Hamann Kirschner Guenther Hofbauer 2012

7/23/2019 Hamann Kirschner Guenther Hofbauer 2012

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Department ofOrthopedics(C. Hamann,

S. Kirschner,K.-P. Günther), Divisionof Endocrinology,Diabetes and MetabolicBone Diseases,Department ofMedicine III(L. C. Hofbauer),Dresden TechnicalUniversity MedicalCenter, Fetscherstrasse74, 01307 Dresden,Germany.

Correspondence to:L. C. [email protected]

Bone, sweet bone—osteoporotic fractures

in diabetes mellitusChristine Hamann, Stephan Kirschner, Klaus-Peter Günther 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. Type 1

diabetes mellitus (T1DM) affects the skeleton more severely than type 2 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 vitamin D repletion, representthe 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. et al. Nat. Rev. Endocrinol. advance online publication 17 January 2012; doi:10.1038/nrendo.2011.233

Introduction

Diabetes mellitus, in particular type 2 diabetes mellitus(T2DM), is a common metabolic disease with increas-ing prevalence throughout the world. Chronic complica-tions adversely affect multiple organ systems, includingbones, and cause an enormous medical and economic

burden. Typical skeletal complications of poorly con-trolled diabetes mellitus include diabetic foot syndromeand Charcot neuroarthropathy,1–3 which account for ahigh percentage of surgical procedures and even ampu-tations.4 Fragility fractures owing to low bone strengthhave become increasingly recognized as skeletal compli-cations.5–7 Patients with type 1 diabetes mellitus (T1DM),which manifests at an adolescent or young adult age, haveinadequate accrual of peak bone mass, and impairedbone formation has been proposed as a major contrib-uting factor.8 Patients with T2DM have not only a higherBMD than non-diabetic individuals but also an increasedrisk of bone fragility, which is thought to be caused by

poor bone quality,5,9,10 although techniques to assess bonequality are still new in clinical practice. Both T1DM andT2DM are associated with hypercalciuria in periods ofglucosuria11 and possibly a higher propensity to falls.12 Skeletal abnormalities can depend on the quality of gly-cemic control, the duration of disease and the presenceof vascular complications of diabetes mellitus.8

Irrespective of diabetes status, osteoporotic fracturesare most frequently seen in the distal radius, proximalhumerus or the hip (Figure 1).7,13,14 When vertebral frac-tures occur, they can go unrecognized for several monthsor years and result in progressive back pain and substan-

tial height loss.15 The risk of falls in the elderly populationis increased by concurrent use of multiple medica-tions, impaired visual acuity, orthostatic dysregulation,impaired balance and gait and impaired proprioception.16 In patients with diabetes mellitus, the propensity for fallsis increased as a result of vascular complications, particu-larly neuropathy.8,12,17–20 Fractures are frequently slower toheal and the risks of infectious and perioperative cardiovascular complications and prolonged hospitalization arehigher in patients with diabetes mellitus than in thosewithout this condition.21–24 Reduced physical activity andmobility after fractures have a negative effect on glycemiccontrol in patients with T2DM.

In this Review, we provide a brief overview on theeffects of diabetes mellitus on osteoporosis and frac-tures. We discuss molecular and cellular data, preclinicalmodels and human data in the context of epidemiol-ogy, pathogenesis and clinical implications of impairedbone health.

Epidemiology and presentation

Osteoporosis and low bone mass

T1DM and T2DM affect BMD differently.8 Low bonemass in the radius has been reported in children and ado-lescents with T1DM25,26 and attributed to reduced boneformation during skeletal growth. In adults with T1DM,

Competing interests:

L. C. Hofbauer declares an association with the followingcompanies: Amgen, Lilly, Merck, Novartis, Nycomed. See thearticle online for full details of the relationships. The otherauthors declare no competing interests.

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femoral BMD is reduced, although, lumbar spine BMDis similar to or slightly lower than that in individualswithout diabetes mellitus.27–30 The presence of vascularcomplications, such as retinopathy and neuropathy,27,28 rather than the duration of disease or poor glycemiccontrol has been associated with low bone mass. Themechanisms underlying the increased vulnerability ofthe proximal femur in patients with advanced diabetesmellitus are unclear. By contrast, adults with T2DM havenormal or slightly elevated BMD values, with T scores

0.3–0.8 higher than those in controls without diabe-tes mellitus matched for age and weight.31–34 In moststudies, BMD has been found to be increased at thelumbar spine, hip and radius.8 Data from three prospec-tive observational studies in older adults (>73 years old)with T2DM suggest that, for a given age and T score,fracture risk is higher than that in individuals withoutdiabetes mellitus.14

Fractures, healing and complications

Patients with T1DM and T2DM have increased risks offractures at most skeletal sites.7,10,35,36 Two large meta-analyses that assessed studies involving 1.3 million

participants, reported an odds ratio (OR) of 6.3–6.9 forhip fractures in patients with T1DM and of 1.4–1.7 inthose with T2DM.7,35 In a case–control study of 124,655patients, the OR for any fracture was 1.3 and the OR forhip fracture was 1.4 in patients with T1DM; the OR forany fracture and hip fracture were 1.2 and 1.7, respec-tively, in patients with T2DM.37 In addition, T1DMconferred an increased risk of spine fracture (OR 2.5),whereas T2DM was associated with an increased risk ofwrist fracture (OR 1.2).37 Of note, diabetic nephropathyseems to increase hip fracture risk 12-fold in patientswith T1DM, whereas the presence of other complica-tions does not confer an additional fracture risk.5 In

the Women’s Health Study, in which 490 hip fractureswere reported among postmenopausal women >300,000person-years,38 the OR for hip fracture was 12.3 inpatients with T1DM and 1.7 in patients with T2DM.Diabetes-related risk factors for fractures include dia-betic complications, such as neuropathy, and the useof treatments such as glitazones (in postmenopausalwomen) and insulin in patients with T2DM (Box 1).39

Cardiac complications and pressure ulcers after hipfracture were twice as common in patients with T2DMas in patients without diabetes mellitus and led to anextension of hospitalization by 4 days in one study,23 butrecovery rates after 1 year were similar. Patients with

Key points

■ Type 1 and type 2 diabetes mellitus are associated with an increased risk of

osteoporotic fractures

■ Bone formation and osteoblast function are impaired in patients with type 1

diabetes mellitus ■ BMD is increased but bone quality is reduced in patients with type 2 diabetes

mellitus

■ Glitazones might promote bone loss and should be avoided in patients with

osteoporosis ■ Comorbidities guide the selection of specific osteoporosis therapies

diabetes mellitus who suffer fractures are at increasedrisk of frequent wound infections, delayed fracturehealing and a high incidence of nonunion or pseud-arthrosis (Figure 1),21,24 complications that prolonghospitalization. In patients with diabetes mellitus butwithout neuropathy, union time of nondisplaced frac-tures has been reported to be 87% longer than that inpatients without diabetes mellitus, although BMDwas not assessed in this study.40 Prospective studies onfracture healing in patients with diabetes mellitus andosteoporotic fractures of the radius, humerus or the hipare not available. Elective ankle arthrodesis in patientswith diabetes mellitus and Charcot neuroarthopathy isassociated with frequent infections and delayed boneregeneration.41–43 The process of osseointegration hasnot been assessed in patients with diabetes mellitus andosteoporosis after hip replacement.

Falls

In patients with advanced diabetes mellitus, falls rep-resent an important triggering event for osteoporotic

fractures,12,17–20 in particular hip fractures.44,45 As lifeexpectancies of the general population and patients withdiabetes mellitus are on the rise, age-related sarcopeniaand frailty are increasing in prevalence.46,47 Impaired vision resulting from retinopathy and altered gait causedby polyneuropathy can lead to falls.47 Advanced diabeticcardiovascular complications leading to heart failure andcardiac arrhythmias also promote falls.12,20,47 Vitamin Ddeficiency increases the risk of falls and, as it affects upto 90% of patients with diabetes mellitus, is a major con-tributing factor to fractures in these individuals.48,49 Themultifaceted pathogenesis of frailty and falls in patientswith diabetes mellitus50 provides rationale for multi-

modal therapeutic intervention, including improvementof muscle strength and balance, prevention of diabeticcomplications and vitamin D supplementation.51

Pathogenesis

Despite emerging clinical and epidemiological evidencethat link diabetes mellitus to low bone mass and frac-tures, the mechanisms underlying skeletal effects arenot completely understood. Most data are derived fromcellular or animal models and have not been validatedin humans.

Alterations in bone cell biology

Bone remodeling depends upon a coordinated sequenceof bone resorption by osteoclasts, followed by bone for-mation by osteoblasts. Whereas osteoblasts are derivedfrom mesenchymal stem cells, osteoclasts are derivedfrom hematopoietic stem cells.52

In vitro data53,54 and in vivo studies involving rodentmodels of T1DM55,56 indicate that bone formation isconsistently impaired in diabetes mellitus, as shownby the expression of osteoblastic transcription factors,for example RUNX2, biochemical markers and histo-morphometric indices (Figure 2). An associationbetween T1DM and low bone formation in humans hasalso been shown.57–59 In the Zucker diabetic, fatty rat, a

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T2DM model, diet-induced obesity was associated withlow bone mass and low bone formation.60 Spontaneouslydiabetic Torii rats, a model of nonobese T2DM, showedreduced bone formation rate that was reversed by insulintreatment.61 Similar findings, however, have not beenseen in humans. Some oral antidiabetic drugs mightspecifically target osteoblasts and affect bone formation.Metformin stimulates osteoblast differentiation throughthe transactivation of Runx2.62 Glitazones activate per-

oxisome proliferator-activating receptor γ which mightshift precursor cells towards the adipocytic lineage at thecost of osteoblast formation (Figure 2).63 Osteocytes havebeen increasingly recognized as key regulators in boneremodeling,64,65 but their contribution to bone health indiabetes mellitus remains unclear.

Bone resorption does not appear to be excessivelyelevated in animal models of diabetes mellitus. In fact,osteoclast differentiation and function were inhibitedin a diabetic microenvironment in several studies.66–70 In patients with diabetes mellitus, concentrations ofbone resorption biomarkers, such as aminoterminaland carboxyterminal crosslinking telopeptide of type I

collagen (NTX and CTX) or deoxypyridinoline, can beincreased, decreased or not altered, depending on thestudy, and differences exist between patients with T1DMand those with T2DM.8

Insulin and other osteotropic hormones

The distinct reduction of peak bone mass in somepatients with T1DM has led to the hypothesis thatinsulin has osteoanabolic effects (Figure 3),8 althoughwhether the effects are caused by poor glycemic controlor other diabetic complications that affect BMD is

a c db

e g hf

Figure 1 | Skeletal complications of diabetes mellitus. Osteoporotic fractures in patients with diabetes mellitus are shownin a | the distal radius, b | subcapital humerus, c | proximal femur and d | vertebrae. Metabolic and postoperative skeletal

complications, include e | Charcot ar thropathy, f | pseudarthrosis, g | periprosthetic fracture and implant loosening andh | osteomyelitis. Fracture sites are indicated by arrows.

Box 1 | 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 >10 years in T2DM

Abbreviations: T1DM, type 1 diabetes mellitus, T2DM, type 2diabetes mellitus.

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unclear. In a review, Thrailkill et al.71 suggested thatinsulin exerts a potent bone anabolic effect on osteo-blasts through receptor-mediated mechanisms. Lack of

insulin led to low bone mass in an uncontrolled studyof 57 patients with T1DM and a mean age of 35 years,who were evaluated before intensive insulin therapyand 7 years later. Treatment was associated with sub-stantial improvement of bone mass and bone turnoverbiomarkers.72 Hyperinsulinemia in patients with T2DMmight contribute to the high BMD, although insulinresistance in bone cells may occur. Differences in skel-etal effects between patients with T1DM and thosewith T2DM are not, therefore, fully explained by the‘insulinopenia’ hypothesis.

In addition to insulin, pancreatic β cells produce otherosteotropic factors, such as islet amyloid polypeptide

(IAPP, also known as amylin)73 and preptin,74 both ofwhich are members of the ca lcitonin-gene-relatedpeptide family. Production of these peptides is abolishedin patients with T1DM. IAPP, a 37-amino-acid peptide,is secreted with insulin. In a streptozotocin-induced rat

model of T1DM, treatment with IAPP increased bonemass and strength by stimulation of bone formationand inhibition of bone resorption in a similar mannerto insulin.75 The receptor through which IAPP exertsits effects on osteoblasts has not been identified.76 Someof its anabolic effects might be mediated by insulin-like growth factor (IGF) I receptors.77 The potent anti-resorptive effect of IAPP was also demonstrated inIapp-deficient mice.76 Preptin, a peptide of 34 aminoacids that shares homology with pro-IGF-II,74 is associ-ated with proliferation and reduced apoptosis of osteo-blasts and increased bone area and mineralizing surfacein mice.74

Pleiotropic functions of osteocalcin

Osteocalcin has been implicated as a common linkbetween bone and glucose metabolism and osteoblastsare becoming increasingly recognized as insulin targets.78 Activation of the osteoblastic insulin receptor increasesosteocalcin activity. Osteocalcin undergoes post-translational γ-carboxylation,79 which occurs in a milieu

with acidic pH. This microenvironment also favorsosteoclastic bone resorption. In mice, undercarboxylatedosteocalcin in turn increases β-cell proliferation andinsulin secretion and sensitivity.80 Osteocalcin also regu-lates testosterone production and male fertility throughits effects on the testes, which regulate bone mass accrualand bone remodeling through testosterone secretion.81 Therefore, if the link with bone turnover is validatedin human physiology, undercarboxylated osteocalcincould become a biomarker and even a potentialtherapeutic target.

Determinants of impaired bone quality

Given that patients with T2DM have an increasedfracture risk despite having higher BMD than patientswith T1DM,14,49 chronic hyperglycemia has been sug-gested to impair bone quality. One plausible mechanismrelates to increased collagen crosslinking by abundant

Metformin

Matureosteoblasts MSC

RUNX2 PPARγ

Adipocytes

Increasedosteogenesis

Increasedadipogenesis

Glitazones

Glitazones

Figure 2 | Skeletal effects of pharmacological treatments for T2DM. Metforminincreases the differentiation of MSCs into osteoblasts through its actions onRUNX2. Glitazones simultaneously suppress RUNX2 and activate PPARγ, whichdrives differentiation of MSCs into adipocytes, thereby reducing osteogenesis.Abbreviations: MSC, mesenchymal stem cell; PPARγ, peroxisome proliferator-activated receptor γ.

Mature osteoblast

Damagedpancreatic β cells

Pancreas

RUNX2

MSC

Osteocalcin

ProliferationDifferentiationApoptosis resistance

Testis

Testiculartestosteronesecretion

Osteocalcin

OsteogenesisLow bone density Increased risk of fracture

Glucose control

Insulin

IAPP

Preptin

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

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glucose, raising concentrations of advanced glycationendproducts, such as pentosidine,82,83 which have beenassociated with increased fracture risk.84,85

DXA is the standard bone imaging method, butadvances such as high-resolution peripheral quan-titative CT (pQCT) and f inite element analysis haveimproved assessment of bone geometry, micro-architecture, and strength.34,86,87 These novel tech-nologies, which are being used increasingly in clinicalresearch and trials, could improve measurement of bonequality and the identification of patients with diabetesmellitus who are at increased risk of fractures. In apQCT-based study of patients with T2DM, trabecularBMD of the femoral neck was 16–30% higher in patientswith diabetes mellitus than that of hea lthy controls,whereas cortical BMD was similar in the two groups.34 Nevertheless, the load-to-strength ratio for hip fractureswas similar in both groups, which indicates no benefitwith increased BMD.

Diagnosis

Identification of individuals with diabetes mellitus andosteoporosis before they have fractures is important.Findings from clinical assessments and BMD should beconsidered together to enable calculation of the 10-yearrisk of sustaining an osteoporotic fracture and the tai-loring of therapy to the individual. The FRAX®tool,from the WHO, is available to facilitate calculation ofrisk.88 The fracture risk of patients with T2DM is higherthan that of people without diabetes mellitus for a givenFRAX®score.14 Although the diagnostic procedure issimilar in individuals with and without diabetes mellitus,some additional considerations must be applied to thosepatients with diabetes mellitus.8

History and physical examination

History reporting and physical examination need to takeinto account the type of diabetes mellitus, age and age-related diseases, FRAX®tool features (Box 2), history offalls and any predisposing risk factors, such as gait dis-turbances, visual impairment, polyneuropathy or hypo-glycemic episodes. In addition, a comprehensive drugreview is essential to identify medications that promotebone loss, such as glitazones, or raise the risk of falls,such as sleeping medications and antidepressants.50

Physical examination might help to identify concur-rent risk factors for low bone mass or falls, such as low

body weight, malnutrition, hypogonadism, muscularatrophy or cardiac arrhythmias. Suitable office-basedtests that could be used to assess muscle strength, gaitand balance include the chair-rising test and the up-and-go test.50 Clinical signs of vertebral fractures include tho-racic kyphosis (often known as dowager hump), gradualloss of body height of >6 cm and progressive back pain.15

Measurement of BMD

Lumbar spine and hip BMD should be measured withDXA.15,89 One potential drawback of DXA when usedfor patients with diabetes mellitus is that it does nottake into account bone size and geometry, owing to 2D

imaging.86,87 For instance, some patients with T1DMcan have small bones. A consistent finding in patientswith T2DM is increased fragility despite normal or high

T scores,14 which indicates poor bone quality. Therefore,normal BMD values should be carefully interpreted.Imaging techniques that use pQCT might overcomesome of these limitations.

Aortic calcification and spinal osteoarthritis mightinterfere with DXA measurement, yielding false-positive(inaccurately high) spinal BMD results.15 Radiographyof the spine should be used in patients with localizedback pain, recent spinal deformities or substantial lossof height, to check for possible vertebral fractures.15,89 Alternatively, the vertebral fracture assessment tool ofDXA enables lateral vertebral morphometric assessmentand can be used to detect vertebral fractures.15

Laboratory assessment

National and international guidelines recommend forall patients with suspected osteoporosis an initial labo-ratory evaluation with a complete blood count, renaland liver function tests and levels of serum calciumand phosphate, C-reactive protein (CRP), bone-specificalkaline phosphatase, serum 25-hydroxyvitamin D,serum thyrotropin, serum protein electrophoresis and,for men, serum testosterone.90 Whereas some of thesemarkers have a low sensitivity and specificity whenassessed individually, such as CRP, together they canexclude secondary causes of osteoporosis such as hyper-

parathyroidism, hyperthyroidism, hypogonadism, renalinsufficiency, Paget disease and multiple myeloma.Further laboratory tests may be required, depending oncomorbidities and clinical findings.

The quality of glycemic control can be determined byblood glucose profiles and measurement of HbA

1c levels

in serum. Measurement of glomerular filtration rate andurinary excretion of albumin helps determine the degreeof diabetic nephropathy, a risk factor for osteoporosis inpatients with diabetes mellitus.5 Measurement of boneturnover markers has limited use in the initial assessmentof osteoporosis but can be useful in differential diagnosisor for monitoring of treatment response.90

Box 2 | 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 oneof the following diagnoses that are strongly associated withosteoporosis: type 1 diabetes mellitus, osteogenesis imperfecta,chronic liver disease, chronic malnutrition or malabsorption,hypogonadism or premature menopause (<45 years) or untreatedchronic hyperthyroidism. Permission obtained from Springer ©Kanis, J. A. et al. Osteoporos. Int. 21 (Suppl. 2), S407–S413 (2010).

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Treatment

Most recommendations for management of osteoporosisin patients with diabetes mellitus represent good clini-cal practice rather than evidence-based guidelines andare also valid for patients with osteoporosis but withoutdiabetes mellitus (Box 3).

Considerations for diabetes therapy

Regimens that ensure normal fasting and postprandialglucose levels minimize most of the pleiotropic adverseeffects of glucose on bone. If no contraindications exist,intensive insulin therapy is the standard treatment for

T1DM91–94 and seems to be associated with improvedskeletal health.72 The risk of hypoglycemic episodes,which constitute an adverse ef fect of intensive insulintherapy, should be minimized by comprehensive patienteducation, frequent self-monitoring of glucose levels andtitration of the insulin dose.95 Glitazones should not begiven to postmenopausal women with T2DM;96–101 dataon bone loss and fractures associated with glitazoneuse in men are less conclusive,96,98 so treatment deci-sions should be made on an individual basis. Weightloss in patients with T2DM needs to be accompanied byincreased physical activity to prevent bone loss.

Prevention of diabetic complicationsVascular diabetic complications, such as nephropathy,retinopathy and polyneuropathy, are associated with lowbone mass and increased risk of falls and osteoporoticfracture.5,27,28,47 Thus, systematic screening for and prevention of these complications are important. Annualscreening for albuminuria can identify nephropathy. Ifmicroalbuminuria (urinary excretion 30–300 mg daily)is detected, aggressive antihypertensive therapy, ideallywith angiotensin-converting-enzyme inhibitors, shouldbe initiated.102 Annual ophthalmologic exams are recom-mended to diagnose retinopathy in its early stages. Ifhypertension is present, improved glycemic control and

the use of angiotensin-converting-enzyme inhibitors areuseful preventive measures. Laser therapy might preventprogression of advanced retinopathy and help to main-tain vision. Annual testing for pressure and vibrationsensation should be used to detect polyneuropathy,103 which might predispose patients to Charcotneuroarthropathy (Figure 1).

Calcium and vitamin D supplementation

Deficiencies of calcium and vitamin D in patientswith diabetes mellitus should be treated before spe-cific osteoporosis drugs are started. A daily uptake of1,200 mg calcium is generally required, ideally through

the diet, but supplementation can be used if dietaryuptake is inadequate. The concurrent use of proton-pump inhibitors or loop diuretics, and the presence ofmalabsorption or diabetic nephropathy might increasethe daily calcium requirement. High doses of calciumsupplementation might have adverse effects on thecardiovascular system.104,105 Patients with T2DM andrenal impairment might be particularly sensitive tocalcium supplements owing to their increased levels ofcalcium-phosphorus product.

No consensus has been reached on optimal vitamin Dserum levels.106 In our view, vitamin D supplementationshould ensure a serum 25-hydroxyvitamin D level of75 nmol/l.107 This target is supported by a comprehen-sive study of 675 individuals, in whom bone mineraliza-tion defects were not seen if serum 25-hydroxyvitamin Dlevels were above 75 nmol/l.108 As most patients do notreach this threshold through consumption of food or sunexposure alone, they typically require supplementationof 800–2,000 IU of vitamin D daily. Obese patients withT2DM require higher doses (≥4,000 IU daily) because

of a large distribution volume. The efficacy of vitamin Dsupplementation in the prevention of falls was demon-strated by a 49% reduction in a cohort of elderly patientswithout diabetes mellitus who received 1,200 mg calciumand 800 IU vitamin D per day for 3 months.109 Whetheror not vitamin D supplementation improves metabolicand vascular parameters, such as β-cell function, vas-cular tone and blood pressure regulation,107 needs to beprospectively assessed.

Osteoporosis therapy

If the FRAX®tool calculates a 10-year absolute risk of 3%for hip fracture and 20% for major osteoporotic fracture

(distal radius, proximal humerus, spine) in previouslyuntreated patients, osteoporosis therapy is indicated. Alarge Danish retrospective cohort study assessed whetherantiresorptive drugs were effective in patients with dia-betes mellitus.110 In patients with and without diabetesmellitus, the efficacy of bisphosphonates, includingalendronate, etidronate, clodronate and raloxifene, wassimilar. In addition to its retrospective nature, a potentiallimitation of this study was the lack of data for drugssuch as zoledronic acid, risedronate, strontium ranelateor denosumab, an inhibitor of receptor activator of NFκBligand (RANKL) that was approved in 2010.111 The riskof hip fractures was comparable in patients with T1DM

and T2DM who received alendronate.110 In a post-hoc subgroup analysis of alendronate in the FractureIntervention Trial (FIT), the gain of BMD at the lumbarspine and the hip was similar in patients with or withoutdiabetes mellitus, although the study was not poweredto demonstrate fracture reduction.112 Thus, the widelyapproved bisphosphonates, alendronate, risedronate andzoledronic acid, seem to be effective for the treatment ofosteoporosis in patients with diabetes mellitus.113 Somepatients with diabetic comorbidities such as gastro-paresis or gastrointestinal adverse effects caused by oralbisphosphonates may benefit from 5 mg parenteral zole-dronic acid once yearly or 60 mg denosumab biannually.

Box 3 | 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

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Zoledronic acid should not be administered in patientswith a glomerular filtration rate <45 ml/min/1.73 m2, butno such restrictions exist for denosumab. Oral hygiene

should be optimized to keep the risk of osteonecrosis ofthe jaw with bisphosphonates and denosumab after inva-sive dental procedures, which is increased by diabetesmellitus, to a minimum.114

On the basis of pathophysiological evidence that sug-gests low bone formation in diabetes mellitus, osteo-anabolic therapies such as parathyroid hormone 1–34(PTH

1–34; also known as teriparatide) or the full-length

PTH1–84

are attractive. Use of PTH1–34

should, however,be limited to patients with two or more established ver-tebral fractures or those with a high risk of fractures.The use of bone anabolic therapies to accelerate fracturehealing in patients with diabetes mellitus is being inves-

tigated. Several drugs have shown antifracture efficacyat the spine and the hip (Table 1), and new therapies arebeing evaluated in phase II and III studies that mightimprove efficacy and long-term adherence.52

Conclusions

Diabetes mellitus predisposes patients to osteoporoticfractures through various mechanisms. In T1DM, lackof osteoanabolic pancreatic hormones, including insulin,prevents accrual of an adequate peak bone mass. InT2DM, frequent falls combined with impaired b onequality causes fragility fractures even when bone massremains normal. Osteocalcin provides important signals

from the bone to β cells, although its role in humans isas yet unclear. Diabetic neuropathy and nephropathy

in patients with chronic and poorly controlled diseasemight lead to surgical complications, such as infectionsand delayed bone healing. Assessment of osteoporosis is

similar in patients with and without diabetes mellitus.After repletion of calcium and vitamin D, most osteo-porosis drugs can be used, but associated comorbiditiesshould be considered, and glitazones should be avoidedin postmenopausal women.

An improved understanding of the effects of insulinsignaling and the paracrine effects of osteocalcin onbone and β cells is needed, along with clarification ofthe role of falls and diabetic complications in fractures,and development of nonpharmacological strategies toprevent them. Optimum calcium and vitamin D supple-mentation levels for patients with diabetes mellitus andidentification of subgroups of patients that could benefit

from anabolic compared with antiresorptive therapy alsoneed to be established. These issues should be investi-gated in adequately powered, prospective, controlledtreatment studies with relevant end points.

Table 1 | Established osteoporosis drugs

Drug Dose Route of administration Fracture efficacy Evaluated in diabetes

Alendronate 70 mg weekly Oral Hip and spine Yes

Risedronate 35 mg weekly Oral Hip and spine No

Ibandronate* 150 mg monthly Oral Spine No

Raloxifene* 60 mg daily Oral Spine No

Strontium ranelate* 2 g daily Oral Hip and spine NoIbandronate* 3 mg every 3 months Intravenous Spine No

Zoledronic acid 5 mg yearly Intravenous Hip and spine No

Denosumab* 60 mg every 6 months Subcutaneous Hip and spine No

PTH1–34 20μg daily Subcutaneous Spine No

PTH1–84 100 μg daily Subcutaneous Spine No

*Only in postmenopausal women. Abbreviation: PTH, parathyroid hormone. Permission obtained from Elsevier Ltd © Rachner, T. D. et al. Lancet 377,1276–1287 (2011).

Review criteria

We searched MEDLINE and PubMed for articles publishedbetween 1995 and 2011, with particular attention to

original papers, reviews and meta-analyses published in the

past 5 years. We used the search terms “osteoporosis”,

“bone mass”, “fractures” and “bone cells” in combinationwith “diabetes mellitus”, “type 1 diabetes mellitus” and

“type 2 diabetes mellitus”. We also screened the reference

sections of selected original articles and reviews.

1. O’Loughlin, A., McIntosh, C., Dinneen, S. F. &O’Brien, T. Review paper: basic concepts tonovel therapies: a review of the diabetic foot. Int.

J. Low Extrem. Wounds 9, 90–102 (2010).2. Carnevale, V., Romagnoli, E. & D’Erasmo, E.

Skeletal involvement in patients with diabetesmellitus. Diabetes Metab. Res. Rev. 20, 196–204(2004).

3. Schwartz, A. V. Diabetes mellitus: does it affectbone? Calcif. Tissue Int. 73, 515–519 (2003).

4. Sumpio, B. E. Foot ulcers. N. Engl. J. Med. 343,787–793 (2000).

5. Vestergaard, P., Rejnmark, L. & Mosekilde, L.Diabetes and its complications and theirrelationship with risk of fractures in type 1 and 2diabetes. Calcif. Tissue Int. 84, 45–55 (2009).

6. Ahmed, L. A., Joakimsen, R. M., Berntsen, G. K.,Fønnebø, V. & Schirmer, H. Diabetes mellitus andthe risk of non-vertebral fractures: the Tromsostudy. Osteoporos. Int. 17, 495–500 (2006).

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Acknowledgments

C. Hamann and L. C. Hofbauer are supported bygrants from Elsbeth Bonhoff Foundation. C. Hamannand L. C. Hofbauer and K.-P. Günther are supported byCenter for Regenerative Therapies Dresden seedgrants. L. C. Hofbauer is also supported by DeutscheForschungsgemeinschaft Transregio-67, project B2.

Author contributions

C. Hamann and L. C. Hofbauer researched the data

for and contributed equally to writing of the article. Allauthors provided a substantial contribution todiscussions of the content and reviewed and/oredited the manuscript before submission.

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Hamann Kirschner Guenther Hofbauer 2012