A systematic review of the clinical trials in osteoarthritis registered on the public website of the Clinical Trials Data Bank at the National Institutes of Health (NIH) has been performed. Such a review should cover the majority of the ongoing or forthcoming trials in the disease. This review focusses on trials designed to test safety and/or efficacy of targeted therapies in osteoarthritis.
Osteoarthritis (OA) represents a major therapeutic challenge. It is related, at least in part, to the lack of effective therapies able to alter the natural history of OA progression. Concerning the symptomatic drugs, they are currently centred on the use of acetaminophen, a poorly effective drug, and non-steroidal anti-inflammatory drugs (NSAIDs), more effective than acetaminophen but with a higher risk profile. Thus, as in rheumatoid arthritis or in ankylosing spondylitis, the future for better effective symptomatic and/or disease-modifying drugs with a better benefit/risk ratio will certainly come from a better understanding of the pathophysiology of the disease to test specific targets involved in pain and in joint degradative processes . In fact, although the optimum design for trials with a potential disease-modifying drug for OA is not yet decided among experts, several companies and institution are testing novel synthetic or biological compounds right now.
The National Institutes of Health (NIH), through its National Library of Medicine (NLM) and with input from the Food and Drug Administration (FDA) and others, developed the Clinical Trials Data Bank. The first version of the Clinical Trials Data Bank was made available to the public on 29 February 2000, on the Internet ( www.clinicaltrials.gov ). The website www.ClinicalTrials.gov facilitates registration of trials in accordance with the International Committee of Medical Journal Editors (ICMJE) initiative requiring prior entry of clinical trials in a public registry as a condition for publication. Therefore, a systematic review of the clinical trials registered in this database should cover the majority of the ongoing or forthcoming trials in a pre-defined disease. This review focusses on trials registered on www.clinicaltrials.gov for treating OA.
Methodology
An exclusive search on www.clinicaltrials.gov using the single search term “osteoarthritis” was performed. The study list was screened and those studies that fit with the definition of a targeted therapy were included. The usual definition of a targeted therapy is a specifically designed treatment to interfere with a specific point in the pathogenesis of a disease. By this way, behavioural interventions, NSAIDs, acetaminophen, tramadol, opioids, nutraceuticals and antidepressants were excluded. In addition, it was decided to exclude devices, procedures and cell therapies in order to focus this analysis on the pharmaceutical compounds. Registered but terminated studies before inclusion were not analysed.
Results
The flow diagram about the results of search and their inclusion for the review are shown in Fig. 1 . As on 5 August 2009, a total of 744 potential studies were identified. Studies were excluded because of a non-pharmacological approach and 267 more studies were also excluded because they did not fit with the definition of a targeted therapy. Of the remaining studies, 33 trials corresponded to the inclusion/exclusion criteria.
1- Targeted symptomatic drugs (Table 1)
| Target | Drug | Mechanism of action | Phase | NCT | Sponsor |
|---|---|---|---|---|---|
| NGF | Tanezumab (RN624/PF-04383119) | Monoclonal Ab anti-NGF | II | 00669409 | Pfizer |
| III | 00863772 | ||||
| 00809783 | |||||
| 00733902 | |||||
| 00744471 | |||||
| 00830063 | |||||
| 00863304 | |||||
| 00864097 | |||||
| 00809354 | |||||
| PG110 | Fully humanized monoclonal Ab anti-NGF | I | 00941746 | PanGenetics UK Limited | |
| Cannabinoid receptor-2 | GW842166 | Non cannabinoid CB2 agonist | II | 00479427 | Glaxo-Wellcome |
| iGluR5 | LY545694 | Synthetic iGluR5 antagonist | II | 00790790 | Eli Lilly |
| TRPV1 | ALGRX-4975 | TRPV1 agonist | II | 00667654 | AlgoRx Pharmaceuticals |
| Bradykinin B2 receptor | Icatibant | B2-kinin receptor antagonist | II | 00303056 | Sanofi Aventis |
1-a NGF (Nerve Growth Factor)
– Description of the target
Nerve growth factor (NGF) is the founding member of the neurotrophin family of structurally related secreted proteins that includes brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT-3) and NT-4. Mature neurotrophins bind to two types of receptors: a common receptor, p75NTR, which binds all neurotrophins with a similar affinity, and members of the trk family of receptor tyrosine kinases, trkA, trkB and trkC, which bind different neurotrophins. TrkA is the receptor tyrosine kinase for NGF . NGF levels are elevated in several painful conditions in humans, including arthritis. Administration of NGF provokes pain and hyperalgesia after local or systemic administration. Inhibition of NGF function reduces pain and hyperalgesia in several animal models .
– Tanezumab (RN624/PF-04383119) (RINAT Neurosciences, Pfizer)
Description of the drug : Tanezumab is a monoclonal antibody raised against NGF.
Phase II studies:
NCT00669409
This is a randomised, placebo-controlled, double-blind, dose-escalation, multicentre study of the safety, tolerability, efficacy and pharmacokinetics of a single intravenous dose of PF-04383119 (10, 25, 50, 100 and 200 mcg kg −1 ) in Japanese patients with moderate-to-severe pain from OA of the knee. The primary outcome measures are safety assessments, Western Ontario and McMaster Universities Osteoarthritis index (WOMAC), visual analogue scale (VAS) for index knee pain during walking in the past 24 h, VAS for index knee pain in the past 24 h and VAS for current index knee pain at 120 days.
Phase III studies:
NCT00863772
This is a randomised, double-blind, placebo-controlled multicentre study of tanezumab (5 and 10 mg every 8 weeks for 6 months, on peripheral nerve function in patients with knee OA. The primary outcome measure is the change from baseline in the composite measure (5NC, the mean sum score of five attributes of nerve conduction + HRdb, the measurement of heart rate variation during forced breathing).
NCT00809783
This is a multicentre, randomised, long-term study of the safety of tanezumab (2.5, 5 or 10 mg) in patients with OA of the knee or hip. The primary outcome measures are haematology, electrocardiogram, clinical chemistry and adverse events during 1 year.
NCT00733902
This is a 16-week randomised, double blind, placebo-controlled, multicentre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 2.5, 5 or 10 mg at one dose every 8 weeks) in patients with OA of the knee. The primary outcome measures are WOMAC function and WOMAC pain at week 16.
NCT00744471
This is a 16-week randomised, double blind, placebo-controlled, multicentre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 2.5, 5 or 10 mg at one dose every 8 weeks) in patients with OA of the hip. The primary outcome measures are WOMAC function, patient global assessment of arthritis and WOMAC pain at week 16.
NCT00830063
This is a 16-week randomised, double-blind, placebo- and naproxen (1 g daily)-controlled multicentre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 5 or 10 mg one dose at week 0 and 8) in patients with OA of the knee. The primary outcome measures are WOMAC function, patient global assessment of arthritis and WOMAC pain at week 12 and week 16.
NCT00863304
This is a 16-week randomised, double-blind, placebo- and naproxen (g daily)-controlled multicentre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 2.5, 5 or 10 mg every 8 weeks through week 16) in patients with OA of the hip. The primary outcome measures are WOMAC function, patient global assessment of arthritis and WOMAC pain at week 12 and week 16.
NCT00864097
This is a 24-week randomised, double-blind, controlled, multicentre study of the analgesic efficacy and safety of tanezumab (IV tanezumab 5 or 10 mg one dose at week 0 and 8) added on to diclofenac SR (75 mg BID through week 32) in patients with OA of the knee or hip. The primary outcome measures are WOMAC function, patient global assessment of arthritis and WOMAC pain at week 24.
NCT00809354
This is a 1-year multicentre, randomised, double-blind, controlled study of the long-term analgesic efficacy and safety of tanezumab alone (IV tanezumab 5 or 10 mg every 8 weeks (through week 48)) or in combination with non-steroidal anti-inflammatory drugs (NSAIDs) (oral naproxen 500 mg BID for 56 weeks or oral celecoxib 100 mg BID for 56 weeks) versus NSAIDs alone in patients with OA of the knee or hip. The primary outcome measures are WOMAC function, patient global assessment of arthritis and WOMAC pain at week 16.
– PG110 (PanGenetics UK Limited)
Description of the drug : PG110 is a fully humanised anti-NGF monoclonal antibody. It prevents the interaction of NGF with its receptors, the high-affinity receptor TrKA and the low affinity receptor p75. PG110 does not cross-react with other neurotrophins and exerts its inhibiting activity at lower than equimolar ratios with respect to NGF.
Phase I study:
NCT00941746
This is a randomised, double-blind, placebo-controlled, single ascending dose study to evaluate the safety, tolerability and pharmacokinetics of PG110 in patients with pain attributed to OA of the knee. The primary outcome measure is the number and severity of adverse events. The result of this study, which will be double-blind, placebo controlled, are expected in mid-2010.
1-b Cannabinoid receptor-2 (CB2)
– Description of the target
Cannabinoid receptors CB1 and CB2 belong to the family of G-protein-coupled receptors, and bind exogenous ligands derived from Cannabis sativa as well as endogenous arachidonic-derived ligands (endocannabinoids). CB2 receptors are primarily expressed in cells of the immune system, including macrophages, and regulate the inflammatory response in various settings. CB2-selective agonists display antinociceptive activity in well-validated models of acute pain, persistent inflammatory pain, postoperative pain, cancer pain and neuropathic pain .
– GW842166 (Glaxo-Wellcome)
Description of the drug : GW842166 is a non-cannabinoid CB2 agonist.
Phase II study:
NCT00479427
This is a double-blind, two-period, placebo-controlled cross-over to evaluate the efficacy and the safety of GW842166 in knee OA patients in a Phase IIa study. The primary outcome measure is the change in pain scores from baseline to the end of treatment using WOMAC on the pain subscore for 6–8 weeks.
1-c iGluR5 antagonists
– Description of the target
A variety of studies has indicated the involvement of kainate receptors in nociception. Kainate receptors are constituted by the low-affinity iGluR5, iGluR6 and iGluR7 and the high-affinity KA1 and KA2 subunits, which form different homomeric or heteromeric assemblies, giving rise to functional receptors .
– LY 545694 (Eli Lilly)
Description of the drug : Ly 545694 is a synthetic iGluR5 antagonist.
Phase II study:
NCT00790790
This is a randomised, double-blind, placebo-controlled study of the effects of LY545694 in the treatment of subjects with OA knee pain. The primary outcome measure is the 24-h average pain score, weekly mean from electronic diary from baseline through 5 weeks.
1-d TRPV1 agonists
– Description of the target
The transient receptor potential (TRP) superfamily of ion channels comprises proteins with six transmembrane domains and cytoplasmic N- and C-termini. TRP proteins assemble as homo- or heterotetramers to form cation-permeable ion channels . Currently, 28 TRP channels have been discovered in mammals, and, based on their sequence homology, are classified into six subfamilies: TRPC, TRPV, TRPM, TRPA, TRPP and TRPML. The vanilloid receptor TRPV1 is a homotetrameric, non-selective cation channel abundantly expressed in the nociceptors (c-fibres). TRPV1 is the obligate receptor for capsaicin, the spicy ingredient in hot chilli peppers . TRPV1 is considered as a highly validated pain target because (i) its agonists such as capsaicin cause desensitisation of TRPV1 channels that relieves pain behaviours in preclinical species and ii) its antagonists relieve pain behaviours in rodent models of inflammation, OA and cancer. Hence, both agonists and antagonists of TRPV1 are being evaluated as potential analgesics in clinical trials.
– ALGRX-4975 (AlgoRx Pharmaceuticals)
Description of the drug : ALGRX-4975 (Adlea*) is a highly purified form of capsaicin (derived from chilli peppers) that acts on TRPV-1 receptors. Adlea* acts as a TRPV-1 agonist to these pain receptors. Importantly, after initial stimulation, desensitisation of the TRPV-1 receptors blocks noxious pain with no effect on adaptive pain or position sense. This leads to a prolonged, reversible and localised desensitisation of the pain fibres. The drug generally has a short half-life of 1–2 h when absorbed into the blood stream, and is undetectable in the blood after 24 h.
A single intra-articular injection of 4975 (dose range: 5 ml of 0.002, 0.02 and 0.06 mg ml −1 ) in patients with end-stage OA of the knee, waiting for knee replacement, revealed no safety concerns and showed a non-statistically significant decrease in VAS pain scores . Further, in a second trial in patients with end-stage OA of the knee waiting for knee replacement, a single intra-articular injection of ALGRX-4975 (0.5 ml of 0.2 mg ml −1 ) lowered pain scores.
Phase II study:
NCT00667654
This is an open-label study to evaluate safety and tolerability and to explore the efficacy of dosing regimens of intra-articular 4975 in patients with chronic moderate-to-severe pain of the knee associated with OA. The primary outcome measure is the evaluation of pain on a numerical rating scale at prescribed times within 2 weeks. This study has been completed.
1-e Bradykinin B2 receptor antagonists
– Description of the target
Kinins are peptidic mediators that are involved in a series of pathophysiological processes. Bradykinin (BK) is known to have potent pro-inflammatory effects and is one of the most potent endogenous algogenic peptides. BK is formed in plasma and inflamed tissues and, by activating the G-protein-coupled receptor, B2 receptor, present in the membrane of several cell types, initiates many processes such as vasodilation, plasma extravasation, activation of immune cells, induction of leucocyte chemotaxis and activation of nociceptive neurons. Compelling evidence has shown that BK participates in a number of hyperalgesic and inflammatory preclinical models . Elevated BK levels have been demonstrated in the synovial fluid of patients with OA.
– Icatibant (Sanofi-Aventis)
Description of the drug : Icatibant (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8] bradykinin) is a potent B2-kinin receptor antagonist that blocks the vasodilatation and the increased vascular permeability associated with exogenous bradykinin administration both in experimental models and in vivo in man.
Phase II study:
NCT00303056
This is a randomised, double-blind, placebo-controlled, safety/efficacy, 13-week, multicentre study of intra-articular multiple doses of 500 μg icatibant including 40 mg triamcinolone as calibrator in patients with symptomatic knee OA. The primary outcome measure is pain during activity, at rest and at night measured daily through an electronic patient diary using a 100-unitVAS.
2- Targeted structure modifying drugs (Table 2)
| Target | Drug | Mechanism of action | Phase | NCT | Sponsor |
|---|---|---|---|---|---|
| MMPs | AGG-523 | Aggrecanase 1/2 inhibitor | II | 00454298 | Wyeth |
| iNOS | SD-6010 | Synthetic inhibitor of iNOS activity | II/III | 00565812 | Pfizer |
| Cathepsin K | balicatib | Inhibitor of cathepsin K activity | II | 00371670 | Novartis |
| Osteogenic protein-1 | Osteogenic protein-1 | Recombinant protein | I | 00456157 | Stryker Biotech |
| FGF-18 | AS902330 | Human recombinant FGF-18 | I | 0000911469 | EMD Serono |
| Calcitonin | SMC021 | Oral salmon calcitonin | I | 0000486369 | Nordic Bioscience & Novartis |
|
| ||||
| 00704847 | |||||
| Vitamin D | Cholecalciferol | Cholecalciferol | II | 00306774 | NIAMS |
| IV | 00599807 | University of Zurich |
2-1 Targeted MMP inhibitors
– Description of the target
Matrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases involved in the degradation and remodelling of extracellular matrix proteins that are associated with the joint degradative process. A vast number of matrix metalloproteinase inhibitors (MMPIs) have been developed in recent years [ ]. As MMPs have an important role in extracellular matrix (ECM) turnover, many groups have investigated if blocking MMPs will prevent tissue destruction. Early challenges involved the development of MMP inhibitors with high potency that would be orally available, avoiding modification or destruction within the gut. Some of these compounds were found to cause musculoskeletal pain and tendonitis was identified as a reversible side effect in treated patients. Such symptoms were seen with a compound Ro 31-9790 (Roche) and this led to its withdrawal from development as an arthritis treatment . Various explanations have been offered to explain why many of the metalloproteinase inhibitors have been unsuccessful in clinical trials in patients with joint diseases.
– AGG-523 (Wyeth)
Description of the drug : AGG-523 is an aggrecanase 1/2 inhibitor.
Phase II study:
NCT00454298
This is a randomised, double-blind, placebo-controlled, multiple-dose regimen study of the safety, tolerability, pharmacokinetics and pharmacodynamics of AGG-523 administered orally to subjects with severe knee OA. The drug was taken during the 4-week period before having a total knee replacement. This study has been completed.
2-2 iNOS inhibitor
– Description of the target
The mammalian nitric oxide synthase (NOS) enzyme family comprises three isoforms: inducible NOS (iNOS), neuronal NOS (nNOS) and endothelial NOS (eNOS). Many studies have indicated that iNOS induction can be evoked by various stimuli, some of which include several cytokines. It is a well-known fact that nitric oxide (NO) exhibits many biological functions that are involved in vasodilation, neurotransmission, tissue homeostasis, wound repair, inflammation and cytotoxicity. Reports have identified NO as one of the pro-inflammatory mediators of arthritis in human and experimental animal studies. Furthermore, increased concentrations of nitrite, a stable metabolite of NO, have been observed in the serum and synovial fluid of patients with OA .
– SD-6010 (Pfizer)
Description of the drug : SD-6010 is a synthetic inhibitor of iNOS activity.
Phase II/III study:
NCT00565812
This is a long-term randomised, double-blind, placebo-controlled safety/efficacy X-ray study of orally administered SD-6010 in subjects with symptomatic OA of the knee. The primary outcome measure is the assessment of the progression rate of joint space narrowing in over a 24-month period. The recruitment was ongoing in July 2009.
2-3 Cathepsin K inhibitor
Description of the target
Cysteine cathepsins are a large family of proteolytic enzymes active at acidic pH as found in lysosomes. Cathepsin K (cat K), a cysteine protease, was identified initially in osteoclasts. Several recent observations have demonstrated up-regulation of cat K in osteoarthritic cartilage and inflamed synovial tissue. As cat K is one of the few extracellular proteolytic enzymes capable of degrading native fibrillar collagen, it may play an important role in the progressive destruction of articular cartilage both in OA and in inflammatory arthritides. Furthermore, in transgenic mice, the overexpression of cat K results in the spontaneous development of synovitis and cartilage degradation .
– Balicatib (Novartis)
Description of the drug : Balicatib is a pharmacological compound, which inhibits cat K activity.
Phase II study:
NCT00371670
This is a 12-month, double-blind, placebo-controlled, dose-finding, multicentre study evaluating the safety, tolerability and disease-modifying efficacy of daily oral AAE581 (10, 25 and 50 mg tablets) in patients with painful knee OA, Kellgren-Lawrence grade 3 by X-ray. The primary outcome measure is a change from baseline in knee cartilage volume in the target compartment after 6 months. This study has been completed.
2-4 Growth factors
a) Osteogenic protein-1
– Description of the target
Osteogenic protein-1 ( OP-1) is a unique growth factor, which, unlike other members of the same bone morphogenetic protein (BMP) family, exhibits, in addition to its strong pro-anabolic activity, very prominent anti-catabolic properties. Animal studies have demonstrated that OP-1 has the ability to repair cartilage in vivo in various models of articular cartilage degradation, including focal osteochondral and chondral defects and OA, as well as models of degeneration in intervertebral disc cartilage. Together, our findings indicate a significant promise for OP-1 as therapeutic in cartilage repair .
– Osteogenic protein-1 (Stryker Biotech)
D escription of the drug : no information found.
Phase I study:
NCT00456157
This is a double-blind, randomised, single-dose-escalation safety study of intra-articular osteogenic protein-1 in subjects with OA of the knee. The primary outcome measure is the determination of the safety and the tolerability as well as the dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of intra-articular OP-1. As of June 2009, the study has been completed.
b) FGF-18
– Description of the target
FGF-18 belongs to the fibroblast growth factor (FGF) family. It plays a central role in skeletal growth and development. FGFs transmit their signals through binding and activation of one of four FGF receptor tyrosine kinases. FGF18 activates the IIIc splice variants of FGFR2 and FGFR3 receptors known to play major roles in bone and cartilage biology. FGF18 has been shown to have significant anabolic effects on chondrocytes. Local delivery of adenovirus-expressing FGF18 into the pinnae of nude mice increased the formation of auricular cartilage expressing high levels of type II collagen and proteoglycans. FGF18 has been shown to stimulate the growth and proteoglycan synthesis of mature primary porcine and human articular chondrocytes and the growth of neonatal rat costal chondrocytes. FGF18-induced dose-dependent increases in cartilage thickness of the tibial plateau, due to new cartilage formation at the articular surface and the joint periphery. The generation of new cartilage resulted in significant reductions in cartilage degeneration scores. The highest dose of FGF18 also induced an increase in chondrophyte size and increased remodelling of the subchondral bone .
– AS902330 (EMD Serono)
Description of the drug : AS902330 is the human recombinant FGF-18.
Phase I study:
NCT00911469
This is a randomised, double-blind, placebo-controlled, multicentre, single and multiple ascending dose study of AS902330 (rhFGF-18) administered intra-articularly in patients with knee primary OA, who are candidates for total knee replacement. The primary outcome measures are the incidence and severity of treatment-emergent adverse events, the proportion of subjects with predefined local adverse events, the local tolerability in the target knee and the laboratory safety parameters up to 24 weeks post-treatment.
2-5 Calcitonin
– Description of the target
Calcitonin is a 32-amino-acid peptide secreted by the C cells of the thyroid in mammals. Calcitonin possesses potent antiresorptive effects, which are mediated by direct binding of calcitonin to its receptor on the osteoclasts . Various sources of calcitonin are found, of which salmon is the most potent. In vitro and ex vivo studies have found that calcitonin has both anti-catabolic and anabolic effects in cartilage, by attenuating proteoglycan and collagen type II degradation as well as by inducing their syntheses. Calcitonin could promote the synthesis of important cartilage matrix such as proteoglycans and collagen II, propelling the regeneration of cartilage and subchondral bone. In various models of cartilage degradation, the effect of calcitonin has been demonstrated .
– Oral salmon Calcitonin (SMC 021, Nordic Bioscience & Novartis)
Description of the drug : This drug is an association of the salmon calcitonin peptide with an oral delivery agent, a caprylic acid derivative. This oral delivery agent uses the body’s natural passive transcellular transport process allowing peptides to cross cell membranes without chemical modification or damage to the biological membrane. Once the peptide crosses the membrane, the delivery agent dissociates from the drug and the drug re-establishes its natural distribution of conformation, ensuring that the delivered drug is in its therapeutically active state.
Phase I study:
NCT00486369
This is a randomised, double-blind, placebo-controlled safety/efficacy study in patients with OA. The primary outcome measures are the assessment of the effect of different doses of oral calcitonin (0.6 mg and 0.8 mg oral) compared with placebo on serum CTX-I and CTX-II and the assessment of the tolerance profile of different doses/formulations of oral calcitonin compared with placebo up to 14 days.
Phase III studies:
NCT00486434
This is a randomised, double-blind, multicentre, placebo-controlled study to evaluate the efficacy and safety of oral salmon calcitonin (0.8 mg SMC021, twice daily) in the treatment of subjects with knee OA. The primary outcome measures are joint space narrowing in the medial tibiofemoral knee joint in signal knee measured by X-ray after 12 and 24 months, pain to be assessed by WOMAC pain subscore in the signal knee and functional disability to be assessed by WOMAC function subscore in the signal knee.
NCT00704847
This is a randomised, double-blind, multicentre, placebo-controlled study to evaluate the efficacy and safety of oral salmon calcitonin (0.8 mg, twice daily) in the treatment of subjects with knee OA. The primary outcome measures are joint space narrowing in the medial tibiofemoral knee joint in the signal knee measured by X-ray after 24 months and pain to be assessed by WOMAC pain subscore in the signal knee. The study is ongoing but not recruiting.
2-6 Vitamin D
– Description of the target
Vitamin D is either produced in the skin by exposure to UVB radiation or is ingested in the diet, and then is converted to 25-hydroxyvitamin D (25OHD) in the liver. 25OHD is then taken up by renal proximal tubule epithelial cells through megalin-dependent endocytosis, and is subjected to 1alpha-hydroxylation to produce 1,25-dihydroxyvitamin D [1,25 (OH) (2)D], an active form of vitamin D. The molecule 1,25 (OH) (2)D exerts various effects through nuclear vitamin D receptor (VDR) in target organs, including kidney, intestine and bone . Preliminary evidence suggests that vitamin D has direct effects on chondrocytes in OA cartilage, and vitamin D receptors have been demonstrated in human articular chondrocytes of OA cartilage. Vitamin D may also exert an effect on OA through bone, and vitamin D insufficiency could impair the ability of bone to respond optimally to insults, thus predisposing to disease progression. Epidemiologic studies have shown that vitamin D deficiency was associated with an increased risk of progression of knee OA (both joint space narrowing (JSN) and osteophytes) and incidence of hip OA (JSN but not osteophytes). However, there are some controversies on such an association.
– Cholecalciferol
Description of the drug : Cholecalciferol is the non-hydroxylated form of vitamin D3.
Phase II study:
NCT00306774, NIAMS
This is a randomised, double-blind efficacy study in patients with symptomatic knee OA assigned to receive vitamin D at 2000 International Units (IU) a day or a placebo for 2 years. The primary outcome measures are cartilage volume loss (MRI) and knee symptoms (WOMAC questionnaire).
Phase IV study:
NCT00599807, University of Zurich
This is a 2-year double-blind randomised controlled trial in 380 community-dwelling individuals age 60 years or older undergoing unilateral total knee replacement due to severe OA of the knee. This study will compare an oral dose of 2000 IU of vitamin D3 per day with 800 IU. The primary outcome measures are pain and disability assessed by the pain and function subscales of WOMAC related to rehabilitation of the operated knee and related to the expected high prevalence of OA in the contralateral knee.
3- Targeted symptomatic with potential structure-modifying activities (Table 3)
| Target | Drug | Mechanism of action | Phase | NCT | Sponsor |
|---|---|---|---|---|---|
| IL-1 | AMG108 | Fully human monoclonal antibody anti-IL-1 | II | 00110942 | Amgen |
| IL-1Ra | IL-1 receptor antagonist | II | 0000110916 | Amgen | |
| II | 00332254 | Duke University | |||
| TNFα | Adalimumab | Fully human monoclonal antibody anti-TNFα | II | 00185562 | Stanford University |
| II | 00296894 | University hospital of Ghent | |||
| II | 00686439 | University of Alberta | |||
| III | 00597623 | Assistance Publique–hôpitaux de Paris & Abbott | |||
| ESBA105 | Single chain (scFv) antibody fragment against TNFα | I/IIa | 00819572 | ESBATech AG | |
| A3AR | CF101 | Oral A3AR agonist | II | 00837291 | Can-Fite BioPharma |
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Targeting subchondral bone for treating osteoarthritis: what is the evidence?
Targeting the synovial tissue for treating osteoarthritis (OA): where is the evidence?
Why is osteoarthritis an age-related disease?
Developing a minimum standard of care for treating people with osteoarthritis of the hip and knee
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