Background Despite therapeutic options for osteoporosis have greatly expanded over the past few decades, the treatment of patients with established severe osteoporosis still remains challenging. Recently the combined teriparatide (TPD) and denosumab therapy was shown to increase bone mineral density (BMD) more than either agent alone. Objectives The aim of this study was to compare the changes in bone turnover markers and in inhibitors of the Wnt canonical pathway in patients treated with either denosumab alone or TPD alone or when TPD was added to patients previously treated with denosumab. Methods Open label prospective randomized study, involving 59 women over 65 years old affected by severe postmenopausal osteoporosis (with the evidence of at least two moderate-severe vertebral fractures), Bone turnover markers C-terminal telopeptide of type I collagen (CTX) and intact N-propeptide of type I collagen ad (P1NP) and inhibitors of the Wnt canonical pathway sclerostin (SOST) and Dickkopf-related protein 1 (DKK1) were evaluated. Results In the groups treated with TPD or with denosumab alone bone turnover markers rose and decreased, respectively. In TPD group a later significant increase in DKK1 was observed, while in denosumab group a progressive increase in SOST was associated with a progressive significant decrease in DKK1. In the group treated first with denosumab and in which TPD was added 3 months later, the rounded values of both CTX and P1NP increased 3 months after the beginning of TPD by approximately the same absolute and percentage value of the group of patients treated with TPD alone, showing that the strong effect of denosumab on bone turnover is easily reversed by TPD treatment. In this group, SOST increased as in the denosumab alone group, while DKK1 progressively increased as in the TPD alone group. Conclusions In conclusion, in this study we showed that TPD is able to express its biological activity even when bone turnover is fully suppressed by denosumab treatment. The combination therapy is associated with significant increases in both DKK1 and SOST, suggesting that the Wnt signalling pathway is not involved in the positive bone balance seen in the combination TPD-denosumab group. Disclosure of Interest None declared

Unfortunately, the sixth author name was incorrectly spelled as “S. Fassio” instead of “A. Fassio” in the original publication.

Background : Osteoporosis is a highly prevalent disease and fractures are a major cause of disability and morbidity. Aim : The purpose of this study was to characterize post-menopausal women attending osteoporosis centers in Italy, to evaluate physician management, and to determine the incidence of first osteoporotic fracture. Subjects and methods : PROTEO-1 was an observational longitudinal study with a 12-month follow-up. Data were collected from women attending osteoporosis centers. Women without prevalent fracture were eligible to enter the 1-yr follow-up phase: the clinical approach to patients according to their fracture risk profile and the incidence of fracture were recorded. Results : 4269 patients were enrolled in 80 centers in the cross-sectional phase; 34.2% had an osteoporotic fracture at baseline. Patients with prevalent fractures were older and more likely to be treated compared with non-fractured patients. The incidence of vertebral or hip fracture after 1 yr was 3.84%, regardless of the calculated risk factor profile, and was significantly higher in patients with back pain at baseline (4.2%) compared with those without back pain (2.2%; p=0.023). Generally, physicians prescribed more blood exams and drugs to patients at higher risk of fracture. Among fractured patients only 24% were properly treated; the rate of non-responders to treatment was about 4%. Conclusions : In a large, unselected sample of post-menopausal women attending osteoporosis centers, those without previous fracture were at substantial risk of future fracture, regardless of their theoretical low 10-yr fracture risk. The presence of back pain in women without previous fracture warrants close attention.

Objective: The aim of this observational study, promoted by the Health Authorities of the Regione Veneto (Italy), is to assess the prevalence of the most relevant environmental and individual risk factors in subjects with a recent hip fracture. Methods: Patients aged more than 60 years of both genders with a recent hip fracture not associated with malignancies, were administered questionnaires on dietary habits, sun exposure, and disability score. A complete family, pharmacological and pathology history was collected together with information on previous falls, details of the fracture index, and anthropometric data. In all subjects, blood was taken for the measurement of serum 25 hydroxy-vitamin D (25OHD). Results: The study included 704 patients (573 women and 131 men). Mean age was 81±8 years (range 60-102). Severe pre-fracture disability was a common feature (58%) associated with multiple co-morbidities (84%), more frequently cardio- vascular and neurological diseases, and specific medications. In a large proportion (86%) of the patients, environmental or individual risk factors for falling were found. Vitamin D insufficiency (serum 25OHD levels <75 nmol/l) was quite common (70%), particularly in the regional Health Districts were strategies for preventing vitamin D deficiency were not implemented (91%). Only a small proportion (17%) of the study population had been evaluated and treated for osteoporosis. Conclusions: In senile patients with a recent hip fracture, pre-existing disability, multiple co-morbidities, high risk of falling and inadequate intake of calcium and vitamin D is relatively common. Community and case-finding interventions aimed at selecting subjects at high risk of osteoporosis, preventing vitamin D and dietary calcium deficiency, and increasing awareness on the environmental risks of falling are highly warranted.

The purpose of this study was to investigate the protective effects of curculigoside A (CA) on adjuvant arthritis (AA) rats and explore its possible mechanisms. AA was induced by intradermal injection of Freund's complete adjuvant (FCA). Male SD rats were treated with CA(10 and 20 mg/kg) from days 18 to 24 after immunization. The levels of interleukin (IL)-6, IL-1β, tumor necrosis factor-α (TNF-α) and prostaglandin E2 (PGE2) in serum were determined by ELISA. Moreover, the levels of super oxide dismutase (SOD) and malondialdehyde (MDA) were determined using commercial kits. In particular, NLRP3 inflammasome and NF-кB pathway were detected by Western blot. As expected, CA at 10 and 20 mg/kg significantly relieved the hind paw swelling and arthritis index, reduced the levels of IL-6 IL-1β, PGE2, TNF-α, MDA and increased SOD activity in serum. In addition, CA effectively down-regulated the expression of NF-кB/NLRP3 pathway. These findings showed that CA exerted beneficial effects on rheumatoid arthritis in rats.

The delayed cutaneous hypersens i t i v i t y to 7 ubiquitous antigens (Mu l t i t es t CMI, I s t i t u t e M~rieux) was evaluated in normal healthy volunteers before and at the time of intramuscular administ rat ion of 50 (12 subjects) or 50+50 (9 subjects)un i ts of salmon ca lc i ton in or 2 mL of sa l ine (8 subjects) . A 65% and a 75% f a l l in the mean number of pos i t i ve tes ts and in the mean score

A number of recent findings seem to indicate that fat and bone metabolism are strictly connected. We investigated the relationship between lipid profile and bone mineral density (BMD) in 236 either pre- or postmenopausal women, aged 35–81 years, attending our osteoporosis center (“clinic group”). In order to verify the consistency of the results, 265 men and 481 women aged 68–75, participating in a population-based epidemiological investigation (“community cohort”), were also studied. Lumbar spine, femoral neck, total hip and total body BMD, total body fat, % fat mass and lean mass were measured using dual energy X-ray absorptiometry (DXA). In the clinic group, lumbar spine and hip BMD Z score values were both strongly related to all measured serum lipids: the relationship was negative for HDL cholesterol (P < 0.05) and Apo A lipoprotein (P < 0.000) and positive for LDL cholesterol (P < 0.05), Apo B lipoprotein (P < 0.001) and triglycerides (P < 0.05). When BMD values were adjusted for body weight and BMI, most relationships remained statistically significant. In the community cohort, total body and hip BMD values were strongly related in both men and women to age, body weight, height, BMI, fat mass, lean mass, % fat mass. Total body and hip BMD were significantly related to serum lipids in both women and men. The relationship was negative for HDL cholesterol and positive for total cholesterol, triglycerides and LDL cholesterol. Most of these relationships (triglycerides, HDL cholesterol, LDL/HDL cholesterol ratio in women, and all measured lipids in men) remained statistically significant (P values ranging from 0.000 to 0.03) when the BMD values were adjusted also for anthropometric measures (body weight, height, fat mass). This study demonstrates for the first time that the lipid profile is strictly related to bone mass in both men and women. The interpretation of this association remains hypothetical but it might open new perspectives for understanding the mechanisms controlling bone metabolism.

Osteogenesis imperfecta (OI) is a heterologous group of rare inherited bone disorders resulting from defect in collagen synthesis or function. In previous studies, bone turnover has been found either increased or low-normal. These contradictory results might result from the study population made of children with prior recent fractures. We measured serum total and bone alkaline phosphatase (total and bone AP) serum osteocalcin (sOC), serum type I collagen C-telopeptide breakdown products (sCTX), urinary free-deoxypyridinoline (ufDPD), and urinary cross-linked N-telopeptides of type I collagen (uNTX) in 39 male and 38 premenopausal patients with different types of 01 aged between 18 and 51 years who had not experienced new clinical fracture during 12 months preceding the laboratory assessment. The study also includes a control group of 29 men and 26 women matched for age and gender.Most bone markers were 50-200% higher in patients than in controls. Only sCTX was comparable to that found in controls. From a subanalysis of the data, a trend for higher bone resorption markers was observed for any OI type, but patients with 01 type III and IV had significantly higher values in ufDPD and uNTX than patients with type 1 OI, and their sOC levels were not significantly higher than in controls. These results provide a strong rational for the use of anti-resorbing agent in OI. (C) 2004 Elsevier Inc. All rights reserved.

In a randomized controlled study, we investigated the effect of treatment with intravenous neridronate in prepubertal children with OI. Our study suggests that quarterly intravenous infusions of the bisphosphonate significantly raise the rate of increase in BMD at both the spine and hip, the projected area of the lumbar vertebrae, and height. These results are associated with a significant decrease in the risk of clinical fractures.Introduction: Osteogenesis imperfecta (01) is a heritable disease of connective tissue, characterized by increased bone fragility. Bisphosphonates currently seem to be the most promising therapy, but randomized, controlled studies are scarce and have never been carried out in prepubertal children.Materials and Methods: This was a randomized, controlled 3-year clinical trial. The Italian Patients' Society of 01 (AsItOI) sent their members affected by any type of OI to two centers at the University of Verona (Italy) to participate in the study. Sixty-four children, 6-11 years of age for boys and 6-9 years of age for girls, with no signs of puberty and who were never treated with bisphosphonates, were randomized to either intravenous neridronate (2 mg/kg infused IV in 30 minutes every 3 months) or no treatment, with a ratio of 2:1. Control patients were given the same bisphosphonate therapy at the end of the first year. BMD and projected bone areas, as measured by DXA, at spine and hip, height, and peripheral fracture incidence, both prospective and retrospective (2 years preceding randomization), were the main outcomes of the study.Results: At the end of the first year, spine and hip BMD rose by 3.5-5.7% in control patients and by 18-25% (p < 0.001 versus controls) in the active group, respectively. During the following 2 years, the treatment in all patients was associated with BMD increases of 1.0-25% per year. Height and the DXA-derived projected area of lumbar spine rose during the first year of observation significantly more in the active group than in the control group (< 0.01 and < 0.05, respectively). Both height and spine projected area continued to rise in the treated patients toward levels found in healthy individuals. During the first year of treatment, 45% of the control patients and 27% of the active group had a nonvertebrat fracture, but this difference was not statistically significant (p = 0.2). The total number of fractures was 18 in the 22 control patients and 13 in the active group (relative risk, 0.36; 95% CI, 0.15-0.87; p < 0.05).Conclusion: Intravenous neridronate infusions, administered quarterly, significantly increase BMD and lower the risk of clinical fracture in prepubertal children with OI.

Bisphosphonates have been used with success in the treatment of osteoporosis, but oral therapy often lacks compliance. Here we report the results of clinical trial with aminobisphosphonate neridronate administered intravenously (i.v.). The study included 78 postmenopausal women with spine bone mineral density (BMD) at least -2.5 SD below peak. Patients were randomized to receive for 2 years either 50 mg i.v. neridronate bimonthly and 500 mg calcium plus 400 U vitamin D supplements daily (n=39) or calcium-vitamin D supplements alone (control group, n=39). Treatment was continued over 2 years with an additional 1 year follow-up of calcium-vitamin D supplements alone. Neridronate was well tolerated with the appearance of typical clinical signs of an acute phase reaction in only 3 of the patients after the first infusion. In the control group no significant changes in BMD or bone markers were observed. In the neridronate group BMD rose progressively at the spine rose up to 7.4% +/- 6.1% (SD) and at the femoral neck up to 5.8% +/- 8.2% (SD) at the end of the second year. In the succeeding follow-up these gains were maintained at both skeletal sites. Serum bone alkaline phosphatase (bone ALP) and serum type I collagen C-telopeptide (s-CTX) significantly decreased within 2 months. The bone ALP values reached a -35% plateau after 6 months, while s-CTX attained the lowest mean value (-47%) only by the end of the treatment with neridronate. Both bone markers returned almost to baseline values 1 year after treatment discontinuation. Treatment of postmenopausal osteoporosis with 50 mg i.v. neridronate bimonthly results in clinically relevant increases in BMD, among the largest so far observed with any other bisphosphonate.