater than the difference in formation markers.
Therefore, obesity is not entirely protective against frac- This results in a higher uncoupling index in obesity, sug-
ture, and there are some site-specific effects on fracture. gesting positive bone balance which helps to maintain bone
There is a positive association between body mass mass in adulthood and with ageing [10]. Menopause causes
index (BMI) and bone mineral density (BMD) [7]. BMD a rapid increase in bone turnover, with net higher bone
by dual-energy X-ray absorptiometry (DXA) is higher in resorption and negative bone balance leading to bone loss.
obese people, but higher BMI and soft tissue thickness Higher body weight is associated with slower menopausal
cause error in DXA measurement [8] through assump- bone loss [19] consistent with a tendency towards positive
tions about abdominal thickness and beam hardening bone balance in obesity.
effects. However, other quantitative imaging methods One possible mechanism for higher BMD in obesity
(CT and ultrasound) also support higher BMD by DXA is increased mechanical loading and strain. Obese adults
(although other methods are also subject to some influ- have increased body fat mass, but also increased lean mass,
ence from surrounding soft tissue). Calcaneus bone stiff- so passive loading and muscle-induced strain may have
ness by ultrasound is greater in obesity [9] and by high- effects on bone modelling, density and geometry. However,
resolution peripheral quantitative computed tomography impaired muscle function due to intramuscular fat accu-
(HR-pQCT), obese adults have higher BMD, higher cor- mulation could attenuate the positive effects of increased
tical BMD, higher trabecular BMD and greater trabecu- muscle mass on bone. If the dominant mechanism acting to
lar number at the distal radius and distal tibia [10, 11]. increase BMD were physical loading, an increase in bone
Radius and tibia strength estimated by finite element size by periosteal apposition might be expected. Hip cross-
analysisfrom HR-pQCT is greater in obesity than in nor- sectional area by DXA and QCT is increased in obesity
mal weight controls [10]. Therefore, BMD probably is [12, 13], but bone size at the radius and tibia by HR-pQCT
truly higher in obesity, and there is no site-specific BMD does not differ between obese and normal weight controls
deficit to explain the site-specific fracture risk. [10]. Therefore, loading probably does not explain all of
It is possible that even if BMD increases in response to the action of obesity on bone.
obesity, the capacity for increase is limited and eventually Obesity has effects on a number of hormones known
the load-to-strength ratio rises far enough to cause frac- to act on bone, and so may act on bone through endocrine
ture in low-trauma injuries. The increase in radius and tibia pathways. Adipocytes produce endocrine factors shown to
strength by HR-pQCT in obesity is proportionally less than influence bone cell number and activity. Leptin is produced
the increase in BMI [11]. At the hip, by QCT and DXA, by adipocytes, and circulating leptin levels reflect body fat
obese people have favourable features for bone strength, mass with a primary role to regulate long-term energy bal-
but the load-to-strength ratio is greater than normal weight ance by signalling satiety in the hypothalamus and reducing
controls [12, 13]. Greater soft-tissue thickness over the food intake. Circulating leptin acts on bone cells directly
lateral hip dissipates fall impact, and so may continue to to increase bone formation [20], but when acting through
protect against hip fracture at high body weight even when the hypothalamus, it may inhibit bone formation through
load-to-strength ratio is exceeded [12, 14]. Intramuscular increased activation of the sympathetic nervous system
fat content is increased in obesity, and may be associated [21]. The evidence from clinical human studies suggests
with poorer muscle function and increased fracture risk that the dominant effect invivo is probably the peripheral
(dynapenic obesity) [15, 16]. Poorer muscle function action to increase BMD [22]. Adiponectin is secreted in
could increase falls and injury when falling, and there are inverse proportion to fat mass, and has roles in the regula-
data showing an excess of falls in obese people [17]. tion of glucose and lipid metabolism. In humans, circulat-
Thus, although BMD is higher in obesity, it may not ing adiponectin levels are inversely related to BMD [23].
be increased sufficiently to resist the greater forces acting Osteoclasts and osteoblasts express adiponectin receptors,
when obese people fall. Non-bone factors such as muscle and there is some experimental evidence that adiponectin

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530 J.S.Walsh, T.Vilaca

could modulate RANK/RANK-ligand/OPG signalling [24]. by the acute response to food intake and more long-term
Similarly to leptin, mouse studies suggest that adiponec- energy balance [27].
tin may also signal through the central nervous system to Serum 25-hydroxy vitamin D (25OHD) is lower in
regulate bone turnover through autonomic innervation [25]. obesity than normal weight controls, but this is likely to
However, the dominant mechanism through which it acts reflect greater volume of distribution (into fat, muscle
on the skeleton in obese humans in vivo is not yet clear. and extracellular fluid). Therefore, serum 25OHD may
Adipocytes express aromatase, and aromatisation of andro- not indicate low whole-body vitamin D status in obesity,
gens is the main source of oestrogen in postmenopausal and it does not seem to be associated with lower BMD or
women and men. High fat mass is associated with higher higher bone turnover. It is possible that the lower vita-
circulating estradiol, and so aromatase activity is likely to min D in obesity would adversely affect BMD, but that
contribute to positive effects of fat on bone, particularly in the other positive effects of obesity on BMD are domi-
postmenopausal women [26]. nant [28].
Pancreatic and gut hormone secretion is altered in obe- Not all fat is the same, and some fat depots could have
sity and may influence bone metabolism. Insulin, amylin negative effects on bone (Fig. 1). Subcutaneous and vis-
and preptin are increased in obesity, and may have direct ceral fat have different metabolic profiles, and pro-inflam-
effects on bone cells to increase bone formation and matory cytokines from visceral fat such as interleukin-6
decrease resorption. Insulin may also have indirect posi- (IL-6) and tumour necrosis factor alpha (TNF-) increase
tive effects on bone by decreasing hepatic sex-hormone bone resorption, so may have harmful effects on BMD [29].
binding globulin production, increasing bioavailability of In support of adverse actions, greater central and visceral
oestrogen and androgens. Ghrelin, gastric inhibitory pol- adiposity is associated with lower BMD and some adverse
ypeptide (GIP) and glucagon-like peptide 2 (GLP-2) have microstructural features from bone biopsy and HR-pQCT
direct and indirect effects on bone metabolism, driven but the relationship may vary with age and gender [3032].

Fig.1Fat depot actions on bone in obesity

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Obesity, Type 2 Diabetes andBone inAdults 531

Fracture Risk Assessment andOsteoporosis impairment and cardiac problems) and recover less well
Treatment inObesity than non-diabetic patients [41, 42].
Although fracture risk is higher, BMD is increased
Fracture risk assessment in clinical practice uses bone in T2DM (lumbar spine Z-score+0.41, total hip
densitometry by DXA and clinical risk factors. This offers Z-score+0.27) [37]. Nearly all people with T2DM are
some challenges in obesitythe precision of DXA meas- obese, and so the higher BMD in T2DM is probably due to
urements is reduced in obesity due to effects of soft tis- similar mechanisms as those acting in non-diabetic obese
sue thickness [8]. Also, because fracture pattern differs people. In addition, high circulating insulin could increase
between obese and normal weight groups, and we do not osteoblast activity and bone formation [43]. The increase in
yet fully understand the cause of fractures in obesity, the foot and ankle fractures is consistent with the pattern seen
usual fracture prediction tools might not be expected to in obesity, but the increase in hip fracture risk is discrepant
perform so well. However, FRAX (with and without BMD) between T2DM and non-diabetic obese, so additional fac-
predicted hip and major osteoporotic fracture with similar tors may be acting to increase bone fragility in T2DM.
accuracy in obese and non-obese postmenopausal women Microarchitecture studies with HR-pQCT suggest a cor-
in the Study of Osteoporotic Fractures [33]. tical strength deficit in T2DM. There is decreased cortical
Most currently used drugs for osteoporosis are anti- thickness and volumetric BMD (vBMD), with increased
resorptive. Because bone turnover and bone resorption are cortical porosity and pore size in T2DM [44] patients with
already reduced in obesity, the question has been raised microvascular disease (retinopathy, neuropathy or nephrop-
whether anti-resorptive treatment is effective for fracture athy). These changes are associated with decreased bone
prevention in obesity. The key clinical trials of bisphospho- strength by finite element analysis [44, 45] and are greater
nates did not include large numbers of obese people, but in T2DM patients with previous fractures [46], suggesting
there are some available data. In the Horizon trial, 3years that they may be clinically significant contributors to frac-
of zoledronic acid decreased vertebral fracture more in ture risk.
postmenopausal women with BMI above 25 kg/m2 than
women with BMI below 25kg/m2 [34]. Non-vertebral frac-
ture reduction did not differ by BMI. In the Freedom trial, Mechanisms ofAction ofT2DM onBone
with 3 years of denosumab, vertebral fracture risk reduc-
tion was independent of BMI, but non-vertebral fracture Bone turnover markers studies in diabetes have had some
reduction was not significant in women with BMI above conflicting results, but the most consistent finding is that
25kg/m2 [35]. 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,
Type 2 Diabetes, Fracture andBMD 48]. Methodological studies have excluded a direct effect
of glucose in the measurements [48], so the bone turnover
A number of meta-analyses have reported an increase in markers probably do reflect a true biological effect. Histo-
the risk of fractures in type 2 diabetes (T2DM) [3640]. morphometry in T2D shows decrease in bone volume,
There is a 1.3- to 2.1-fold increased risk of hip fracture osteoid volume, thickness and osteoblast surface, and poor
[36, 37, 39, 40] and 1.2-fold increased risk of other frac- uptake of label indicating reduced bone formation [49, 50]
tures [36, 37], but vertebral fracture risk does not seem to consistent with lower turnover from biochemical markers.
be increased [37, 40] (Table 1). The size of the fracture One important factor which may contribute to bone
risk increase may be modest, but it is important to recog- fragility in T2DM is post-translational glycation of colla-
nise that after fracture, patients with diabetes have greater gen in bone matrix. Enzymatic cross-linking of collagen
mortality, develop more complications (such as renal maintains the strength of normal bone matrix because the

Table1Risk of hip, spine and Study Hip fractures Spine fractures Other fractures
other any fractures in T2DM
according to meta-analyses Janghorbani [32] 1.7 (1.32.2)* 1.2 (0.72.2) Any fracture 1.2 (1.011.5)*
Vestergaard [33] 1.38 (1.251.53)* 0.93 (0.631.37) Any fractures 1.19 (1.111.27)*
Fan [35] 2.07 (1.832.33)*
Dytfeld [36] 1.26 (1.071.57)* 1.13 (0.941.37)

*Statistically significant increase in the risk

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532 J.S.Walsh, T.Vilaca

collagen matrix confers toughness, allowing the bone to through increased renal phosphate reabsorption leading to
endure plastic strain without breaking. Increasing numbers increased parathyroid hormone (PTH) and increased bone
of cross-links reduces the plasticity of the matrix, and the resorption [65]. Gut peptides such as GLP-2 decrease turn-
bone breaks at lower strain. Older collagen has more cross- over in response to feeding, and there has been interest in
links and less plasticity. Exposure to high glucose levels the possible bone effects of GLP-1 analogues and dipepti-
promotes glycation of proteins [advanced glycation end dyl peptidase 4 (DPP-4) inhibitors in diabetes treatment. So
products (AGEs)]. In collagen, AGEs lead to non-enzy- far, there is no clear evidence of an effect on fracture risk
matic cross-linking [51], and so could decrease plasticity [66]. Fracture risk is higher in people treated with insulin
and bone material strength [52]. Higher urine pentosidine than with oral agents, but this may reflect insulin use as a
(a marker of AGEs) is associated with higher vertebral marker of longer duration of disease, poorer control and
fracture risk in post-menopausal non-diabetic women [53]. more microvascular complications rather than a direct bio-
Bone material strength can be evaluated invivo by ref- logical effect.
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 Fracture Risk Assessment andOsteoporosis
is correlated with average HbA1c [54]. Indirect measure- Treatment inT2DM
ment of AGEs using skin auto fluorescence explains 26%
of the reduced bone strength by indentation, and is asso- Because BMD is increased in T2DM, and there are dis-
ciated with lower P1NP in patients with T2D [55]. There- ease-specific risk factors such as microvascular disease and
fore, there is some evidence for an association of glucose collagen glycation, standard fracture risk assessments using
exposure with poor bone material quality in T2DM, and DXA and clinical risk factors (including FRAX) underesti-
collagen glycation is a plausible contributor to increased mate fracture risk in T2DM [67]. Inadequate or inaccurate
fracture risk. risk assessment is reflected in the observation that people
Particularly for foot and ankle fracture, it is possible that with diabetes are less likely to be prescribed bisphospho-
neuropathy and vasculopathy in T2DM could have effects nates than those without diabetes [68]. This may be partly
on bone cell function or bone material properties. Symp- due to underestimation of risk by assessment tools, but also
thetic tone contributes to the regulation of bone turnover, because clinicians do not recognise that people with diabe-
and the extreme example of Charcot foot demonstrates the tes are at risk of fracture, so do not assess their risk or treat.
potential for bone to dysfunction when normal sensory Although the pathophysiology of fracture in T2DM dif-
and autonomic innervation is lost. However, these factors fers from postmenopausal osteoporosis, (particularly in that
have not yet been investigated in the context of diabetes bone turnover is low in T2DM), osteoporosis treatments do
and fracture. Besides the intrinsic bone properties, other reduce fracture in T2DM. In post hoc analysis of the FIT
factors could increase the risk of fractures in T2DM. Poor alendronate and HORIZON zoledronic acid trial, fracture
metabolic control, hypoglycaemia and neuropathy increase reduction was similar in participants with and without dia-
falls risk [56, 57], and in meta-analysis, hypoglycaemia betes [69]. Teriparatide and sclerostin antibodies increase
was associated with fracture (OR 1.92) [58]. However, BMD in Zucker diabetic rats, but the rats bone phenotype
increased fracture risk persists after correction for falls is different from human T2DM, and there is not yet avail-
[59]. able information on these drugs in humans with T2DM [70,
Diabetes treatment may also modulate fracture risk [60]. 71].
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- Summary andDiscussion
related transcription factor 2 (Runx2) signalling. Thiazoli-
dinediones (TZDs, glitazones) activate peroxisome prolif- Obesity in adults is protective against some fractures, par-
erator-activated receptor gamma (PPAR) which decreases ticularly hip fractures. However, some fractures, such as
insulin resistance. Activation of PPAR suppresses IGF-1 ankle and humerus are more common in obesity, and the
expression in bone and drives differentiation of mesenchy- prevalence of low-trauma fractures is similar in obese and
mal stem cells to adipocytes rather than to osteoblasts [62]. non-obese women. BMD in obese people is higher at all
TZD use is associated with increased fracture riskthe sites, bone turnover is lower, and bone strength measures
ADOPT study reported cumulative incidence of fractures of suggest that obesity is favourable for bone strength, but
15.1% with rosiglitazone versus 7.3% with metformin [63]. bone strength does not seem sufficiently increased to pro-
Sodiumglucose cotransporter-2 (SGLT2) inhibitors have tect against all fractures. Therefore, explanations for the
been associated with increased fracture risk [64], possibly fracture pattern in obesity need to consider other factors

13
Obesity, Type 2 Diabetes andBone inAdults 533

such as load-to-strength ratio, soft tissue padding, muscle a predictor of fracture risk: a meta-analysis. Osteoporos Int 16
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Open Access This article is distributed under the terms of the geometry, strength, and estimated fracture risk in women with
Creative Commons Attribution 4.0 International License (http:// anorexia nervosa and overweight/obese women. J Clin Endo-
creativecommons.org/licenses/by/4.0/), which permits unrestricted crinol Metab 99(12):46644673. doi:10.1210/jc.2014-2104
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appropriate credit to the original author(s) and the source, provide a Orwoll ES, Osteoporotic Fractures in Men Mr OSRG (2015)
link to the Creative Commons license, and indicate if changes were The association between BMI and QCT-derived proximal hip
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