ABSTRACT
Osteoarthritis (OA) is the most common form of arthritis, yet has historically lagged far behind rheumatoid
arthritis in terms of drug development. Despite the many challenges presented by clinical trials in OA,
improvements in our understanding of disease pathogenesis and a move to treat pain, as well as underlying
disease process, mean there are now many new pharmacological therapies currently in various stages of
clinical trials. The medical need for these therapies and the evidence for recent tissue and molecular targets
are reviewed. Current therapeutic examples in each area are discussed, including both novel therapeutics
and existing agents which may be repurposed from other disease areas. Some challenges remain, but
opportunities for improving symptoms and disease process in OA in the clinic with new pharmacological
agents would appear to be on the close horizon.
Older, >˜55
Radiographic stage
Moderate
Younger, <˜55
Mild
Repair and
Inflammation
remodelling
Pain
New formulations of drug classes in current disease, and closely mirrors changes within the
clinical use, notably NSAIDs, steroids, or articular cartilage.15 Bone marrow lesions (BMLs)
viscosupplementation, have not been included. evident on magnetic resonance imaging (MRI)
Similarly, nutraceuticals and botanicals are not are associated with pain and progression16,17 and
reviewed here, as they are subject to different new bone formation occurs, including osteophyte
regulation, and often have ill-defined and potentially formation. This process has been somewhat
multiple active ingredients which make them underestimated on two-dimensional imaging
difficult to assess pharmacologically; an excellent and is often extensive and a hallmark of disease.18
review of this area has been carried out recently.11 Such remodelling appears to be a repair attempt;
Stem cell and cell-based therapies and platelet-rich whether this is sometimes beneficial, stabilising or
plasma therapy are beyond the scope of this review. splinting a joint, or whether it is always a primary
driver of pain and other symptoms, is a matter
TISSUE AND MOLECULAR TARGETS of debate.
FOR OSTEOARTHRITIS Therapeutic targets will be reviewed relevant to
cartilage, bone, inflammation/repair, and pain, with
Overview
examples of drugs targeting pain, structure, or both.
OA is now considered a disease of the whole
Cartilage
joint, with most of the affected connective tissues
being targets for novel therapeutics (Figure 2).12 There has been long-standing emphasis on
Changes within articular cartilage occur early in the disease modification in articular cartilage. It was
disease and include excessive action of proteinases demonstrated in two reports in 2005 that the key
(aggrecanases and collagenases) causing loss of enzyme responsible for the specific cleavage of
proteoglycan and Type II collagen, both critical aggrecan seen in mouse OA was a disintegrin and
matrix molecules. Structurally compromised metalloproteinase with thrombospondin motifs-5
articular cartilage is then vulnerable to further (ADAMTS-5); knockout of this gene significantly
damage.13,14 Bone remodelling occurs early in the inhibited OA development.19,20 This also appears
In an osteoporosis RCT, it was noted that there Several anti-cytokines licensed for use in RA have
was substantial radiographic improvement of OA also been studied in OA. Perhaps the only surprise
with strontium ranelate.30 In a subsequent RCT is that there is still an incomplete picture. In a small
in knee OA (SEKOIA trial), effects of 1 g or 2 g of RCT of the anti-TNF adalimumab in hand OA, 50%
the drug were examined.31 Paradoxically, structure pain reduction was seen in 35.1% of the active arm
improved most at 1 g dosing, but pain benefit was and 27.3% of the placebo arm, with the conclusion
only seen with 2 g. Bruyère et al.32 noted a clinically that adalimumab was not superior to placebo.46
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