Total compared with partial pancreatectomy for pancreatic adenocarcinoma: assessment of resection margin, readmission rate, and survival from the U.S. National Cancer Database.

Introduction: Total pancreatectomy for pancreatic ductal adenocarcinoma has historically been associated with substantial patient morbidity and mortality. Given advancements in perioperative and postoperative care, evaluation of the surgical treatment options for pancreatic adenocarcinoma should consider patient outcomes and long-term survival for total pancreatectomy compared with partial pancreatectomy. Methods: The U.S. National Cancer Database was queried for patients undergoing total pancreatectomy or partial pancreatectomy for pancreatic adenocarcinoma during 1998-2006. Demographics, tumour characteristics, operative outcomes, 30-day mortality, 30-day readmission, additional treatment, and Kaplan-Meier survival curves were compared. Results: The database query returned 807 patients who underwent total pancreatectomy and 5840 who underwent partial pancreatectomy. More patients who underwent total pancreatectomy than a partial pancreatectomy had a margin-negative resection (p < 0.0001). Mortality and readmission rates were similar in the two groups, as was long-term survival on Kaplan-Meier curves (p = 0.377). A statistically significant difference in the rate of surgery only (without additional treatment) was observed for patients in the total pancreatectomy group (p = 0.0003). Conclusions: Although total compared with partial pancreatectomy was associated with a higher rate of margin-negative resection, median survival was not significantly different for patients undergoing either procedure. Patients who underwent total pancreatectomy were significantly less likely to receive adjuvant therapy.

Characterization of endocrine features and genotype-phenotypes correlations in blepharophimosis-ptosis-epicanthus inversus syndrome type 1.

OBJECTIVE: Blepharophimosis syndrome (BPES) is an autosomal dominant genetic condition resulting from heterozygous mutations in the FOXL2 gene and clinically characterized by an eyelid malformation associated (type I) or not (type II) with premature ovarian failure. The distinction between the two forms is critical for female patients, as it may allow to predict fertility and to plan an appropriate therapy. Identifying an underlying causative mutation is not always predictive of the clinical type of BPES since genotype-phenotype correlations are not yet fully delineated. Here, we describe the clinical and hormonal phenotypes of three female patients with BPES type 1 from two novel families, correlate their phenotypes with identified mutations, and investigate the effects of hormone replacement therapy (HRT). METHODS: Clinical, biochemical, and genetic evaluation were undertaken in all the patients and genotype-phenotype correlation was analyzed. The effects of substitutive hormonal therapy on secondary sexual characteristics development and induction of menarche were evaluated. RESULTS: All patients presented with primary amenorrhea or other signs of ovarian dysfunction. Two distinct mutations, a missense p.H104R change and an in-frame p.A222_A231dup10 duplication in the FOXL2 gene were identified. Observed phenotypes were not in accordance with the prediction based on the current genotype-phenotype correlations. HRT significantly improved secondary sexual characteristics development, as well as the induction of menarche. CONCLUSIONS: This study highlights the importance of early recognition of BPES and emphasizes the need of personalized therapy and follow-up in female patients carrying distinct FOXL2 mutations.

The immune system in extreme longevity.

Recent observations indicate that immunosenescence is not accompanied by an unavoidable and progressive deterioration of the immune function, but is rather the result of a remodeling where some functions are reduced, others remain unchanged or even increased. In addition, it appears that the ancestral/innate compartment of the immune system is relatively preserved during aging in comparison to the more recent and sophisticated adaptive compartment that exhibit more profound modifications. The T-cell branch displays an age-dependent decline of the absolute number of total T-cells (CD3+), involving both CD4+ and CD8+ subsets, accompanied by an increase of NK cells with well-preserved cytotoxic function and by a reduction of B-cells. One of the main characteristics of the immune system during aging is a progressive, age-dependent decline of the virgin T-cells (CD95-), which is particularly profound at the level of the CD8+ subpopulation of the oldest old subjects. The progressive exhaustion of this important T-cell subpopulation dedicated primarily to the defense against new antigenic challenges (viral, neoplastic, bacterial ones), could be a consequence of both the thymic involution and the lifelong chronic antigenic stimulation. The immune function of the elderly, is therefore weakened by the exhaustion of CD95- virgin cells that are replaced by large clonal expansions of CD28- T-cells. The origin of CD28- cells has not been completely clarified yet, but it is assumed that they represent cells in the phase of replicative senescence characterized by shortening telomers and reduced proliferative capacity. A major characteristic of the immune system during aging is the up-regulation of the inflammatory responses which appears to be detrimental for longevity. In this regard, we have recently observed a progressive age-dependent increase of type 1(IL-2, IFN-gamma, TNF-alpha) and type 2 (IL-4, IL-6, IL-10) positive CD8+ T-cells; in particular, type 1 cytokine-positive cells significantly increased, with age, in all CD8+ subsets particularly among effector/cytotoxic and memory cells. A major force able to drive a chronic pro-inflammatory state during aging may be represented by persistent viral infections by EBV and CMV. Therefore, we have determined the frequency and the absolute number of viral antigen-specific CD8+ T-cells in subjects older than 85 years, who were serologically positive for CMV or EBV. In the majority of these subjects we detected the presence of T lymphocytes positive for epitopes of CMV or EBV. In all subjects the absolute number of CMV-positive CD8+ cells outnumbered that of EBV-positive ones. In addition, the majority of CMV+ T cells were included within the CD28- subpopulation, while EBV+ T cells belonged mainly to the CD28+ subset. These data indicate that the chronic antigenic stimulation induced by persistent viral infections during aging bring about important modifications among CD8+ subsets, which are particularly evident in the presence of CMV persistence. The age-dependent expansions of CD8+CD28- T-cells, mostly positive for pro-inflammatory cytokines and including the majority of CMV-epitope-specific cells, underlines the importance of chronic antigenic stimulation in the pathogenesis of the main immunological alterations of aging and may favour the appearance of several pathologies (arteriosclerosis, dementia, osteoporosis, cancer) all of which share an inflammatory pathogenesis.

New insights into the biological and clinical significance of fecal calprotectin in inflammatory bowel disease.

Nowadays, calprotectin, a cytoplasmatic protein, released by activated neutrophilic polymorphonuclear cells (PMN) and/or monocytes-macrophages (MØ), is considered a good indicator of inflammation in several diseases. Accordingly, fecal calprotectin represents a good predictor of clinical relapse in ulcerative colitis (UC) patients, whereas conflicting results have been reported in Crohn's disease (CD) patients. In our study, in 76 IBD patients (29 CD and 47 UC) fecal calprotectin has been evaluated by a commercial ELISA kit. Results demonstrate that levels of this protein in the stool are significantly more elevated in active CD and UC patients than in normal volunteers. In quiescent CD and UC a trend to higher levels of calprotectin than in the normal counterpart is, however, evident. These data suggest that a low-grade inflammation of the intestinal wall is always present in CD and UC patients, which may predict a clinical relapse risk. In the same group of patients calprotectin levels also were analyzed according to sex and age. A trend to higher values of calprotectin was present in male patients with active or quiescent CD than in their female counterparts. Only in UC patients in remission a trend to calprotectin increase was more marked in the male group than in the female counterpart. When CD and UC patients were divided up according to age, calprotectin positivity peaked between 30-39 years in active CD patients, while in quiescent CD maximum positivity was between 40 and 49 years. However, in both active and quiescent UC patients, calprotectin positivity increased with age. The more precocious detectability of fecal calprotectin in CD patients, as a marker of intestinal mucosa inflammation, may be related to the different histopathology of the two diseases (CD versus UC). However, reduced PMN and/or MØ trafficking from peripheral blood to intestinal mucosa with age by effects of chronic treatment should not be ignored in CD patients.

Ablation of T-helper 1 cell derived cytokines and of monocyte-derived tumor necrosis factor-alpha in hereditary hemorrhagic telangiectasia: immunological consequences and clinical considerations.

Experimental evidences on the adaptive immune response in patients with hereditary hemorragic telagiectasia (HHT) are lacking. Here, we report in 9 patients with HHT a multiple deficit involving the intracellular expression of T helper (h)1-derived cytokines [Interferon (IFN)-gamma, Interleukin (IL)-2 and Tumor Necrosis Factor (TNF)-alpha] and of monocyte-derived TNF-alpha. On the other hand, percentages of Th2-derived cytokines (IL-4, IL-5 and IL-10) were normal or, in some cases, above normality. Quite interestingly, monocyte-derived IL-10 was detectable in 5 out of 9 patients in a percentage of cells comparable to controls or exceeding normal levels. Taken together, these data point out, in HHT, an ablation of Th1-responses, while Th2-type cytokines are preserved, thus exerting either a suppressive effect on Th1-cells (via IL-4 and IL-10) or an antiinflammatory response on monocyte-derived TNF-alpha (via IL-10). Furthermore, monocyte-derived IL-10 may also contribute to the antiinflammatory activity seen in HHT. According to current literature even if patients with HHT do not exhibit certain diseases, such as autoimmune diseases, cancer and abnormal responses to pathogens, the observed immune deficits need to be diagnosed and therapeutically corrected.

Taking advantage of viral immune evasion: virus-derived proteins represent novel biopharmaceuticals.

In healthy individuals, natural and adaptive immune responses are able to control virus entry into the host. In particular, CD8(+)-mediated cytotoxicity, sustained by the intervention of CD4+ cells, represents the major key event leading to virus eradication. On the other hand, viruses are able to evade from host immune response via several mechanisms, and special emphasis will be placed on hepatitis C virus and chronic Epstein-Barr infections also in view of personal data. Virokines, viroreceptors, and serpins greatly contribute to viral immune escape, and, among virokines, interleukin (IL)-10 has been object of intensive studies. Finally, all these products have been used as biopharmaceuticals, and, for instance, viral IL-10, chemokine-binding proteins, and serpins exhibit in animal models immunosuppressive, anti-inflammatory, and antiatherogenic activities. As far as their use in human trials is concernded, many cautions are required in order to avoid deleterious side effects and, in particular, the purity of the product, its route and frequency of administration, as well as the immune status of the patient should be taken into serious account.

High risk for microcarcinoma in thyroid benign diseases. Incidence in a one year period of total thyroidectomies.

Over the last few years, incidental thyroid microcarcinoma (TMC) has become a frequent disease and its incidence in some reports is considerable. The discovery of new cases depends on the progress of the diagnostics (US scan, fine needle biopsy and cytology, CT, MRI), on the extended indications to thyroidectomy for benign disease and on the attention in pathologic examination of the specimen. The clinical evolution of this disease is not well known: in spite of a high incidence reported in some autoptic series, suggesting that this tumour could have a good prognosis, some authors report an overall incidence of up to 11% of local recurrence, metastasis and mortality. For these reasons the treatment of TMC is still controversial today. Aim of this study was to estimate the incidence and the clinico-pathological findings of TMC over a one year period of total thyroidectomies for diffuse benign thyroid diseases, and to evaluate, on the basis of the frequency of incidental microcarcinoma, if the surgical procedure of complete removal of the gland should be adopted in any case. In this series no patient had pre-operative diagnosis or tentative diagnosis of carcinoma and the incidence of TMC at the final histologic examination was 27.4%. Total thyroidectomy confirmed to be the treatment of choice for diffuse benign diseases and appeared necessary to obtain both, diagnosis and treatment of incidental TMC.

Characteristics of adult patients with growth hormone deficiency who underwent neurosurgery for functioning and non-functioning pituitary adenomas and craniopharyngiomas.

The aim of the present study was to evaluate the characteristics of GH deficiency (GHD) in adult patients after neurosurgery for pituitary adenomas and craniopharingiomas. One hundred and one GHD patients, (42 F/59 M), aged 47.58+/-14.4 yr (mean+/-SD; range 21-78), body mass index (BMI) 28.6+/-0.6, with a history of adult-onset hypothalamic-pituitary disease, were recruited for the study. The whole group included: 45 non-functioning pituitary adenomas, 23 craniopharyngiomas, 16 PRLomas, 8 GHomas, 7 ACTHomas and 2 FSHomas; in particular 51 were macroadenomas and 27 microadenomas. At study entry, GHD diagnosis was carried out by assessing GH secretion after GHRH+arginine. All patients were submitted to the study at least 12 months after neurosurgery and, where needed, subjects were replaced with an appropriate treatment. GHD was mild in 3/101 (3%) and severe in 98/101 patients (97%). Other hormone deficiencies associated with GHD were considered: TSH, ACTH, FSH/LH, ADH. The distribution of peak GH among all patients, according to the type of disease before neurosurgery, showed that patients with Cushing disease were characterized by the presence of higher peak GH. According to the number of additional hormone deficits, the distribution of peak GH among all patients was as follows: GHD was isolated in 4/101 subjects (4%; group A), while it was associated with 1 (14/101, 14%; group B), 2 (22/101, 22%; group C), 3 (44/101, 43%; group D) and 4 hormone deficits (17/101, 16%; group E). GHD was severe in all patients in the panhypopituitaric group. Total IGF-I plasma levels in the whole group of GHD patients were 95.2+/-4.2 microg/l. In all groups of patients IGF-I was lower in subjects with severe GHD than in those with mild GHD (93.6+/-4.1 vs 148.6+/-33.6 microg/l, p<0.03). In particular, according to the type of disease presented before neurosurgery, patients with Cushing disease were characterized by the presence of higher IGF-I plasma levels compared to the other. According to the number of additional deficits, the distribution of IGF-I plasma levels was characterized by higher values when GHD was isolated than when it was associated with multiple hormone deficiencies. IGF-I plasma levels were positively associated to peak GH during GHRH+arginine (r=0.4, p<0.0005). We conclude that patients after neurosurgery approach for sellar and parasellar neoplasia, within an appropriate clinical context, and both the presence of additional pituitary hormone deficiency and low levels of IGF-I can be considered a clear GHD condition, and therefore do not require provocative tests evaluating GH secretion.

Serum interleukin-6, soluble interleukin-6 receptor and soluble gp130 exhibit different patterns of age- and menopause-related changes.

Growing evidence suggests that interleukin-6 (IL-6) may play a pathogenetic role in postmenopausal bone loss and in other age-related pathological conditions. In this study, we have examined the age-related changes in the serum levels of IL-6 and the soluble receptors that modulate its biological activity--soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130)--in 220 women (from 25 to 104yr old), including 22 centenarians. Serum IL-6 rose exponentially with age (r=0.74, p<0.0001). The median level of IL-6 increased almost ten-fold with age, from 1.16pg/ml in premenopausal women to 10.27pg/ml in centenarians. Serum sIL-6R and sgp130 showed an increase until the seventh decade and a progressive decrease in older ages (r=0.39, p<0.0001 and r=0.26, p=0.008, respectively). IL-6, sIL-6R and sgp130 were significantly higher in women within 10yr of menopause as compared to premenopausal subjects (1.51 vs. 1.16pg/ml, p=0.012; 41.9 vs. 35.7ng/ml, p=0.002; and 253.4 vs. 230.7ng/ml, p=0.008, respectively). In postmenopausal women, a negative correlation was found between sIL-6R and the lumbar bone mineral density (BMD) (r=-0.28, p=0.002) even after adjusting for age and weight. Furthermore, sIL-6R levels were higher in osteoporotic compared to normal women (47.9 vs. 39.5ng/ml, p=0.001). In conclusion, our results show that the serum levels of IL-6, sIL-6R and sgp130 exhibit different patterns of age- and menopause-related changes, and that the biological activity of IL-6 may be increased with age with potential implications in the age-related diseases such as osteoporosis.

Shortage of circulating naive CD8(+) T cells provides new insights on immunodeficiency in aging.

Clinical observations indicate that elderly people are prone to severe, often lethal infectious diseases induced by novel pathogens. Since the ability to mount primary immune responses relies on the availability of naive T cells, the circulating naive T-cell reservoir was evaluated throughout the human life span. Naive T cells were identified as CD95(-) T lymphocytes for their phenotypic and functional features. Indeed, the lack of CD95 marker is sufficient to identify a population of naive T cells, as defined by coincidence with previously characterized CD45RA(+) CD62L(+) T cells. Naive CD95(-) T cells, as expected, require a costimulatory signal, such as CD28, to optimally proliferate after anti-CD3 stimulation. Cytofluorimetric analysis of circulating T lymphocytes from 120 healthy subjects ranging in age from 18 to 105 years revealed that naive T cells decreased sharply with age. The younger subjects had a naive T-lymphocyte count of 825 +/- 48 cells/microL, and the centenarians had a naive T-lymphocyte count of 177 +/- 28 cells/microL. Surprisingly, the naive T-cell count was lower in CD8(+) than in CD4(+) subsets at any age, and the oldest individuals were almost completely depleted of circulating naive CD8(+) T cells (13 +/- 4 cells/microL). Concomitantly, a progressive expansion of CD28(-) T cells occurs with age, which can be interpreted as a compensatory mechanism. These data provide new insights into age-related T-cell-mediated immunodeficiency and reveal some analogies of T-cell dynamics between advanced aging and human immunodeficiency virus (HIV) infection. In conclusion, the exhaustion of the naive CD8(+) T-cell reservoir, which has never been reported before, suggests that this T-cell pool is a major target of the aging process and may define a parameter possibly related to the life span of humans. (Blood. 2000;95:2860-2868)

Sleep disturbances in children with human immunodeficiency virus infection.

OBJECTIVE: To describe the sleep patterns and level of fatigue in children and adolescents (6-18 years of age) with HIV infection, compared with ethnic-, gender-, and age-matched healthy children in the home setting. DESIGN: Descriptive, comparative. SETTING: Conducted in each child's home environment. STUDY PARTICIPANTS: Eighteen HIV-infected and 15 noninfected children completed the study. The Centers for Disease Control and Prevention HIV classifications for the 18 HIV-infected children were: A (n = 7), B (n = 6), and C (n = 5). METHODS: A symptom diary was developed using a previously validated fatigue assessment scale, modified for use with children. Content validity of the diary was established with a panel of 5 experts in child development and pediatric HIV disease. Children were asked to complete the diary each morning and evening for 3 days. Each child wore a wrist actigraph during the same period. RESULTS: The HIV-infected children had significantly more wake time after sleep onset, compared with noninfected children (13.55% vs 7. 47%). The HIV-infected children had more awakenings (25.33 vs 16.71) and were awake for longer periods (3.01 vs 1.01 minutes), compared with noninfected children. By parent report, 7 HIV-infected children napped and 2 noninfected children napped, indicating greater daytime fatigue in the HIV-infected children. HIV-infected children also reported a greater level of evening tiredness (2.47 vs 1.8). CONCLUSIONS: The findings from this study suggest that sleep disturbances occur in HIV-infected children, similar to findings previously described in HIV-infected adults. Additional research is necessary to characterize the nature and patterns of sleep disturbance and fatigue related to pediatric HIV-infection, to assess the impact these may have on daily activities, and to develop strategies to improve sleep for these children.

Risk factors for hip fracture in men from southern Europe: the MEDOS study. Mediterranean Osteoporosis Study.

The aims of this study were to identify risk factors for hip fracture in men aged 50 years or more. We identified 730 men with hip fracture from 14 centers from Portugal, Spain, France, Italy, Greece and Turkey during the course of a prospective study of hip fracture incidence and 1132 age-stratified controls selected from the neighborhood or population registers. The questionnaire examined aspects of work, physical activity past and present, diseases and drugs, height, weight, indices of co-morbidity and consumption of tobacco, alcohol, calcium, coffee and tea. Significant risk factors identified by univariate analysis included low body mass index (BMI), low sunlight exposure, a low degree of recreational physical activity, low consumption of milk and cheese, and a poor mental score. Co-morbidity including sleep disturbances, loss of weight, impaired mental status and poor appetite were also significant risk factors. Previous stroke with hemiplegia, prior fragility fractures, senile dementia, alcoholism and gastrectomy were associated with significant risk, whereas osteoarthrosis, nephrolithiasis and myocardial infarction were associated with lower risks. Taking medications was not associated with a difference in risk apart from a protective effect with the use of analgesics independent of co-existing osteoarthrosis and an increased risk with the use of anti-epileptic agents. Of the potentially 'reversible' risk factors, BMI, leisure exercise, exposure to sunlight and consumption of tea and alcohol and tobacco remained independent risk factors after multivariate analysis, accounting for 54% of hip fractures. Excluding BMI, 46% of fractures could be explained on the basis of the risk factors sought. Of the remaining factors low exposure to sunlight and decreased physical activity accounted for the highest attributable risks (14% and 9% respectively). The use of risk factors to predict hip fractures had relatively low sensitivity and specificity (59.6% and 61.0% respectively). We conclude that lifestyle factors are associated with significant differences in the risk of hip fracture. Potentially remediable factors including a low degree of physical exercise and a low BMI account for a large component of the total risk.

Importance of bioavailable calcium drinking water for the maintenance of bone mass in post-menopausal women.

The aim of this research was to establish the importance of calcium intake through mineral water on vertebral bone density in women. To this purpose, we examined 255 women divided into two groups: those regularly drinking a high calcium content mineral water (group A; no.=175) and those using different type of water with a lower calcium content (group B; no.=80). Their dietary daily calcium intake was determined by means of a validated questionnaire (N.I.H. Consensus statement) and vertebral bone density was measured by Dual-Energy X-ray absorptiometry (Unigamma-plus ACN densitometer). Women in group A ingested a significantly higher quantity of calcium in water than women in group B (mean difference 258 mg; 95% confidence limits: 147-370 mg). The average bone density values were slightly but significantly higher in group A as compared to group B (mean+/-SD: 1.044+0,15 vs 1.002+0,14; p=0.03). In addition to age, BMI and menopausal status, calcium intake was a significant predictor of spinal BMD. These 4 variables explained about 35% of the spinal BMD variance. When the analysis was repeated separately for pre- and post-menopausal subjects, calcium remained a significant predictor in post-menopausal women (t=2.28; p=0.02), but not in premenopausal women. These results underline the importance of a lifelong daily calcium intake, resulting by the regular drinking of high bioavailable calcium water, in order to maintain bone mass after the menopause, in comparison to the use of a lower content calcium water.

Effect of ipriflavone--a synthetic derivative of natural isoflavones--on bone mass loss in the early years after menopause.

OBJECTIVE: We studied whether oral administration of ipriflavone, a synthetic derivative of naturally occurring isoflavones, could prevent bone loss occurring shortly after menopause. DESIGN: Fifty-six women with low vertebral bone density and with postmenopausal age less than five years were randomly allocated to receive either ipriflavone, 200 mg three times daily, or placebo. All subjects also received 1,000 mg elemental calcium daily. RESULTS: Vertebral bone density declined after two years in women taking only calcium (4.9 +/- 1.1%, SEM, p = 0.001), but it did not change in those receiving ipriflavone (-0.4 +/- 1.1%, n.s.). A significant (p = 0.010) between-treatment difference was evidenced at both year 1 and year 2. At the end of the study, urine hydroxyproline/creatinine excretion was higher in the control group than in the ipriflavone group, as compared to no difference at baseline. Five patients taking ipriflavone and five taking placebo experienced gastrointestinal discomfort or other adverse reactions, but only one and four subjects, respectively, had to discontinue the study. CONCLUSIONS: Ipriflavone prevents the rapid bone loss following early menopause. This effect is associated with a reduction of bone turnover rate.

The possible role of hematin and Mössbauer effect in the inhibition of osteosarcoma cell proliferation.

Hematin, like many hematoporphyrines and porphyrin derivatives, shows a higher affinity and preferential localization for tumor cells. These properties are particularly interesting in view of their possible applications in tumor treatment. The aim of the present work was to test the capability of porphyrines and resonant low energy gamma rays to produce some kind of selective inhibition of tumor cell proliferation. We investigated the role of hematin to potentiate the killing capability of 14.4 keV resonant gamma rays from a 57Co Mössbauer source. Human osteosarcoma cell cultures "MG-63" were incubated in the presence or absence of hematin (10(-4) to 10(-5) M) for 24 hours. They were successively irradiated for 4 hours with 14.4 keV gamma rays from a 3.7 GBq 57Co source. The combined effects of hematin and resonant gamma radiation were then examined and tested statistically for significance. Different degrees of growth inhibition were observed when hematin alone, radiation alone, and hematin plus gamma rays were administered to the cultures. Hematin, at the concentrations of 10(-4) M is capable of inhibiting tumor cells growth. While no significant effect is attributable to irradiation alone, hematin plus irradiation show a larger inhibition than that expected for purely additive effects.

A double blind, placebo-controlled trial of ipriflavone for prevention of postmenopausal spinal bone loss.

One hundred ninety-eight postmenopausal women (aged 50-65 years) with vertebral bone density (VBD) 1 SD below the mean value for normal, age-matched, postmenopausal subjects were enrolled in six Italian centers and 134 completed 2 years of treatment. All subjects were randomly allocated to a 2-year treatment with oral ipriflavone (200 mg t.i.d.) or a matching placebo, according to a double-blind, parallel group design. All patients also received an oral daily calcium supplement of 1 g as calcium carbonate. VBD and markers of bone turnover were measured at baseline, and every 6 months. A complete routine analysis of liver and kidney functions along with hematological parameters were measured before and at the end of treatment period. The valid completers analysis showed a significant increase of VBD in ipriflavone-treated women with average percent changes of +1.4 after 1 year, and +1% at the end of treatment period (P < 0.05). The placebo group presented a significant decrease of VBD after 2 years of treatment (P < 0.05). The difference between treatments was significant (P < 0.01). The intention to treat analysis confirmed the significant decrease of VBD in the placebo group, with no changes in ipriflavone-treated women. Skeletal ALP significantly decreased in ipriflavone-treated women (P < 0.05). Serum BGP and urine HOP/Cr showed a significant decrease only in ipriflavone-treated women, suggesting an inhibitory effect on bone turnover rate. Adverse reactions, mainly gastrointestinal, occurred to a similar extent in the two treatment groups. The evaluation of patients' compliance, assessed by residual tablets count, revealed a drug intake of more than 80% after 2 years in 92.5% and 92.8% of patients treated with ipriflavone or placebo, respectively. This study demonstrates that ipriflavone can prevent bone loss in postmenopausal women with low bone mass.