Effects Of Diphosphonate Research Articles

MO740EFFECT OF DIPHOSPHONATES FOR VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE: A META-ANALYSIS

Abstract Background and Aims Vascular calcification is an independent predict factor of cardiovascular mortality and all-cause mortality in chronic kidney disease (CKD) patients. Animals experiments and clinical studies showed the inhibition effect of diphosphonates in vascular calcification, but the results of the studies remains controversial. This meta-analysis aims to evaluate the effects of diphosphonates on vascular calcification in patients with CKD. Method Randomized controlled trials (RCT) and non-RCTs of diphosphonates for the treatment of vascular calcification in CKD patients until September 2020 were searched in the database of PubMed, Embase, Cochrane library, CNKI and Wanfang. Literatures were screened according to the inclusion and exclusion criteria and quality was evaluated by two investigators independently. The standard deviation from mean (SMD) and 95% confidence interval (CI) were used to representthe counting data. Data extracted from the literatures were analyzed with Stata software (version 15.0). Results A total of 6 RCTs and 1 non-RCT with 272 patients were included, characteristics of the studies included are shown in Table 1. Meta-analysis indicated that diphosphonates inhibit vascular calcification in CKD [SMD =-0.297, 95% CI = (-0.591, -0.002), P = 0.049] (Figure 1). Etidronate is the most effective one in treating with vascular calcification (P = 0.020) (Figure 2). But there isn’t significant difference in aortic artery calcification and coronary artery calcification compared with the control group (P>0.05). There was no statistically significant difference in the change of blood calcium, blood phosphate, and serum parathyroid hormone between two groups (all P>0.05). Conclusion Diphosphonates can inhibit the progression of vascular calcification in CKD patients, and it hasn’t obvious effect on blood calcium, blood phosphate, and serum parathyroid hormone. Etidronate is the most promising therapeutic agent.

Effect of Diphosphonates on Bone Mineral Density in Men Receiving Androgen Deprivation Therapy for Prostate Cancer

Patients receiving androgen deprivation therapy are associated with increasing loss of bone mineral density (BMD) and higher risk of skeletal-related events. We reviewed and analyzed the influence of diphosphonates on BMD change. A systemic literature research was conducted in PubMed and related bibliographies. The focus of data extraction was BMD percentage change of lumbar spine, total hip, and femoral neck after 12 months. Standardized mean difference (SMD) was pooled with the random-effects model, and metaregression and subgroup analysis were performed to explore heterogeneity. Nine articles (n = 920) were included and finally analyzed after screening 118 articles. We found significant improvement in BMD percentage changes of the lumbar spine, total hip, and femoral neck at 1 year (respectively, SMD = 6.379, 95% confidence interval [CI] = 3.740-9.018, P < .001, I2 = 98.8%, P < .001; SMD = 4.870, 95% CI, 2.256-7.485, P < .001, I2 = 98.9%, P < .001; SMD = 3.634, 95% CI, 1.989-5.279, P < .001, I2 = 97.3%, P < .001). In individual variable metaregression analysis, application zoledronic acid or not showed a statistically significant influence on BMD percentage change of total hip (P = .018). In subgroup analyses, both zoledronic acid and alendronate showed a significant improvement in BMD percentage changes. Diphosphonates significantly increased BMD percentage changes of the lumbar spine, total hip, and femoral neck in men receiving androgen deprivation therapy for prostate cancer. Patients with androgen deprivation therapy should be evaluated BMD loss, and timely therapy with diphosphonates may be an appropriate strategy to prevent osteoporosis.

Effect of diphosphonate on biochemistry change in subchondral bone of unstable rabbit knee joints

Objective To explore the effect of diphosphonate on expression of matrix metalloproteinase-9(MMP-9) and cathepsin K(CK) in subchondral bone of unstable rabbit knee joints.Methods Fifty male New Zealand white rabbits were divided randomly into three groups according to random digits table:the control group (n=10),the model group (n=20).the diphosphonate group (n=20).Hulth model of unstable rabbit knee joint was achieved in the right knee joint.Ten rabbits from the diphosphonate group and 5 rabbits from the control group were sacrificed by aeroembolism at the second and tenth week postoperatively,respectively.Then the medial femoral condyles of the right knee were harvested.Specimens were processed for immunohistochemical analysis of MMP-9 and CK.Results Cells with expression of MMP-9 and CK could be found in the three groups at the second and tenth week after operation.Compared with the control group,there was a significant increase in the number of cells with expression of MMP-9 and CK in model group at the second and tenth week after operation.Diphosphonate could inhibit expression of MMP-9 and CK in cells.Compared with the model group,the number of cells with expression of MMP-9 and CK in diphosphonate group was fewer; there was a statistical significance between them.Conclusion Diphosphonate can inhibit the expression of MMP-9 and CK in subchondral bone of unstable rabbit knee joints,which can resist the bone resorption and protect articular cartilage. Key words: Osteoarthritis; Matrix metalloproteinase 9; Cathepsins; Diphosphonates

The effect of prostaglandin synthesis inhibitors and diphosphonates on tumour-mediated osteolysis.

Previous studies have shown that the prostaglandin synthesis inhibitor indomethacin reduced osteolysis produced by the experimental VX2 carcinoma, probably by inhibiting the stimulation of osteoclasts by prostaglandin E2. This study was carried out to determine whether prostaglandin inhibitors affect the tumour osteolysis produced by human mammary carcinoma as well as the VX2 carcinoma. The effect of diphosphonates on reducing tumour osteolysis was also investigated, since diphosphonates directly affect bone resorption. The results indicated that various non-steroidal, anti-inflammatory agents which inhibit prostaglandin synthesis reduced the osteolysis produced by human mammary or rabbit VX2 carcinomas. The diphosphonate compounds also produced a significant inhibition of tumour osteolysis. The results confirm the findings of Powles and his colleagues (1) that aspirin (also a prostaglandin synthesis inhibitor) reduced the osteolysis induced by human mammary carcinoma. It is suggested that these agents be evaluated as adjuvant therapy in patients with apparently 'early' mammary cancer in a controlled clinical trial.

Developmental disturbances of the rat molar induced by two diphosphonates.

Very few reports have been published about the effects of diphosphonates on the cells and tissues of developing teeth. The present study was designed to investigate possible morphological changes in ameloblasts and odontoblasts and relate these changes to defects in the enamel surface of erupted teeth. Young rats were injected subcutaneously with single or multiple doses of HEDP or Cl2MDP (10 mg P/kg b.w.). Light microscopic examination of developing maxillary first molars showed that single injections of HEDP or Cl2MDP induced subameloblastic cysts between the secretory ameloblasts and the developing enamel. The ameloblastic lining of the cysts contained numerous calcified deposits. A few days after injection, hypoplasias were seen in the enamel in areas previously occupied by cysts. In the erupted teeth, scanning electron microscopic examination revealed enamel hypoplasias which were mainly localized on the mesial sides of the cusps. In addition to the previously mentioned disturbances, multiple injections resulted in more extensive cysts, some of which contained non-mineralized enamel matrix. Inhibition of the mineralization of dentin and alveolar bone was also noticed.

Effects of diphosphonate and x-rays on bone lesions induced in rats by prostate cancer cells.

Prostate adenocarcinoma-III (PA-III) cells deposited over the scapula of Lobund-Wistar (L-W) rats induced osteolytic and osteoplastic changes in that bone. The osteolytic process was prevented and interrupted by administrations of dichloromethylene diphosphonate (Cl2MDP); but the osteoplastic process, once initiated, continued. The latter process was interrupted by ionizing radiation. Treatments of PA-III-affected bones with Cl2MDP and x-rays immobilized both osteolytic and osteoplastic processes.

Ultrastructural Effects of Diphosphonates On Dental Enamel

Initial experiments were designed to test the effects of two diphosphonates on acid dissolution of mature human enamel. Polished facets of enamel were treated with 10 mmol/L of EHDP or Cl2MDP (pH 7.4) for five min, H20-washed, acid-etched with 0.01 N lactic acid (pH 5.4) for 15 min, and examined in the scanning electron microscope. Controls were run with distilled H2O substituted for diphosphonates. In addition, the experimental window was outlined with lacquer, thus providing a reference to the original polished enamel surface. Results showed that EHDP markedly reduced enamel dissolution, with less than 1 μm of enamel removed, while Cl2MDP was similar to controls, with approximately 4-5 μm of enamel dissolved. It was decided to initiate further experiments with the objective of determining effects of diphosphonates on developing enamel during the secretory stage in rat molars. Five-day-old animals were injected s.c. with one of the following: EHDP, ADP, Cl2MDP, or NaCl (0.9% control). The diphosphonate dosages were 2.5, 5, 10, and 20 mg P/kg. Rat incisors were also examined in initial experiments on older rats (21-day) following daily s.c. injections of EHDP. Twenty-four hr after the injections, all rats were killed by perfusion fixation and routinely prepared with and without decalcification for light and transmission electron microscopy. Light microscopic examination of developing maxillary first molars frequently revealed subameloblastic cyst formation, which was used as an indicator of severe cellular alteration of overlying secretory ameloblasts. By this criterion, the EHDP- and ADP-treated rats showed more severe cellular effects at lower dosages (2.5 and 5 mg P/kg) than did the Cl2MDP-treated rats. In addition, when undecalcified sections were examined in the transmission electron microscope, disturbances in crystal formation were observed. Since both the cyst formation and the disturbed enamel beneath the cyst had many similarities to previous results reported on the effects of high doses of fluoride, the majority of results observed may be due to a non-specific cellular toxicity. However, some crystal growth effects appear to be specific for diphosphonates, as indicated by preliminary results with daily injections of EHDP. In the rat incisor, a definitive banding that shows both inhibition and return to more normal development within a 24-hour cycle has been detected. In the ultrastructure examination of undecalcified sections, the reaction to EHDP is clearly defined as bands of normal crystal size, electron density, and orientation alternating with disturbed bands of small crystal size and decreased electron density. The bands are approximately 2-3 μm in width.

Effect of diphosphonates on the precipitation of calcium carbonate in aqueous solutions

The effect of two diphosphonates, ethane-1-hydroxy-1, 1-diphosphonic acid (EHDP) and 1,2-dihydroxy-1,2-bis(dihydroxyphosphonyl)ethane (DDPE) on the precipitation of calcium carbonate has been investigated. EHDP and DDPE were found to reduce markedly the rate of crystallization at solution concentrations as low as 10–7 mol dm–3, both in cases where precipitation was spontaneous and when it took place on well characterized calcite crystals introduced in the supersaturated solutions. In spontaneously precipitating supersaturated solutions, small concentrations of the additives caused a marked increase in the induction period preceding precipitation. Inhibition was mainly at the crystal-growth step by adsorption at the active-growth sites. The adsorption isotherms of EHDP and DDPE showed that these compounds adsorb extensively on to calcite surfaces. Interpretation of the kinetics and adsorption data in terms of the Langmuir isotherm gave good agreement for the ‘affinity’ parameter obtained by these two methods.

Effect of diphosphonate on the prevention of X-radiation-induced inhibition of bone formation in rats.

A histologic and histometric study of the effect of EHDP (ethane-1-hydroxy-1,1-diphosphonate) on the alveolar wound healing of irradiated animals is presented. This drug was selected based on its osteosclerotic effect when applied at low doses. The three left mandibular molars of 80 male Wistar rats were extracted. The rats were grouped into 4 sets of 20 rats each. Group I received no further treatment; Group II received daily intraperitoneal injections of EHDP (7.5 mg/Kg of body weight during 10 days); Group III: 15 Gy of X-radiation were applied to the head; and Group IV were irradiated and injected with EHDP as were animals of Groups III and II. Half of the animals were killed after 14 days and the other half 30 days post-extraction. Sections were made at the level of the mesial socket of the first molar in a bucco-lingual orientation, on which histometric determinations of bone activity were made. The results showed the attenuation of the inhibitory effect of radiation on bone formation when the animals were treated with EHDP.

The Beneficial Effects of Diphosphonate and Piroxicam on the Osteolytic and Metastatic Spread of Rat Prostate Carcinoma Cells

Transplantable rat prostate adenocarcinoma III cells produce local tumors and osteolytic and osteoplastic lesions and they metastasize through defined lymphatic channels to the lungs in which they produce expanding focal tumors. The bone lesions were prevented by treatments with dichloromethane diphosphonate (C12MDP). Treatment of rats with piroxicam, a nonsteroidal antiinflammatory drug, suppressed to some extent tumor growth, bone destruction, and metastasis. However, simultaneous treatments of rats with both drugs (C12MDP and piroxicam) prevented bone damage and suppressed tumor growth and metastatic spread very significantly without evidence of toxicity.

Effect of polyvinyl phosphonates and ethane hydroxy diphosphonate on mineralization of ectopic bone

The effects of polymeric polyphosphonate and of ethane hydroxydiphosphonate on the development of ectopic bone were compared at different stages of bone development. The diphosphonate affected bone development at different stages, as reflected by alkaline phosphatase and aryl sulphatase activities, as well as by the creation of calcium ions by bone and on its readiness to undergo isotopic exchange. The polymeric polyphosphonate (mol. wt., 3500–8000), on the other hand, did not exhibit any of these effects, although it did inhibit the activity of the enzymes in vitro to an extent comparable with that of the diphosphonate. The results corroborate the assumption that the effects of polymeric polyphosphonates on hard tissues are confined to the extracellular space while the effects of diphosphonates on bone development are due to intracellular activity and not to sequestering of extracellular calcium.

Cutaneous calciphylactic reactions in the mouse and the rat and the effects of diphosphonates on the reaction in the rat.

Calciphylaxis is a local tissue calcific reaction at the site of an injection of challenger substance given a critical time period after the oral administration of a sensitizer substance such as dihydrotachysterol (DHT), vitamin D or parathormone. Cutaneous calciphylaxis is readily induced in the rat but not in the mouse and this may be because, in the latter, the challenger substance is absorbed rapidly by macrophages. In the rat the administration of 500 micrograms/0.1 ml of DHT followed after 24 h by the subcutaneous (SC) injection of ferric chloride (FeCl3) (30 micrograms/0.1 ml) is followed rapidly by calcification of the SC site. There is an early transient acute inflammatory reaction with the incrustation of collagen fibres by the iron salt and an apparent exudation of calcium and phosphate ions from the bloodstream. These ions also become associated with collagen fibres. Two days after injection macrophages and multinucleated giant cells become the dominant cells. Calciphylaxis is a useful experimental model of ectopic calcification and is associated with an initial hypercalcaemia. The diphosphonates ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl2MDP) are effective inhibitors of the calciphylactic reaction when administered prior to the initiation of the experimental procedure.

The effect of diphosphonates on heterotopic ossification in regenerating Achilles tendon of the mouse.

Midpoint tenotomy of the mouse Achilles tendon is followed by regeneration with heterotopic ossification at the junction of tendon stump and the regenerated segment. This heterotopic bone formation occurs through a process of endochondral ossification and the cartilage cells appear to arise by a process of fibroblast transformation. Five weeks after tenotomy 60 per cent. of specimens show cartilage and bone formation whilst the remaining 40 per cent. show chondrification only. After 10 weeks all specimens showed bone formation with trabecular bone and haemopoietic marrow. The treatment of tenotomised animals with either disodium ethane-1, 1-diphosphonate (EHDP) or disodium dichloromethylene diphosphonate (Cl2MDP) has no effect on the process of heterotopic ossification which can be detected at the radiological or light microscopical level.

Effect of diphosphonates on ATP and Pi content, Pi uptake and energy charge of cultured calvaria cells.

In previous studies we have shown that glycolysis is strongly inhibited in cultured calvaria cells treated with ethane-1-hydroxy-1, 1-diphosphonate (EHDP) or dichloromethanediphosphonate (Cl2MDP). This study shows that the energy charge of the adenylate pool, and the ATP and Pi content, were not changed by treatment with diphosphonates except for a slight decrease of ATP and Pi at 0.25 mM Cl2 MDP. The uptake of Pi was diminished by 50% and 20% in cells treated for 6 days with Cl2MDP or EHDP, respectively, but not when diphosphonates were present only during the uptake studies.

Effects of diphosphonates (DPs) on rat adjuvant arthritis (AA)

Effects of diphosphonates (DPs) on rat adjuvant arthritis (AA)

Effect of diphosphonates on the synthesis of prostaglandins in cultured calvaria cells.

The calvaria cells cultured for 6 days in the presence of dichloromethanediphosphonate (Cl2MDP) (0.025-250 microM), the synthesis of prostaglandin E2 (PGE2) was inhibited by up to 90%. Inhibition of PGE2 synthesis might be one mechanism whereby this diphosphonate inhibits bone resorption. This effect is not common to all diphosphates since 25 microM 3-amino-1-hydroxypropane-1,1-diphosphonate (AHPDP) stimulated the synthesis of PGE2.

The effect of diphosphonates on periosteal and bone cells in culture.

Calvaria cells were separated into periosteal and bone cells and cultured in the presence of ethane-1-hydroxy-1,1-diphosphonate (EHDP) or dichloromethanediphosphonate (Cl2MDP). Both cell types were affected to the same degree with respect to the effect on cell number and lactate production. The action of the diphosphonates seems therefore not to be specific for one of the cell types.

Effect of diphosphonates on glycogen content of rabbit ear cartilage cells in culture.

The diphosphonates dichloromethanediphosphonate (Cl2MDP) and to a minor degree 1-hydroxyethane-1,1-diphosphonate (EDHP) increased the glycogen content in cultured cartilage cells of rabbit ear. This effect was not due to different concentrations of glucose in the medium.

Effect of diphosphonates on hydroxyapatite formation induced by calcium-phospholipid-phosphate complexes.

The diphosphonates disodium ethane-1-hydroxy-1, 1-diphosphonate (EHDP) and disodium dichloromethylene diphosphonate (Cl2MDP) prevent hydroxyapatite (HA) formation in metastable calcium phosphate solutions, induced by calcium-phospholipid-phosphate complexes and by the acidic phospholipids phosphatidyl serine and phosphatidyl inositol. The diphosphonates appear to act not only as HA crystal poisons but also as surfactants which probably change the nature of the lipid micelle and the charge and conformational properties of the lipid molecules. The surfactants sodium dodecyl sulfate (SDS) and Non-Idet P-40 (NP-40), like the diphosphonates, prevent HA formation by the acidic phospholipids and complexed lipids, but do not act as HA surface poisons. The lipid surfactant lyso-phosphatidyl serine did not induce HA formation from solution. The relevance of the ability of the diphosphonates to act as lipid surfactants to the in vivo use of these agents is discussed.

Effects of diphosphonate and colchicine administration upon acid-base changes induced in rats by bilateral nephrectomy.

1. The effects of disodium ethane-1-hydroxy-1,1-diphosphonate (EHDP) and colchicine on acid--base balance were examined in intact and nephrectomized rats. 2. Both drugs increased extracellular hydrogen ion concentrations and depressed extracellular bicarbonate concentrations in nephrectomized rats compared with controls but did not alter these parameters in intact animals. 3. Intracellular hydrogen ion concentrations in the skeletal muscle of nephrectomized rats given EHDP were higher than those of control animals. 4. It is postulated that colchicine and EHDP inhibit skeletal buffering of non-volatile acids produced endogenously in nephrectomized rats.