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Cathepsin K (Cat K) is a predominant cysteine protease and highly potent collagenase expressed in osteoclasts. Cat K inhibitors are anti-resorptive agents to treat osteoporosis. A novel scaffold of cathepsin K inhibitors, exemplified by lead compound 1x, was used as the template for designing and synthesizing a total of 61 derivatives that have not been reported before. An exploratory structure–activity relationship analysis identified the potent Cat K inhibitor A22, which displayed an IC50 value of 0.44 μM against Cat K. A22 was very specific for Cat K and caused a significantly higher in vitro inhibition of the enzyme as compared to that of lead compound 1x. A surface plasmon resonance analysis confirmed in vitro binding of A22 to Cat K. Molecular docking studies indicated several favourable interaction sites for A22 within the active pocket of Cat K. Furthermore, A22 also blocked active osteoclasts in vitro and increased spinal bone density in zebrafish, in which it showed an activity that was higher than that of the marketed therapeutic bone metabolizer etidronate disodium. A22 represents a very promising lead compound for the development of novel antiresorptive agents functioning as orthosteric inhibitors of Cat K.

The first clinical use of bisphosphonates was in Paget's disease of bone (PDB) when disodium etidronate was found to be effective at suppressing metabolic activity of the disease. Subsequently, PDB became a testing ground for many bisphosphonates using changes in alkaline phosphatase (ALP) as the primary outcome measure in clinical trials. Bisphosphonates are now considered to be the treatment of choice for PDB since they are highly effective at suppressing the elevations in bone turnover that are characteristic of the disease. Short term studies have shown that treatment with alendronate and risedronate can promote formation of lamellar bone in affected sites and improve x-ray appearances in some patients. Bisphosphonates have also been shown to improve bone pain in PDB and within the bisphosphonates, zoledronic acid (ZA) is most likely to give a favourable pain response. Many patients with PDB do not have pain however, even when there is increased metabolic activity and more research is needed to find out why this is the case. The effects of bisphosphonates on complications of PDB such as deformity, pathological fractures and deafness have not been adequately studied since most clinical trials have been short term and have not collected information on these important outcomes. The PRISM and PRISM-EZ studies investigated the long-term effects of bisphosphonates in patients with established PDB using a treat-to-target approach and showed that intensive bisphosphonate therapy aimed at normalising ALP was no more effective than symptom directed treatment with bisphosphonates at preventing complications of PDB. The Zoledronate in the Prevention of Paget's Disease (ZiPP) trial, which is currently in progress, seeks to determine whether early intervention with this potent bisphosphonate might be effective in preventing disease progression. Should the ZiPP study yield positive results, genetic testing coupled to prophylactic bisphosphonate therapy might represent a new indication for these highly effective inhibitors of bone resorption in future years.

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive disease. There is no definitive treatment available. Case; A 13-year-old male with no remarkable medical history presented with a sore throat. Chest X-ray performed because of prolonged symptoms. He referred to pediatric pulmonology department because of the reticulonodular opacities in X-ray. Physical examination was normal and no clinical complaints. X-ray revealed reticulonodular opacities that had a greater distribution in the middle and lower lung zones. PFT showed a mild restrictive pattern. CT images were consistent with interstitial lung disease. The patient underwent open lung biopsy, and histopathologic analysis results confirmed a diagnosis of pulmonary alveolar microlithiasis. The patient started disodium etidronate treatment. Sandstorm-like appearance on chest x-ray decrease and restrictive pattern in PFT improved after three months of treatment. There was no significant change in parenchymal findings on CT. In follow up concomitant thoracic CT and MRG performed. However, the micronodular pattern observed in CT was not present in MRG. Conclusion: There is no known effective treatment for PAM. Number of the report describes the beneficial effects of long-term treatment with disodium etidronate but in a certain case, it seems ineffective. Our patient’s chest X-ray and PFT improved after three months of disodium etidronate treatment. However, there was no major change in CT. It is possible to observe parenchymal improvement in long term treatment. CT is a major tool for the detection and follows up the patients. We performed thoracic MRG in follow up however the parenchymal patterns of PAM could not be detected in MRG.

Introduction: Heterotopic ossification (HO) is the formation of lamellar bone within connective and other tissue where bone should not form and is a rare complication after burn injury. However, it leads to severe pain and distress, marked reduction in joint range of motion (ROM), impaired function and increased hospital length of stay. The pathophysiology, incidence and risk factors of HO remain poorly understood in burns and other traumas and the management, controversial. The aim of this comprehensive review, therefore, was to synthesise the available evidence on the development and treatment of HO after acute burn injury. Methods: The review was based on a systematic search of five electronic databases PubMed, EMBASE, CINAHL, LILACS and Scopus. Results: Synthesis and analysis of the data highlighted that, despite the passage of time, little translatable evidence is available to guide any prevention, screening, diagnostic or pharmacological or physical management protocols. Discussion: Causes of HO remain confounded, therefore prevention is difficult. Although spontaneous resolution is possible, surgical resection remains the recommended treatment when ROM and activities of daily living are severely affected. Conclusion: The findings from this review indicate that multicentre data pooling is needed to understand the optimum pathway to prevention, identification and treatment of HO in acute burn patients., Lay Summary Background to this subject: Heterotopic ossification (HO) is the formation of bone within the tissue where bone should not form and is a rare complication after burn injury. However, it leads to severe pain and distress, marked reduction in joint range of motion (ROM), impaired function and increased hospital length of stay. The pathophysiology, incidence and risk factors of HO remain poorly understood in burns and other traumas and the management, controversial. Question being asked or issue explored: The aim of this comprehensive review was to synthesise the available evidence on the development and treatment of HO after acute burn injury. Details of how the work was conducted: The review was based on a systematic search of medical electronic databases to identify relevant published literature. What we did and did not learn from this study: Synthesis and analysis of the data highlighted that, despite the passage of time, little translatable evidence is available to guide any prevention, screening, diagnostic or pharmacological or physical management protocols. Causes of HO remain confounded, therefore prevention is difficult. Although spontaneous resolution is possible, surgical resection remains the recommended treatment when ROM and activities of daily living are severely affected. The findings from this review indicate that multicentre data pooling is needed to understand the optimum pathway to prevention, identification and treatment of HO in acute burn patients.

Ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) was originally reported as a responsible gene for generalized arterial calcification in infancy (GACI). Though the prognosis of GACI patients is poor because of myocardial infarction and heart failure in relation to medial calcification of the coronary arteries, some patients rescued by bisphosphonate treatment have been reported. Recently, ENPP1 is also reported as responsible for autosomal recessive hypophosphatemic rickets type 2. We show here a boy with homozygous ENPP1 mutations diagnosed as having GACI in early infancy. After the diagnosis, he was treated with etidronate disodium (EHDP) in combination with antihypertensive drugs. The calcification of major arteries was diminished and disappeared by the age of eight months. He also showed mild hypophosphatemia (2.6–3.7 mg/dl) from the age of one year. After the treatment with EHDP for five years, he showed genu valgum with hypophosphatemia (2.6 mg/dl). He was diagnosed as having hypophosphatemic rickets at the age of seven years. The findings that hyper-mineralization of the arteries and hypo-mineralization of the bone observed in the same patient are noteworthy. ENPP1 could be regarded as a controller of the calcification of the whole body at least in part., Highlights • A boy with homozygous ENPP1 mutation suffered GACI and subsequent hypophosphatemic rickets. • ENPP1 mutation caused both hyper-mineralization in the arteries and hypo-mineralization in the bone in the same patient. • ENPP1 could be regarded as a mineralization controller of the body.

Pulmonary alveolar microlithiasis (PAM) is a rare genetic disease caused by mutations in sodium-phosphate co-transporter (SLC34A2), which encodes a type 2b sodium phosphate co-transporter. Disease is characterized by intra-alveolar microlith formation of phosphate. Turkey has a high prevalence of PAM. Herein, we report the clinical and radiological findings of three patients diagnosed with PAM and treated with disodium etidronate.

Pulmonary alveolar microlithiasis (PAM) is a rare chronic genetic lung disease in childhood with no proven therapy. It is characterized by the deposition of calcium phosphate microliths within the alveolar air spaces. The effect of disodium etidronate (DE) treatment on PAM is controversial. We report 3 siblings (an 11-year-old boy and 4-year-old twin girls) with PAM diagnosed by chest X-ray, thoracic high-resolution computed tomography, technetium-99m bone scan and bronchoalveolar lavage fluid findings. After the administration of DE (200 mg/day) for a 1-year period, 2 siblings showed radiological improvement, while 1 sibling did not. No drug side effects were observed within the treatment period. (C) 2015 S. Karger AG, Basel

Pulmonary alveolar microlithiasis (PAM) is a rare autosomal recessive lung disease. It is characterized by the accumulation of calculi called microliths. There is no definitive treatment. Disodium etidronate has been administered due to its alleged calcium phosphate precipitation-reducing effect; however, its effectiveness is controversial. Case; A 13-year-old male referred because of the reticulonodular opacities in chest X-ray detected during evaluation for upper respiratory tract infection. Pulmonary function test results showed a mild restrictive pattern. Findings on computed tomographic (CT) images were consistent with interstitial lung disease. Open lung biopsy confirmed a diagnosis of PAM. The patient started disodium etidronate treatment. Sandstorm-like appearance on chest x-ray decrease and restrictive pattern in pulmonary function test improved after six months of treatment. There was no significant change in CT. After cessation of treatment, the patient remains stable clinically. His asymptomatic sister also screened and similar mutation in SLC34A2 detected. However, because of his sister asymptomatic and younger, she is followed without treatment and remained stable clinically. Conclusion: Currently, there is no consensus on the treatment of PAM. The number of the report describes the beneficial effects of long-term treatment with disodium etidronate, but in a certain case, it seems ineffective. Our patient9s chest X-ray and pulmonary function improved after six months of disodium etidronate treatment. However, there was no major change in CT. He remains asymptomatic after discontinuation of treatment. Therefore, the effectiveness of disodium etidronate still remains controversial.

SituationA 30 week gestation male weighing 1.66kg presented with metabolic acidosis and high lactate and subsequently developed heart failure and hypertension. He initially started enteral feeds but these were later not tolerated and TPN commenced. On day 8 calcification of the aorta was identified on echocardiogram. CT scans showed extensive arterial calcification including the thoracic and abdominal aorta, subclavian and common carotid arteries, coeliac axis, SMA, renal arteries and iliac vessels. Generalised arterial calcification of infancy (GACI) due to ENPP1 mutation was suspected.BackgroundGACI, a rare autosomal recessive condition can be caused by ENPP1 mutation leading to low levels of inorganic pyrophosphate (PPi), a negative regulator of calcification. GACI has a high mortality rate, up to 55% at 6 months. Mortality has been shown to improve in those who survive the first few months of life.1TreatmentIntravenous sodium thiosulfate, licensed for cyanide poisoning and used off-label for calciphylaxis in adults,2 was commenced to try and reduce existing calcification. Dosing that has been known to be used in three other babies from two different centres,3 was used - 12.5g/m2 over 30minutes on alternate days for 2 weeks followed by 12.5g/m2 five days a week. This is in the same scale as adult calciphylaxis dosing and up to 400mg/kg can be used in paediatric cyanide poisoning. Bisphosphonates were commenced to prevent further calcification. Etidronate, a non-nitrogen containing bisphosphonate, was preferred due to its closer structural similarity to PPi than second generation bisphosphonates. Etidronate has been discontinued in the UK so was not initially available and a dose of pamidronate was given. A Canadian import of etidronate was sourced and commenced a week later. Due to SMA and coeliac axis calcification there were concerns regarding bowel perfusion and he was TPN fed except for 20ml/kg/day EBM. Etidronate 20mg/kg/day was commenced in three divided doses to improve gastrointestinal tolerance.OutcomeInitially his heart failure stabilised and hypertension managed with carvedilol. By day 35 full enteral feeds were reached and he was breathing unassisted in air. CT after one month’s treatment showed no worsening of vascular calcification, though unfortunately calcification did not appear to have improved. At 7 weeks he became tachypnoeic due to worsening heart failure and required respiratory support. Despite ongoing medical therapies he passed away at 8 weeks of age.Challenges and lessons learntDue to the rarity of the condition information on treatment options, dosing and monitoring are limited and the need to use an imported product lead to a short delay in treatment. Etidronate is only available in tablet form but Didronel brand can be crushed and suspended in water,4 Information about the suspension’s uniformity is unavailable but due to a lack of alternatives this was the option taken. A two hour break either side of etidronate while recommended, was compromised to ninety minutes as he required three hourly feeds. Combination treatment was used to try to reduce the calcification; however the extent of calcification had already caused significant cardiac compromise which ultimately led to his demise.ReferencesFerreira C, Ziegler S, Gahl WA. Generalized Arterial Calcification of Infancy. 2014 In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Online]. Seattle (WA): University of Washington, Seattle; 1993–2018. Available from: https://www.ncbi.nlm.nih.gov/books/NBK253403Nigwekar SU, Brunelli SM, Meade D, et al. Sodium thiosulfate therapy for calcific uremic arteriolopathy. Clin J Am Soc Nephrol, 2013;8:1162–70.Personal communication: Medicines Information, Alder Hey Children’s NHS Foundation Trust. Email sent to: Leeds Medicines Advisory Service. 28th June 2018.White R, Bradnam V. Handbook of Drug Administration via Enteral Feeding Tubes, Third ed. Cornwall: Pharmaceutical Press; 2015. www.medicinescomplete.com (accessed August 2018).

Background Here we report the first autopsied case involving pathological examination after two resections of symptomatic ossification of the anterior longitudinal ligament with anterior osteophytes and etidronate treatment with more than 8 years of follow-up. Case presentation A 51-year-old Japanese man complained of severe dysphagia due to esophageal compression by ossification of his anterior longitudinal ligament with anterior cervical osteophytes. Although surgical removal of the anterior cervical osteophytes was performed following etidronate treatment (800 mg/day for 6 months), dysphagia occurred secondary to recurrent ossification of his anterior longitudinal ligament with anterior osteophytes 7 years after the initial resection. A second resection of the anterior cervical osteophytes was performed, and cyclic administration of etidronate disodium (1000 mg/day, 3-month administration and 3-month cessation) did not result in re-outgrowth of ossification of his anterior longitudinal ligament with anterior osteophytes. At 1 year and 6 months after the second surgery, he suddenly died. The pathological findings associated with the ossification of his anterior longitudinal ligament during etidronate therapy showed no recurrence of ossification of the anterior longitudinal ligament with anterior osteophytes. Conclusion A recurrence of ossification of the anterior longitudinal ligament with anterior osteophytes formation, which caused dysphagia, was not observed with the cyclic administration of etidronate disodium at a dose of 1000 mg/day every 3 months for a period of 1 year and 5 months in the present case.

1. The diphosphonate, disodium etidronate (disodium ethane-1-hydroxy-1,1-diphosphonate; EHDP), is known to increase plasma inorganic phosphate in man. The present study examines the mechanism of this effect. 2. When EHDP was given by mouth at a dose of 80 μmol (20 mg) kg−1 day−1, plasma phosphate was significantly increased 24 h after the first dose but did not reach its maximum value for 2–3 weeks. When the drug was stopped, plasma phosphate returned to pretreatment values within 3 weeks. 3. Urinary excretion rate of phosphate was not greatly changed during treatment with EHDP despite the large increase in plasma phosphate, suggesting an alteration in renal handling. This was examined directly by infusing phosphate and inulin in six patients off and on EHDP. 4. EHDP had no effect on glomerular filtration rate (GFR) but produced a large increase in the maximum rate of renal tubular reabsorption of phosphate (Tm,P). The ratio Tm,P/GFR increased from a mean value of 1.15 mmol/l to 2.10 mmol/l on EHDP. This increase accounted for the hyperphosphataemia. 5. The same amount of phosphate infused at the same rate produced a greater rise in plasma phosphate when patients were on EHDP than when they were not, indicating a reduced net rate of entry of phosphate into tissues other than kidney. 6. Fasting total plasma calcium concentration and urine calcium excretion rate were not significantly altered by EHDP but the ability of infused phosphate to decrease plasma calcium was diminished. 7. It is suggested that EHDP alters phosphate transport in kidney and other tissues by a mechanism which is probably independent of the known hormonal influences on phosphate metabolism.

Twelve patients with Paget's disease of bone were treated with high doses of disodium etidronate for one month and compared with patients given treatments for longer periods. The effects of treatment for one month with etidronate 20 mg/kg daily were indistinguishable from six months' continuous treatment with the same dose but significantly better than treatment with 5 mg/kg daily in suppressing biochemical indices of disease activity. Treatment for one month was associated with transient osteomalacia but sustained suppression of bone resorption. Short term treatments with high doses of disodium etidronate may maximise suppression of disease activity but decrease exposure to unwanted effects.

Fourteen patients with Paget's disease of bone were treated with disodium etidronate in doses of 5 to 7 mg/kg per day. Skeletal blood flow (SBF), was measured by the modified 18F clearance technique of Wootton et al. (1976) before treatment and again during treatment. In 10 patients restudied 3-4 months after the start of therapy, SBF had fallen by a mean of 21% of the initial value, and the individual differences correlated well with the individual reductions in serum alkaline phosphatase (r = 0.77, P less than 0.01). The results were similar to those seen in an earlier study in patients treated with calcitonin. However, no early reduction in SBF was seen in six repeat studies performed at the end of the second week of treatment, in contrast with our previous findings with calcitonin.

Introduction Osteolytic bone lesion is a hallmark of multiple myeloma (MM). Bisphosphonates have been shown to be effective inhibitors of osteoclastic activity, leading to improvement of skeletal related morbidity in MM. Based on their chemical structure, bisphosphonates can be classified into two categories: amino bisphosphonates (ibandronate, pamidronate and zoledronate) and non-amino bisphosphonates (clodronate, etidronate). Although both categories are efficient for the management of myeloma related bone disease, their effect on mortality has been controversial. Some studies demonstrated beneficial effect associated with the administration of amino bisphosphonates, while others showed no such effect. We evaluated if amino bisphosphonates improve survival compared with non-amino bisphosphonates, when added to standard therapy for myeloma. Methods To address our objectives, we conducted a systematic review and network meta-analysis of all randomized controlled trials (RCT) estimating the effect of bisphosphonates in MM. We identified trials by searching electronic databases such as MEDLINE, CENTRAL and EMBASE. We compared the effect of amino bisphosphonates group to non-amino bisphosphonates group, versus the reference placebo group or no treatment. The primary outcome was overall mortality. We conducted a network meta-analysis under a random effects model. Pooled hazard ratios (HR) with 95% confidence intervals were estimated. To further evaluate the effect between the groups, a test for subgroup differences was applied. All analysis were conducted using Revman and R. Results Overall 14 studies were identified from 1982 to 2015, enrolling a total of 2706 patients: 5 studies tested bisphosphonates with non-amino group and 9 with amino group. The results from the network meta-analysis (Figure 1) showed a decrease in overall mortality for the amino bisphosphonates (HR 0.76, 95% CI 0.62 to 0.94) compared to the non-amino bisphosphonates (HR 1.06, 95% 0.87 to 1.3) and placebo. The statistical test for subgroup differences was significant (Q=4.69, p=0.03). Conclusion Based on the totality of randomized evidence, we showed for the first time that amino bisphosphonates compared to non-amino bisphosphonates versus placebo or no treatment reduce mortality in MM. The use of amino bisphosphonate should be further encouraged as anti-myeloma treatment and not solely as supportive treatment. Disclosures No relevant conflicts of interest to declare.

The goal of this study is to determine whether the previously observed, short-term protective effect of estrogen and diphosphonate compounds against osteopenia in ovariectomized (OVX) rats can be maintained for an entire year. Sham-operated control and OVX rats were treated intermittently with vehicle alone, estrogen, or the diphosphonate compounds etidronate disodium (EHDP) and risedronate (NE-58095) for 360 days after surgery. Their proximal tibiae and first lumbar vertebrae were processed undecalcified for quantitative bone histomorphometry. Both skeletal sites in vehicle-treated OVX rats were characterized by decreased cancellous bone volume and increases in most cellular and fluorochrome-based indices of bone formation and resorption. Treatment of OVX rats with estrogen or diphosphonate compounds depressed bone turnover and provided nearly complete protection against cancellous bone loss. Long-term EHDP treatment induced a moderate mineralization defect, as indicated by increased absolute osteoid volume and a high proportion of osteoid surfaces devoid of adjacent osteoblasts. In contrast, NE-58095 had minimal effects on bone mineralization. These findings indicate that diphosphonate compounds and estrogen provide long-term protection against tibial and vertebral osteopenia in OVX rats. They further indicate that diphosphonate compounds merit consideration as an alternative to estrogen for the prevention of postmenopausal bone loss.

We provide a 20 year follow-up of a family with three siblings affected by hereditary hyperphosphatasia (HH). An iliac crest bone biopsy was performed on one of the siblings following double-tetracycline labeling, with results reported quantitatively in a standard histomorphometric format. Biochemical parameters of disease activity were monitored in the patient before and after treatment with oral etidronate disodium, 20 mg/kg/day taken for 5 weeks. Biochemical evidence of intense disease activity continued 20 years after the initial diagnosis of HH in the sibling studied. His bone biopsy specimen also revealed extremely high bone turnover but low cancellous bone volume and osteoclasts unlike those found in Paget's disease. Treatment with etidronate disodium resulted in a temporary 40% reduction in serum alkaline phosphatase and 24 h urine hydroxyproline excretion, with reduction in serum osteocalcin from two times the upper limit of normal to a subnormal level. We conclude that disease activity in HH can continue unabated for two decades. Our bone biopsy finding of low cancellous bone volume, the consistent lack of pagetic-looking osteoclasts in our and other studies, plus the clinical features of HH (childhood onset and extremely diffuse disease with gross skeletal deformation) serve to distinguish HH from Paget's disease. Bisphosphonates may be of value in treating HH.

Treatment of Paget's disease of bone was done in 32 patients using monotherapy with disodium etidronate (Diphos). A further 19 patients underwent combined treatment with etidronate and human calcitonin. Both monotherapy and combined treatment led to marked regression of disease activity in most patients as measured be decreased activity of alkaline phosphatase. In most cases this coincided with improvement of complaints. In two cases with initial monotherapy and in six with combined treatment success of treatment remained unsatisfactory. The latter group comprised patients with very serious illness. Our experience suggests that etidronic acid is an effective and well tolerated drug relatively free of side-effects for the treatment of Paget's disease of bone.

This paper describes the development and validation of a rapid, direct, and stability-indicating method for analysis of etidronate, a bisphosphonate compound without a UV chromophore. A mixed-mode column was used to separate etidronate from its impurities in an 8-min gradient method and a charged aerosol detector (CAD) was used for detection. The developed HPLC method was validated with respect to specificity, linearity, accuracy, precision, sensitivity, and stability. The method can be used for release and stability testing of etidronate and has applicability to other similar bisphosphonate compounds.

Bisphosphonate drugs are the major treatment options for primary and secondary osteoporosis and other demineralizing bone diseases. This class of drugs was presaged over a decade ago when etidronate disodium, the "mother compound" for modern-day bisphosphonates, was first used in the treatment of osteoporosis. The cyclic use of etidronate in therapy, which is known mainly to specialists in the field, is not approved in the United States. The drug does, however, have a worldwide reputation as a relatively inexpensive, efficacious, and highly tolerable treatment for osteoporosis. Many studies still describe its use for primary osteoporosis and some have described use in immobilization bone loss, periprosthetic bone loss, and even glucocorticoid-induced osteoporosis. This review highlights some of these uses.

Generalized arterial calcification of infancy is an intractable ectopic mineralization disorder caused by mutations in the ENPP1 gene, resulting in reduced plasma inorganic pyrophosphate (PPi) levels. We previously characterized the Enpp1(asj) mutant mouse as a model of generalized arterial calcification of infancy, and we have now explored the potential efficacy of bisphosphonates, nonhydrolyzable PPi analogs, in preventing ectopic mineralization in these mice. The mice were maintained on either basic diet (control) or diets containing etidronate or alendronate in three different concentrations (experimental). Considering low bioavailability of bisphosphonates when administered orally, subsequent studies tested the mice with subcutaneous injections of etidronate. The treatments were initiated at 4 weeks of age, and the degree of mineralization was assessed at 12 weeks of age by quantitation of calcium deposits in the muzzle skin containing dermal sheath of vibrissae and in aorta. We found that bisphosphonate treatments significantly reduced mineralization in skin and aorta. These changes in treated mice were accompanied with restoration of their bone microarchitecture, determined by microcomputed tomography. The inhibitory capacity of bisphosphonates, with mechanistic implications, was confirmed in a cell-based mineralization assay in vitro. Collectively, these results suggest that bisphosphonate treatment may be beneficial by a dual effect for preventing ectopic soft tissue mineralization while correcting decreased bone mineralization in generalized arterial calcification of infancy caused by ENPP1 mutations.

A 59-year-old woman with a 10-year history of hemodialysis was admitted to our hospital for painful skin ulcers on her right thigh, right calf, and left upper arm. A whole-body plain computed tomographic scan showed diffuse calcification of the uterus and marked calcification of the mitral valve. Skin biopsy specimens from the left thigh showed calcium deposition in numerous small blood vessels in the dermis and fat, leading to a diagnosis of calcific uremic arteriolopathy (CUA). Despite antibiotic therapy and aggressive wound care for 2 months, the skin ulcers enlarged and the patient's general condition worsened. Surprisingly, oral administration of etidronate disodium (200 mg/d) strikingly improved the focal infection and decreased the size of the skin ulcers within several days. She was discharged from the hospital 2 months later, when epithelialization of the ulcers was almost complete. We report a case of CUA that was improved dramatically by treatment with etidronate. Etidronate therapy should be considered for refractory CUA.

This study was conducted to identify bone resorption and anti-inflammatory effects with intermittent cyclical etidronate therapy (ICET) in patients with rheumatoid arthritis, and anti-inflammatory effect of etidronate in vitro. We compared bone mineral density (BMD), urinary deoxypyridinoline (DPD) level, bone alkaline phosphatase (BAP) level and Larsen damage scores between the ICET and the non-ICET groups for 3 years. The levels of interleukin-6 (IL-6), prostaglandin E2 (PGE2), substance P and vascular endothelial growth factor (VEGF) in synovial cells from arthritis models were measured following the addition of etidronate. In the ICET group, BMD and BAP levels increased. Urinary DPD level and the Larsen damage score were significantly lower than that in the non-ICET group. In the in vitro study, the production of IL-6, PGE2, substance P and VEGF were inhibited in a dose-dependent manner. Bone resorption and destruction inhibition effect of etidronate remained for 3 years. In vitro study showed that the production of inflammatory cytokines and an angiogenesis factor were inhibited.

Background We have recently shown that early postmenopausal but not premenopausal asthmatic women treated with inhaled corticosteroids demonstrate reduced bone mineral density(BMD)and decreased serum intact osteocalcin levels. Thus, the development of therapeutic approaches would be desirable for the prevention and intervention of BMD reduction in postmenopausal asthmatic women receiving inhaled corticosteroids. Methods This study was aimed at examining the effects of etidronate disodium on BMD in 20 postmenopausal asthmatic women with reduced BMD of the lumbar spine(T score ; − 1.5 or less). These patients had been managed by inhaled beclomethasone dipropionate or inhaled fluticasone propionate, without regular use of oral or parentheral corticosteroids. They were given a 200 mg/day oral dose of etidronate disodium for 14 days every three months. BMD of the lumbar spine was determined at baseline and at 1 or 3 years after the treatment. Results The baseline BMD was 0.692±0.018(SE)g/cm 2 (T score, − 3.0±0.8). The BMD significantly increased by 5.2±2.0% at 1 year( P = 0.022)and by 7.3±2.9% at 3 years( P = 0.037)after the treatment. Conclusions : Intermittent cyclical treatment with ethidronate improves reduced BMD in postmenopausal asthmatic women on inhaled corticosteroid therapy.

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巨大石灰化がエチドロン酸ニナトリウム (EHDP) (ダイドロネル®) 低用量, 長期内服にて著明な改善を認めた2症例を経験したので報告する. 症例1は56歳女性, 透析歴8年. 平成9年頃より, 両肩, 股関節に疼痛出現. 腫瘤を触知するようになる. 平成10年X線上両肩関節に散在性に, 右股関節に9×13cm, 左股関節に16×9cmの異所性石灰化を認めた. 同年8月より発熱を認め, EHDP 300mg/日を内服開始した. 内服後14日目より発熱は改善. 疼痛も徐々に改善した. 平成13年11月にはX線上, 右股関節は6.5×5cm, 左股関節は最大の腫瘤が8×6cmと石灰化腫瘤の縮小を認めた. 症例2は55歳男性, 透析歴10年. 平成7年頃より, 両肩, 股関節に疼痛出現. 平成10年3月X線上右肩関節に11×9cm, 右股関節に8×10cm, 左股関節に15×11cmの異所性石灰化を認め, EHDP 400mg/日を内服開始した. 同年9月X線上石灰化腫瘤は若干の増大がみられたが, 疼痛は著明な改善を認めたため, 内服を継続. 平成13年10月にはX線上異所性石灰化は右肩関節に2×3cm, 右股関節の石灰化は消失し, 左股関節は1×1cmと著明に縮小した. 異所性石灰化に対する治療は, 基本的にはカルシウム・リン値のコントロールを行うが, 巨大な石灰化の場合, それのみでの改善は難しい. EHDPが異所性石灰化に有効であったとの報告は多くみられるが, その治療法はまだ確立されていない. この2症例の経験から, 巨大な異所性石灰化にEHDP低用量長期投与が有効である可能性が示された.