Moisture sorption properties research of chemical reference substances based on dynamic vapor sorption analysis technology / 中国药学杂志

OBJECTIVE: To investigate the moisture sorption properties of chemical reference substances (CRSs) by using dynamic vapor sorption (DVS) analysis technology in order to establish the distribution conditions, packaging materials, and usages of national chemical reference substances. METHODS: DVS analysis was adopted to acquire the moisture sorption dynamic profiles of five chemical reference substances of different moisture sorption types to evaluate their moisture sorption trend and capacities under different humidities. RESULTS: According to moisture sorption dynamics, we can found the hygroscopicity of disodium etidronate, sodium aminosalicylate, valaciclovir hydrochloride, aspirin and bosentan, and we have given advices about how to use these CRSs and what kind of bottles they should be packed in. CONCLUSION: DVS analysis can be used to record moisture sorption data in real time and visually observe water-CRS interactions under different humidities, which is an important technology for guiding the establishment and distribution of CRSs.

Evaluation of antiosteoporotic activity for micro amount icariin and epimedin B based on the osteoporosis model using zebrafish / 中国药学杂志

OBJECTIVE: Prednisolone-induced osteoporosis model using zebrafish was used to evaluate the antiosteoporotic activity of micro amount icariin and epimedin B. METHODS: Zebrafish larvae were co-exposed with 25 μmol·L-1 prednisolone and a series of icariin and epimedin B solutions with a range of concentration (0.2, 1, 5 and 10 μmol·L-1) from 4 to 9 days post fertilization(dpf), 25 μmol·L-1 prednisolone was selected as model group, 15 μg·mL-1 etidronate disodium with 25 μmol·L-1 prednisolone as positive group, 0.5% DMSO as the vehicle control group, the medium as a negative blank control group, all groups were incubated in 24-well plates (28.5°C) until 9 dpf. The medium/solution was changed half every day. Zebrafish skeleton at 9 dpf were anesthetized and fixed for staining with alizarin red. Quantitative analysis of the stained area was performed by microscopic inspection and digital imaging methods to reflect the amount of zebrafish head skeleton mineralization. RESULTS: The results indicated head skeleton mineral aera and integrated optical density (IOD) of 25 μmol·L-1 prednisolone model group were significantly decreased when compared with vehicle control group and negative control group; and 15 μg·mL-1 etidronate disodium can increase the mineralized matrix of zebrafish head skeleton when compared with model group and prevent osteoporosis induced by prednisolone; head skeleton mineral area and IOD of 10 and 5 μmol·L-1 icariin groups and 1μmol·L-1 epimedin B groups were significantly increased when compared with model group, which indicated that icariin and epimedin B can prevent zebrafish osteoporosis induced by prednisolone. CONCLUSION: This novel osteoporosis model using zebrafish has advantages of simple, high efficiency, far less amount of compound needed and easy to perform, and it was successfully applied in quickly evaluating the antiosteoporosis activity of micro amount compounds such as icariin and epimedin B.

1-34 PTH Could Reverse Impaired Bone Mineralization Induced By the Overdose of Bisphosphonate

Bisphosphonates are the mainstay of osteoporosis treatment. Despite the fact that bisphosphonates have a relatively good safety record and are tolerated well by the majority of patients, serious adverse events have been associated with their use. A 41-year-old man had been diagnosed with osteoporosis and had taken etidronate 200 mg/day daily for 2 years due to the judgmental error. He was referred for the management of refractory bone pain and generalized muscle ache. Serum calcium, phosphate, 25-hydroxy-vitamin D (25(OH)D), and immunoreactive parathyroid hormone (iPTH) were within normal range. Plain X-ray showed multiple fractures. Whole body bone scan confirmed multiple sites of increased bone uptakes. Tetracycline-labeled bone biopsy showed typical findings of osteomalacia. He was diagnosed with iatrogenic, etidronate-induced osteomalacia. The patient received daily parathyroid hormone (PTH) injection for 18 months. PTH effectively reverses impaired bone mineralization caused by etidronate misuse. Currently, he is doing well without bone pain. Bone mineral density significantly increased, and the increased bone uptake was almost normalized after 18 months. This case seems to suggest that human PTH (1-34) therapy, possibly in association with calcium and vitamin D, is associated with important clinical improvements in patients with impaired bone mineralization due to the side effect of bisphosphonate.

The Effect of Etidronate Disodium on Rat's Bone and Soft Tissue

OBJECTIVE: To evaluate the effects of etidronate disodium on bone and soft tissue, especially on bone mineral density, and mucosal changes of the aorta and esophagus. METHOD: Male Sprague-Dawley rats were randomly divided into 2 separate groups: one with etidronate disodium and one without etidronate disodium. Bone mineral density (BMD) in lumbar vertebrae, femur, and a simple X-ray of the whole body were obtained. The abdominal aorta and esophagus were assessed histopathologically in post treatment. RESULTS: In post treatment for 12 weeks, the extent of decrease in BMD of the group with etidronate disodium was less than that of the group without etidronate disodium (p<0.05). There was no evidence of aorta and heart valve calcification in the simple X-ray, nor was there intima-media thickening, atheroma formation and calcification in aorta and esophageal irritation findings in pathologic examinations in both groups. CONCLUSION: The results suggested that etidronate disodium had an inhibitory effect on bone mineral loss and had the esophageal tolerability and safety, but no difference in aorta calcification and antiarthrogenic effects, including aorta wall thickness in this study.

Drug inhibition of wear particles induced osteolysis in rabbits / 中国矫形外科杂志

[Objective]To study the possibility of drug inhibition of wear particle induced osteolysis and aseptic prosthesis loosening in vivo.[Methods]4?8 mm transverse holes were made in femur condyle and tibia plateau of 12 adult rabbits bilaterally.One milligram of CoCr alloy(mean 5.38 ?m),Ti-6Al-4V(mean 3.21 ?m) and UHMWPE(12～200 ?m) particles were implanted into the holes separately.The animals were divided into 4 groups and each group had the same particles combination.Oral drug therapy twice a day was adopted with non-selective COX inhibitor(indomethacin,0.5 mg/kg BW),membrane Ca2+ channel inhibitor(nitrendipine,0.1 mg/kg BW),osteoclast inhibitor(alendronate sodium,0.1mg/kg BW) and blank control(0.9% saline) to the 4 groups separately and randomly according to the double blind principle,which started on the 2nd day postoperatively until 12 weeks at the time of sacrifice.Routine histological observation and calculation of the ratio of bone area(BA) to total tissue area(TTA) were done under the computerized analysis system.[Results]CoCr and Ti alloy particles could seldom be seen in the slices of the groups which showed normal cancellous bone.There were obvious macrophage infiltration and fibroblast proliferation round the particulate UHMWPE in the group of blank controls.It was similar in the groups of indomethacin and nitrendipine though the histological reaction was a little bit weaker and osteotoid tissue could occasionally be seen.UHMWPE particles were totally enclosed in the cancellous bone with little fibrous tissue proliferation in the group of alendronate sodium and the BA/TTA ratio was significantly higher than those at the other groups(P0.05).[Conclusion]This indicates the possibility of inhibition or prevention of osteolysis induced by wear particles by drug therapy especially when alendronate sodium is adopted,and it has significant clinical implications for controlling the most common cause of implant failure.

Efficacy of Oral Etidronate for Skeletal Diseases in Japan

Etidronate is an oral bisphosphonate compound that is known to reduce bone resorption through the inhibition of osteoclastic activity. The efficacy of etidronate for involutional (postmenopausal and senile) and glucocorticoid-induced osteoporosis, as well as that for other skeletal diseases, was reviewed in Japanese patients. Cyclical etidronate treatment (200 mg or 400mg/day for 2 weeks about every 3 months) increases the lumbar bone mineral density (BMD) in patients with involutional osteoporosis and prevents incident vertebral fractures in patients with glucocorticoid-induced osteoporosis. The losses of the lumbar BMD in patients with liver cirrhosis and the metacarpal BMD in hemiplegic patients after stroke are prevented, and the lumbar BMD is possibly increased, preventing fragile fractures in adult patients with osteogenesis imperfecta type I. Furthermore, proximal bone resorption around the femoral stem is reduced and some complications may be prevented in patients who undergo cementless total hip arthroplasty. Oral etidronate treatment may also help to transiently relieve metastatic cancer bone pain followed by a decrease in abnormally raised bone resorption in patients with painful bone metastases from primary cancer sites, such as the lung, breast and prostate. Thus, oral etidronate treatment is suggested to be efficacious for osteoporosis, as well as other skeletal diseases associated with increased bone resorption, in Japanese patients. Randomized controlled trials needed to be conducted on a large number of patients to confirm these effects.

Comparison of Effect of Treatment with Etidronate and Alendronate on Lumbar Bone Mineral Density in Elderly Women with Osteoporosis

The purpose of this open-labeled prospective study was to compare the treatment effects of cyclical etidronate and alendronate on the lumbar bone mineral density (BMD), bone resorption, and back pain in elderly women with osteoporosis. Fifty postmenopausal women with osteoporosis, age ranging from 55 to 86 years (mean: 70.7 years), were randomly divided into two groups with 25 patients in each group: the cyclical etidronate group (etidronate 200 mg daily for 2 weeks every 3 months) and the alendronate group (5 mg daily). The BMD of the lumbar spine (L1-L4) measured by DXA, the urinary cross-linked N-terminal telopeptides of type I collagen (NTX) level measured by the enzyme-linked immunosorbent assay, and back pain evaluated by the face scale score were assessed at baseline, 6 months, and 12 months. There were no significant differences in baseline characteristics including age, body mass index, years since menopause, lumbar BMD, urinary NTX level, and face scale score between the two treatment groups. Etidronate treatment sustained the lumbar BMD following a reduction in the urinary NTX level and improved back pain, while alendronate treatment reduced the urinary NTX level more significantly, resulting in an increase in the lumbar BMD, and similarly improved back pain. No serious adverse events were observed in either group. This study confirmed that alendronate treatment had a greater efficacy than etidronate treatment in increasing the lumbar BMD through the reduction of bone resorption in elderly women with osteoporosis.

Effect of Intermittent Etidronate Therapy on the Prevention of Bone Loss after Kidney Transplantation / 대한내분비학회지

BACKGROUND: Osteopenia or osteoporosis is one of the most frequently encountered complications in patients receiving various immunosuppressants after kidney transplantation. The few available preventive strategies for these complications tend to result in various outcomes. In this study, we evaluated the effect of intermittent etidronate therapy for the prevention of bone loss after kidney transplantation. METHODS: Fifty patients who received kidney transplantation for various reasons were recruited and followed for one year. Thirty-eight of these patients commenced etidronate treatment 7 days after operation, the other 12 were followed without etidronate therapy. The treatment consisted of 400mg of etidronate administered orally for 14 days, then repeated four-times every three months. Blood chemistry, iPTH and aluminium levels were tested periodically in all patients. Also checked were bone mineral density of the lumbar spine(L2-4) and femur at baseline, 6 and 12 months after kidney transplantation, as well as D-L spine lateral x-ray at baseline and 12 months. Serum osteocalcin and urine deoxypyridinoline were measured at baseline, 7 days and then every 3 months. RESULTS: Both the etidronate-treated and control groups showed significant decreases in bone mineral densities of the lumbar spine, femur neck and total femur at 6 and 12 months after kidney transplantation(p<0.005). Bone loss was significantly lower in the etidronate-treated group than the control at 12 months after kidney transplantation; lumbar spine(-3.54% vs. -9.51%, p<0.0005), femur neck (-5.41% vs. -8.91%, p<0.0005), total femur (-7.59% vs. -9.07%, p<0.005). Osteocalcin was decreased and deoxypyridinoline increased in both groups. No significant differences in the level or pattern of osteocalcin and deoxypyridinoline were observed in either group. New radiologic compression fractures were found in two patients of the treated group who exhibited severe osteoporosis at baseline during follow-up. CONCLUSIONS: The intermittent administration of etidronate seems to be effective in preventing rapid bone loss after kidney transplantation. Furthermore, this method is safe and convenient for administration and follow-up. Further studies will be required to elucidate the most effective treatment course for the prevention of fractures after kidney transplantation, especially in patients with established severe osteoporosis.

A Clinical Study and Prevention Effects of Etidronate Disodium(EHDP) on Heterotopic Ossification Formation in Spinal Cord Injuries

Heterotopic ossification(HO) is a formation of ectopic bone around joints in the soft tissues. It often occurs after the central nervous system injuries, burns, and joint replacements. It causes an important morbidity in the rehabilitation population. The etiology, pathogenesis, prophylaxis, and treatment of HO are still unclear even though there have been many investigation on the prevention of HO among the patients with spinal cord injury. The prevention effect of EHDP on HO formation still remains controversial. A randomized clinical trial was performed to assess the prevention effect of EHDP on HO formation in 73 patients (control group: 40 cases, study group: 33 cases) as a prospective study. EHDP was given to the study group for 12 weeks; 20 mg /kg /day for 2 weeks followed by 10 mg/kg/day for 10 weeks. The patients were followed up with the serial physical examinations, serum alkaline phosphatase levels, and plane radiographs for one year period after the injury. The results revealed that HO developed in eight cases(20.0%) among the control group and two cases(9.1%) among the study group. There was no significant difference in the incidence of HO between two groups(p>0.05). The mean duration from the injury to the detection of HO was 113 days. Twelve of 15 HO sites(80.0%) were detected within the 6 months after injury. Seven patients developed the HO in one site, two in two sites, and one in three sites. The sites of HO were 6 in hips, 4 in knees, 2 in shoulders, 2 in pelvis, and one in elbow. The results of this study do not support the prevention effect of EHDP on HO formation among the patients with spinal cord injury.

Effects of Etidronate Therapy on Osteoporosis in Spinal Cord Injury Patients

One of the sequelae of spinal cord trauma which start soon after the onset of injury is the loss of the calcium from bone. Bone mineral and matrix resorption causes negative calcium balance, and eventually osteoporosis. Etidronate disodium(etidronate) is an oral diphosphonate compound known to reduce bone resorption through the inhibition of osteoclasic activity. Since continuous oral treatment with high doses of etidronate may lead to the impairment of bone mineralization and the cessation of bone remodeling, a ideal therapeutic regimen consist of the intermittent cyclical administration of the diphosphonate in a dose that inhibits bone resorption. To assess the effect of etidronate on bone metabolism and bone mineral density after spinal cord injury, we studied two groups of 7 spinal cord injury(SCI) patients with etidronate and 7 SCI patients without etidronate. Seven patients of treatment group received oral etidronate (5 mg/kg/day) for 2 weeks followed by a 10-week period in which no drugs were given. This sequence was repeated 4 times, for a total of 48 weeks. The results showed that the patients receiving etidronate had siginificant decrease in the serum osteocalcin(OC), urine deoxypyridinoline(D-PYD) level but no increase in their mean bone density. We can carefully conclude that intermittent cyclical therapy with etidronate siginificantly reduces bone metabolic rate and inhibit bone mineral loss on osteoporosis in spinal cord injury patients.

Clinical efficacy of bisphosphonates in the treatment of postmenopausal osteoporosis / 中华骨科杂志

Objective To evaluate the clinical efficacy of domestic bisphosphonates (etidronate and alendronate) in the treatment of postmenopausal osteoporosis. Methods Eighty three patients with postmenopausal osteoporosis were divided randomly into three groups: group Ⅰ(37 cases),group Ⅱ(15 cases) and group Ⅲ(31 cases). Etidronate(400 mg/d) and placebo were given with intermittent cyclical therapy in group Ⅰ and group Ⅲ respectively, and alendronate(10 mg/d) was given continuously in groupⅡ for 9 months. Eeach group was given calcium agents(equal to elementary calcium 500 mg/d). Before and after treatment, the bone mineral density(BMD) was measured by dual energy X ray absorptiometry. The biochemical markers such as blood calcium, phosphate, alkaline phosphatase and urine calcium/creatinin were examined. Results After treatment the BMD of groupⅠ and groupⅡ wee increased obviously(P0.05). The BMD of group Ⅱ was increased more than that of groupⅠ(P

The Effect of Disodium Etidronate on Phosphatase Activity in Experimental bone Formation of Rats / 대한정형외과학회잡지

The bone formation of periarticular connective tissue after head injury and total hip arthroplasty is included in the category of heterotopic ossification. Induction of a new bone formation in the soft tissue is related to various materials such as bone morphogenic protein. The alkaline phosphatase and acid phosphatase act as important factors in the formation and absorption of the bone. The acid phospatase has the important function of acting as the control with specific activity of phosphatase in vivo. Cholecalciferol induces absorption of the calcium in the alimentary tract and bone resorption and increment of bone calcification, whereas disodium etidronate inhibits the deposition and dissolution of calcium salt and formation of heterotopic bone. This paper reports on the relationship of alkaline phosphatase and various phosphoaminoacid phosphatase which affect the cellular differentiation and remodelling in the heterotopic ossification, with the effect of cholecalciferol and disodium etidronate on the heterotopic bone induction in rats. The following results were obtained: 1. The contents of the calcium in the implanted bone matrix increased markedly from two to five weeks. There was no changes in the calcium content by cholecalciferol or in the administration of small doses of disodium etidronate (5mg/kg). However, in the administration of large dose of disodium etidronate (25mg/kg), calcium mobilization was totally suppressed for the whole period of the experiment. 2. The protein content in the implanted bone matrix did not much change for the whole period of the experiment and the administratinn of cholecalciferol or disodium etidronate also had no effect on the protein content. 3. The activities of alkaline phosphatase in the implanted bone matrix peaked at two weeks in control or cholecalciferol group, whereas disodium etidronate admninstration caused the highest activity in the third week. 4. The activity of acid phosphatase in the implanted bone matrix increased in first and third weeks by cholecalciferol treatment. Disoidum etidronate inhibited the activity of the acid phosphatase in the first, fourth & sixth weeks of implantation. 5. The activity of phosphoserine phosphatase increased due to cholecalciferol treatment, but was significantly inhibited by disodium etidronate (25mg/kg) treatment. 6. The activity of phosphothreonine phosphatase in the implanted bone matrix slightly increased due to cholecalciferol treatment, whereas the activity decreased significantly for the whole period of the experiment by disodium etidronate (25mg/kg) treatment. 7. The activity of phosphotyrosine phosphatase in the implanted bone matrix was not change much for the whole period of the experiment and the administration of cholecalciferol or disodium etidronate had no effect on the activity of phosphotyrosine phosphatase. In conclusion, the disodium etidronate (25mg/kg) almost completely inhibited the molilization of calcium and the activities of acid phosphatase, phosphoserine and phosphothreonine phosphatases. Therefore, it can be suggested that the above phosphatases are closely related to the action mechanism of disodium etidronate.

Experimental Study of Disodium Etidronate for the Growth of MC3T3-E1 Osteoblastic Cell Line / 대한정형외과학회잡지

In the general, Disodium estdronate (EHDP) had effects of inhibition in bone resorption, dissolution of hydroxyapatite crystal and decreasing the turn over rate in Paget's disease. Clinically it is used as the drug of treatment for the osteoporosis, heterotropic ossificatiom and Paget's disease inspite of some, controvesies, but there is few article about the effect of EHDP on osteoblast. Authors tries to observe the effect of EHDP on osteoblast using the MC3T3-El osteoblast cell line which has very similar chrateristics with human osteoblast and evaluate the effect by the criteria of changes of morphology, number of osteoblast, and alkaline phosphatase activity. The results are obtained as following: l. EHDP has direct inhibitory effect on the proliferation of osteoblast. 2. EHDP increase the alkaline phosphatase activity in vitro.