Abstract
Subjects with type 1 diabetes mellitus (T1DM) have decreased bone mineral density and an up to sixfold increase in fracture risk. Yet bone fragility is not commonly regarded as another unique complication of diabetes. Both animals with experimentally induced insulin deficiency syndromes and patients with T1DM have impaired osteoblastic bone formation, with or without increased bone resorption. Insulin/IGF1 deficiency appears to be a major pathogenetic mechanism involved, along with glucose toxicity, marrow adiposity, inflammation, adipokine and other metabolic alterations that may all play a role on altering bone turnover. In turn, increasing physical activity in children with diabetes as well as good glycaemic control appears to provide some improvement of bone parameters, although robust clinical studies are still lacking. In this context, the role of osteoporosis drugs remains unknown.
Invited Author's profile
Serge Ferrari is a Professor of Medicine at the Faculty of Medicine, University of Geneva, Switzerland. He is also the Head of the Clinical Service and Research Laboratory of Bone Diseases at the Department of Internal Medicine Specialties, Geneva University Hospital. Prof. Ferrari obtained his medical degree from the Faculty of Medicine, University of Geneva in 1989. He is vice-chair of the Council of Scientific Advisors of the International Osteoporosis Foundation, past president of the Swiss Bone and Mineral Society, and current vice-president of the Swiss Association against Osteoporosis. Prof. Ferrari has published over 200 articles and book chapters in the field of osteoporosis and bone and mineral metabolism.
Introduction
Despite the wealth of information available concerning the various systemic complications of chronic diabetes, the effects of this disease on the metabolism of minerals and the integrity of bone, particularly bone fragility, are not yet fully appreciated. The earliest influence of the diabetic environment on bone is seen in the increased prevalence of skeletal malformations in the foetuses of diabetic mothers. Hypoplasia or deformities of the extremities, dislocation of the hips and agenesis of the sacrum or lumbar vertebrae occur three to five times as frequently among these infants as among non-diabetic controls (1). The second category of bone abnormalities known to occur in those with diabetes results from the continuing trauma following diabetic neuropathy and is characterized by focal osteolysis, bone fragmentation, sclerosis and Charcot's neurogenic arthropathy. This condition is usually evident in the small bones of the feet and less frequently involves the knees, upper extremities or vertebrae (2). Hand abnormalities, including carpal tunnel syndrome, sclerodactyly, acro-osteolysis and Dupuytren's contracture also occur more frequently in diabetes. Diabetic muscle infarction is a rare complication seen in poorly controlled diabetics with advanced microvascular complications (3). Late complications of diabetes may also impact negatively on skeletal health, e.g. renal osteodystrophy, falls and fractures secondary to poor vision, neuropathy or cerebrovascular disease.
As early as 1927, Morrison & Bogan (4) documented decreased skeletal mass and bone development in children with longstanding diabetes. In 1934 several cases of diabetes associated with vertebral crush fractures were reported from the Joslin clinic (5). Albright & Reifenstein (6) confirmed these findings and Hernberg (7) reported in 1952 that osteoporosis was much more severe in young adults with diabetes at post mortem. Subsequently, Berney and others (8, 9) reemphasized the coexistence of diabetes and radiologic evidence of decreased bone mass. In 1970 Jurist (10), employing resonant frequency analysis, reported decreased skeletal strength in diabetic women compared with age-matched controls. Diabetes was found to occur in more than 20% of patients with vertebral crush fractures in a large epidemiologic study from Israel (11). Applying single photon absorptiometry, Ringe et al. (12), Levin et al. (13) and McNair et al. (14) documented a 31–48% decrease in bone mineral density (BMD) in insulin requiring diabetic patients. A 25–30% decrease in metacarpal cortical thickness was subsequently reported by Santiago et al. (15) and Hough (16).
It is, however, the role of diabetes and its treatment as the cause of a metabolic bone disease resulting in a generalised decrease in bone mass and/or compromised bone quality that has attracted much attention of late. It is now well established that osteoporotic fractures occur significantly more commonly in subjects with type 1 diabetes mellitus (T1DM) (17). Whether this merely reflects the common co-existence of the two diseases or whether involvement of the skeleton should be regarded as yet another unique complication of diabetes needs to be ascertained.
Fracture risk
Following earlier (4, 5, 6, 7, 8, 9) suggestions of an increased prevalence of fractures in T1DM, the results of the Iowa Women's Health Study, an 11-year follow-up of 32 089 postmenopausal women, were reported in 2001 (18). Hip fractures were found to be 12 times more common in women with T1DM compared to matched controls. Men with T1DM were found to have a 17.8-fold increased risk of hip fractures in a 6-year follow up of 27 159 Norwegian subjects (19). Miao et al. (20) reported a similar eight- to 12-fold increase in hip fracture risk in a Swedish cohort of more than 24 000 patients with T1DM. In 2007, two large meta-analyses were published, reporting a near identical 6.9- and 6.3-fold (17, 21) increase in hip fracture risk in patients with T1DM compared to subjects without diabetes. A less marked but significant (OR=2.5 95%CI: 1.3–4.6) increase in vertebral fracture risk has also been reported in T1DM (22). While no large studies evaluating the risk of vertebral fracture in T1DM are available, there is data suggesting higher prevalence of morphometric vertebral fractures, assessed by VFA, in cross-sectional study (23). A more recent meta-analysis showed that T1DM was associated with a threefold higher risk of any fracture, and up to fivefold concerning hip fractures in women (24). T1DM is also associated with higher fracture risk than type 2 diabetes mellitus (T2DM) (17). A retrospective cohort study from the THIN database in the UK determined that the association between T1DM and increased risk of fracture of lower extremities especially was lifelong, starting during childhood and lasting into advanced age (25).
Fracture risk appeared to be related to the duration of diabetes, with some studies revealing a near linear relationship between duration of diabetes and fracture risk (18, 20). Other studies (19) failed to document any association with duration, whereas yet others (22) proposed a bimodal relationship with the highest incidence occurring within the first 2.5 years and again beyond 5 years of diabetes being diagnosed. Most, but not all (26), studies failed to document a relationship between the risk of fracture and glycemic control. An association between the presence of microvascular complications of diabetes and the increase in fracture risk was, however, reported in most studies (17, 18, 19, 20, 21, 22).
Quantitative and structural bases of bone fragility
Bone mineral density and ultrasound parameters
Table 1 lists more recent studies, using more sensitive dual energy X-ray absorptiometry (DXA) techniques, to measure axial BMD in younger subjects with T1DM. Most (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44), although not all (45, 46, 47, 48, 49), studies report a significant decrease in BMD at either the spine, hip or total body. The magnitude of the decrease in BMD varied quite markedly from 8 to 67%, and large gender differences appear to be present, with many studies documenting changes in BMD in either males or females only. A recent meta-analysis (17) reported an average decrease in spine BMD of −22% and a hip Z-score of −37% compared to that of age- and gender-matched controls. Many (27, 30, 36, 43), but not all (29, 35), studies suggested that a decrease in BMD occurred more frequently in those with longstanding diabetes. Some studies, however, documented the presence of osteopenia at diagnosis of diabetes (35). As depicted in Table 1, BMD correlated poorly with glycaemic control in most (29, 33, 34, 35, 36, 37), but not all (28, 31, 32), studies. However many studies reported an association between the presence of microvascular complications of diabetes and the presence and/or progression of a decreased BMD (27, 28, 38, 40, 42, 50). In these studies, the nature of the microvascular complication ranged from nephropathy to neuropathy to retinopathy, and no consistent pattern was apparent. The Vestergaard meta-analysis (17) also documented an association between the decreased BMD observed in patients with T1DM and the presence of a microvascular complication but failed to document an association between BMD and glycaemic (HbA1c) control.
DXA measurement of BMD in type 1 diabetes.
| n | F/M | Age | Duration | Site | MVC | GC | |
|---|---|---|---|---|---|---|---|
| Decreased BMD | |||||||
| Munoz-Torres et al. (38) | 94 | 49/45 | 30 | 12 | H and S | Yes | NR |
| Clausen (1997) (27) | 36 | 0/36 | 48 | 27 | Hip | Yes | NR |
| Gunczler (1998) (29) | 26 | 11/15 | 12 | 4 | H and S | NR | No |
| Hampson et al. (30) | 31 | 31/0 | 42 | 20 | Hip | NR | NR |
| Tuominen et al. (43) | 56 | 27/29 | 62 | 18 | Hip* | NR | NR |
| Rozadilla et al. (40) | 88 | 43/45 | 29 | 11 | Spine | Yes | NR |
| Kemink et al. (33) | 35 | 14/21 | 38 | 9 | H and S | NR | No |
| Campos Pastor (2000) (50) | 57 | 30/27 | 35 | 17 | H and S | Yes | NR |
| Lopez-Ibarra et al. (35) | 32 | 10/22 | 30 | 0 | H and S | NR | No |
| Valerio et al. (44) | 27 | 12/15 | 13 | 7 | Hip* | NR | Yes |
| Leger et al. (34) | 127 | 73/54 | 14 | 6 | S and TB | NR | No |
| Rakic et al. (39) | 34 | 11/23 | 48 | 14 | H and S | NR | NR |
| Strotmeyer et al. (42) | 67 | 67/0 | 32 | 5 | Hip | Yes | NR |
| Miazgowski et al. (37) | 36 | 36/0 | 44 | 22 | Spine | No | No |
| Mastrandrea et al. (36) | 63 | 63/0 | 21 | NR | Hip | NR | No |
| Heilman et al. (31) | 30 | 11/19 | 13 | 5 | Spine* | NR | Yes |
| Hamilton (2009) (58) | 102 | 52/50 | 38 | 14 | H and S | NR | NR |
| Eller-Vainicher (2011) (28) | 175 | 104/71 | 33 | 9 | H and S | Yes | Yes |
| Soto et al. (41) | 45 | 45/0 | 23 | 13 | H and TB | NR | No |
| Joshi et al. (32) | 86 | 22/53 | 27 | 15 | S and TB | NR | Yes |
| No change in BMD | |||||||
| Pascual (1998) (49) | 55 | 29/26 | 11 | 3 | |||
| Lunt (1998) (48) | 99 | 99/0 | 42 | 27 | |||
| Liu (2003) (47) | 72 | 72/0 | 16 | 7 | |||
| Ingberg (2004) (46) | 38 | 20/18 | 43 | 33 | |||
| Bridges (2005) (45) | 35 | 0/35 | 49 | 20 |
F/M, female/male; Duration, duration of diabetes in years; Site, skeletal site demonstrating a decreased bone mineral density (BMD); MVC, correlation between BMD and diabetic microvascular complication(s); GC, correlation between BMD and glycaemic control (usually the mean HbA1c); NR, not reported; H, hip; S, spine; TB, total body; Hip*, only site measured; Spine*, only site measured.
A few studies (45, 51, 52, 53, 54, 55, 56, 57) have employed peripheral quantitative computer tomography (pQCT) or peripheral DXA (pDXA) to study the BMD of the distal forearm or tibia in T1DM. Some (45, 56) have reported no difference in the BMD between diabetics and controls, whereas others (51, 52, 53, 54, 55, 57) have documented a decrease in either trabecular and/or cortical BMD at these sites.
Although the decreased BMD reported in subjects with T1DM (27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 50, 58) may largely explain the higher fracture risk observed in these patients (17, 18, 19, 20, 21, 22, 26), alterations in bone quality, as described below, may also contribute and actually confer its specific nature to diabetic bone disease.
Quantitative ultrasound (QUS) parameters, including speed of sound (SOS), broadband ultrasound attenuation (BUA) and derived variables like ultrasound BMD or stiffness index of the radius, tibia, calcaneus or phalanges, have been reported in patients with T1DM in a limited number of studies (42, 59, 60, 61, 62, 63). Low values for these parameters were reported in T1DM, which appeared to correlate with the duration of diabetes (59, 60, 61) and the degree of metabolic control (61, 62, 63).
Bone size and microstructure
A number of studies have documented a smaller cross-sectional radial or tibial bone area in T1DM compared to controls (51, 56, 57), especially during childhood (57, 64), but with a normalization with age (65), and reported an association between glycaemic control and decreased bone size (52, 54).
High-resolution (HR)-pQCT measurements at the ultradistal radius and tibia showed in a cross-sectional study that T1DM patients as a group have lower total and trabecular volumetric BMD compared to healthy subjects, and these alterations are more prominent in those subjects with chronic microvascular diseases (MVD). They also exhibit lower trabecular and cortical thickness at the tibia, resulting in decreased estimated bone strength compared to healthy patients with MVD (66). It is notable, however, that cortical porosity, another important determinant of bone strength, was not increased in T1DM subjects, even those with MVD. These data suggest that MVD may be an independent risk factor of fractures. By magnetic resonance imaging (MRI), Adbalrahaman confirmed trabecular deficits with reduced bone volume and trabecular number at the proximal tibia of young adults with childhood onset of T1DM, as well as increased medullary fat in the vertebrae (67).
Fracture toughness, the ability of the bone material to resist to crack initiation and propagation is another determinant of fracture risk besides bone strength. Nuclear magnetic resonance spectroscopy (NMR) and reference point indentation (RPI) have been shown to be useful clinical surrogates to assess fracture toughness. In their study, Granke et al. (68) showed that the fracture toughness properties decreased with age. NMR-derived properties such as pore water RPI-derived tissue stiffness correlated with fracture toughness on human femoral bone.
Bone turnover
A variety of animal models of T1DM (streptozotocin-induced, spontaneously diabetic NOD mice) have been shown to exhibit bone loss/impaired bone strength. Both animals with experimentally induced diabetes and patients with T1DM demonstrate similar metabolic bone profiles, namely, impaired bone formation and low levels of osteocalcin/bone-specific alkaline phosphatase, whereas it is less clear whether increased bone resorption also occurs. Employing short-term (2-week) animal models of streptozotocin diabetes, the low BMD observed in insulinopenic diabetes was earlier explained by secondary hyperparathyroidism and increased bone resorption resulting from a negative calcium balance (impaired intestinal calcium absorption; hypercalciuria) (69, 70). Using more appropriate animal models of chronic diabetes (8–10 weeks), and employing time-spaced tetracycline labelled bone histomorphometry, bone formation and resorption were found to be markedly suppressed (71, 72, 73, 74).
Subsequently, low bone formation has been confirmed in patients with T1DM, using biomarkers of bone turnover like serum osteocalcin (33, 75, 76, 77, 78, 79). In some human studies, bone resorption in T1DM is either decreased or unaltered and does not explain the low BMD observed in this disease (80). In children and young adults, T1DM patients had lower PINP and CTX levels compared to controls (67, 81). However enzymatic cross-linking of collagen is reduced in diabetes (82). Thus bone resorption assessed with CTX assay may be underestimated seeing that CTX assay measures cross-linked telopeptides.
Unfortunately, bone histology data in patients with T1DM are scarce. Only one study with two biopsies from patients with T1DM and six with T2DM showed markedly depressed bone formation rate compared to non-diabetic patients (83). Although a larger case-control study of 18 patients with T1DM and relatively good glycemic control (average HbA1C 6.8%) showed no bone structural or dynamic differences between groups, bone formation was significantly less in the small group of subjects who had fractures compared with T1DM patients without fractures (84). A recent reanalysis of these biopsies further indicates an increased degree of bone mineralization and non-enzymatic collagen crosslinks in diabetes subjects, particularly those with fractures, which would be consistent with a lower bone turnover. Moreover, these parameters were positively correlated with HbA1C, indicating that poor glycemic control has consequences on material bone properties (85).
Cellular and molecular mechanisms of diabetes bone disease
The pathogenesis of diabetic bone fragility is probably multifactorial. T1DM can directly influence bone quantity and quality in a number of ways or indirectly impact on skeletal health by causing hypogonadism (86, 87), hypercalciuria (88, 89), alterations in vitamin D metabolism (89, 90) or because of its association with certain diseases known to adversely influence bone (e.g. Coeliac disease (91)) (Fig. 1).
Pathological mechanisms that may be involved in the development of diabetic osteopenia.
Citation: European Journal of Endocrinology 174, 4; 10.1530/EJE-15-0820
Pathological mechanisms that may be involved in the development of diabetic osteopenia.
Citation: European Journal of Endocrinology 174, 4; 10.1530/EJE-15-0820
Pathological mechanisms that may be involved in the development of diabetic osteopenia.
Citation: European Journal of Endocrinology 174, 4; 10.1530/EJE-15-0820
Insulin, incretin and IGF1
Insulin has been shown to have anabolic actions on bone in vitro (92). Furthermore, in knockout models of insulin receptor substrate 1 or 2 (IRS1; IRS2), the main intracellular substrates of the insulin receptor, bone formation and resorption are markedly reduced (93, 94). The administration of insulin to animals with experimental diabetes has also been shown to correct the decreased bone turnover that characterizes the chronic diabetic state (71, 95). Insulin deficiency as a cause of the low bone formation in T1DM therefore appears attractive. However, no changes in bone turnover were observed in global knockout of the mouse insulin receptor (IR), subsequently rescued by transgenic expression of the human IR in the liver, pancreas and brain, but not bone (96). Decreased insulin signalling alone cannot therefore account for the low bone turnover in T1DM. These knockout mice have elevated insulin levels which increase IGF1 signalling. Sufficient signalling through either IR or IGF1 is therefore required for optimal bone turnover (80, 97). Human data support the notion that the lack of insulin may affect negatively osteoblasts. In T1DM adolescents, bone phosphatase alkaline (ALP), osteocalcin and IGF1 levels were significantly lower compared to healthy controls (75) and lower IGF1 were associated with osteopenia (33). The decreased levels of IGF1 seen in T1DM but not in T2DM are not fully explained.
Incretin peptides, especially glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP1) are gut hormones known to potentiate the secretion of glucose-dependent insulin from the pancreas. GLP1 agonists and dipeptidyl peptidase-4 (DDP4) inhibitors are a new class of incretin-based therapies for the treatment of type 2 diabetes, which play an important role in the regulation of bone turnover (98). Recent data suggest that incretins could also have a positive effect on bone quality in T1DM. In streptozotocin-treated mice, incretin peptides were able to prevent the alterations of cortical microarchitecture and the deterioration of bone quality (99). Clinical studies are needed to determine if the rodent data is applicable and to elucidate the effects of incretin on fracture risk.
Hyperglycaemia and AGEs
Hyperglycaemia is known to suppress osteoblastic differentiation and signalling, potentially resulting in impaired bone formation (80, 100). Chronic hyperglycaemia may also result in the non-enzymatic glycosylation of proteins (e.g. collagen) and other cell components (e.g. DNA), collectively referred to as advanced glycation end products (AGES) (101). Various AGES and their receptors (RAGES) have been implicated in the development of complications of diabetes, including diabetic bone disease. In a cross-sectional study, T1DM people with fracture were having higher serum levels of pentosidine, an AGE product, compared to non-fracture ones, although values largely overlapped with those of non-fractured diabetics (102).
Marrow adiposity
In the bone marrow, mesenchymal stromal cells (MSC) are the common progenitors that give rise to osteoblasts, adipocytes and chondrocytes. A reciprocal relationship exists between adipogenesis, which is largely driven by the pro-adipogenic transcription factor, peroxisome proliferator-activated receptor (PPARγ2) and osteoblastogenesis. Stimulation of PPARγ2 expression in vitro has been shown to promote adipocyte maturation of MSCs and to reduce the number of mature osteoblasts (103). Marrow adiposity has been demonstrated in a number of conditions where increased adipogenesis has occurred at the expense of impaired osteoblastogenesis e.g. glucocorticoid excess, old age. McCabe (80) and others (103) have also demonstrated increased bone marrow PPARγ2 activity and increased bone marrow adiposity in mice with T1DM. Whether marrow adiposity is causally related to the low BMD observed in T1DM remains unclear. A direct link in all forms of bone loss appears unlikely, since PPARγ2 antagonists, capable of preventing marrow adiposity, did not prevent T1DM bone loss (104).
Inflammation
Type 2 diabetes is often referred to as a state of accelerated ageing and chronic low-grade inflammation (‘inflammaging’). T1DM is, however, also known to upregulate a number of inflammatory genes, and the pathogenesis of various complications of T1DM is thought to have, at least in part, an inflammatory basis (105).
Inflammatory cytokines like IL1 classically stimulate osteoclastic bone resorption. However, inflammatory cytokines like TNFα have been shown to inhibit osteoblastogenesis from MSC through several mechanisms (106). Moreover, the inflammatory milieu appears to dictate whether osteoblastic bone formation is impaired (e.g., in rheumatoid arthritis) or whether osteoblastic bone formation is stimulated (e.g., at sites of enthesis in ankylosing spondylitis) (107). Further studies are required to determine whether bone loss in T1DM has an inflammatory basis and whether anti-inflammatory agents impact on this process.
Osteocyte function
The low bone formation rate that is characteristic of T1DM (see above) suggests that in addition to its direct negative effects on osteoblasts, diabetes could also affect the function of osteocytes, i.e., the master regulator of bone cells functions. Sclerostin is an osteocyte-derived inhibitor of Wnt signalling pathway, essential for osteoblast differentiation and bone formation (108). In humans, sclerostin levels have been shown to be higher in patients with T1DM compared to controls in a cross-sectional study (102). Catalano et al. (109) showed that sclerostin levels are higher in females with T1DM compared to males and that the duration of the disease was associated with higher levels of sclerostin. Sclerostin levels are also higher in prediabetic subjects (110). These findings suggest that sclerostin expression and/or osteocytes viability and functions could be impaired in diabetes. Whether the mechanostatic response to skeletal loading is impaired in these subjects however remains unknown.
Others
Nutritional deprivation and keto-acidosis, still too commonly encountered in the patient with poorly controlled T1DM, are well known to impair bone formation (16). Poorly controlled T1DM is often attended by dyslipidaemia, which is associated with increased PPARγ2 expression, impaired osteoblast differentiation and marrow adiposity (80). Finally, theories derived to account for the bone loss in T1DM must also acknowledge reports of abnormalities in circulating levels of the adipokines (leptin, adiponectin), amylin, prostaglandins and glucocorticoids in both experimental and human T1DM, which may negatively impact on bone health (16, 111, 112, 113).
Evaluation and management of bone fragility in T1DM
In children and adolescents with T1DM, diagnosis of low bone mass should follow paediatric guidelines, i.e., BMD Z-score below −2.0 and a fragility fracture (114). But it is not clear who should undergo a BMD test among T1DM patients. In young adults, diagnosis of osteoporosis rely not only on aBMD (T-score and not Z-score) but also on multiple fragility fractures (115). Early onset of T1DM can negatively affect bone size and mass. The use of markers of bone turnover to investigate osteoporosis in this age category remains controversial (116).
FRAX algorithm (www.shef.ac.uk/FRAX) was developed to estimate an individual's 10-year probability of major osteoporotic fracture and hip fracture in subjects older than 40 years of age. T1DM is considered as one of the causes of secondary osteoporosis and not as risk factor and therefore it increases fracture probability only when BMD is not included in the calculation, as illustrated in Table 2. Trabecular bone score (TBS) is a new texture parameter derived from DXA image of the spine and provides information related to bone microarchitecture and fracture risk. TBS was shown not to be significantly different between T1DM and healthy persons but to be lower in T1DM patients with prevalent fractures (117). A low TBS value increases the predicted fracture probability in T1DM to the same degree as in non-diabetic subjects (Table 2).
Ten-year probability of major osteoporotic fracture in T1DM patients (UK).
| FRAX | FRAX+BMD | FRAX+BMD+TBS | ||||
|---|---|---|---|---|---|---|
| No diabetes | Diabetes | No diabetes | Diabetes | No diabetes | Diabetes | |
| Woman, 52 years olda | 3.9 | 5.3 | 4.4 | 4.4 | 6.6 | 6.6 |
| Woman, 62 years old with a vertebral fractureb | 14.0 | 20.0 | 17.0 | 17.0 | 20.0 | 20.0 |
Woman, 52 years old, 60 kg, 163 cm, T-score −1.5, TBS 1.16, no other FRAX clinical risk factor.
Woman, 62 years old, 60 kg, 163 cm, T-score −2.5, TBS 1.16, with a vertebral fracture.
In young adults, general recommendations should therefore be followed to diagnose low bone mass in T1DM individuals (118), whereas after the age of 40, fracture risk evaluation can be performed using FRAX, ideally including femoral neck BMD and other DXA-derived information (TBS and VFA).
Fracture prevention
It needs to be reiterated that no RCTs are available to guide the treatment of bone fragility in diabetes and that management is entirely empirical and derives from the good clinical practice and experience of the physician. Many osteoporosis guidelines mentioned T1DM as a risk factor for osteoporosis and fracture and suggest earlier bone evaluation in those patients. In contrast, recommendations on osteoporosis screening are not found in most diabetes guidelines. In a recent publication Zhukouskaya proposed a flow chart for evaluation, management and treatment of T1DM patients at risk of poor bone health (119).
Non-pharmacologic measures
General measures to prevent osteoporosis also apply to the patient with T1DM, especially to children with early onset of diabetes, who could have difficulties reaching peak bone mass during growth (120). These include a balanced diet rich in dairy, ensuring an adequate calcium (1000 mg/day) and vitamin D (1000 IU/day) intake, regular weight-bearing exercise (40 min walk 3×/week), limiting alcohol to <3 units per day, stopping smoking, the avoidance of other bone toxins and the prevention of falls (121). In children and adolescents, physical activity is the best way to build up bone mass and strength. Maggio et al. (81) have shown that regular weight-bearing exercise increases bone mineral accretion in T1DM children similarly to non-diabetic children. In the older patient with T1DM, especially those with neuropathy, poor vision or gait and balance problems, fall prevention is paramount.
Optimise metabolic control
Controversy exists as to the role of glycaemic control on BMD and fracture risk. Given the fact that a lot of in vitro data (80, 100) suggest that hyperglycaemia and hyperlipidaemia are toxic to osteoblasts, and at least some clinical reports (18, 19, 20) have confirmed a relationship between glycaemic control and fracture incidence, it is our contention that every effort should be made to optimise metabolic control in patients with T1DM at risk of fracture; this is especially relevant to T1DM in the young. Optimization of the insulin treatment remains a major point for normalization of glycaemia, prevention of diabetic complications and even prevention of bone health. In a prospective study, there was a trend for higher BMD in T1DM young adults treated with insulin for 7 years (50). However, in order to avoid hypoglycaemia, insulin is given at a dose that produces a slight hyperglycaemia compared to non-diabetic subjects. Thus it is possible that this slight chronic hyperglycaemia may affect bone quality and account for the increased risk of fracture.
Management of associated disorders
T1DM is associated with a number of disorders known to impact adversely on skeletal health. Hypogonadism, although more commonly encountered in T2DM and the metabolic syndrome, also occurs more commonly in T1DM and should be assessed and managed if present. In poorly controlled diabetes, excessive renal loss of calcium and magnesium may occur. Coeliac disease occurs in 4–11% of patients with T1DM as opposed to <1% in the general population and should be screened for with serum endomysial antibody assays in those at risk of fracture (91, 122, 123). If the diagnosis is confirmed with intestinal histology, a gluten-free diet is indicated.
Bone active medications
None of the anti-osteoporotic agents have been tested for their anti-fracture efficacy in T1DM subjects. Given the fact that bone formation is generally impaired in T1DM, one would intuitively deduce that treatment with anti-resorptive agents would be less effective and that an anabolic agent should be preferred. Intermittent parathyroid hormone (PTH), known to have bone-forming effects on bone, and more generally to increase bone turnover, has in fact been shown to improve trabecular bone volume in animals with experimental T1DM (124). To date, however, there are no human data on the effect of intermittent PTH in T1DM patients. Sclerostin antibody has been tested in animal models with T2DM, where it increased bone mass and strength, but not in the setting of T1DM (125). Unfortunately no clinical studies are yet available to confirm this in humans. Bisphosphonates, known for their anti-fracture effects in high-turnover (e.g., postmenopausal) as well as low-formation (e.g., glucocorticoid-induced) osteoporosis are usually recommended as first-line treatment for diabetic bone disease, but no studies are available to support this contention. A cohort study showed no difference in anti-fracture efficacy of bisphosphonates in patients with diabetes compared to control non-diabetic patients, or between patients with T1DM and T2DM (126). However, atypical femoral fracture occurred twice more often in postmenopausal women with diabetes (type 1 and 2) compared to those without diabetes (11.6% vs 5.6%) (127), so bisphosphonates should be used with caution and at least for limited durations in T1DM patients with established bone fragility, especially in children and young adults with T1DM. Strontium ranelate is contraindicated in patients at risk of cardiovascular disease. Both bisphosphonates and strontium ranelate are contraindicated in patients with significant renal impairment and a creatinine clearance <30 ml/min. Denosumab has been shown to increase cortical density and thickness but it has not yet been tested in the context of diabetes either in animal models or in humans.
As the onset of T1DM happens often during childhood, specific attention should be directed towards growing children who have not yet reached their peak bone mass.
Conclusions
T1DM confers significant increased fracture risk throughout life. Therefore, fragility fractures should be considered as a (new) major complication of this disease and fracture risk should be properly evaluated and regularly re-evaluated in these patients. Since areal BMD is usually decreased in T1DM, the common fracture prediction algorithms such as FRAX can be used to evaluate fracture probability in T1DM without further adjustments (contrary to T2DM). However, the development of non-invasive or minimally invasive methods to evaluate bone quality parameters, such as HR pQCT and micro-point indentation, might be useful to further identify T1DM subjects at increased fracture risk. Clinical trials evaluating the benefits/risk of osteoporosis drugs on skeletal health in subjects with this common disease are also urgently needed.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the review.
Funding
This review did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
References
- 1↑
Williams G, Pickup JC. Handbook of Diabetes: Pregancy and Diabetes. London: Blackwell Sciencepp 191–196.2000
- 2↑
Rogers LC, Frykberg RG. The Charcot foot. Medical Clinics of North America 2013 97 847–856. (doi:10.1016/j.mcna.2013.04.003).
- 3↑
Grigoriadis E, Fam AG, Starok M, Ang LC. Skeletal muscle infarction in diabetes mellitus. Journal of Rheumatology 2000 27 1063–1068.
- 4↑
Morrison LB, Bogan IK. Bone development in diabetic children: a roentgen study. American Journal of the Medical Sciences 1927 174 313–319. (doi:10.1097/00000441-192709000-00003).
- 5↑
Root HF, White P, Marble A. Abnormalities of calcium deposition in diabetes mellitus. Archives of Internal Medicine 1934 53 46–52. (doi:10.1001/archinte.1934.00160070051004).
- 6↑
Albright F, Reifenstein EC. Parathyroid Glands and Metabolic Bone Disease: Selected Studies. Baltimore: Williams & Wilkinspp 145–204.1948
- 7↑
Hernberg CA. Skeletal variations in adults with diabetes mellitus. Acta Medica Scandinavica 1952 143 1–14. (doi:10.1111/j.0954-6820.1952.tb14247.x).
- 8↑
Alffram PA. An epidemiologic study of cervical and trochanteric fractures of the femur in an urban population. Analysis of 1,664 cases with special reference to etiologic factors. Acta Orthopaedica Scandinavica. Supplementum 1964 65 (Suppl 65) 61–109.
- 9↑
Berney PW. Osteoporosis and diabetes mellitus; report of a case. Journal. Iowa State Medical Society 1952 42 10–12.
- 10↑
Jurist JM. In vivo determination of the elastic response of bone. II. Ulnar resonant frequency in osteoporotic, diabetic and normal subjects. Physics in Medicine and Biology 1970 15 427–434. (doi:10.1088/0031-9155/15/3/003).
- 11↑
Menczel J, Makin M, Robin G, Jaye I, Naor E. Prevalence of diabetes mellitus in Jerusalem; its association with presenile osteoporosis. Israel Journal of Medical Sciences 1972 8 918–919.
- 12↑
Ringe JD, Kuhlencordt F, Kruse HP. Proceedings: bone mineral determinations on long-term diabetics. AJR. American Journal of Roentgenology 1976 126 1300–1301. (doi:10.2214/ajr.126.6.1300).
- 13↑
Levin ME, Boisseau VC, Avioli LV. Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes. New England Journal of Medicine 1976 294 241–245. (doi:10.1056/NEJM197601292940502).
- 14↑
McNair P, Madsbad S, Christensen MS, Christiansen C, Faber OK, Binder C, Transbol I. Bone mineral loss in insulin-treated diabetes mellitus: studies on pathogenesis. Acta Endocrinologica 1979 90 463–472.
- 15↑
Santiago JV, McAlister WH, Ratzan SK, Bussman Y, Haymond MW, Shackelford G, Weldon VV. Decreased cortical thickness & osteopenia in children with diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1977 45 845–848. (doi:10.1210/jcem-45-4-845).
- 16↑
Hough FS. Alterations of bone and mineral metabolism in diabetes mellitus. Part I. An overview. South African Medical Journal 1987 72 116–119.
- 17↑
Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes – a meta-analysis. Osteoporosis International 2007 18 427–444. (doi:10.1007/s00198-006-0253-4).
- 18↑
Nicodemus KK, Folsom AR. Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 2001 24 1192–1197. (doi:10.2337/diacare.24.7.1192).
- 19↑
Ahmed LA, Joakimsen RM, Berntsen GK, Fonnebo V, Schirmer H. Diabetes mellitus and the risk of non-vertebral fractures: the Tromso study. Osteoporosis International 2006 17 495–500. (doi:10.1007/s00198-005-0013-x).
- 20↑
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. (doi:10.2337/diacare.28.12.2850).
- 21↑
Janghorbani M, Van Dam RM, Willett WC, Hu FB. Systematic review of type 1 and type 2 diabetes mellitus and risk of fracture. American Journal of Epidemiology 2007 166 495–505. (doi:10.1093/aje/kwm106).
- 22↑
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. (doi:10.1007/s00125-005-1786-3).
- 23↑
Zhukouskaya VV, Eller-Vainicher C, Vadzianava VV, Shepelkevich AP, Zhurava IV, Korolenko GG, Salko OB, Cairoli E, Beck-Peccoz P, Chiodini I. Prevalence of morphometric vertebral fractures in patients with type 1 diabetes. Diabetes Care 2013 36 1635–1640. (doi:10.2337/dc12-1355).
- 24↑
Shah VN, Shah CS, Snell-Bergeon JK. Type 1 diabetes and risk of fracture: meta-analysis and review of the literature. Diabetic Medicine 2015 32 1134–1142. (doi:10.1111/dme.12734).
- 25↑
Weber DR, Haynes K, Leonard MB, Willi SM, Denburg MR. Type 1 diabetes is associated with an increased risk of fracture across the life span: a population-based cohort study using the health improvement network (THIN). Diabetes Care 2015 38 1913–1920. (doi:10.2337/dc15-0783).
- 26↑
Neumann T, Samann A, Lodes S, Kastner B, Franke S, Kiehntopf M, Hemmelmann C, Lehmann T, Muller UA, Hein G et al.. Glycaemic control is positively associated with prevalent fractures but not with bone mineral density in patients with type 1 diabetes. Diabetic Medicine 2011 28 872–875. (doi:10.1111/j.1464-5491.2011.03286.x).
- 27↑
Clausen P, Feldt-Rasmussen B, Jacobsen P, Rossing K, Parving HH, Nielsen PK, Feldt-Rasmussen U, Olgaard K. Microalbuminuria as an early indicator of osteopenia in male insulin-dependent diabetic patients. Diabetic Medicine 1997 14 1038–1043. (doi:10.1002/(SICI)1096-9136(199712)14:12<1038::AID-DIA509>3.0.CO;2-1).
- 28↑
Eller-Vainicher C, Zhukouskaya VV, Tolkachev YV, Koritko SS, Cairoli E, Grossi E, Beck-Peccoz P, Chiodini I, Shepelkevich AP. Low bone mineral density and its predictors in type 1 diabetic patients evaluated by the classic statistics and artificial neural network analysis. Diabetes Care 2011 34 2186–2191. (doi:10.2337/dc11-0764).
- 29↑
Gunczler P, Lanes R, Paz-Martinez V, Martins R, Esaa S, Colmenares V, Weisinger JR. Decreased lumbar spine bone mass and low bone turnover in children and adolescents with insulin dependent diabetes mellitus followed longitudinally. Journal of Pediatric Endocrinology & Metabolism 1998 11 413–419. (doi:10.1515/JPEM.1998.11.3.413).
- 30↑
Hampson G, Evans C, Petitt RJ, Evans WD, Woodhead SJ, Peters JR, Ralston SH. Bone mineral density, collagen type 1 α 1 genotypes and bone turnover in premenopausal women with diabetes mellitus. Diabetologia 1998 41 1314–1320. (doi:10.1007/s001250051071).
- 31↑
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. Journal of Bone and Mineral Metabolism 2009 27 598–604. (doi:10.1007/s00774-009-0076-4).
- 32↑
Joshi A, Varthakavi P, Chadha M, Bhagwat N. A study of bone mineral density and its determinants in type 1 diabetes mellitus. Journal of Osteoporosis 2013 2013 397814. (doi:10.1155/2013/397814).
- 33↑
Kemink SA, Hermus AR, Swinkels LM, Lutterman JA, Smals AG. Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. Journal of Endocrinological Investigation 2000 23 295–303. (doi:10.1007/BF03343726).
- 34↑
Leger J, Marinovic D, Alberti C, Dorgeret S, Chevenne D, Marchal CL, Tubiana-Rufi N, Sebag G, Czernichow P. Lower bone mineral content in children with type 1 diabetes mellitus is linked to female sex, low insulin-like growth factor type I levels, and high insulin requirement. Journal of Clinical Endocrinology and Metabolism 2006 91 3947–3953. (doi:10.1210/jc.2006-0711).
- 35↑
Lopez-Ibarra PJ, Pastor MM, Escobar-Jimenez F, Pardo MD, Gonzalez AG, Luna JD, Requena ME, Diosdado MA. Bone mineral density at time of clinical diagnosis of adult-onset type 1 diabetes mellitus. Endocrine Practice 2001 7 346–351. (doi:10.4158/EP.7.5.346).
- 36↑
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. (doi:10.2337/dc07-2426).
- 37↑
Miazgowski T, Pynka S, Noworyta-Zietara M, Krzyzanowska-Swiniarska B, Pikul R. Bone mineral density and hip structural analysis in type 1 diabetic men. European Journal of Endocrinology/European Federation of Endocrine Societies 2007 156 123–127. (doi:10.1530/eje.1.02309).
- 38↑
Munoz-Torres M, Jodar E, Escobar-Jimenez F, Lopez-Ibarra PJ, Luna JD. Bone mineral density measured by dual X-ray absorptiometry in Spanish patients with insulin-dependent diabetes mellitus. Calcified Tissue International 1996 58 316–319. (doi:10.1007/BF02509378).
- 39↑
Rakic V, Davis WA, Chubb SA, Islam FM, Prince RL, Davis TM. Bone mineral density and its determinants in diabetes: the Fremantle Diabetes Study. Diabetologia 2006 49 863–871. (doi:10.1007/s00125-006-0154-2).
- 40↑
Rozadilla A, Nolla JM, Montana E, Fiter J, Gomez-Vaquero C, Soler J, Roig-Escofet D. Bone mineral density in patients with type 1 diabetes mellitus. Joint Bone Spine 2000 67 215–218.
- 41↑
Soto N, Pruzzo R, Eyzaguirre F, Iniguez G, Lopez P, Mohr J, Perez-Bravo F, Cassorla F, Codner E. Bone mass and sex steroids in postmenarcheal adolescents and adult women with type 1 diabetes mellitus. Journal of Diabetes and its Complications 2011 25 19–24. (doi:10.1016/j.jdiacomp.2009.10.002).
- 42↑
Strotmeyer ES, Cauley JA, Orchard TJ, Steenkiste AR, Dorman JS. Middle-aged premenopausal women with type 1 diabetes have lower bone mineral density and calcaneal quantitative ultrasound than nondiabetic women. Diabetes Care 2006 29 306–311. (doi:10.2337/diacare.29.02.06.dc05-1353).
- 43↑
Tuominen JT, Impivaara O, Puukka P, Ronnemaa T. Bone mineral density in patients with type 1 and type 2 diabetes. Diabetes Care 1999 22 1196–1200. (doi:10.2337/diacare.22.7.1196).
- 44↑
Valerio G, del Puente A, Esposito-del Puente A, Buono P, Mozzillo E, Franzese A. The lumbar bone mineral density is affected by long-term poor metabolic control in adolescents with type 1 diabetes mellitus. Hormone Research 2002 58 266–272. (doi:10.1159/000066441).
- 45↑
Bridges MJ, Moochhala SH, Barbour J, Kelly CA. Influence of diabetes on peripheral bone mineral density in men: a controlled study. Acta Diabetologica 2005 42 82–86. (doi:10.1007/s00592-005-0183-1).
- 46↑
Ingberg CM, Palmer M, Aman J, Arvidsson B, Schvarcz E, Berne C. Body composition and bone mineral density in long-standing type 1 diabetes. Journal of Internal Medicine 2004 255 392–398. (doi:10.1046/j.1365-2796.2003.01283.x).
- 47↑
Liu EY, Wactawski-Wende J, Donahue RP, Dmochowski J, Hovey KM, Quattrin T. Does low bone mineral density start in post-teenage years in women with type 1 diabetes? Diabetes Care 2003 26 2365–2369. (doi:10.2337/diacare.26.8.2365).
- 48↑
Lunt H, Florkowski CM, Cundy T, Kendall D, Brown LJ, Elliot JR, Wells JE, Turner JG. A population-based study of bone mineral density in women with longstanding type 1 (insulin dependent) diabetes. Diabetes Research and Clinical Practice 1998 40 31–38. (doi:10.1016/S0168-8227(98)00012-6).
- 49↑
Pascual J, Argente J, Lopez MB, Munoz M, Martinez G, Vazquez MA, Jodar E, Perez-Cano R, Hawkins F. Bone mineral density in children and adolescents with diabetes mellitus type 1 of recent onset. Calcified Tissue International 1998 62 31–35. (doi:10.1007/s002239900390).
- 50↑
Campos Pastor MM, Lopez-Ibarra PJ, Escobar-Jimenez F, Serrano Pardo MD, Garcia-Cervigon AG. Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporosis International 2000 11 455–459. (doi:10.1007/s001980070114).
- 51↑
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. (doi:10.1542/peds.2005-2193).
- 52↑
Danielson KK, Elliott ME, LeCaire T, Binkley N, Palta M. Poor glycemic control is associated with low BMD detected in premenopausal women with type 1 diabetes. Osteoporosis International 2009 20 923–933. (doi:10.1007/s00198-008-0763-3).
- 53↑
Forst T, Pfutzner A, Kann P, Schehler B, Lobmann R, Schafer H, Andreas J, Bockisch A, Beyer J. Peripheral osteopenia in adult patients with insulin-dependent diabetes mellitus. Diabetic Medicine 1995 12 874–879. (doi:10.1111/j.1464-5491.1995.tb00389.x).
- 54↑
Heap J, Murray MA, Miller SC, Jalili T, Moyer-Mileur LJ. Alterations in bone characteristics associated with glycemic control in adolescents with type 1 diabetes mellitus. Journal of Pediatrics 2004 144 56–62. (doi:10.1016/j.jpeds.2003.10.066).
- 55↑
Lettgen B, Hauffa B, Mohlmann C, Jeken C, Reiners C. Bone mineral density in children and adolescents with juvenile diabetes: selective measurement of bone mineral density of trabecular and cortical bone using peripheral quantitative computed tomography. Hormone Research 1995 43 173–175. (doi:10.1159/000184273).
- 56↑
Roggen I, Gies I, Vanbesien J, Louis O, De Schepper J. Trabecular bone mineral density and bone geometry of the distal radius at completion of pubertal growth in childhood type 1 diabetes. Hormone Research in Pædiatrics 2013 79 68–74. (doi:10.1159/000346686).
- 57↑
Saha MT, Sievanen H, Salo MK, Tulokas S, Saha HH. Bone mass and structure in adolescents with type 1 diabetes compared to healthy peers. Osteoporosis International 2009 20 1401–1406. (doi:10.1007/s00198-008-0810-0).
- 58↑
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. Diabetic Medicine 2009 26 45–52. (doi:10.1111/j.1464-5491.2008.02608.x).
- 59↑
Chobot AP, Haffke A, Polanska J, Halaba ZP, Deja G, Jarosz-Chobot P, Pluskiewicz W. Quantitative ultrasound bone measurements in pre-pubertal children with type 1 diabetes. Ultrasound in Medicine & Biology 2012 38 1109–1115. (doi:10.1016/j.ultrasmedbio.2012.02.012).
- 60↑
Damilakis J, Galanakis E, Mamoulakis D, Sbyrakis S, Gourtsoyiannis N. Quantitative ultrasound measurements in children and adolescents with: type 1 diabetes. Calcified Tissue International 2004 74 424–428. (doi:10.1007/s00223-003-0164-8).
- 61↑
Valerio G, del Puente A, Buono P, Esposito A, Zanatta M, Mozzillo E, Moretto E, Mastidoro L, Franzese A. Quantitative ultrasound of proximal phalanxes in patients with type 1 diabetes mellitus. Diabetes Research and Clinical Practice 2004 64 161–166. (doi:10.1016/j.diabres.2003.10.021).
- 62↑
Catalano A, Morabito N, Di Vieste G, Pintaudi B, Cucinotta D, Lasco A, Di Benedetto A. Phalangeal quantitative ultrasound and metabolic control in pre-menopausal women with type 1 diabetes mellitus. Journal of Endocrinological Investigation 2013 36 347–251. (doi:10.3275/8646).
- 63↑
Chobot AP, Haffke A, Polanska J, Halaba ZP, Deja G, Jarosz-Chobot P, Pluskiewicz W. Bone status in adolescents with type 1 diabetes. Diabetologia 2010 53 1754–1760. (doi:10.1007/s00125-010-1782-0).
- 64↑
Moyer-Mileur LJ, Dixon SB, Quick JL, Askew EW, Murray MA. Bone mineral acquisition in adolescents with type 1 diabetes. Journal of Pediatrics 2004 145 662–669. (doi:10.1016/j.jpeds.2004.06.070).
- 65↑
Bechtold S, Putzker S, Bonfig W, Fuchs O, Dirlenbach I, Schwarz HP. Bone size normalizes with age in children and adolescents with type 1 diabetes. Diabetes Care 2007 30 2046–2050. (doi:10.2337/dc07-0142).
- 66↑
Shanbhogue VV, Hansen S, Frost M, Jorgensen NR, Hermann AP, Henriksen JE, Brixen K. Bone geometry, volumetric density, microarchitecture, and estimated bone strength assessed by HR-pQCT in adult patients with type 1 diabetes mellitus. Journal of Bone and Mineral Research 2015 30 2188–2199. (doi:10.1002/jbmr.2573).
- 67↑
Abdalrahaman N, McComb C, Foster JE, McLean J, Lindsay RS, McClure J, McMillan M, Drummond R, Gordon D, McKay GA et al.. Deficits in trabecular bone microarchitecture in young women with type 1 diabetes mellitus. Journal of Bone and Mineral Research 2015 30 1386–1393. (doi:10.1002/jbmr.2465).
- 68↑
Granke M, Makowski AJ, Uppuganti S, Does MD, Nyman JS. Identifying novel clinical surrogates to assess human bone fracture toughness. Journal of Bone and Mineral Research 2015 30 1290–1300. (doi:10.1002/jbmr.2452).
- 69↑
Schedl HP, Heath H III, Wenger J. Serum calcitonin and parathyroid hormone in experimental diabetes: effects of insulin treatment. Endocrinology 1978 103 1368–1373. (doi:10.1210/endo-103-4-1368).
- 70↑
Schneider LE, Nowosielski LM, Schedl HP. Insulin-treatment of diabetic rats: effects on duodenal calcium absorption. Endocrinology 1977 100 67–73. (doi:10.1210/endo-100-1-67).
- 71↑
Hough S, Avioli LV, Bergfeld MA, Fallon MD, Slatopolsky E, Teitelbaum SL. Correction of abnormal bone and mineral metabolism in chronic streptozotocin-induced diabetes mellitus in the rat by insulin therapy. Endocrinology 1981 108 2228–2234. (doi:10.1210/endo-108-6-2228).
- 72↑
Hough S, Fausto A, Sonn Y, Dong Jo OK, Birge SJ, Avioli LV. Vitamin D metabolism in the chronic streptozotocin-induced diabetic rat. Endocrinology 1983 113 790–796. (doi:10.1210/endo-113-2-790).
- 73↑
Hough S, Russell JE, Teitelbaum SL, Avioli LV. Calcium homeostasis in chronic streptozotocin-induced diabetes mellitus in the rat. American Journal of Physiology 1982 242 E451–E456.
- 74↑
Hough S, Slatopolsky E, Avioli LV. Hormonal alterations in experimental diabetes: role of a primary disturbance in calcium homeostasis. Calcified Tissue International 1983 35 615–619. (doi:10.1007/BF02405103).
- 75↑
Bouillon R, Bex M, Van Herck E, Laureys J, Dooms L, Lesaffre E, Ravussin E. Influence of age, sex, and insulin on osteoblast function: osteoblast dysfunction in diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1995 80 1194–1202. (doi:10.1210/jcem.80.4.7714089).
- 76↑
Fowlkes JL, Bunn RC, Liu L, Wahl EC, Coleman HN, Cockrell GE, Perrien DS, Lumpkin CK Jr, Thrailkill KM. Runt-related transcription factor 2 (RUNX2) and RUNX2-related osteogenic genes are down-regulated throughout osteogenesis in type 1 diabetes mellitus. Endocrinology 2008 149 1697–1704. (doi:10.1210/en.2007-1408).
- 77↑
Lumachi F, Camozzi V, Tombolan V, Luisetto G. Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus. Annals of the New York Academy of Sciences 2009 1173 (Suppl 1) E64–E67. (doi:10.1111/j.1749-6632.2009.04955.x).
- 78↑
Maggio AB, Ferrari S, Kraenzlin M, Marchand LM, Schwitzgebel V, Beghetti M, Rizzoli R, Farpour-Lambert NJ. Decreased bone turnover in children and adolescents with well controlled type 1 diabetes. Journal of Pediatric Endocrinology & Metabolism 2010 23 697–707. (doi:10.1515/JPEM.2010.23.7.697).
- 79↑
Pater A, Sypniewska G, Pilecki O. Biochemical markers of bone cell activity in children with type 1 diabetes mellitus. Journal of Pediatric Endocrinology & Metabolism 2010 23 81–86. (doi:10.1515/JPEM.2010.23.1-2.81).
- 80↑
McCabe LR. Understanding the pathology and mechanisms of type I diabetic bone loss. Journal of Cellular Biochemistry 2007 102 1343–1357. (doi:10.1002/jcb.21573).
- 81↑
Maggio AB, Rizzoli RR, Marchand LM, Ferrari S, Beghetti M, Farpour-Lambert NJ. Physical activity increases bone mineral density in children with type 1 diabetes. Medicine and Science in Sports and Exercise 2012 44 1206–1211. (doi:10.1249/MSS.0b013e3182496a25).
- 82↑
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. Osteoporosis International 2006 17 1514–1523. (doi:10.1007/s00198-006-0155-5).
- 83↑
Krakauer JC, McKenna MJ, Buderer NF, Rao DS, Whitehouse FW, Parfitt AM. Bone loss and bone turnover in diabetes. Diabetes 1995 44 775–782. (doi:10.2337/diab.44.7.775).
- 84↑
Armas LA, Akhter MP, Drincic A, Recker RR. Trabecular bone histomorphometry in humans with type 1 diabetes mellitus. Bone 2012 50 91–96. (doi:10.1016/j.bone.2011.09.055).
- 85↑
Farlay D, Armas LA, Gineyts E, Akhter MP, Recker RR, Boivin G. Nonenzymatic glycation and degree of mineralization are higher in bone from fractured patients with type 1 diabetes mellitus. Journal of Bone and Mineral Research 2016 31 190–195. (doi:10.1002/jbmr.2607).
- 86↑
Maric C, Forsblom C, Thorn L, Waden J, Groop PH. Association between testosterone, estradiol and sex hormone binding globulin levels in men with type 1 diabetes with nephropathy. Steroids 2010 75 772–778. (doi:10.1016/j.steroids.2010.01.011).
- 87↑
van Dam EW, Dekker JM, Lentjes EG, Romijn FP, Smulders YM, Post WJ, Romijn JA, Krans HM. Steroids in adult men with type 1 diabetes: a tendency to hypogonadism. Diabetes Care 2003 26 1812–1818. (doi:10.2337/diacare.26.6.1812).
- 88↑
Raskin P, Stevenson MR, Barilla DE, Pak CY. The hypercalciuria of diabetes mellitus: its amelioration with insulin. Clinical Endocrinology 1978 9 329–335. (doi:10.1111/j.1365-2265.1978.tb02218.x).
- 89↑
Zhang Y, Papasian CJ, Deng HW. Alteration of vitamin D metabolic enzyme expression and calcium transporter abundance in kidney involved in type 1 diabetes-induced bone loss. Osteoporosis International 2011 22 1781–1788. (doi:10.1007/s00198-010-1404-1).
- 90↑
Frazer TE, White NH, Hough S, Santiago JV, McGee BR, Bryce G, Mallon J, Avioli LV. Alterations in circulating vitamin D metabolites in the young insulin-dependent diabetic. Journal of Clinical Endocrinology and Metabolism 1981 53 1154–1159. (doi:10.1210/jcem-53-6-1154).
- 91↑
Tiberti C, Panimolle F, Bonamico M, Filardi T, Pallotta L, Nenna R, Pontone S, Dotta F, Pugliese G, Lenzi A et al.. Long-standing type 1 diabetes: patients with adult-onset develop celiac-specific immunoreactivity more frequently than patients with childhood-onset diabetes, in a disease duration-dependent manner. Acta Diabetologica 2014 51 675–678. (doi:10.1007/s00592-013-0536-0).
- 92↑
Kream BE, Smith MD, Canalis E, Raisz LG. Characterization of the effect of insulin on collagen synthesis in fetal rat bone. Endocrinology 1985 116 296–302. (doi:10.1210/endo-116-1-296).
- 93↑
Akune T, Ogata N, Hoshi K, Kubota N, Terauchi Y, Tobe K, Takagi H, Azuma Y, Kadowaki T, Nakamura K et al.. Insulin receptor substrate-2 maintains predominance of anabolic function over catabolic function of osteoblasts. Journal of Cell Biology 2002 159 147–156. (doi:10.1083/jcb.200204046).
- 94↑
Ogata N, Chikazu D, Kubota N, Terauchi Y, Tobe K, Azuma Y, Ohta T, Kadowaki T, Nakamura K, Kawaguchi H. Insulin receptor substrate-1 in osteoblast is indispensable for maintaining bone turnover. Journal of Clinical Investigation 2000 105 935–943. (doi:10.1172/JCI9017).
- 95↑
Verhaeghe J, Suiker AM, Visser WJ, Van Herck E, Van Bree R, Bouillon R. The effects of systemic insulin, insulin-like growth factor-I and growth hormone on bone growth and turnover in spontaneously diabetic BB rats. Journal of Endocrinology 1992 134 485–492. (doi:10.1677/joe.0.1340485).
- 96↑
Irwin R, Lin HV, Motyl KJ, McCabe LR. Normal bone density obtained in the absence of insulin receptor expression in bone. Endocrinology 2006 147 5760–5767. (doi:10.1210/en.2006-0700).
- 97↑
Rosen CJ. Sugar and bone: a not-so sweet story. Journal of Bone and Mineral Research 2008 23 1881–1883. (doi:10.1359/jbmr.081001).
- 98↑
Meier C, Schwartz AV, Egger A, Lecka-Czernik B. Effects of diabetes drugs on the skeleton. Bone 2016 82 93–100. (doi:10.1016/j.bone.2015.04.026).
- 99↑
Mansur SA, Mieczkowska A, Bouvard B, Flatt PR, Chappard D, Irwin N, Mabilleau G. Stable incretin mimetics counter rapid deterioration of bone quality in type 1 diabetes mellitus. Journal of Cellular Physiology 2015 230 3009–3018. (doi:10.1002/jcp.25033).
- 100↑
Botolin S, McCabe LR. Chronic hyperglycemia modulates osteoblast gene expression through osmotic and non-osmotic pathways. Journal of Cellular Biochemistry 2006 99 411–424. (doi:10.1002/jcb.20842).
- 101↑
Sanguineti R, Puddu A, Mach F, Montecucco F, Viviani GL. Advanced glycation end products play adverse proinflammatory activities in osteoporosis. Mediators of Inflammation 2014 2014 975872. (doi:10.1155/2014/975872).
- 102↑
Neumann T, Lodes S, Kastner B, Franke S, Kiehntopf M, Lehmann T, Muller UA, Wolf G, Samann A. High serum pentosidine but not esRAGE is associated with prevalent fractures in type 1 diabetes independent of bone mineral density and glycaemic control. Osteoporosis International 2014 25 1527–1533. (doi:10.1007/s00198-014-2631-7).
- 103↑
Diascro DD Jr, Vogel RL, Johnson TE, Witherup KM, Pitzenberger SM, Rutledge SJ, Prescott DJ, Rodan GA, Schmidt A. High fatty acid content in rabbit serum is responsible for the differentiation of osteoblasts into adipocyte-like cells. Journal of Bone and Mineral Research 1998 13 96–106. (doi:10.1359/jbmr.1998.13.1.96).
- 104↑
Botolin S, McCabe LR. Inhibition of PPARγ prevents type I diabetic bone marrow adiposity but not bone loss. Journal of Cellular Physiology 2006 209 967–976. (doi:10.1002/jcp.20804).
- 105↑
Jin Y, Sharma A, Carey C, Hopkins D, Wang X, Robertson DG, Bode B, Anderson SW, Reed JC, Steed RD et al.. The expression of inflammatory genes is upregulated in peripheral blood of patients with type 1 diabetes. Diabetes Care 2013 36 2794–2802. (doi:10.2337/dc12-1986).
- 106↑
Kotake S, Nanke Y. Effect of TNFα on osteoblastogenesis from mesenchymal stem cells. Biochimica et Biophysica Acta 2014 1840 1209–1213. (doi:10.1016/j.bbagen.2013.12.013).
- 107↑
Baum R, Gravallese EM. Impact of inflammation on the osteoblast in rheumatic diseases. Current Osteoporosis Reports 2014 12 9–16. (doi:10.1007/s11914-013-0183-y).
- 108↑
Baron R, Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nature Medicine 2013 19 179–192. (doi:10.1038/nm.3074).
- 109↑
Catalano A, Pintaudi B, Morabito N, Di Vieste G, Giunta L, Bruno ML, Cucinotta D, Lasco A, Di Benedetto A. Gender differences in sclerostin and clinical characteristics in type 1 diabetes mellitus. European Journal of Endocrinology/European Federation of Endocrine Societies 2014 171 293–300. (doi:10.1530/EJE-14-0106).
- 110↑
Daniele G, Winnier D, Mari A, Bruder J, Fourcaudot M, Pengou Z, Tripathy D, Jenkinson C, Folli F. Sclerostin and insulin resistance in prediabetes: evidence of a cross talk between bone and glucose metabolism. Diabetes Care 2015 38 1509–1517. (doi:10.2337/dc14-2989).
- 111↑
Horcajada-Molteni MN, Chanteranne B, Lebecque P, Davicco MJ, Coxam V, Young A, Barlet JP. Amylin and bone metabolism in streptozotocin-induced diabetic rats. Journal of Bone and Mineral Research 2001 16 958–965. (doi:10.1359/jbmr.2001.16.5.958).
- 112↑
Kassem HS, Arabi A, Zantout MS, Azar ST. Negative effect of leptin on bone mass in type 1 diabetes. Acta Diabetologica 2008 45 237–241. (doi:10.1007/s00592-008-0050-y).
- 113↑
Martos-Moreno GA, Barrios V, Soriano-Guillen L, Argente J. Relationship between adiponectin levels, acylated ghrelin levels, and short-term body mass index changes in children with diabetes mellitus type 1 at diagnosis and after insulin therapy. European Journal of Endocrinology/European Federation of Endocrine Societies 2006 155 757–761. (doi:10.1530/eje.1.02273).
- 114↑
Gordon CM, Leonard MB, Zemel BS. 2013 Pediatric Position Development Conference: executive summary and reflections. Journal of Clinical Densitometry 2014 17 219–224. (doi:10.1016/j.jocd.2014.01.007).
- 115↑
Ferrari S, Bianchi ML, Eisman JA, Foldes AJ, Adami S, Wahl DA, Stepan JJ, de Vernejoul MC, Kaufman JM. Osteoporosis in young adults: pathophysiology, diagnosis, and management. Osteoporosis International 2012 23 2735–2748. (doi:10.1007/s00198-012-2030-x).
- 116↑
Vasikaran S, Eastell R, Bruyere O, Foldes AJ, Garnero P, Griesmacher A, McClung M, Morris HA, Silverman S, Trenti T et al.. Markers of bone turnover for the prediction of fracture risk and monitoring of osteoporosis treatment: a need for international reference standards. Osteoporosis International 2011 22 391–420. (doi:10.1007/s00198-010-1501-1).
- 117↑
Neumann T, Lodes S, Kastner B, Lehmann T, Hans D, Lamy O, Muller UA, Wolf G, Samann A. Trabecular bone score in type 1 diabetes-a cross-sectional study. Osteoporosis International 2016 27 127–133. (doi:10.1007/s00198-015-3222-y).
- 118↑
Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society for Clinical Densitometry Position Development Conference on bone densitometry. Journal of Clinical Densitometry 2013 16 455–466. (doi:10.1016/j.jocd.2013.08.004).
- 119↑
Zhukouskaya VV, Eller-Vainicher C, Shepelkevich AP, Dydyshko Y, Cairoli E, Chiodini I. Bone health in type 1 diabetes: focus on evaluation and treatment in clinical practice. Journal of Endocrinological Investigation 2015 38 941–950. (doi:10.1007/s40618-015-0284-9).
- 120↑
Hofbauer LC, Brueck CC, Singh SK, Dobnig H. Osteoporosis in patients with diabetes mellitus. Journal of Bone and Mineral Research 2007 22 1317–1328. (doi:10.1359/jbmr.070510).
- 121↑
Hernlund E, Svedbom A, Ivergard M, Compston J, Cooper C, Stenmark J, McCloskey EV, Jonsson B, Kanis JA. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Archives of Osteoporosis 2013 8 136. (doi:10.1007/s11657-013-0136-1).
- 122↑
Camarca ME, Mozzillo E, Nugnes R, Zito E, Falco M, Fattorusso V, Mobilia S, Buono P, Valerio G, Troncone R et al.. Celiac disease in type 1 diabetes mellitus. Italian Journal of Pediatrics 2012 38 10. (doi:10.1186/1824-7288-38-10).
- 123↑
Ergur AT, Ocal G, Berberoglu M, Adiyaman P, Siklar Z, Aycan Z, Evliyaoglu O, Kansu A, Girgin N, Ensari A. Celiac disease and autoimmune thyroid disease in children with type 1 diabetes mellitus: clinical and HLA-genotyping results. Journal of Clinical Research in Pediatric Endocrinology 2010 2 151–154. (doi:10.4274/jcrpe.v2i4.151).
- 124↑
Motyl KJ, McCauley LK, McCabe LR. Amelioration of type I diabetes-induced osteoporosis by parathyroid hormone is associated with improved osteoblast survival. Journal of Cellular Physiology 2012 227 1326–1334. (doi:10.1002/jcp.22844).
- 125↑
Hamann C, Rauner M, Hohna Y, Bernhardt R, Mettelsiefen J, Goettsch C, Gunther KP, Stolina M, Han CY, Asuncion FJ et al.. Sclerostin antibody treatment improves bone mass, bone strength, and bone defect regeneration in rats with type 2 diabetes mellitus. Journal of Bone and Mineral Research 2013 28 627–638. (doi:10.1002/jbmr.1803).
- 126↑
Vestergaard P. Risk of newly diagnosed type 2 diabetes is reduced in users of alendronate. Calcified Tissue International 2011 89 265–270. (doi:10.1007/s00223-011-9515-z).
- 127↑
Park-Wyllie LY, Mamdani MM, Juurlink DN, Hawker GA, Gunraj N, Austin PC, Whelan DB, Weiler PJ, Laupacis A. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. Journal of the American Medical Association 2011 305 783–789. (doi:10.1001/jama.2011.190).
(IOF CSA Bone and Diabetes Working Group: K Akesson, B Abrahamsen, M S M Ardawi, M Chandran, C Cooper, R Eastell, G El Hajj Fuleihan, S Ferrari, S Hough, R Josse, D Kendler, M Kraenzlin, W Leslie, M Massi Benedetti, A Mithal, N Napoli, A Schwartz and A Suzuki)
