Maria Luisa BRANDI, PhD
Gerard KARSENTY, MD, PhD
Metabolic Bone Diseases
Department of Internal Medicine
University of Medicine
Medical School, Florence
by M. L . Brandi,Italy
The association between diabetes and bone health has long been a matter of debate. Both type 1 diabetes and type 2 diabetes have been linked to increased risk of fractures, with bonemineral density being decreased in type 1 diabetes and increased in type 2 diabetes. Insulin has an anabolic effect on bone, and the qualitatively different effects of type 1 and type 2 diabetes on bone mass are consistent with the opposite insulin-secretory states (hypoinsulinemia vs hyperinsulinemia). The existence of an elevated fracture risk in type 2 diabetes, despite the underlying hyperinsulinemia, has led to speculation about differences in bone quality between type 1 diabetes and type 2 diabetes. This could be explained by the fact that increased blood glucose levels are associated with increased urinary calcium loss, resulting in a negative calcium balance. There is also speculation about the role of the resistance to parathyroid hormone observed in diabetes, and its effect on calcium and bone turnover. Also, collagen glycosylation may alter bone biomechanical competence. Falls associated with diabetes-related comorbidities are another possible cause of low-trauma fractures. Adequate glycemic control and prevention of diabetic complications are the mainstay of therapy to lower fracture risk, with the caveat that thiazolidinediones increase fracture risk in postmenopausal women with type 2 diabetes. In conclusion, bone health is an important consideration in diabetes, and caution should be exercised in prescribing thiazolidinediones to postmenopausal women with low bonemass and patients with prior fragility fracture. This article reviews the current state of knowledge on the association between diabetes and bone health.
More than 180 million people worldwide suffer from type 2 diabetes, a disease that more than doubles the risk of death, mainly from cardiovascular disease.1 Interestingly, the medical literature provides evidence of a convergence between diabetes, a metabolic disease, and potential mechanisms accounting for osteoporosis. Skeletal involvement in diabetes was first suggested more than 80 years ago, prompted by radiological findings of retarded bone development and bone atrophy in children with type 1 diabetes.2 In 2007, a systematicmeta-analysis in women with type 2 diabetes reported that, although there was no significant increase in vertebral or distal forearm fractures, hip fracture risk was elevated 1.7- fold.3 Furthermore, it is now recognized that diabetes and hip fractures share common risk factors. Nevertheless, despite a large body of accumulated data on the skeletal effects of diabetes, many questions remain unresolved, with biochemical and imaging studies producing conflicting findings. This is likely to be due in large part to the complex pathophysiology of diabetes, the diversity of skeletal sites examined, the multitude of techniques used for measuring bone mass, and variations in the duration, severity, and treatment of diabetes in the different studies. This paper reviews our current understanding of the pathogenetic bases of bone disease in diabetes.
Figure 1. Current model of the leptindependent regulation of bone mass.
Modified from reference 7: Karsenty G. Cell Metab. 2006;4:341-348. © 2006, Elsevier Ltd.
_ The biological relevance of bone remodeling
There is a constant turnover of bone through bone remodeling, via a biphasic process occurring throughout the skeleton over a period of approximately 3 months.4 It includes destruction (resorption) of preexisting bone, a function exerted by a specialized bone-specific cell, the osteoclast, followed by de novo bone formation, a function exerted by another bonespecific cell, the osteoblast. Normally, resorption and formation of bone occur not only sequentially, but in a balanced manner in order to maintain bone mass nearly constant during most of adulthood. This qualifies bone remodeling as a true homeostatic function controlled by cytokines acting locally and hormones acting systemically.
Maintenance of constant bone mass is the aspect of bone remodeling we are most familiar with, because osteoporosis, the most frequent bone disorder, is a bone-remodeling disease.5 Osteoporosis results from an increase in bone resorption exceeding bone formation.6 Bone remodeling can be studied by means of biological markers in serum and urine, or bone mineral density (BMD). BMD is a strong predictor of fracture risk, but bone mineral quantity is only one component of bone strength, and various disorders, including diabetes, can be associated with poor bone quality.
The relatively recent observation of a convergence between bone and energy homeostasis suggests that energy metabolism and bone mass are regulated by the same hormones, such as leptin (Figure 1),7 adiponectin,8 neuropeptide Y,9 and substance P.10 A remarkable feature of most types of hormonal regulation is that they are controlled by feedback loops, such that the cells targeted by a hormone send signals influencing the hormone-producing cells. When applied to skeletal biology, the concept of feedback regulation suggests that bone cells exert an endocrine function.
This was recently demonstrated by the finding that the skeleton exerts an endocrine regulation of glucose homeostasis through the “secretion” of osteocalcin, one of the very few osteoblast- specific proteins, which improves glucose homeostasis by favoring β-cell proliferation and insulin secretion (Figure 2, page 366).11 Teleologically, the proliferation function of osteocalcin may have arisen during evolution to maintain the size of the pancreatic islets constant in periods of food deprivation.
_ Bone phenotypes in type 1 and type 2 diabetes
Type 1 diabetes, also called insulin-dependent diabetes mellitus, is characterized by little or no insulin production and hyperglycemia. Improved glucose monitoring, insulin delivery methods, and pharmacologic treatments are increasing patient lifespan. However, as a result, there is a parallel increase in the risk of complications due to extended exposure to diabetes. Attention has been recently focused on diabetic bone pathology, as type 1 diabetes was found to be clearly associated with bone loss and suppressed bone formation. As reported by McCabe comparing type 1 diabetic patients and healthy age-matched subjects, it is estimated that more than 50% of type 1 diabetic patients have bone loss and almost 20% of patients aged 20 to 56 meet the criteria for osteoporosis.12 Quite logically in this connection, type 1 diabetes has been shown to be a risk factor for delayed fracture healing.13 Bone loss can begin as early as at onset of diabetes in children, but there are reports of children with type 1 diabetes who do not exhibit bone loss.14,15 Bone loss occurs predominantly in the appendicular skeleton. A concern is that existing bone loss in type 1 diabetic patients could compound the fracture risk associated with conditions such as menopause and aging.
Figure 2. Regulation of energy metabolism by the skeleton.
Abbreviation: OST-PTP, osteotesticular protein tyrosine phosphatase.
Modified from reference 7: Karsenty G. Cell Metab. 2006;4:341-348. © 2006, Elsevier Ltd.
The mechanisms contributing to type 1 diabetic bone loss are unknown, but several theories have been put forward. Analysis of type 1 diabetic bone remodeling serum markers suggests that bone turnover is unaltered or decreased, while bone formation is decreased, as indicated by reduced serum levels of osteocalcin and histomorphometric studies.16,17 The potential contributors to type 1 diabetic bone phenotypes are listed in Table I.
Type 2 diabetes, also called non–insulin-dependent diabetes mellitus, develops when cells become resistant to insulin signaling, and accounts for more than 90% of diabetes cases. Diet, obesity, and reduced physical activity are several of the factors that are thought to contribute to the development of type 2 diabetes. Available data concerning an association between reduced BMD and type 2 diabetes are equivocal. Type 2 diabetes mellitus in the literature has been reported to be associated with increased,18 unchanged,19 or decreased20 BMD. However, most large-scale epidemiological studies indicate normal or above-normal BMD.21 Possible contributing factors to the higher BMD of type 2 diabetes mellitus are listed in Table II.
Table I. potential contributors of the bone phenotypes in type 1
Table II. Potential contributors of high BMD in type 2 diabetes
_ Risk of fracture in type 1 and type 2 diabetes mellitus
The most convincing evidence that osteoporosis is a complication of diabetesmellitus comes fromepidemiological studies that have shown an increased risk of fragility fractures. Diabetes and hip fracture share common risk factors (eg, physical inactivity, advanced age); in contrast, obesity, a risk factor for diabetes, is associated with a lower risk of fractures, and any apparent modification in fracture risk by diabetes is likely to reflect a confounding effect of these and other extraneous factors.
Investigations into fracture risk in type 1 diabetes have yielded inconsistent results, with increased incidence of hip fracture being reported in some studies, but not in others.22-28 A recent meta-analysis in patients with type 1 diabetes mellitus reported that this population is at six- to sevenfold higher risk of hip fracture than nondiabetic individuals.3 Cross-sectional and prospective studies have shown type 1 diabetes to confer an increased risk of fragility fracture at other sites, in both men and women.26,29,30
Even though a recentmeta-analysis involving a total of 836000 participants concluded that hip fracture risk was elevated 1.7- fold in women with type 2 diabetes mellitus,3 some studies have reported either no increase in hip fractures27,31 or risks restricted to patients with a higher duration of disease.22,32,33 The reports of increased fracture risk are somewhat unexpected because 2-dimensional areal BMD is normal or elevated in persons with type 2 diabetes,21,34 and this implies that diabetic individuals are at decreased risk of fracture. Moreover, the meta-analysis found no significant increase in vertebral or distal forearm fractures in these patients.3 At present, there is no clear explanation for this apparent contradiction. An increased risk of falling in diabetic patients35 could account for the elevated hip fracture risk in the face of normal or elevated BMD. A possible explanation for increased bone fragility in diabetes mellitus is the accumulation of advanced glycation end products within bone collagen, leading to increased stiffness of the collagen network.36 Increased blood glucose levels could also have direct deleterious effects on bone cells,37 with consequences on bone biomechanical competence.38 Moreover, adipose tissue (usually increased in type 2 diabetes mellitus) produces cytokines, namely, adipokines, such as leptin, resistin, and adiponectin, which may negatively modulate BMD.39 Figure 3 depicts the potential mechanisms contributing to fracture susceptibility in diabetes mellitus.
Effects of antidiabetic agents on bone
Oral antidiabetic drugs are commonly used to improve glycemic control, but there are concerns that some may increase the risk of cardiovascular events.40 Moreover, several epidemiological studies have investigated the effects of antihyperglycemic treatment on fracture risk in diabetes. In the largest of these, in which all individuals diagnosed with fracture in Denmark in 2000 were matched with controls, it was reported that metformin and sulfonylurea treatments were associated with reduced incidences of fracture, while insulin was associated with a nonsignificant trend toward reduced risk of hip, forearm, and spine fractures.26
Conversely, recent evidence suggests that the thiazolidinediones, first introduced for the treatment of type 2 diabetes mellitus in 1999, may affect the skeleton, with an increase in fracture risk in women randomized to rosiglitazone versus those randomized to metformin or glyburide monotherapy.41 In this study, fracture events were not increased in men and did not increase with time.41 These results were also confirmed in preliminary data from another study.42
Interestingly, pioglitazone, the other currently available thiazolidinedione, may have similar skeletal effects, with the majority of fractures occurring at nonvertebral sites, including the lower limb and distal upper limb.43
As these findings support the hypothesis of a class effect of thiazolidinediones in increasing fracture risk in women with type 2 diabetes mellitus, letters to health care providers have been issued by the manufacturers.44,45 However, doubts still exist about the clinical relevance of this phenomenon, and more studies are needed to address a number of still pending questions,21,46 such as the precise mechanism of action of these agents (Figure 4).
Figure 3. Potential mechanisms contributing to low bone mass and increased fracture susceptibility in diabetes mellitus.
Abbreviations: IGF-1, insulin-like growth factor–1; RANK, receptor activator of nuclear factor-kappaB; RANKL, receptor activator of nuclear factor-kappaB ligand; T1DM, type 1 diabetes mellitus; T2DM, type 2 diabetes mellitus.
Modified from reference 34: Hofbauer et al. J Bone Miner Res. 2007;22:1317- 1328. © 2007, American Society for Bone and Mineral Research.
Physicians should carefully check for the existence of risk factors for osteoporosis and fractures in their patients before putting them on thiazolidinedione treatment, and an adequate clinical follow-up of treated patients is strongly recommended.
Figure 4. Potential mechanisms for bone fracture
with thiazolidinediones (TZDs).
Modified from reference 21: Adami. Curr Med Res Opin. 2009;5:1057-1072. © 2009, Informa UK Ltd.
The prevalence of diabetes mellitus is increasing rapidly in the population, with the implication that adverse outcomes of the condition are likely to grow in importance as well. Considerable concern has been expressed about fracture risk in these patients. Although fractures may now be prevented thanks to the availability of effective treatments, no clear rationale exists for treating patients with type 2 diabetes with antifracture agents able to increase BMD, and our knowledge base is not strong enough for a more effectively tailored prophylaxis to be designed for this group. Additional research is needed to better define the determinants of bone strength in diabetic individuals, including the abnormal properties of bone that might respond to treatment of diabetes itself. Conversely, the differences between type 1-diabetic- and age-associated bone loss stress the importance of selecting condition-specific individualized treatments for osteoporosis. Because in type 1 diabetes the bone defect results predominantly from a decrease in bone formation, anabolic therapies appear likely to be the most effective treatment.
Future studies should contribute to a more thorough understanding of the mechanisms of diabetic bone loss, enabling the development of newer and more effective drugs. Optimizing therapies that prevent bone loss or restore bone density will allow diabetic patients to live longer, with strong healthy bones. _
1. World Health Organization. Diabetes. 2008. www.who.int/mediacentre/fact sheets/fs312/ en/index.htlm.
2. Morrison LB, Bogan IK. Bone development in diabetic children: a roentgen study. Am J Med Sci. 1927;174:313-318.
3. Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. Am J Epidemiol. 2007;166: 495-505.
4. Rodan GA, Martin TJ. Therapeutic approaches to bone diseases. Science. 2000;289:1508-1514.
5. Cooper C, Melton LJI. Magnitude and impact of osteoporosis and fractures. In: Marcus R, Feldman D, Kelsey J, eds. Osteoporosis. san Diego, Calif: Academic Press; 2001:419-434.
6. Raisz LG. Clinical practice. Screening for osteoporosis. N Engl J Med. 2005; 353:164-171.
7. Karsenty G. Convergence between bone and energy homeostases: leptin regulation of bone mass. Cell Metab. 2006;4:341-348.
8. Kanazawa I, Yamaguchi T, Yano S, Yamauchi M, Yamamoto M, Sugimoto T. Adiponectin and AMP kinase activator stimulate proliferation, differentiation and mineralization of osteoblastic MC3T3-E1 cells. BMC Cell Biol. 2007;8:51-62.
9. Allison SJ, Baldock PA, Enriquez RF, et al. Critical interplay between neuropeptide Y and sex steroid pathways in bone and adipose tissue homeostasis. J Bone Miner Res. 2009;24:294-304.
10. Wang L, Zhao R, Shi X, et al. Substance P stimulates bone marrow stromal cell osteogenic activity, osteoclast differentiation, and resorption activity in vitro. Bone. 2009;45:309-320.
11. Lieben L, Callewaert F, Bouillon R. Bone and metabolism: a complex crosstalk. Horm Res. 2009;71(suppl 1):134-138.
12. McCabe LR. Understanding the pathology and mechanisms of type 1 diabetic bone loss. J Cell Biochem. 2007;102:1343-1357.
13. White CB, Turner NS, Lee GC, Haidukewych GJ. Open ankle fractures in patients with diabetes mellitus. Clin Orthop. 2003;414:37-44.
14. Bechtold S, Dirlenbach I, Raile K, Noelle V, Bonfig W, Schwarz HP. Early manifestation of type 1 diabetes in children is a risk factor for changed bone geometry. Data using peripheral quantitative computed tomography. Pediatrics. 2006; 118:e627-e634.
15. Valerio G, Del Puente A, Esposito-Del Puente A, Buono P, Mozzillo E, Francese A. The lumbar bone mineral density is affected by long-term poor metabolic control in adolescents with type 1 diabetes mellitus. Horm Res. 2002;58: 266-272.
16. Lu H, Kraut D, Gerstenfeld LC, Graves DT. Diabetes interferes with the bone formation by affecting the expression of transcription factors that regulate osteoblast differentiation. Endocrinology. 2003;144:346-352.
17. Thrailkill KM, Liu L, Wahl EC, Bunn RC, et al. Bone formation is impaired in a model of type 1 diabetes. Diabetes. 2005;54:2875-2881.
18. van Daele PL, Stork RP, Burger H, etal. Bone density in non-insulin-dependent diabetes mellitus. The Rotterdam Study. Ann Intern Med. 1995;122:409-414.
19. Wakasugi M, Wakao R, Tawata M, Gan N, Koizumi K, Onaya T. Bone mineral density measured by dual energy x-ray absorptiometry in patients with non-insulin- dependent diabetes mellitus. Bone. 1993;14:29-33.
20. Ishida H, Seino Y, Matsukura S, et al. Diabetic osteopenia and circulating levels of vitamin D metabolism in Type 2 (noninsulin-dependent) diabetes. Metabolism. 1985;34:797-801.
21. Adami S. Bone health in diabetes: considerations for clinical management. Curr Med Res Opin. 2009;5:1057-1072.
22. Forsen L, Meyer HE, Midthjell K, Edna TH. Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia. 1999;42:920-925.
23. Janghorbani M, Hu FB, Willett WC, Li TY, Manson JE, Logroscino G, Rexrode KM. Prospective study of type 1 and 2 diabetes and risk of stroke subtypes: The Nurse’s Health Study. Diabetes Care. 2007;30:1730.1735.
24. Miao J, Brismar K, Nyren O, Ugarph-Morawski A, Ye W. Elevated hip fracture risk in type 1 diabetic patients: a population-based cohort study in Sweden. Diabetes Care. 2005;28:2850-2855.
25. Nicodemus KK, Folsom AR. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care. 2001;24:1192-1197.
26. Vestergaard P, Rejnmark L. Mosekilde L. Relative fracture risk in patients with diabetes mellitus, and the impact of insulin and oral antidiabetic medication on relative fracture risk. Diabetologia. 2005;48:1292-1299.
27. Heath III H, Melton III LJ, Chu Cp. Diabetes mellitus and risk of skeletal fracture. 1980;303:567-570.
28. Melchior TM, Sorensen H, Torp-Pedersen C. Hip and distal arm fracture rates in peri- and post-menopausal insulin-treated diabetic females. J Intern Med. 1994;236:203-208.
29. Ahmed LA; Joakimsen RM, Berntsen GK, Fønnebø V, Joakimsen RM. Diabetes mellitus and the risk of non-vertebral fractures: the Tromsø study. Osteoporos Int. 2006;17:495-500.
30. Kelòsey JL, Browner WS, Seeley DG, Nevitt MC, Cummings SR. Risk factors for fractures of the distal forearm and proximal humerus. The Study of Osteoporotic Fractures Research Group. Am J Epidemiol. 1992;135:477-489.
31. Ivers RQ, Cumming RG, Mitchell P, Peduto AJ; Blue Mountains Eye Study Group. Diabetes and risk of fracture: the Blue Mountains Eye Study. Diabetes. 2001;24:1198-1203.
32. Leslie WD, Lix LM, Prior HJ, Derksen S, Metge C, O’Neil J. Biphasic fracture risk in diabetes: a population-based study. Bone. 2007;40:1595-1601.
33. de Liefde I, van der Klift M, de Laet CE, van Daele PL, Hofman A, Pols HA. Bone mineral density and fracture risk in type 2-diabetesmellitus: the Rotterdam Study. Osteoporos Int. 2005;16:1713-1720.
34. Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. J Bone Miner Res. 2007;22:1317-1328.
35. Schwartz AV, Sellmeyer DE. Women, type 2 diabetes and fracture risk. Curr Diab Rep. 2004;4:364-369.
36. Paul RG, Bailey AJ. Glycation of collagen: the basis of its central role in the late complications of ageing and diabetes. Int J Biochem Cell Biol. 1996;28:1297- 1310.
37. Gopalakrishnan V, VigneshbRC, Arunakaran J, Aruldhas MM, Srinivasan N. Effects of glucose and its modulation by insulin and estradiol on BMSC differentiation into osteoblastic lineages. Biochem Cell Biol. 2006;84:93-101.
38. Saito M, Fujii K, Soshi S, Tanaka T. Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation-induced pentosidine in the femoral neck cortex in cases of femoral neck frature. Osteoporos Int. 2006;17:986-995.
39. Kanazawa I, Yamaguchi T, Yamamoto M, Yamauchi M, Yano S, Sugimoto T. Relationships between serum adiponectin levels versus bone mineral density, bone metabolic markers, and vertebral fractures in type 2 diabetes mellitus. Eur J Endocrinol. 2009;160:265-273.
40. Tzoulaki I, Molokhia M, Curcin V, et al. Risk of cardiovascular disease and all cause mortality among patients with type 2 diabetes prescribed oral antidiabetes drugs: retrospective cohort study using UK general practice research database. BMJ. 2009;339:b4731-b4739.
41. Kahn SE, Haffner S, Heise MA; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006;355:2427- 2443.
42. Home PD, Jones NP, Pocock SJ; RECORD Study Group. Rosiglitazone RECORD study: glucose control outcomes at 18 months. Diabet Med. 2007;24:626-634.
43. Dormandy JA, Charbonnel B, Eckland D; PROactive investigators. Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective PioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial. Lancet. 2005;366:1279-1289.
44. Takeda. Dear Healthcare Provider Letter. Observation of an increased incidence of fractures in female patients who received long-term treatments with Actos (pioglitazone HCl) tablets for type 2 diabetes mellitus. Available from http: //www.fda.gov/medwatch/safety/2007/Actosma0807.pdf.
45. GlaxoSmithKline. Dear Healthcare Provider Letter, re: clinical trial observation of an increased risk of fractures in female patients who received long-termtreatment with Avandia (rosiglitazone maleate) tablets for type 2 diabetes mellitus. Available from http://www.fda.gov/MedWaatch/safety/2007/Avandia_GSK_Ltr.pdf.
46. Falchetti A, Masi L, Brandi ML. Thiazolidinediones and bone. Clin Cases Miner Bone Metab. 2007;4:103-107.
Keywords: osteoporosis; fracture risk; bone mineral density; diabetes; postmenopause; parathyroid hormone; leptin; thiazolidinedione