Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT).

SUMMARY: A 12-month extension phase of DIRECT in Japanese subjects with osteoporosis showed that total 3 years of denosumab treatment in Japanese postmenopausal women and men with osteoporosis was associated with low fracture rates, persistent bone turnover marker (BTM) reductions, continuous bone mineral density (BMD) increases, and a favorable overall benefit/risk profile. INTRODUCTION: The DIRECT trial demonstrated that 2 years of treatment with denosumab 60 mg subcutaneously every 6 months significantly reduced the incidence of vertebral fracture compared to placebo in Japanese postmenopausal women and men with osteoporosis. The purpose of this study is to evaluate the efficacy and safety of denosumab treatment for up to 3 years. METHODS: This study includes a 2-year randomized, double-blind, placebo-controlled phase and a 1-year open-label extension phase in which all subjects received denosumab. The data correspond to 3 years of denosumab treatment in subjects who received denosumab (long-term group) and 1 year of denosumab treatment in subjects who received placebo (cross-over group) in the double-blind phase. RESULTS: Eight hundred and ten subjects who completed the double-blind phase enrolled into the extension phase, and 775 subjects completed the study. All subjects received denosumab with daily supplements of calcium and vitamin D. The cumulative 36-month incidences of new or worsening vertebral fractures and new vertebral fractures were 3.8 and 2.5 %, respectively, in the long-term group. In this group, the BMD continued to increase, and the reduction in BTMs was maintained. In the cross-over group, comparable BMD increases and BTMs reductions to those of in their first year of the long-term group were confirmed. Adverse events did not show a notable increase with long-term denosumab administration. One event of osteonecrosis of the jaw occurred in the cross-over group. CONCLUSIONS: Three-year denosumab treatment in Japanese subjects with osteoporosis showed a favorable benefit/risk profile.

15-Deoxyspergualin "rescue therapy" for methylprednisolone-resistant rejection of renal transplants as compared with anti-T cell monoclonal antibody (OKT3).

A randomized trial with OKT3, an anti-T cell monoclonal antibody or with 15-deoxyspergualin against methylprednisolone-resistant rejection crisis was performed in 25 posttransplant patients immunosuppressed with prednisolone and cyclosporine. At least temporary reversal of rejection was observed in 58.3% of patients treated with 15-deoxyspergualin. This reversal rate may be quite comparable to 61.5% seen in patients treated with OKT3. Adverse effects with 15-deoxyspergualin were related to bone marrow suppression, while those with OKT3 were pyrexia, gastrointestinal symptoms, and herpes infection. In contrast to OKT3, which may act by modulating T cell surface antigen, 15-deoxyspergualin may be effective somewhere in the later stages of the rejection cascade.

Age- and gender-related changes in ligament components.

The age- and gender-related changes in extracellular matrix components (elastin, elastin cross-links, fibrillin, collagen and glycoprotein) and mineral components (calcium, Ca; phosphorus, P) in human lumbar yellow ligaments were investigated using samples obtained from surgical specimens. The mineral (Ca and P) contents increased with ageing (r = 0.703 and r = 0.772, respectively), whereas the contents of matrix components tended to decrease with ageing (elastin r = -0.261, elastin cross-links r = -0.213, fibrillin r = 0.494; collagen r = -0.322 and glycoprotein r = -0.143). Comparison of the male and female groups revealed that the ligament elastin content and elastin cross-links decreased in the male group, whereas the ligament collagen content decreased in the female group significantly in an age-dependent manner (r = -0.788, r = -0.753 and r = -0.721, respectively). These findings demonstrate age- and gender-related changes in mineral and matrix components (especially elastin and collagen) in the lumbar yellow ligaments in the Japanese population. It is suggested that elastin and collagen metabolism in ligaments changes both with age and according to gender.

[Qualitative change in the elastin from the calcified portion of human artery].

To examine the qualitative changes of elastin and the aorta related to calcification of human arteries, biochemical properties were measured, including calcium (Ca), phosphorus (P) and magnesium (Mg) contents in the aorta or in the elastin fraction in calcification, cholesterol content in atherosclerosis, desmosine content of cross-link, free thiol contents (free SH/total SH) and hydrophobic properties in the elastin fraction from the calcified portion, adjacent sites and another normal artery. The results from different sites of the calcified abdominal artery are as follows: The contents of Ca, P and Mg in aorta and the elastin fraction from the calcification site were higher than those at other sites. Moreover, Ca in the aorta and elastin fraction correlated positively with P and Mg. The content of cholesterol in the calcification site was the same as at other sites and did not correlate with Ca, P or Mg. The content of desmosine in the calcification site was significantly lower than that in different sites. In addition, its content was negatively associated with Ca and P in the elastin fraction and with the aortic Mg. The content of free thiol in the calcification site was similar to the other sites and correlated negatively with Ca and P in the aorta. The hydrophobicity in the calcification was similar to that at other sites, and was negatively associated with Ca and Mg in the elastin fraction.

[Quantitative changes of elastin, fibrillin and collagen in abdominal aortic aneurysms].

To examine quantitative changes of elastin, fibrillin and collagen in abdominal aortic aneurysms, including ruptured abdominal aortic aneurysms (RAAA), inflammatory abdominal aortic aneurysms (IAAA) and abdominal aortic aneurysms (AAA) were measured. Items measured included the desmosine content of the aorta (desmosine 1) or of the elastin fraction (desmosine 2), fibrillin content in the aorta, hydroxyproline in the aorta, collagen percent and elastin percent, and were compared with control samples from the nonaneurysmal aortic segments. The elastin contents (desmosine 2) in RAAA, IAAA and AAA were significantly lower than those of controls. The content of the desmosine 2 from IAAA and AAA did not show a negative association with Ca. The fibrillin contents of the aorta from RAAA, IAAA and AAA were significantly higher than those of controls. The collagen content in the RAAA aorta was significantly higher than that of controls. There was a correlation of the ratio of fibrillin to elastin components (fibrillin/desmosine 1 or fibrillin/desmosine 2 or fibrillin/elastin%) and the ratio of collagen to elastin components (collagen/desmosine 1 or collagen/desmosine 2 or collagen/elastin%). These results indicated that increasing fibrillin and collagen might be a complementary result of decreasing elastin crosslinks in the aorta. This phenomenon was markedly in RAAA.

[Canine orthotopic liver transplantation].

For the purpose of increasing long-term survival in canine orthotopic hepatic allotransplantation, immunosuppression by mizoribine and/or cyclosporin was instituted with the following results: 1) The survival of control dogs without treatment (n = 5) was 10.0 +/- 2.9 days (Mean +/- S.E.), and the survival of dogs treated with mizoribine (n = 15) was 44.6 +/- 31.8 days. There was no statistical difference between the two groups. On the other hand, the mean survival of dogs that were initially treated with cyclosporin and were then switched to mizoribine at one to three months after transplantation reached 145.4 +/- 70.8 days. The survival rate of dogs in the cyclosporin-mizoribine group was significantly greater than that of control group (p less than 0.02); and the survival rate of the former group proved also significantly better than that of the mizoribine group at 20 days after transplantation (X2, p less than 0.05); 2) in cases of acute rejection of the allograft, a gradual increase of the serum bilirubin level with a concomitant rise of S-GPT and alkaline phosphatase was generally observed. For an accurate diagnosis, however, an assessment of the biopsy findings of the allograft is important; 3) in chronic rejection, one animal developed the selective disappearance of interlobular bile ducts, often referred to as the "vanishing bile duct syndrome"; and 4) for differential diagnosis of vascular and/or biliary tract complications, specific morphological diagnostic procedures such as vascular and/or biliary tract angiographies are needed.