Does moderate intensity impact exercise and non-impact exercise induce acute changes in collagen biochemical markers related to osteoarthritis? - An exploratory randomized cross-over trial.

OBJECTIVE: To investigate acute changes in biochemical markers of cartilage turnover in response to moderate intensity exercise with and without joint impact in humans with knee osteoarthritis. DESIGN: We conducted a randomized, cross-over, exploratory clinical study. Twenty subjects with knee osteoarthritis (OA) were randomized, of which twenty completed 30 min of cycling and 15 completed 30 min of running on days 1 week apart. Fasting blood samples were taken before, immediately after and 1, 2, 3, and 24 h after activity was initiated. Midstream spot urine was sampled before and after activity. Serum samples were analyzed for concentrations of fragment of type II collagen degradation, C2M, fragment of type VI collagen degradation, C6M, cartilage oligomeric matrix protein, COMP, marker of type II collagen formation, PRO-C2, and urine for marker of crosslinked type II collagen degradation, CTX-II. To establish a reference, all subjects had similar samples taken during rest on a separate day. Data was analyzed in a restricted maximum likelihood based random effects linear mixed model. RESULTS: C2M trended to increase after cycling compared running (13.49%, 95%CI: -0.36-27.34%) and resting (12.88%, 95%CI: 0.2-25.6%) and the type II collagen formation/degradation ratio switched towards degradation after cycling, but not running. C6M trended to decrease after cycling (-8.1%, 95%CI: -14.8 to -1.4%) and running (-6.8%, 95%CI: -14.16-0.55%). CONCLUSION: In persons with knee OA moderate intensity exercise without joint impact may induce acute changes in circulating levels of biochemical markers reflecting type II and VI collagen degradation.

Matrix Metalloproteinase Mediated Type I Collagen Degradation - An Independent Risk Factor for Mortality in Women.

Chronic fibro-proliferative diseases are associated with nearly 45% of all deaths in the developed world. Matrix metalloproteinase (MMP) mediated remodeling of the extracellular matrix (ECM) plays an important role in disease development. Degradation of type I collagen is considered having a major role in this matter. C1M is a biomarker measuring type I collagen degradation fragments in blood. The aim of the current study was to investigate whether MMP mediated type I collagen degradation (C1M) was predictive of mortality in a large prospective cohort of Danish women aged 48-89 (n = 5855). Subjects with high serum C1M showed significant increased mortality. The adjusted three year HR was 2.02 [95% CI: 1.48-2.76] for all-cause mortality, 2.32 [95% CI: 1.51-3.56] for cancer and 1.77 [95% CI: 0.98-3.17] for cardiovascular diseases. The adjusted nine year HR was 1.50 [95% CI: 1.28-1.75] for all-cause mortality, 1.49 [95% CI: 1.16-1.90] for cancer and 1.69 [95% CI: 1.27-2.24] for cardiovascular diseases. High MMP-mediated type I collagen degradation was associated with increased mortality. Subjects with high C1M had a 2-fold increase in mortality compared to subjects with low levels of this collagen degradation product.

Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials.

PURPOSE: 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. METHODS AND DESIGN: 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). RESULTS: 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. CONCLUSIONS: The present formulation of oral sCT did not provide reproducible clinical benefits in patients with symptomatic knee OA (NCT00486434, NCT00704847).

OA phenotypes, rather than disease stage, drive structural progression--identification of structural progressors from 2 phase III randomized clinical studies with symptomatic knee OA.

BACKGROUND/PURPOSE: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.

Novel serological neo-epitope markers of extracellular matrix proteins for the detection of portal hypertension.

BACKGROUND: The hepatic venous pressure gradient (HVPG) is an invasive, but important diagnostic and prognostic marker in cirrhosis with portal hypertension (PHT). During cirrhosis, remodelling of fibrotic tissue by matrix metalloproteinases (MMPs) is a permanent process generating small fragments of degraded extracellular matrix (ECM) proteins known as neoepitopes, which are then released into the circulation. AIM: To investigate their potential as plasma markers for detection of PHT. METHODS: Ninety-four patients with alcoholic cirrhosis and 20 liver-healthy controls were included. Clinical and laboratory data of the patients were collected. All patients received HVPG measurement with blood sampling. In these samples, the following degradation or formation markers were measured: C1M (type I-collagen), C3M and PRO-C3 (type III collagen), C4M and P4NP 7S (type IV collagen), C5M (type V collagen), C6M (type VI collagen), BGM (biglycan), ELM (elastin), CRPM (CRP). RESULTS: All ECM markers except for CRPM correlated significantly with HVPG. Interestingly, C4M, C5M and ELM levels were significantly higher in patients with HVPG >10 mmHg. Multiple regression analysis identified PRO-C3, C6M and ELM as significant determinants, while the models A and B including PRO-C3, ELM, C6M and model for end-stage liver disease (MELD) provided better description of PHT (r = 0.75, P < 0.0001). The models provided odds ratios of >100 for having clinical significant PHT. CONCLUSIONS: These novel non-invasive extracellular matrix markers reflect the degree of liver dysfunction. The different degrees of portal hypertension correlated with these circulating neoepitopes. Using a single blood sample, these neoepitopes in combination with MELD detect the level of portal hypertension.

Evaluation of the efficacy, safety and pharmacokinetic profile of oral recombinant human parathyroid hormone [rhPTH(1-31)NH(2)] in postmenopausal women with osteoporosis.

CONTEXT: Treatment of osteoporosis with subcutaneous (SC) injections of rhPTH(1-34) or rhPTH(1-84) is associated with significant improvements in BMD and reductions in osteoporotic fractures. However, subcutaneous injections can be associated with discomfort and thus deteriorating compliance. OBJECTIVE: The UGL-OR1001 trial aimed to establish the efficacy and safety parameters of a novel oral tablet formulation of rhPTH(1-31)NH(2) and matching placebo tablets and open-label teriparatide positive control in postmenopausal women with osteoporosis. DESIGN: 24 weeks of randomized, double-blind treatment with once daily doses of 5mg oral treatment or corresponding placebo, or open-label subcutaneous teriparatide. PATIENTS OR OTHER PARTICIPANTS: Women diagnosed with postmenopausal osteoporosis as detected by lumbar spine DXA, with an exclusion of those with prior treatment with bone active agents. INTERVENTION(S): Orally formulated recombinant human PTH(1-31)NH(2) and placebo, or open-label subcutaneous teriparatide as a positive control. MAIN OUTCOME MEASURE(S): The primary endpoint was to characterize the percent change from baseline in bone mineral density (BMD) at L1-L4 axial lumbar spine after 24 weeks in the rhPTH(1-31)NH(2) arm. Secondary and exploratory endpoints included safety and tolerability of the oral formulation, measurement of biochemical markers of bone turnover, and evaluation of the PK profile at first and last dose. The study was registered at ClinicalTrials.gov with the identifier: NCT01321723. RESULTS: The oral tablet formulation of rhPTH(1-31)NH(2) resulted in similar PK profiles at both timepoints with mean C(max) values similar to subcutaneous administration. In the rhPTH(1-31)NH(2) arm, a 2.2% increase in lumbar spine BMD was observed compared to baseline (p<0.001), while no change was observed in the placebo arm. Open-label teriparatide resulted in a 5.1% increase in LS BMD (p<0.001). In the oral PTH study arm, the bone formation marker osteocalcin was increased by 32%, 21% and 23% at Weeks 4, 12 and 24, respectively. There was no significant increase in the level of the bone resorption marker CTx-1. CONCLUSIONS: In summary, these data demonstrate that enteric-coated oral tablet formulation technology consistently generated robust levels of exposure of rhPTH(1-31)NH(2) leading to induction of bone formation without inducing bone resorption resulting in significantly increased levels of LS BMD. Few adverse events were observed, recommending this orally delivered drug candidate for further development.

Oral salmon calcitonin reduces cartilage and bone pathology in an osteoarthritis rat model with increased subchondral bone turnover.

OBJECTIVES: Traumatic osteoarthritis (OA) is possibly augmented by effects from loss of sex hormones. Salmon calcitonin is shown to reduce OA pathogenesis and bone resorption. We investigated the effects of oral salmon calcitonin treatment and ovariectomy on cartilage and bone pathology in a traumatic OA model. METHODS: Six groups with 10 7-month-old female Sprague Dawley rats each were subjected to bilateral meniscectomy (MNX), ovariectomy (OVX) or Sham surgery and treated for 8 weeks with oral salmon calcitonin (CT) or vehicle (V) in the following way: (1) Sham+V; (2) MNX+V; (3) MNX+CT; (4) OVX+V; (5) MNX/OVX+V; (6) MNX/OVX+CT. Weights were recorded weekly and CTX-II was measured in serum. At termination 56 days post-surgery, the right tibia was analyzed for changes in articular cartilage thickness, extent of cartilage damage and subchondral bone changes in predefined zones, as recommended in the novel OARSI histopathology score. RESULTS: The combined MNX/OVX model produced a significantly reduced cartilage thickness (P=0.033) in the outer zone (Z1) of the tibial plateau and increased calcified cartilage damage (P=0.0004) and serum CTX-II (P=0.003). Addition of OVX to MNX significantly increased the width of matrix damage at the surface (P=0.025) and 50% cartilage depth (P=0.004). Treatment with oral salmon calcitonin counteracted the loss of cartilage thickness (P=0.055), significantly reduced subchondral bone damage score (P=0.019) and reduced the type II collagen degradation (P=0.009). CONCLUSIONS: Addition of ovariectomy augmented site-specific traumatic OA pathology, which was reduced by oral salmon calcitonin treatment. Treatments for OA might ideally affect both bone and cartilage.

Strontium ranelate effect in postmenopausal women with different clinical levels of osteoarthritis.

OBJECTIVE: The objective of this post hoc analysis was to investigate the effect of strontium ranelate on a cartilage degradation marker in postmenopausal women who participated in a randomized, placebo-controlled osteoporosis study. Women were stratified according to reported symptoms of osteoarthritis and to the baseline levels of a cartilage degradation marker. METHODS: The analysis included the 2617 postmenopausal women (75 years old) with osteoporosis randomized to strontium ranelate or placebo for a 36-month period. Cartilage degradation was evaluated using a validated urinary marker adjusted for creatinine (CTX-II/cr), whereas bone resorption was assessed by serum CTX-I. The presence of osteoarthritis was determined by individual interviews. RESULTS: CTX-II was significantly elevated at baseline in subjects with a history of osteoarthritis (OA+) compared to subjects who did not (OA-) (p < 0.0001), whereas CTX-I was unaffected by osteoarthritis status. Strontium ranelate caused a significant decrease from baseline in CTX-II over a 12-month period whatever the osteoarthritis status. Strontium ranelate-treated patients had a significant decrease in CTX-II compared to placebo in both OA+ and OA- groups up to 12 months, the difference remaining still significant at 36 months in patients from the OA- group (p < 0.001). CONCLUSIONS: The CTX-II profile of changes over 3 years may reflect efficacy of strontium ranelate against cartilage degradation, with an enhanced beneficial effect in subjects with early or mild clinical osteoarthritis, probably exerting its putative chondroprotective influence in early stages of the disease. Carefully controlled studies in targeted populations with early osteoarthritis are warranted to assess the role of strontium ranelate halting osteoarthritis progression.

Lessons learned from the development of oral calcitonin: the first tablet formulation of a protein in phase III clinical trials.

Oral delivery of proteins has been hampered by an array of difficulties. However, promising novel oral delivery systems have been developed. 5-CNAC, formulated with the peptide salmon calcitonin, is in phase III clinical trials for the treatment of osteoporosis or osteoarthritis and could become the first marketed oral peptide. This article reviews key findings and implications from studies undertaken to date with this oral formulation. Findings include these: (1) the optimal calcitonin tablet dose is 0.8 mg; (2) 0.8 mg of oral calcitonin is rapidly absorbed, reaching maximum concentration in 15 to 30 minutes, and is eliminated from plasma with a short half-life-9 to 15 minutes; (3) the 0.8-mg tablet is more highly absorbed than the marketed nasal formulation, with biomarker levels indicating significantly greater efficacy in suppression of bone resorption; (4) drug absorption is increased with dosing at least 10 minutes before a meal rather than postprandially and also with 50 mL of water; (5) the optimal timing of dosing for osteoporosis therapy is in the evening to mitigate the circadian peak in bone resorption; and (6) the oral formulations of synthetic and recombinant calcitonin have similar pharmacokinetic and pharmacodynamic properties. These key findings may aid researchers in the development of other oral formulations.

Serum N-Terminal Propeptide of Collagen Type I is Associated with the Number of Bone Metastases in Breast and Prostate Cancer and Correlates to Other Bone Related Markers.

BACKGROUND: A number of biomarkers have been proven potentially useful for their ability to indicate bone metastases (BM) in cancer patients. The aim of this study was to investigate the relative utility of a newly developed N-terminal propeptide of collagen type I (PINP) human serum assay for the detection of BM in cancer patients. This assay has a corresponding rat PINP assay which in the future might help in translational science between rodent and human trials. METHODS: Participants were 161 prostate, lung and breast cancer patients stratified by number of BM (Soloway score). PINP was assessed and correlated to number of BM. Additionally, the PINP marker was correlated to bone resorption of young (ALPHA CTX-I)- and aged bone (BETA CTX-I); number of osteoclasts (Tartrate-resistant acid phosphatase 5b, TRACP5B) and osteoclast activity (CTX-I/ TRACP5B). RESULTS: PINP was significantly elevated in breast- and prostate cancer patients +BM, compared to -BM (P < 0.001), however not in lung cancer patients. A strong linear association was seen between PINP and the number of BMs. Significant elevation of PINP was observed at Soloway scores 1-4 (<0 BM) compared with score 0 (0 BM) (P < 0.001). The correlation between bone resorption of young bone or aged bone and bone formation was highly significant in patients +BM and -BM (P < 0.0001). CONCLUSIONS: Data suggest that the present PINP potentially could determine skeletal involvement in patients with breast or prostate cancer. Correlations suggested that coupling between bone resorption and bone formation was maintained in breast- and prostate cancer patients.

Enzyme-linked immunosorbent serum assays (ELISAs) for rat and human N-terminal pro-peptide of collagen type I (PINP)--assessment of corresponding epitopes.

OBJECTIVES: The present study describes two newly developed N-terminal pro-peptides of collagen type I (PINP) competitive enzyme-linked immunosorbent assays (ELISAs) for the assessment of corresponding PINP epitopes in the rat- and human species. METHODS: Monoclonal antibodies were raised against corresponding rat and human PINP sequences and competitive assays were developed for each species. They were evaluated in relevant pre-clinical or clinical studies. RESULTS: The antibody characterizations indicated that PINP indeed was recognized. Technical robust assays were obtained. Rat PINP and tALP showed similar patterns in the gold standard osteoporosis rat ovariectomized (OVX) model. No liver contribution was observed in the liver fibrosis rat bile duct ligation model (BDL). In an osteoporosis study, the human serum PINP levels were significantly decreased after ibandronate treatment compared to placebo. CONCLUSIONS: The two corresponding PINP assays were specific and these bone turnover markers may improve translational science for the evaluation for bone-related diseases.

Biochemical markers identify influences on bone and cartilage degradation in osteoarthritis--the effect of sex, Kellgren-Lawrence (KL) score, body mass index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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. TRIAL REGISTRATION: Clinical trial registration number (EUDRACT2006-005532-24 & NCT00486369).

The effect of oral salmon calcitonin delivered with 5-CNAC on bone and cartilage degradation in osteoarthritic patients: a 14-day randomized study.

BACKGROUND: The aim of this study was to investigate the pharmacokinetic and pharmacodynamic parameters of oral salmon calcitonin (oSCT) administered over 14 days to men and women presenting with osteoarthritis (OA). MATERIALS AND METHODS: The study was a phase-I, 2-week, placebo-controlled, double-blind, double-dummy, randomized, gender-stratified study including 73 subjects aged 57-75 years. Patients had painful OA with a Kellgren and Lawrence index score of I-III. Treatment allocations were; 0.6 mg, 0.8 mg of oSCT, or placebo. Treatment was given twice daily for 14 days. The morning dose was administered between 07:00 and 08:00 at least 30 min before breakfast. The second dose was administered 30 min before evening dinner. On treatment day 1 and 14, the morning dose was followed by 5h of fasting, and blood samples and urine were collected immediately prior to dosing and according to the protocol. Study parameters were: plasma sCT levels, bone resorption by CTX-I (serum C-terminal telopeptide of collagen type I), bone formation by osteocalcin (serum OC), and cartilage degradation by CTX-II (urine C-terminal telopeptide of collagen type II) (clinicaltrials.gov identifier: NCT00486369). RESULTS: Doses of 0.8 mg compared with 0.6 mg produced significantly higher C(max) and AUC(0-4 hrs), of calcitonin, P=0.03. This resulted in significant reductions in CTX-I and CTX-II, [P<0.0001; P=0.007]. No differences were observed between baseline and follow-up at day 14 in pharmacokinetic and pharmacodynamic parameters. Gender had no observable influence on results. CONCLUSIONS: oSCT given twice daily with a pre-dinner and morning fasting dosing resulted in reductions in markers of bone resorption and cartilage degradation.

Biochemical markers and the FDA Critical Path: how biomarkers may contribute to the understanding of pathophysiology and provide unique and necessary tools for drug development.

The aim of this review is to discuss the potential usefulness of a novel class of biochemical markers, neoepitopes, in the context of the US Food and Drug Administration (FDA) Critical Path Initiative, which emphasizes biomarkers of safety and efficacy as areas of pivotal interest. Examples of protein degradation fragments--neoepitopes--that have proven useful for research on bone and cartilage are collagen type I and collagen type II degradation products, respectively. These markers have utility in the translational approach, as they can be used to estimate safety and efficacy in both preclinical models and clinical settings. Biochemical markers of tissue degradation may provide optimal tools, which in combination with other techniques, prove essential to drug discovery and development.

Is bone quality associated with collagen age?

The World Health Organization defines osteoporosis as a systemic disease characterized by decreased bone tissue mass and microarchitectural deterioration, resulting in increased fracture risk. Since this statement, a significant amount of data has been generated showing that these two factors do not cover all risks for fracture. Other independent clinical factors, such as age, as well as aspects related to qualitative changes in bone tissue, are believed to play an important role. The term "bone quality" encompasses a variety of parameters, including the extent of mineralization, the number and distribution of microfractures, the extent of osteocyte apoptosis, and changes in collagen properties. The major mechanism controlling these qualitative factors is bone remodeling, which is tightly regulated by the osteoclast/osteoblast activity. We focus on the relationship between bone remodeling and changes in collagen properties, especially the extent of one posttranslational modification. In vivo, measurements of the ratio between native and isomerized C-telopeptides of type I collagen provides an index of bone matrix age. Current preclinical and clinical studies suggests that this urinary ratio provides information about bone strength and fracture risk independent of bone mineral density and that it responds differently according to the type of therapy regulating bone turnover.

Increased urinary excretion of C-telopeptides of type II collagen (CTX-II) predicts cartilage loss over 21 months by MRI.

OBJECTIVE: Osteoarthritis (OA) is characterized by increased bone and cartilage metabolism leading to joint damage. The urinary excretion of C-telopeptides of type II collagen (CTX-II) has earlier predicted progression in radiographic OA (ROA)--useful for participant selection in clinical studies of potential disease modifying OA drugs (DMOADs). We investigated the longitudinal interrelationship between CTX-II and knee cartilage volume quantified from magnetic resonance imaging (MRI). METHODS: We followed 158 subjects [48% females, 36 with knee ROA at baseline (BL)] for 21 months. The Kellgren and Lawrence (KL) index and joint space width were assessed from radiographs (acquired load-bearing, semi-flexed). MRI scans were acquired from a 0.18 T Esaote scanner (40 degrees flip angle (FA), TR 50 ms, TE 16 ms, scan time 10 min, resolution 0.7 mm x 0.7 mm x 0.8 mm) and medial tibial and femoral cartilage volume was quantified. Radiographs and MRI were acquired at BL and follow-up. Fasting morning urine samples (second void) were collected for BL CTX-II measurement. RESULTS: CTX-II was 56% higher in ROA subjects (P=0.0001). In addition, elevated BL CTX-II was associated with radiographic progression (by KL or joint space narrowing) although not statistically significant. Contrarily, elevated BL CTX-II predicted longitudinal cartilage loss by MRI (middle/high tertiles had odds ratios 4.0/3.9, P<0.01) corresponding to 3.1% increased yearly cartilage loss. CONCLUSION: Prognostic markers in study selection criteria must ensure that placebo-treated participants progress to enable efficacy demonstration. And efficacy markers must allow progression detection within the study period. Our results support applying CTX-II for selection of high risk subjects and applying the fully automatic MRI-based framework for quantification of cartilage loss.

Investigation of the diurnal variation in bone resorption for optimal drug delivery and efficacy in osteoporosis with oral calcitonin.

BACKGROUND: Bone resorption displays marked diurnal variation. Reversible inhibition of bone resorption may result in best possible efficacy when bone resorption peaks. The aim of the study was to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral salmon calcitonin (sCT) and the effect of timing of drug intake. METHODS: The study was a randomized, double-blind, double-dummy, placebo-controlled, phase I study to assess the pharmacokinetic (PK) and pharmacodynamic (PD) profiles of 0.8 mg of oral sCT in healthy postmenopausal women. Totally 81 subjects were included, aimed at investigation of a morning dose given at 8:00 (n = 42), a pre-dinner dose given at 17:00 (n = 20), and an evening dose given at 22:00 (n = 19). Plasma sCT concentrations and bone resorption (C-terminal-telopeptide of collagen type I (CTX-I)) was assessed. RESULTS: Morning and pre-dinner dosing led to comparable concentration of sCT of 45 pg/ml, whereas there was a tendency towards lower Cmax for the evening dosing having a mean of 24 pg/ml. The maximum difference from placebo was observed 1 to 3 hours post-dose with a 40 to 50% suppression consequent to morning dose, and about 75% suppression after pre-dinner and evening dose, due to the increase bone resorption as a result of circadian variation. CONCLUSION: The study suggests that orally administered 0.8 mg of salmon calcitonin was effective in suppression of serum CTX irrespective of time of dosing. The pre-dinner dosing resulted in optimum efficacy response corresponding to an overall suppression of bone resorption by 25%.

Tibolone inhibits bone resorption without secondary positive effects on cartilage degradation.

BACKGROUND: Osteoarthritis is associated with increased bone resorption and increased cartilage degradation in the subchondral bone and joint. The objective of the present study was to determine whether Tibolone, a synthetic steroid with estrogenic, androgenic, and progestogenic properties, would have similar dual actions on both bone and cartilage turnover, as reported previously with some SERMS and HRT. METHODS: This study was a secondary analysis of ninety-one healthy postmenopausal women aged 52-75 yrs entered a 2-yr double blind, randomized, placebo-controlled study of treatment with either 1.25 mg/day (n = 36), or 2.5 mg/day Tibolone (n = 35), or placebo (n = 20), (J Clin Endocrinol Metab. 1996 Jul;81(7):2419-22) Second void morning urine samples were collected at baseline, and at 3, 6, 12, and 24 months. Urine CrossLaps ELISA (CTX-I) and Urine CartiLaps ELISA (CTX-II) was investigated as markers of bone resorption and cartilage degradation, respectively. RESULTS: Tibolone significantly (P < 0.001) suppressed bone resorption by approximately 60%. In contrast, no effect was observed on cartilage degradation. CONCLUSION: These data suggest uncoupling of the bone and cartilage effects of the synthetic steroid, Tibolone. Bone resorption was significantly decreased, whereas cartilage degradation was unchanged. These effects are in contrast to those observed some SERMs with effects on both bone and cartilage degradation. These effects may in part be described by the complicated pharmacology of Tibolone on testosterone, estrogen and progesterone receptors.

The effects of oral calcitonin on bone collagen maturation: implications for bone turnover and quality.

UNLABELLED: Anti-resorptive strategies may affect bone collagen maturation differently depending on the mode of action. Orally administrated calcitonin resulted in a dose dependent inhibition of bone resorption but did not change bone collagen maturation. This may reflect aspects of bone quality. INTRODUCTION: The aim of the present study was to evaluate the effect of oral calcitonin on bone collagen maturation measured as the ratio between the degradation products of newly synthesized C-telopeptides of type I collagen (alphaalphaCTX) and mature isomerized betabetaCTX in postmenopausal women. METHODS: Participants were from a phase II study. A total of 168 postmenopausal women were included and treated with placebo, 0.15, 0.4, 1, or 2.5 mg calcitonin daily. The non-isomerized alphaalphaCTX and isomerized betabetaCTX were measured in 24-hour urine samples obtained at baseline, and after 1 day, 1 month and 3 months of therapy. RESULTS: Calcitonin, significantly and dose-dependently inhibited bone resorption by up to 50% as measured by alphaalphaCTX and isomerized betabetaCTX. Bone collagen maturation measured as the ratio between alphaalphaCTX and betabetaCTX remained unchanged during treatment with calcitonin. CONCLUSIONS: Calcitonin dose-dependently and significantly reduced both alphaalphaCTX to betabetaCTX levels in urine without affecting the alphaalphaCTX to betabetaCTX ratio. This is in direct contrast to other anti-resorptive therapies, in which strong treatment-dependent effect on the endogenous age profile of bone has been observed. These data highlight that even though the treatments may have comparable effects on BMD, endogenous bone composition, which may be associated to bone quality, is strongly affected by the type of intervention, in which calcitonin display highly divergent effects from that of other anti-resorptives.