O s t e o p o ro s i s - a s s o c i a t e d F r a c t u re and Diabetes Salila Kurra,
MD
a,
*, Dorothy A. Fink,
MD
b
, Ethel S. Siris,
MD
c
KEYWORDS Bone Osteoporosis Diabetes Diabetes complications Fracture Skeletal disorder KEY POINTS Because osteoporosis and diabetes mellitus are chronic diseases that are increasing in prevalence, understanding their complex interaction is integral to providing optimal care for patients. Osteoporosis-associated fracture is an important complication of diabetes to consider when evaluating patients with diabetes. Given the different causes of type 1 and type 2 diabetes, they have a unique relationship with bone but also have similar effects on bone when not treated adequately. Osteoporosis treatment options for diabetic patients are the same as for nondiabetic patients, including ensuring normal renal function before starting a bisphosphonate.
INTRODUCTION
Osteoporosis and diabetes mellitus (DM) are chronic diseases with increasing prevalence. Both have significant associated morbidity and mortality and may lead to severe debilitation if not treated adequately. Osteoporosis is a skeletal disorder characterized by reduced bone quantity and quality, which predisposes to fracture.1,2 Fragility fractures, or low-trauma fractures, are common, affecting almost 1 in 2 older women and 1 in 3 older men.3 The global burden of osteoporosis is significant, with approximately 9 million new osteoporotic fractures worldwide in the year 2000.4 Diabetes is also increasing in prevalence. Prevalence of diabetes for all age groups is estimated to be 4.4% of the worldwide population by the year 2030.5 Disclosures: Dr E.S. Siris is a consultant for Amgen, Eli Lilly, Merck, Novartis, and Pfizer, and a speaker for Amgen, Eli Lilly. a Metabolic Bone Diseases Unit, Department of Medicine, Toni Stabile Osteoporosis Center, Columbia University Medical Center, 180 Fort Washington Avenue, 9-904, New York, NY 10032, USA; b Division of Endocrinology, Department of Medicine, Columbia University Medical Center, 630 West 168th Street, PH8, New York, NY 10032, USA; c Metabolic Bone Diseases Unit, Department of Medicine, Toni Stabile Osteoporosis Center, Columbia University Medical Center, New York-Presbyterian Hospital, 180 Fort Washington Avenue, 9-904, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected] Endocrinol Metab Clin N Am 43 (2014) 233–243 http://dx.doi.org/10.1016/j.ecl.2013.09.004 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
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Kurra et al
Recent evidence shows that both type 1 and type 2 DM are associated with an increased fracture risk.6 Although microvascular and macrovascular complications are the complications most commonly associated with diabetes, osteoporosis and risk of fracture must also be considered when treating patients with diabetes. Type 1 diabetes (T1D) is defined as a state of insulin deficiency, whereas type 2 diabetes (T2D) is characterized by insulin resistance with increased insulin levels. Given the different causes of T1D and T2D, they have unique interactions with bone. Skeletal disorders often associated with diabetes include osteoporosis-associated fracture, Charcot arthropathy, and renal osteodystrophy secondary to end-stage renal disease as a complication of diabetes.7,8 Like others in the past,9,10 this article focuses on osteoporosis-associated fracture as a metabolic complication of diabetes. In recent years, osteoporosis-associated fracture has come to the forefront of complications associated with diabetes. Controversy exists over the exact mechanisms of bone loss in the setting of diabetes, but there is significant evidence to support that diabetes affects bone health. The meta-analysis by Vestergaard11 showed that adults with T1D have a 6.9 relative risk of hip fracture and adults with T2D have a 1.3 relative risk of hip fracture. In addition, a meta-analysis by Janghorbani and colleagues12 showed similar results with a 6.3 relative risk of hip fracture in adults with T1D and a 2.8 relative risk of hip fracture in adults with T2D. In the Vestergaard11 study, patients with T1D had decreased bone mineral density (BMD) and increased fracture risk, but although the study noted a 6.9 relative risk of hip fracture, the BMD expected relative risk was only 1.4, suggesting that there are additional factors contributing to fracture risk. Another finding of the Vestergaard11 study was that, despite an increased fracture risk, patients with T2D had higher than expected BMD. With data from the Health, Aging, and Body Composition (Health ABC) Study, Schwartz and colleagues13 showed increased incidence of vertebral fracture in T2D despite increased BMD. The interaction between diabetes and bone health is complex and requires further exploration. T1D VERSUS T2D AND BONE: SIMILARITIES
Despite their different underlying causes, without proper treatment or compliance with treatment both T1D and T2D can be complicated by hyperglycemia. Hyperglycemia in turn can be detrimental to bone; it has been shown that glucose can be toxic to osteoblasts, the cells associated with bone formation. High glucose concentrations impair the ability of osteoblastic cells to synthesize osteocalcin, which is a protein integral to bone formation.14 Also serum osteocalcin levels seem to be suppressed by hyperglycemia in diabetic patients.15 Bone biopsies done on individuals with diabetes have shown low bone formation on histomorphometry.16 For a given BMD, diabetic bone seems to be less strong and therefore more likely to fracture.17,18 Chronic hyperglycemia also promotes advanced glycation and accumulation of advanced glycation end products (AGEs), which contribute to diabetes complications. Impaired renal function is also thought to lead to accumulation of AGEs. They are formed through a nonenzymatic reaction between reducing sugars and amine residues. AGEs act directly to induce cross-linking of long-lived proteins, resulting in alteration of vascular structure and function.19 Accumulation of AGEs in bone collagen likely contributes to the reduction in bone strength for a given BMD.20 The prime targets of AGE accumulation are the structural components of the connective tissue matrix. This accumulation can alter collagen function and thereby alter the function of bone.
Osteoporosis-associated Fracture and Diabetes
Pentosidine is the most commonly measured AGE because of its intrinsic fluorescence.19 Complications of diabetes including nephropathy, retinopathy, neuropathy, atherosclerotic disease, cardiomyopathy, and peripheral arterial disease have been studied extensively with regard to AGEs, and diabetes-associated bone disease has also come to the forefront of AGE-related complications.13,21–23 Katayama and colleagues24 showed that AGE modification of type 1 collagen impaired osteoblast cell differentiation and function in rodent models. AGEs may exert their effects on the receptor for advanced glycation end products (RAGE). Zhou and colleagues25 showed that RAGE knockout mice had increased bone mass with decreased resorption ability, leading the investigators to conclude that RAGE enhances bone resorption through osteoclasts, the cells associated with bone resorption. In postmenopausal women with T2D and vertebral fractures, Yamamoto and colleagues21 found that there were higher serum pentosidine levels compared with controls independently of BMD and osteoporosis risk factors and even after adjusting for diabetes duration, complications, and treatment with insulin or pioglitazone. Studies examining glycemic control and its implications on the skeleton have not shown that tight control limits osteoporosis-related fracture.26,27 However, in most studies, a single hemoglobin A1c (HbA1c) is the only measure of diabetes control and only represents glycemic control over a short period of time. Most postmenopausal women and men with T1D and T2D who develop fractures have had diabetes for decades and it is challenging to adequately assess an individual’s lifetime diabetes control. Regardless, several studies have documented increased fracture rates associated with longer duration of diabetes in patients with both T1D and T2D.28,29 Challenges to many of these studies include confounding factors such as other complications of diabetes, which may increase fracture risk as well. For example, the aforementioned study by Ivers and colleagues29 showed that patients with both T1D and T2D who develop the visual complications of diabetes such as diabetic retinopathy and advanced cortical cataract are also at increased risk for fracture. Based on prospective data on falls from the Study of Osteoporotic Fractures, Schwartz and colleagues30 found an increased risk of falls in women older than 65 years with diabetes with a further increased risk in the setting of insulin use. This increased risk of falls likely contributes to the increased risk of fracture noted in this population. Although this increased fall risk is multifactorial, the complications commonly seen with diabetes, such as poor vision, peripheral neuropathy, reduced balance, and treatment-associated hypoglycemia, are themselves risk factors for falls. However, a case-control study by Vestergaard and colleagues31 showed that both T1D and T2D confer an increased risk of fracture, but, except for diabetic kidney disease, the other complications associated with diabetes added little to the overall risk of fracture. The investigators concluded that the hyperglycemia likely contributes to decreases in bone strength. Low states of bone turnover have been documented in both T1D and T2D, which may lead to lower mechanical strength and an increased risk of fracture.16,32,33 Gennari and colleagues33 recently showed that sclerostin, which is a protein that inhibits osteoblastic bone formation, is higher in T2D compared with T1D and controls, even after adjusting for age and body mass index (BMI). However, the negative association between sclerostin and parathyroid hormone (PTH) that is normally seen was not documented in patients with T1D or T2D, leading the investigators to conclude that PTH suppression of sclerostin may be impaired in both T1D and T2D. This mechanism may be another reason for bone loss in patients with diabetes.
235
236
Kurra et al
T1D VERSUS T2D AND BONE: DIFFERENCES
Although T1D and T2D both result in states of chronic hyperglycemia, the underlying pathophysiology of T1D and T2D is different. The anabolic hormone insulin is absent in T1D and present (often increased) in T2D. However, given the changing milieu of diabetes, many patients with T1D who are insulin deficient have a BMI in the obese range and develop an insulin-resistant phenotype. In addition, many patients with T2D require insulin as their disease progresses, further complicating the effects that diabetes has on bone health. Literature describing bone disease in patients with T1D dates to the 1920s.34 Although there is controversy in the literature over the mechanisms of increased fracture risk, the occurrence of low BMD and fractures is well documented in patients with T1D.35,36 Several studies have postulated that patients with T1D do not achieve peak bone mass during adolescence, which leads to a lower lifetime BMD and may ultimately increase risk of fracture.37,38 Although T1D may be diagnosed after puberty, peak bone mass accrual continues into the early 20s and thus may be affected by hyperglycemia as well. Insulinlike growth factor 1 (IGF-1), which is also a marker of bone formation, has been noted to be low in patients with uncomplicated insulin-dependent DM.39 Kemink and colleagues39 showed that, in diabetic patients with femoral neck osteopenia, the mean plasma IGF-I level was significantly lower (P
MD
a,
*, Dorothy A. Fink,
MD
b
, Ethel S. Siris,
MD
c
KEYWORDS Bone Osteoporosis Diabetes Diabetes complications Fracture Skeletal disorder KEY POINTS Because osteoporosis and diabetes mellitus are chronic diseases that are increasing in prevalence, understanding their complex interaction is integral to providing optimal care for patients. Osteoporosis-associated fracture is an important complication of diabetes to consider when evaluating patients with diabetes. Given the different causes of type 1 and type 2 diabetes, they have a unique relationship with bone but also have similar effects on bone when not treated adequately. Osteoporosis treatment options for diabetic patients are the same as for nondiabetic patients, including ensuring normal renal function before starting a bisphosphonate.
INTRODUCTION
Osteoporosis and diabetes mellitus (DM) are chronic diseases with increasing prevalence. Both have significant associated morbidity and mortality and may lead to severe debilitation if not treated adequately. Osteoporosis is a skeletal disorder characterized by reduced bone quantity and quality, which predisposes to fracture.1,2 Fragility fractures, or low-trauma fractures, are common, affecting almost 1 in 2 older women and 1 in 3 older men.3 The global burden of osteoporosis is significant, with approximately 9 million new osteoporotic fractures worldwide in the year 2000.4 Diabetes is also increasing in prevalence. Prevalence of diabetes for all age groups is estimated to be 4.4% of the worldwide population by the year 2030.5 Disclosures: Dr E.S. Siris is a consultant for Amgen, Eli Lilly, Merck, Novartis, and Pfizer, and a speaker for Amgen, Eli Lilly. a Metabolic Bone Diseases Unit, Department of Medicine, Toni Stabile Osteoporosis Center, Columbia University Medical Center, 180 Fort Washington Avenue, 9-904, New York, NY 10032, USA; b Division of Endocrinology, Department of Medicine, Columbia University Medical Center, 630 West 168th Street, PH8, New York, NY 10032, USA; c Metabolic Bone Diseases Unit, Department of Medicine, Toni Stabile Osteoporosis Center, Columbia University Medical Center, New York-Presbyterian Hospital, 180 Fort Washington Avenue, 9-904, New York, NY 10032, USA * Corresponding author. E-mail address: [email protected] Endocrinol Metab Clin N Am 43 (2014) 233–243 http://dx.doi.org/10.1016/j.ecl.2013.09.004 0889-8529/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
endo.theclinics.com
234
Kurra et al
Recent evidence shows that both type 1 and type 2 DM are associated with an increased fracture risk.6 Although microvascular and macrovascular complications are the complications most commonly associated with diabetes, osteoporosis and risk of fracture must also be considered when treating patients with diabetes. Type 1 diabetes (T1D) is defined as a state of insulin deficiency, whereas type 2 diabetes (T2D) is characterized by insulin resistance with increased insulin levels. Given the different causes of T1D and T2D, they have unique interactions with bone. Skeletal disorders often associated with diabetes include osteoporosis-associated fracture, Charcot arthropathy, and renal osteodystrophy secondary to end-stage renal disease as a complication of diabetes.7,8 Like others in the past,9,10 this article focuses on osteoporosis-associated fracture as a metabolic complication of diabetes. In recent years, osteoporosis-associated fracture has come to the forefront of complications associated with diabetes. Controversy exists over the exact mechanisms of bone loss in the setting of diabetes, but there is significant evidence to support that diabetes affects bone health. The meta-analysis by Vestergaard11 showed that adults with T1D have a 6.9 relative risk of hip fracture and adults with T2D have a 1.3 relative risk of hip fracture. In addition, a meta-analysis by Janghorbani and colleagues12 showed similar results with a 6.3 relative risk of hip fracture in adults with T1D and a 2.8 relative risk of hip fracture in adults with T2D. In the Vestergaard11 study, patients with T1D had decreased bone mineral density (BMD) and increased fracture risk, but although the study noted a 6.9 relative risk of hip fracture, the BMD expected relative risk was only 1.4, suggesting that there are additional factors contributing to fracture risk. Another finding of the Vestergaard11 study was that, despite an increased fracture risk, patients with T2D had higher than expected BMD. With data from the Health, Aging, and Body Composition (Health ABC) Study, Schwartz and colleagues13 showed increased incidence of vertebral fracture in T2D despite increased BMD. The interaction between diabetes and bone health is complex and requires further exploration. T1D VERSUS T2D AND BONE: SIMILARITIES
Despite their different underlying causes, without proper treatment or compliance with treatment both T1D and T2D can be complicated by hyperglycemia. Hyperglycemia in turn can be detrimental to bone; it has been shown that glucose can be toxic to osteoblasts, the cells associated with bone formation. High glucose concentrations impair the ability of osteoblastic cells to synthesize osteocalcin, which is a protein integral to bone formation.14 Also serum osteocalcin levels seem to be suppressed by hyperglycemia in diabetic patients.15 Bone biopsies done on individuals with diabetes have shown low bone formation on histomorphometry.16 For a given BMD, diabetic bone seems to be less strong and therefore more likely to fracture.17,18 Chronic hyperglycemia also promotes advanced glycation and accumulation of advanced glycation end products (AGEs), which contribute to diabetes complications. Impaired renal function is also thought to lead to accumulation of AGEs. They are formed through a nonenzymatic reaction between reducing sugars and amine residues. AGEs act directly to induce cross-linking of long-lived proteins, resulting in alteration of vascular structure and function.19 Accumulation of AGEs in bone collagen likely contributes to the reduction in bone strength for a given BMD.20 The prime targets of AGE accumulation are the structural components of the connective tissue matrix. This accumulation can alter collagen function and thereby alter the function of bone.
Osteoporosis-associated Fracture and Diabetes
Pentosidine is the most commonly measured AGE because of its intrinsic fluorescence.19 Complications of diabetes including nephropathy, retinopathy, neuropathy, atherosclerotic disease, cardiomyopathy, and peripheral arterial disease have been studied extensively with regard to AGEs, and diabetes-associated bone disease has also come to the forefront of AGE-related complications.13,21–23 Katayama and colleagues24 showed that AGE modification of type 1 collagen impaired osteoblast cell differentiation and function in rodent models. AGEs may exert their effects on the receptor for advanced glycation end products (RAGE). Zhou and colleagues25 showed that RAGE knockout mice had increased bone mass with decreased resorption ability, leading the investigators to conclude that RAGE enhances bone resorption through osteoclasts, the cells associated with bone resorption. In postmenopausal women with T2D and vertebral fractures, Yamamoto and colleagues21 found that there were higher serum pentosidine levels compared with controls independently of BMD and osteoporosis risk factors and even after adjusting for diabetes duration, complications, and treatment with insulin or pioglitazone. Studies examining glycemic control and its implications on the skeleton have not shown that tight control limits osteoporosis-related fracture.26,27 However, in most studies, a single hemoglobin A1c (HbA1c) is the only measure of diabetes control and only represents glycemic control over a short period of time. Most postmenopausal women and men with T1D and T2D who develop fractures have had diabetes for decades and it is challenging to adequately assess an individual’s lifetime diabetes control. Regardless, several studies have documented increased fracture rates associated with longer duration of diabetes in patients with both T1D and T2D.28,29 Challenges to many of these studies include confounding factors such as other complications of diabetes, which may increase fracture risk as well. For example, the aforementioned study by Ivers and colleagues29 showed that patients with both T1D and T2D who develop the visual complications of diabetes such as diabetic retinopathy and advanced cortical cataract are also at increased risk for fracture. Based on prospective data on falls from the Study of Osteoporotic Fractures, Schwartz and colleagues30 found an increased risk of falls in women older than 65 years with diabetes with a further increased risk in the setting of insulin use. This increased risk of falls likely contributes to the increased risk of fracture noted in this population. Although this increased fall risk is multifactorial, the complications commonly seen with diabetes, such as poor vision, peripheral neuropathy, reduced balance, and treatment-associated hypoglycemia, are themselves risk factors for falls. However, a case-control study by Vestergaard and colleagues31 showed that both T1D and T2D confer an increased risk of fracture, but, except for diabetic kidney disease, the other complications associated with diabetes added little to the overall risk of fracture. The investigators concluded that the hyperglycemia likely contributes to decreases in bone strength. Low states of bone turnover have been documented in both T1D and T2D, which may lead to lower mechanical strength and an increased risk of fracture.16,32,33 Gennari and colleagues33 recently showed that sclerostin, which is a protein that inhibits osteoblastic bone formation, is higher in T2D compared with T1D and controls, even after adjusting for age and body mass index (BMI). However, the negative association between sclerostin and parathyroid hormone (PTH) that is normally seen was not documented in patients with T1D or T2D, leading the investigators to conclude that PTH suppression of sclerostin may be impaired in both T1D and T2D. This mechanism may be another reason for bone loss in patients with diabetes.
235
236
Kurra et al
T1D VERSUS T2D AND BONE: DIFFERENCES
Although T1D and T2D both result in states of chronic hyperglycemia, the underlying pathophysiology of T1D and T2D is different. The anabolic hormone insulin is absent in T1D and present (often increased) in T2D. However, given the changing milieu of diabetes, many patients with T1D who are insulin deficient have a BMI in the obese range and develop an insulin-resistant phenotype. In addition, many patients with T2D require insulin as their disease progresses, further complicating the effects that diabetes has on bone health. Literature describing bone disease in patients with T1D dates to the 1920s.34 Although there is controversy in the literature over the mechanisms of increased fracture risk, the occurrence of low BMD and fractures is well documented in patients with T1D.35,36 Several studies have postulated that patients with T1D do not achieve peak bone mass during adolescence, which leads to a lower lifetime BMD and may ultimately increase risk of fracture.37,38 Although T1D may be diagnosed after puberty, peak bone mass accrual continues into the early 20s and thus may be affected by hyperglycemia as well. Insulinlike growth factor 1 (IGF-1), which is also a marker of bone formation, has been noted to be low in patients with uncomplicated insulin-dependent DM.39 Kemink and colleagues39 showed that, in diabetic patients with femoral neck osteopenia, the mean plasma IGF-I level was significantly lower (P
