Safety, tolerability and pharmacokinetic characterisation of DACRA KBP-042 in healthy male subjects.

There is a need for antidiabetic agents successfully targeting insulin sensitivity and treating obesity control at the same time. The aim of this first-in-human study was (a) to evaluate safety and tolerability, (b) to evaluate pharmacokinetics and (c) to assess indications of receptor engagement of single ascending doses of KBP-042, a dual amylin and calcitonin receptor agonist (DACRA) that has shown promising preclinical data, with superior activity in terms of typical amylin-induced responses including reduction of food intake, weight loss and gluco-regulatory capacities. A randomised double-blind placebo-controlled single ascending dose study was performed with six dose levels of KBP-042 (5, 7.5, 10, 20, 20 (evening), 40 ug) in healthy male adults. KBP-042 or placebo was administered as a single dose after an overnight fast, followed by a standardized lunch after 4 hours. KBP-042 was associated with dose-dependent complaints of nausea and vomiting, with a lack of tolerability at doses of 20 µg and above. Doses of 5-40 µg KBP-042 behaved according to a linear pharmacokinetic profile. Indications of target receptor engagement were observed at the level of glucose control and lowering of bone resorption, compared to placebo. The results of this study showed that doses up to 40 µg were safe, although tolerability was not present at the highest doses. The study confirmed target receptor engagement at the studied doses.

Successful treatment for bilateral femoral neck insufficiency fractures: a rare lesion case report and an updated review of the literature.

BACKGROUND: The incidence of insufficiency fracture (IF) at femoral neck is low, accounting for about 5% of all insufficiency fractures, and IF at bilateral femoral neck is less common with more occurrence in athlete or serviceman. With the aging of populations, more cases of bilateral femoral neck IF have occurred recently, while the standard clinical treatment still remains lacking due to the complexity of these patients. CASE PRESENTATION: A 55-year-old male patient complained pain in his bilateral hip, with no history of trauma, glucocorticoid hormone consumption or radiotherapy, and imaging examination revealed fracture nonunion and shortening in his left femoral neck, and double fracture line on the right femoral neck. The patient received a cementless THA for the left femoral neck fracture and conservative treatment for the right side, followed by Elcatonin injection and oral administration of Carbonate D3 Granules. After 4 months of fellow-up, the patient presented improved functional scorings in bilateral hip joints, with no signs of prothesis infection or loosening. CONCLUSION: We present a rare case of bilateral femoral neck IF in a middle-aged male and the treatment is successful. The timely CT and MRI examinations of bilateral hip joints for patients was necessary for orthopedists to select proper therapeutic regimen. In addition, the choice for therapeutic regimen of bilateral femoral IF should not only be based on the professional judgement of orthopedists, but also on the wishes of patients.

A dual amylin and calcitonin receptor agonist inhibits pain behavior and reduces cartilage pathology in an osteoarthritis rat model.

OBJECTIVES: Pain and disability are the main clinical manifestations of osteoarthritis, for which only symptomatic therapies are available. Hence, there is a need for therapies that can simultaneously alter disease progression and provide pain relief. KBP is a dual amylin- and calcitonin-receptor agonist with antiresorptive and chondroprotective properties. In this study we investigated the effect of KBP in a rat model of osteoarthritis. METHODS: Medial meniscectomy (MNX) was performed in 39 rats, while 10 underwent sham surgery. Rats were treated with KBP and/or naproxen. Nociception was assessed by mechanical and cold allodynia, weight bearing asymmetry, and burrowing behavior. Blood samples were collected for biomarker measurements, and knees for histology. Cartilage histopathology was evaluated according to the advanced Osteoarthritis Research International (OARSI) score and KBPs in vitro antiresorptive effects were assessed using human osteoclasts cultured on bone. RESULTS: The MNX animals displayed an increased nociceptive behavior. Treatment with KBP attenuated the MNX-induced osteoarthritis-associated joint pain. The cartilage histopathology was significantly lower in rats treated with KBP than in MNX animals. Bone and cartilage degradation, assessed by CTX-I and CTX-II plasma levels, were decreased in all KBP-treated groups and KBP potently inhibited bone resorption in vitro. CONCLUSIONS: Our study demonstrates the effectiveness of KBP in ameliorating osteoarthritis-associated joint pain and in protecting the articular cartilage, suggesting KBP as a potential drug candidate for osteoarthritis.

Efficacy and safety of elcatonin in postmenopausal women with osteoporosis: a systematic review with network meta-analysis of randomized clinical trials.

The present systematic review aimed to evaluate bone mineral density (BMD) change and complication rates of elcatonin on treating postmenopausal osteoporosis. The result confirmed efficacy of elcatonin and safety in combination therapies of elcatonin (C-E). INTRODUCTION: Postmenopausal osteoporosis is an important issue in global aging trends. One treatment of osteoporosis is elcatonin, a kind of calcitonin. However, it has been challenged for long time because of safety. Many trials investigated on this topic, but they were designed differently. Those designs can be categorized in monotherapy of elcatonin (M-E) and C-E. Unfortunately, no synthesized evidence dealt this topic. METHODS: This study systematically identified target trials from six important databases and only included randomized controlled trial for synthesis. Two investigators assessed quality of eligible trials using the Cochrane Risk of Bias Tool, and they independently extracted data. Network meta-analysis performed Peto odds ratio (POR, used for dealing with zero cell) or weighted mean difference (WMD, for continuous data) with 95% confidence intervals (CI) and consistency H. RESULTS: Sixteen trials recruiting 2754 women with postmenopausal osteoporosis were included in our study. Elcatonin therapies and non-elcatonin medications had comparable fracture rates and bone mineral density change. Yet, C-E (WMD, - 18.93; 95% CI, - 23.97 to - 13.89) and M-E (WMD, - 13.72; 95% CI, - 19.51 to - 7.94) had significantly lower pain score than non-elcatonin medications. However, M-E (POR = 8.413, 95% CI, 2.031 to 34.859) and non-elcatonin medication (Peto OR, 7.450; 95% CI, 1.479 to 37.530) had significantly higher complication rates than placebo. No evidence detected inconsistency and small study effect in this network model. CONCLUSIONS: Based on current evidence, C-E may be considered for treating postmenopausal osteoporosis because it benefits on pain relief and complications. Moreover, it shows comparable fracture rate and bone mineral density change as compared with anti-osteoporosis and calcium supplements. Nevertheless, further trials are needed to investigate formula and dosages of elcatonin.

Detection of Biosynthetic Precursors, Discovery of Glycosylated Forms, and Homeostasis of Calcitonin in Human Cancer Cells.

The peptide hormone calcitonin is intimately connected with human cancer development and proliferation. Its biosynthesis is reasoned to proceed via glycine-, α-hydroxyglycine-, glycyllysine-, and glycyllysyllysine-extended precursors; however, as a result of the limitations of current analytical methods, until now, there has been no procedure capable of detecting these individual species in cell or tissue samples. Therefore, their presence and dynamics in cancer had not been established. Here, we report the first methodology for the separation, detection, and quantification of calcitonin and each of its precursors in human cancer cells. We also report the discovery and characterization of O-glycosylated calcitonin and its analogous biosynthetic precursors. Through direct and simultaneous analysis of the glycosylated and nonglycosylated species, we interrogate the hormone biosynthesis. This shows that the cellular calcitonin level is maintained to mitigate effects of biosynthetic enzyme inhibitors that substantially change the proportions of calcitonin-related species released into the culture medium.

The Dual Amylin- and Calcitonin-Receptor Agonist KBP-042 Works as Adjunct to Metformin on Fasting Hyperglycemia and HbA1c in a Rat Model of Type 2 Diabetes.

KBP-042 is a dual amylin and calcitonin receptor agonist that increases glucose tolerance and insulin action and reduces body weight in rat models of obesity and prediabetes. The objective of the present study was to 1) evaluate KBP-042 as a treatment of late-stage type 2 diabetes in a rat model and 2) assess the value of adding KBP-042 to the standard of care, metformin, to consider KBP-042 as a relevant drug for treating patients with type 2 diabetes. Two studies were included: an intervention study and a prevention study. In the intervention study, treatment with 5 µg/kg KBP-042 was initiated in 11-week-old Zucker diabetic fatty (ZDF) rats, in which glucose tolerance, fasting glycemia, and glycated hemoglobin were assessed after 4 weeks. In the prevention study, either metformin (400 mg/kg), KBP-042 (5 µg/kg), or a combination of both were administered to ZDF rats for a total of 9 weeks. Glycemia, glucose tolerance, and insulin tolerance were tested. Furthermore, fasting plasma insulin and glucagon levels were evaluated. Finally, pancreatic content of insulin was assessed as a surrogate marker of beta-cell mass. It was found that KBP-042 was efficient in lowering fasting plasma glucose as well as improving glucose tolerance, both as prevention and intervention of disease progression. Furthermore, KBP-042 was efficient in combination with metformin and had additional effects compared with either therapy alone. In conclusion, KBP-042 is a highly relevant therapeutic candidate against type 2 diabetes, effective both as an add-on therapy to metformin and as a stand-alone therapy.

Effect of elcatonin versus nonsteroidal anti-inflammatory medications for acute back pain in patients with osteoporotic vertebral fracture: a multiclinic randomized controlled trial.

The aim of this study was to compare the efficacy of elcatonin injections and oral nonsteroidal anti-inflammatory drugs (NSAIDs) for patients with osteoporosis who have acute lumbar pain after experiencing new vertebral compression fractures. Two hundred twenty-eight Japanese female patients (mean age 77.3 years) with acute lumbar pain from osteoporotic vertebral fractures were randomly divided into two groups. Patients in one group were given an NSAID (NSAIDs group) and patients in the other group were given weekly intramuscular injections of 20 units of elcatonin (elcatonin group). All patients underwent follow-up examinations up to 6 weeks from the start of the trial. Outcome measures were the level of functional impairment according to the Japan Questionnaire for Osteoporotic Pain (JQ22), the Roland-Morris Disability Questionnaire (RDQ), and a visual analog scale (VAS) of pain intensity. Statistical analyses focused on (1) the time course of pain and functional level using linear mixed effects models to analyze the longitudinal data and (2) the effectiveness of elcatonin injection with mean difference values and 95 % confidence intervals. Significant differences were seen over time between the initial values and the postintervention values (4 and 6 weeks) in JQ22, RDQ, and VAS scores (effect size d > 0.4) in each group. The mean differences between the elcatonin group and the NSAIDs group in each measure at 4 and 6 weeks were -4.8 and -8.3 for the JQ22, -1.3 and -2.6 for the RDQ, and -11.3 and -11.5 for the VAS, shifted to elcatonin. Once weekly elcatonin injection was more effective than NSAIDs for treating acute lumbar pain and improving mobility in Japanese women with osteoporotic vertebral fractures.

Sardine procalcitonin amino-terminal cleavage peptide has a different action from calcitonin and promotes osteoblastic activity in the scales of goldfish.

The nucleotide sequence of a sardine preprocalcitonin precursor has been determined from their ultimobranchial glands in the present study. From our analysis of this sequence, we found that sardine procalcitonin was composed of procalcitonin amino-terminal cleavage peptide (N-proCT) (53 amino acids), CT (32 amino acids), and procalcitonin carboxyl-terminal cleavage peptide (C-proCT) (18 amino acids). As compared with C-proCT, N-proCT has been highly conserved among teleosts, reptiles, and birds, which suggests that N-proCT has some bioactivities. Therefore, both sardine N-proCT and sardine CT were synthesized, and their bioactivities for osteoblasts and osteoclasts were examined using our assay system with goldfish scales that consisted of osteoblasts and osteoclasts. As a result, sardine N-proCT (10-7M) activated osteoblastic marker enzyme activity, while sardine CT did not change. On the other hand, sardine CT (10-9 to 10-7M) suppressed osteoclastic marker enzyme activity, although sardine N-proCT did not influence enzyme activity. Furthermore, the mRNA expressions of osteoblastic markers such as type 1 collagen and osteocalcin were also promoted by sardine N-proCT (10-7M) treatment; however, sardine CT did not influence their expressions. The osteoblastic effects of N-proCT lack agreement. In the present study, we can evaluate exactly the action for osteoblasts because our scale assay system is very sensitive and it is a co-culture system for osteoblasts and osteoclasts with calcified bone matrix. Both CT and N-proCT seem to influence osteoblasts and osteoclasts and promote bone formation by different actions in teleosts.

Additive effect of elcatonin to risedronate for chronic back pain and quality of life in postmenopausal women with osteoporosis: a randomized controlled trial.

Calcitonin has been reported to reduce acute and chronic back pain in osteoporotic patients. The additive effect of calcitonin with a bisphosphonate on chronic back pain remains unclear. The purpose of this study was to evaluate the effect of combining elcatonin (eel calcitonin) with risedronate for patients with chronic back pain. Forty-five postmenopausal women diagnosed as having osteoporosis with chronic back pain persisting for more than 3 months, after excluding women with fresh vertebral fractures within the last 6 months, were randomly allocated to a risedronate group (risedronate alone, n = 22) and a combined group (risedronate and elcatonin, n = 23). The study period was 6 months. Pain was evaluated with a visual analogue scale (VAS) and the Roland-Morris questionnaire (RDQ). Back extensor strength, bone mineral density, and quality of life on the SF-36 and the Japanese osteoporosis quality of life score were also evaluated. Significant improvements were found in the combined group for VAS at final follow-up compared with baseline and 3 months, mental health status on the SF-36, and JOQOL domains for back pain and general health. The JOQOL domain for back pain improved significantly, but no change was found in the VAS or other domains in the risedronate group. Bone mineral density increased significantly in the two groups, but no significant difference was found between the groups. Back extensor strength did not change in both groups. In conclusion, the use of elcatonin in addition to risedronate for more than 3 months reduced chronic back pain. The additional therapy of risedronate with elcatonin may be a useful and practical choice for the treatment of osteoporosis with chronic back pain persisting more than 3 months.

Vasodilator Effects of Elcatonin, a Synthetic Eel Calcitonin, on Retinal Blood Vessels in Rats.

The aim of this study was to examine the effects of elcatonin, a synthetic derivative of eel calcitonin, on rat retinal blood vessels, and to determine how diabetes affects the retinal vascular responses. Ocular fundus images were captured with an original high-resolution digital fundus camera in vivo. The retinal vascular responses were evaluated by measuring the diameter of retinal blood vessels contained in the digital images. Both systemic blood pressure and heart rate were continuously recorded. Elcatonin increased the diameter of retinal blood vessels but decreased mean blood pressure in a dose-dependent manner, whereas it had no significant effect on heart rate. A diminished retinal vasodilator response and significant pressor response to elcatonin were observed in rats injected intravenously with N(G)-nitro-L-arginine methyl ester, a nitric oxide (NO) synthase inhibitor. Intravitreal injection of indomethacin, a non-selective cyclooxygenase (COX) inhibitor, and SQ22536, an adenylyl cyclase inhibitor, markedly attenuated the vasodilator effects of elcatonin on retinal blood vessels. The retinal vasodilator responses to elcatonin were unaffected 2 weeks after the induction of diabetes by a combination of streptozotocin treatment and D-glucose feeding. These results suggest that elcatonin dilates rat retinal blood vessels via NO- and COX-dependent mechanisms and that the adenylyl cyclase-adenosine 3',5'-cyclic monophosphate system plays a major role in the vasodilator mechanisms. The retinal vasodilatory effects of elcatonin seem to be preserved at early stages of diabetes.

A novel oral dual amylin and calcitonin receptor agonist (KBP-042) exerts antiobesity and antidiabetic effects in rats.

The present study investigated a novel oral dual amylin and calcitonin receptor agonist (DACRA), KBP-042, in head-to-head comparison with salmon calcitonin (sCT) with regard to in vitro receptor pharmacology, ex vivo pancreatic islet studies, and in vivo proof of concept studies in diet-induced obese (DIO) and Zucker diabetic fatty (ZDF) rats. In vitro, KBP-042 demonstrated superior binding affinity and activation of amylin and calcitonin receptors, and ex vivo, KBP-042 exerted inhibitory action on stimulated insulin and glucagon release from isolated islets. In vivo, KBP-042 induced a superior and pronounced reduction in food intake in conjunction with a sustained pair-fed corrected weight loss in DIO rats. Concomitantly, KBP-042 improved glucose homeostasis and reduced hyperinsulinemia and hyperleptinemia in conjunction with enhanced insulin sensitivity. In ZDF rats, KBP-042 induced a superior attenuation of diabetic hyperglycemia and alleviated impaired glucose and insulin tolerance. Concomitantly, KBP-042 preserved insulinotropic and induced glucagonostatic action, ultimately preserving pancreatic insulin and glucagon content. In conclusion, oral KBP-042 is a novel DACRA, which exerts antiobesity and antidiabetic efficacy by dual modulation of insulin sensitivity and directly decelerating stress on the pancreatic α- and ß-cells. These results could provide the basis for oral KBP-042 as a novel therapeutic agent in type 2 diabetes.

Comparison of the effects of single doses of elcatonin and pregabalin on oxaliplatin-induced cold and mechanical allodynia in rats.

Oxaliplatin frequently causes peripheral neuropathy. Clinical studies have indicated that pregabalin ameliorates oxaliplatin-induced peripheral neuropathy. However, pregabalin frequently causes dizziness and somnolence. We previously reported that elcatonin, a synthetic analog of eel calcitonin, attenuated oxaliplatin-induced cold and mechanical allodynia in rats. The aim of the present study was to compare the anti-allodynic effects of elcatonin and pregabalin in the rats developing the oxaliplatin-induced neuropathy. Male Sprague-Dawley rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)) to induce cold and mechanical allodynia. We assessed the effects of subcutaneous elcatonin (20 U/kg) and oral pregabalin (30 mg/kg) on cold and mechanical allodynia by cold stimulation (8°C) to the hind paw of the rats and the von Frey test, respectively. Elcatonin reversed the effects of oxaliplatin-induced cold and mechanical allodynia in rats for a longer time period than pregabalin does. These results suggested that elcatonin might be useful for the clinical treatment of oxaliplatin-induced neuropathy.

The rhPTH treatment elevates plasma secreted protein acidic and rich in cysteine levels in patients with osteoporosis.

UNLABELLED: The secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin, plays an important role in osteoblast formation, maturation, and survival. Here, we report the effects of recombinant human parathyroid hormone (1-34) [rhPTH (1-34)], a bone formation-stimulating agent, and elcatonin on plasma SPARC levels in patients with osteoporosis. The rhPTH (1-34) treatment significantly increased plasma SPARC levels, and the change of plasma SPARC correlated positively with changes of lumbar bone mineral density (BMD) at L2-L4. These results unveil that SPARC may be a novel marker related to the regulation of bone formation. INTRODUCTION: rhPTH (1-34) is known to influence osteoclast maturation and activity through modulation of osteoblast-derived cytokines. SPARC is the most abundant noncollagenous extracellular matrix protein in the bone. So far, however, no study has reported the effects of rhPTH (1-34) administration on plasma SPARC levels in patients with osteoporosis. The purpose of this study was to compare the response of SPARC and BMD to rhPTH (1-34) and elcatonin in postmenopausal women with osteoporosis. METHODS: Women were randomized to either once-daily subcutaneous injection of rhPTH (1-34) (20 µg, N = 89) or once-weekly intramuscular injection of elcatonin (200 U, N = 35) for 12 months. Plasma biochemical markers of bone turnover and BMD were measured at baseline, 6 and 12 months after treatment. RESULTS: At baseline, plasma SPARC levels correlated positively with lumbar spine BMD in all patients (r = 0.45, p = 0.001). Compared with baseline, at 12 months, rhPTH (1-34) significantly increased lumbar spine BMD and plasma SPARC levels (p = 0.008 and p = 0.001, respectively), whereas elcatonin was ineffective. More importantly, the changes of plasma SPARC correlated positively with changes of lumbar BMD at L2-L4 (r = 0.47, p = 0.001) in the rhPTH (1-34)-treated group, but not in the elcatonin group. CONCLUSION: The increase in plasma SPARC levels during the rhPTH (1-34) treatment may have contributed to the anabolic effect on bone formation, and SPARC may be a novel marker related to the regulation of bone formation.

Anti-hyperalgesic effects of calcitonin on neuropathic pain interacting with its peripheral receptors.

BACKGROUND: The polypeptide hormone calcitonin is clinically well known for its ability to relieve neuropathic pain such as spinal canal stenosis, diabetic neuropathy and complex regional pain syndrome. Mechanisms for its analgesic effect, however, remain unclear. Here we investigated the mechanism of anti-hyperalgesic action of calcitonin in a neuropathic pain model in rats. RESULTS: Subcutaneous injection of elcatonin, a synthetic derivative of eel calcitonin, relieved hyperalgesia induced by chronic constriction injury (CCI). Real-time reverse transcriptase-polymerase chain reaction analysis revealed that the CCI provoked the upregulation of tetrodotoxin (TTX)-sensitive Nav.1.3 mRNA and downregulation of TTX-resistant Nav1.8 and Nav1.9 mRNA on the ipsilateral dorsal root ganglion (DRG), which would consequently increase the excitability of peripheral nerves. These changes were reversed by elcatonin. In addition, the gene expression of the calcitonin receptor and binding site of 125I-calcitonin was increased at the constricted peripheral nerve tissue but not at the DRG. The anti-hyperalgesic effect and normalization of sodium channel mRNA by elcatonin was parallel to the change of the calcitonin receptor expression. Elcatonin, however, did not affect the sensitivity of nociception or gene expression of sodium channel, while it suppressed calcitonin receptor mRNA under normal conditions. CONCLUSIONS: These results suggest that the anti-hyperalgesic action of calcitonin on CCI rats could be attributable to the normalization of the sodium channel expression, which might be exerted by an unknown signal produced at the peripheral nerve tissue but not by DRG neurons through the activation of the calcitonin receptor. Calcitonin signals were silent in the normal condition and nerve injury may be one of triggers for conversion of a silent to an active signal.

Elcatonin in combination with risedronate is more effective than risedronate alone for relieving back pain in postmenopausal women with osteoporosis.

Intramuscularly administered elcatonin (ECT) reduces pain via the central nervous system. A prospective study was performed to determine whether ECT has a beneficial effect on back pain and function in postmenopausal women with osteoporosis during bisphosphonate therapy. Sixty-one postmenopausal osteoporotic women with back pain (mean age: 73.7 years, range: 54-96 years) were divided into two groups: the control group (n=30) and the ECT (intramuscular, 20 units a week) group (n=31). All patients received treatment with risedronate (17.5 mg weekly). The duration of the study was 8 weeks. Urinary levels of cross-linked N-terminal telopeptides of type I collagen (NTX), visual analogue scale (VAS) for back pain at rest and movement, and Roland-Morris Disability Questionnaire (RDQ) score for function were assessed. Urinary NTX levels, VAS at rest and movement, and RDQ score markedly decreased during 8 weeks of treatment in both ECT and control groups. A significant reduction in VAS at movement, but not in VAS at rest and RDQ score, was noted in the ECT group than in the control group. This effect was observed from 2 weeks after the start of therapy. These results suggested that ECT in combination with risedronate was more effective than risedronate alone for reducing back pain in postmenopausal women with osteoporosis.

Impact of Alendronate Sodium plus Elcatonin on Postoperative Bone Pain in Patients with Osteoporotic Fractures.

Objective: This research aims to investigate and analyze the impact of alendronate sodium (ALN) plus elcatonin (EC) in treating postoperative bone pain (BP) in patients with osteoporotic fractures (OPFs). Methods: One hundred and thirty-eight cases of OPFs admitted between July 2018 and July 2021 were selected, of which 68 cases receiving ALN were set as the control group and 70 cases receiving ALN plus EC were set as the research group. Intercomparisons were performed in terms of BP, curative effect, complication rate, and serum bone metabolism indexes such as bone Gla protein (BGP), parathyroid hormone (PTH), and bone alkaline phosphatase (BALP). Results: Better postoperative BP relief, higher overall response rate, and lower complication rate were identified in the research group versus the control group. On the other hand, the research group presented with increased BGP and BALP after treatment, higher than those in the control group, while the posttreament PTH decreased obviously and was lower versus the control group. Conclusions: For OPF patients, ALN plus EC contributes to significantly reduced postoperative BP, improved clinical efficacy, higher treatment safety, and better bone metabolism, which has high clinical application value.

Alendronate is more effective than elcatonin in improving pain and quality of life in postmenopausal women with osteoporosis.

UNLABELLED: A randomized controlled trial was performed to compare the short-term effects of alendronate (ALN) and ECT on pain and quality of life (QOL) in postmenopausal women with osteoporosis. Back pain and QOL [Short-Form Health Survey (SF-8)] significantly improved at 1, 3, and 6 months in both groups, with greater improvements in the ALN group than in the ECT group. These results suggested that ALN reduced back pain and improved QOL more markedly than ECT in postmenopausal osteoporotic women with back pain. INTRODUCTION: Intramuscular ECT is known to reduce pain via the central nervous system. A multicenter randomized controlled trial was performed to compare the short-term effects of ALN and ECT on pain and QOL in postmenopausal women with osteoporosis. METHODS: One hundred and 94 postmenopausal osteoporotic women with back pain (mean age 79.8 years, range 60-96 years) were randomly divided into two groups: the ALN group (35 mg weekly) and the ECT group (intramuscular 20 units a week). The duration of the study was 6 months. The trial was completed in 97 (100%) women of the ALN group and 96 (99.0%) women of the ECT group. Urinary levels of cross-linked N-terminal telopeptide of type I collagen (NTX), serum alkaline phosphatase (ALP), face scale score (FSS, back pain), and SF-8 (QOL) were monitored. RESULTS: Urinary NTX levels significantly decreased at 3 months in the ALN group, but not in the ECT group. Serum ALP levels significantly decreased at 6 months in the both groups, with a greater reduction in the ALN group. The FSS and SF-8 significantly improved at 1, 3, and 6 months in both groups, with greater improvements in the ALN group than in the ECT group. CONCLUSIONS: ALN suppressed bone turnover, reduced back pain, and improved QOL more markedly than ECT in postmenopausal osteoporotic women with back pain.

Comparison of the effects of elcatonin and risedronate on back and knee pain by electroalgometry using fall of skin impedance and quality of life assessment using SF-36.

Back and knee pain is a widespread health problem and a serious threat to the quality of life (QOL) in middle-aged and older adults, as it frequently accompanies osteoporosis and osteoarthritis. In order to compare the effects of elcatonin and risedronate on such pain, 20 units of elcatonin was intramuscularly injected to 18 patients, and 5 mg of risedronate was orally administered daily to 20 others with similar backgrounds. Exercise-induced pain was analyzed by measuring the fall of skin impedance by electroalgometry (EAM), and subjective pain was recorded by a visual rating system (VRS) on a scale of 0 (no pain) to 100 (unbearable pain). In patients treated with elcatonin, the mean EAM-estimated pain was significantly reduced after 4, 5 and 6 months of treatment, and the VRS score after 3, 5 and 6 months, indicating a significant analgesic effect. In the risedronate group, however, improvement was less remarkable. Two-way analysis of variance using pain as a dependent variable and treatment group and time as independent variables revealed a significantly greater effect of elcatonin over risedronate on both the EAM and VRS scores, and the influence of treatment time on pain was indistinguishable between the two treatment groups. Effect of exercise load on pain was less on knee load than knee and spine load and spine load, but indistinguishable between the two groups. Changes in QOL were evaluated by the SF-36 system. Norm-based scoring showed significant improvements in 3 of 4 categories for elcatonin and in 2 of 4 for risedronate, suggesting comparable effects on the physical aspects of QOL, whereas responses to emotionally and socially directed questions indicated significant improvements in all 4 categories for risedronate, but none for elcatonin, suggesting a more physical than emotional component in elcatonin effects compared to risedronate.

Successful steroid treatment of a patient with autosomal dominant polycystic kidney disease complicated by sarcoidosis.

The patient was a 54-year-old woman with autosomal dominant polycystic kidney disease (ADPKD) who developed complicating systemic sarcoidosis. Hypercalcemia and an abrupt increase in serum creatinine levels were observed during the clinical course. Steroid therapy was initiated and produced a distinct improvement in renal function. A kidney biopsy was not feasible because ADPKD is a contraindication for renal needle biopsy. The clinical findings strongly suggested renal disorder secondary to tubulointerstitial nephritis caused by renal sarcoidosis with complicating hypercalcemia. In addition to controlling hypertension and improving the hypercalcemia and dehydration, steroid therapy also improved the renal function in this patient.

Development of High Affinity Calcitonin Analog Fragments Targeting Extracellular Domains of Calcitonin Family Receptors.

The calcitonin and amylin receptors (CTR and AMY receptors) are the drug targets for osteoporosis and diabetes treatment, respectively. Salmon calcitonin (sCT) and pramlintide were developed as peptide drugs that activate these receptors. However, next-generation drugs with improved receptor binding profiles are desirable for more effective pharmacotherapy. The extracellular domain (ECD) of CTR was reported as the critical binding site for the C-terminal half of sCT. For the screening of high-affinity sCT analog fragments, purified CTR ECD was used for fluorescence polarization/anisotropy peptide binding assay. When three mutations (N26D, S29P, and P32HYP) were introduced to the sCT(22-32) fragment, sCT(22-32) affinity for the CTR ECD was increased by 21-fold. CTR was reported to form a complex with receptor activity-modifying protein (RAMP), and the CTR:RAMP complexes function as amylin receptors with increased binding for the peptide hormone amylin. All three types of functional AMY receptor ECDs were prepared and tested for the binding of the mutated sCT(22-32). Interestingly, the mutated sCT(22-32) also retained its high affinity for all three types of the AMY receptor ECDs. In summary, the mutated sCT(22-32) showing high affinity for CTR and AMY receptor ECDs could be considered for developing the next-generation peptide agonists.