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Utility of QUS assessment in COPD patients treated with GCS: The EOLO study
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Abstracts / Bone 45 (2009) S137–S145
osteogenic genes and BMP-2 production in culture in keeping with the constitutive tendency to migrate toward the bone damaged sites. Thus, UC-MSCs engineered with BMP-2 or other bone morphogenetic proteins, may provide a new approach of the gene therapy devoted to the bone regenerative medicine in a number of skeleton resorbing or devastating diseases.
Conclusions: Our data confirm that teriparatide decreases the risk of new clinical fractures, even in patients with osteoporosis associated with an active rheumatic disease and chronic steroid therapy.
doi:10.1016/j.bone.2009.07.069
Utility of QUS assessment in COPD patients treated with GCS: The EOLO study S. Gonnellia, C. Caffarellia, S. Maggib, S. Rossia, P. Sivierob, G. Crepaldib, R. Nutia a Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy b CNR Aging Branch, University of Padua, Italy
Use of teriparatide in osteoporosis due to active rheumatic diseases S. Salvina, M. Maseta, L. Quartuccioa, S. Saccoa, G. De Marchib, S. De Vitaa a Clinic of Rheumatology, Hospital of Udine, Italy b Department of General Medicine, Hospital of San Daniele (Ud), Italy Introduction: In inflammatory arthritis and active connective tissue diseases osteoporosis is the most frequent extra-articular clinical manifestation, associated with an high fracturative risk in trabecular bone (i.e. in lumbar spine), due to the level of disease activity, chronic corticosteroid intake and concomitant immunosuppressive therapies. Patients and methods: 28 patients (all females, age 73 ± 6 years) suffering from severe osteoporosis (in according to OMS definition) were treated with teriparatide (a fragment of human PTH hormone) in order to FDA and AIFA indication in our rheumatology Clinic from 2005 to 2009. Eleven out of 28 pt (43%) were affected by inflammatory rheumatic diseases (active in 4/11 pt and ongoing low doses of corticosteroids in 3/11); the baseline mean number of vertebral fractures was 4.8 ± 1.6 (median 4, range 3–9). Twenty-one pt (75%) were previously treated with one or more biphosphonates for at least 2 years. BMD (gr/cm2) were evaluated with Explorer Hologic® (S/N 90954). Clinical characteristics and rheumatic disease diagnosis other than osteoporosis were reported in Table 1. Results: The 18 months of teriparatide therapy were completed in Table 1 Inflammatory rheumatic diseases Rheumatoid arthritis Polymialgia reumatica Connective tissues disease (SLE, crest) Spondiloarthritis Vasculitis Osteoporosis risk factors Chronic steroid therapy (>12 months) Early menopause (<45 years) Femural fractures in parents
No. of pt: 11 4 3 2
Moderate-severe vertebral fractures 3 vertebral fractures 4 vertebral fractures ≥ 5 vertebral fractures
1 1 N° pt: 28 12
Femural fractures Colles fractures Previous balloon kyphoplasty Previous anti-osteoporotic therapies Alendronate
8 7
Clodronate Strontium ranelate Risedronate
No. of pt: 28 6 8 13 5 4 6 12 9 7 6
eleven pt (39%) while in 11/28 pt the treatment is still ongoing. In six pt (21%) teriparatide was early suspended (after 4 ± 3 months of therapy) due to lack of compliance (2/6 pt) or adverse events (2/6 for severe and persistent headache, 1/6 for nausea and 1/6 for diffuse arthromyalgias). Treatment was well tolerated without serious adverse events. New clinical vertebral or non vertebral fractures were not detected up to now (in particular in patient with ongoing steroid therapy or with previous balloon kyphoplasty). Lumbar BMD was not evaluated due to poor technical accuracy (i.e. presence of scoliosis, lumbar osteoarthritis, previous kyphoplasty). Femural BMD was stabilized (0.590 ± 0.103 g/cm2 at baseline vs 0.612 ± 0.148 g/cm2 at the end of treatment). After teriparatide, alendronate is used in five pt, ibandronate in four pt and risedronate in two pt.
doi:10.1016/j.bone.2009.07.070
Glucocorticoid-induced osteoporosis (GIO) is a common and serious complication of systemic glucocorticoid (GCs) use and today represents the first cause of secondary osteoporosis. Even though it is cumulative dose of GCs that correlates with bone loss, it has recently been demonstrated that the risk of fracture is more closely related to daily dose than to cumulative dose. Moreover, it has been reported that fractures in oral glucocorticoid users occur in the presence higher bone mineral density (BMD) than in patients with involutive osteoporosis. This may suggest that the risk of fracture may indeed be substantially higher in GCs treated patients at a similar level of BMD, compared to postmenopausal osteoporosis. This raises the possibility that GCs affect aspects of bone fragility not detected by conventional X-ray absorptiometry (DXA). These findings have stimulated a growing scientific and clinical interest in quantitative ultrasound (QUS) as an alternative method to DXA for assessing skeletal status in GIO. In fact QUS is thought to reflect not only bone density, but also some structural properties of bone, such as elasticity, trabecular stiffness and connectivity, which could be closely connected to bone strength. Some prospective studies have demonstrated that QUS are independent predictors of fragility fractures in postmenopausal women. Even though the extent to which QUS detects microarchitectural aspects of bone structure, independently of BMD, is uncertain, QUS may pick up microarchitectural changes induced by glucocorticoids. The present study aimed to evaluate the ability of QUS, in detecting bone impairment and in the assessing the odds of fracture in patients taking GCs. A total of fifty-seven Italian outpatient pneumological centres were invited to participate in the Evaluation of Obstructive Lung disease and Osteoporosis (EOLO) study. A total of 3030 ambulatory patients (1778 men and 1262 women) aged 50 years or over with COPD were enrolled. Information about glucocorticoid therapy (dosages, route of administration, years of use) was collected from patient interviews and medical records. In all subjects we measured ultrasound parameters at calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles plus (GE, Lunar); the patients were divided in to three groups: low risk of having osteoporosis (Stiffness ≥78%), high risk of having osteoporosis (Stiffness <57%) and moderate risk of having osteoporosis (Stiffness 57–77%). In a sub-group of subjects BMD at lumbar spine and at femoral subregions were assessed. In COPD patients the treatment with GCs significantly influenced QUS parameters (namely Stiffness) as well as DXA parameters (p < 0.01 one way ANOVA). Moreover, the mean values of both Stiffness and DXA parameters were markedly reduced in COPD patient treated with oral GCs with respect to the other groups. The multinomial logistic repression analysis was used to assess the relationships between the classification of patients according to the severity of Stiffness and possible categorical risk factors. Age, gender and BMI are associated with both moderate and high risk classes of Stiffness; moreover COPD patients treated with GCs therapy were more likely to present Stiffness values lower than 57% (OR = 1.95; 95% CI 1.25–3.02 and OR = 1.52; 95% CI 1.10–2.10 for oral and inhaled GCs respectively). The patients classified on the basis of Stiffness as having
Abstracts / Bone 45 (2009) S137–S145
high risk or moderate risk of osteoporosis presented an increased risk of vertebral fractures (OR = 2.71; 95% CI 2.04–3.60 and OR = 1.54 95% CI 1.26–1.88). The inclusion in the model of GCs treatment did not change the risk predictivity. In conclusion our findings indicate that both inhaled and oral GCs are associated with reduced values of Stiffness and support the usefulness of using QUS at calcaneous in COPD patients. Therefore in COPD patients the presence of reduced values of Stiffness could markedly increase the risk of vertebral fracture and could be a crucial element in the planning of further examination or adequate therapeutic intervention in individual patients. doi:10.1016/j.bone.2009.07.071
25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in endogenous hypercortisolism F. Sanguina, G. Luisettoa, M. Piccoloa, N. Albigera, N. Vajenteb, M. Zaninottob, C. Scaronia, F. Manteroa, V. Camozzia a Department of Medical and Surgical Sciences, Division of Endocrinology, University of Padua, Italy b Department of Laboratory Medicine, University of Padua, Italy Introduction: The role of vitamin D on bone metabolism and calcium homeostasis is well known. Calcium and vitamin D supplementation is usually recommended in the management of osteoporosis and particularly in glucocorticoid-induced osteoporosis. The syndrome of glucocorticoid excess, among the multiple systemic damages, alters bone metabolism and causes bone loss, but there are poor and not univocal data on vitamin D status in patients with endogenous hypercortisolism. The aim of our study is to investigate 25-Hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in patients with Cushing's syndrome (CS). Methods: 50 patients affected by endogenous hypercortisolism [42 patients (6 men, 36 women) with pituitary CS, 6 (6 women) with adrenocortical adenoma, 2 (2 men) with ectopic CS] and 51 healthy
S145
sex-, age- and Body Mass Index (BMI)-matched controls were studied. All patients were studied in autumnal season for laboratory analysis [25OHD, 1,25(OH)2D, S-PTH, S-Ca, S-P, S-bALP, serum crosslaps (sCTX), S-Osteocalcin (OC), glycaemia, total and HDL cholesterol, triglycerides)]. Metabolic features [(BMI, waist circumference (WC), waist/hip ratio (WHR), arterial blood pressure)], dietary calcium intake and sunlight exposure questionnaires were also collected. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry at lumbar spine and femoral site. Results: 25OHD was significantly lower in CS than in controls (35.3 ± 15.8 and 58 ± 31 nmol/L respectively, p = 0.0001); no differences in 1,25(OH)2D (107.5 ± 58.6 and 96.9 ± 55.2 pmol/L respectively) and PTH levels (63 ± 17 and 57.3 ± 25.5 pmol/L respectively) were found between the two groups; serum calcium was significantly higher in CS than in controls meanwhile serum phosphorus was equal. OC levels were lower in CS without reaching the statistical significance; no difference between sCTX was found between the two groups. BMD was significantly lower in CS than in controls at any measured sites. CS patients showed a higher WC and WHR than controls (p = 0.03 and 0.005 respectively). We found an inverse correlation between 25OHD and PTH only in controls (p = 0.011) and a direct correlation between 1,25(OH)2D and PTH both in CS and in controls (p = 0.048 and p = 0.05 respectively). Conclusions: We found a severe hypovitaminosis D in patients with endogenous hypercortisolism, regardless of the etiology of cortisol secretion. The normality of 1,25(OH)2D and PTH levels in CS, despite very low levels of 25OHD, could be explained by an increased extra-renal production of 1,25(OH)2D. This effect might be due to an enhanced expression of 1-α-hydroxylase in fat tissue, where the enzymatic activity seems to be independent of 25OHD and serum calcium levels, as demonstrated by Li et al. (2008). Our data confirmed the increased presence of central adiposity in CS, measured by WC an WHR. doi:10.1016/j.bone.2009.07.072
Abstracts / Bone 45 (2009) S137–S145
osteogenic genes and BMP-2 production in culture in keeping with the constitutive tendency to migrate toward the bone damaged sites. Thus, UC-MSCs engineered with BMP-2 or other bone morphogenetic proteins, may provide a new approach of the gene therapy devoted to the bone regenerative medicine in a number of skeleton resorbing or devastating diseases.
Conclusions: Our data confirm that teriparatide decreases the risk of new clinical fractures, even in patients with osteoporosis associated with an active rheumatic disease and chronic steroid therapy.
doi:10.1016/j.bone.2009.07.069
Utility of QUS assessment in COPD patients treated with GCS: The EOLO study S. Gonnellia, C. Caffarellia, S. Maggib, S. Rossia, P. Sivierob, G. Crepaldib, R. Nutia a Department of Internal Medicine, Endocrine-Metabolic Science and Biochemistry, University of Siena, Italy b CNR Aging Branch, University of Padua, Italy
Use of teriparatide in osteoporosis due to active rheumatic diseases S. Salvina, M. Maseta, L. Quartuccioa, S. Saccoa, G. De Marchib, S. De Vitaa a Clinic of Rheumatology, Hospital of Udine, Italy b Department of General Medicine, Hospital of San Daniele (Ud), Italy Introduction: In inflammatory arthritis and active connective tissue diseases osteoporosis is the most frequent extra-articular clinical manifestation, associated with an high fracturative risk in trabecular bone (i.e. in lumbar spine), due to the level of disease activity, chronic corticosteroid intake and concomitant immunosuppressive therapies. Patients and methods: 28 patients (all females, age 73 ± 6 years) suffering from severe osteoporosis (in according to OMS definition) were treated with teriparatide (a fragment of human PTH hormone) in order to FDA and AIFA indication in our rheumatology Clinic from 2005 to 2009. Eleven out of 28 pt (43%) were affected by inflammatory rheumatic diseases (active in 4/11 pt and ongoing low doses of corticosteroids in 3/11); the baseline mean number of vertebral fractures was 4.8 ± 1.6 (median 4, range 3–9). Twenty-one pt (75%) were previously treated with one or more biphosphonates for at least 2 years. BMD (gr/cm2) were evaluated with Explorer Hologic® (S/N 90954). Clinical characteristics and rheumatic disease diagnosis other than osteoporosis were reported in Table 1. Results: The 18 months of teriparatide therapy were completed in Table 1 Inflammatory rheumatic diseases Rheumatoid arthritis Polymialgia reumatica Connective tissues disease (SLE, crest) Spondiloarthritis Vasculitis Osteoporosis risk factors Chronic steroid therapy (>12 months) Early menopause (<45 years) Femural fractures in parents
No. of pt: 11 4 3 2
Moderate-severe vertebral fractures 3 vertebral fractures 4 vertebral fractures ≥ 5 vertebral fractures
1 1 N° pt: 28 12
Femural fractures Colles fractures Previous balloon kyphoplasty Previous anti-osteoporotic therapies Alendronate
8 7
Clodronate Strontium ranelate Risedronate
No. of pt: 28 6 8 13 5 4 6 12 9 7 6
eleven pt (39%) while in 11/28 pt the treatment is still ongoing. In six pt (21%) teriparatide was early suspended (after 4 ± 3 months of therapy) due to lack of compliance (2/6 pt) or adverse events (2/6 for severe and persistent headache, 1/6 for nausea and 1/6 for diffuse arthromyalgias). Treatment was well tolerated without serious adverse events. New clinical vertebral or non vertebral fractures were not detected up to now (in particular in patient with ongoing steroid therapy or with previous balloon kyphoplasty). Lumbar BMD was not evaluated due to poor technical accuracy (i.e. presence of scoliosis, lumbar osteoarthritis, previous kyphoplasty). Femural BMD was stabilized (0.590 ± 0.103 g/cm2 at baseline vs 0.612 ± 0.148 g/cm2 at the end of treatment). After teriparatide, alendronate is used in five pt, ibandronate in four pt and risedronate in two pt.
doi:10.1016/j.bone.2009.07.070
Glucocorticoid-induced osteoporosis (GIO) is a common and serious complication of systemic glucocorticoid (GCs) use and today represents the first cause of secondary osteoporosis. Even though it is cumulative dose of GCs that correlates with bone loss, it has recently been demonstrated that the risk of fracture is more closely related to daily dose than to cumulative dose. Moreover, it has been reported that fractures in oral glucocorticoid users occur in the presence higher bone mineral density (BMD) than in patients with involutive osteoporosis. This may suggest that the risk of fracture may indeed be substantially higher in GCs treated patients at a similar level of BMD, compared to postmenopausal osteoporosis. This raises the possibility that GCs affect aspects of bone fragility not detected by conventional X-ray absorptiometry (DXA). These findings have stimulated a growing scientific and clinical interest in quantitative ultrasound (QUS) as an alternative method to DXA for assessing skeletal status in GIO. In fact QUS is thought to reflect not only bone density, but also some structural properties of bone, such as elasticity, trabecular stiffness and connectivity, which could be closely connected to bone strength. Some prospective studies have demonstrated that QUS are independent predictors of fragility fractures in postmenopausal women. Even though the extent to which QUS detects microarchitectural aspects of bone structure, independently of BMD, is uncertain, QUS may pick up microarchitectural changes induced by glucocorticoids. The present study aimed to evaluate the ability of QUS, in detecting bone impairment and in the assessing the odds of fracture in patients taking GCs. A total of fifty-seven Italian outpatient pneumological centres were invited to participate in the Evaluation of Obstructive Lung disease and Osteoporosis (EOLO) study. A total of 3030 ambulatory patients (1778 men and 1262 women) aged 50 years or over with COPD were enrolled. Information about glucocorticoid therapy (dosages, route of administration, years of use) was collected from patient interviews and medical records. In all subjects we measured ultrasound parameters at calcaneus: speed of sound (SOS), broadband ultrasound attenuation (BUA) and Stiffness, by Achilles plus (GE, Lunar); the patients were divided in to three groups: low risk of having osteoporosis (Stiffness ≥78%), high risk of having osteoporosis (Stiffness <57%) and moderate risk of having osteoporosis (Stiffness 57–77%). In a sub-group of subjects BMD at lumbar spine and at femoral subregions were assessed. In COPD patients the treatment with GCs significantly influenced QUS parameters (namely Stiffness) as well as DXA parameters (p < 0.01 one way ANOVA). Moreover, the mean values of both Stiffness and DXA parameters were markedly reduced in COPD patient treated with oral GCs with respect to the other groups. The multinomial logistic repression analysis was used to assess the relationships between the classification of patients according to the severity of Stiffness and possible categorical risk factors. Age, gender and BMI are associated with both moderate and high risk classes of Stiffness; moreover COPD patients treated with GCs therapy were more likely to present Stiffness values lower than 57% (OR = 1.95; 95% CI 1.25–3.02 and OR = 1.52; 95% CI 1.10–2.10 for oral and inhaled GCs respectively). The patients classified on the basis of Stiffness as having
Abstracts / Bone 45 (2009) S137–S145
high risk or moderate risk of osteoporosis presented an increased risk of vertebral fractures (OR = 2.71; 95% CI 2.04–3.60 and OR = 1.54 95% CI 1.26–1.88). The inclusion in the model of GCs treatment did not change the risk predictivity. In conclusion our findings indicate that both inhaled and oral GCs are associated with reduced values of Stiffness and support the usefulness of using QUS at calcaneous in COPD patients. Therefore in COPD patients the presence of reduced values of Stiffness could markedly increase the risk of vertebral fracture and could be a crucial element in the planning of further examination or adequate therapeutic intervention in individual patients. doi:10.1016/j.bone.2009.07.071
25-Hydroxyvitamin D and 1,25-dihydroxyvitamin D levels in endogenous hypercortisolism F. Sanguina, G. Luisettoa, M. Piccoloa, N. Albigera, N. Vajenteb, M. Zaninottob, C. Scaronia, F. Manteroa, V. Camozzia a Department of Medical and Surgical Sciences, Division of Endocrinology, University of Padua, Italy b Department of Laboratory Medicine, University of Padua, Italy Introduction: The role of vitamin D on bone metabolism and calcium homeostasis is well known. Calcium and vitamin D supplementation is usually recommended in the management of osteoporosis and particularly in glucocorticoid-induced osteoporosis. The syndrome of glucocorticoid excess, among the multiple systemic damages, alters bone metabolism and causes bone loss, but there are poor and not univocal data on vitamin D status in patients with endogenous hypercortisolism. The aim of our study is to investigate 25-Hydroxyvitamin D (25OHD) and 1,25-dihydroxyvitamin D [1,25(OH)2D] levels in patients with Cushing's syndrome (CS). Methods: 50 patients affected by endogenous hypercortisolism [42 patients (6 men, 36 women) with pituitary CS, 6 (6 women) with adrenocortical adenoma, 2 (2 men) with ectopic CS] and 51 healthy
S145
sex-, age- and Body Mass Index (BMI)-matched controls were studied. All patients were studied in autumnal season for laboratory analysis [25OHD, 1,25(OH)2D, S-PTH, S-Ca, S-P, S-bALP, serum crosslaps (sCTX), S-Osteocalcin (OC), glycaemia, total and HDL cholesterol, triglycerides)]. Metabolic features [(BMI, waist circumference (WC), waist/hip ratio (WHR), arterial blood pressure)], dietary calcium intake and sunlight exposure questionnaires were also collected. Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry at lumbar spine and femoral site. Results: 25OHD was significantly lower in CS than in controls (35.3 ± 15.8 and 58 ± 31 nmol/L respectively, p = 0.0001); no differences in 1,25(OH)2D (107.5 ± 58.6 and 96.9 ± 55.2 pmol/L respectively) and PTH levels (63 ± 17 and 57.3 ± 25.5 pmol/L respectively) were found between the two groups; serum calcium was significantly higher in CS than in controls meanwhile serum phosphorus was equal. OC levels were lower in CS without reaching the statistical significance; no difference between sCTX was found between the two groups. BMD was significantly lower in CS than in controls at any measured sites. CS patients showed a higher WC and WHR than controls (p = 0.03 and 0.005 respectively). We found an inverse correlation between 25OHD and PTH only in controls (p = 0.011) and a direct correlation between 1,25(OH)2D and PTH both in CS and in controls (p = 0.048 and p = 0.05 respectively). Conclusions: We found a severe hypovitaminosis D in patients with endogenous hypercortisolism, regardless of the etiology of cortisol secretion. The normality of 1,25(OH)2D and PTH levels in CS, despite very low levels of 25OHD, could be explained by an increased extra-renal production of 1,25(OH)2D. This effect might be due to an enhanced expression of 1-α-hydroxylase in fat tissue, where the enzymatic activity seems to be independent of 25OHD and serum calcium levels, as demonstrated by Li et al. (2008). Our data confirmed the increased presence of central adiposity in CS, measured by WC an WHR. doi:10.1016/j.bone.2009.07.072