Department of Orthopedics (C. Hamann, S. Kirschner, K.-P. Günther), 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.
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, 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. et al. Nat. Rev. Endocrinol. advance online publication 17 January 2012; doi:10.1038/nrendo.2011.233
IntroductionDiabetes 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, including bones, and cause an enormous medical and economic burden. Typical skeletal complications of poorly con-trolled dia betes mellitus include diabetic foot syndrome and Charcot neuroarthropathy,1–3 which account for a high percentage of surgical procedures and even ampu-tations.4 Fragility fractures owing to low bone strength have 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, have inadequate accrual of peak bone mass, and impaired bone formation has been proposed as a major contrib-uting 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 gly-cemic control, the duration of disease and the presence of vascular complications of diabetes mellitus.8
Irrespective of diabetes status, osteoporotic fractures are most frequently seen in the distal radius, proximal humerus or the hip (Figure 1).7,13,14 When vertebral frac-tures occur, they can go unrecognized for several months or years and result in progressive back pain and substan-tial height loss.15 The risk of falls in the elderly population is 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 falls is increased as a result of vascular complications, particu-larly neuropathy.8,12,17–20 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.21–24 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 frac-tures. We discuss molecular and cellular data, preclinical models and human data in the context of epidemiol-ogy, pathogenesis and clinical implications of impaired bone health.
Epidemiology and presentationOsteoporosis and low bone massT1DM and T2DM affect BMD differently.8 Low bone mass in the radius has been reported in children and ado-lescents with T1DM25,26 and attributed to reduced bone formation during skeletal growth. In adults with T1DM,
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.
femoral BMD is reduced, although, lumbar spine BMD is similar to or slightly lower than that in individuals without diabetes mellitus.27–30 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 T scores 0.3–0.8 higher than those in controls without diabe-tes mellitus matched for age and weight.31–34 In most studies, BMD has been found to be increased at the lumbar 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 without diabetes mellitus.14
Fractures, healing and complicationsPatients with T1DM and T2DM have increased risks of fractures 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 for hip fractures in patients with T1DM and of 1.4–1.7 in those with T2DM.7,35 In a case–control 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, respec-tively, 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 complica-tions does not confer an additional fracture risk.5 In the Women’s 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 dia-betic complications, such as neuropathy, and the use of treatments such as glitazones (in postmenopausal women) and insulin in patients with T2DM (Box 1).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 4 days in one study,23 but recovery 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 increased risk of frequent wound infections, delayed fracture healing and a high incidence of nonunion or pseud-arthrosis (Figure 1),21,24 complications that prolong hospitalization. In patients with diabetes mellitus but without neuro pathy, union time of nondisplaced frac-tures 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.41–43 The process of osseointegration has not been assessed in patients with diabetes mellitus and osteoporosis after hip replacement.
FallsIn 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 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 con-tributing factor to fractures in these indivi duals.48,49 The multifaceted pathogenesis of frailty and falls in patients with diabetes mellitus50 provides rationale for multi-modal therapeutic intervention, including improvement of muscle strength and balance, prevention of diabetic complications and vitamin D supplementation.51
PathogenesisDespite emerging clinical and epidemiological evidence that link diabetes mellitus to low bone mass and frac-tures, 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 biologyBone remodeling depends upon a coordinated sequence of bone resorption by osteoclasts, followed by bone for-mation by osteoblasts. Whereas osteoblasts are derived from mesenchymal stem cells, osteoclasts are derived from hematopoietic stem cells.52
In vitro data53,54 and in vivo studies involving rodent models of T1DM55,56 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.57–59 In the Zucker diabetic, fatty rat, a
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 per-oxisome proliferator-activating receptor γ which might shift precursor cells towards the adipocytic lineage at the cost of osteoblast formation (Figure 2).63 Osteocytes have been increasingly recognized as key regulators in bone remodel ing,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.66–70 In patients with diabetes mellitus, concentrations of bone resorption biomarkers, such as aminoterminal and carboxy terminal crosslinking telopeptide of type I
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 hormonesThe distinct reduction of peak bone mass in some patients with T1DM has led to the hypothesis that insulin has osteoanabolic effects (Figure 3),8 although whether the effects are caused by poor glycemic control or 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 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.
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 2 diabetes mellitus.
unclear. In a review, Thrailkill et al.71 suggested that insulin exerts a potent bone anabolic effect on osteo-blasts 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 35 years, who were evaluated before intensive insulin therapy and 7 years later. Treatment was associated with sub-stantial 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 skel-etal effects between patients with T1DM and those with T2DM are not, therefore, fully explained by the ‘insulinopenia’ hypothesis.
In addition to insulin, pancreatic β cells produce other osteotropic factors, such as islet amyloid poly peptide (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
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 insulin-like 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-IGF-II,74 is associ-ated with proliferation and reduced apoptosis of osteo-blasts and increased bone area and mineralizing surface in mice.74
Pleiotropic functions of osteocalcinOsteocalcin 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 γ-carboxylation,79 which occurs in a milieu with acidic pH. This microenvironment also favors osteoclastic bone resorption. In mice, under carboxylated osteocalcin in turn increases β-cell proliferation and insulin secretion and sensitivity.80 Osteocalcin also regu-lates 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 osteo calcin could become a biomarker and even a potential therapeutic target.
Determinants of impaired bone qualityGiven that patients with T2DM have an increased fracture risk despite having higher BMD than patients with T1DM,14,49 chronic hyperglycemia has been sug-gested to impair bone quality. One plausible mechanism relates 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. Metformin increases the differentiation of MSCs into osteoblasts through its actions on RUNX2. Glitazones simultaneously suppress RUNX2 and activate PPARγ, which drives 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 densityIncreased risk of fracture
Glucose control
Insulin
IAPP
Preptin
Figure 3 | Impaired osteogenesis in T1DM. Pancreatic β-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 apoptosis—preventing osteogenesis and bone mass accrual. Moreover, reduced insulin secretion in patients with T1DM prevents stimulation of osteoblasts to produce osteocalcin, which stimulates β-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.
glucose, raising concentrations of advanced glycation end products, 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 quan-titative CT (pQCT) and finite element analysis have improved assessment of bone geometry, micro-architecture, and strength.34,86,87 These novel tech-nologies, 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 16–30% 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.
DiagnosisIdentification 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 tai-loring 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 FRAX® score.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 examinationHistory reporting and physical examination need to take into account the type of diabetes mellitus, age and age-related diseases, FRAX® tool features (Box 2), history of falls and any predisposing risk factors, such as gait dis-turbances, visual impairment, polyneuropathy or hypo-glycemic 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 concur-rent 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-and-go test.50 Clinical signs of vertebral fractures include tho-racic kyphosis (often known as dowager hump), gradual loss of body height of >6 cm and progressive back pain.15
Measurement of BMDLumbar 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
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 T scores,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 assessmentNational and international guidelines recommend for all patients with suspected osteoporosis an initial labo-ratory evaluation with a complete blood count, renal and liver function tests and levels of serum calcium and phosphate, C-reactive protein (CRP), bone-specific alkaline phosphatase, serum 25-hydroxyvitamin D, serum thyro tropin, serum protein electrophoresis and, for men, serum testosterone.90 Whereas some of these markers have a low sensitivity and specificity when assessed indivi dually, 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
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
TreatmentMost recommendations for management of osteoporosis in patients with diabetes mellitus represent good clini-cal practice rather than evidence-based guidelines and are also valid for patients with osteoporosis but without diabetes mellitus (Box 3).
Considerations for diabetes therapyRegimens 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 T1DM91–94 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;96–101 data on bone loss and fractures associated with glitazone use in men are less conclusive,96,98 so treatment deci-sions 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 complicationsVascular 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 pre-vention of these complications are important. Annual screening for albuminuria can identify nephropathy. If microalbuminuria (urinary excretion 30–300 mg 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 main-tain vision. Annual testing for pressure and vibration sensation should be used to detect poly neuropathy,103 which might predispose pat ients to Charcot neuro arthropathy (Figure 1).
Calcium and vitamin D supplementationDeficiencies of calcium and vitamin D in patients with diabetes mellitus should be treated before spe-cific osteoporosis drugs are started. A daily uptake of 1,200 mg calcium is generally required, ideally through
the diet, but supplementation can be used if dietary uptake is inadequate. The concurrent use of proton-pump 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 vitamin D serum levels.106 In our view, vitamin D supplementation should ensure a serum 25-hydroxyvitamin D level of 75 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 D levels were above 75 nmol/l.108 As most patients do not reach this threshold through consumption of food or sun exposure alone, they typically require supplementation of 800–2,000 IU of vitamin D daily. Obese patients with T2DM require higher doses (≥4,000 IU daily) because of a large distribution volume. The efficacy of vitamin D supplementation in the prevention of falls was demon-strated by a 49% reduction in a cohort of elderly patients without diabetes mellitus who received 1,200 mg calcium and 800 IU vitamin D per day for 3 months.109 Whether or not vitamin D supplementation improves metabolic and vascular parameters, such as β-cell function, vas-cular tone and blood pressure regulation,107 needs to be prospectively assessed.
Osteoporosis therapyIf 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 previously untreated patients, osteoporosis therapy is indicated. A large Danish retrospective cohort study assessed whether antiresorptive drugs were effective in patients with dia-betes 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 NFκB 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 post-hoc 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 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
Zoledronic acid should not be administered in patients with a glomerular filtration rate <45 ml/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 inva-sive dental procedures, which is increased by diabetes mellitus, 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 (PTH1–34; 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 fracture healing in patients with diabetes mellitus is being inves-tigated. Several drugs have shown antifracture efficacy at the spine and the hip (Table 1), and new therapies are being evaluated in phase II and III studies that might improve efficacy and long-term adherence.52
ConclusionsDiabetes 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 β cells, although its role in humans is as yet unclear. Diabetic neuropathy and nephropathy
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 osteo-porosis 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 β 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 supple-mentation 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 investi-gated in adequately powered, prospective, controlled treatment 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 No
Ibandronate* 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
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 5 years. We used the search terms “osteoporosis”, “bone mass”, “fractures” and “bone cells” in combination with “diabetes mellitus”, “type 1 diabetes mellitus” and “type 2 diabetes mellitus”. We also screened the reference sections of selected original articles and reviews.
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AcknowledgmentsC. Hamann and L. C. Hofbauer are supported by grants from Elsbeth Bonhoff Foundation. C. Hamann and L. C. Hofbauer and K.-P. Günther are supported by Center for Regenerative Therapies Dresden seed grants. L. C. Hofbauer is also supported by Deutsche Forschungsgemeinschaft Transregio-67, project B2.
Author contributionsC. 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.
