Role of insulin-like growth factor-I in primary osteoporosis: a correlative study.

Osteoporosis is characterized by impairment of bone mass and deterioration of bone microscopic structure, resulting in increased bone fragility and susceptibility to fracture. Recent reports have indicated that reduced plasma levels of IGF-I are associated with osteoporosis in both males and females. Moreover, there is accumulating clinical evidence that treatment with GH or IGF-I has beneficial effects on bone mass and bone remodeling in men with idiopathic osteoporosis, in the elderly and in hypopituitary patients. As correlative studies on IGF-I, IGF-BP3 and bone mass in the elderly are lacking, we studied the relationships between serum IGF-I, IGF-BP3, bone mineral density (BMD), body mass index (BMI), calciotropic hormones and age in 102 premenopausal and postmenopausal women. Our study indicates that the reduction of the anabolic processes mediated by IGF-I may account for the slow and progressive loss of bone mass that take place after the age of 40-50 years. In addition, nutritional caloric or proteic deficit may add to the effects of GH, age and other factors in decreasing IGF-I synthesis and therefore further contribute to the development of primary osteoporosis.

Effect of doxazosin in mild to moderate hypertensive patients with insulin-dependent diabetes mellitus.

Diabetic patients often develop hypertension, and the presence of both hypertension and diabetes doubles the risk of death from coronary heart disease (CHD). Moreover, the presence and importance of abnormalities such as high low-density lipoprotein (LDL) cholesterol and triglycerides levels as CHD risk factors in insulin-dependent diabetes mellitus type 1 have been downplayed, while increasing evidence suggests that the management of type 1 patients should include control of dyslipidemia and hyperglycemia and an effective antihypertensive treatment able also to reduce risk factors for coronary artery events. In this study we assessed the antihypertensive and metabolic effects of doxazosin in hypertensive patients with type 1 diabetes. We show that the drug normalizes blood pressure, and while no improvement in glucose control was observed, it reduced total cholesterol and increased HDL cholesterol as well as the HDL to total cholesterol ratio. The changes of the various parameters studied, including the calculated CHD risk score based on the Framingham equation, suggest that doxazosine can reduce the CHD risk for hypertensive type 1 patients.

Effects of one-year cyclical treatment with clodronate on postmenopausal bone loss.

We studied 60 women with postmenopausal bone loss randomly allocated to the following treatments: Group 1 (20 patients), no treatment; Group 2 (20 patients), clodronate 400 mg daily by mouth for 30 consecutive days, followed by 60 days of no treatment; Group 3 (20 patients) oral calcitriol 2 mcg by mouth for 5 days and oral clodronate 400 mg daily for additional 25 days, followed by 60 days of no treatment. The therapeutic cycles were repeated four times in the 12-month study period. In the 36 treated patients of Groups 2 and 3 who completed the study period we observed a progressive and significant increase in lumbar bone density both at 6 and 12 months of therapy, without significant differences between the two treatment protocols (+3.88 +/- 0.65%, P < 0.001 and +3.21 +/- 0.89%, P < 0.005 in Groups 2 and 3, respectively, at the end of the study). In contrast, there was a progressive and significant decline of bone mineral density in untreated patients (-2.34 +/- 0.49%, P < 0.001). After 12 months serum calcium values in treated subjects were higher than in untreated patients (P < 0.05). Serum phosphate was raised only in Group 2, mean values being higher after 12 months than before treatment (P < 0.05); parathyroid hormone (PTH) declined in all treated patients, the fall being significant in Group 2 (P < 0.02). No important side effects were observed with treatment and no patient withdrew because of these. We conclude that cyclical low dose clodronate therapy induced a gain in lumbar spine bone mass in patients with postmenopausal osteoporosis.

Possible link between vitamin D and hyperoxaluria in patients with renal stone disease.

1. Vitamin D seems to play an essential role in the pathogenesis of idiopathic hypercalciuria at least in part via intestinal hyperabsorption of calcium. Hyperabsorption of calcium, in turn, might enhance the intestinal uptake of free oxalate, thus leading to hyperoxaluria. To verify this hypothesis we studied 75 calcium-stone-formers subdivided as follows: group 1 (15 patients) with isolated hyperoxaluria; group 2 (25 patients) with hyperoxaluria and hypercalciuria; group 3 (22 patients) with isolated hypercalciuria; group 4 (12 patients) with no metabolic abnormalities. 2. As expected, urinary calcium excretion differed in the various groups (P < 0.001), being highest in groups 2 and 3; urinary oxalate excretion, by definition highest in groups 1 and 2, was even more pronounced in group 2 than in group 1 (P < 0.05). Although in the normal range, the serum 1,25-dihydroxyvitamin D concentration was higher (P < 0.001) in the two hypercalciuric groups (2 and 3), showing peak levels in group 2. 3. When the data from the 75 stone-formers were pooled, there was a positive correlation between the serum concentration of 1,25-dihydroxyvitamin D and urinary calcium excretion (P < 0.001) and urinary oxalate excretion (P < 0.003), the latter relationship also being present when only the two hypercalciuric groups (groups 2 and 3) were considered together (P < 0.05). 4. Our data seem to confirm a relevant role for the vitamin D system in the pathogenesis of calcium nephrolithiasis due to increased intestinal calcium absorption, but also because this in turn induces a greater intestinal absorption of oxalate, thus leading to the occurrence or exacerbation of hyperoxaluria.

Hyperparathyroidism: cause or consequence of recurrent calcium nephrolithiasis?

Primary hyperparathyroidism (PHP) might be characterized by either prevailing bone or renal stone patterns with different metabolic features. To explore the possibility of different hormonal patterns we studied 129 patients with PHP: 95 stone formers (SF) and 34 nonstone formers (NSF). Females prevailed over males in both groups. Severe and specific bone lesions were more evident in NSF than SF. Parathyroid gland histology displayed a prevalence of adenoma in NSF, whereas isolated hyperplasia prevailed in SF. SF had lower levels of serum Ca, urinary Ca, ALP and serum PTH than NSF. As expected serum 1,25-dihydroxyvitamin D [1,25(OH)2 D] levels were greater in both groups of patients than in controls but we found no difference between the two groups. 25-Hydroxyvitamin D was neither increased with respect to controls nor different between groups. We conclude that patients with PHP may represent well separated metabolic and clinical entities, but we cannot confirm that serum 1,25(OH)2D levels play a key role in discriminating the different clinical features. In addition, the findings of predominant parathyroid hyperplasia in SF and the clinical evidence of recurrent hyperparathyroidism only in these patients suggest the possibility that the endocrine disorder might be the consequence over time rather than the cause of nephrolithiasis.

Longitudinal study on osteodystrophy in primary biliary cirrhosis (PBC) and a pilot study on calcitonin treatment.

The aims of this study were to evaluate bone metabolism in primary biliary cirrhosis (PBC) and the effect of ADFR (activate, depress, free, repeat) therapy with vitamin D, calcium and calcitonin in preventing bone resorption. Sixty-nine female subjects entered the study: 38 PBC (AMA + ve) patients, 11 AMA-negative chronic liver disease patients and 20 age-matched healthy controls. Bone metabolism was evaluated by biochemical parameters and dual-photon absorptiometry of the lumbar spine at time 0, 6 and 18 months. Both PBC and chronic liver disease (CLD) patients showed low levels of serum 25-hydroxyvitamin D, osteocalcin and bone mineral content expressed as AAD (average area density) compared to healthy controls. Serum parathyroid hormone in PBC patients was at the lower limit of the normal range and was significantly lower than patients with chronic liver disease. At a 6-month interval, AAD significantly decreased in PBC patients (p less than 0.005). At the 6-month period PBC patients were allocated into two groups according to a cut-off AAD of 0.800 g/cm2: group A (no treatment, AAD greater than 0.800, n = 11), group B (treatment, AAD less than 0.800, n = 13). The latter group received a 4-week course with oral calcium carbonate (1500 mg daily) + oral 1,25-dihydroxyvitamin D (0.5 micrograms twice a day for 5 days) + carbocalcitonin (40 U MRC) i.m. thrice a week. The treatment was repeated with the same protocol at 2-month intervals for 12 months.(ABSTRACT TRUNCATED AT 250 WORDS)

Is hydrochlorothiazide-induced hypocalciuria due to inhibition of prostaglandin E2 synthesis?

1. Since prostaglandin E2 could play a role in idiopathic hypercalciuria, and considering the well-established hypocalciuric action of hydrochlorothiazide, we have evaluated the effect of 15 days' treatment with hydrochlorothiazide in 10 hypercalciuric male stoneformers on urinary Ca2+ and prostaglandin E2, as well as on plasma bicyclo-prostaglandin E2, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D and parathyroid hormone. 2. In addition to lowering urinary Ca2+ (P less than 0.001), hydrochlorothiazide also promoted a significant fall in urinary prostaglandin E2 (P less than 0.001), plasma bicyclo-prostaglandin E2 (P less than 0.001) and 1,25-dihydroxyvitamin D (P less than 0.01), and an increase in plasma parathyroid hormone (P less than 0.025), whereas plasma 25-hydroxyvitamin D was unchanged. 3. A positive correlation between urinary Ca2+ and prostaglandin E2 was present before (P less than 0.00005), but not after, hydrochlorothiazide. Plasma bicyclo-prostaglandin E2 and plasma 1,25-dihydroxyvitamin D were positively correlated both before (P less than 0.005) and after (P less than 0.005) hydrochlorothiazide, as was also the percentage change in each induced by the drug (P less than 0.05). Furthermore, the changes in plasma 25-hydroxyvitamin D and plasma 1,25-dihydroxyvitamin D after hydrochlorothiazide were negatively correlated (P less than 0.05). 4. It is suggested that a block of prostaglandin E2 synthesis plays a role in the effect of hydrochlorothiazide on Ca2+ metabolism, most probably through an inhibition of 1 alpha-hydroxylase activity.

A single-blind study of doxazosin in the treatment of mild-to-moderate essential hypertensive patients with concomitant noninsulin-dependent diabetes mellitus.

Doxazosin, a selective alpha 1-inhibitor, was assessed for antihypertensive efficacy, effect on lipid parameters, and safety profile in 21 hypertensive patients with noninsulin-dependent diabetes mellitus. The study involved a 2- to 4-week baseline period, a 10-week period in which patients received doxazosin, 1 to 8 mg, once daily, and a 4-week maintenance period. All 16 of the efficacy evaluable patients (100%) had their blood pressure controlled (sitting diastolic blood pressure less than or equal to 90 mm Hg) at a mean dose of 3.6 mg once daily. For efficacy evaluable patients mean sitting blood pressure was significantly (p less than 0.05) reduced by 26/17 mm Hg at the final visit. Five patients each reported a single side effect and none was severe. No patients required dose reduction or discontinuation of therapy because of side effects. No clinically significant laboratory changes were apparent, and no trends were observed with regard to organ systems or correlations with dose or duration of treatment. The investigators' global assessment of efficacy of once-daily doxazosin therapy was excellent or good for 15 patients and fair for six patients. The overall assessment of patient toleration was excellent or good for 19 patients, fair for one, and not reported for one. High-density lipoprotein cholesterol was significantly increased (p = 0.03). From baseline to final visit, there was a highly significant reduction of 30% (p less than 0.005) in calculated coronary heart disease risk score on the basis of the Framingham equation.

Efficacy of captopril in hypertensive diabetic patients.

Twenty hypertensive diabetic patients (10 with type I and 10 with type II) were treated with captopril, 50 mg twice a day, for three months. The drug was effective as monotherapy in 16 patients. An additional nine months of follow-up was obtained in 12 of these patients (four with type I and eight with type II) who did not need the addition of diuretics to achieve normal blood pressure. For these patients with long-term treatment, since there was no substantial difference between those with type I and those with type II, the data were pooled. Mean arterial pressure significantly decreased shortly after treatment was begun and the reduction was maintained. No significant change was induced by captopril in urine volume, osmolar clearance, and serum and urinary values of sodium, chloride, calcium, and magnesium, whereas significant reduction was found in fractional excretion of potassium and phosphate. The baseline levels of proteinuria were only slightly elevated, yet they fell in all patients during treatment. All patients maintained satisfactory control of carbohydrate metabolism, and none of them required substantial changes in hypoglycemic treatment. The administration of captopril as monotherapy appears to be an effective and safe way of lowering blood pressure in diabetic hypertensive patients, even in the long term, without effects on renal function and in carbohydrate metabolism.

Exogenous calcitonin protects against renal bone disease in rats with early renal failure.

Chronic renal failure was induced in four groups of male Sprague-Dawley rats by unilateral nephrectomy followed by removal of the outer poles and cautery of the remnant kidney. The four groups of animals received isocaloric diets with normal (groups 1 and 4) or low (groups 2 and 3) phosphate contents and variable amounts of calcium. In addition, rats in group 4 were given salmon calcitonin. After 90-160 days the 4 groups of rats had developed comparable levels of chronic renal failure. The serum phosphate values were significantly lower in rats on low phosphate intake than in those on normal phosphate diet. Bone histology was evaluated on tibiae, lumbar vertebrae and ribs. The rats kept on low phosphate diet (groups 2 and 3) had significantly lower frequency of osteomalacia and bone resorption than those fed a normal phosphate diet. Rats treated with calcitonin (group 4) had the lowest frequency of osteomalacia and virtually no association with bone resorption, despite normal phosphate intake. The serum levels of parathyroid hormone were not significantly different in rats in groups 1 and 4 as compared to controls. Serum 1,25-dihydroxycholecalciferol levels were significantly lower in group 1 than in controls and were significantly higher in group 4 than in group 1. These data show that calcitonin effectively prevents bone lesions in rats with early chronic renal failure.