REVIEWS

Bone, sweet boneosteoporotic fractures

in diabetes mellitus
Christine Hamann, Stephan Kirschner, Klaus-Peter Gnther and Lorenz C. Hofbauer
Abstract | Diabetes mellitus adversely affects the skeleton and is associated with an increased risk of
osteoporosis and fragility fractures. The mechanisms underlying low bone strength are not fully understood but
could include impaired accrual of peak bone mass and diabetic complications, such as nephropathy. Type1
diabetes mellitus (T1DM) affects the skeleton more severely than type2 diabetes mellitus (T2DM), probably
because of the lack of the bone anabolic actions of insulin and other pancreatic hormones. Bone mass can
remain high in patients with T2DM, but it does not protect against fractures, as bone quality is impaired. The
class of oral antidiabetic drugs known as glitazones can promote bone loss and osteoporotic fractures in
postmenopausal women and, therefore, should be avoided if osteoporosis is diagnosed. A physically active,
healthy lifestyle and prevention of diabetic complications, along with calcium and vitaminD repletion, represent
the mainstay of therapy for osteoporosis in patients with T1DM or T2DM. Assessment of BMD and other risk
factors as part of the diagnostic procedure can help design tailored treatment plans. All osteoporosis drugs
seem to be effective in patients with diabetes mellitus. Increased awareness of osteoporosis is needed in
view of the growing and aging population of patients with diabetes mellitus.
Hamann, C. etal. Nat. Rev. Endocrinol. advance online publication 17 January 2012; doi:10.1038/nrendo.2011.233

Introduction
Diabetes mellitus, in particular type2 diabetes mellitus
(T2DM), is a common metabolic disease with increasing prevalence throughout the world. Chronic complications adversely affect multiple organ systems, including
bones, and cause an enormous medical and economic
burden. Typical skeletal complications of poorly controlled diabetes mellitus include diabetic foot syndrome
and Charcot neuroarthropathy,13 which account for a
high percentage of surgical procedures and even amputations.4 Fragility fractures owing to low bone strength
have become increasingly recognized as skeletal complications.57 Patients with type1 diabetes mellitus (T1DM),
which manifests at an adolescent or young adult age, have
inadequate accrual of peak bone mass, and impaired
bone formation has been proposed as a major contributing factor.8 Patients with T2DM have not only a higher
BMD than non-diabetic individuals but also an increased
risk of bone fragility, which is thought to be caused by
poor bone quality,5,9,10 although techniques to assess bone
quality are still new in clinical practice. Both T1DM and
T2DM are associated with hypercalciuria in periods of
glucosuria11 and possibly a higher propensity to falls.12
Skeletal abnormalities can depend on the quality of glycemic control, the duration of disease and the presence
of vascular complications of diabetes mellitus.8
Competing interests:
L.C. Hofbauer declares an association with the following
companies: Amgen, Lilly, Merck, Novartis, Nycomed. See the
article online for full details of the relationships. The other
authors declare no competing interests.

Irrespective of diabetes status, osteoporotic fractures

are most frequently seen in the distal radius, proximal
humerus or the hip (Figure1).7,13,14 When vertebral fractures occur, they can go unrecognized for several months
or years and result in progressive back pain and substantial height loss.15 The risk of falls in the elderly population
is increased by concurrent use of multiple medications, impaired visual acuity, orthostatic dysregulation,
impaired balance and gait and impaired proprioception.16
In patients with diabetes mellitus, the propensity for falls
is increased as a result of vascular complications, particularly neuropathy.8,12,1720 Fractures are frequently slower to
heal and the risks of infectious and perioperative cardio
vascular complications and prolonged hospitalization are
higher in patients with diabetes mellitus than in those
without this condition.2124 Reduced physical activity and
mobility after fractures have a negative effect on glycemic
control in patients with T2DM.
In this Review, we provide a brief overview on the
effects of diabetes mellitus on osteoporosis and fractures. We discuss molecular and cellular data, preclinical
models and human data in the context of epidemiology, pathogenesis and clinical implications of impaired
bone health.

Epidemiology and presentation

Osteoporosis and low bone mass
T1DM and T2DM affect BMD differently.8 Low bone
mass in the radius has been reported in children and adolescents with T1DM25,26 and attributed to reduced bone
formation during skeletal growth. In adults with T1DM,

NATURE REVIEWS | ENDOCRINOLOGY

Department of
Orthopedics
(C.Hamann,
S.Kirschner,
K.-P.Gnther), Division
of Endocrinology,
Diabetes and Metabolic
Bone Diseases,
Department of
Medicine III
(L.C.Hofbauer),
Dresden Technical
University Medical
Center, Fetscherstrasse
74, 01307 Dresden,
Germany.
Correspondence to:
L.C. Hofbauer
lorenz.hofbauer@
uniklinikum-dresden.de

ADVANCE ONLINE PUBLICATION | 1

2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
Key points
Type1 and type2 diabetes mellitus are associated with an increased risk of
osteoporotic fractures
Bone formation and osteoblast function are impaired in patients with type1
diabetes mellitus
BMD is increased but bone quality is reduced in patients with type2 diabetes
mellitus
Glitazones might promote bone loss and should be avoided in patients with
osteoporosis
Comorbidities guide the selection of specific osteoporosis therapies

femoral BMD is reduced, although, lumbar spine BMD

is similar to or slightly lower than that in individuals
without diabetes mellitus.2730 The presence of vascular
complications, such as retinopathy and neuropathy,27,28
rather than the duration of disease or poor glycemic
control has been associated with low bone mass. The
mechanisms underlying the increased vulnerability of
the proximal femur in patients with advanced diabetes
mellitus are unclear. By contrast, adults with T2DM have
normal or slightly elevated BMD values, with Tscores
0.30.8 higher than those in controls without diabetes mellitus matched for age and weight.3134 In most
studies, BMD has been found to be increased at the
lumbar spine, hip and radius.8 Data from three prospective observational studies in older adults (>73 years old)
with T2DM suggest that, for a given age and Tscore,
fracture risk is higher than that in individuals without
diabetes mellitus.14

Fractures, healing and complications

Patients with T1DM and T2DM have increased risks of
fractures at most skeletal sites.7,10,35,36 Two large metaanalyses that assessed studies involving 1.3 million
participants, reported an odds ratio (OR) of 6.36.9 for
hip fractures in patients with T1DM and of 1.41.7 in
those with T2DM.7,35 In a casecontrol study of 124,655
patients, the OR for any fracture was 1.3 and the OR for
hip fracture was 1.4 in patients with T1DM; the OR for
any fracture and hip fracture were 1.2 and 1.7, respectively, in patients with T2DM.37 In addition, T1DM
conferred an increased risk of spine fracture (OR 2.5),
whereas T2DM was associated with an increased risk of
wrist fracture (OR 1.2).37 Of note, diabetic nephropathy
seems to increase hip fracture risk 12-fold in patients
with T1DM, whereas the presence of other complications does not confer an additional fracture risk.5 In
the Womens Health Study, in which 490 hip fractures
were reported among postmenopausal women >300,000
person-years, 38 the OR for hip fracture was 12.3 in
patients with T1DM and 1.7 in patients with T2DM.
Diabetes-related risk factors for fractures include diabetic complications, such as neuropathy, and the use
of treatments such as glitazones (in postmenopausal
women) and insulin in patients with T2DM (Box1).39
Cardiac complications and pressure ulcers after hip
fracture were twice as common in patients with T2DM
as in patients without diabetes mellitus and led to an
extension of hospitalization by 4days in one study,23 but
recovery rates after 1year were similar. Patients with

diabetes mellitus who suffer fractures are at increased

risk of frequent wound infections, delayed fracture
healing and a high incidence of nonunion or pseudarthrosis (Figure1), 21,24 complications that prolong
hospitalization. In patients with diabetes mellitus but
without neuropathy, union time of nondisplaced fractures has been reported to be 87% longer than that in
patients without diabetes mellitus, although BMD
was not assessed in this study.40 Prospective studies on
fracture healing in patients with diabetes mellitus and
osteoporotic fractures of the radius, humerus or the hip
are not available. Elective ankle arthrodesis in patients
with diabetes mellitus and Charcot neuroarthopathy is
associated with frequent infections and delayed bone
regeneration.4143 The process of osseointegration has
not been assessed in patients with diabetes mellitus and
osteoporosis after hip replacement.

Falls
In patients with advanced diabetes mellitus, falls represent an important triggering event for osteoporotic
fractures,12,1720 in particular hip fractures.44,45 As life
expectancies of the general population and patients with
diabetes mellitus are on the rise, age-related sarcopenia
and frailty are increasing in prevalence.46,47 Impaired
vision resulting from retinopathy and altered gait caused
by polyneuropathy can lead to falls.47 Advanced diabetic
cardiovascular complications leading to heart failure and
cardiac arrhythmias also promote falls.12,20,47 Vitamin D
deficiency increases the risk of falls and, as it affects up
to 90% of patients with diabetes mellitus, is a major contributing factor to fractures in these individuals.48,49 The
multifaceted pathogenesis of frailty and falls in patients
with diabetes mellitus50 provides rationale for multimodal therapeutic intervention, including improvement
of muscle strength and balance, prevention of diabetic
complications and vitamin D supplementation.51

Pathogenesis
Despite emerging clinical and epidemiological evidence
that link diabetes mellitus to low bone mass and fractures, the mechanisms underlying skeletal effects are
not completely understood. Most data are derived from
cellular or animal models and have not been validated
in humans.

Alterations in bone cell biology

Bone remodeling depends upon a coordinated sequence
of bone resorption by osteoclasts, followed by bone formation by osteoblasts. Whereas osteoblasts are derived
from mesenchymal stem cells, osteoclasts are derived
from hematopoietic stem cells.52
Invitro data53,54 and invivo studies involving rodent
models of T1DM 55,56 indicate that bone formation is
consistently impaired in diabetes mellitus, as shown
by the expression of osteoblastic transcription factors,
for example RUNX2, biochemical markers and histo
morphometric indices (Figure 2). An association
between T1DM and low bone formation in humans has
also been shown.5759 In the Zucker diabetic, fatty rat, a

2 | ADVANCE ONLINE PUBLICATION

www.nature.com/nrendo
2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
a

Figure1 | Skeletal complications of diabetes mellitus. Osteoporotic fractures in patients with diabetes mellitus are shown
in a | the distal radius, b | subcapital humerus, c | proximal femur and d | vertebrae. Metabolic and postoperative skeletal
complications, include e | Charcot arthropathy, f | pseudarthrosis, g | periprosthetic fracture and implant loosening and
h | osteomyelitis. Fracture sites are indicated by arrows.

T2DM model, diet-induced obesity was associated with

low bone mass and low bone formation.60 Spontaneously
diabetic Torii rats, a model of nonobese T2DM, showed
reduced bone formation rate that was reversed by insulin
treatment.61 Similar findings, however, have not been
seen in humans. Some oral antidiabetic drugs might
specifically target osteoblasts and affect bone formation.
Metformin stimulates osteoblast differentiation through
the transactivation of Runx2.62 Glitazones activate peroxisome proliferator-activating receptor which might
shift precursor cells towards the adipocytic lineage at the
cost of osteoblast formation (Figure2).63 Osteocytes have
been increasingly recognized as key regulators in bone
remodeling,64,65 but their contribution to bone health in
diabetes mellitus remains unclear.
Bone resorption does not appear to be excessively
elevated in animal models of diabetes mellitus. In fact,
osteoclast differentiation and function were inhibited
in a diabetic microenvironment in several studies. 6670
In patients with diabetes mellitus, concentrations of
bone resorption biomarkers, such as aminoterminal
and carboxyterminal crosslinking telopeptide of type I

Box1 | Risk factors for fractures

Diagnosis of T1DM
Presence of diabetic nephropathy in T1DM and T2DM
Presence of diabetic neuropathy in T2DM
High serum levels of pentosidine in T2DM
Use of glitazones in postmenopausal women with T2DM
Insulin therapy in T2DM
Disease duration >10years in T2DM

Abbreviations: T1DM, type1 diabetes mellitus, T2DM, type2

diabetes mellitus.

collagen (NTX and CTX) or deoxypyridinoline, can be

increased, decreased or not altered, depending on the
study, and differences exist between patients with T1DM
and those with T2DM.8

Insulin and other osteotropic hormones

The distinct reduction of peak bone mass in some
patients with T1DM has led to the hypothesis that
insulin has osteoanabolic effects (Figure3),8 although
whether the effects are caused by poor glycemic control
or other diabetic complications that affect BMD is

NATURE REVIEWS | ENDOCRINOLOGY

ADVANCE ONLINE PUBLICATION | 3

2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
Increased
osteogenesis

PPAR

RUNX2

Mature
osteoblasts

Metformin

model of T1DM, treatment with IAPP increased bone

mass and strength by stimulation of bone formation
and inhibition of bone resorption in a similar manner
to insulin.75 The receptor through which IAPP exerts
its effects on osteoblasts has not been identified.76 Some
of its anabolic effects might be mediated by insulinlike growth factor (IGF)I receptors.77 The potent anti
resorptive effect of IAPP was also demonstrated in
Iapp-deficient mice.76 Preptin, a peptide of 34 amino
acids that shares homology with pro-IGFII,74 is associated with proliferation and reduced apoptosis of osteoblasts and increased bone area and mineralizing surface
in mice.74

Increased
adipogenesis

Glitazones

MSC

Glitazones

Adipocytes

Figure2 | Skeletal effects of pharmacological treatments for T2DM. Metformin

increases the differentiation of MSCs into osteoblasts through its actions on
RUNX2. Glitazones simultaneously suppress RUNX2 and activate PPAR, which
drives differentiation of MSCs into adipocytes, thereby reducing osteogenesis.
Abbreviations: MSC, mesenchymal stem cell; PPAR, peroxisome proliferatoractivated receptor.

unclear. In a review, Thrailkill etal.71 suggested that

insulin exerts a potent bone anabolic effect on osteoblasts through receptor-mediated mechanisms. Lack of
insulin led to low bone mass in an uncontrolled study
of 57 patients with T1DM and a mean age of 35years,
who were evaluated before intensive insulin therapy
and 7years later. Treatment was associated with substantial improvement of bone mass and bone turnover
biomarkers.72 Hyperinsulinemia in patients with T2DM
might contribute to the high BMD, although insulin
resistance in bone cells may occur. Differences in skeletal effects between patients with T1DM and those
with T2DM are not, therefore, fully explained by the
insulinopenia hypothesis.
In addition to insulin, pancreatic cells produce other
osteotropic factors, such as islet amyloid polypeptide
(IAPP, also known as amylin)73 and preptin,74 both of
which are members of the calcitonin-gene-related
peptide family. Production of these peptides is abolished
in patients with T1DM. IAPP, a 37-amino-acid peptide,
is secreted with insulin. In a streptozotocin-induced rat

Pleiotropic functions of osteocalcin

Osteocalcin has been implicated as a common link
between bone and glucose metabolism and osteoblasts
are becoming increasingly recognized as insulin targets.78
Activation of the osteoblastic insulin receptor increases
osteocalcin activity. Osteocalcin undergoes post-
translational carboxylation,79 which occurs in a milieu
with acidic pH. This microenvironment also favors
osteoclastic bone resorption. In mice, undercarboxylated
osteocalcin in turn increases cell proliferation and
insulin secretion and sensitivity.80 Osteocalcin also regulates testosterone production and male fertility through
its effects on the testes, which regulate bone mass accrual
and bone remodeling through testosterone secretion.81
Therefore, if the link with bone turnover is validated
in human physiology, undercarboxylated osteocalcin
could become a biomarker and even a potential
therapeutic target.
Determinants of impaired bone quality
Given that patients with T2DM have an increased
fracture risk despite having higher BMD than patients
with T1DM,14,49 chronic hyperglycemia has been suggested to impair bone quality. One plausible mechanism
relates to increased collagen crosslinking by abundant

Osteocalcin

Osteocalcin

Pancreas

Insulin
IAPP

Testis

Mature osteoblast
RUNX2

Proliferation
Differentiation
Apoptosis resistance

Osteogenesis
Low bone density
Increased risk of fracture

Testicular
testosterone
secretion

Preptin
Damaged
pancreatic cells

Glucose control

MSC

Figure 3 | Impaired osteogenesis in T1DM. Pancreatic -cell destruction in patients with T1DM prevents secretion of
insulin, IAPP and preptin, thereby reducing their effects on the RUNX2 gene. This reduction decreases proliferation and
differentiation of MSCs into osteoblasts and their resistance to apoptosispreventing osteogenesis and bone mass
accrual. Moreover, reduced insulin secretion in patients with T1DM prevents stimulation of osteoblasts to produce
osteocalcin, which stimulates -cell proliferation and acts on the testes to produce testosterone, a hormone that increases
osteogenesis. Abbreviations: IAPP, islet amyloid peptide; MSC, mesenchymal stem cell; T1DM, type 1 diabetes mellitus.

4 | ADVANCE ONLINE PUBLICATION

www.nature.com/nrendo
2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
glucose, raising concentrations of advanced glycation
endproducts, such as pentosidine,82,83 which have been
associated with increased fracture risk.84,85
DXA is the standard bone imaging method, but
advances such as high-resolution peripheral quantitative CT (pQCT) and finite element analysis have
improved assessment of bone geometry, micro
architecture, and strength. 34,86,87 These novel technologies, which are being used increasingly in clinical
research and trials, could improve measurement of bone
quality and the identification of patients with diabetes
mellitus who are at increased risk of fractures. In a
pQCT-based study of patients with T2DM, trabecular
BMD of the femoral neck was 1630% higher in patients
with diabetes mellitus than that of healthy controls,
whereas cortical BMD was similar in the two groups.34
Nevertheless, the load-to-strength ratio for hip fractures
was similar in both groups, which indicates no benefit
with increased BMD.

Diagnosis
Identification of individuals with diabetes mellitus and
osteoporosis before they have fractures is important.
Findings from clinical assessments and BMD should be
considered together to enable calculation of the 10-year
risk of sustaining an osteoporotic fracture and the tailoring of therapy to the individual. The FRAX tool,
from the WHO, is available to facilitate calculation of
risk.88 The fracture risk of patients with T2DM is higher
than that of people without diabetes mellitus for a given
FRAXscore.14 Although the diagnostic procedure is
similar in individuals with and without diabetes mellitus,
some additional considerations must be applied to those
patients with diabetes mellitus.8

History and physical examination

History reporting and physical examination need to take
into account the type of diabetes mellitus, age and agerelated diseases, FRAXtool features (Box2), history of
falls and any predisposing risk factors, such as gait disturbances, visual impairment, polyneuropathy or hypoglycemic episodes. In addition, a comprehensive drug
review is essential to identify medications that promote
bone loss, such as glitazones, or raise the risk of falls,
such as sleeping medications and antidepressants.50
Physical examination might help to identify concurrent risk factors for low bone mass or falls, such as low
body weight, malnutrition, hypogonadism, muscular
atrophy or cardiac arrhythmias. Suitable office-based
tests that could be used to assess muscle strength, gait
and balance include the chair-rising test and the up-andgo test.50 Clinical signs of vertebral fractures include thoracic kyphosis (often known as dowager hump), gradual
loss of body height of >6cm and progressive back pain.15
Measurement of BMD
Lumbar spine and hip BMD should be measured with
DXA.15,89 One potential drawback of DXA when used
for patients with diabetes mellitus is that it does not
take into account bone size and geometry, owing to 2D

Box2 | FRAX tool fracture risk criteria

Age
Sex
Height and weight
Previous fracture
Parent hip fracture
Current smoking
Glucocorticoid therapy
Rheumatoid arthritis
Secondary osteoporosis*
Excessive alcohol consumption (3 units per day)
DXA-based femoral BMD

*Secondary osteoporosis should be indicated if a patient has one

of the following diagnoses that are strongly associated with
osteoporosis: type1 diabetes mellitus, osteogenesis imperfecta,
chronic liver disease, chronic malnutrition or malabsorption,
hypogonadism or premature menopause (<45years) or untreated
chronic hyperthyroidism. Permission obtained from Springer
Kanis, J.A. et al. Osteoporos. Int. 21 (Suppl. 2), S407S413 (2010).

imaging.86,87 For instance, some patients with T1DM

can have small bones. A consistent finding in patients
with T2DM is increased fragility despite normal or high
Tscores,14 which indicates poor bone quality. Therefore,
normal BMD values should be carefully interpreted.
Imaging techniques that use pQCT might overcome
some of these limitations.
Aortic calcification and spinal osteoarthritis might
interfere with DXA measurement, yielding false-positive
(inaccurately high) spinal BMD results.15 Radiography
of the spine should be used in patients with localized
back pain, recent spinal deformities or substantial loss
of height, to check for possible vertebral fractures.15,89
Alternatively, the vertebral fracture assessment tool of
DXA enables lateral vertebral morphometric assessment
and can be used to detect vertebral fractures.15

Laboratory assessment
National and international guidelines recommend for
all patients with suspected osteoporosis an initial laboratory evaluation with a complete blood count, renal
and liver function tests and levels of serum calcium
and phosphate, Creactive protein (CRP), bone-specific
alkaline phosphatase, serum 25-hydroxyvitaminD,
serum thyrotropin, serum protein electrophoresis and,
for men, serum testosterone.90 Whereas some of these
markers have a low sensitivity and specificity when
assessed individually, such as CRP, together they can
exclude secondary causes of osteoporosis such as hyper
parathyroidism, hyperthyroidism, hypogonadism, renal
insufficiency, Paget disease and multiple myeloma.
Further laboratory tests may be required, depending on
comorbidities and clinical findings.
The quality of glycemic control can be determined by
blood glucose profiles and measurement of HbA1c levels
in serum. Measurement of glomerular filtration rate and
urinary excretion of albumin helps determine the degree
of diabetic nephropathy, a risk factor for osteoporosis in
patients with diabetes mellitus.5 Measurement of bone
turnover markers has limited use in the initial assessment
of osteoporosis but can be useful in differential diagnosis
or for monitoring of treatment response.90

NATURE REVIEWS | ENDOCRINOLOGY

ADVANCE ONLINE PUBLICATION | 5

2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
Box3 | Therapeutic considerations
Avoid glitazones
Aggressive prevention of diabetic complications,
especially kidney disease
Assess and prevent falls
Replete calcium and vitamin D levels
Selection of specific osteoporosis drugs is frequently
based on comorbidities

Treatment
Most recommendations for management of osteoporosis
in patients with diabetes mellitus represent good clinical practice rather than evidence-based guidelines and
are also valid for patients with osteoporosis but without
diabetes mellitus (Box3).

Considerations for diabetes therapy

Regimens that ensure normal fasting and postprandial
glucose levels minimize most of the pleiotropic adverse
effects of glucose on bone. If no contraindications exist,
intensive insulin therapy is the standard treatment for
T1DM9194 and seems to be associated with improved
skeletal health. 72 The risk of hypoglycemic episodes,
which constitute an adverse effect of intensive insulin
therapy, should be minimized by comprehensive patient
education, frequent self-monitoring of glucose levels and
titration of the insulin dose.95 Glitazones should not be
given to postmenopausal women with T2DM;96101 data
on bone loss and fractures associated with glitazone
use in men are less conclusive,96,98 so treatment decisions should be made on an individual basis. Weight
loss in patients with T2DM needs to be accompanied by
increased physical activity to prevent bone loss.
Prevention of diabetic complications
Vascular diabetic complications, such as nephropathy,
retinopathy and polyneuropathy, are associated with low
bone mass and increased risk of falls and osteoporotic
fracture.5,27,28,47 Thus, systematic screening for and prevention of these complications are important. Annual
screening for albuminuria can identify nephropathy. If
microalbuminuria (urinary excretion 30300mg daily)
is detected, aggressive antihypertensive therapy, ideally
with angiotensin-converting-enzyme inhibitors, should
be initiated.102 Annual ophthalmologic exams are recom
mended to diagnose retinopathy in its early stages. If
hypertension is present, improved glycemic control and
the use of angiotensin-converting-enzyme inhibitors are
useful preventive measures. Laser therapy might prevent
progression of advanced retinopathy and help to maintain vision. Annual testing for pressure and vibration
sensation should be used to detect polyneuropathy,103
w hich mig ht pre disp os e p at ients to C harcot
neuroarthropathy (Figure1).
Calcium and vitamin D supplementation
Deficiencies of calcium and vitamin D in patients
with diabetes mellitus should be treated before specific osteoporosis drugs are started. A daily uptake of
1,200mg calcium is generally required, ideally through

the diet, but supplementation can be used if dietary

uptake is inadequate. The concurrent use of protonpump inhibitors or loop diuretics, and the presence of
malabsorption or diabetic nephropathy might increase
the daily calcium requirement. High doses of calcium
supplementation might have adverse effects on the
cardiovascular system. 104,105 Patients with T2DM and
renal impairment might be particularly sensitive to
calcium supplements owing to their increased levels of
calcium-phosphorus product.
No consensus has been reached on optimal vitaminD
serum levels.106 In our view, vitamin D supplementation
should ensure a serum 25-hydroxyvitamin D level of
75nmol/l.107 This target is supported by a comprehensive study of 675 individuals, in whom bone mineralization defects were not seen if serum 25-hydroxyvitaminD
levels were above 75nmol/l.108 As most patients do not
reach this threshold through consumption of food or sun
exposure alone, they typically require supplementation
of 8002,000IU of vitamin D daily. Obese patients with
T2DM require higher doses (4,000IU daily) because
of a large distribution volume. The efficacy of vitamin D
supplementation in the prevention of falls was demonstrated by a 49% reduction in a cohort of elderly patients
without diabetes mellitus who received 1,200mg calcium
and 800IU vitamin D per day for 3months.109 Whether
or not vitamin D supplementation improves metabolic
and vascular parameters, such as cell function, vascular tone and blood pressure regulation,107 needs to be
prospectively assessed.

Osteoporosis therapy
If the FRAXtool calculates a 10-year absolute risk of 3%
for hip fracture and 20% for major osteoporotic fracture
(distal radius, proximal humerus, spine) in previously
untreated patients, osteoporosis therapy is indicated. A
large Danish retrospective cohort study assessed whether
antiresorptive drugs were effective in patients with diabetes mellitus.110 In patients with and without diabetes
mellitus, the efficacy of bisphosphonates, including
alendronate, etidronate, clodronate and raloxifene, was
similar. In addition to its retrospective nature, a potential
limitation of this study was the lack of data for drugs
such as zoledronic acid, risedronate, strontium ranelate
or denosumab, an inhibitor of receptor activator of NFB
ligand (RANKL) that was approved in 2010.111 The risk
of hip fractures was comparable in patients with T1DM
and T2DM who received alendronate. 110 In a posthoc subgroup analysis of alendronate in the Fracture
Intervention Trial (FIT), the gain of BMD at the lumbar
spine and the hip was similar in patients with or without
diabetes mellitus, although the study was not powered
to demonstrate fracture reduction.112 Thus, the widely
approved bisphosphonates, alendronate, risedronate and
zoledronic acid, seem to be effective for the treatment of
osteoporosis in patients with diabetes mellitus.113 Some
patients with diabetic comorbidities such as gastro
paresis or gastrointestinal adverse effects caused by oral
bisphosphonates may benefit from 5mg parenteral zoledronic acid once yearly or 60mg denosumab biannually.

6 | ADVANCE ONLINE PUBLICATION

www.nature.com/nrendo
2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
Table 1 | Established osteoporosis drugs
Drug

Dose

Route of administration

Fracture efficacy

Evaluated in diabetes

Alendronate

70mg weekly

Oral

Hip and spine

Yes

Risedronate

35mg weekly

Oral

Hip and spine

No

Ibandronate*

150mg monthly

Oral

Spine

No

Raloxifene*

60mg daily

Oral

Spine

No

Strontium ranelate*

2g daily

Oral

Hip and spine

No

Ibandronate*

3mg every 3months

Intravenous

Spine

No

Zoledronic acid

5mg yearly

Intravenous

Hip and spine

No

Denosumab*

60mg every 6months

Subcutaneous

Hip and spine

No

PTH134

20g daily

Subcutaneous

Spine

No

PTH184

100g daily

Subcutaneous

Spine

No

*Only in postmenopausal women. Abbreviation: PTH, parathyroid hormone. Permission obtained from Elsevier Ltd Rachner, T.D. et al. Lancet 377,
12761287 (2011).

Zoledronic acid should not be administered in patients

with a glomerular filtration rate <45ml/min/1.73 m2, but
no such restrictions exist for denosumab. Oral hygiene
should be optimized to keep the risk of osteonecrosis of
the jaw with bisphosphonates and denosumab after invasive dental procedures, which is increased by diabetes
mellitus, to a minimum.114
On the basis of pathophysiological evidence that suggests low bone formation in diabetes mellitus, osteoanabolic therapies such as parathyroid hormone 134
(PTH134; also known as teriparatide) or the full-length
PTH184 are attractive. Use of PTH134 should, however,
be limited to patients with two or more established vertebral fractures or those with a high risk of fractures.
The use of bone anabolic therapies to accelerate fracture
healing in patients with diabetes mellitus is being investigated. Several drugs have shown antifracture efficacy
at the spine and the hip (Table1), and new therapies are
being evaluated in phaseII and III studies that might
improve efficacy and long-term adherence.52

in patients with chronic and poorly controlled disease

might lead to surgical complications, such as infections
and delayed bone healing. Assessment of osteoporosis is
similar in patients with and without diabetes mellitus.
After repletion of calcium and vitamin D, most osteoporosis drugs can be used, but associated comorbidities
should be considered, and glitazones should be avoided
in postmenopausal women.
An improved understanding of the effects of insulin
signaling and the paracrine effects of osteocalcin on
bone and cells is needed, along with clarification of
the role of falls and diabetic complications in fractures,
and development of nonpharmacological strategies to
prevent them. Optimum calcium and vitamin D supplementation levels for patients with diabetes mellitus and
identification of subgroups of patients that could benefit
from anabolic compared with antiresorptive therapy also
need to be established. These issues should be investigated in adequately powered, prospective, controlled
treatment studies with relevant end points.

Conclusions
Diabetes mellitus predisposes patients to osteoporotic
fractures through various mechanisms. In T1DM, lack
of osteoanabolic pancreatic hormones, including insulin,
prevents accrual of an adequate peak bone mass. In
T2DM, frequent falls combined with impaired bone
quality causes fragility fractures even when bone mass
remains normal. Osteocalcin provides important signals
from the bone to cells, although its role in humans is
as yet unclear. Diabetic neuropathy and nephropathy
1.

2.

3.
4.

OLoughlin, A., McIntosh, C., Dinneen, S.F. &

OBrien, T. Review paper: basic concepts to
novel therapies: a review of the diabetic foot. Int.
J. Low Extrem. Wounds 9, 90102 (2010).
Carnevale, V., Romagnoli, E. & DErasmo, E.
Skeletal involvement in patients with diabetes
mellitus. Diabetes Metab. Res. Rev. 20, 196204
(2004).
Schwartz, A.V. Diabetes mellitus: does it affect
bone? Calcif. Tissue Int. 73, 515519 (2003).
Sumpio, B.E. Foot ulcers. N. Engl. J. Med. 343,
787793 (2000).

5.

6.

7.

Review criteria
We searched MEDLINE and PubMed for articles published
between 1995 and 2011, with particular attention to
original papers, reviews and meta-analyses published in the
past 5years. We used the search terms osteoporosis,
bone mass, fractures and bone cells in combination
with diabetes mellitus, type1 diabetes mellitus and
type2 diabetes mellitus. We also screened the reference
sections of selected original articles and reviews.

Vestergaard, P., Rejnmark, L. & Mosekilde, L.

Diabetes and its complications and their
relationship with risk of fractures in type1 and 2
diabetes. Calcif. Tissue Int. 84, 4555 (2009).
Ahmed, L.A., Joakimsen, R.M., Berntsen, G.K.,
Fnneb, V. & Schirmer, H. Diabetes mellitus and
the risk of non-vertebral fractures: the Tromso
study. Osteoporos. Int. 17, 495500 (2006).
Janghorbani, M., Van Dam, R.M., Willett, W.C. &
Hu, F.B. Systematic review of type1 and type2
diabetes mellitus and risk of fracture. Am. J.
Epidemiol. 166, 495505 (2007).

NATURE REVIEWS | ENDOCRINOLOGY

8.

Hofbauer, L.C., Brueck, C.C., Singh, S.K. &

Dobnig, H. Osteoporosis in patients with diabetes
mellitus. J. Bone Miner. Res. 22, 13171328
(2007).
9. Schwartz, A.V. & Sellmeyer, D.E. Women, type2
diabetes, and fracture risk. Curr. Diab. Rep. 4,
364369 (2004).
10. Strotmeyer, E.S. & Cauley, J.A. Diabetes mellitus,
bone mineral density, and fracture risk. Curr. Opin.
Endocrinol. Diabetes Obes. 14, 429435 (2007).
11. Nagasaka, S., Murakami, T., Uchikawa, T.,
Ishikawa, S.E. & Saito, T. Effect of glycemic

ADVANCE ONLINE PUBLICATION | 7

2012 Macmillan Publishers Limited. All rights reserved

REVIEWS

12.

13.

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

25.
26.

27.

28.

29.

30.

31.

control on calcium and phosphorus handling and

parathyroid hormone level in patients with
noninsulindependent diabetes mellitus. Endocr.
J. 42, 377383 (1995).
Volpato, S., Leville, S.G., Blaum, C., Fried, L.P. &
Guralnik, J.M. Risk factors for falls in older
disabled women with diabetes: the womens
health and aging study. J. Gerontol. A Biol. Sci.
Med. Sci. 60, 15391545 (2005).
Holmberg, A.H. etal. Risk factors for fragility
fracture in middle age. A prospective populationbased study of 33,000 men and women.
Osteoporos. Int. 17, 10651077 (2006).
Schwartz, A.V. etal. Association of BMD and
FRAX score with risk of fracture in older adults
with type2 diabetes. JAMA 305, 21842192
(2011).
Ensrud, K.E. & Schousboe, J.T. Clinical practice.
Vertebral fractures. N. Engl. J. Med. 364,
16341642 (2011).
Tinetti, M.E. Clinical Practice. Preventing falls in
elderly persons. N. Engl. J. Med. 348, 4249
(2003).
Bonds, D.E. etal. Risk of fracture in women with
type2 diabetes: the Womens Health Initiative
Observational Study. J. Clin. Endocrinol. Metab.
91, 34043410 (2006).
de Liefde, I.I. et al. Bone mineral density and
fracture risk in type2 diabetes mellitus:
the Rotterdam Study. Osteoporos. Int. 16,
17131720 (2005).
Strotmeyer, E.S. etal. Nontraumatic fracture risk
with diabetes mellitus and impaired fasting
glucose in older white and black adults:
the health, aging and body composition study.
Arch. Intern. Med. 165, 16121617 (2005).
Wallace, C. etal. Incidence of falls, risk factors
for falls, and fall-related fractures in individuals
with diabetes and prior foot ulcer. Diabetes Care
25, 19831986 (2002).
Chaudhary, S.B. etal. Complications of ankle
fracture in patients with diabetes. J. Am. Acad.
Orthop. Surg. 16, 159170 (2008).
Wukich, D.K. & Kline, A.J. The management of
ankle fractures in patients with diabetes. J. Bone
Joint Surg. Am. 90, 15701578 (2008).
Norris, R. & Parker, M. Diabetes mellitus and hip
fracture: A study of 5966 cases. Injury 42,
13131316 (2011).
Retzepi, M. & Donos, N. The effect of diabetes
mellitus on osseous healing. Clin. Oral Implants
Res. 21, 673681 (2010).
Weber, G. etal. Bone mass in young patients with
typeI diabetes. Bone Miner. 8, 2330 (1990).
Hui, S.L., Epstein, S. & Johnston, C.C. Jr.
Aprospective study of bone mass in patients
with typeI diabetes. J. Clin. Endocrinol. Metab.
60, 7480 (1985).
Forst, T. etal. Peripheral osteopenia in adult
patients with insulin-dependent diabetes
mellitus. Diabet. Med. 12, 874879 (1995).
Kayath, M.J., Dib, S.A. & Vieira, J.G. Prevalence
and magnitude of osteopenia associated with
insulin-dependent diabetes mellitus. J. Diabetes
Complications 8, 97104 (1994).
Compston, J.E., Smith, E.M., Matthews, C. &
Schofield, P. Whole body composition and
regional bone mass in women with insulindependent diabetes mellitus. Clin. Endocrinol.
(Oxf.) 41, 289293 (1994).
Mastrandrea, L.D. etal. Young women with
type1 diabetes have lower bone mineral density
that persists over time. Diabetes Care 31,
17291735 (2008).
Barrett-Connor, E. & Holbrook, T.L. Sex
differences in osteoporosis in older adults with
noninsulindependent diabetes mellitus. JAMA
268, 33333337 (1992).

32. van Daele, P.L. etal. Bone density in

noninsulindependent diabetes mellitus. The
Rotterdam Study. Ann. Intern. Med. 122,
409414 (1995).
33. Strotmeyer, E.S. etal. Diabetes is associated
independently of body composition with BMD
and bone volume in older white and black men
and women: The Health, Aging, and Body
Composition Study. J. Bone Miner. Res. 19,
10841091 (2004).
34. Melton, L.J. 3rd etal. A bone structural basis for
fracture risk in diabetes. J. Clin. Endocrinol.
Metab. 93, 48044809 (2008).
35. Vestergaard, P. Discrepancies in bone mineral
density and fracture risk in patients with type1
and type2 diabetesa meta-analysis.
Osteoporos. Int. 18, 427444 (2007).
36. Merlotti, D., Gennari, L., Dotta, F., Lauro, D. &
Nuti, R. Mechanisms of impaired bone strength
in type1 and 2 diabetes. Nutr. Metab.
Cardiovasc. Dis. 20, 683690 (2010).
37. Vestergaard, P., Rejnmark, L. & Mosekilde, L.
Relative fracture risk in patients with diabetes
mellitus, and the impact of insulin and oral
antidiabetic medication on relative fracture risk.
Diabetologia 48, 12921299 (2005).
38. Nicodemus, K.K. & Folsom, A.R. Type1 and
type2 diabetes and incident hip fractures in
postmenopausal women. Diabetes Care 24,
11921197 (2001).
39. Melton, L.J. 3rd, Leibson, C.L., Achenbach, S.J.,
Therneau, T.M. & Khosla, S. Fracture risk in
type2 diabetes: update of a population-based
study. J. Bone Miner. Res. 23, 13341342
(2008).
40. Loder, R.T. The influence of diabetes mellitus on
the healing of closed fractures. Clin. Orthop.
Relat. Res. 232, 210216 (1988).
41. Stuart, M.J. & Morrey, B.F. Arthrodesis of the
diabetic neuropathic ankle joint. Clin. Orthop.
Relat. Res. 253, 209211 (1990).
42. Papa, J., Myerson, M. & Girard, P. Salvage, with
arthrodesis, in intractable diabetic neuropathic
arthropathy of the foot and ankle. J. Bone Joint
Surg. Am. 75, 10561066 (1993).
43. Tisdel, C.L., Marcus, R.E. & Heiple, K.G. Triple
arthrodesis for diabetic peritalar
neuroarthropathy. Foot Ankle Int. 16, 332338
(1995).
44. Johal, K.S., Boulton, C. & Moran, C.G. Hip
fractures after falls in hospital: a retrospective
observational cohort study. Injury 40, 201204
(2009).
45. Barrett-Connor, E., Weiss, T.W., McHorney, C.A.,
Miller, P.D. & Siris, E.S. Predictors of falls
among postmenopausal women: results from
the National Osteoporosis Risk Assessment
(NORA). Osteoporos. Int. 20, 715722 (2009).
46. Christensen, K., Doblhammer, G., Rau, R. &
Vaupel, J.W. Ageing populations: the challenges
ahead. Lancet 374, 11961208 (2009).
47. Mayne, D., Stout, N.R. & Aspray, T.J. Diabetes,
falls and fractures. Age Ageing 39, 522525
(2010).
48. Thacher, T.D. & Clarke, B.L. Vitamin D
insufficiency. Mayo Clin. Proc. 86, 5060 (2011).
49. Dobnig, H. etal. Type2 diabetes mellitus in
nursing home patients: effects on bone turnover,
bone mass, and fracture risk. J. Clin. Endocrinol.
Metab. 91, 33553363 (2006).
50. Kannus, P., Sievnen, H., Palvanen, M.,
Jrvinen,T. & Parkkari, J. Prevention of falls and
consequent injuries in elderly people. Lancet
366, 18851893 (2005).
51. Vischer, U.M. etal. A call to incorporate the
prevention and treatment of geriatric disorders
in the management of diabetes in the elderly.
Diabetes Metab. 35, 168177 (2009).

8 | ADVANCE ONLINE PUBLICATION

52. Rachner, T.D., Khosla, S. & Hofbauer, L.C.

Osteoporosis: now and the future. Lancet 377,
12761287 (2011).
53. Inaba, M. etal. Influence of high glucose on
1,25-dihydroxyvitamin D3-induced effect on
human osteoblast-like MG63 cells. J. Bone
Miner. Res. 10, 10501056 (1995).
54. Gopalakrishnan, V., Vignesh, R.C.,
Arunakaran,J., Aruldhas, M.M. & Srinivasan, N.
Effects of glucose and its modulation by insulin
and estradiol on BMSC differentiation into
osteoblastic lineages. Biochem. Cell Biol. 84,
93101 (2006).
55. Botolin, S. etal. Increased bone adiposity and
peroxisomal proliferator-activated receptorgamma2 expression in typeI diabetic mice.
Endocrinology 146, 36223631 (2005).
56. Lu, H., Kraut, D., Gerstenfeld, L.C. &
Graves,D.T. Diabetes interferes with the bone
formation by affecting the expression of
transcription factors that regulate osteoblast
differentiation. Endocrinology 144, 346352
(2003).
57. Gunczler, P. etal. Decreased bone mineral
density and bone formation markers shortly
after diagnosis of clinical type1 diabetes
mellitus. J. Pediatr. Endocrinol. Metab. 14,
525528 (2001).
58. Gunczler, P. etal. Decreased lumbar spine bone
mass and low bone turnover in children and
adolescents with insulin dependent diabetes
mellitus followed longitudinally. J. Pediatr.
Endocrinol. Metab. 11, 413419 (1998).
59. Mass, P.G. etal. Bone metabolic
abnormalities associated with well-controlled
type1 diabetes (IDDM) in young adult women:
a disease complication often ignored or
neglected. J. Am. Coll. Nutr. 29, 419429
(2010).
60. Liu, Z. etal. A novel rat model for the study of
deficits in bone formation in type2 diabetes.
Acta Orthop. 78, 4655 (2007).
61. Fujii, H., Hamada, Y. & Fukagawa, M. Bone
formation in spontaneously diabetic Torii-newly
established model of non-obese type2
diabetes rats. Bone 42, 372379 (2008).
62. Jang, W.G. etal. Metformin induces osteoblast
differentiation via orphan nuclear receptor SHPmediated transactivation of Runx2. Bone 48,
885893 (2011).
63. Kawai, M., Sousa, K.M., MacDougald, O.A. &
Rosen, C.J. The many facets of PPARgamma:
novel insights for the skeleton. Am. J. Physiol.
Endocrinol. Metab. 299, E3E9 (2010).
64. Nakashima, T. etal. Evidence for
osteocyteregulation of bone homeostasis
through RANKL expression. Nat. Med. 17,
12311234 (2011).
65. Xiong, J., Onal, M., Jilka, R.L., Weinstein, R.S.,
Manolagas, S.C. & OBrien, C.A. Matrixembedded cells control osteoclast formation.
Nat. Med. 17, 12351241 (2011).
66. Wittrant, Y. etal. High D(+)glucose concentration
inhibits RANKL-induced osteoclastogenesis.
Bone 42, 11221130 (2008).
67. Kim, J.M. etal. Osteoclast precursors display
dynamic metabolic shifts toward accelerated
glucose metabolism at an early stage of RANKLstimulated osteoclast differentiation. Cell.
Physiol. Biochem. 20, 935946 (2007).
68. Williams, J.P. etal. Regulation of osteoclastic
bone resorption by glucose. Biochem. Biophys.
Res. Commun. 235, 646651 (1997).
69. Dienelt, A. & zur Nieden, N.I. Hyperglycemia
impairs skeletogenesis from embryonic stem
cells by affecting osteoblast and osteoclast
differentiation. Stem Cells Dev. 20, 465474
(2011).

www.nature.com/nrendo
2012 Macmillan Publishers Limited. All rights reserved

REVIEWS
70. Kasahara, T. etal. Malfunction of bone marrowderived osteoclasts and the delay of bone
fracture healing in diabetic mice. Bone 47,
617625 (2010).
71. Thrailkill, K.M., Lumpkin, C.K. Jr, Bunn, R.C.,
Kemp, S.F. & Fowlkes, J.L. Is insulin an anabolic
agent in bone? Dissecting the diabetic bone for
clues. Am. J. Physiol. Endocrinol. Metab. 289,
E735E745 (2005).
72. Campos Pastor, M.M., Lpez-Ibarra, P.J.,
Escobar-Jimnez, F., Serrano Pardo, M.D. &
Garca-Cervign, A.G. Intensive insulin therapy
and bone mineral density in type1 diabetes
mellitus: a prospective study. Osteoporos. Int. 11,
455459 (2000).
73. Naot, D. & Cornish, J. The role of peptides and
receptors of the calcitonin family in the
regulation of bone metabolism. Bone 43,
813818 (2008).
74. Cornish, J. etal. Preptin, another peptide product
of the pancreatic beta-cell, is osteogenic invitro
and invivo. Am. J. Physiol. Endocrinol. Metab.
292, E117E122 (2007).
75. Horcajada-Molteni, M.N. etal. Amylin and bone
metabolism in streptozotocin-induced diabetic
rats. J. Bone Miner. Res. 16, 958965 (2001).
76. Dacquin, R. etal. Amylin inhibits bone resorption
while the calcitonin receptor controls bone
formation invivo. J. Cell Biol. 164, 509514
(2004).
77. Cornish, J. etal. Shared pathways of osteoblast
mitogenesis induced by amylin, adrenomedullin,
and IGF1. Biochem. Biophys. Res. Commun. 318,
240246 (2004).
78. Clemens, T.L. & Karsenty, G. The osteoblast:
an insulin target cell controlling glucose
homeostasis. J. Bone Miner. Res. 26, 677680
(2011).
79. Ferron, M. etal. Insulin signaling in osteoblasts
integrates bone remodeling and energy
metabolism. Cell 142, 296308 (2010).
80. Lee, N.K. etal. Endocrine regulation of energy
metabolism by the skeleton. Cell 130, 456469
(2007).
81. Oury, F. etal. Endocrine regulation of male fertility
by the skeleton. Cell 144, 796809 (2011).
82. Hein, G.E. Glycation endproducts in
osteoporosisis there a pathophysiologic
importance? Clin. Chim. Acta 371, 3236 (2006).
83. Saito, M., Fujii, K., Mori, Y. & Marumo, K. Role of
collagen enzymatic and glycation induced crosslinks as a determinant of bone quality in
spontaneously diabetic WBN/Kob rats.
Osteoporos. Int. 17, 15141523 (2006).
84. Yamamoto, M., Yamaguchi, T., Yamauchi, M. &
Sugimoto, T. Low serum level of the endogenous
secretory receptor for advanced glycation end
products (esRAGE) is a risk factor for prevalent
vertebral fractures independent of bone mineral
density in patients with type2 diabetes.
Diabetes Care 32, 22632268 (2009).
85. Schwartz, A.V. etal. Pentosidine and increased
fracture risk in older adults with type2 diabetes.
J. Clin. Endocrinol. Metab. 94, 23802386
(2009).

86. Bouxsein, M.L. Bone structure and fracture

risk: Do they go arm in arm? J. Bone Miner. Res.
26, 13891391 (2011).
87. Seeman, E. & Delmas, P.D. Bone qualitythe
material and structural basis of bone strength
and fragility. N. Engl. J. Med. 354, 22502261
(2006).
88. Kanis, J.A. etal. Development and use of FRAX
in osteoporosis. Osteoporos. Int. 21 (Suppl. 2),
S407S413 (2010).
89. Raisz, L.G. Clinical practice. Screening for
osteoporosis. N. Engl. J. Med. 353, 164171
(2005).
90. Ebeling, P.R. Clinical practice. Osteoporosis in
men. N. Engl. J. Med. 358, 14741482 (2008).
91. [No authors listed] The effect of intensive
treatment of diabetes on the development and
progression of long-term complications in
insulin-dependent diabetes mellitus. The
Diabetes Control and Complications Trial
Research Group. N. Engl. J. Med. 329, 977986
(1993).
92. Nathan, D.M. etal. Intensive diabetes
treatment and cardiovascular disease in
patients with type1 diabetes. N. Engl. J. Med.
353, 26432653 (2005).
93. Egger, M., Davey Smith, G., Stettler, C. &
Diem,P. Risk of adverse effects of intensified
treatment in insulin-dependent diabetes
mellitus: a meta-analysis. Diabet. Med. 14,
919928 (1997).
94. [No authors listed] Lifetime benefits and costs
of intensive therapy as practiced in the
diabetes control and complications trial. The
Diabetes Control and Complications Trial
Research Group. JAMA 276, 14091415
(1996).
95. Hypoglycemia in the Diabetes Control and
Complications Trial. The Diabetes Control and
Complications Trial Research Group. Diabetes
46, 271286 (1997).
96. Schwartz, A.V. etal. Thiazolidinedione use and
bone loss in older diabetic adults. J. Clin.
Endocrinol. Metab. 91, 33493354 (2006).
97. Grey, A. etal. The peroxisome proliferatoractivated receptor-gamma agonist rosiglitazone
decreases bone formation and bone mineral
density in healthy postmenopausal women:
arandomized, controlled trial. J. Clin.
Endocrinol. Metab. 92, 13051310 (2007).
98. Yaturu, S., Bryant, B. & Jain, S.K.
Thiazolidinedione treatment decreases bone
mineral density in type2 diabetic men.
Diabetes Care 30, 15741576 (2007).
99. Meier, C. etal. Use of thiazolidinediones and
fracture risk. Arch. Intern. Med. 168, 820825
(2008).
100. Habib, Z.A. etal. Thiazolidinedione use and the
longitudinal risk of fractures in patients with
type2 diabetes mellitus. J. Clin. Endocrinol.
Metab. 95, 592600 (2010).
101. Bilik, D. etal. Thiazolidinediones and fractures:
evidence from translating research into action
for diabetes. J. Clin. Endocrinol. Metab. 95,
45604565 (2010).

NATURE REVIEWS | ENDOCRINOLOGY

102. [No authors listed] Standards of medical care in

diabetes-2011. Diabetes Care 34 (Suppl. 1),
S11S61 (2011).
103. Bao, X.H., Wong, V., Wang, Q. & Low, L.C.
Prevalence of peripheral neuropathy with
insulin-dependent diabetes mellitus. Pediatr.
Neurol. 20, 204209 (1999).
104. Bolland, M.J. etal. Vascular events in healthy
older women receiving calcium
supplementation: randomised controlled trial.
BMJ 336, 262266 (2008).
105 Bolland, M.J., Grey, A., Avenell, A.,
Gamble,G.D. & Reid, I.R. Calcium
supplements with or without vitamin D and risk
of cardiovascular events: reanalysis of the
Womens Health Initiative limited access
dataset and meta-analysis. BMJ 342, d2040
(2011).
106. Maxmen, A. Nutrition advice: The
vitaminDlemma. Nature 475, 2325 (2011).
107. Holick, M.F. Vitamin D deficiency. N. Engl. J.
Med. 357, 266281 (2007).
108. Priemel, M. etal. Bone mineralization defects
and vitamin D deficiency: histomorphometric
analysis of iliac crest bone biopsies and
circulating 25-hydroxyvitamin D in 675 patients.
J. Bone Miner. Res. 25, 305312 (2010).
109. Bischoff, H.A. etal. Effects of vitamin D and
calcium supplementation on falls: a randomized
controlled trial. J. Bone Miner. Res. 18, 343351
(2003).
110. Vestergaard, P., Rejnmark, L. & Mosekilde, L.
Are antiresorptive drugs effective against
fractures in patients with diabetes? Calcif.
Tissue Int. 88, 209214 (2011).
111. Cummings, S.R. etal. Denosumab for
prevention of fractures in postmenopausal
women with osteoporosis. N. Engl. J. Med. 361,
756765 (2009).
112. Keegan, T.H., Schwartz, A.V., Bauer, D.C.,
Sellmeyer, D.E. & Kelsey, J.L. Effect of
alendronate on bone mineral density and
biochemical markers of bone turnover in type2
diabetic women: the fracture intervention trial.
Diabetes Care 27, 15471553 (2004).
113. Favus, M.J. Bisphosphonates for osteoporosis.
N. Engl. J. Med. 363, 20272035 (2010).
114. Hofbauer, L.C., Jakob, F. & Felsenberg, D.
Bisphosphonates and atypical femoral
fractures. N. Engl. J. Med. 363, 1084 (2010).
Acknowledgments
C. Hamann and L.C. Hofbauer are supported by
grants from Elsbeth Bonhoff Foundation. C. Hamann
and L.C. Hofbauer and K.P. Gnther are supported by
Center for Regenerative Therapies Dresden seed
grants. L.C. Hofbauer is also supported by Deutsche
Forschungsgemeinschaft Transregio67, project B2.
Author contributions
C. Hamann and L.C. Hofbauer researched the data
for and contributed equally to writing of the article. All
authors provided a substantial contribution to
discussions of the content and reviewed and/or
edited the manuscript before submission.

ADVANCE ONLINE PUBLICATION | 9

2012 Macmillan Publishers Limited. All rights reserved