Review Open Access
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Diabetes. Mar 15, 2011; 2(3): 41-48
Published online Mar 15, 2011. doi: 10.4239/wjd.v2.i3.41
Osteoporosis in diabetes mellitus: Possible cellular and molecular mechanisms
Kannikar Wongdee, Narattaphol Charoenphandhu, Consortium for Calcium and Bone Research (COCAB), Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Kannikar Wongdee, Faculty of Allied Health Sciences, Burapha University, Chonburi 20131, Thailand
Narattaphol Charoenphandhu, Department of Physiology, Faculty of Science, Mahidol University, Bangkok 10400, Thailand
Author contributions: Wongdee K and Charoenphandhu N contributed equally to the literature review, data analysis and preparation of the manuscript.
Correspondence to: Narattaphol Charoenphandhu, MD, PhD, Associate Professor, Department of Physiology, Faculty of Science, Mahidol University, Rama VI Road, Bangkok 10400,Thailand.
Telephone: +66-2-3547154  Fax: +66-2-3547154
Received: October 12, 2010
Revised: December 13, 2010
Accepted: December 20, 2010
Published online: March 15, 2011


Osteoporosis, a global age-related health problem in both male and female elderly, insidiously deteriorates the microstructure of bone, particularly at trabecular sites, such as vertebrae, ribs and hips, culminating in fragility fractures, pain and disability. Although osteoporosis is normally associated with senescence and estrogen deficiency, diabetes mellitus (DM), especially type 1 DM, also contributes to and/or aggravates bone loss in osteoporotic patients. This topic highlight article focuses on DM-induced osteoporosis and DM/osteoporosis comorbidity, covering alterations in bone metabolism as well as factors regulating bone growth under diabetic conditions including, insulin, insulin-like growth factor-1 and angiogenesis. Cellular and molecular mechanisms of DM-related bone loss are also discussed. This information provides a foundation for the better understanding of diabetic complications and for development of early screening and prevention of osteoporosis in diabetic patients.

Key Words: Bone remodeling, Bone strength, Diabetes, Fragility fracture, Insulin, Osteoblast, Osteoclast, Osteopenia, Osteoporosis, Pregnancy


Being a primary structural framework of the body, bone undergoes dynamic microstructural remodeling throughout life to accommodate mechanical stress and calcium demand[1]. Bone remodeling is a coupled process of bone resorption and formation, and requires coordination of all three types of bone cells, namely osteocytes, osteoblasts and osteoclasts[1,2]. Under mechanical stress, osteocytes act as mechanosensors to detect changes in the flow of bone fluid within bone canaliculi, and respond by transmitting signals to the osteoblasts via their syncytial processes. Osteoblasts later stimulate osteoclast differentiation and subsequent bone resorption. Normally, osteoblast-mediated bone formation takes place at the same site to fill up the resorption pit with new bone[1,2].

Osteoclastic bone resorption occurs in areas of structurally weak bone caused by mechanical stress or disuse. At the cellular and molecular level, osteoclast-mediated bone resorption commences by osteoblasts initiating proliferation of osteoclast precursors and their differentiation into mature osteoclasts by secreting a cytokine called macrophage colony stimulating factor (MCSF)[2,3]. Osteoblasts also secrete the key mediator for osteoclastogenesis, receptor activator of nuclear factor-κB (RANK) ligand (RANKL), which binds to its receptor (RANK) on the plasma membrane of osteoclast precursors, thereby stimulating differentiation of pre-osteoclasts into mature osteoclasts. RANKL and MCSF are differentially upregulated by various osteoclastogenic factors, such as parathyroid hormone (PTH), PTH-related peptide and prolactin[2,4,5]. Moreover, to counterbalance RANKL action, osteoblasts synthesize and secrete osteoprotegerin (OPG), a soluble decoy receptor capable of inhibiting RANK-RANKL interaction and osteoclastogenesis[2,6]. In the presence of activated osteoclasts, bone resorption begins with dissolution of inorganic and organic components by hydrochloric acid, cathepsin K and lysosomal protease from osteoclasts[2,7].

Following bone resorption, osteoblast-mediated bone formation takes place to fill the resorption pits with newly mineralized bone. The type I collagen fibrils secreted by osteoblasts are arranged into the organic matrix osteoid, which is subsequently mineralized by calcium and phosphate in the presence of alkaline phosphatase, osteocalcin and osteopontin. Eventually, hydroxide ions are gradually added and mature hydroxyapatite crystals [Ca10(PO4)6(OH)2] are formed[1]. Humoral factors, such as insulin-like growth factor (IGF)-1, insulin, bone morphogenetic proteins and OPG, serve as anabolic signals to promote bone formation[5,8-10]. Among these anabolic mediators, liver-derived IGF-1 is of particular interest since profound growth retardation, small bone size, low bone mineral density (BMD) and osteoporosis were reported in IGF-1 and IGF-1 receptor deficiencies[5,10,11]. Furthermore, insulin was found to directly induce osteogenic action by increasing cell proliferation, differentiation, alkaline phosphatase activity and expression of type I collagen and osteocalcin in human osteoblast-like MG-63 cells[12]. Matrix mineralization was also found to be enhanced by IGF-1 and insulin[11,12].


Osteoporosis is a global health care problem characterized by a reduction in BMD with increased porosity and susceptibility to fractures[13]. It can be caused by acceleration of bone resorption and/or deceleration of bone formation. Clinically, osteoporosis most often results from a combination of postmenopausal estrogen deficiency and age-related bone loss[2,14]. Irreversible bone loss can result from an imbalance between osteoclast and osteoblast activities, i.e. enhanced bone resorption and/or suppressed bone formation, resulting in an uncoupling event that can prolong duration of the bone remodeling cycle[5,13]. Other risk factors for osteoporosis are abnormally high plasma PTH levels, advancing age, genetic background, cigarette smoking, alcohol consumption, physical inactivity and the chronic use of some medications, such as corticosteroids. Low physical activity as found in the sedentary lifestyle of elderly, paralyzed or immobilized patients is also associated with accelerated bone loss[13,15-17]. Furthermore, other medical conditions, particularly hyperparathyroidism and diabetes mellitus (DM) are also risk factors for osteoporotic bone loss[13,16,17].

Regardless of the etiology, osteoporosis is initiated by the uncoupling of bone resorption and bone formation[5,13,17]. At the molecular level, enhanced bone resorption and osteoporosis generally result, in part, from the overproduction of RANKL and other cytokines/mediators regulating osteoclast differentiation and function. These include cyclooxygenase (Cox)-2, prostaglandin (PG) E2, tumor necrosis factor (TNF)-α, interleukin (IL)-1, IL-6 or IL-11[5,18,19], all of which lead to recruitment and differentiation of pre-osteoclasts[5,18,19]. Thus, the greater the increase in the levels of these osteoclastogenic cytokines, the faster the progression of bone loss.


DM is a group of pandemic debilitating metabolic diseases featuring chronic hyperglycemia which results from defective insulin secretion and/or insulin actions[20]. Such chronic hyperglycemia typically elicits dysfunction and failure of various organs, particularly the eyes (diabetic retinopathy and cataract), kidneys (diabetic nephropathy), nerves (diabetic neuropathy), heart (diabetic cardiomyopathy) and blood vessels (microangiopathy)[20]. In addition, DM has been found to be associated with metabolic bone diseases, osteoporosis and low-impact fractures, as well as other bone-related events including falls in geriatric patients[15,21]. Indeed, DM not only aggravates osteopenia (T-scores between -1 and -2.5, as determined by dual energy X-ray absorptiometry; DXA) and osteoporosis (T-scores ≤ -2.5), but is also one of the “causes” of both conditions. Nevertheless, bone deteriorations differ markedly between type 1 and type 2 DM and possibly stem from different cellular and molecular mechanisms[22-27].

Type 1 DM, also known as insulin-dependent DM, results from insulin insufficiency which leads to hyperglycemia in the young[20]. Besides the usual neurovascular complications, both male and female patients with type 1 DM manifest low bone mass at the hip, femoral neck and spine (Table 1), which may eventually lead to an increased incidence of bone fractures[22-25,28,29]. In contrast, data on skeletal abnormalities in type 2 DM, or non-insulin-dependent DM, appear conflicting, and the exact explanation of this is still unknown[26,27,30]. For example, by using DXA Yamaguchi and colleagues demonstrated that, of 187 males with type 2 DM, there was an increase in BMD at the femoral neck with low prevalence of vertebral fracture in diabetic men with metabolic syndromes[26]. Similarly, Petit and colleagues reported a higher BMD in elderly patients with type 2 DM when compared to age-matched non-DM volunteers[27]. In contrast, several other investigators reported a negative effect of type 2 DM on BMD. For instance, Yaturu and colleagues found a significantly low BMD of hip in type 2 DM patients when compared to age-matched normal subjects[30]. Moreover, an increased fracture risk at several sites, including spine and hip has been reported[31]. However, these fractures and falls could have resulted from visual impairment (from diabetic retinopathy and cataract), gait imbalance (from peripheral neuropathy) and overweight, all of which are common clinical features in type 2 DM. Peripheral neuropathy in type 2 DM may also lead to local destruction of bones around the weight-bearing joints (especially in the ankle and foot), known as Charcot osteoarthropathy, which can cause pain, fracture and joint deformity[21].

Table 1 Bone changes in patients with type 1 diabetes mellitus.
ReferencesSample sizeAgeGender (F/M)Major findings
Hamilton et al, 200910220-7152/50Adult males with type 1 DM had lower BMD at hip, femoral neck and spine compared with age-matched controls (P ≤ 0.048). No significant difference in BMD between female type 1 DM vs age-matched controls.
Mastrandrea et al, 2008632-3763/0Type 1 DM women ≥ 20 years of age had a reduction in BMD at hip, femoral neck and whole body.
No significant difference in BMD between type 1 DM women < 20 years of age vs age-matched controls.
Soto et al, 20104515-3945/0Adolescent and adult women with type 1 DM had lower BMD at spine, femoral neck and whole body. No correlation between decreased BMD and sex steroid hormones.
Saha et al, 20094812-1826/22Adolescent men and women with type 1 DM had lower BMC at the proximal femur.
Men with type 1 DM had lower cortical bone mass and cross-sectional size than age-matched women with type 1 DM.
Lumachi et al, 20091836-518/10Type 1 DM patients had ~60% lower BMD compared with age-matched controls.
Heilman et al, 2009305-1911/19Type 1 DM patients had lower total BMC and lumbar BMD. Type 1 DM men had less physical activity than age-matched male controls.

Type 1 DM featuring low circulating insulin and IGF-1 levels usually occurs in young children prior to peak bone mass attainment, whereas type 2 DM is common in adults who have already attained peak bone mass[32,33]. Thus, type 1 and 2 DM induce detrimental skeletal complications of different magnitudes. Specifically, in both genders, BMD of the proximal femur appears to be significantly lower in type 1 DM than in type 2 DM[34]. This difference in severity might be because type 1 DM patients lack insulin, which is an osteogenic factor capable of stimulating osteoblast proliferation and differentiation[12]. Alternatively, different the time course of type 1 and 2 DM might contribute to their different outcomes and prognosis. A recent population-based investigation on 1964 diabetic patients in Rochester, Minnesota, revealed that the incidence of hip fractures, one of the most common osteoporotic fractures, increased only over 10 years of follow-up, and was not correlated with obesity or prolonged DM treatments[35]. However, other factors, including advanced age, previous fracture and long-term corticosteroid use, might also predispose DM patients to osteoporosis and low-impact fracture, whereas physical activity/exercise and high body mass index are protective[35].


Pregnancy and lactation increase calcium demand for fetal skeletal development and milk production, respectively, and bone serves to supply calcium during these reproductive periods[36-38]. Although maternal BMD is not decreased during pregnancy in humans and rodents[36,37], our recent histomorphometric study in rats showed that osteoclastic bone resorption was indeed enhanced at trabecular sites from mid-pregnancy to late lactation[39]. Significant bone loss with a decrease in BMD was, therefore, observed in late lactation. Maternal BMD is usually restored within 12 mo post-weaning. However, some breastfeeding mothers manifest a long-term sequela known as pregnancy/lactation-induced osteoporosis, which features back pain, height loss and/or vertebral fracture[38,40].

Bone loss is, therefore, expected to be greater in mothers with previously diagnosed DM or even with gestational DM (GDM; which affects ~4% of all pregnant women without previous history of DM[41]). A recent densitometric study in GDM women revealed a reduction in vertebral BMD when compared with non-DM pregnant women[42]. Moreover, it has been reported that greater than normal bone loss is present in ~40% of GDM women within 3 mo postpartum[15]. Nevertheless, the effects of previously diagnosed DM on maternal bone resorption and the long-term sequelae remain to be elucidated.


Although several investigators have long addressed the question of how DM induces osteopenia and osteoporosis, the exact underlying mechanism is still elusive. However, it is widely accepted that hyperglycemia is a salient factor that has direct and indirect deleterious effects on osteoblast function and bone formation (Figure 1). At the cellular level, a recent in vitro study in osteoblast-like MG63 cells demonstrated that high glucose concentrations markedly suppressed cell growth, mineralization, and expression of various osteoblast-related markers, including runt-related transcription factor-2 (Runx2), type I collagen, osteocalcin and osteonectin, while stimulating the expression of adipogenic markers, such as peroxisome proliferator-activated receptor (PPAR)-γ, adipocyte fatty acid binding protein (aP2), resistin and adipsin[43,44]. Consistent with the in vitro findings, a histomorphometric analysis in streptozotocin-induced DM mice showed increases in osteoclast numbers and expression of osteoclastogenic mediators, including TNF-α, MCSF, RANKL and vascular endothelial growth factor (VEGF)-A[45]. Moreover, there were upregulations of PPAR-γ, aP2 and resistin mRNAs, as well as increases in lipid-dense adipocytes in the bone marrow of these streptozotocin-induced DM mice, whereas adipose tissues at other sites, such as liver and peripheral areas, were decreased[44]. It is thus plausible that, in addition to direct interference with osteoblast function and bone formation, DM also induces lipid accumulation in the marrow of long bones, thereby leading to the expansion of marrow cavity and thinning of cortical envelope. The osteoblast-to-adipocyte shift might also reduce the number of differentiated osteoblasts available for bone formation.

Figure 1
Figure 1 Possible deleterious effects of diabetes mellitus on bone metabolism and bone quality. Diabetes mellitus (DM) increases osteoclast function but decreases osteoblast function, thereby leading to accelerated bone loss, osteopenia and osteoporosis. DM/hyperglycemia induces production of macrophage colony stimulating factor (MCSF), tumor necrosis factor (TNF)-α and receptor activator of nuclear factor-κB ligand (RANKL), all of which are osteoblast-derived activators of osteoclast proliferation and differentiation. Moreover, DM/hyperglycemia suppresses osteoblast proliferation and function, in part, by decreasing runt-related transcription factor (Runx)-2, osteocalcin and osteopontin expressions. Adipogenic differentiation of mesenchymal stem cells is increased as indicated by the overexpression of adipocyte differentiation markers, including peroxisome proliferator-activated receptor (PPAR)-γ, adipocyte fatty acid binding protein (aP2), adipsin and resistin. A decrease in neovascularization may further aggravate bone loss. Bone quality is also reduced as a result of advanced glycation end products (AGE) production, which may eventually result in low-impact or fragility fractures.

Other cell types, such as endothelial progenitor cells (EPCs) lining the blood vessels, are also affected by hyperglycemia. It was shown that the streptozotocin-induced DM mice exhibit a reduction in circulating bone marrow-derived EPCs when compared to non-DM control mice[46]. Such decreases in circulating EPCs could retard angiogenesis essential for the repair process at fracture sites. Moreover, as demonstrated by the three-point bending mechanical test, DM was found to be associated with a reduction in parameters, such as bone rigidity, yield moment, ultimate moment, yield stress and energy to fracture, all of which are related to bone strength or “bone quality”[47,48]. Regarding the possible mechanisms underlying impaired mechanical properties, several investigations have demonstrated an increase in advanced glycation end products (AGE) or non-enzymatic cross-links within collagen fibers, which, in turn, lead to deterioration in the structural and mechanical properties of bone, and eventually to a decrease in bone strength[47]. In vivo studies in both type 1 and type 2 DM rats have confirmed that an increase in AGE production is negatively correlated with BMD and bone strength[49,50].

In addition to hyperglycemia, dysautonomia and impaired leptin function may indirectly contribute to osteopenia and osteoporosis in DM since both the sympathetic nervous system and leptin are known to modulate bone remodeling in a complex interdependent manner (for review Reference[51]). The final outcome of sympathetic stimulation (bone loss vs bone gain) depends on the relative distribution of activated adrenergic receptor subtypes (β1, β2 or β3), expressed in osteoblasts[52]. β2-adrenergic receptor and leptin receptor knockout mice showed an increase in bone mass compared to normal mice, suggesting that β2 agonists and leptin are activators of bone resorption[53,54]. In contrast, osteoblast-like UMR106 cells exhibited the lower expression ratio of RANKL and OPG after exposure to β3-adrenergic agonist, suggesting a protective effect of β3-adrenergic receptor activation against bone resorption[52]. However, the possible direct link between the DM-induced autonomic neuropathy and impaired bone remodeling remains to be elucidated experimentally.

Several lines of evidence also suggest that DM-induced bone loss could be mediated, in part, by the humoral factors, kinins, which normally regulate blood circulation, inflammation and pain. Kinin dysfunctions could be responsible for several DM complications, such as hyperalgesia, cardiomyopathy and retinopathy[55-58]. In diabetic Akita mice with mutation in the insulin-2 gene, the lack of bradykinin receptor-1 (B1R) and receptor-2 (B2R) (i.e. B1R/B2R double knockout) induces profound diabetic complications, including massive albuminuria, glomerulosclerosis, reduction of nerve conduction velocity, and marked bone mineral loss[59]. It is thus possible that B1R/B2R and their related kinin signaling participate in the DM-induced bone loss.


Since it is evident that most detrimental effects of DM on bone emanate from hyperglycemia and its consequences (e.g. AGE production and impaired vascularization), effective glycemic control and restoration of proper intraosseous blood supply should be of paramount importance for treatment and prevention of diabetic osteoporosis. The appropriate uses of antidiabetic agents should further help promote bone formation and/or prevent bone resorption. Recombinant insulin therapy might be a promising choice for diabetic intervention with its direct osteogenic effect through its receptors on osteoblasts. An in vitro study of insulin-treated bone marrow mesenchymal stem cells (BMSC; progenitors of both osteoblasts and adipocytes) cultured in high-glucose condition showed a significant increase in the activity of alkaline phosphatase, a representative of osteoblast differentiation, when compared to the control BMSC[60]. In addition, insulin also elicited synergistic effect when combined with supplementary 17β-estradiol by increasing type I collagen production and bone mineralizing nodules in vitro[60]. Furthermore, insulin should indirectly benefit bone by reducing the negative effects of chronic hyperglycemia[61]. Besides lowering plasma glucose levels and promoting anabolic bone function, insulin also enhances production of proteoglycans, the components of the gel-like extracellular matrix of cartilage, in the articular cartilage of streptozotocin-induced DM mice, suggesting that insulin might also protect against osteoarthritis in overweighed DM patients[61].

Among the wide variety of antidiabetic drugs, some have been reported to be favourable to osteogenesis, through their direct actions on osteoblasts or BMSC, while reducing adipogenesis. For instance, a recent investigation in metformin-treated streptozotocin-induced DM rats showed positive effects of metformin on osteoblast differentiation and function, including upregulation of Runx2 and osteocalcin protein expression, as well as increases in alkaline phosphatase activity, type I collagen synthesis and bone calcium accretion[62]. Similarly, glimepiride has been shown to stimulate proliferation and differentiation of primary rat osteoblasts in vitro[63]. In addition to synthetic drugs, certain herbal preparations, such as cinnamon bark extract, have been found to increase serum insulin levels and improve insulin sensitivity in adipose tissue by increasing serum adiponectin levels as well as upregulating PPAR-α and -γ mRNA expression[64], thereby inducing both antihyperglycemic and antihyperlipidemic actions. Thus, cinnamon extract probably helps reduce fat accumulation in bone marrow and indirectly facilitates bone formation[64].

In contrast, thiazolidinediones antidiabetic drugs, such as rosiglitazone, should be used with caution especially in postmenopausal DM patients since they may contribute to bone loss and fracture. Thiazolidinediones may decrease bone formation and BMD, while increasing bone resorption, as indicated by the reduced syntheses of alkaline phosphatase, osteocalcin, and procollagen type I N-terminal propeptide[33,65]. However, further investigations are needed to better understand the effects of thiazolidinediones on bone remodeling in DM patients at the cellular and molecular level.

Alleviation of microangiopathy and restoration of microcirculation in diabetic bone may be additional benefits of insulin and antihyperglycemic drugs. Xu and co-workers (2009) demonstrated that injection of BMSC treated with pancreatic extract into streptozotocin-induced DM rats not only normalized plasma glucose and prevented apoptosis of islet cells, but also elevated production of VEGF, IGF-1 and basic fibroblast growth factor (bFGF), all of which are known to have anti-apoptotic and angiogenic effects[66]. A recent in vivo study in type 2 DM (db/db) mice with ischemic hind limbs showed that injection of epidermal growth factor (EGF)-treated BMSC into the affected hind limbs increased angiogenesis by over 90%[67]. Such angiogenesis was due to the fact that the injected BMSC differentiated into new microvessels (neovascularization), using intercellular adhesion molecule-1 and vascular cell adhesion protein-1 for adhesion and migration[67].Overall, it is possible that antidiabetic agents with angiogenic activity could be used to enhance blood flow to fracture sites, which may in turn accelerate bone healing, and might also prevent osteopenia/osteoporosis. Conversely, certain rheological drugs, such as pentoxifylline, which increase blood flow and osteoblast activity, might be promising as anti-osteoporotic agents in both DM and non-DM patients[68].

In addition to medications, alternative interventions often prescribed to DM patients, such as exercise/physical activity, may be indirectly useful since they are expected to mitigate microangiopathy in bone by increasing neovascularization and blood flow. In vivo investigation in swimming rats showed higher bone capillary vascularity compared with sedentary controls[69]. Such higher vasculogenesis following exercise has been postulated to result from an increase in circulating EPCs[70,71]. Adams and colleagues demonstrated the elevation of EPC levels after single-exercise stress in patients with coronary artery disease[70]. An increase in EPC level was accompanied by an elevation of plasma VEGF[70,71], a crucial growth factor for EPC proliferation, differentiation and migration[70,71]. Thus, certain physical activities/interventions, such as appropriate endurance exercise, should improve perfusion in bone and alleviate bone loss in DM patients. Nevertheless, in “high-risk” individuals, including DM patients with very low BMD, previous low-impact/non-traumatic fractures and/or chronic use of corticosteroids, specific treatments for osteoporosis are still necessary (for reviews regarding the treatments of osteoporosis in DM patients, please see Refrences [15,21]).


In addition to neurovascular, ocular and renal complications, osteopenia and osteoporosis are important debilitating problems in DM patients. Osteoporosis and several other DM complications (e.g. visual impairment and gait imbalance) increase the risk of falls, fragility and low-impact fractures. It is apparent that hyperglycemia in DM directly suppresses osteoblast-mediated bone formation, while conversely promoting osteoclast-mediated bone resorption, adipogenic differentiation of mesenchymal stem cells (also precursors of osteoblasts), and fat accumulation in the marrow cavity, all of which deteriorate bone quality and strength and increase susceptibility to fracture. Therefore, an effective glycemic control should be the hallmark of prevention and treatment of DM-induced osteoporosis. Lowering of plasma glucose by appropriate antidiabetic drugs, recombinant insulin, herbal medications and/or lifestyle interventions (e.g. exercise) should help promote osteoblast function, angiogenesis (neovascularization) and bone perfusion, and help reduce fat accumulation in the marrow cavity, all of which eventually lead to better bone health for the DM patients.


Peer reviewers: Kevin CJ Yuen, MBChB, MRCP, CCST, MD, Department of Endocrinology, Oregon Health and Science University, 3181 SW Sam Jackson Park Road, Mailcode L607, Portland, OR 97239, United States; Nikolaos Papanas, MD, Assistant Professor in Internal Medicine, Democritus University of Thrace, G. Kondyli 22, Alexandroupolis 68100, Greece

S- Editor Zhang HN L- Editor Hughes D E- Editor Liu N

1.  Sims NA, Gooi JH. Bone remodeling: Multiple cellular interactions required for coupling of bone formation and resorption. Semin Cell Dev Biol. 2008;19:444-451.  [PubMed]  [DOI]  [Cited in This Article: ]
2.  Teitelbaum SL. Bone resorption by osteoclasts. Science. 2000;289:1504-1508.  [PubMed]  [DOI]  [Cited in This Article: ]
3.  Matsuo K, Irie N. Osteoclast-osteoblast communication. Arch Biochem Biophys. 2008;473:201-209.  [PubMed]  [DOI]  [Cited in This Article: ]
4.  Seriwatanachai D, Thongchote K, Charoenphandhu N, Pandaranandaka J, Tudpor K, Teerapornpuntakit J, Suthiphongchai T, Krishnamra N. Prolactin directly enhances bone turnover by raising osteoblast-expressed receptor activator of nuclear factor κB ligand/osteoprotegerin ratio. Bone. 2008;42:535-546.  [PubMed]  [DOI]  [Cited in This Article: ]
5.  Zaidi M. Skeletal remodeling in health and disease. Nat Med. 2007;13:791-801.  [PubMed]  [DOI]  [Cited in This Article: ]
6.  Asagiri M, Takayanagi H. The molecular understanding of osteoclast differentiation. Bone. 2007;40:251-264.  [PubMed]  [DOI]  [Cited in This Article: ]
7.  Supanchart C, Kornak U. Ion channels and transporters in osteoclasts. Arch Biochem Biophys. 2008;473:161-165.  [PubMed]  [DOI]  [Cited in This Article: ]
8.  Dobnig H, Turner RT. Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells. Endocrinology. 1995;136:3632-3638.  [PubMed]  [DOI]  [Cited in This Article: ]
9.  Jilka RL. Molecular and cellular mechanisms of the anabolic effect of intermittent PTH. Bone. 2007;40:1434-1446.  [PubMed]  [DOI]  [Cited in This Article: ]
10.  Mohan S, Baylink DJ. Impaired skeletal growth in mice with haploinsufficiency of IGF-I: genetic evidence that differences in IGF-I expression could contribute to peak bone mineral density differences. J Endocrinol. 2005;185:415-420.  [PubMed]  [DOI]  [Cited in This Article: ]
11.  Zhang M, Xuan S, Bouxsein ML, von Stechow D, Akeno N, Faugere MC, Malluche H, Zhao G, Rosen CJ, Efstratiadis A. Osteoblast-specific knockout of the insulin-like growth factor (IGF) receptor gene reveals an essential role of IGF signaling in bone matrix mineralization. J Biol Chem. 2002;277:44005-44012.  [PubMed]  [DOI]  [Cited in This Article: ]
12.  Yang J, Zhang X, Wang W, Liu J. Insulin stimulates osteoblast proliferation and differentiation through ERK and PI3K in MG-63 cells. Cell Biochem Funct. 2010;28:334-341.  [PubMed]  [DOI]  [Cited in This Article: ]
13.  Inzerillo AM, Epstein S. Osteoporosis and diabetes mellitus. Rev Endocr Metab Disord. 2004;5:261-268.  [PubMed]  [DOI]  [Cited in This Article: ]
14.  Pogoda P, Priemel M, Rueger JM, Amling M. Bone remodeling: new aspects of a key process that controls skeletal maintenance and repair. Osteoporos Int. 2005;16 Suppl 2:S18-S24.  [PubMed]  [DOI]  [Cited in This Article: ]
15.  Chau DL, Edelman SV. Osteoporosis and diabetes. Clin Diabetes. 2002;20:153-157.  [PubMed]  [DOI]  [Cited in This Article: ]
16.  Schousboe JT, Taylor BC, Ensrud KE. Assessing fracture risk: who should be screened? 6ed: American Society for Bone and Mineral Research 2006; 262-267.  [PubMed]  [DOI]  [Cited in This Article: ]
17.  Merlotti D, Gennari L, Dotta F, Lauro D, Nuti R. Mechanisms of impaired bone strength in type 1 and 2 diabetes. Nutr Metab Cardiovasc Dis. 2010;20:683-690.  [PubMed]  [DOI]  [Cited in This Article: ]
18.  Han SY, Lee NK, Kim KH, Jang IW, Yim M, Kim JH, Lee WJ, Lee SY. Transcriptional induction of cyclooxygenase-2 in osteoclast precursors is involved in RANKL-induced osteoclastogenesis. Blood. 2005;106:1240-1245.  [PubMed]  [DOI]  [Cited in This Article: ]
19.  Ragab AA, Nalepka JL, Bi Y, Greenfield EM. Cytokines synergistically induce osteoclast differentiation: support by immortalized or normal calvarial cells. Am J Physiol Cell Physiol. 2002;283:C679-C687.  [PubMed]  [DOI]  [Cited in This Article: ]
20.  American diabetes association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2009;32 Suppl 1:S62-S67.  [PubMed]  [DOI]  [Cited in This Article: ]
21.  Brown SA, Sharpless JL. Osteoporosis: an under-appreciated complication of diabetes. Clin Diabetes. 2004;22:10-20.  [PubMed]  [DOI]  [Cited in This Article: ]
22.  Hamilton EJ, Rakic V, Davis WA, Chubb SA, Kamber N, Prince RL, Davis TM. Prevalence and predictors of osteopenia and osteoporosis in adults with type 1 diabetes. Diabet Med. 2009;26:45-52.  [PubMed]  [DOI]  [Cited in This Article: ]
23.  Mastrandrea LD, Wactawski-Wende J, Donahue RP, Hovey KM, Clark A, Quattrin T. Young women with type 1 diabetes have lower bone mineral density that persists over time. Diabetes Care. 2008;31:1729-1735.  [PubMed]  [DOI]  [Cited in This Article: ]
24.  Saha MT, Sievänen H, Salo MK, Tulokas S, Saha HH. Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers. Osteoporos Int. 2009;20:1401-1406.  [PubMed]  [DOI]  [Cited in This Article: ]
25.  Lumachi F, Camozzi V, Tombolan V, Luisetto G. Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus. Ann N Y Acad Sci. 2009;1173 Suppl 1:E64-E67.  [PubMed]  [DOI]  [Cited in This Article: ]
26.  Yamaguchi T, Kanazawa I, Yamamoto M, Kurioka S, Yamauchi M, Yano S, Sugimoto T. Associations between components of the metabolic syndrome versus bone mineral density and vertebral fractures in patients with type 2 diabetes. Bone. 2009;45:174-179.  [PubMed]  [DOI]  [Cited in This Article: ]
27.  Petit MA, Paudel ML, Taylor BC, Hughes JM, Strotmeyer ES, Schwartz AV, Cauley JA, Zmuda JM, Hoffman AR, Ensrud KE. Bone mass and strength in older men with type 2 diabetes: the Osteoporotic Fractures in Men Study. J Bone Miner Res. 2010;25:285-291.  [PubMed]  [DOI]  [Cited in This Article: ]
28.  Soto N, Pruzzo R, Eyzaguirre F, Iñiguez G, López P, Mohr J, Pérez-Bravo F, Cassorla F, Codner E. Bone mass and sex steroids in postmenarcheal adolescents and adult women with type 1 diabetes mellitus. J Diabetes Complications. 2011;25:19-24.  [PubMed]  [DOI]  [Cited in This Article: ]
29.  Heilman K, Zilmer M, Zilmer K, Tillmann V. Lower bone mineral density in children with type 1 diabetes is associated with poor glycemic control and higher serum ICAM-1 and urinary isoprostane levels. J Bone Miner Metab. 2009;27:598-604.  [PubMed]  [DOI]  [Cited in This Article: ]
30.  Yaturu S, Humphrey S, Landry C, Jain SK. Decreased bone mineral density in men with metabolic syndrome alone and with type 2 diabetes. Med Sci Monit. 2009;15:CR5-CR9.  [PubMed]  [DOI]  [Cited in This Article: ]
31.  Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes-a meta-analysis. Osteoporos Int. 2007;18:427-444.  [PubMed]  [DOI]  [Cited in This Article: ]
32.  Zofková I. Pathophysiological and clinical importance of insulin-like growth factor-I with respect to bone metabolism. Physiol Res. 2003;52:657-679.  [PubMed]  [DOI]  [Cited in This Article: ]
33.  Adami S. Bone health in diabetes: considerations for clinical management. Curr Med Res Opin. 2009;25:1057-1072.  [PubMed]  [DOI]  [Cited in This Article: ]
34.  Tuominen JT, Impivaara O, Puukka P, Rönnemaa T. Bone mineral density in patients with type 1 and type 2 diabetes. Diabetes Care. 1999;22:1196-1200.  [PubMed]  [DOI]  [Cited in This Article: ]
35.  Melton LJ 3rd, Leibson CL, Achenbach SJ, Therneau TM, Khosla S. Fracture risk in type 2 diabetes: update of a population-based study. J Bone Miner Res. 2008;23:1334-1342.  [PubMed]  [DOI]  [Cited in This Article: ]
36.  Bowman BM, Miller SC. Skeletal adaptations during mammalian reproduction. J Musculoskelet Neuronal Interact. 2001;1:347-355.  [PubMed]  [DOI]  [Cited in This Article: ]
37.  Charoenphandhu N, Wongdee K, Krishnamra N. Is prolactin the cardinal calciotropic maternal hormone? Trends Endocrinol Metab. 2010;21:395-401.  [PubMed]  [DOI]  [Cited in This Article: ]
38.  Kovacs CS. Calcium and bone metabolism during pregnancy and lactation. J Mammary Gland Biol Neoplasia. 2005;10:105-118.  [PubMed]  [DOI]  [Cited in This Article: ]
39.  Suntornsaratoon P, Wongdee K, Goswami S, Krishnamra N, Charoenphandhu N. Bone modeling in bromocriptine-treated pregnant and lactating rats: possible osteoregulatory role of prolactin in lactation. Am J Physiol Endocrinol Metab. 2010;299:E426-E436.  [PubMed]  [DOI]  [Cited in This Article: ]
40.  Ofluoglu O, Ofluoglu D. A case report: pregnancy-induced severe osteoporosis with eight vertebral fractures. Rheumatol Int. 2008;29:197-201.  [PubMed]  [DOI]  [Cited in This Article: ]
41.  American Diabetes Association What is gestational diabetes?. 6ed: American Society for Bone and Mineral Research 2010; [cited 2010 October, 11]; Available from:  [PubMed]  [DOI]  [Cited in This Article: ]
42.  To WW, Wong MW. Bone mineral density changes in gestational diabetic pregnancies-a longitudinal study using quantitative ultrasound measurements of the os calcis. Gynecol Endocrinol. 2008;24:519-525.  [PubMed]  [DOI]  [Cited in This Article: ]
43.  Wang W, Zhang X, Zheng J, Yang J. High glucose stimulates adipogenic and inhibits osteogenic differentiation in MG-63 cells through cAMP/protein kinase A/extracellular signal-regulated kinase pathway. Mol Cell Biochem. 2010;338:115-122.  [PubMed]  [DOI]  [Cited in This Article: ]
44.  Botolin S, Faugere MC, Malluche H, Orth M, Meyer R, McCabe LR. Increased bone adiposity and peroxisomal proliferator-activated receptor-γ2 expression in type I diabetic mice. Endocrinology. 2005;146:3622-3631.  [PubMed]  [DOI]  [Cited in This Article: ]
45.  Kayal RA, Tsatsas D, Bauer MA, Allen B, Al-Sebaei MO, Kakar S, Leone CW, Morgan EF, Gerstenfeld LC, Einhorn TA. Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res. 2007;22:560-568.  [PubMed]  [DOI]  [Cited in This Article: ]
46.  Kang L, Chen Q, Wang L, Gao L, Meng K, Chen J, Ferro A, Xu B. Decreased mobilization of endothelial progenitor cells contributes to impaired neovascularization in diabetes. Clin Exp Pharmacol Physiol. 2009;36:e47-e56.  [PubMed]  [DOI]  [Cited in This Article: ]
47.  Saito M, Marumo K. Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int. 2010;21:195-214.  [PubMed]  [DOI]  [Cited in This Article: ]
48.  Silva MJ, Brodt MD, Lynch MA, McKenzie JA, Tanouye KM, Nyman JS, Wang X. Type 1 diabetes in young rats leads to progressive trabecular bone loss, cessation of cortical bone growth, and diminished whole bone strength and fatigue life. J Bone Miner Res. 2009;24:1618-1627.  [PubMed]  [DOI]  [Cited in This Article: ]
49.  Tomasek JJ, Meyers SW, Basinger JB, Green DT, Shew RL. Diabetic and age-related enhancement of collagen-linked fluorescence in cortical bones of rats. Life Sci. 1994;55:855-861.  [PubMed]  [DOI]  [Cited in This Article: ]
50.  Saito M, Fujii K, Mori Y, Marumo K. Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int. 2006;17:1514-1523.  [PubMed]  [DOI]  [Cited in This Article: ]
51.  Elefteriou F. Regulation of bone remodeling by the central and peripheral nervous system. Arch Biochem Biophys. 2008;473:231-236.  [PubMed]  [DOI]  [Cited in This Article: ]
52.  Nuntapornsak A, Wongdee K, Thongbunchoo J, Krishnamra N, Charoenphandhu N. Changes in the mRNA expression of osteoblast-related genes in response to β3-adrenergic agonist in UMR106 cells. Cell Biochem Funct. 2010;28:45-51.  [PubMed]  [DOI]  [Cited in This Article: ]
53.  Elefteriou F, Ahn JD, Takeda S, Starbuck M, Yang X, Liu X, Kondo H, Richards WG, Bannon TW, Noda M. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434:514-520.  [PubMed]  [DOI]  [Cited in This Article: ]
54.  Shi Y, Yadav VK, Suda N, Liu XS, Guo XE, Myers MG Jr, Karsenty G. Dissociation of the neuronal regulation of bone mass and energy metabolism by leptin in vivo. Proc Natl Acad Sci USA. 2008;105:20529-20533.  [PubMed]  [DOI]  [Cited in This Article: ]
55.  Phipps JA, Feener EP. The kallikrein-kinin system in diabetic retinopathy: lessons for the kidney. Kidney Int. 2008;73:1114-1119.  [PubMed]  [DOI]  [Cited in This Article: ]
56.  Westermann D, Walther T, Savvatis K, Escher F, Sobirey M, Riad A, Bader M, Schultheiss HP, Tschöpe C. Gene deletion of the kinin receptor B1 attenuates cardiac inflammation and fibrosis during the development of experimental diabetic cardiomyopathy. Diabetes. 2009;58:1373-1381.  [PubMed]  [DOI]  [Cited in This Article: ]
57.  Gabra BH, Sirois P. Role of bradykinin B(1) receptors in diabetes-induced hyperalgesia in streptozotocin-treated mice. Eur J Pharmacol. 2002;457:115-124.  [PubMed]  [DOI]  [Cited in This Article: ]
58.  Marceau F, Regoli D. Bradykinin receptor ligands: therapeutic perspectives. Nat Rev Drug Discov. 2004;3:845-852.  [PubMed]  [DOI]  [Cited in This Article: ]
59.  Kakoki M, Sullivan KA, Backus C, Hayes JM, Oh SS, Hua K, Gasim AM, Tomita H, Grant R, Nossov SB. Lack of both bradykinin B1 and B2 receptors enhances nephropathy, neuropathy, and bone mineral loss in Akita diabetic mice. Proc Natl Acad Sci USA. 2010;107:10190-10195.  [PubMed]  [DOI]  [Cited in This Article: ]
60.  Gopalakrishnan V, Vignesh RC, 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.  [PubMed]  [DOI]  [Cited in This Article: ]
61.  Cai L, Okumu FW, Cleland JL, Beresini M, Hogue D, Lin Z, Filvaroff EH. A slow release formulation of insulin as a treatment for osteoarthritis. Osteoarthritis Cartilage. 2002;10:692-706.  [PubMed]  [DOI]  [Cited in This Article: ]
62.  Molinuevo MS, Schurman L, McCarthy AD, Cortizo AM, Tolosa MJ, Gangoiti MV, Arnol V, Sedlinsky C. Effect of metformin on bone marrow progenitor cell differentiation: in vivo and in vitro studies. J Bone Miner Res. 2010;25:211-221.  [PubMed]  [DOI]  [Cited in This Article: ]
63.  Ma P, Gu B, Ma J, E L, Wu X, Cao J, Liu H. Glimepiride induces proliferation and differentiation of rat osteoblasts via the PI3-kinase/Akt pathway. Metabolism. 2010;59:359-366.  [PubMed]  [DOI]  [Cited in This Article: ]
64.  Kim SH, Choung SY. Antihyperglycemic and antihyperlipidemic action of Cinnamomi Cassiae (Cinnamon bark) extract in C57BL/Ks db/db mice. Arch Pharm Res. 2010;33:325-333.  [PubMed]  [DOI]  [Cited in This Article: ]
65.  Debiais F. Thiazolidinediones: antidiabetic agents with effects on bone. Joint Bone Spine. 2009;76:221-223.  [PubMed]  [DOI]  [Cited in This Article: ]
66.  Xu YX, Chen L, Hou WK, Lin P, Sun L, Sun Y, Dong QY, Liu JB, Fu YL. Mesenchymal stem cells treated with rat pancreatic extract secrete cytokines that improve the glycometabolism of diabetic rats. Transplant Proc. 2009;41:1878-1884.  [PubMed]  [DOI]  [Cited in This Article: ]
67.  Amin AH, Abd Elmageed ZY, Nair D, Partyka MI, Kadowitz PJ, Belmadani S, Matrougui K. Modified multipotent stromal cells with epidermal growth factor restore vasculogenesis and blood flow in ischemic hind-limb of type II diabetic mice. Lab Invest. 2010;90:985-996.  [PubMed]  [DOI]  [Cited in This Article: ]
68.  Kinoshita T, Kobayashi S, Ebara S, Yoshimura Y, Horiuchi H, Tsutsumimoto T, Wakabayashi S, Takaoka K. Phosphodiesterase inhibitors, pentoxifylline and rolipram, increase bone mass mainly by promoting bone formation in normal mice. Bone. 2000;27:811-817.  [PubMed]  [DOI]  [Cited in This Article: ]
69.  Viboolvorakul S, Niimi H, Wongeak-in N, Eksakulkla S, Patumraj S. Increased capillary vascularity in the femur of aged rats by exercise training. Microvasc Res. 2009;78:459-463.  [PubMed]  [DOI]  [Cited in This Article: ]
70.  Adams V, Lenk K, Linke A, Lenz D, Erbs S, Sandri M, Tarnok A, Gielen S, Emmrich F, Schuler G. Increase of circulating endothelial progenitor cells in patients with coronary artery disease after exercise-induced ischemia. Arterioscler Thromb Vasc Biol. 2004;24:684-690.  [PubMed]  [DOI]  [Cited in This Article: ]
71.  Miller-Kasprzak E, Jagodziński PP. Endothelial progenitor cells as a new agent contributing to vascular repair. Arch Immunol Ther Exp (Warsz). 2007;55:247-259.  [PubMed]  [DOI]  [Cited in This Article: ]