SNOWMASS, COLO. — Calcium crystals are likely to become a major target for future osteoarthritis therapies, Geraldine M. McCarthy, M.D., predicted at a symposium sponsored by the American College of Rheumatology.
Calcium crystals may actually be related to glucosamine's mechanism of action, said Dr. McCarthy, of the division of rheumatology at Mater Misericordiae Hospital and the Royal College of Surgeons, Dublin, Ireland.
Studies have shown that anywhere from 30% to 70% of patients with osteoarthritis of the knee have calcium crystals in their synovial fluid, Dr. McCarthy said at the meeting.
And yet because the crystals are extremely small, they're difficult to detect, making more precise estimates of their prevalence difficult to obtain.
Dr. McCarthy's interest in arthritis and the role of calcium crystals was spurred by her training at the University of Wisconsin, where Milwaukee shoulder syndrome was identified as the first osteoarthritis entity found to be associated with basic calcium phosphate crystals.
The idea is that these crystals “synergize with other pathogenic mediators of osteoarthritis, thus contributing to the degenerative process,” she said.
Calcium pyrophosphate dihydrate crystals in the synovium are believed to cause pseudogout and pseudo-rheumatoid arthritis.
Basic calcium phosphate crystals, by comparison, are believed to play a role in all osteoarthritis, Dr. McCarthy explained at the meeting.
Research into the role of basic calcium phosphate crystals has been hindered, however, by the size of the crystals. As small as calcium pyrophosphate dihydrate crystals are, basic calcium phosphate crystals are even smaller.
Basic calcium phosphate crystals clump as submicroscopic aggregates ranging in size from 1 μm to 50 μm in diameter.
A radiolabeled bisphosphonate that can detect the crystals has been available at the Medical College of Wisconsin, Milwaukee, but supply is dwindling, and at present no company has stepped up to manufacture more, Dr. McCarthy said.
Studies have shown that as people age basic calcium phosphate crystals tend to accumulate in the synovial fluid, synovial lining, and hyaline cartilage, and that the presence of these crystals correlates strongly with radiographic evidence of cartilage degeneration. In vitro experiments have shown that the crystals induce mitogenesis and increase production of prostaglandins and metalloproteinases.
The presence of crystals also is associated with the increased production and activation of cyclooxygenase-1 and -2.
Interestingly, COX-1 is not usually upregulated by disease processes, so this finding may explain why some osteoarthritis patients do not respond to selective COX-2 inhibitor therapy, Dr. McCarthy suggested.
The crystals appear to be actively generated by articular cartilage matrix vesicles.
“These crystals are not present in other destructive arthropathies,” Dr. McCarthy noted. But they are associated with Milwaukee shoulder syndrome, so it's likely that the crystals are also associated with joint destruction, she continued.
Further investigations are needed to identify therapeutic interventions and to determine why some individuals with basic calcium phosphate crystals have symptomatic degeneration while others do not, she said.
Calcium-chelating agents have been tried in the treatment of Milwaukee shoulder syndrome, but their use has caused severe arthritis flares.
In vitro experiments have shown that misoprostol can inhibit crystal formation, and glucosamine appears to directly inhibit the effects of the calcium crystals on mitogenesis and metalloproteinase production.