Evaluation of crystallographic orientation of biological apatite in vertebral cortical bone in ovariectomized cynomolgus monkeys treated with minodronic acid and alendronate

Quantitative analysis of the orientational distribution of biological apatite (BAp) crystals is proposed as a new index of bone quality. This study aimed to analyze BAp c-axis orientation in ovariectomized (OVX) monkeys treated with amino-bisphosphonates minodronic acid and alendronate as reference. Sixty female monkeys aged 9–17 years were divided into five groups: one sham group and four OVX groups. The sham group and one OVX group were treated daily with vehicle for 17 months. The other three groups were treated daily with minodronic acid at doses of 0.015 and 0.15 mg/kg, and alendronate at 0.5 mg/kg orally, respectively. The seventh lumbar vertebrae were subjected to analysis of the preferential BAp c-axis orientation in the ventral cortical bone. The BAp c-axis orientation along the craniocaudal axis was significantly increased in the OVX monkeys. The high dose of minodronic acid suppressed the OVX-induced increase in the BAp c-axis orientation, whereas alendronate showed a non-significant tendency to suppress the increase in the orientation. In analysis with other parameters, the BAp c-axis orientation was positively correlated with bone formation indices in biochemical markers and bone histomorphometry and negatively correlated with the increase in lumbar bone mineral density. On the other hand, the BAp c-axis orientation was not correlated with bone resorption indices, except for the eroded surface. These results indicate that the increase in BAp c-axis orientation was ameliorated by minodronic acid treatment in OVX monkeys, mainly by suppression of bone formation increase.     

Differences in vertebral,tibial, and iliac cancellous bone metabolism in ovariectomized rats

Bone histomorphometry is usually performed on the iliac bone in humans and the tibia or vertebrae in rats. Bone metabolism differences among skeletal sites may be problematic when translating experimental results from rats to humans, but data on such differences in rats are lacking. Therefore, we examined the differences in bone structure and metabolism among skeletal sites using the lumbar vertebra (LV), tibia, and iliac bone obtained from ovariectomized or sham-operated rats preoperatively and at various times from 3 days to 26 weeks postoperatively. The trabeculae were thicker in the LV, where bone metabolism was less active than at other sites, and numerous fine trabeculae were observed in the tibia, where bone metabolism was more active. The iliac bone structure and metabolism were intermediate between those of the tibia and LV. Ovariectomy induced lower bone volume and higher bone metabolism in all skeletal sites, but the changes were greatest and occurred earliest in the tibia, followed by the iliac bone and then LV. Ovariectomy caused changes in bone metabolic markers, which occurred earlier than those in bone tissue. Activation frequency (Ac.f) increased after ovariectomy. At week 26 in ovariectomized rats, Ac.f was highest in the tibia (3.13 N/year) but similar between iliac bone (0.87 N/year) and LV (1.39 N/year). Ac.f is reportedly 0.3–0.4 N/year in the iliac bone of postmenopausal women, suggesting that bone turnover in rats is several times higher than in humans. The reference values reported here are useful for translating experimental results from rats to humans.     

Characteristics of Persistent Hyperparathyroidism After Renal Transplantation

Background

Persistent hyperparathyroidism (HPT) after renal transplantation (RTx), termed tertiary HPT (THPT), is not uncommon. However, risk factors and appropriate operative procedures for THPT are poorly understood.

Methods

A retrospective study of patients who underwent RTx without pre-transplant parathyroidectomy (PTx) was performed at our hospital between January 2001 and March 2011. Risk factors for the development of THPT were investigated by comparing THPT and non-THPT groups. We retrospectively analyzed patients with THPT who underwent total PTx with forearm autograft. Pre- and postoperative (1 year after PTx) laboratory results were analyzed for PTx efficacy.

Results

Data for 520 patients were analyzed. On multivariate analysis, long dialysis duration (p = 0.009, hazard ratio (HR) 1.01), large maximum parathyroid gland size before RTx (p = 0.003, HR 1.23), pre-RTx high intact parathyroid hormone (iPTH) (p = 0.041, HR 1.01), post-RTx (<2 weeks) high calcium (Ca) (p < 0.001, HR 25.04), and post-RTx high alkaline phosphatase (ALP) (p = 0.027, HR 0.99) were identified as risk factors for THPT. Patients who underwent PTx showed significant improvement compared with baseline for serum Ca, phosphorus, iPTH, and ALP. Serum creatinine showed no significant difference.

Conclusions

Several risk factors for THPT development were identified. PTx for patients with THPT significantly improved serum Ca, iPTH, ALP, and phosphorous levels. There was no significant difference in renal function after PTx. Therefore, total PTx with forearm autograft may be an appropriate surgical approach for patients with THPT.

     

Pharmacodynamic Actions of a Long‐Acting PTH Analog (LA‐PTH) in Thyroparathyroidectomized (TPTX) Rats and Normal Monkeys

Hypoparathyroidism is a disease of chronic hypocalcemia and hyperphosphatemia due to a deficiency of parathyroid hormone (PTH). PTH and analogs of the hormone are of interest as potential therapies. Accordingly, we examined the pharmacological properties of a long‐acting PTH analog, [Ala^1,3,12,18,22, Gln¹⁰,Arg¹¹,Trp¹⁴,Lys²⁶]‐PTH(1‐14)/PTHrP(15‐36) (LA–PTH) in thyroparathyroidectomized (TPTX) rats, a model of HP, as well as in normal monkeys. In TPTX rats, a single intravenous administration of LA‐PTH at a dose of 0.9 nmol/kg increased serum calcium (sCa) and decreased serum phosphate (sPi) to near‐normal levels for longer than 48 hours, whereas PTH(1‐34) and PTH(1‐84), each injected at a dose 80‐fold higher than that used for LA‐PTH, increased sCa and decreased sPi only modestly and transiently (<6 hours). LA‐PTH also exhibited enhanced and prolonged efficacy versus PTH(1‐34) and PTH(1‐84) for elevating sCa when administered subcutaneously (s.c.) into monkeys. Daily s.c. administration of LA‐PTH (1.8 nmol/kg) into TPTX rats for 28 days elevated sCa to near normal levels without causing hypercalciuria or increasing bone resorption markers, a desirable goal in the treatment of hypoparathyroidism. The results are supportive of further study of long‐acting PTH analogs as potential therapies for patients with hypoparathyroidism. © 2016 American Society for Bone and Mineral Research.     

Impact of synthetic ghrelin administration for patients with severe body weight reduction more than 1 year after gastrectomy: a phase II clinical trial

Purpose

Ghrelin is mainly secreted from the stomach and plays a role in appetite, weight gain, and the promotion of a positive energy balance. The levels of ghrelin decrease immediately after gastrectomy. We herein investigated the effect of the administration of synthetic ghrelin to treat postoperative severe weight loss in a prospective, one-arm clinical trial to develop new strategies for weight gain.

Methods

Ten patients (four distal gastrectomy and six total gastrectomy) received ghrelin treatment. Eligibility criteria included patients who underwent gastrectomy more than 1 year previously and 15 % body weight loss from the preoperative weight or a body mass index under 19. Synthetic human ghrelin (3 μg/kg) was administered to the patients twice a day for 1 week. Oral intake of calories, appetite [evaluated using the visual analog scale (VAS)], and body weight before and during administration of ghrelin were compared.

Results

There was a significant difference in the oral food intake before and during treatment (before treatment: 1236 ± 409 kcal vs. during treatment: 1398 ± 365 kcal, p = 0.039), and the VAS for appetite significantly improved with each day of ghrelin administration (p < 0.05). Significant amounts of body weight were gained (39.5 ± 6.8 vs. 40.1 ± 6.9, p = 0.037).

Conclusions

The administration of synthetic ghrelin improved the food intake and was effective for treating appetite loss and body weight loss. Synthetic ghrelin may be a promising new therapy for severe body weight loss following gastrectomy.

     

Trials of vaccines for pancreatic ductal adenocarcinoma: Is there any hope of an improved prognosis?

Pancreatic tumors are chemoresistant and malignant, and there are very few therapeutic options for pancreatic cancer, as the disease is normally diagnosed at an advanced stage. Although attempts have been made to develop vaccine therapies for pancreatic cancer for a couple of decades, none of the resultant protocols or regimens have succeeded in improving the clinical outcomes of patients. We herein review vaccines tested within the past few years, including peptide, biological and multiple vaccines, and describe the three sets of criteria used to evaluate the therapeutic activity of vaccines in solid tumors.