Biomarkers and personalised medicine in rheumatoid arthritis: a proposal for interactions between academia, industry and regulatory bodies.

Rheumatoid arthritis (RA) is one of the most appropriate conditions for the application of personalised medicine as a high degree of heterogeneity has been recognised, which remains to be explained. Such heterogeneity is also reflected in the large number of treatment targets and options. A growing number of biologics as well as small molecules are already in use and there are promising new drugs in development. In order to make the best use of treatment options, both targeted and non-targeted biomarkers have to be identified and validated. To this aim, new rules are needed for the interaction between academia and industry under regulatory control. Setting up multi-centre biosample collections with clear definition of access, organising early, possibly non-committing discussions with regulatory authorities, and defining a clear route for the validation, qualification and registration of the biomarker-drug combination are some of the more critical areas where effective collaboration between the drug industry, academia and regulators is needed.

Adherence to treatment of osteoporosis: a need for study.

UNLABELLED: Adherence to anti-osteoporosis medications is currently low and is associated with poor anti-fracture efficacy. This manuscript reviews the potential design of clinical studies that aim to demonstrate improved adherence, with new chemical entities to be used in the management of osteoporosis. INTRODUCTION: Several medications have been unequivocally shown to decrease fracture rates in clinical trials. However, in real life settings, long-term persistence and compliance to anti-osteoporosis medication is poor, hence decreasing the clinical benefits for patients. METHODS: An extensive search of Medline from 1985 to 2006 retrieved all trials including the keywords osteoporosis, compliance, persistence or adherence followed by a critical appraisal of the data obtained through a consensus expert meeting. RESULTS: The impact of non-adherence on the clinical development of interventions is reviewed, so that clinicians, regulatory agencies and reimbursement agencies might be better informed of the problem, in order to stimulate the necessary research to document adherence. CONCLUSION: Adherence to therapy is a major problem in the treatment of osteoporosis. Both patients and medication factors are involved. Adherence studies are an important aspect of outcomes studies, but study methodologies are not well developed at the moment and should be improved. Performing adherence studies will be stimulated when registration authorities accept the result of these studies and include the relevant information in Sect. 5.1 of the summary of product characteristics. Reimbursement authorities might also consider such studies as important information for decisions on reimbursement.

Longitudinal study of magnetic resonance imaging and standard X-rays to assess disease progression in osteoarthritis.

OBJECTIVE: To investigate, over 1-year, the relationship between X-ray and magnetic resonance imaging (MRI) findings in patients with knee osteoarthritis (OA). METHODS: Sixty-two osteoarthritic patients (46 women) were followed for 1 year. At baseline and after 1 year, volume and thickness of cartilage of the medial tibia, the lateral tibia and the femur were assessed by MRI. A global score from the multi-feature whole-organ MRI scoring system (WORMS) was calculated for each patient at baseline and after 1 year. This score combined individual scores for articular cartilage, osteophytes, bone marrow abnormality, subchondral cysts and bone attrition in 14 locations. It also incorporated scores for the medial and lateral menisci, anterior and posterior cruciate ligaments, medial and lateral collateral ligaments and synovial distension. Lateral and medial femoro-tibial joint space width (JSW) measurements, performed by digital image analysis, were assessed from fixed-flexion, postero-anterior knee radiographs. RESULTS: One-year changes in medial femoro-tibial JSW reach 6.7 (20.5) % and changes in medial cartilage volume and thickness reach 0.4 (16.7) % and 2.1 (11.3) %, respectively. Medial femoro-tibial joint space narrowing (JSN) after 1 year, assessed by radiography, was significantly correlated with a loss of medial tibial cartilage volume (r=0.25, P=0.046) and medial tibial cartilage thickness (r=0.28, P=0.025), over the same period. We found also a significant correlation between the progression of the WORMS and radiographic medial JSN over 1 year (r=-0.35, P=0.006). All these results remained statistically significant after adjusting for age, sex and body mass index. CONCLUSION: This study shows a moderate but significant association between changes in JSW and changes in cartilage volume or thickness in knee joint of osteoarthritic patients.

Osteoarthritis, magnetic resonance imaging, and biochemical markers: a one year prospective study.

OBJECTIVE: To investigate the relation between biochemical markers of bone, cartilage, and synovial remodelling and the structural progression of knee osteoarthritis. METHODS: 62 patients of both sexes with knee osteoarthritis were followed prospectively for one year. From magnetic resonance imaging (MRI), done at baseline and after one year, the volume and thickness of cartilage of the femur, the medial tibia, and the lateral tibia were assessed. A whole organ magnetic resonance imaging score (WORMS) of the knee was calculated for each patient at baseline and at the one year visits. This score consists in a validated, semiquantitative scoring system for whole organ assessment of the knee in osteoarthritis using MRI. Biochemical markers (serum hyaluronic acid, osteocalcin, cartilage glycoprotein 39 (YKL-40), cartilage oligomeric matrix protein (COMP), and C-telopeptide of type I collagen (CTX-I), and urine C-telopeptide of type II collagen (CTX-II)) were measured at baseline and after three months. RESULTS: Baseline markers were not correlated with one year changes observed in cartilage volume and thickness. However, an increase in CTX-II after three months was significantly correlated with a one year decrease in mean thickness of medial tibial and lateral tibial cartilage. Patients in the highest quartile of three month changes in CTX-II experienced a mean loss of 0.07 (0.08) mm of their medial thickness, compared with a mean increase of 0.05 (0.19) mm for patients in the lowest quartile (p = 0.04) Multiple regression analysis showed that high baseline levels of hyaluronic acid are predictive of a worsening in WORMS (p = 0.004). CONCLUSIONS: These results suggest that a single measurement of serum hyaluronic acid or short term changes in urine CTX-II could identify patients at greatest risk of progression of osteoarthritis.

Effect of high doses of oral risedronate (20 mg/day) on serum parathyroid hormone levels and urinary collagen cross-link excretion in postmenopausal women with spinal osteoporosis.

The present study describes the biological effects of risedronate, a pyridinyl bisphosphonate, on bone and assesses the safety and tolerability of risedronate when given at high doses, with or without calcium, to postmenopausal women with spinal osteoporosis. This single-center descriptive, double-blind, placebo-controlled, randomized, parallel group study included 32 postmenopausal white women with at least one radiographically confirmed vertebral compression fracture. Patients were randomized to one of four different dose regimen groups: (i) R-P, risedronate 20 mg/day for 14 days, followed by placebo for 42 days; (ii) R-CP-P, risedronate 20 mg/day for 14 days, followed by elemental calcium 1000 mg/day and placebo for 14 days, then by placebo for 28 days; (iii) R-CP-R-CP, risedronate 20 mg/day for 7 days, followed by elemental calcium 1000 mg/day and placebo for 21 days, then risedronate 20 mg/day for 7 days, and finally elemental calcium 1000 mg/day and placebo for 21 days; and (iv) P, placebo for 56 days. The biological response was investigated by measuring serum calcium, parathyroid hormone (PTH), and 2 h urinary pyridinoline/creatinine (Pyr/Cr) and deoxypyridinoline/creatinine (DPyr/Cr) ratios at baseline and at days 3, 7, 14, 21, 28, 35, 42, 49, 56, and 84. Overall, there were no consistent trends observed between the active group and placebo for serum calcium. In groups R-P, R-CP-P, and R-CP-R-CP, mean serum PTH levels were elevated above baseline values for the entire 56 day treatment period and remained elevated, although to a lesser extent, at the day 84 follow-up visit. The effect of calcium supplementation on PTH was variable. Urinary Pyr/Cr and DPyr/Cr ratios were decreased from baseline over the entire study period in all groups receiving risedronate. The maximum observed percent decreases from baseline for Pyr/Cr and DPyr/Cr were -46.9% and -58.8%, respectively, at day 49 in the R-CP-R-CP group. In conclusion, risedronate given orally at a dose of 20 mg/day, continuously for 7 or 14 days, resulted in the expected biological response in osteoporotic women. The time course of changes in PTH levels following cessation of dosing was unaffected by calcium supplementation. There was no evidence of a PTH-mediated rebound in bone resorption following cessation of therapy. Furthermore, based on collagen cross-link data, patients did not show an excessive reduction in bone turnover.

Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group.

Our objective was to investigate the efficacy and tolerability of risedronate in postmenopausal women with low bone mass. Women with a mean lumbar spine T-score of -2 or less (n = 543) received 24 months of placebo or risedronate (2.5 or 5 mg/day). All received calcium (1 g/day). The principal outcome measures were bone mineral density (BMD) at the lumbar spine, femoral neck, and femoral trochanter. At 24 months, lumbar spine BMD increased from baseline by 4% with 5 mg risedronate and 1.4% in the 2.5-mg group, compared with no change with placebo. Efficacy was similar in women who were less than 5 yr and more than 5 yr postmenopausal. At 24 months, risedronate (5 mg) had also increased BMD at the femoral neck and trochanter, whereas BMD decreased in the placebo group. BMD increases were seen at all three sites with risedronate (5 mg) after only 6 months of therapy. Risedronate was well tolerated; upper gastrointestinal adverse events were similar to placebo. We conclude that risedronate (5 mg) increases BMD rapidly and effectively and is well tolerated in postmenopausal women with low bone mass, regardless of time since menopause.

Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral Efficacy with Risedronate Therapy (VERT) Study Group.

The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n = 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p = 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease.

Efficacy and tolerability of a new formulation of oral tiludronate (tablet) in the treatment of Paget's disease of bone.

We sought to assess efficacy and safety of a new oral formulation (tablet) of tiludronate in Paget's disease of bone. We studied 128 patients with Paget's disease in an open-label uncontrolled trial. Patients received a daily dose of 400 mg oral tiludronate (two tablets). Treatment was for 6 months. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatine (OH/Cr) were measured every 3 months, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale (VAS). Statistical analysis revealed a significant reduction from baseline in SAP and OH/Cr levels, as well as VAS scores. In the whole population with evaluation under treatment, there was a reduction in initial SAP activity after 3 months (47.2 +/- 2.2%, mean +/- SEM) and 6 months (58.3 +/- 2.3%). In the population with SAP levels above twice the upper limit at inclusion and with evaluation at month 3 and month 6 (n = 96), the reduction in SAP levels was 49.3 +/- 2.4% after 3 months and of 59.5 +/- 2.6% after 6 months (ANOVA time effect, p = 0.0001). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance was good. Exhaustive biochemical investigation failed to reveal significant toxicity of tiludronate tablets at the dose of 400 mg/day. The dose of 400 mg daily of this new formulation appears to be a satisfactory tiludronate regimen for the treatment of Paget's disease of bone.

Paget's disease of bone treated with a five day course of oral tiludronate.

Chloro-4-phenyl thiomethylene bisphosphonate (tiludronate) is a new drug which can be used as an inhibitor of bone resorption. As it remains in bone for a long time, and as mineralisation defects have only been seen at doses much higher than those required to decrease osteoclastic activity, it could be given at high doses over a short period of time. Eighteen patients with Paget's disease of bone were randomly allocated to three therapeutic groups receiving respectively 600, 800, and 1200 mg/day tiludronate for five days. Serum alkaline phosphatase activity and the urinary hydroxyproline/creatinine ratio were quickly and drastically reduced in all three groups. A significant reduction of serum alkaline phosphatases and the hydroxyproline/creatinine ratio was still present six months after the five day therapeutic course, reflecting a sustained activity of tiludronate even after stopping treatment. Dose dependent short and long term reductions of bone turnover rate were observed. Biochemical assessment of haematological, renal, or hepatic tolerance did not show any toxicity of tiludronate. Fifty per cent of patients treated by a dose of 1200 mg/day reported gastrointestinal disturbances, however, making this dosage unsuitable for clinical practice.

Evaluation of the efficacy and safety of oral tiludronate in Paget's disease of bone. A double-blind, multiple-dosage, placebo-controlled study.

OBJECTIVE: To assess the optimal dosage of oral tiludronate in Paget's disease of bone. METHODS: We studied 149 patients with Paget's disease, in a double-blind, randomized, placebo-controlled trial. Patients were randomly assigned to 1 of 5 therapeutic groups: a daily dose of 100 mg, 200 mg, 400 mg, or 800 mg of oral tiludronate, or a placebo. Treatment was for 3 months, followed by 3 months of placebo-controlled followup. Serum alkaline phosphatase activity (SAP) and fasting urinary excretion of hydroxyproline/creatinine (OH/Cr) were measured monthly, as were biochemical parameters reflecting renal, hepatic, and hematologic functions. Analgesic efficacy was self-evaluated from a visual analog scale and a global pain index. RESULTS: Statistical analysis revealed that beginning at a dosage of 200 mg/day, there was a direct dose-dependent effect on the reduction of SAP and OH/Cr levels. Reduction of SAP levels was clinically significant at a dosage of 400 mg (44.9 +/- 4.2% reduction at 90 days and 49.2 +/- 4.5% at 180 days, mean +/- SEM) and at 800 mg (53.4 +/- 5% at 90 days and 59.3 +/- 4.6% at 180 days). There was a significant reduction in pain in all groups, including the group taking placebo. In only those taking 800 mg/day of tiludronate was there a significant frequency of complete resolution of pain (versus placebo). Aside from mild gastrointestinal disturbances, as experienced with other oral bisphosphonates, clinical tolerance of all 5 regimens was good. Exhaustive biochemical investigations failed to reveal significant toxicity of tiludronate up to the 800-mg daily dose investigated. CONCLUSION: Because of its significantly better antiresorptive effects and greater analgesic properties (compared with lower dosages), combined with the excellent clinical and biochemical tolerance, the 800-mg daily dose of tiludronate appears to be optimal for the treatment of Paget's disease of bone.

Prevention of postmenopausal bone loss by tiludronate.

76 healthy women, who had been menopausal for less than 96 months and who had never received any form of treatment to prevent bone loss, were entered into a randomised double-blind study. For the first 6 months, half the patients received tiludronate 100 mg daily, while the others received placebo. During the second 6 months, all patients received placebo. Bone mineral density of the lumbar spine decreased significantly by 2.1% (SE 0.8%) in the placebo group and did not significantly change in the tiludronate group (+1.33 [0.8]%). The difference in response between the groups was significant, as were the differences between values for corrected urinary hydroxyproline and calcium. Treatment with tiludronate was not followed by increased secretion of parathyroid hormone. A 6 month course of oral tiludronate may counteract postmenopausal bone loss for at least a year by decreasing bone resorption.

[Scintigraphic study of reflex algodystrophy]. / Etude scintigraphique des algodystrophies réflexes.

Isotope investigation of reflex sympathetic dystrophy is not limited to an evaluation of bony up-take, it also includes examination of the early dynamic scintigraphy of the vessels. The late views of bone scans reflect, above all, the bone's affinity for phosphate complexes i.e. the degree of osteoblast activity. Generally, dystrophies, independent of their site, show increased locoregional uptake, often quite intense, which appears early in the course of the disease. This supports histopathological findings. There are several advantages in using the bone scan in the investigation of reflex dystrophy: early diagnosis before the development of radiological signs, precise evaluation of the local extension of the dystrophic process and detection of the incidence of multifocal forms, follow-up of the course of the disease, definition of new clinical forms: patchy algodystrophy partial, decalcifying dystrophy, sub-radiological dystrophy, the aetiology in certain sites (especially the hip). Early dynamic scans that dystrophy is accompanied by an increase in the vascular compartment and decreased circulatory flow, a sign of the local stage of the disease. There is also an increase of the interstitial compartment, greater than that of the vascular compartment, explaining the presence of edema. The pathophysiological information gained from dynamic studies is matched by the therapeutic information: evaluation, or even prediction, of the effect of a given drug (cortisone, calcitonin).