calcitonin and Osteoarthritis--Knee

Osteoarthritis (OA) is a disease with multiple endotypes. A hallmark of OA is loss of cartilage; however, it is evident that the rate of cartilage loss differs among patients, which may partly be attributed to differential capacity for cartilage repair. We hypothesize that a low cartilage repair endotype exists and that such endotypes are more likely to progress radiographically. The aim of this study is to examine the associations of level of cartilage formation with OA severity and radiographic OA progression. We used the blood-based marker PRO-C2, reflecting type II collagen formation, to assess levels of cartilage formation.. The type II collagen propeptide PRO-C2 was measured in the serum/plasma of knee OA subjects from New York University (NYU, n = 106) and a subcohort of the phase III oral salmon calcitonin (sCT) trial SMC021-2301 (SMC, n = 147). Risk of radiographic medial joint space narrowing (JSN) over 24 months was compared between quartiles (very low, low, moderate, and high) of PRO-C2. Associations were adjusted for age, gender, BMI, race, baseline pain levels, and baseline joint space width.. In both the NYU and SMC cohorts, subjects with low PRO-C2 levels had greater JSN compared with subjects with high PRO-C2. Mean difference in JSN between subjects with very low and high levels of PRO-C2 was 0.65 mm (p = 0.002), corresponding to a 3.4 (1.4-8.6)-fold higher risk of progression. There was no significant effect of sCT treatment, compared with placebo, on JSN over 2 years before stratification based on baseline PRO-C2. However, there were proportionately fewer progressors in the sCT arm of the very low/low PRO-C2 group compared with the moderate/high group (Chi squared = 6.5, p = 0.011).. Serum/plasma level of type II collagen formation, PRO-C2, may be an objective indicator of a low cartilage repair endotype, displaying radiographic progression and superior response to a proanabolic drug.. Level III post hoc exploratory analysis of one longitudinal cohort and a sub-study from one phase III clinical trial.

Topics: Aged; Biomarkers; Bone Density Conservation Agents; Calcitonin; Calcium-Binding Proteins; Cartilage, Articular; Chondrogenesis; Cohort Studies; Collagen Type II; Disease Progression; Female; Humans; Male; Middle Aged; Osteoarthritis, Knee; Predictive Value of Tests; Radiography

The aim of this study was to identify key characteristics of disease progression through investigation of the association of radiographic progression over two years with baseline Joint Space Width (JSW), Kellgren-Lawrence (KL) grade, Western Ontario and McMaster Universities Arthritis Index (WOMAC) pain, Joint Space Narrowing (JSN), and BMI.. Data from 2206 subjects (4390 knees) were combined for this post-hoc analysis of two randomized, double-blind, multi-center, placebo-controlled phase III trials (NCT00486434 and NCT00704847) that evaluated the efficacy and safety of 2-years treatment with oral salmon calcitonin of subjects with painful knee osteoarthritis (OA).. There was a clear positive and significant correlation between KL grade and WOMAC pain and total WOMAC, albeit the variance in pain measures was from min-to-max for all KL categories, emphasizing the heterogeneity of this patient population and pain perception. 32% of target knees did not progress, and only 51% had changes over minimum significant change (MSC). BMI, KL-Score and WOMAC pain was diagnostic, but only KL-score and pain had prognostic value, albeit pain in a non-linear manner.. These data clearly describe significant associations between KL grade, JSW, pain and BMI in patients with symptomatic knee OA. KL grade, BMI and WOMAC pain were diagnostically associated with OA based on JSW but only KL-score and pain in a non-linier fashion was prognostic. 50% of patients did not progress more than MSC, highlighting the importance for identification of structural progressors and the phenotypes associated with these. These results suggest that disease phenotypes, rather than disease status, are responsible for disease progression.

Topics: Aged; Arthralgia; Body Mass Index; Bone Density Conservation Agents; Calcitonin; Disease Progression; Double-Blind Method; Female; Humans; Incidence; Knee Joint; Male; Middle Aged; Osteoarthritis, Knee; Pain Measurement; Phenotype; Prognosis; Radiography; Treatment Outcome

To evaluate the structure-modifying and symptom efficacy, as well as safety and tolerability of oral salmon calcitonin (sCT) formulated with a 5-CNAC carrier (a molecule based on Eligen(®) technology), in osteoarthritis (OA) patients with moderate to severe knee pain and joint structural damage classified as Kellgren and Lawrence (KL)2-3.. This is the combined reporting of two randomized, double-blind, multi-center, placebo-controlled trials (CSMC021C2301 and CSMC021C2302), evaluating the efficacy and safety of oral sCT in patients with painful knee OA with structural manifestations, enrolling 1176 and 1030 patients, respectively. Study subjects were randomized (1:1) to oral sCT 0.8 mg twice daily or placebo (PBO) for 24 months. The primary efficacy objectives were to examine the treatment effect compared to placebo on change over 24 months in joint space width (JSW) in the signal knee measured by X-ray, and to examine the change in pain and function using the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) questionnaire. Other study parameters included patient and physician global assessment, and biochemical markers of bone (CTX-I) and cartilage degradation (CTX-II).. At the 24 month endpoint there was no statistically significant treatment effect on joint space narrowing (JSN) in any of the two studies. In CSMC021C2301 there was a treatment effect on WOMAC (sum of pain, function, stiffness, and total scores) as well as on the biomarkers of bone and joint metabolism, but due to the hierarchical testing procedure the treatment effect was not claimed statistically significant.. The present formulation of oral sCT did not provide reproducible clinical benefits in patients with symptomatic knee OA (NCT00486434, NCT00704847).

Topics: Administration, Oral; Aged; Biomarkers; Bone Density Conservation Agents; Calcitonin; Collagen Type I; Collagen Type II; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Knee Joint; Male; Middle Aged; Osteoarthritis, Knee; Peptide Fragments; Peptides; Radiography; Treatment Outcome

This study was conducted to determine if nasal salmon calcitonin has additional beneficial effects on clinical symptoms, serum NO, IL-1β, matrix metalloproteinase 3, urinary C-terminal telopeptide type II collagen (CTX-II) levels and MRI findings in knee osteoarthritis (OA) when used concomitantly with exercise therapy. Fifty female patients with knee OA were randomized into two groups. The first group (n = 30) received 200 IU/day nasal salmon calcitonin and a home exercise program; the second group (n = 20) received a home exercise program for 6 months. Compared with baseline,while significant improvements were observed in visual analogue scale (VAS), WOMAC pain, physical function scores, 20-m walking time (P < 0.001) and WOMAC stiffness score (P = 0.041) in the first group, walking and resting VAS, and WOMAC physical function scores were improved (P = 0.029) in the second group after treatment. Significantly increased levels of serum NO and urinary CTX-II (P < 0.001) and significant improvements in the area of medial femoral condyle (P < 0.05) were noted only in the first group. There were significant differences in VAS activation values (P = 0.032) and NO levels (P < 0.001) in the favor of the first group. In conclusion, nasal salmon calcitonin may have possible chondroprotective effects besides its known effects on symptoms in patients with knee OA.

Topics: Aged; Bone Density Conservation Agents; Calcitonin; Collagen Type II; Exercise Therapy; Female; Humans; Interleukin-1beta; Magnetic Resonance Imaging; Matrix Metalloproteinase 3; Middle Aged; Nitric Oxide; Osteoarthritis, Knee; Peptide Fragments; Radiography; Respiratory Therapy; Severity of Illness Index; Treatment Outcome; Walking

Osteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation.. This study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I), or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II) were investigated.. At baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men (p = 0.04 and p = 0.06, respectively). Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women (p = 0.007). BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 (p = 0.002), but showed only a borderline positive correlation to CTX-II, r = 0.25 (p = 0.12). Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p < 0.001) between changes in both CTX-I and CTX-II was seen. In the placebo group a weakly significant correlation between changes in both markers was found on day 1 (r = 0.49, p = 0.02), but not on day 14.. Bone resorption was higher in females than males, while cartilage degradation was correlated with increasing KL-score and only weakly associated with BMI. Bone and cartilage degradation were not correlated in untreated individuals, but dosing with oral sCT with or without food, and a mid-day meal, decreased bone and cartilage degradation and induced a correlation between both markers. Changes in bone and cartilage markers may aid in the identification of potential new treatment opportunities for OA.. Clinical trial registration number (EUDRACT2006-005532-24 & NCT00486369).

Topics: Administration, Oral; Aged; Animals; Biomarkers; Body Mass Index; Bone and Bones; Bone Density; Calcitonin; Cartilage, Articular; Circadian Rhythm; Disease Progression; Double-Blind Method; Female; Humans; Knee Joint; Male; Middle Aged; Osteoarthritis, Knee; Outcome Assessment, Health Care; Placebos; Predictive Value of Tests; Salmon; Severity of Illness Index; Sex Characteristics

To evaluate the effects of oral salmon calcitonin (sCT) on Lequesne's algofunctional index scores and on biomarkers of joint metabolism in knee osteoarthritis.. In this randomized, double-blind trial, patients received either placebo (n = 18), 0.5 mg of sCT (n = 17), or 1 mg of sCT (n = 18) daily for 84 days. Biomarkers included C-telopeptide of type II collagen (CTX-II), type II collagen neoepitope C2C, collagenases (matrix metalloproteinase 1 [MMP-1], MMP-8, and MMP-13), stromelysin (MMP-3), tissue inhibitors of metalloproteinases 1 and 2, and hyaluronan. Statistical analysis included nonparametric tests.. A total of 41 patients completed the study (13 in the group receiving 0.5 mg of sCT and 14 in each of the other 2 other groups). Although, on day 84, patients in both the placebo group and the group receiving 1 mg of sCT exhibited a similar significant decrease in pain scores, a significant reduction in the function score was observed only in the 2 sCT groups. On day 84, there was no significant decrease in biomarker levels in the placebo group, whereas significant reductions in the levels of both MMP-3 and hyaluronan were observed in the 2 sCT groups. The group of patients receiving 1 mg of sCT exhibited significant decreases in the levels of CTX-II, C2C, and MMP-13.. By improving functional disability and by reducing levels of biomarkers that are thought to be predictive of joint space narrowing (and thus cartilage loss), oral sCT at a dose of 1 mg might be a useful pharmacologic agent in human knee OA.

Topics: Aged; Aged, 80 and over; Biomarkers; Calcitonin; Collagen Type II; Double-Blind Method; Female; Gene Expression Regulation; Humans; Hyaluronic Acid; Knee Joint; Male; Matrix Metalloproteinase 13; Matrix Metalloproteinase 3; Middle Aged; Osteoarthritis, Knee; Pain; Severity of Illness Index; Treatment Outcome

There is a continuous search for a better therapy in osteoarthritis (OA) management. Therefore, this study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3) relative to diclofenac sodium (DF) in induced knee osteoarthritic male Wistar rats.. The 40 rats that were used in this study were divided into 8 groups (n=5 rats), viz: Normal control; OA control; OA+N-3; OA+Low dose of Sct (Sct.Lw); OA+High dose of Sct (Sct.Hi); OA+N-3+SCt.Lw; OA+N-3+Sct.Hi; and, OA+DF. OA was induced with 4 mg of sodium monoiodoacetate in 40 μL of saline. The solution was injected into the left knee joint space of anaesthetised rats. Sct was administered at 2.5 and 5.0 IU/kg b.w. (im), whereas N-3 and DF were administered at 200 and 1 mg/kg b.w. (p.o.), respectively. Treatments commenced 9 days after the induction of OA, and they lasted for 28 days.. Sct and/or N-3 significantly reduced c-telopeptide of type 1 collagen (CTX-1), collagen type 2 α-1 (C2M), malondialdehyde (MDA), uric acid (UA), and interleukin-6 (IL-6), but, significantly increased superoxide dismutase (SOD) after OA induction. Both therapies had additive effects on C2M, MDA, SOD, and catalase (CAT), but, non-additive actions on UA, IL-6, and CTX-1. Like the Sct and N-3, DF significantly reduced CTX-1, C2M, UA, and IL-6. However, it had no significant effect on SOD and MDA, even though it significantly reduced CAT activity. None of the therapies had significant effect on total alkaline phosphatase activity, except N-3+Sct.Lw.. The combined, and sometimes the single administration of Sct and N-3 proved to be better therapies in OA management than DF.

Topics: Alkaline Phosphatase; Animals; Calcitonin; Collagen Type I; Collagen Type II; Diclofenac; Dose-Response Relationship, Drug; Drug Therapy, Combination; Fatty Acids, Omega-3; Interleukin-6; Iodoacetic Acid; Male; Malondialdehyde; Osteoarthritis, Knee; Rats; Superoxide Dismutase; Uric Acid

It has been opined that a combined therapeutic approach should be considered in the optimal management ofosteoarthritis (OA). Therefore, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids (N-3), relative to diclofenac sodium (DF) on selected biochemical parameters in induced osteoarthritic rats. Forty (40) adultmale Wistar rats were used for this study. The rats were divided into 8 groups (n=5), viz: Group 1-Normal control; Group 2-OA control; Group 3-OA+N-3 (200 mg/kg, p.o.); Group 4-OA + low dose of Sct (Sct.Lw-2.5 IU/kg, i.m.); Group 5-OA +high dose of SCT (Sct.Hi-5.0 IU/kg, i.m.); Group 6-OA+N-3+Sct.Lw; Group 7-OA+N-3+Sct.Hi; and, Group 8-OA+DF (1mg/kg, p.o.). Osteoarthritis was induced with 4 mg of sodium monoiodoacetate in 40 µl of saline. The solution was injectedintra-articularly into the left knee joint space of anaesthetised (sodium pentobarbital - 40 mg/kg, i.p.) rats. Nine (9) daysafterwards, treatments started, and they lasted for 28 days. The results showed that Sct has hypocalcaemic, hypocortisolism,and anti-dyslipidaemic effects. It significantly inhibited nitric oxide (NO) production and insulin release. Like Sct, N-3 havehypocortisolism and anti-dyslipidaemic actions. Nevertheless, they caused significant increases in hepatic glycogen contentand plasma levels of calcium ion, insulin and NO. Although DF was also observed to stimulate insulin release and NOsynthesis, it significantly increased plasma level of LDL-c, but significantly decreased HDL-C. In conclusion, N-3 annul theundesirable effect of Sct, presenting it as a better anti-arthritic drug. Moreover, the combined administration of bothpharmacological agents proffer preferable therapeutic benefits in OA condition relative the single or DF therapy.

Topics: Animals; Antioxidants; Biomarkers; Calcitonin; Fatty Acids, Omega-3; Insulin; Knee Joint; Lipids; Osteoarthritis, Knee; Rats, Wistar

The aim of this project was to perform an empirical evaluation of the impact of on site source data verification (SDV) on the data quality in a clinical trial database to guide an informed decision on selection of the monitoring approach.. We used data from three randomized phase III trials monitored with a combination of complete SDV or partial SDV. After database lock, individual subject data were extracted from the clinical database and subjected to post hoc complete SDV. Error rates were calculated with focus on the degree of on study monitoring and relevance and analyzed for potential impact on end points.. Data from a total of 2566 subjects including more than 3 million data fields were 100% source data verified post hoc. An overall error rate of 0.45% was found. No sites had 0% errors. 100% SDV yielded an error rate of 0.27% as compared with partial SDV having an error rate of 0.53% (P < 0.0001). Comparing partly and fully monitored subjects, minor differences were identified between variables of major importance to efficacy or safety.. The findings challenge the notion that a 0% error rate is obtainable with on site monitoring. Data indicate consistently low error rates across the three trials analyzed. The use of complete vs. partial SDV offers a marginal absolute error rate reduction of 0.26%, i.e. a need to perform complete SDV of about 370 data points to avoid one unspecified error and does not support complete SDV as a means of providing meaningful improvements in data accuracy.

Topics: Calcitonin; Clinical Trials, Phase III as Topic; Data Accuracy; Databases, Factual; Electronic Health Records; Female; Forms and Records Control; Humans; Osteoarthritis, Knee; Osteoporosis, Postmenopausal; Randomized Controlled Trials as Topic

There has been a recent interest in calcitonin as a potential treatment for osteoarthritis, based on its metabolic activities in both bone turnover and cartilage. The aim of this study was to evaluate the effects of nasal form calcitonin on knee osteoarthritis and quality of life in women who receive calcitonin treatment for postmenopausal osteoporosis. Two hundred and twenty postmenopausal women, aged between 55 and 65 years with knee pain and knee osteoarthritis, graded II-III by using Kellgren-Lawrence radiographic scoring system, were included. Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, the quality of life questionnaire of the European Foundation for Osteoporosis (QALEFFO-41) and visual analog scale were used for the algofunctional assessments. Need of rescue analgesic was recorded. Pain (P < 0.001), stiffness (P < 0.05), functional capability (P < 0.05) and total score of WOMAC (P < 0.05) revealed statistically significant improvements after 3 months of the treatment and remained consistent throughout 1 year of the treatment period. Participants experienced significant reductions in WOMAC perceptions of pain (-53 %), joint stiffness (-44 %) and limitations in physical function (-49 %) at the end of 1 year of calcitonin treatment. Need of rescue analgesic intake was reported to have decreased approximately by 60 % at the end of the 1-year treatment period. QUALEFFO_41 scores improved: 37.6 (baseline), 30.9 (3 months), 28.0 (6 months) and 24.4 (1 year). In conclusion, nasal calcitonin treatment provided dual action on osteoporosis and osteoarthritis with significant improvements in quality of life and algofunctional results in knee osteoarthritis.

Topics: Administration, Intranasal; Aged; Bone Density; Bone Density Conservation Agents; Calcitonin; Chondrocytes; Female; Humans; Middle Aged; Osteoarthritis, Knee; Quality of Life