Gianluca Isaia

Bone metabolism in type 2 diabetes mellitus

Abstract Several conditions have been described to cause osteoporosis, including diabetes mellitus. While the relationship between type 1 diabetes and osteopenia is well documented in the literature, data on the presence of this complication in type 2 diabetes have not been well established. We studied a population composed of 66 post-menopausal women with type 2 diabetes and a control population. We examined bone mineral density with the dual-energy X-ray absorptiometry (DXA) technique at the lumbar and femoral levels and, in a subgroup of patients, we also measured the levels of markers of bone remodelling. We found significantly higher levels of bone mineral density at the femoral (but not lumbar) level in the diabetic subjects compared with the control population in all the examined subregions, except Wards triangle. Moreover, we found higher levels of some markers of bone resorption (urinary calcium and hydroxyproline, telopeptide) in the patients with diabetes, while urinary crosslinks were higher in the controls. On the basis of these results, we suggest that osteoporosis cannot be considered a complication of type 2 diabetes and that, from a metabolic point of view, bone resorption is greater in diabetic patients than in normal subjects, as suggested by the high levels of most of the markers of osteoclastic activity.

Effects of potassium citrate supplementation on bone metabolism.

Western diets rich in animal protein result in long-term acid loading that, despite corresponding increases in net renal acid excretion, may induce a chronic state of acidemia. This may have deleterious effects on both the kidney and bone, by increasing the risk of calcium stone in the former and leading to chemical dissolution of mineral alkaline salts in the latter. Whereas supplementation with alkaline citrate has been shown to reduce stone recurrences, its effect on bone turnover has received less attention. The aim of the present study was to evaluate whether potassium citrate favorably affects bone turnover markers in postmenopausal females with low bone density. Thirty women, aged 58 ± 8.1 years, were enrolled and studied on basal conditions and after a 3-month course of potassium citrate supplementation (0.08–0.1 g/kg b.w. daily). Twenty-two women concluded the study while 8 withdrew. Twenty-four age-matched healthy women were taken as control cases. All were evaluated for electrolyte and acid–base balance-related parameters, bone turnover, markers and renal function. A significant decrease in net acid excretion was observed upon citrate supplementation, and this was paralleled by a significant decrease of urinary deoxypyridinolines, hydroxyproline-to-creatinine ratios, and, to a lesser extent, serum osteocalcin. Percent variations of urine citrate were inversely related to those of deoxypyridinolines and hydroxyproline. No change in these chemistries occurred in the control group. Our results suggest that treatment with an alkaline salt, such as potassium citrate, can reduce bone resorption thereby contrasting the potential adverse effects caused by chronic acidemia of protein-rich diets.

Strontium ranelate reduces the risk of vertebral fracture in young postmenopausal women with severe osteoporosis

Objectives: Early osteoporotic fractures have a great impact on disease progression, the first fracture being a major risk factor for further fractures. Strontium ranelate efficacy against vertebral fractures is presently assessed in a subset of women aged 50–65 years. Methods: The Spinal Osteoporosis Therapeutic Intervention (SOTI) was an international, double blind, placebo controlled trial, supporting the efficacy of strontium ranelate 2 g/day in reducing the risk of vertebral fractures in postmenopausal women with osteoporosis and a prevalent vertebral fracture. 353 of these randomly assigned women were included in this analysis. Results: Over 4 years, strontium ranelate significantly reduced the risk of vertebral fracture by 35% (relative risk 0.65; 95% CI 0.42 to 0.99, p<0.05). In the strontium ranelate group, the bone mineral density increased from baseline by 15.8% at lumbar spine and 7.1% at femoral neck. Conclusion: These data demonstrate a significant vertebral antifracture efficacy of strontium ranelate in young postmenopausal women aged 50–65 years with severe osteoporosis and confirm the efficacy of this antiosteoporotic treatment to prevent vertebral fractures, whatever the age of the patient.

Hospital at Home for Elderly Patients With Acute Decompensation of Chronic Heart Failure A Prospective Randomized Controlled Trial

BACKGROUND Although the hospital is the standard venue for short-term medical care, it may be hazardous for older persons. This study was performed to evaluate the feasibility and effectiveness of a physician-led hospital-at-home service for selected elderly patients with acute decompensation of chronic heart failure (CHF). METHODS Prospective, single-blind, randomized controlled trial with 6-month follow-up for patients 75 years or older admitted to the hospital from April 1, 2004, through April 31, 2005, for acute decompensation of CHF. Patients were randomly assigned to the general medical ward (n = 53) or to the Geriatric Home Hospitalization Service (GHHS; n = 48). The GHHS provides diagnostic and therapeutic treatments by hospital health care professionals in the home of the patient. RESULTS Patient mortality at 6 months was 15% in the total sample, without significant differences between the 2 settings of care. The number of subsequent hospital admissions was not statistically different in the 2 groups, but the mean (SD) time to first additional admission was longer for the GHHS patients (84.3 [22.2] days vs 69.8 [36.2] days, P = .02). Only the GHHS patients experienced improvements in depression, nutritional status, and quality-of-life scores. CONCLUSIONS Substitutive hospital-at-home care is a viable alternative to traditional hospital inpatient care for elderly patients with acutely decompensated CHF. This type of care demonstrated clinical feasibility and efficacy in comparison with its alternative. Trial Registration clinicaltrials.gov Identifier: NCT00623571.

Ipriflavone prevents radial bone loss in postmenopausal women with low bone mass over 2 years

Two hundred and fifty-five postmenopausal women with distal forearm bone mineral density (BMD) 1 SD below the mean value for normal age-matched postmenopausal subjects were randomly allocated to a 2-year treatment with oral ipriflavone (200 mg t.i.d.) or a matched placebo, according to a double-masked, parallel-group design. All patients also received a 1 g/day calcium supplement. Distal radius BMD and bone metabolism markers were measured at baseline, and every 6 months. Blood haematology and chemistry and physical parameters were monitored at the same time. One hundred and ninety-six patients completed 2 years of treatment. BMD changes from baseline were analysed according to valid completers (VC) and intention to treat (ITT) analyses. In both cases radial BMD was maintained in patients treated with ipriflavone while it decreased in those receiving the placebo, the between-treatment difference being significant at year 1 and year 2. Urinary hydroxyproline/creatinine levels were decreased in the ipriflavone-treated group and increased in the placebo group, with a significant between-treatment difference. Adverse reactions, mainly gastrointestinal, occurred to a similar extent in the two treatment groups.

Bone turnover in children and adolescents with McCune-Albright syndrome treated with pamidronate for bone fibrous dysplasia

Bone fibrous dysplasia is one of the main features of McCune-Albright syndrome, a rare genetic condition caused by constitutive activating mutations of Gs-protein and defined by skin dysplasia, bone fibrous dysplasia, and autonomous multiple endocrinopathies. Raised serum alkaline phosphatase (ALP) and urinary hydroxyproline levels indicating bone metabolic hyperactivity have been reported in these patients. Encouraging therapeutic results have been achieved, mainly in adults, with pamidronate, an aminobisphosphonate. In this study we investigate newer bone metabolic indices in a cohort of 11 children and adolescents treated with pamidronate. Tenfold increases of bone ALP and urinary pyridinoline cross-links were found and osteocalcin levels were twofold higher compared with reference values. After treatment, significant decreases in bone ALP and cross-links (Wilcoxon test P < 0.06) were found. Bone mineral density (BMD) significantly increased during treatment. There were signs of radiological healing as thickening of the cortical bone was found in some cases.

Effect of chronic treatment with ipriflavone in postmenopausal women with low bone mass

We present the results of two multicenter, double-blind, placebo-controlled, 2-year studies to evaluate the efficacy and tolerability of ipriflavone in postmenopausal women (PMW) with low bone mass. 453 PMW (aged 50–65 years) with a vertebral (VMD) or radial (RMD) mineral density value 1 SD lower compared with age-matched controls, were randomly selected to receive oral ipriflavone (200 mg T.I.D. at meals) or matching placebo, plus 1 g oral calcium daily. Vertebral (study A, by dual X-ray absorptiometry-DXA) and radial (study B, by dual photon absorptiometry-DPA) bone density, serum bone Gla-protein (BGP), and urinary hydroxyproline/creatinine (HOP/Cr) were measured every 6 months. In both studies, the Valid Completers (VC) analysis showed a maintenance of bone mass in ipriflavone-treated women, whereas in the placebo group, bone mineral density (BMD) was significantly decreased. The final outcome was a bone-sparing effect of 1.6% in study A, and of 3.5% in study B after 2 years. The Intention to Treat (ITT) analysis confirmed the decrease in the placebo group, with no changes in iprifla-vone-treated women. A significant (P < 0.05) between-treatment difference was found in both studies. Biochemical markers of bone turnover decreased in patients treated with ipriflavone, thus suggesting a reduction of bone turnover rate. Twenty-six women treated with ipriflavone and 28 receiving the placebo dropped out because of side effects, mainly gastrointestinal. The compliance to the oral longterm treatment was good. The results of these studies show that ipriflavone is able to prevent both axial and peripheral bone loss in PMW with low bone mass, and is well tolerated.

Role of iron metabolism and oxidative damage in postmenopausal bone loss

It has been suggested that iron-deficient rats have lower bone mass than iron-replete animals, but a clear association between bone and iron repletion has not been demonstrated in humans. A growing body of evidences also suggests a relation between lipid oxidation and bone metabolism and between iron metabolism and LDL oxidation. Iron availability to cells also depends on haptoglobin (Hp) phenotypes. Hp has also important antioxidant properties according to its phenotype, hence we evaluate whether Hp phenotype could influence bone density, iron metabolism and lipid oxidation. This cross-sectional study enrolled 455 postmenopausal women affected by osteoporosis (260) or not (195). Bone mineral density, markers of bone and iron metabolism, levels of oxidized LDL (oxLDL) and Hp phenotype were measured in all the subjects. Hp 1.1 and 2.2 frequency was higher and Hp 2.1 was lower in the patients with fragility fractures (80) compared with the controls. We therefore evaluate different Hp phenotypes as risk or protective factors against fragility fracture: Hp 2.1 is a protective factor against fracture while 1.1 is an important and 2.2 a moderate risk factor for fragility fractures. Lower serum iron was associated with elevated transferrin in patients with Hp 1.1; moreover patients had relative iron deficiency compared with the controls and fractured patients had higher level of oxLDL. We found that both iron metabolism and oxLDL varies according to Hp phenotypes and are predictive of bone density. Our data indicate that Hp 2.1 is a protective factor for fragility fractures, depending on its role on iron metabolism and its antioxidant properties.

Effect of testosterone on bone in hypogonadal males

Bone mineral content (BMC) and testosterone levels were evaluated and compared in 10 hypogonadal males and 10 normal, age-matched controls. In 6 of the subjects an investigation was also carried out into the effects of testosterone administration on lumbar BMC, calcitonin (CT) response to hypercalcaemia, osteocalcin (BGP) and the fasting urinary calcium/creatinine and hydroxyproline/creatinine ratios. Our results confirm that male hypogonadism is characterized by a low BMC and that testosterone administration is able to improve this parameter and to increase both basal BGP and CT response to hypercalcaemia. Testosterone therefore probably acts on bone tissue through both a direct action on osteoblast cells and an improvement in CT secretion.

Osteoporosis: still a typical complication of primary biliary cirrhosis?

BACKGROUND Osteoporosis is a recognized complication of primary biliary cirrhosis but it has been suggested that its prevalence may overlap that observed among postmenopausal women. AIM To evaluate prevalence and risk factors of osteoporosis in primary biliary cirrhosis. PATIENTS A total of 133 female patients (age 53+/-10 years, menopausal status 70%, histological stage I-II 61%, portal hypertension 28%, Mayo Risk Score 4.11+/-0.59) were enrolled. METHODS Dual X-ray absorptiometry of the lumbar spine. RESULTS Mean bone mineral density, T and Z score were 0.861+/-0.160 g/cm2, -1.87+/-1.45 and -0.78+/-2.63, respectively. At multivariate analysis, bone mineral density was inversely correlated with age (p<0.05). Osteoporosis was present in 39/92 (41%) postmenopausal and 8/41 (20%) premenopausal patients. In the premenopausal group, osteoporosis was significantly correlated with serum albumin (p<0.05) and Mayo Risk score (p<0.005). No significant correlation was present in the postmenopausal group. CONCLUSIONS Despite the accepted wisdom that osteoporosis is a common complication of primary biliary cirrhosis, its frequency in post-menopausal patients overlaps that observed in the general population, but is much more frequent in premenopausal patients, where it appears to be related to severity of liver disease and cholestasis.