Biochemical markers identify influences on bone and cartilage degradation in osteoarthritis--the effect of sex, Kellgren-Lawrence (KL) score, body mass index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation

Abstract

Background: Osteoarthritis (OA) involves changes in both bone and cartilage. These processes might be associated under some circumstances. This study investigated correlations between bone and cartilage degradation in patients with OA as a function of sex, Kellgren-Lawrence (KL) score, Body Mass Index (BMI), oral salmon calcitonin (sCT) treatment and diurnal variation.

Methods: This study was a 2-week, double-blind, double-dummy, randomized study including 37 postmenopausal women and 36 men, aged 57-75 years, with painful knee OA, and a KL-score of I - III. Subjects were allocated to one of three treatment arms: 0.6 mg or 0.8 mg oral sCT, or placebo given twice-daily for 14 days. Correlations between gender, KL score, or BMI and the bone resorption marker, serum C-terminal telopeptide of collagen type I (CTX-I), or the cartilage degradation marker, urine C-terminal telopeptide of collagen type II (CTX-II) were investigated.

Results: At baseline, biomarkers indicated women with OA experienced higher bone and cartilage degradation than men. CTX-I levels were significantly higher, and CTX-II levels only marginally higher, in women than in men (p = 0.04 and p = 0.06, respectively). Increasing KL score was not correlated with bone resorption, but was significantly associated with the cartilage degradation CTX-II marker in both men and women (p = 0.007). BMI was significantly and negatively correlated to the bone resorption marker CTX-I, r = -0.40 (p = 0.002), but showed only a borderline positive correlation to CTX-II, r = 0.25 (p = 0.12). Before morning treatments on days 1 and 14, no correlation was seen between CTX-I and CTX-II in either the sCT or placebo group. However, oral sCT and food intake induced a clear correlation between these bone and cartilage degradation markers. Four hours after the first sCT dose on treatment days 1 and 14, a significant correlation (r = 0.71, p < 0.001) between changes in both CTX-I and CTX-II was seen. In the placebo group a weakly significant correlation between changes in both markers was found on day 1 (r = 0.49, p = 0.02), but not on day 14.

Conclusion: Bone resorption was higher in females than males, while cartilage degradation was correlated with increasing KL-score and only weakly associated with BMI. Bone and cartilage degradation were not correlated in untreated individuals, but dosing with oral sCT with or without food, and a mid-day meal, decreased bone and cartilage degradation and induced a correlation between both markers. Changes in bone and cartilage markers may aid in the identification of potential new treatment opportunities for OA.

Trial registration: Clinical trial registration number (EUDRACT2006-005532-24 & NCT00486369).

Figure 1

Baseline concentrations of serum CTX-I and urinary CTX-II measured in samples collected immediately prior to first dosing at treatment day 1 stratified according to gender. Values shown are geometric mean +1 SEM.

Figure 2

Baseline concentrations of A) serum CTX-I and B) urinary CTX-II, corrected to creatinine, measured in samples collected immediately prior to first dosing at treatment day 1 and stratified according to KL-score index for each gender. Values shown are geometric mean +1 SEM.

Figure 3

Relationship between baseline concentrations of BMI and A) serum CTX-I and B) urinary CTX-II measured in samples collected immediately prior to first dosing at treatment day 1. Females: filled circles; Males: open circles.

Figure 4

Relationship between serum CTX-I and urinary CTX-II (corrected to creatinine) in untreated subjects and subjects treated with sCT. A) & C) Concentrations in samples collected at 08:00 immediately prior to first dosing at treatment day 1. B) & D) Concentrations measured in samples collected at 12:00, i.e. 4 hours post-morning dose, relative to pre-dose at 08:00. C) & I) Concentrations measured in samples collected at 21:00, i.e. 4 hours after the pre-dinner dose, relative to pre-dose at 17:00. D) & J) Concentrations in samples collected at 08:00 immediately prior to dosing at treatment day 14. E) & K) Concentrations measured in samples collected at 12:00, i.e. 4 hours post morning dose, relative to pre-dose at 08:00. F) & L) Concentrations measured in samples collected at 21:00, i.e. 4 hours post pre-dinner dose, relative to pre-dose at 17:00.

Figure 5

Time course during the day of concentrations serum CTX-I (filled circles) and urinary CTX-II (open circles) in A) untreated subjects and B) subjects treated with sCT. Values shown are concentrations relative to pre-dose at 08:00 and given as mean ± 1 SEM for serum CTX-I and geometric mean ± SEM for urinary CTX-II. A meal was given at 13.00 hours and a light meal at 15.30 as described in the material and methods. Dinner was served at 18.00. Modified from [46].