Diabetes Mellitus and the Risk of Fracture
Dong Hyeok Cho, Jin Ook Chung, Min Young Chung, Dong Jin Chung Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
The bone mass is known to be decreased in patients with type 1 diabetes, and this is primarily due to osteoblastic dysfunction. A number of epidemiologic studies have consistently shown a significantly higher risk of fractures in type 1 diabetic patients as compared to that of healthy subjects. The data on bone mineral density (BMD) in patients with type 2 diabetes has been inconsistent. However, many recent epidemiologic studies have shown that the osteoporotic fracture risk, and especially at the hip, is also increased in patients with type 2 diabetes, and even in patients with normal or higher BMD. Meanwhile, several studies have shown higher bone mass and a lower fracture risk in subjects with recent onset type 2 diabetes or impaired glucose tolerance with hyperinsulinemia. Poor bone quality and an increased risk of falling are thought to be important contributing factors for the higher fracture risk in patients with type 2 diabetes. Collagen overglycosylation by accumulation of advanced glycation end products (AGE) is thought to be one of the possible mechanisms underlying poor bone quality. The risk of falling in patients with diabetes is increased due to hypoglycemia, visual impairment from retinopathy and cataracts, altered balance, gait problems due to neuropathy and foot ulcers, associated cardiovascular diseases and medication use. Insulin-sensitizing agents, such as thiazolidinediones, are also associated with a higher fracture risk through an increase in bone marrow adiposity and a decrease in osteoblastogenesis.
Because diabetes and osteoporosis are highly prevalent chronic diseases in the aging population and the incidences are increasing worldwide, understanding the risk factors that predispose patients to such conditions is very important. On considering the potential mechanisms associated with bone metabolism, adequate glycemic control while minimizing the episodes of hypoglycemia is the most important first step in the medical management to prevent osteoporotic fractures in patients with diabetes.
Key Words: Bone mineral density, Bone quality, Diabetes, Fracture, Osteoporosis
Received: April 13, 2010 Revised: June 29, 2010 Accepted: July 8, 2010
Corresponding Author: Dong Jin Chung, Department of Internal Medicine, Chonnam National University Medical School, Hak-dong, Dong-gu, Gwangju 501-746, Korea
Tel: +82-62-220-6501, Fax: +82-62-225-8578 E-mail: [email protected]
The incidences of diabetes mellitus and osteoporosis are significantly increased with aging. Both are related to increased morbidity and mortality due to chronic late complications in diabetics and the fragile fractures and deformities in patients with osteoporosis. A considera- ble number of patients have both diseases, which might
cause much more devastating results. Traditionally, type 1 diabetes is well known to be associated with low bone mineral density (BMD) and a higher fracture risk due to the osteoblastic dysfunction that is caused by insulin deficiency because of failure of pancreatic β -cells.1 Although a higher BMD and a lower fracture risk in patients with type 2 diabetes have been reported in several studies, most of the recent large scale epidemiologic data has emphasized a higher fracture risk, especially at the hip, in type 2 diabetic patients regardless of the BMD status.2-4
The higher fracture risk even in patients with higher
A. Potential factors associated with bone metabolism - Insulin: insulin deficiency, hyperinsulinemia, insulin
treatment
- The duration of diabetes - Diabetic late complications
- Associated components of metabolic syndrome;
obesity etc.
- The glycemic control status - Oxidative stress
- Drugs: Thiazolidinediones (TZDs), Metformin, GLP-1 agonist?
B. Risk factors for osteoporosis - Type 1 diabetes
- Poor glycemic control - Diabetic nephropathy
- Abnormalities of calcium and vitamin D metabolism - Peripheral neuropathy
- Diabetic nephropathy - Diabetic gastroparesis - Diabetic diarrhea
- Thiazolidinediones (TZDs)
Table 1. Potential factors associated with bone meta- bolism and osteoporosis in diabetes
BMD suggests another factors might be involved in the pathogenesis of fracture. One of the possible mecha- nisms is poor bone quality related to a long duration of hyperglycemia. Another important risk factor for fracture is thought to be an increase in the falling risk that is associated with various conditions in patients with type 2 diabetes. Many factors, such as the insulin level, the glycemic control status, advanced glycation end products (AGE), the duration of diabetes, the presence of diabetic chronic late complications such as peripheral neuropathy, retinopathy and nephropathy, and the change of calcium and vitamin D metabolism are all thought to be related to the BMD and fracture risk in diabetic patients5-10 (Table 1). Several antidiabetic drugs are also known to be associated with bone metabolism. However, in spite of increasing evidence, diabetes is not widely recognized as a risk factor for osteoporotic fracture. In this review, we will discuss the potential factors associated with bone metabolism in diabetics.
BMD AND FRACTURE RISK
In most of the studies on type 1 diabetic patients, the lumbar spine and proximal femur BMD have been lower than that in the controls.11,12 The fracture risk is significantly increased in type 1 diabetic patients compared with that of the nondiabetic population.13-16 However, low, normal and increased BMD values have been reported in the previous studies with type 2 diabetic patients.12,17-20
In a population-based, 6-year follow-up of 27,159 subjects from the municipality of Tromsø, type 1 diabetic men had an increased risk of all non-vertebral (relative risk [RR] 3.1, 95% CI: 1.3～7.4) and hip fractures (RR 17.8, 95% CI: 5.6～56.8). Diabetic women, regardless of the type of diabetes, had a significantly increased hip fracture risk (RR 8.9, 95%
CI: 1.2～64.4 and RR 2.0, 95% CI: 1.2～3.6 for type 1 and type 2 diabetes, respectively).13 In a case-control study with subjects with a fracture (n=124,655) and control subjects (n=373,962) in Denmark, type 1 and type 2 diabetes were associated with an increased risk of any type of fracture (odds ratio [OR] 1.3, 95% CI:
1.2～1.5 for type 1 diabetes and 1.2, 95% CI: 1.1～1.3 for type 2 diabetes) and hip fractures (OR 1.7, 95% CI:
1.3～2.2 for type 1 diabetes and 1.4, 95% CI: 1.2～1.6 for type 2 diabetes).21 In the Nurses’ Health Study of 109,983 women aged 34～59 years, the age-adjusted relative risk (RR) of hip fracture was 7.1 (95% CI: 4.4
～11.4) for women with type 1 diabetes and 1.7 (95%
CI: 1.4～2.0) for those with type 2 diabetes.22 In the Women’s Health Initiative (WHI) study of post- menopausal women (n=93,676), diabetic women had a higher hip and spine BMD than did the non-diabetic women. However, the overall risk of fracture after 7 year of follow up was significantly higher in the women with diabetes (adjusted relative risk [RR]: 1.20, 95% CI: 1.11～1.30).23 Diabetic women had a 46%
increased risk of having a fracture of the hip/pelvis/
upper leg (RR 1.46, 95% CI: 1.17～1.83) and they
were approximately 30% more likely to have a fracture of the foot or spine.23 In a prospective cohort of 32,089 postmenopausal women who were followed for 11 years in Iowa, the type 2 diabetic women had a 1.70～
fold higher risk (95% CI: 1.21～2.38) of hip fracture than did the women without diabetes.15 In the Rotterdam study with 6,655 men and women aged 55 years and over [792 elderly patients with type 2 diabetes (483 women and 309 men; mean age: 74 years) and 5863 nondiabetic controls with an average follow-up period of 6.8 years], although the subjects with diabetes had a higher BMD at the lumbar spine and the femoral neck, they had an increased non- vertebral fracture risk (hazard ratio [HR] 1.33, 95% CI:
1.00～1.77).24 Finally, meta-analysis of the 16 eligible studies15,21,25-33 (two case-control studies and 14 cohort studies) that included 836,941 participants and 139,531 incident cases of fracture showed that type 2 diabetes was associated with an increased risk of hip fracture in both men (relative risk [RR] 2.8, 95% CI: 1.2～6.6) and women (relative risk [RR] 2.1, 95% CI: 1.6～2.7).3 The association with hip fracture was stronger for type 1 diabetes (RR 6.3, 95% CI: 2.6～15.1) than for type 2 diabetes (RR 1.7, 95% CI: 1.3～2.2).3
However, several studies showed no risk or a decreased fracture risk in the subjects with elevated 2-h glucose levels,34 IGT24 or type 2 diabetes.29,35 Type 2 diabetic men and women had increased BMD compared to that of the subjects with normal glucose tolerance in the Rotterdam study, which consisted of 5931 residents (2481 men, 3450 women) aged 55 years or more. Type 2 diabetic women was associated with a lower fre- quency of nonvertebral fractures than the women without diabetes (adjusted odds ratio [OR], 0.63; 95% CI: 0.44 to 0.90).35 In the osteoporosis prospective risk assess- ment (OPRA) study, 1,132 women who were all 75 years old or older were randomly recruited. In this study, women with diabetes had a higher BMD of the femoral neck and lumbar spine,29 and they had no more lifetime fractures (52%) than did the women without diabetic
disease (57%).29 A retrospective, population-based mat- ched cohort study with 82,094 diabetic adults and 236,682 non-diabetic matched controls was performed using the Population Health Information System (POPULIS) for the Province of Manitoba, Canada. In this study, the patients with newly diagnosed diabetes showed a reduction in osteoporotic fractures (rate ratio [RR] 0.91, 95% CI: 0.86～0.95) and hip fractures (RR 0.83, 95% CI: 0.75～0.92).36 According to the Rotterdam study, the subjects with IGT had a higher BMD, but in contrast to the subjects with treated diabetes (hazard ratio [HR] 1.69, 95% CI: 1.16～2.46), they had a lower nonvertebral fracture risk (HR 0.80, 95% CI: 0.63～
1.00).24 The Malmo Preventive Project consisted of 33,346 [22,444 men (44± 6.6 yr) and 10,902 women (50±7.4 yr)] with a follow-up of 19 yr (±3.9) and 15 yr (±4.5), respectively, for the incident of fractures. In these middle- aged men and women, elevated 2-h glucose levels were associated with decreased risks of multiple and osteoporotic fractures, suggesting there was a positive effect on bone from hyperglycemia and hyperinsulinemia.34
BONE TURNOVER MARKERS
Most studies on the bone turnover rate in diabetes were performed on a small number of samples.
Usually, they showed low or normal serum levels of osteocalcin, a marker of bone formation.37 On the other hand, the levels of bone resorption markers were not consistent.38 The serum osteocalcin level was signi- ficantly lower than that of the control group in many studies.29,39-42 The bone resorption markers CTx,29,40 NTx/Cr39 and urine-DPD/Cr29 were lower in diabetics in some studies, whereas the serum concentrations of tartrate resistant acid phosphatase (TRAP),41,42 urine CTx,41 DPD41 and NTx41 were reported to be signi- ficantly increased in diabetic patients in other studies.
Osteocalcin, which is one of the bone formation markers, has recently been identified as an important
hormone associated with insulin secretion and glucose metabolism, and this suggests there is crosstalk between bone and energy metabolism.43 Mice lacking the osteoblast-secreted molecule osteocalcin display dec- reased beta-cell proliferation, glucose intolerance and insulin resistance.43 In several clinical studies, the serum osteocalcin level was negatively correlated with fasting plasma glucose and glycosylated hemoglo- bin.44-47 In our study with postmenopausal type 2 diabetic women (the duration of diabetes was 9.9 years and the level of glycosylated hemoglobin was 8.2%), the serum osteocalcin and CTx levels were significantly increased when compared to the normal reference levels of premenopausal women. The serum osteocalcin was significantly lower in the postmenopausal type 2 diabetic women than that of the non-diabetic post- menopausal women, whereas the serum CTx was not different between the two groups.47
It has been suggested that low bone turnover in diabetes can slow the rate of bone loss and may cause a higher BMD.40 However, this might also increase the microdamage and skeletal fragility, independent of bone density.48 Suppression of osteocalcin in type 1 diabetic mouse bones suggests that hyperglycemia may contri- bute to the suppression of osteoblastic function and bone loss.49 Adequate glycemic control in patients with diabetes may play an important role for bone turnover improvement.50
BONE HISTOMORPHOMETRY
Animal studies with streptozotocin (STZ)-induced type 1 diabetic mice or rats have shown deterioration of the osteoblastic function parameters such as the number of osteoblasts, the osteoid thickness and the mineral apposition rate on bone histomorphometric analysis. Likewise, most bone histomorphometric studies have indicated that diabetes may induce a low turnover osteopenia due to the decreased recruitment and function of osteoblasts.51 This mechanism could
result in a reduced accumulation of bone during the period of skeletal growth in patients with type 1 diabetes.48 In an animal study with type 2 diabetic Goto-Kakizaki rats, there were fewer tetracycline labeled surfaces than those in the controls, suggesting an increased risk of fracture owing to the decreased bone formation even in type 2 diabetes.52
POTENTIAL MECHANISMS FOR THE ASSOCIATIONS OF DIABETES, BMD AND FRACTURE
1. Insulin
Insulin and insulin-like growth factor-I (IGF-1) are known to play important anabolic roles in the recruitment of osteoblasts.53,54 Insulin deficiency in patients with type 1 diabetes and some patients with a long duration of type 2 diabetes results in increased bone loss and lower bone mass. However, the subjects with hyperinsulinemia or insulin resistance have shown a higher BMD and a lower fracture risk than that of the general populations in several studies. Higher BMD and a lower fracture risk were reported in the Rotterdam study.35 Positive correlation with BMD was also noted in the Bernardo study, suggesting that hyperinsulinemia may be responsible for the association of both diabetes and obesity with BMD in women.55 In a Hertfordshire Cohort Study, the BMD was higher in the newly diagnosed diabetic subjects, with a stronger relationship for the women than for the men.56 In a more recent study of the Malmo Preventive Project, elevated 2-hour glucose levels, which are characterized by peripheral insulin resistance with a high insulin level, were associated with decreased risks of multiple and osteoporotic fractures.34 These findings suggest that insulin can preserve and increase the BMD and bone strength through an anabolic effect on bone tissue, and type 2 diabetes may be preceded by a period of insulin resistance leading to hyperinsulinemia.56,57 Consistent with the evidence of an association of insulin defi-
ciency with a low bone mass, the positive skeletal effects of a 7 year course of intensive insulin therapy on bone metabolism was noted.58
2. Glycemic control status
Poor glycemic control may increase osmotic diuresis with increased urinary calcium excretion, and this can cause a negative calcium balance, which causes com- pensatory PTH elevation and increased bone loss. The osteoblastic and osteoclastic response to 1,25(OH)2D3 is also decreased in this condition. Hyperglycemia may modulate the osteoblast gene expression and function and bone formation, and so this contributes to bone loss.49 The bone loss was higher in the patients with poorly controlled diabetes than that in those patients whose diabetes was in good control.59 Poor metabolic control is related to the risk of osteopenia, and this suggests optimization of metabolic control may contri- bute to the prevention of osteoporosis.60
3. Duration of diabetes
In a prospective cohort study in Iowa, a longer duration of type 2 diabetes was associated with a higher incidence of hip fracture.15 In the Nurses’ Health Study, the relative risk of hip fracture was significantly increased with a longer duration of type 2 diabetes (RR 3.1, 95% CI: 2.3～4.0) for ≥12 years as compared with that of no diabetes.22 Similarly, the fracture risk was increased in the patients with duration of diabetes more than 10 years (RR 3.3, 95% CI: 1.3～8.2) in the Blue Mountains Eye Study.32 However, in the population- based Tromsø Study, the duration of diabetes did not alter the hip fracture risk.13 Similarly, in the case-control study in Denmark, there was no significant association between the fracture risk and the duration of type 1 or type 2 diabetes.21
However, as already described, the subjects with IGT or newly diagnosed type 2 diabetes showed a lower risk of fracture.24,34,36,56
In a retrospective, population- based matched cohort study using the Population Health
Information System (POPULIS), long-term diabetes was associated with an increased fracture risk, whereas newly diagnosed diabetes showed a reduction in the fracture risk.36 These results may suggest that the initial positive effect on bone mass appears to be ameliorated as the patient’s age or disease duration advances.36,61 On the contrary, the relative risk of fracture tended to be higher in those with less than a 3 year duration of diabetes than that in those patients with diabetes of a longer duration in the study in Denmark.21 The authors suggested that initial poor control of diabetes may increase the initial fracture risk.21
As described above, the epidemiologic studies about the relationship between the duration of diabetes and the fracture risk frequently show conflicting results.
Because the onset of type 2 diabetes may variably precede the actual diagnosis by 5～10 years, or patients may have been asymptomatic for a long period before the diagnosis, the duration of diabetes may not accurate or appropriate.21,62
4. Diabetic chronic complications
Poor balance due to diabetic polyneuropathy and poor vision due to diabetic retinopathy and cataract are important risk factors for the fall-related fracture risk.
Patel et al. reported that the QUS variables were lower in the fracture group, and the fallers had a higher vibration perception threshold (VPT), suggesting that peripheral neuropathy is an important risk factor for falling.63 Vestergaard et al reported that diabetic kidney disease increases the fracture risk.64 Several studies have investigated the possible role of vitamin D in the pathogenesis of skeletal fracture. Suzuki et al shows that the co-existence of hypovitaminosis D is possibly related to the risk of osteoporotic fracture.8 In that report, the serum 25OHD was significantly decreased in patients with proliferative retinopathy or with multiple late diabetic complications.8 In the Blue Mountains Eye Study, the presence of diabetic retinopathy (adjusted RR 5.4, 95% CI: 2.7～10.8) and cortical cataract
involving ≥25% of the lens area (adjusted RR 2.5, 95% CI: 1.3～4.7) were significantly associated with all fracture risks.32 Yet Yamamoto et al. recently reported that type 2 diabetic patients have an increased risk of vertebral fracture and this is independent of BMD or the diabetic complication status, suggesting that bone quality may define bone fragility in patients with type 2 diabetes.65
5. Obesity, Metabolic syndrome
Metabolic syndrome is associated with decreased physical activity and an increased incidence of diabetes.
Many people with diabetes have hypertension, hyperli- pidemia and obesity. The obesity that commonly presents in people with type 2 diabetes may have a protective effect on bone density.66 However, the combination of obesity with hyperglycemia was a risk factor for vertebral fractures in type 2 diabetic men.67 A study with 2,475 Korean women demonstrated that the mean vertebral BMD was significantly lower in women with metabolic syndrome.68 Moreover, the age- and weight-adjusted vertebral BMDs were significantly decreased with additional components of metabolic syndrome in this study.68 The plasma levels of various inflammatory mediators (IL-6, TNF-α, CRP) are increased in obesity.69 These mediators may cause an increase in bone resorption and a decrease in the BMD.
Increased serum hsCRP concentrations were associated with a lower BMD and a higher bone turnover rate in a large population of healthy Korean women.70 Further studies may be needed to elucidate the relationship between bone metabolism and metabolic syndrome.
6. Overglycosylation and poor bone quality The accumulation of advanced glycation end-products (AGEs) has been implicated in patients with chronic diabetic complications and this causes loss of minerali- zation and mature bone nodule formation, and this suggests there is a deleterious effect of AGEs in diabetic bone disease.71,72 The increased bone fragility
of WBN/Kob rats is closely connected with the accumulation of advanced glycation end-products (AGEs) in bone collagen.73 A higher trabecular bone volume and a decrease in the number of tartrate- resistant acid phosphatase (TRAP)-positive osteoclasts in RAGE (Receptor for AGEs) knock-out mice suggest that AGE-RAGE interaction has an important role in the pathogenesis of diabetic bone disease.74 Thus, overglycosylation by AGE accumulation in the bone collagen may cause lower levels of pyridinium cross- links and lower tensile strength of the fibril, with diminished resistance of the structural framework.71,75 Poor bone quality due to abnormal collagen overgly- cosylation and cross-linking of bone protein by long- term chronic hyperglycemia might explain the recent data showing a higher fracture rate in spite of higher BMD in type 2 diabetic patients.
7. Oxidative stress
Oxidative stress is induced by a variety of mechani- sms, including the glycation reaction, which is increa- sed in the diabetic condition. In vitro studies have shown that oxidative stress inhibits osteoblastic diffe- rentiation76 and it induces osteoblast apoptosis.77 In one animal study, all the bone formation parameters were significantly decreased in the STZ-induced diabetic group as compared with that of the control or insulin treated groups.78 In this study, the markers of oxidative stress were inversely associated with the histomor- phometric parameters of bone formation, suggesting oxidative stress may be a therapeutic target in patients with diabetic bone disease.78
8. Falls
The risk of falling is increased due to hypoglycemia, peripheral neuropathy, a history of foot ulcer, ampu- tations, diabetic retinopathy, cataract, the association of cardiovascular disease, drugs, nocturia, orthostatic hypo- tension, decreased neuromuscular function, autonomic neuropathy and inadequate exercise5,6,23 (Table 2). The
A. Poor bone quality
- Collagen overglycosylation due to AGEs (Advanced glycation endproducts)
B. Risk factors for falls - Episodes of hypoglycemia
- Visual impairment; diabetic retinopathy, advanced cataracts, laser therapy for retinopathy (peripheral and night vision decreases)
- Altered proprioception, balance & gait problems from diabetic neuropathy
- Poor balance due to foot ulcers or amputations - Decreased reflexes
- Orthostatic hypotension
- Impaired joint motility due to cheiropathy - Episodes of nocturia
- Urgent and frequent trips to the restroom, especially at night
- Associated cardiovascular diseases - Physical inactivity
Table 2. Risk factors for osteoporotic fractures in patients with diabetes
proportion of injuries caused by low falls is increased and this is possibly due to a hypoglycemic episode in insulin-treated patients.79 In the Tromsø study, the use of insulin was associated with an increased hip fracture risk in both men and women, and the duration of insulin use was the major predictor of the fracture risk.13 There is a possibility of more episodes of hypoglycemia and falls in insulin-treated diabetics than that in diabetics who are not using insulin.13 Further- more, there are more chances of having chronic complications in insulin-treated patients who have a long duration of diabetes. The vibration perception threshold (VPT) was lower in the older type 2 diabetic women with a history of falling.80 Early recognition and adequate glycemic control of diabetes by reducing the incidence of neuropathy may help reduce falls.80 Falls due to diabetes-related comorbidities are another possible cause of low-trauma fracture.81
9. Antidiabetic agents
Bone homeostasis is maintained by the balance between osteoblastic bone formation and osteoclastic bone resorption. Because both osteoblasts and marrow
adipocytes originate from a common multipotential mesenchymal stem cell (MSC) progenitor, an increase in adipogenesis causes a decrease in the number of osteoblasts and bone loss.82,83 The peroxisome proliferator- activated receptor gamma (PPAR-γ) pathway not only determines the adipocyte differentiation from mesenchy- mal progenitors, but it also inhibits osteoblast differen- tiation. Furthermore, Wan et al.84 reported a role for PPAR- γ in promoting osteoclast differentiation and bone resorption when activated by rosiglitazone. In animal studies, antidiabetic thiazolidinediones (TZDs) treatment have demonstrated decreased bone formation and bone mass.85,86 In human studies, the bone formation markers and BMD were decreased by rosiglitazone therapy,87 and a significantly higher incidence of appendicular skeleton fracture was demonstrated in women who were rando- mized to the rosiglitazone group in the ADOPT (A Diabetes Outcome Progression Trial) study.88 In one study, although the number of subjects was small, the use of rosiglitazone was associated with an increased prevalence of vertebral fractures in males with type 2 diabetes.89 In a recent prospective cohort study with 84,339 patients, treatment with a thiazolidinedione was associated with a 28% increased risk of peripheral fractures, as compared with treatment with a sulfonylurea (HR 1.28; 1.10～1.48).
However, when compared to the previous studies, the fracture risk was significantly increased in both men and women, and pioglitazone was more strongly associated with fractures than rosiglitazone in this study.90 Several studies have recently shown that metformin has some beneficial effects on bone.91,92 A direct osteogenic effect of metformin on osteoblasts was noted,91,93 and it was suggested to be mediated by Runx2/Cbfa1 and AMPK activation.91 In other studies, metformin reverses the deleterious effects of high glucose and AGEs on osteoblasts.92,94 GLP-1 is an incretin with glucose-dependent insulinotrophic and insulin-independent antidiabetic properties that exerts insulin-like effects upon glucose transport and/or meta- bolism. In a study with Wistar rats, GLP-1 infusion
increased the OPG/RANKL ratio in insulin-resistant (IR) rats by higher increments of the OPG gene expression, and this induced recovery of the normal trabecular structure in type 2 diabetic (T2D) rats.95 These findings suggest that GLP-1 might be useful as a pharmacological agent for improving the deficient bone formation and bone structure associated with glucose intolerance.95 However, further longitudinal studies are needed to clarify the effects of metformin and GLP-1 on the BMD and fracture risks of patients with type 2 diabetes.
PREVENTION AND MANAGEMENT
As discussed, many factors such as insulin, the glycemic control status, overglycosylation of collagen, the duration of diabetes, chronic late complications (neuropathy, retinopathy, nephropathy), oxidative stress, foot ulcers and drugs are associated with bone metabolism, osteoporosis and the fracture risk in diabetic patients. Prevention or delay of diabetic late chronic complications by strict glycemic control with a minimum frequency of hypoglycemia should be emphasized as the first step to reduce osteoporosis and the fracture risk in diabetic patients. Reducing the risk of falling is another important issue. Drug therapy for osteoporosis should be considered for diabetic patients who have a high risk of fracture. However, many potential osteoporotic subjects with diabetes may not be recognized as high fracture risk patients under the present treatment guideline.96 The diagnostic work-up should be tailored according to the individual condition and the various risk factors of each diabetic patient.38 In view of the low bone turnover with reduced osteo- blastic function, anabolic agents would be an appro- priate choice. The combination of insulin and hPTH was more effective in improving the bone mass and strength than was insulin or hPTH alone in streptozotocin-induced diabetic rats.97 As bisphospho- nates effectively reduce the fracture risk in glucocorti-
coid induced osteoporosis, which is associated with osteoblastic dysfunction, it may be useful in patients with diabetes.98 The increases in the BMD with alendronate therapy, as compared with placebo, were similar between the women with and without diabetes.99
CONCLUSION
It has become clear that patients with type 1 diabetes have lower BMD and a higher risk of fractures.
Increasing evidence indicates that type 2 diabetic patients also have a higher risk of fractures regardless of the BMD status. Although the underlying mechanism of this is not clear and it is likely multifactorial, poor bone quality and an increased risk of falling are thought to be important factors associated with the higher incidence of fragile fractures. Therefore, type 2 diabetes should be recognized as an important risk factor for osteoporotic fractures. All the diabetes-related risk factors should be carefully assessed, and the decision to initiate therapy for reducing the fracture risk should be individualized.
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Peer Reviewers' Commentary
The author discussed potential factors associated with bone metabolism in diabetes. Diabetes mellitus and osteoporosis are related to increased morbidity and mortality due to chronic late complications in diabetes and the fragile fractures and deformities in patient with osteoporosis. Many factors are associated with bone metabolism, osteoporosis and the fracture risk in diabetic patients. The author summarized that patient with type 1 diabetes have lower BMD and a higher risk of fractures. Increasing evidence indicates that type 2 diabetic patients also have higher risk of fractures regardless of the BMD status. Prevention or delay of diabetic late chronic complications by strict glycemic control with a minimum frequency of hypoglycemia should be emphasized as the first step to reduce osteoporosis and the fracture risk in diabetic patients.
(Summary: Editorial Committee)
