Effects of salmon calcitonin on trabecular microarchitecture as determined by magnetic resonance imaging: results from the QUEST study

Abstract

The unique noninvasive MRI technique was used to assess trabecular microarchitecture at multiple skeletal sites in 91 postmenopausal osteoporotic women receiving nasal spray salmon calcitonin (CT-NS) or placebo over 2 years. In the distal radius and lower trochanter of the hip, individuals treated with CT-NS exhibited significant preservation of trabecular bone microarchitecture compared with placebo, where significant deterioration was shown. MRI analyses of os calcis or microCT/histomorphometric analyses of bone biopsies did not reveal consistent differences in architecture between CT-NS and placebo.

Introduction: It is postulated that the reduction in osteoporotic fracture risk in response to certain antiresorptive osteoporosis therapies is caused less by effects on bone quantity than on bone quality (specifically trabecular microarchitecture). To test this hypothesis, the QUEST study was conducted to assess the effects of nasal spray salmon calcitonin (CT-NS) or placebo on parameters of trabecular microarchitecture at multiple skeletal sites using noninvasive MRI technology and iliac crest bone biopsies by microCT/histomorphometry.

Materials and methods: Ninety-one postmenopausal osteoporotic women were followed for 2 years (n = 46 for CT-NS, n = 45 for placebo); all women received 500 mg calcium daily. MRI measurements at distal radius, hip (T2 relaxation time [T2*]), and os calcis (obtained yearly), iliac crest bone biopsies with 2D histomorphometry and 3D microCT (obtained at study onset and conclusion), DXA-BMD at spine/hip/wrist/os calcis (obtained yearly), and markers of bone turnover (obtained at 2-week to 12-month intervals) were analyzed, with an analysis of covariance model used to assess treatment effect for parameters of interest.

Results and conclusions: MRI assessment of trabecular microarchitecture at individual regions of the distal radius revealed significant improvement, or preservation (no significant loss), in the CT-NS-treated group compared with significant deterioration in the placebo control group, as reflected in apparent BV/TV (p < 0.03), apparent trabecular number (p < 0.01), and apparent trabecular spacing (p < 0.01). Also, at the hip, the CT-NS group exhibited preservation of trabecular microarchitecture at the lower trochanter (p < 0.05) as determined by T2* MRI technology. Significant deterioration of trabecular bone architecture was noted in the placebo group at the femoral neck, Ward's triangle, and lower trochanteric sites. Apart from a significant increase in apparent trabecular number in the CT-NS group, significant changes within or between groups were not noted at the os calcis. Combined microCT/histomorphometric analysis of iliac crest bone biopsies did not reveal significant differences between treated and placebo groups. In the CT-NS group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, preservation of parameters of trabecular microarchitecture was noted, whereas in the placebo group, regardless of the change in BMD (gain or loss) at the spine, hip, or distal radius, loss or preservation was noted; however, changes in DXA/BMD (of the spine, hip, wrist, os calcis) between CT-NS and placebo groups were not significant. Serum C-telopeptide (S-CTx), a specific bone resorption marker, was reduced by 22.5% at 24 months (p = 0.056). The results of the QUEST study suggest therapeutic benefit of CT-NS compared with placebo in maintaining trabecular microarchitecture at multiple skeletal sites and support the use of MRI technology for assessment of trabecular microarchitecture in clinical research trials. However, the results also highlight site specific differences in response to antiresorptive therapies and the importance of sufficiently large sampling volumes (areas) to obtain reliable assessment of bone architecture.

FIG. 1

Representative MRI images at the (A) radius, (B) os calcis, (C) and hip (proximal femur), acquired using a 1.5-T General Electric Systems scanner with high resolution array coils (radius and os calcis). For the radius, four distal axial regions were assessed, three of which are shown. Region 1 is 7 mm from the distal endplate, and regions 1–4 are each 2.5 mm thick, corresponding to five MRI slices. For the hip, a coronal image with four regions of interest was obtained; for the os calcis, a sagittal image was obtained with a circular region of interest in the calcaneal area.

FIG. 2

Percentage change (±SE), CT-NS versus placebo, in high-resolution MRI–acquired measurements of trabecular microarchitecture at the distal radius from baseline to 24 months: (A) apparent bone volume/total volume; (B) apparent trabecular number, (C) apparent trabecular spacing, and (D) apparent trabecular thickness. The number of subjects for each region (n), CT-NS: region 1, 28/26; region 2, 30/28; region 3, 31/29; region 4, 30/22 (all parameters). *Change from baseline within group; [], change from baseline between groups.

FIG. 3

Percentage change (±SE), CT-NS versus placebo, in MRI-derived T2* relaxation times at four sites of the proximal femur, from baseline to 24 months. The number of subjects for each region (n), CT-NS/placebo: 30/32. *Change from baseline within group; [], change from baseline between groups.

FIG. 4

(A and B) Relationships of percent changes (±SE; gain or loss) in BMD at the distal radius or spine to percent changes in MRI microarchitecture parameters (apparent trabecular number at the radius; region 4) in CT-NS/placebo subjects from baseline to 24 months. (C and D) Relationships of percent changes (±SE; gain or loss) in BMD at the femoral neck or total hip to percent changes in MRI microarchitecture parameters (T2* at the femoral neck or lower trochanter) in CT-NS/placebo subjects from baseline to 24 months. *Change from baseline within group; [], change from baseline between groups.