Giovanni Luisetto

Efficacy and safety of alendronate for the treatment of osteoporosis in diffuse connective tissue diseases in children: a prospective multicenter study.

OBJECTIVE Osteopenia/osteoporosis is being increasingly reported as a complication of many chronic diseases, even in children. In this preliminary study, we evaluated the effect of an oral bisphosphonate (alendronate) on bone mass in children with diffuse connective tissue diseases. METHODS Thirty-eight children with low bone mass were treated with alendronate for 1 year; 38 children who had the same primary disorders as the study patients but in a less severe form served as untreated control patients. We were also able to evaluate changes in bone mass (before and after alendronate) in 16 of the treated patients whose bone mineral density (BMD) had been routinely measured before the present study was initiated. RESULTS BMD increased by a mean +/- SD of 14.9 +/- 9.8% (P < 0.002 versus baseline) in the treated patients (reaching the normal range in 13 patients), while the BMD was 2.6 +/- 5% (not significant versus baseline) in the control group (15 had a decrease). Most interestingly, there was a large increase in BMD (15.3 +/-9.9%) after alendronate therapy in the 16 children who had their BMD followed up in the year before the study, during which time they had shown little increase in BMD (1.03 +/- 6.3%), and often a decrease. Considering their condition, increases in the height of all patients was satisfactory. No new fractures were observed after alendronate therapy was initiated. CONCLUSION Bisphosphonates can be considered essential components of the treatment of secondary osteoporosis, not only in adults, but also in pediatric patients. Alendronate has a positive effect on secondary osteopenia/osteoporosis in children with connective tissue diseases.

Evolution of osteopenia in inflammatory bowel disease

Objective:Our aim was the assessment of frequency and evolution of osteopenia in patients with inflammatory bowel disease and identification of related factors.Methods:Bone mineral density (BMD) of the lumbar spine was measured in 54 patients with Crohns disease (CD) and in 49 patients with ulcerative colitis (UC) and was repeated after a mean observation period of 21 (range, 8–50) months in 30 CD and 14 UC patients. Eighteen age-matched healthy subjects served as controls. Serum biochemistry (parathyroid hormone, osteocalcin, alkaline phosphatase, insulin-like growth factor 1, minerals, and markers of inflammation) was assessed at the time of the second BMD measurement.Results:Reduced BMD values were found in 48% of CD, and in 38% of UC patients. Compared with control subjects, the mean BMD was significantly lower in CD p < 0.003 and UC p < 0.0001 patients. BMD was positively correlated with the body mass index p < 0.05 and inversely correlated with the lifetime steroid dose p < 0.03. After 21 months the BMD of CD patients was virtually unchanged, with an annual variation (%ΔBMD/yr) of −0.31 ± 0.49, whether treated with steroids or not, whereas in UC patients the BMD decreased significantly p < 0.02 with a %ΔBMD/yr of −2.47 ± 0.82 (p < 0.02vs CD). This decrease can be attributed to steroid treatment. No biochemical alterations were detected in patients with rapid bone loss, compared with those with stable BMD.Conclusions:Low bone density is frequent in both CD and UC, but apparently stable in CD. The evolution of BMD suggests that low bone density is associated with the pathogenesis of CD, whereas in UC it seems to be correlated with the side effects of corticosteroid treatment.

Fracture Incidence and Characterization in Patients on Osteoporosis Treatment: The ICARO Study

None of the available osteoporosis therapies have been shown to completely abolish the risk of fractures. In clinical practice, the outcome may be even poorer. In 880 patients prescribed with antiresorptives (alendronate, risedronate, and raloxifene) for >1 year, a fragility fracture was recorded in 8.9%/year of them. This incidence is considerably higher than that observed in randomized clinical trials, and it was significantly related to poor compliance and lack of supplementation with calcium and vitamin D.

Endocrine Therapy of Breast Cancer

Breast cancer remains one of the first leading causes of death in women, and currently endocrine treatment is of major therapeutic value in patients with estrogen-receptor positive tumors. Selective estrogen-receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and GnRH agonists are the drugs of choice. Tamoxifen, a partial nonsteroidal estrogen agonist, is a type II competitive inhibitor of estradiol at its receptor, and the prototype of SERMs. Aromatase inhibitors significantly lower serum estradiol concentration in postmenopausal patients, having no detectable effects on adrenocortical steroids formation, while GnRH agonists suppress ovarian function, inducing a menopause-like condition in premenopausal women. Endocrine therapy has generally a relatively low morbidity, leading to a significant reduction of mortality for breast cancer. The aim of chemoprevention is to interfere early with the process of carcinogenesis, reducing the risk of cancer development. As preventive agents, raloxifene and tamoxifene are equivalent, while raloxifene has more potent antiresorptive effects in postmenopausal osteoporosis. Endocrine treatment is usually considered a standard choice for patients with estrogen-receptor positive cancers and non-life-threatening advanced disease, or for older patients unfit for aggressive chemotherapy regimens. Several therapeutic protocols used in patients with breast cancer are associated with bone loss, which may lead to an increased risk of fracture. Bisphosphonates are the drugs of choice to treat such a drug-induced bone disease. The aim of this review is to outline current understanding on endocrine therapy of breast cancer.

Bone metabolism and gonad function in male patients undergoing liver transplantation: a two-year longitudinal study.

Osteodystrophy is a major complication of end-stage liver disease, especially in postmenopausal women. Our aim in this study was to evaluate bone metabolism and gonad function in men undergoing orthotopic liver transplantation (OLTx). Twenty-three consecutive men (mean age 48 ± 13 years) evaluated for OLTx were studied, assessing the following parameters at baseline and 3, 6, 12 and 24 months after OLTx: lumbar spine (L2–L4) bone mineral density (BMD), parathyroid hormone (PTH), osteocalcin (BGP), 25-hydroxyvitamin D (25OHD), free testosterone (FT) and gonadotropins (FSH, LH). At baseline, 12 patients (52%) had a T-score <–2.5 SD and the mean BMD was 0.806 ± 0.11 g/cm2 (range 0.470–1.045 g/cm2). The BMD was lower 3 months after OLTx and significantly higher 12 and 24 months after OLTx. A significant increase in serum BGP was observed at 6, 12 (p<0.05) and 24 months (p<0.005) after OLTx. The mean serum PTH level was 26.6 ± 3.1 pg/ml at baseline and increased significantly at 12 and 24 months (to 49.4 ± 9.9 and 61.2 ± 10.1 pg/ml, respectively; p<0.05). 25OHD serum levels were low at baseline and returned to the normal range after 12 and 24 months (baseline, 8.73 ± 1.54 ng/ml; 12 months, 16.4 ± 2.6 ng/ml; 24 months, 17.67 ± 3.1 ng/ml; p<0.05). FT was significantly lower at baseline than in a group of 10 healthy controls (5.09 ± 10.99, vs 10.3 ± 1.1 pg/ml; p<0.0001). After OLTx a significant increase in FT was recorded at 6, 12 (p<0.05) and 24 months (p<0.005). FT was not correlated with BMD, however. After OLTx an increase in FSH and LH was observed (but failed to reach statistical significance) at 3 and 6 months, followed by a slight reduction at 12 and 24 months. Thus a high proportion of men with end-stage liver disease do have osteoporosis. After OLTx, an early recovery of gonad function is observed, followed by an increase in bone mass, which occurs from the sixth month onward.

Bone mineral density, osteocalcin, and bone-specific alkaline phosphatase in patients with insulin-dependent diabetes mellitus

The aims of this study were to evaluate the prevalence of osteopenia and the relationships between osteocalcin (OC), bone alkaline phosphatase (bALP), and bone mineral density (BMD) in patients with insulin‐dependent diabetes mellitus (IDDM). A group of 18 patients (median age 47, range 36–51) with uncomplicated IDDM (Group A) were matched by sex, age, and body mass index with 21 healthy control volunteers (Group B). All subjects underwent osteodensitometry with measurement of BMD at the lumbar spine and femoral neck. Osteopenia was present in 11 (61.1%) and 2 (9.5%) of Group A and B patients (P= 0.01), respectively. Both OC (28.4 ± 16.4 versus 41.2 ± 14.6 ng/mL; P= 0.005) and bALP (51.3 ± 11.8 versus 61.7 ± 10.6 U/L; P= 0.006) serum levels were significantly lower in patients with IDDM. BMD did not correlate with either OC or bALP. In conclusion, osteopenia is common among patients with IDDM, but the relationship between bone formation markers and BMD is still unclear.

Bone mass and mineral metabolism in Klinefelter's syndrome

A reduced bone mineral density (BMD) is frequently observed in hypogonadal males; however, very little is known on bone and mineral metabolism in Klinefelters syndrome (KS). In this study 32 XXY KS patients and 24 healthy age-matched male controls were examined. Serum total and free testosterone (TT and FT) were significantly lower in patients than in controls (TT in KS, 15.1±7.8 nmol/l; controls, 30.4±9.1;p<0.001. FT in KS, 81.8±24.9 pmol/l; controls, 135.7±16.4;p<0.001). 17β-Estradiol was slightly higher in KS patients (KS, 49.0±27.1 pg/ml; controls, 39.3±16.4 pg/ml), but the difference was not significant. BMD, measured at the spine (L2–4) and at the proximal epiphysis of the left femur, was similar in patients and in the control group (spine: KS, 1.016±0.142; controls, 1.085±0.144 g/cm2;p=not significant. Femoral neck: KS, 0.926±0.149; controls, 0.926±0.122 g/cm2;p=not significant). Bone GLA protein (BGP) was significantly higher in the KS group (12.7±4.8 vs 8.9±5.2 ng/ml;p<0.02), while serum calcium, serum phosphate, calciotrophic hormones and the fasting urinary hydroxyproline/creatinine ratio (OHP/Creat) were similar in the two groups. A positive relationship between FT and both spine and femoral BMD was found in KS patients. Furthermore, OHP/Creat ratio was inversely related to BMD at the femur, and positively related to BGP in KS patients, but not in normal subjects. These findings suggest that (1) KS patients have normal bone mass, most probably because the hypogonadism is moderate; and (2) patients with lower bone mass appear to have higher bone turnover.

Influence of aging and menopause in determining vertebral and distal forearm bone loss in adult healthy women.

In order to assess the relative influence of aging and menopause in determining the decrease of bone mass in adult women, two groups of normal subjects were examined in this retrospective, cross-sectional study. In group A, bone mineral density (BMD) was evaluated at spine (L2-L4) by dual X-ray absorptiometry (DXA) (Hologic QDR-1000); in group B, BMD was measured at the distal forearm by single photon absorptiometry (SPA) (Osteometer DT 100). Both groups were further divided into two subgroups: A1 and B1 included women with the same postmenopausal, but different chronological age; A2 and B2 included women with the same chronological, but different postmenopausal age. BMD and BMI-corrected BMD (cBMD) were plotted versus age and years since menopause, respectively. Mathematical analysis of the correlation curves between BMD and chronological age showed that the decrease of BMD is very similar at spine and forearm, and is better fitted by a quadratic function. Age-related fractional bone diminution shows a progressive increase with aging (at spine: -0.38%/year at 45 years, -0.81%/year at 50, -1.3%/year at 55 and -1.9%/year at 60. At forearm: -0.5%/year at 50 years, -1.1%/year at 55 and -1.68%/year at 60). On the other hand, menopause-related BMD decrement is very evident during the first year since menopause (at spine: -8.1%/year; at forearm: -3.4%/year), and progressively decreases, according to a logarithmic function. Ten years later, yearly diminution of BMD is below 1%/year and 0.4%/year at spine and forearm, respectively. At this time, age contributes to determine bone loss for 2/3 and menopause for 1/3.

Glucose-Induced Insulin Secretion in Uremia: Role of 1α,25(HO)2-Vitamin D3

To evaluate the role and mechanism of action of calcitriol on glucose-induced insulin secretion in uremia, 17 patients with severe chronic renal failure were studied. Glucose metabolism was investigated by the intravenous glucose tolerance test (IVGTT) before and after treatment for 21 days with 0.5 µg/day of calcitriol and 500 mg/day of calcium (C + Ca) (6 cases) or 0.5 µg/day of calcitriol alone (C) (11 cases). After these evaluations the patients on C + Ca were shifted to C and 6 patients on C were shifted to C + Ca, and IVGTT was repeated 21 days after the shift. For each test plasma glucose (G), immunoreactive insulin (IRI) and C-peptide (C-p) were measured at -30,0,2,5,15,30,45,60 min, and baseline plasma values of 1α,25(HO)2-vitamin D3, C-terminal parathyroid hormone (PTH-C), intact parathyroid hormone (PTH-I), calcitonin, and serum values of total and ionized calcium were dosed. Also, glucose constant decay (K-G), insulin response (IRI area), C-p production (C-p area), insulinogenic index (IGI) and insulin resistance index (RI) were calculated. A historical group of 21 healthy volunteers formed the normal controls. 1α,25(HO)2-vitamin D3 plasma levels in uremic patients before treatment were significantly lower than normal range. As compared to controls, uremic patients showed significantly lower K-G, IRI area and IGI values and significantly higher RI values. After treatment with C or C + Ca, the insulin response improved significantly at 2 and 5 min and G decrement was more marked at 30,45 and 60 min. K-G and 0-15 min IRI area, 0-15 min IGI and 0-15 min C-p area values increased significantly but did not reach the normal values. Serum calcium and plasma 1α,25(HO)2-vitamin D3 levels significantly increased after treatment but no correlations were found between changes in glucose metabolism parameters and changes in total or ionized serum calcium or changes in 1α,25(HO)2-vitamin D3 plasma levels. Serum calcium values significantly decreased after shift from C + Ca to C and significantly increased after shift from C to C + Ca, but glucose metabolism parameters showed no further changes. From these data we inferred that 1α,25(HO)2-vitamin D3 deficiency may contribute to the inhibition of glucose-induced insulin secretion in uremia. Calcitriol mainly influences the first phase of insulin release and its effect may be due to a direct action on the pancreatic β-cell.

Recovery of Bone Mineral Density after Surgical Cure, but not by Ketoconazole Treatment, in Cushing’s Syndrome

Abstract: The aim of our study was to retrospectively assess the effect of treatment on bone mineral density (BMD) in patients with Cushing’s syndrome. Nineteen patients (17 women, 2 men; mean age ± SD, 41 ± 10 years; preoperative duration of disease 20 ± 15 months) were studied. Six patients had a cortisol-producing adenoma and 13 had pituitary-dependent bilateral adrenal hyperplasia. BMD of the lumbar spine (L2–L4) was measured by dual-energy X-ray absorptiometry just before and 1–10 years after adrenalectomy or pituitary adenomectomy. Patients were divided in two groups. The first group of 9 patients (6 adrenal and 3 pituitary adenomas; group A) included those treated successfully by surgery (>5 years follow-up in the case of pituitary surgery). The second group of 10 patients (group B) included those treated with the steroidogenesis inhibitor ketoconazole, 300–600 mg/day, after unsuccessful pituitary surgery. In group A, restoration of normal cortisol was associated with a significant increase in BMD (from 829 ± 112 mg/cm2 to 952 ± 107 mg/cm2; p = 0.002). In group B, no changes in BMD were observed (from 857 ± 160 to 847 ± 163 mg/cm2), in spite of markedly decreased or normalized cortisol levels during ketoconazole treatment. These findings indicate that definitive correction of hypercortisolism restores BMD to normal levels in patients with Cushing’s syndrome. In patients treated with ketoconazole after unsuccessful pituitary surgery, even when normalization of cortisol levels was achieved, BMD remained low. This would suggest an interfering effect of this drug on bone metabolism.