Osteoprotegerin serum levels in children with type 1 diabetes: a potential modulating role in bone status

in European Journal of Endocrinology
View More View Less
  • 1 Department of Paediatrics, A Meyer Children’s Hospital,Via Luca Giordano 13, 50132 Florence, Italy and 1Department of Internal Medicine, University of Florence, Florence, Italy

Objective: Children and adolescents with type 1 (insulin-dependent) diabetes mellitus (T1DM) show several impairment of bone metabolism and structure, resulting in a higher risk of decreased bone mass and its related complications later in life. Alterations of the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) system have been implicated in several metabolic bone diseases characterized by increased osteoclast differentiation and activation and enhanced bone resorption.

Design: We aimed to assess OPG levels and to investigate the possible relation between OPG levels, bone status and glycemic control in a group of prepubertal children with T1DM without microvascular complications.

Methods: Twenty-six prepubertal T1DM children (median age 9.9 years, range 4.1–13.1 years) were studied. In all patients, serum OPG, hemoglobin (Hb)A1c, parathyroid hormone (PTH) and 25-dihy-droxyvitamin D (25-D) levels were evaluated. Bone quality was determined by measuring the attenuation of ultrasound waves by bone (broadband ultrasound attenuation (BUA)) at the calcaneal site. The data were compared with those of a group of 45 age-, sex-and body-size-matched healthy children.

Results: Children with T1DM showed a reduced Z-score BUA in comparison with the control group (Student’s t-test, P < 0.0001). Plasma OPG levels were significantly higher in diabetic children than in controls (Student’s t-test, P < 0.0001). In T1DM children, Z-score BUA values displayed a significant correlation with OPG (Student’s t-test, r = −0.62; P = 0.001), and HbA1c (r = −0.59; P = 0.007). OPG levels were significantly correlated with HbA1c (r = 0.56; P = 0.008). In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P = 0.003).

Conclusions: Prepubertal children with T1DM have a significant increase of OPG levels. OPG serum concentrations are correlated to calcaneal BUA and HbA1c values. OPG could be a new marker of reduced bone mass in children with T1DM.

Abstract

Objective: Children and adolescents with type 1 (insulin-dependent) diabetes mellitus (T1DM) show several impairment of bone metabolism and structure, resulting in a higher risk of decreased bone mass and its related complications later in life. Alterations of the nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) system have been implicated in several metabolic bone diseases characterized by increased osteoclast differentiation and activation and enhanced bone resorption.

Design: We aimed to assess OPG levels and to investigate the possible relation between OPG levels, bone status and glycemic control in a group of prepubertal children with T1DM without microvascular complications.

Methods: Twenty-six prepubertal T1DM children (median age 9.9 years, range 4.1–13.1 years) were studied. In all patients, serum OPG, hemoglobin (Hb)A1c, parathyroid hormone (PTH) and 25-dihy-droxyvitamin D (25-D) levels were evaluated. Bone quality was determined by measuring the attenuation of ultrasound waves by bone (broadband ultrasound attenuation (BUA)) at the calcaneal site. The data were compared with those of a group of 45 age-, sex-and body-size-matched healthy children.

Results: Children with T1DM showed a reduced Z-score BUA in comparison with the control group (Student’s t-test, P < 0.0001). Plasma OPG levels were significantly higher in diabetic children than in controls (Student’s t-test, P < 0.0001). In T1DM children, Z-score BUA values displayed a significant correlation with OPG (Student’s t-test, r = −0.62; P = 0.001), and HbA1c (r = −0.59; P = 0.007). OPG levels were significantly correlated with HbA1c (r = 0.56; P = 0.008). In a multiple regression analysis including age, duration of diabetes, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c significantly predicted serum OPG levels (beta 0.67; P = 0.003).

Conclusions: Prepubertal children with T1DM have a significant increase of OPG levels. OPG serum concentrations are correlated to calcaneal BUA and HbA1c values. OPG could be a new marker of reduced bone mass in children with T1DM.

Introduction

Bone metabolism and density in patients with type 1 (insulin-dependent) diabetes mellitus (T1DM) have been extensively investigated, and these patients seem to be at risk of decreased bone mass (1), impairing the attainment of peak bone mass and increasing the risk of osteoporosis with its related complications in later life (24). These patients also have accelerated atherosclerosis and a greater incidence of morbidity and mortality, secondary to premature cardiovascular disease, than in the general population (5, 6). Osteoprotegerin (OPG) is a member of the tumor necrosis factor receptor (TNFR) family (7). In mice, OPG mRNA expression has been demonstrated in numerous tissues, including calvaria, skin, liver, lung and heart (8). OPG is a circulating secretory glycoprotein without a trans-membrane domain, and it works as a decoy receptor for the receptor-activator of the nuclear factor-κB ligand (RANKL) (9). RANKL and OPG are a key agonist/antagonist cytokine system, regulating important aspects of osteoclast biology, such as differentiation, fusion, survival, activation and apoptosis (8). RANKL increases the pool of active osteoclasts by activating its specific receptor RANK located on osteoclastic cells, thus increasing bone resorption, whereas OPG, which neutralizes RANKL, has the opposite effect. Alterations or abnormalities of the RANKL/OPG system have been implicated in different metabolic bone diseases characterized by increased osteoclast differentiation and activation, and by enhanced bone resorption, including glucocorticoid-induced osteoporosis, hyperparathyroidism, Paget’s disease, rheumatoid arthritis and bone malignancies (10, 11).

OPG is expressed also in the heart and vascular wall in the rodent, and OPG-deficient mice exhibit severe osteoporosis and vascular calcification of the aorta and renal arteries (12). In vitro OPG prolongs endothelial cell survival by preventing apoptosis (12). In man, OPG has also been implicated in atherogenesis (13). Serum OPG levels have been associated with fatal strokes and overall vascular mortality in elderly women (14) and coronary artery disease in men (15, 16). The quantitative high-frequency ultrasound technique (QUS) has been proposed to assess bone density and bone structure (1719) in adults and children, as well as in T1DM patients (20). By this technique, two parameters can be simultaneously determined: speed of sound (SOS) and broadband ultrasound attenuation (BUA). In normal adults and children, BUA seems to be the parameter that shows the highest correlation index with bone mineral density (BMD) determined by dual energy X-ray absorptiometry (DEXA) (21, 22), currently considered the reference standard in the evaluation of bone mass (23, 24). However, this diagnostic procedure presents some limits, in that it exposes subjects to ionizing radiation and does not provide a measure of true bone density (25, 26). In this study, we evaluated OPG levels and bone status in a group of prepubertal T1DM children. We also investigated the possible relationship between OPG levels, bone status and glycemic control in these patients.

Subjects and methods

Subjects

The study consisted of 26 prepubertal children with T1DM, 18 boys and 7 girls (median age 9.9 years; range 4.1–13.1), recruited from September 2003 to May 2004 at Meyer Children’s Hospital in Florence, Italy. T1DM was defined by the National Diabetes Data Group (27). All children had T1DM for at least 1 year. The duration of their diabetes was 5.5 ± 3.2 years (range 1.4–10.2). They were taking no medications other than insulin at the moment of study. Children with hypertension, signs of diabetic retinopathy or nephropathy, and electrophysiologic abnormalities of autonomic or peripheral neuropathy were excluded. Forty-five age-, sex- and body-size-matched healthy children (median age 9.6 ± 3.3 years; range 6.3–12.8) were also recruited. Written, informed consent was obtained from all participants after the appropriate institutional review boards had approved the study protocol.

Study protocol

Participants completed a questionnaire that was reviewed by an interviewer during the baseline examination. The questionnaire related to current medications, family and personal medical history, fracture history, age of diabetes onset, insulin regimen, calcium intake and physical activity. At baseline examination, we measured height, weight, body-mass index (BMI) and gross nutritional status. BMI was calculated as weight divided by height squared (kg/m2). Age-related reference values of height, bone age and BMI were those currently used in Italy, obtained from a wide sample of Italian children (28). Bone age was evaluated through radiographs of the left hand and wrist, and was calculated by Greulich and Pyle’s method (29). Height, bone age and BMI were normalized for chronological age by conversion to s.d. score (SDS). SDS was calculated by the following formula: patient value – mean of age-related reference value/s.d. of the age-related reference value. Gross nutritional status was evaluated by concentrations of serum albumin, urea, calcium, parathyroid hormone (PTH), 25-dihydroxyvitamin D (25-D), erythrocyte count and hemoglobin, and average corpuscular hemoglobin concentration and corpuscular volume. In these patients, clinical (diabetes duration, blood pressure and insulin dose) and laboratory data (glucose, hemoglobin (Hb)A1c and serum creatinine concentration) were also evaluated. Blood pressure was measured by a standard clinical sphygmomanometer on the right arm after a 10-min supine rest. Physical activity was assessed by a modified activity score composed of the scores for sports/leisure activities (0, <2 or >2 h per week) (30). This information was obtained with an activity questionnaire. In all T1DM patients, the presence of microvascular complications was evaluated. Retinopathy was excluded by stereoscopic fundal photography of seven fields. Microalbuminuria was assessed by the mean albumin excretion rate (AER), calculated from three consecutive, timed, overnight urine collections. Microalbuminuria was defined as AER of ≥20 μg/min in two of three samples or an albumin/creatinine ratio of ≥2.5 mg/mmol.

Laboratory methods

Serum OPG levels were measured by enzyme-linked immunosorbent assay (ELISA) with a mouse monoclonal antibody as capture antibody and a rabbit polyclonal antibody for detection (Immundiagnostik, Bensheim, Germany). The assay detects both monomeric and dimeric forms of OPG, including OPG bound to its ligand. The detection limit of this assay is 2.8 pg/ml. Intra- and interassay variabilities are less than 10%. All samples were measured in duplicate and averaged. Glycosylated hemoglobin (HbA1c) values were recorded for the previous 12-month period from the participant’s clinic record and then averaged. HbA1c was measured by HPLC (DIAMAT; Bio-Rad). The normal range is 4.1–1.4%. Serum intact (1–84) PTH concentrations were determined by a two-site chemiluminescent immunometric assay (Nichols Diagnostics, San Juan Capistrano, CA, USA). The normal range is 10–65 pg/ml. The interassay coefficient of variation was 10%. Serum 25-dihydroxy-vitamin D (25-D) was determined by competitive binding protein assay (Nichols Diagnostics). The inter-assay coefficient of variation was 8%. The normal range is 28–65 nmol/l.

Calcaneal determination

Bone quality was determined by measurement of the ultrasound wave attenuation by bone (BUA) in the frequency range 200–600 kHz. BUA (dB/MHz) was measured at the calcaneal site by two 12.5 mm transducers mounted in hand-held calipers linked to the pediatric contact ultrasound bone analyzer (CUBA) (McCue Ultrasonics Limited, Compton, Winchester, UK) (3133). The pediatric CUBA is a specific system containing normative data for children aged 5–15 years (Z-score = 0; s.d. = 1). We have established reference values for children younger than 5 years. These reference values were fully comparable to CUBA normative data. For the present study, we also evaluated an age-, sex- and body-size-matched control group of 45 children. Z-scores (difference between the patient value and the age-specific mean value divided by the normal group’s s.d.) were calculated in each patient (31, 34). The evaluations were made and analyzed by the same operator, and each value was the average of three consecutive calculations. Quality assurance was performed daily. The in vitro coefficient of variation for BUA using phantoms was 1.8%, and the in vivo coefficient of variation for BUA was 3.7%.

Statistical analysis

The data was processed by the SPSSX (SPSS Inc., Chicago, IL, USA) statistical package. All results are expressed as mean ± s.d. Comparison among groups was made by Student’s t-test (unpaired). For noncontinuous variables, the chi-square test with Yates correction was used. Spearman’s (rank) correlation test was used to determine the correlation coefficients, and multiple stepwise regression was used to determine the variables that may correlate independently with Z-score BUA values. P values of <0.05 were considered statistically significant.

Results

Clinical and laboratorycharacteristics of the subjects and controls are shown in Table 1. No statistically significant differences were found among our group of patients with T1DM and controls in height, bone age and BMI, all expressed as SDS (Table 1). As expected, HbA1c values were higher in children with T1DM than in controls (8.4 ± 1.1% vs 4.2 ± 0.2%; P < 0.0001). Z-score BUA (Table 1) appeared to be reduced in patients with T1DM (−0.46 ± 0.84 vs 0.21 ± 0.65; P < 0.0001). Plasma OPG levels (Table 1) were significantly higher in children with T1DM than in controls (71.6 ± 14.6 pg/ml vs 40.2 ± 12.0 pg/ml; P < 0.0001). The quantitative assessment of physical activity in T1DM and controls showed no significant differences. The percentage of current physical activity levels of the three categories was similar in the two groups (0 h per week group, 21% and 25% respectively; <2 h per week group, 56% and 49% respectively; >2 h per week group, 23 and 25% respectively). No statistically significant differences were found between our group of children with T1DM and controls in nutritional status markers, particularly calcium intake, PTH and 25-OH-D vitamin levels (Table 1). Nor were statistically significant differences found between the two groups in history of fractures and mean creatinine and blood pressure values. Spearman’s rank correlation test showed that, in children with T1DM, Z-score BUA values displayed a significant correlation with OPG (r = −0.62; P = 0.001) (Fig. 1A), and HbA1c (r = −0.59; P = 0.007) (Fig. 1B). Furthermore, OPG levels were significantly correlated with HbA1c (r = 0.56; P = 0.008) (Fig. 1C). Duration of diabetes was not correlated with OPG levels and BUA Z-score measurements. In a multiple regression analysis including age, duration of diabetes, insulin regimen, physical activity, calcium intake, mean HbA1c and Z-score BUA, only HbA1c was identified as a significant predictor of serum OPG (beta 0.67; P = 0.003).

Discussion

The major finding of this study is the presence of increased serum concentration of OPG in children with T1DM. OPG is an osteoclastogenesis inhibitory factor, a critical molecule for the morphogenesis and remodeling of bone, and a number of studies have been performed to assess its importance with respect to the human skeletal system (35). Increased OPG levels have been demonstrated in several chronic diseases, such as arthritis, and in T2DM adults (35). OPG has been hypothesized as representing a compensatory response to bone and vascular damage. Children and adolescents with T1DM are at risk of decreased bone mass and its related complications later in life (24), and our data confirm that these patients show reduced bone mass (35, 23, 24) and significant impairment of bone quality (7). Patients with T1DM also seemed to show reduced bone mass at the time of clinical diagnosis (36), and cohort studies indicate that diabetic patients may have a higher risk of fractures (37). Skeletal involvement in patients with T1DM has a complex pathogenesis (36), and, despite numerous papers on this problem, many questions remain unanswered. In these patients, several mechanisms may contribute to skeletal damage, such as increased urinary excretion coupled with lower intestinal absorption of calcium, inappropriate homeostatic response to PTH, impaired vitamin D metabolism regulation, reduced or increased insulin-like growth factor (IGF)-I concentration, the effects of the accumulation of glycation end products on bone tissue, and extraskeletal factors due to neuropathic and microangiopathic complications (37). Furthermore, the results regarding the metabolic disturbances leading to skeletal involvement in patients with diabetes have given nonuniform, contradictory results, and these apparent discrepancies may be ascribed to the different selection criteria of several studies, in terms of possible confounders, such as patients’ age, pathogenesis of diabetes, degree of metabolic control, and presence or absence of complications (37). In these patients, urinary calcium excretion has been found to be normal (38), increased (37), and possibly associated with lower duodenal calcium absorption. Physiologically, the reduced intestinal absorption, together with the increased urinary calcium excretion, should induce a compensatory increase of PTH secretion. Even though increased circulating PTH has been reported in one study on a small group of poorly controlled T2DM patients (39), most studies demonstrated normal or even low PTH concentrations (38, 40, 41). These patients showed PTH secretion lower than expected for homeostatic needs (42), configuring a state of ‘functional hypoparathyroidism’, as confirmed by dynamic challenge studies, such as during citrate-induced hypocalcemia (43) or hyperinsulinemic hypoglycemia (44), or after an oral glucose tolerance test (45). This functional hypoparathyroidism has been considered responsible for the low bone turnover (46). Several studies have demonstrated, in T1DM, an altered balance among vitamin D metabolites, showing a marked reduction of 24,25-D levels (47), or a decreased synthesis of vitamin D-binding protein by the liver, decreased renal 1α-hydroxylase activity, and reduced vitamin D receptor concentrations (37). Patients with T1DM also showed impaired bone structure, and decreased collagen strength, probably derived from abnormal glycosylation and cross-linking of skeletal collagen, was observed in chronically uncompensated diabetes mellitus (37). These qualitative changes may induce bone fragility that exceeds even the effects of reduced bone mass. To the best of our knowledge, our study is the first to assess bone mass and quality by the ultrasound technique at the calcaneal site in children with T1DM. QUS is a useful method for measuring the physiologic bone development in childhood and adolescence (48); the diagnostic accuracy of ultrasound measurements in identification of fracture risk associated with osteoporosis has been demonstrated in adults in both retrospective (49, 50) and prospective (51, 52) studies. Previous studies utilizing single-photon absorptiometry of the distal forearm showed that, in T1DM, a moderate decrease in cortical appendicular BMD was already present in the first years after manifestation of diabetes (36, 5355). In our patients, we did not find a significant history of fractures, even though we reported a degree of osteopenia, averaging 0.8–1.0 s.d. below that of controls. Since childhood and adolescence are crucial periods of life for the attainment of optimal bone mass (56, 57), we could speculate that T1DM children seem to be at risk of decreased bone mass (2, 3, 5861), which may restrict the attainment of peak bone mass (62) and, eventually, lead to increased risk of osteoporosis and its related complications in later life (63). Our data also confirm that, in these patients, bone mass is inversely correlated with HbA1c (4). In adults with T2DM, increased OPG values appear to be related to cardiovascular risk (14) and microvascular complications (13). OPG is abundantly expressed in the media of large arteries (7), in atherosclerotic plaques (64), and in vascular smooth muscle cells (65). Furthermore, OPG has been demonstrated to act as a survival factor for endothelial cells (66), and mice lacking the ability to produce OPG develop vascular calcification (67). Diabetes mellitus is a well-established risk factor for the early development of accelerated atherosclerosis and microangiopathy (68, 69). These vascular complications of diabetes are not clinically evident in children (68). However, subclinical vascular involvement, in the form of impaired endothelial function and increased carotid intimal-medial thickness, has been demonstrated in young subjects with T1DM (68, 70). Further prospective studies are needed to establish whether increased OPG levels in diabetic children can predict later development of endothelial dysfunction and vascular complications. In conclusion, OPG levels are significantly higher in children with T1DM; a significant correlation between OPG, bone mass, bone quality and HbA1c values has also been demonstrated. OPG could be a marker of reduced bone mass and vascular damage in children with diabetes.

Table 1

Baseline characteristics of children with T1DM and controls.

T1DM (n = 26)Controls (n = 45)P
Reference range: *10–65 pg/ml; §28–65 nmol/l.
Age (years)9.8±3.39.9±3.3NS
Sex (M/F)19/733/12NS
(%)(73/27%)(73/27%)
Diabetes duration (years)5.5±3.2
Height (SDS)−0.2±1.1−0.1±0.9NS
BMI (SDS)−0.2±0.70.3±1.0NS
Bone age (SDS)0.1±1.30.3±0.6NS
Calcium intake (mg/day)790±260825±302NS
Serum intact PTH (pg/ml)*22.6±9.025.7±12.9NS
Serum 25-OH-D (nmol/l)§37.1±18.341.6±13.5NS
HbA1c (%)8.4±1.14.2±0.2<0.0001
OPG (pg/ml)71.6±14.540.2±12.0<0.0001
Z-score BUA−0.46±0.840.21±0.65<0.0001
Figure 1
Figure 1

Relationship between (A) Z-score BUA values and osteoprotegerin (OPG) serum levels (r = −0.62; P = 0.001; (B) Z-score BUA values and HbA1c (r = −0.59; P = 0.007; and (C) OPG serum levels and HbA1c (r = 0.56; P = 0.008).

Citation: European Journal of Endocrinology eur j endocrinol 153, 6; 10.1530/eje.1.02052

References

  • 1

    Carnevale V, Romagnoli E & D’Erasmo E. Skeletal involvement in patients with diabetes mellitus. Diabetes Metabolism Research and Reviews 2004 20 196–204.

    • Search Google Scholar
    • Export Citation
  • 2

    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.

    • Search Google Scholar
    • Export Citation
  • 3

    Gunczler P, Lanes R, Paz-Martinex 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 and Metabolism 1998 11 413–419.

    • Search Google Scholar
    • Export Citation
  • 4

    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.

    • Search Google Scholar
    • Export Citation
  • 5

    Dorman JS, Laporte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE & Drash AL. The Pitts-burgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study: mortality results. Diabetes 1984 33 271–276.

    • Search Google Scholar
    • Export Citation
  • 6

    Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes mellitus, Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes mellitus. New England Journal of Medicine 2003 348 2294–2303.

    • Search Google Scholar
    • Export Citation
  • 7

    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliot R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R & Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997 89 309–319.

    • Search Google Scholar
    • Export Citation
  • 8

    Horowitz MC, Xi Y, Wilson K & Kacena MA. Control of osteoclas-togenesis and bone resorption by members of the TNF family of receptors and ligands. Cytokine and Growth FactorReviews 2001 12 9–18.

    • Search Google Scholar
    • Export Citation
  • 9

    Oh KW, Rhee EJ, Lee WY, Kim SW, Oh ES, Baek KH, Kang MI, Choi MG, Yoo HJ & Park SW. The relationship between circulating osteoprotegerin levels and bone mineral metabolism in healthy women. Clinical Endocrinology 2004 61 244–249.

    • Search Google Scholar
    • Export Citation
  • 10

    Masi L, Simonini G, Piscitelli E, Del Monte F, Giani T, Cimaz R, Vierucci S, Brandi ML & Falcini F. Osteoprotegerin (OPG)/RANK-L system in juvenile idiopathic arthritis: is there a potential modulating role for OPG/RANK-L in bone injury? Journal of Rheumatology 2004 31 986–991.

    • Search Google Scholar
    • Export Citation
  • 11

    Jones DH, Kong YY & Penninger JM. Role of RANKL and RANK in bone loss and arthritis. Annals of the Rheumatic Diseases 2002 61 32–39.

  • 12

    Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B & Hofbauer LC. Increased osteoprotegerin serum levels in men with coronary artery disease. Journal of Clinical Endocrinology and Metabolism 2003 88 1024–1028.

    • Search Google Scholar
    • Export Citation
  • 13

    Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, Santer P, Smolen J, Poewe W & Willeit J. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004 109 2175–2180.

    • Search Google Scholar
    • Export Citation
  • 14

    Browner WS, Lui LY & Cumming SR. Association of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. Journal of Clinical Endocrinology and Metabolism 2001 86 631–637.

    • Search Google Scholar
    • Export Citation
  • 15

    Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K & Nishirawa Y. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002 106 1192–1194.

    • Search Google Scholar
    • Export Citation
  • 16

    Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B & Hofbauer LC. Increased serum levels in men with coronary artery disease. Journal of Clinical Endocrinology and Metabolism 2003 88 1024–1028.

    • Search Google Scholar
    • Export Citation
  • 17

    Gluer CC. Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. International Quantitative Ultrasound Consensus Group. Journal of Bone and Mineral Research 1997 12 1280–1288.

    • Search Google Scholar
    • Export Citation
  • 18

    Mughal MZ, Ward K, Qayyum N & Langton CM. Assessment of bone status using the contact ultrasound bone analyzer. Archives of Disease in Childhood 1997 76 535–536.

    • Search Google Scholar
    • Export Citation
  • 19

    Prins SH, Jørgensen HL, Jørgensen LV & Hassager C. The role of quantitative ultrasound in the assessment of bone: a review. Clinical Physiology 1998 18 3–17.

    • Search Google Scholar
    • Export Citation
  • 20

    Rix M, Andreassen H & Eskildsen P. Impact of peripheral neuropathy on bone density in patients with type 1 diabetes. Diabetes Care 1999 22 827–831.

    • Search Google Scholar
    • Export Citation
  • 21

    Roux C, Fournier B, Laugier P, Chappard C, Kolta S, Dougados M & Berger G. Broadband ultrasound attenuation imaging: a new imaging method in osteoporosis. Journal of Bone and Mineral Research 1996 11 1112–1118.

    • Search Google Scholar
    • Export Citation
  • 22

    Massie A, Reid DM & Porter RW. Screening for osteoporosis: comparison between dual energy x-ray absorptiometry and broadband ultrasound attenuation in 1000 perimenopausal women. Osteoporosis International 1993 3 107–110.

    • Search Google Scholar
    • Export Citation
  • 23

    Cadogan J, Eastell R, Jones N & Barker ME. Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. British Medical Journal 1997 315 1255–1260.

    • Search Google Scholar
    • Export Citation
  • 24

    Del Rio L, Carrascosa A, Pons F, Gusinyé M, Yeste D & Domenech FM. Bone mineral density of lumbar spine in white Mediterranean Spanish children and adolescents: changes related to age, sex and puberty. Pediatric Research 1994 35 362–366.

    • Search Google Scholar
    • Export Citation
  • 25

    Prentice A, Parsons TJ & Cole TJ. Uncritical use of bone mineral density in absorptiometry may lead to size-related artefacts in the identification of bone mineral determinants. American Journal of Clinical Nutrition 1994 60 837–842.

    • Search Google Scholar
    • Export Citation
  • 26

    Compston JE. Bone density: BMC, BMD, or corrected BMD? Bone 1995 16 5–7.

  • 27

    ADA, Diagnosis classification of diabetes mellitus. Diabetes Care 2005 28 S37–S42.

  • 28

    Nicoletti I. Auxologia normale e patologica. Firenze: Centro Studi Auxologici, 1994.

  • 29

    Greulich WW & Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, CA: Stanford University Press, 1959.

  • 30

    Pitsavos C, Panagiotakos DP, Lentzas Y & Stefanadis C. Epidemiology of leisure-time physical activity in socio-demographic, lifestyle and psychological characteristics of men and women in Greece: the ATTICA Study. BMC Public Health 2005 5 37–46.

    • Search Google Scholar
    • Export Citation
  • 31

    Falcini F, Bindi G, Ermini M, Galluzzi F, Poggi G, Rossi S, Masi L, Cimaz R & Brandi ML. Comparison of quantitative calcaneal ultrasound and dual energy X-ray absorptiometry in the evaluation of osteoporotic risk in children with chronic rheumatic diseases. Calcified Tissue International 2000 67 19–23.

    • Search Google Scholar
    • Export Citation
  • 32

    Falcini F, Bindi G, Simonini G, Stagi S, Galluzzi F, Masi L & Cimaz R. Bone status evaluation with calcaneal ultrasound in children with chronic rheumatic diseases. A one year follow-up study. Journal of Rheumatology 2003 30 179–184.

    • Search Google Scholar
    • Export Citation
  • 33

    Stagi S, Bindi G, Galluzzi F, Galli L, Salti R & de Martino M. Changed bone status in HIV-1 perinatally infected children is related to low serum free insulin-like growth factor I (IGF-I). Clinical Endocrinology 2004 61 692–699.

    • Search Google Scholar
    • Export Citation
  • 34

    Simonini G, Giani T, Stagi S, de Martino M & Falini F. Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis. Rheumatology 2005 44 777–780.

    • Search Google Scholar
    • Export Citation
  • 35

    Hofbauer LC & Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004 292 490–495.

    • Search Google Scholar
    • Export Citation
  • 36

    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 in adult-onset type 1 diabetes mellitus. Endocrine Practice 2001 7 346–351.

    • Search Google Scholar
    • Export Citation
  • 37

    Carnevale V, Romagnoli E & D’Erasmo E. Skeletal involvement in patients with diabetes mellitus. Diabetes Metabolism Research and Reviews 2004 20 196–204.

    • Search Google Scholar
    • Export Citation
  • 38

    Kemink SAG, Hermus ARMM, Swinkels LMJW, Lutterman JA & Smals AGH. Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. Journal of Endocrinological Investigation 2000 23 295–303.

    • Search Google Scholar
    • Export Citation
  • 39

    Gregorio F, Cristallini S, Santeusanio P, Filipponi F & Fumelli P. Osteopenia associated with non-insulin dependent diabetes mellitus. What are the causes? Diabetes Research and Clinical Practice 1994 23 43–54.

    • Search Google Scholar
    • Export Citation
  • 40

    Heath H 3rd, Lambert PW, Service FJ & Arnaud SB. Calcium homeostasis in diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1979 49 462–466.

    • Search Google Scholar
    • Export Citation
  • 41

    Piepkorn B, Kann P, Forst T, Andreas J, Pfutzner A & Beyer J. Bone mineral density and bone metabolism in diabetes mellitus. Hormone and Metabolic Research 1997 29 584–591.

    • Search Google Scholar
    • Export Citation
  • 42

    McNair P, Christensen MS, Madsbad S, Christiansen C & Transbol I. Hypoparathyroidism in diabetes mellitus. Acta Endocrinologica 1981 96 81–86.

    • Search Google Scholar
    • Export Citation
  • 43

    Schwarz P, Sorensen HA, Momsen G, Friis T, Transbol I & McNair P. Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clamp study. Acta Endocrinologica 1992 126 260–263.

    • Search Google Scholar
    • Export Citation
  • 44

    Clowes JA, Robinson RT, Heller SR, Eastell R & Blumsohn A. Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies. Journal of Clinical Endocrinology and Metabolism 2002 87 3324–3329.

    • Search Google Scholar
    • Export Citation
  • 45

    D’Erasmo E, Pisani D, Ragno A, Raejntroph N, Vecci E & Acca M. Calcium homeostasis during oral glucose load in healthy women. Hormone and Metabolic Research 1999 31 271–273.

    • Search Google Scholar
    • Export Citation
  • 46

    Inaba M, Nagasue K, Okuno S, Ueda M, Kumeda Y, Imanishi Y, Shoji T, Ishimura E, Ohta T, Nakatani T, Kim M & Nishizawa Y. Impaired secretion of parathyroid hormone, but not refractoriness of osteoblast, is a major mechanism of low bone turnover in hemodialyzed patients with diabetes mellitus. American Journal of Kidney Diseases 2002 39 1261–1269.

    • Search Google Scholar
    • Export Citation
  • 47

    Christiansen C, Christensen MS, McNair P, Nielsen B & Madsbad S. Vitamin D metabolites in diabetic patients: decreased serum concentration of 24,25dihydroxyvitamin D. Scandinavian Journal of Clinical and Laboratory Investigation 1982 42 487–491.

    • Search Google Scholar
    • Export Citation
  • 48

    Wunsche K, Wunsche B, Fahnrich H, Mentzel HJ, Vogt S, Abendroth K & Kaiser WA. Ultrasound bone densitometry of the os calcis in children and adolescents. Calcified Tissue International 2000 67 39–355.

    • Search Google Scholar
    • Export Citation
  • 49

    Stewart A, Reid DM & Porter RW. Broadband ultrasound attenuation and dual energy X-ray absorptiometry in patients with hip fractures: which technique discriminates fracture risk? Calcified Tissue International 1994 54 466–469.

    • Search Google Scholar
    • Export Citation
  • 50

    Turner CH, Peacock M, Timmerman L, Neal JM & Johnson CC Jr. Calcaneal ultrasonic measurements discriminate hip fracture independently of bone mass. Osteoporosis International 1995 5 130–135.

    • Search Google Scholar
    • Export Citation
  • 51

    Porter RW, Miller CG, Grainger D & Palmer SB. Prediction of hip fracture in elderly women: a prospective study. British Medical Journal 1990 301 638–641.

    • Search Google Scholar
    • Export Citation
  • 52

    Khaw KT, Reeve J, Luben R, Bingham S, Welch A, Wareham N, Oakes S & Day N. Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study. Lancet 2004 363 197–202.

    • Search Google Scholar
    • Export Citation
  • 53

    Krakauer JC, McKenna MJ, Buderer NF, Rao S, Whitehouse FW & Parfitt AM. Bone loss and bone turnover in diabetes. Diabetes 1995 44 775–782.

    • Search Google Scholar
    • Export Citation
  • 54

    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.

    • Search Google Scholar
    • Export Citation
  • 55

    Hui SL, Epstein S & Johnston CCA. Prospective study on bone mass in patients with type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 1985 60 74–80.

    • Search Google Scholar
    • Export Citation
  • 56

    Bachrach L. Acquisition of optimal bone mass in childhood and adolescence. Trends in Endocrinology and Metabolism 2001 12 22–28.

  • 57

    Mora S & Gilsanz V. Establishment of peak bone mass. Endocrinology and Metabolism Clinics of North America 2003 32 39–63.

  • 58

    Lettgen B, Hauffa B, Mohlmann C, Jaken C & Reiners C. Bone mineral density in children and adolescents with juvenile diabetes: selective measurement of bone mineral of trabecular and cortical bone using peripheral quantitative computer tomography. Hormone Research 1995 43 173–175.

    • Search Google Scholar
    • Export Citation
  • 59

    Campos-Pastor MM, Lopez-Ibarra PJ, Escobar-Jimenez F, Serrano-Pardo MD & Garcia-Cervignon AG. Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporosis International 2000 11 455–459.

    • Search Google Scholar
    • Export Citation
  • 60

    Leidig-Bruckner G & Ziegler R. Diabetes mellitus: a risk for osteoporosis? Experimental and Clinical Endocrinology and Diabetes 2001 109 S493–S514.

    • Search Google Scholar
    • Export Citation
  • 61

    Gunczler P, Lanes R, Paoli M, Martinez V, Villarel O & Weisinger JR. Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 2001 14 525–528.

    • Search Google Scholar
    • Export Citation
  • 62

    Nevitt MA, Johnell O, Black DM, Ensrud K, Genant HK & Cummings SR. Bone mineral density predicts non-spine fractures in very elderly women. Study of Osteoporotic Fractures Research Group. Osteoporosis International 1994 4 325–331.

    • Search Google Scholar
    • Export Citation
  • 63

    Melton LJ, Atkinson EF, O’Fallon WM, Wahner HW & Riggs BL. Long-term fracture prediction by bone mineral assessed at different skeletal sites. Journal of Bone and Mineral Research 1993 8 1227–1233.

    • Search Google Scholar
    • Export Citation
  • 64

    Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, Tordoir JH, Spronk HM, Vermeer C & Daemen MJ. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arteriosclerosis, Thrombosis and Vascular Biology 2001 21 1998–2003.

    • Search Google Scholar
    • Export Citation
  • 65

    Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X & Chen YE. PDGF induced osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Letters 2002 521 180–184.

    • Search Google Scholar
    • Export Citation
  • 66

    Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA & Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. Journal of Biological Chemistry 2000 275 959–962.

    • Search Google Scholar
    • Export Citation
  • 67

    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ & Simonet WS. Osteo-protegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes and Development 1998 12 1260–1268.

    • Search Google Scholar
    • Export Citation
  • 68

    Singh TP, Groehn H & Kazmers A. Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. Journal of the American College of Cardiology 2003 41 661–665.

    • Search Google Scholar
    • Export Citation
  • 69

    Nathan DM. Long-term complications of diabetes mellitus. New England Journal of Medicine 1993 328 1676–1685.

  • 70

    Järvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, Lehtimaki T, Ronnemaa T, Viikari J & Raitakari OT. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004 109 1750–1755.

    • Search Google Scholar
    • Export Citation

 

     European Society of Endocrinology

Sept 2018 onwards Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 808 94 11
PDF Downloads 258 58 3
  • View in gallery

    Relationship between (A) Z-score BUA values and osteoprotegerin (OPG) serum levels (r = −0.62; P = 0.001; (B) Z-score BUA values and HbA1c (r = −0.59; P = 0.007; and (C) OPG serum levels and HbA1c (r = 0.56; P = 0.008).

  • 1

    Carnevale V, Romagnoli E & D’Erasmo E. Skeletal involvement in patients with diabetes mellitus. Diabetes Metabolism Research and Reviews 2004 20 196–204.

    • Search Google Scholar
    • Export Citation
  • 2

    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.

    • Search Google Scholar
    • Export Citation
  • 3

    Gunczler P, Lanes R, Paz-Martinex 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 and Metabolism 1998 11 413–419.

    • Search Google Scholar
    • Export Citation
  • 4

    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.

    • Search Google Scholar
    • Export Citation
  • 5

    Dorman JS, Laporte RE, Kuller LH, Cruickshanks KJ, Orchard TJ, Wagener DK, Becker DJ, Cavender DE & Drash AL. The Pitts-burgh insulin-dependent diabetes mellitus (IDDM) morbidity and mortality study: mortality results. Diabetes 1984 33 271–276.

    • Search Google Scholar
    • Export Citation
  • 6

    Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes mellitus, Intensive diabetes therapy and carotid intima–media thickness in type 1 diabetes mellitus. New England Journal of Medicine 2003 348 2294–2303.

    • Search Google Scholar
    • Export Citation
  • 7

    Simonet WS, Lacey DL, Dunstan CR, Kelley M, Chang MS, Luthy R, Nguyen HQ, Wooden S, Bennett L, Boone T, Shimamoto G, DeRose M, Elliot R, Colombero A, Tan HL, Trail G, Sullivan J, Davy E, Bucay N, Renshaw-Gegg L, Hughes TM, Hill D, Pattison W, Campbell P, Sander S, Van G, Tarpley J, Derby P, Lee R & Boyle WJ. Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 1997 89 309–319.

    • Search Google Scholar
    • Export Citation
  • 8

    Horowitz MC, Xi Y, Wilson K & Kacena MA. Control of osteoclas-togenesis and bone resorption by members of the TNF family of receptors and ligands. Cytokine and Growth FactorReviews 2001 12 9–18.

    • Search Google Scholar
    • Export Citation
  • 9

    Oh KW, Rhee EJ, Lee WY, Kim SW, Oh ES, Baek KH, Kang MI, Choi MG, Yoo HJ & Park SW. The relationship between circulating osteoprotegerin levels and bone mineral metabolism in healthy women. Clinical Endocrinology 2004 61 244–249.

    • Search Google Scholar
    • Export Citation
  • 10

    Masi L, Simonini G, Piscitelli E, Del Monte F, Giani T, Cimaz R, Vierucci S, Brandi ML & Falcini F. Osteoprotegerin (OPG)/RANK-L system in juvenile idiopathic arthritis: is there a potential modulating role for OPG/RANK-L in bone injury? Journal of Rheumatology 2004 31 986–991.

    • Search Google Scholar
    • Export Citation
  • 11

    Jones DH, Kong YY & Penninger JM. Role of RANKL and RANK in bone loss and arthritis. Annals of the Rheumatic Diseases 2002 61 32–39.

  • 12

    Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B & Hofbauer LC. Increased osteoprotegerin serum levels in men with coronary artery disease. Journal of Clinical Endocrinology and Metabolism 2003 88 1024–1028.

    • Search Google Scholar
    • Export Citation
  • 13

    Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, Santer P, Smolen J, Poewe W & Willeit J. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004 109 2175–2180.

    • Search Google Scholar
    • Export Citation
  • 14

    Browner WS, Lui LY & Cumming SR. Association of serum osteoprotegerin levels with diabetes, stroke, bone density, fractures, and mortality in elderly women. Journal of Clinical Endocrinology and Metabolism 2001 86 631–637.

    • Search Google Scholar
    • Export Citation
  • 15

    Jono S, Ikari Y, Shioi A, Mori K, Miki T, Hara K & Nishirawa Y. Serum osteoprotegerin levels are associated with the presence and severity of coronary artery disease. Circulation 2002 106 1192–1194.

    • Search Google Scholar
    • Export Citation
  • 16

    Schoppet M, Sattler AM, Schaefer JR, Herzum M, Maisch B & Hofbauer LC. Increased serum levels in men with coronary artery disease. Journal of Clinical Endocrinology and Metabolism 2003 88 1024–1028.

    • Search Google Scholar
    • Export Citation
  • 17

    Gluer CC. Quantitative ultrasound techniques for the assessment of osteoporosis: expert agreement on current status. International Quantitative Ultrasound Consensus Group. Journal of Bone and Mineral Research 1997 12 1280–1288.

    • Search Google Scholar
    • Export Citation
  • 18

    Mughal MZ, Ward K, Qayyum N & Langton CM. Assessment of bone status using the contact ultrasound bone analyzer. Archives of Disease in Childhood 1997 76 535–536.

    • Search Google Scholar
    • Export Citation
  • 19

    Prins SH, Jørgensen HL, Jørgensen LV & Hassager C. The role of quantitative ultrasound in the assessment of bone: a review. Clinical Physiology 1998 18 3–17.

    • Search Google Scholar
    • Export Citation
  • 20

    Rix M, Andreassen H & Eskildsen P. Impact of peripheral neuropathy on bone density in patients with type 1 diabetes. Diabetes Care 1999 22 827–831.

    • Search Google Scholar
    • Export Citation
  • 21

    Roux C, Fournier B, Laugier P, Chappard C, Kolta S, Dougados M & Berger G. Broadband ultrasound attenuation imaging: a new imaging method in osteoporosis. Journal of Bone and Mineral Research 1996 11 1112–1118.

    • Search Google Scholar
    • Export Citation
  • 22

    Massie A, Reid DM & Porter RW. Screening for osteoporosis: comparison between dual energy x-ray absorptiometry and broadband ultrasound attenuation in 1000 perimenopausal women. Osteoporosis International 1993 3 107–110.

    • Search Google Scholar
    • Export Citation
  • 23

    Cadogan J, Eastell R, Jones N & Barker ME. Milk intake and bone mineral acquisition in adolescent girls: randomised, controlled intervention trial. British Medical Journal 1997 315 1255–1260.

    • Search Google Scholar
    • Export Citation
  • 24

    Del Rio L, Carrascosa A, Pons F, Gusinyé M, Yeste D & Domenech FM. Bone mineral density of lumbar spine in white Mediterranean Spanish children and adolescents: changes related to age, sex and puberty. Pediatric Research 1994 35 362–366.

    • Search Google Scholar
    • Export Citation
  • 25

    Prentice A, Parsons TJ & Cole TJ. Uncritical use of bone mineral density in absorptiometry may lead to size-related artefacts in the identification of bone mineral determinants. American Journal of Clinical Nutrition 1994 60 837–842.

    • Search Google Scholar
    • Export Citation
  • 26

    Compston JE. Bone density: BMC, BMD, or corrected BMD? Bone 1995 16 5–7.

  • 27

    ADA, Diagnosis classification of diabetes mellitus. Diabetes Care 2005 28 S37–S42.

  • 28

    Nicoletti I. Auxologia normale e patologica. Firenze: Centro Studi Auxologici, 1994.

  • 29

    Greulich WW & Pyle SI. Radiographic Atlas of Skeletal Development of the Hand and Wrist. Stanford, CA: Stanford University Press, 1959.

  • 30

    Pitsavos C, Panagiotakos DP, Lentzas Y & Stefanadis C. Epidemiology of leisure-time physical activity in socio-demographic, lifestyle and psychological characteristics of men and women in Greece: the ATTICA Study. BMC Public Health 2005 5 37–46.

    • Search Google Scholar
    • Export Citation
  • 31

    Falcini F, Bindi G, Ermini M, Galluzzi F, Poggi G, Rossi S, Masi L, Cimaz R & Brandi ML. Comparison of quantitative calcaneal ultrasound and dual energy X-ray absorptiometry in the evaluation of osteoporotic risk in children with chronic rheumatic diseases. Calcified Tissue International 2000 67 19–23.

    • Search Google Scholar
    • Export Citation
  • 32

    Falcini F, Bindi G, Simonini G, Stagi S, Galluzzi F, Masi L & Cimaz R. Bone status evaluation with calcaneal ultrasound in children with chronic rheumatic diseases. A one year follow-up study. Journal of Rheumatology 2003 30 179–184.

    • Search Google Scholar
    • Export Citation
  • 33

    Stagi S, Bindi G, Galluzzi F, Galli L, Salti R & de Martino M. Changed bone status in HIV-1 perinatally infected children is related to low serum free insulin-like growth factor I (IGF-I). Clinical Endocrinology 2004 61 692–699.

    • Search Google Scholar
    • Export Citation
  • 34

    Simonini G, Giani T, Stagi S, de Martino M & Falini F. Bone status over 1 yr of etanercept treatment in juvenile idiopathic arthritis. Rheumatology 2005 44 777–780.

    • Search Google Scholar
    • Export Citation
  • 35

    Hofbauer LC & Schoppet M. Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA 2004 292 490–495.

    • Search Google Scholar
    • Export Citation
  • 36

    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 in adult-onset type 1 diabetes mellitus. Endocrine Practice 2001 7 346–351.

    • Search Google Scholar
    • Export Citation
  • 37

    Carnevale V, Romagnoli E & D’Erasmo E. Skeletal involvement in patients with diabetes mellitus. Diabetes Metabolism Research and Reviews 2004 20 196–204.

    • Search Google Scholar
    • Export Citation
  • 38

    Kemink SAG, Hermus ARMM, Swinkels LMJW, Lutterman JA & Smals AGH. Osteopenia in insulin-dependent diabetes mellitus; prevalence and aspects of pathophysiology. Journal of Endocrinological Investigation 2000 23 295–303.

    • Search Google Scholar
    • Export Citation
  • 39

    Gregorio F, Cristallini S, Santeusanio P, Filipponi F & Fumelli P. Osteopenia associated with non-insulin dependent diabetes mellitus. What are the causes? Diabetes Research and Clinical Practice 1994 23 43–54.

    • Search Google Scholar
    • Export Citation
  • 40

    Heath H 3rd, Lambert PW, Service FJ & Arnaud SB. Calcium homeostasis in diabetes mellitus. Journal of Clinical Endocrinology and Metabolism 1979 49 462–466.

    • Search Google Scholar
    • Export Citation
  • 41

    Piepkorn B, Kann P, Forst T, Andreas J, Pfutzner A & Beyer J. Bone mineral density and bone metabolism in diabetes mellitus. Hormone and Metabolic Research 1997 29 584–591.

    • Search Google Scholar
    • Export Citation
  • 42

    McNair P, Christensen MS, Madsbad S, Christiansen C & Transbol I. Hypoparathyroidism in diabetes mellitus. Acta Endocrinologica 1981 96 81–86.

    • Search Google Scholar
    • Export Citation
  • 43

    Schwarz P, Sorensen HA, Momsen G, Friis T, Transbol I & McNair P. Hypocalcemia and parathyroid hormone responsiveness in diabetes mellitus: a tri-sodium-citrate clamp study. Acta Endocrinologica 1992 126 260–263.

    • Search Google Scholar
    • Export Citation
  • 44

    Clowes JA, Robinson RT, Heller SR, Eastell R & Blumsohn A. Acute changes of bone turnover and PTH induced by insulin and glucose: euglycemic and hypoglycemic hyperinsulinemic clamp studies. Journal of Clinical Endocrinology and Metabolism 2002 87 3324–3329.

    • Search Google Scholar
    • Export Citation
  • 45

    D’Erasmo E, Pisani D, Ragno A, Raejntroph N, Vecci E & Acca M. Calcium homeostasis during oral glucose load in healthy women. Hormone and Metabolic Research 1999 31 271–273.

    • Search Google Scholar
    • Export Citation
  • 46

    Inaba M, Nagasue K, Okuno S, Ueda M, Kumeda Y, Imanishi Y, Shoji T, Ishimura E, Ohta T, Nakatani T, Kim M & Nishizawa Y. Impaired secretion of parathyroid hormone, but not refractoriness of osteoblast, is a major mechanism of low bone turnover in hemodialyzed patients with diabetes mellitus. American Journal of Kidney Diseases 2002 39 1261–1269.

    • Search Google Scholar
    • Export Citation
  • 47

    Christiansen C, Christensen MS, McNair P, Nielsen B & Madsbad S. Vitamin D metabolites in diabetic patients: decreased serum concentration of 24,25dihydroxyvitamin D. Scandinavian Journal of Clinical and Laboratory Investigation 1982 42 487–491.

    • Search Google Scholar
    • Export Citation
  • 48

    Wunsche K, Wunsche B, Fahnrich H, Mentzel HJ, Vogt S, Abendroth K & Kaiser WA. Ultrasound bone densitometry of the os calcis in children and adolescents. Calcified Tissue International 2000 67 39–355.

    • Search Google Scholar
    • Export Citation
  • 49

    Stewart A, Reid DM & Porter RW. Broadband ultrasound attenuation and dual energy X-ray absorptiometry in patients with hip fractures: which technique discriminates fracture risk? Calcified Tissue International 1994 54 466–469.

    • Search Google Scholar
    • Export Citation
  • 50

    Turner CH, Peacock M, Timmerman L, Neal JM & Johnson CC Jr. Calcaneal ultrasonic measurements discriminate hip fracture independently of bone mass. Osteoporosis International 1995 5 130–135.

    • Search Google Scholar
    • Export Citation
  • 51

    Porter RW, Miller CG, Grainger D & Palmer SB. Prediction of hip fracture in elderly women: a prospective study. British Medical Journal 1990 301 638–641.

    • Search Google Scholar
    • Export Citation
  • 52

    Khaw KT, Reeve J, Luben R, Bingham S, Welch A, Wareham N, Oakes S & Day N. Prediction of total and hip fracture risk in men and women by quantitative ultrasound of the calcaneus: EPIC-Norfolk prospective population study. Lancet 2004 363 197–202.

    • Search Google Scholar
    • Export Citation
  • 53

    Krakauer JC, McKenna MJ, Buderer NF, Rao S, Whitehouse FW & Parfitt AM. Bone loss and bone turnover in diabetes. Diabetes 1995 44 775–782.

    • Search Google Scholar
    • Export Citation
  • 54

    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.

    • Search Google Scholar
    • Export Citation
  • 55

    Hui SL, Epstein S & Johnston CCA. Prospective study on bone mass in patients with type 1 diabetes. Journal of Clinical Endocrinology and Metabolism 1985 60 74–80.

    • Search Google Scholar
    • Export Citation
  • 56

    Bachrach L. Acquisition of optimal bone mass in childhood and adolescence. Trends in Endocrinology and Metabolism 2001 12 22–28.

  • 57

    Mora S & Gilsanz V. Establishment of peak bone mass. Endocrinology and Metabolism Clinics of North America 2003 32 39–63.

  • 58

    Lettgen B, Hauffa B, Mohlmann C, Jaken C & Reiners C. Bone mineral density in children and adolescents with juvenile diabetes: selective measurement of bone mineral of trabecular and cortical bone using peripheral quantitative computer tomography. Hormone Research 1995 43 173–175.

    • Search Google Scholar
    • Export Citation
  • 59

    Campos-Pastor MM, Lopez-Ibarra PJ, Escobar-Jimenez F, Serrano-Pardo MD & Garcia-Cervignon AG. Intensive insulin therapy and bone mineral density in type 1 diabetes mellitus: a prospective study. Osteoporosis International 2000 11 455–459.

    • Search Google Scholar
    • Export Citation
  • 60

    Leidig-Bruckner G & Ziegler R. Diabetes mellitus: a risk for osteoporosis? Experimental and Clinical Endocrinology and Diabetes 2001 109 S493–S514.

    • Search Google Scholar
    • Export Citation
  • 61

    Gunczler P, Lanes R, Paoli M, Martinez V, Villarel O & Weisinger JR. Decreased bone mineral density and bone formation markers shortly after diagnosis of clinical type 1 diabetes mellitus. Journal of Pediatric Endocrinology and Metabolism 2001 14 525–528.

    • Search Google Scholar
    • Export Citation
  • 62

    Nevitt MA, Johnell O, Black DM, Ensrud K, Genant HK & Cummings SR. Bone mineral density predicts non-spine fractures in very elderly women. Study of Osteoporotic Fractures Research Group. Osteoporosis International 1994 4 325–331.

    • Search Google Scholar
    • Export Citation
  • 63

    Melton LJ, Atkinson EF, O’Fallon WM, Wahner HW & Riggs BL. Long-term fracture prediction by bone mineral assessed at different skeletal sites. Journal of Bone and Mineral Research 1993 8 1227–1233.

    • Search Google Scholar
    • Export Citation
  • 64

    Dhore CR, Cleutjens JP, Lutgens E, Cleutjens KB, Geusens PP, Kitslaar PJ, Tordoir JH, Spronk HM, Vermeer C & Daemen MJ. Differential expression of bone matrix regulatory proteins in human atherosclerotic plaques. Arteriosclerosis, Thrombosis and Vascular Biology 2001 21 1998–2003.

    • Search Google Scholar
    • Export Citation
  • 65

    Zhang J, Fu M, Myles D, Zhu X, Du J, Cao X & Chen YE. PDGF induced osteoprotegerin expression in vascular smooth muscle cells by multiple signal pathways. FEBS Letters 2002 521 180–184.

    • Search Google Scholar
    • Export Citation
  • 66

    Malyankar UM, Scatena M, Suchland KL, Yun TJ, Clark EA & Giachelli CM. Osteoprotegerin is an alpha vbeta 3-induced, NF-kappa B-dependent survival factor for endothelial cells. Journal of Biological Chemistry 2000 275 959–962.

    • Search Google Scholar
    • Export Citation
  • 67

    Bucay N, Sarosi I, Dunstan CR, Morony S, Tarpley J, Capparelli C, Scully S, Tan HL, Xu W, Lacey DL, Boyle WJ & Simonet WS. Osteo-protegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes and Development 1998 12 1260–1268.

    • Search Google Scholar
    • Export Citation
  • 68

    Singh TP, Groehn H & Kazmers A. Vascular function and carotid intimal-medial thickness in children with insulin-dependent diabetes mellitus. Journal of the American College of Cardiology 2003 41 661–665.

    • Search Google Scholar
    • Export Citation
  • 69

    Nathan DM. Long-term complications of diabetes mellitus. New England Journal of Medicine 1993 328 1676–1685.

  • 70

    Järvisalo MJ, Raitakari M, Toikka JO, Putto-Laurila A, Rontu R, Laine S, Lehtimaki T, Ronnemaa T, Viikari J & Raitakari OT. Endothelial dysfunction and increased arterial intima-media thickness in children with type 1 diabetes. Circulation 2004 109 1750–1755.

    • Search Google Scholar
    • Export Citation