Treatment effects of bisphosphonates on ovariectomy-induced osteopenia in rats: Comparison between clodronate and etidronate

We studied the effects of clodronate and etidronate on bone loss induced by ovariectomy (OVX) in rats. Drug administration was initiated 8 weeks after the surgery and continued for 12 weeks (twice per week, s.c.). Lumbar (L4–L5) bone mineral density (BMD) and femoral BMD in the sham-operated group were increased to 113% and 114%, respectively, whereas those in OVX group were suppressed to 98.8% and 105%. Clodronate significantly restored the suppressed BMD over the entire dose range used (4–25 mg/kg). Etidronate restored BMD only at 4 mg/kg. In a histomorphometric analysis of lumbar vertebrae, both bisphosphonates depressed the amount of labeled surface, which was increased by OVX, to 11.9%–20.1% of the OVX group value for clodronate and to 0.23%–9.7% of the OVX group value for etidronate. The osteoid area was significantly increased by etidronate treatment over the entire dose range (OS/BS, 175%–295%). On the other hand, the osteoid area in the clodronate group did not increase at any dose tested (OS/BS, 38.1%–49.9%). Urinary excretion of deoxypyridinoline and plasma level of osteocalcin were elevated in the OVX group (162%–182% and 123%, respectively), suggesting that OVX enhanced bone turnover. Both bisphosphonates suppressed the bone turnover accelerated by OVX, and the data indicated that both bisphosphonates recovered BMD by means of inhibition of bone resorption. These data suggested that clodronate and etidronate reversed osteopenia induced by ovariectomy in rats. As judged from the dose response of BMD and histomorphometric findings, clodronate showed a wider safety margin than etidronate. Received: Dec. 11, 1998 / Accepted: March 17, 1999     

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.     

Effects of bisphosphonates on joint damage and bone loss in rat adjuvant-induced arthritis

Objective and design: Examination of the effects of bisphosphonates on joint damage and generalized bone loss.Materials: Adjuvant-arthritis was induced by injection of Mycobacterium butyricum into the footpad of the right hind paw of Lewis rats (8 animals/group) on day 0.Treatment: Arthritic rats were treated with the vehicle (saline), etidronate or alendronate (subcutaneously, daily 5 times a week for 3 weeks from day 1 to day 21). Experiment-1: Etidronate (0.1, 0.5, 2.5, 12.5 mg/kg) or alendronate (0.02, 0.1, 0.5, 2.5 mg/kg), Experiment-2: Etidronate (2.5, 5, 10mg/ kg) or alendronate (0.001, 0.01, 0.1 mg/kg).Methods: In the adjuvant-injected side of the hind limbs, paw swelling was evaluated at 1-week intervals, and bone mineral density (BMD) in the proximal tibia, histopathology and radiographical findings in the tibio-tarsal region were evaluated at the time of sacrifice (on day 21).Results: In all treatment schedules, both bisphosphonates significantly prevented paw swelling and bone loss. Alendronate reduced paw swelling at higher doses (over 0.1 mg/ kg) compared with its effect on BMD decrease (over 0.001 mg/kg). In contrast, etidronate reduced paw swelling and joint damage at doses similar to those (over 2.5 mg/kg) prevented BMD decrease.Conclusions: Both etidronate and alendronate are effective in reducing arthritic damage, but their effective dose ranges for inflammatory responses and BMD decrease clearly differ; i.e., the etidronate dose ranges for anti-inflammatory and anti-resorptive effects are similar, whereas the dose range for anti-inflammatory effects of alendronate is 100-fold higher than that for its anti-resorptive effects.Received 21 January 2003; returned for revision 14 July 2003; accepted by M. Katori 15 August 2003     

Clinical usefulness of measurements of urinary deoxypyridinoline (DPD) in patients with postmenopausal osteoporosis receiving intermittent cyclical etidronate: advantage of free form of DPD over total DPD in predicting treatment efficacy

 Deoxypyridinoline (DPD) in urine, which reflects systemic bone resorption, is considered useful for assessing the effects of osteoporosis treatment. However, there are various methods of measuring DPD in urine but have been few comparative studies of the effectiveness of these methods. In this study, we investigated 94 postmenopausal women (63 patients administered with intermittent cyclical etidronate (ICE), and 31 control patients) focusing on total DPD and free DPD, measured by high-performance liquid chromatography (HPLC) and enzyme-linked immunosorbent assay (ELISA), respectively. For other metabolic bone markers, i.e., tartrate-resistant acid phosphatase (TRAP), bone-specific alkaline phosphatase (BAP), and osteocalcin (OC), we also investigated the ability of these markers to predict increases in bone mineral density (BMD), by employing receiver operating characteristic (ROC) analysis in relation to increasing BMD following ICE therapy, and we determined the usefulness of the different metabolic bone markers, using the signal-noise ratio derived from the mean significant change (MSC), which is double the day-to-day coefficient of variation in healthy volunteers. In the same way, we defined a significant change in BMD as double the mean change in BMD for 6 months after the initiation of observation in the control group, and we used this value as the cutoff value for ROC analysis. It was found that the assessment of urinary DPD was useful for assessing the treatment efficacy of ICE, and the assessment of changes at week 12 of therapy was most effective. In order to recognize changes in metabolic bone markers when the MSC is considered as the cutoff value, it is useful to assess the change in total DPD by HPLC. However, in order to predict increases in BMD 6 months or more after the initiation of ICE, it seems more effective to measure free DPD by ELISA. We conclude, therefore, that the measurement of free DPD by ELISA is more useful, especially when treatment efficacy of ICE is clinically predicted in individual patients with osteoporosis. Received: July 27, 2002/Accepted: January 20, 2003 RID="*" ID="*" Offprint requests to: K. Nakatsuka     

Organic Tissue Dissolution in Clodronate and Etidronate Mixtures with Sodium Hypochlorite

IntroductionMixtures of clodronate with sodium hypochlorite (NaOCl) better maintain free available chlorine (FAC) than etidronate-hypochlorite mixtures. This research aimed to compare organic tissue dissolution and residual FAC between clodronate and etidronate mixtures. Additionally, clodronate-hypochlorite mixtures lose no FAC over several hours. The second aim was to examine how well such mixtures dissolve organic material 6 hours from mixing.MethodsSoon after mixing, porcine palatal mucosa samples were added to 32°C solutions containing 0.26 mol/L clodronate and 5% NaOCl (0.26 mol/L-5% NaOCl), 0.26 mol/L etidronate-5% NaOCl, 5% NaOCl, 0.26 mol/L clodronate, 0.26 mol/L etidronate, or phosphate-buffered saline. Weights and FAC, where applicable, were recorded initially and at 15 minutes. FAC was measured by iodometric titration. Secondly, 6 hours after mixing, mucosa was added to 0.26 mol/L clodronate-2.5% NaOCl, 2.5% NaOCl, 0.52 mol/L clodronate-5% NaOCl, 5% NaOCl, or phosphate-buffered saline. Sample weights at 0, 5, 10, and 15 minutes were recorded. Analysis of variance was used for statistical analyses (α < .05).ResultsSoon after mixing, 0.26 mol/L clodronate-5% NaOCl dissolved mucosa as well as 5% NaOCl and better than 0.26 mol/L etidronate-5% NaOCl compared with which it retained more FAC. At 6 hours after mixing, 0.26 mol/L clodronate-2.5% NaOCl dissolved organic material as well as 2.5% NaOCl. However, 0.52 mol/L clodronate-5% NaOCl dissolved less mucosa than 5% NaOCl.ConclusionsSoon after mixing, clodronate mixtures better dissolve organic material than etidronate mixtures and have higher residual FAC. Six hours from mixing, 0.26 mol/L clodronate-2.5% NaOCl mixtures dissolve organic material similarly to controls.     

依替二膦酸锶对大鼠腰椎及股骨骨密度的影响

目的观察新合成的抗骨质疏松化合物依替二膦酸锶对骨代谢的影响。方法以去势SD大鼠为基础,对依替二膦酸锶、依替二膦酸二钠和二氯化锶以及不同剂量依替二膦酸锶对大鼠股骨及腰椎的骨密度的影响进行动态观察和比较。结果依替二膦酸锶与相同摩尔剂量的依替二膦酸二钠和二氯化锶相比,对去势大鼠腰椎和股骨骨密度的影响更为明显。其干预后去势大鼠骨密度增加的出现更早,且其升高的幅度也较高。50 mg/(kg·d)、100 mg/(kg·d)和150 mg/(kg·d)3种不同剂量的依替二膦酸锶均能有效地增加去势大鼠椎体和股骨的骨密度,且其增加骨密度的能力无明显差异。结论新化合物中的骨吸收抑制物依替二膦酸和骨形成促进物锶进入大鼠体内后,两者的生物学效应可能存在互补性。     

Treatment of Heterotopic Ossification After Spinal Cord Injury

Abstract

A new protocol in management of heterotopic ossification (HO) was evaluated in 46 patients after spinal cord injury (SCI). A group of 24 paraplegic and 22 tetraplegie patients was involved in a prospective study. Diagnosis of HO was made by bone scintigraphy and radiographic evaluation. Patients were divided into two groups. Group I was made up of 33 patients with positive bone scintigraphy and negative evidence of HO and Group II was made up of 13 patients with positive bone scintigraphy and positive radiographic evidence of HO. Etidronate was started intravenously (300 mg/day) for three days followed by oral therapy for six months (20 mg/kg/day). Follow-up of patients was 15.7±8 months after SCI. In Group I, etidronate therapy prevented the development of HO in 79 percent of patients; in 21 percent of patients, a low degree of tissue ossification was found which was not clinically significant. In Group II, there was an inhibitory effect of etidronate on progression of soft tissue ossification in six patients. The remaining seven patients did not respond to therapy and showed an increased growth of HO. Our data indicate that etidronate may prevent HO in the majority of patients when administered at an early stage of HO development and in higher doses than are routinely recommended. (J Spinal Cord Med 1997; 20:60-65)     

Myositis ossificans progressiva: a 10-year follow-up on a patient treated with etidronate disodium

We describe a child who was treated for 10 years with etidronate disodium for myositis ossificans. There were no typical bouts of swelling, reddening or hardening of areas over the skeletal muscles with this treatment and there were no side effects. Nevertheless, a constant gradual progression of the disease led to severe limitation of joint movement. This is the first report on long-term treatment with etidronate disodium.