Paolo Filipponi

Osteopenia associated with non-insulin-dependent diabetes mellitus: what are the causes?

This study investigated whether alterations in bone mineral content (BMC) and/or in the phosphate-calcium metabolism exist in non-insulin-dependent diabetes mellitus (NIDDM); whether they are linked to glycaemic control and whether antidiabetic therapy--oral agents or insulin--influences BMC and mineral metabolism. A cross-section assessment compared BMC and mineral metabolism in 60 well-controlled and 50 poorly controlled diabetic patients under oral hypoglycaemic therapy with 50 healthy controls. A longitudinal assessment improved the high glucose levels of the poorly controlled diabetic group either by increasing oral treatment or by adding a bedtime NPH insulin. Glycaemic control, BMC and mineral metabolism were followed-up for 1 year. In NIDDM patients BMC is reduced. This reduction is more marked in poorly controlled diabetic patients. In well-controlled diabetes osteocalcin levels are low. In poorly controlled patients glycosuria, hypercalcuria and parathyroid hyperactivity are present. In both groups vitamins 25(OH)-D, 1,25(OH)2-D and calcitonin levels are normal. Improving metabolic control increased BMC, normalized urinary calcium excretion and parathyroid activity and reduced osteocalcin levels. The type of anti-diabetic therapy does not have any significant effect upon BMC or upon phosphate-calcium metabolism. In conclusion, in NIDDM a hard-to-define osteoblast deficit appears to exist. In poorly controlled diabetes the loss of BMC is aggravated by the negative calcium balance caused by the renal calcium leak. This is due to glucosuric-induced osmotic diuresis and is maintained by parathyroid activation.

Cyclical Intravenous Clodronate in Postmenopausal Osteoporosis: Results of a Long-Term Clinical Trial

We report the results of long-term cyclical clodronate therapy (200 mg IV infusion every 3 weeks) on 235 women with postmenopausal osteoporosis recruited over 6 years. A retrospective analysis of clinical and instrumental findings in 183 postmenopausal osteoporotic patients was used as control data. Clodronate was well-tolerated and compliance was good. Bone mineral density (BMD) increased significantly and the upward trend persisted for all 6 years of therapy (5.69 +/- 0.184%) vs. controls: -1.47% +/- 0.813%, p <0.0001). The increase in BMD was greater in the 145 patients without vertebral fractures before starting clodronate. From year 3 onward clodronate reduced the incidence of new vertebral fractures. In closed subsets of patients and controls monitored for 3 and 4 years, respectively, the number of patients developing new vertebral fractures fell significantly in the clodronate group (two-sided p value = 0.0671 and p <0.0026, respectively). This trend was more marked in patients who were fracture-free at the beginning of each year. Cyclical clodronate is a safe and effective therapy for established osteoporosis, but clinical trials are necessary to compare its efficacy versus continuous therapy and, as in the case of the other bisphosphonates, to investigate its mechanisms of action in depth.

Effect of Age, Weight and Lifestyle Factors on Calcaneal Quantitative Ultrasound in Premenopausal Women: The ESOPO Study

The objective of this study was to identify the determinants of bone mass as measured by quantitative ultrasound (QUS) in premenopausal women. The study population is part of the “Epidemiological Study On the Prevalence of Osteoporosis” (ESOPO) on risk of the general population of Italy. We report the data on 2727 premenopausal women aged 40–50 years who are still regularly menstruating. Bone stiffness (called simplicity stiffness), which is derived from the values of broadband ultrasound attenuation (BUA) and speed of sound (SoS), was measured by a heel QUS device (Achilles Apparatus, Lunar, Co. USA). The most commonly recognized determinants of bone mass were modelled with stiffness by multiple regression analysis or analysis of variance (ANOVA). Bone stiffness was negatively related to age and number of cigarettes and positively to body weight, body weight at 25 years, height and estimated daily calcium intake. By multiple regression analysis, independent, positive, predictors of bone stiffness were age, weight at 25 years and daily calcium intake. Bone stiffness adjusted for age and body weight at 25 years was positively associated with outdoor activity score and negatively with number of pregnancies, chronic use of any drug, smoking and subjective health status. Bone stiffness was also somewhat (p < 0.015) negatively related to history of prolonged bedrest and thyroxin use. In conclusion, our results indicate that risk factors usually associated in other studies with DXA-BMD in elderly women are also associated with calcaneal bone stiffness, as measured by QUS in premenopausal women. These findings should help to identify premenopausal women at risk and to design an early strategy for osteoporosis prevention based on eliminating modifiable risks.

Partial gastrectomy and mineral metabolism: effects on gastrin-calcitonin release

Bone mineral metabolism was studied in 20 male patients, between 8 and 18 years, after surgical treatment for peptic ulcer (ten Billroth 1 and ten Billroth 2 gastrectomies) and in 16 sex- and aged-matched healthy controls. The bone mineral content was statistically reduced only in the Billroth 2 group. Serum 25(OH)D was lower in all patients, but fractional calcium absorption was similar to the control value. This may be due to increases in 1,25(OH)2D and parathyroid activity (particularly in Billroth 2). Serum osteocalcin levels and hydroxyproline excretion were higher than in the controls. A positive linear correlation emerged not only between serum 1,25(OH)2D and PTH levels but also between each of these and serum osteocalcin and urine hydroxyproline. Both PTH and calcitriol were inversely correlated with the bone mineral mass in Billroth 2, confirming a trend observed in Billroth 1. Although calcitonin values were normal, basal gastrin levels were severely impaired in all patients. In response to a mixed meal, increases in gastrin and calcitonin were significantly lower than in the controls. The calcitonin response to intravenous calcium and pentagastrin infusion was not significantly different to the controls. The percentage increase in gastrin and calcitonin responses to oral calcium correlated positively with the reduction in bone mineral content only in the Billroth 2 group, suggesting a reduction in calcitonin release may contribute to gastric surgery osteopenia in these patients.

Evidence for a prostaglandin-mediated bone resorptive mechanism in subjects with fasting hypercalciuria.

SummaryThis study was performed to assess whether treatment with prostaglandin synthesis inhibitors decreases calcium excretion in patients with idiopathic hypercalciuria. Nineteen hypercalciuric (12 with fasting hypercalciuria (FH), 7 with nonfasting hypercalciuria (NFH) and 8 control nonhypercalciuric stone formers were treated with sodium diclofenac, 50 mg t.i.d. for 2 weeks. After a washout phase, 7 FH patients received 200 mg/day of sulindac (a nonsteroidal antiinflammatory agent (NSAID) inactive on renal prostaglandin synthetase) for 14 more days. Diclofenac reduced urine calcium excretion in subjects with idiopathic hypercalciuria with either normal or elevated fasting urinary calcium (from 387±26 to 240±23 mg/day,P<0.001; and from 370±39 to 246±40 mg/day,P<0.05, respectively), whereas it was ineffective in normocalciuric stone formers. Similar antihypercalciuric effectiveness was exerted by sulindac in the seven FH patients. The antihypercalciuric action exerted by diclofenac in subjects with FH was associated with a significant increment in serum PTH (48±4 vs, 70±9 pmol/liter,P<0.05), whereas in NFH subjects, the antihypercalciuric effect of diclofenac on NFH was not associated with a change in parathyroid activity. Since the major effect of NSAIDs is to decrease prostaglandin synthesis, these data suggest that prostaglandins may play a pathogenetic role in idiopathic hypercalciuria. Furthermore, they suggest that PTH is suppressed in patients with FH, possibly due to stimulation of prostaglandin-mediated bone resorption process.

Extending SAR of bile acids as FXR ligands: discovery of 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine.

Within our efforts in the discovery of novel potent and selective ligands for the FXR receptor, 23-N-(carbocinnamyloxy)-3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-amine was synthesized and evaluated for its ability to activate and modulate the biological response of the receptor. Alphascreen and RT-PCR revealed that the 6α-ethyl-24-norcholanyl-23-amine derivate behaves as full FXR agonist endowed with high binding affinity and efficacy, representing a promising lead candidate for further optimization. In addition, docking studies provide new insights into the molecular basis governing the partial and full agonist activity at FXR.

Effects of two different bisphosphonates on Paget's disease of bone: ICTP assessed

Clodronate and alendronate were compared in 27 patients with active Pagets bone disease. Carboxyterminal crosslinked telopeptide of type I collagen (ICTP) was evaluated as a marker of bone turnover in Pagets bone disease. Group 1. Nineteen patients received clodronate infusions (300 mg/daily) on 5 consecutive days. After 1 year, 12 patients (63%) were still in remission; urinary hydroxyproline (64.8%) and serum alkaline phosphatase (59.4%) were significantly reduced and had returned to normal in 30%. Patients in remission had significantly higher basal values of urinary hydroxyproline. No adverse side effects were observed. Group 2. One year after clodronate, seven relapsing patients retrospectively underwent five consecutive infusions of alendronate (5 mg/daily). Within 12 months, urinary hydroxyproline fell by 74.7%, alkaline phosphatase dropped by 75.2%, osteocalcin by 47.3%, and ICTP by 56.4%. In all patients, urinary hydroxyproline and alkaline phosphatase returned to normal within 3 months and remained within the normal range during the 12-month follow-up. Most patients had mild, short course fever and arthromyalgia. Group 3. Eight newly diagnosed pagetics, received alendronate alone (5 mg/daily for 5 days). All patients responded well to alendronate within the first month. None suffered a relapse during the follow-up. At month 12, urinary hydroxyproline was down by 71.4%, alkaline phosphatase by 75.3%, osteocalcin by 58.1%, and ICTP by 67.4%. In all patients, markers of bone remodeling were in the normal range at the end of the follow-up. Moderate, transitory arthromyalgia, and fever (high and lasting for 7 days in only one case) were observed in half of the patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Intermittent versus continuous clodronate administration in postmenopausal women with low bone mass

The aim of the study was to compare the effects on bone mass and turnover of continuous vs. intermittent clodronate administration on 120 postmenopausal women (average age 61 years) with low bone mass (femoral neck bone mineral density [BMD] of at least -1 SD or more, T-score), with another 30 women as a control group. Participants were given 1800 mg of clodronate every 6 months over 2 years using different treatment patterns: a) two continuous regimens, consisting of a daily oral dose of 400 mg or 100 mg every 10 days by intramuscular injection, the latter being considered continuous because the interval between injections is shorter than the time employed by each bone remodelling unit to complete the resorption phase of a remodelling cycle; and b) two intermittent regimens, consisting of 1800 mg every 6 months administered either as a single 18-h intravenous infusion or by separate infusions of 300 mg over 6 consecutive days. All women, including those in the control group, received calcium and vitamin D supplementation. After 2 years, continuous clodronate regimens caused an increase in BMD both at lumbar spine and proximal femur (L(1-4) BMD = 3.07% and 2.69%; femoral neck = 2.12% and 2.09%, respectively, with intramuscular and oral regimens). Intermittent clodronate administration was associated with a small increase or a stabilization in bone mass (L(1-4) BMD = 0.53% and 1.22%; femoral neck = 0.30% and 0.77%, respectively, with 1- and 6-day intravenous infusion regimens). From the 12th month, changes in spine and femoral neck BMD after continuous regimens were statistically different compared with that obtained with intermittent ones. Twenty-five of the 150 women (16.7%) discontinued the study before the end of the 2-year follow-up, but of these, only 7 dropped out because of adverse events related to the treatment itself. To summarize, intermittent clodronate administration could be a suitable option for the prevention of osteoporosis.

Low dose metformin in the treatment of type II non-insulin-dependent diabetes: Clinical and metabolic evaluations

SummaryLow doses of metformin (500 mg twice daily) were administered to 20 diabetic patients, combined with the original sulfonylurea treatment which had become ineffective even at full dosage. After 1 and 5 weeks, the effects of the drug on glycemic control, blood intermediate metabolites and monocyte insulin receptors were monitored. Metformin clearly improved glycemic control by reducing both fasting blood glucose from 189.88±21.11 mg/dl to 131.12±16.02 mg/dl after 1 week and to 130.11±13.29 mg/dl after 5 weeks (p<0.025 both after 1 and 5 weeks); the diurnal blood glucose average fell from 235.33±24.11 mg/dl to 174.66±23.45 mg/dl (p<0.0025) after 1 week and to 177.65±21.71 mg/dl (p<0.0005) after 5 weeks. Consequently both blood glycosylated hemoglobin (p=n.s. after 1 week, p<0.025 after 5 weeks) and serum fructosamine (p<0.0025 after both 1 and 5 weeks) also decreased after metformin treatment. No change in plasma insulin and C-peptide levels was reported and no modification in diurnal rhythms of blood lactate, pyruvate, alanine glycerol and β-OH-butyrate was detected at any time during metformin treatment. All the changes documented in the binding values were already complete at the end of the first week: insulin binding to monocytes increased slightly but significantly (p<0.05) and the number of receptors per cell rose (p<0.05) but could not be correlated to any index of glycemic control. These data suggest that the antidiabetic action of metformin is neither related to its lactate-increasing activity nor does it depend upon its inducing an increase in insulin binding values. This metformin-related hypoglycemic effect might be the result, at least in part, of a reduced oxidative phosphorylation without inhibition of hepatic guconeogenesis and/or of decreased hepatic glucose output. Moreover, our data are also consistent with the hypothesis that metformin might affect insulin action at a post-receptor level.

Building a sulfonamide library by eco-friendly flow synthesis.

A rapid and eco-friendly synthesis of a sulfonamide library under flow conditions is described. The study illustrates an efficient, safe, and easily scalable preparation of sulfonamides by use of a meso-reactor apparatus, thus demonstrating the impact of flow technologies within drug discovery. Waste minimization, employment of green media, and nontoxic reactants are achieved by the optimization of the flow setup and experimental protocol designed to sequentially synthesize primary, secondary, and tertiary sulfonamides. Isolation of the products involves only extraction and precipitation affording pure compounds in good to high yields without further purification for biological evaluation.