"[C]alcitonin treatment may counter the acceleration of cartilage degradation and the related increase in surface erosions. These findings indicate that calcitonin has important chondroprotective properties, which need to be further explored in upcoming clinical trials," writes lead author Bodil-Cecilie Sondergaard, MSc, at Nordic Bioscience Diagnostics, in Herlev.
Drs. Steven B. Abramson and Stephen Honig, both with the Hospital for Joint Diseases, in New York City, write in an accompanying editorial that "the study remains an intriguing one, since it reinforces the possibility that currently available antiresorptive drugs may have DMOAD [disease-modifying osteoarthritis drug] properties."2
Sondergaard et al allocated 50 rats into one of five groups: sham-operated, ovariectomy, ovariectomy plus subcutaneously implanted 17β-estradiol pellet, ovariectomy plus 2 mg/kg salmon calcitonin in 50 mg/kg of 5CNAC as a carrier, or ovariectomy plus only the 5CNAC carrier. Treatment continued for 9 weeks after ovariectomy.
Ovariectomy causes collagen loss; calcitonin protects it
The investigators found that ovariectomy significantly increased serum levels of the collagen degradation marker C-telopeptide of type II collagen (CTX-II). As expected, estradiol reversed this effect. "Oral administration of calcitonin elicited similar decreases in serum levels of CTX-II (P <.001)," they report. The calcitonin-treated rats also had significantly less cartilage erosion (P <.01).
"The in vivo effects of calcitonin in rats suggest that calcitonin is able to counteract CII degradation and the accompanying structural disintegration of articular cartilage promoted by estrogen deficiency," Ms. Sondergaard points out.
Estradiol prevented the weight gain associated with ovariectomy, raising the possibility that the benefit of estrogen therapy reduced load on weight-bearing joints. Interestingly, calcitonin protected the joints but had no effect on body weight. The investigators comment, "Accordingly, whereas uncertainties remain regarding the direct effect of estrogen on cartilage, as compared with its effect on body weight, the effects of calcitonin do not seem to be confounded by body weight."
Drs. Abramson and Honig highlight the need for DMOADs. They note that while research in this area has focused on articular cartilage, recent recognition of the role of subchondral bone in OA has led to reconsideration of the cartilage effects of a number of older, bone-protective drugs such as calcitonin and risedronate.
They comment that risedronate has been tested as a means of slowing radiographic progression of OA in a 2-year randomized study of >2000 patients that showed a dose-dependent reduction of CTX-II but no significant effects on symptom relief or radiographic progression (shown by joint space narrowing) [Figure 1]. However, the rate of OA progression in the control group (13%) was far lower than expected, suggesting that the study may have been underpowered. "However, for each antiresorptive agent, one could persuasively propose that sufficient preclinical and clinical data are available to warrant further randomized clinical studies in human OA, regardless of the precise site of action, cartilage, or bone," the doctors write.
Better imaging, biomarkers needed for clinical trials of potential DMOADs
Drs. Abramson and Honig warn that the Sondergaard study was in rats and "a rodent is not a human" and that calcitonin was given as a preventive rather than a therapeutic treatment. "Therefore, it is possible that the beneficial effects of either calcitonin or estrogen occur in the early stages of the disease, well before a patient would come to the attention of the physician. Further studies will be necessary to establish the efficacy of these treatments in established OA."
Looking to the future, Drs. Abramson and Honig highlight the need for better imaging to replace the relatively unreliable routine radiographic techniques used now, as well as the need for validated biochemical markers that might help identify patients at high risk for OA progression or markers that could be used to monitor response to treatment.
"The most important role of biomarkers in the near future may therefore be to predict a population at risk for progression, in order to allow enrichment of a clinical trial with 'progressors,' and thereby avoid a study's being underpowered to demonstrate a treatment effect over a 1-2 year follow-up period," they write.
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Figure 1: Calcitonin effects on cartilage turnover and surface erosion in ovariectomized rats. |
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l Reduced cartilage turnover, as shown by decreased serum CTX-II |
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l Completely prevented development of cartilage erosions |
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l Did not affect body weight |
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l Suppressed cartilage degradation to levels seen in nonovariectomized rats |
References
1. Sondergaard B-C, Oestergaard S, Christiansen C, et al. The effect of oral calcitonin on cartilage turnover and surface erosion in an ovariectomized rat model. Arthritis Rheum. 2007;56:2674-2678.
2. Abramson SB, Honig S. Antiresorptive agents and osteoarthritis: More than a bone to pick? Arthritis Rheum. 2007;56:2469-2473.
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