Effects of bisphosphonates on matrix mineralization.

Bone strength is determined not only by the volume of bone tissue and the microarchitectural organization of this bone, but also by the degree of mineralization of bone matrix. The mineralization process consists of a primary deposition of mineral substance on the calcification front, followed by a slow and progressive increase of the mineral deposition named secondary mineralization. In osteoporosis, there is a negative imbalance between bone resorption and bone formation, resulting in bone loss, and microarchitectural deterioration of the trabecular network. Therapeutic agents for osteoporosis could increase bone strength by three separate, but interrelated effects on bone tissue: 1) the prevention of bone loss and thus the preservation of bone microarchitecture, 2) an increase in the volume of bone matrix, and 3) an increase in the degree of mineralization to a level similar to that seen in healthy premenopausal women, through a prolongation of the duration of secondary mineralization. Therefore the use of antiresorptive agents that reduce bone turnover, as bisphosphonates, provide a rational approach to treatment of osteoporosis. Extensive phase III clinical trials have shown that osteoporotic women treated orally with alendronate (ALN) for 3 years or more had substantial increases in bone mineral density (BMD) of approximately 10% at the spine together with reductions of about 50% in the incidence of vertebral fractures. Since a marked reduction in activation frequency was evidenced in the transiliac biopsies taken after treatment with ALN compared to placebo (PLA), without detectable increase in cancellous bone volume, it was hypothesized that the increase in BMD and the reduction in the incidence of fragility fractures were due, in a substantial part, to an increase in the degree of mineralization of bone (DMB). The mean DMB was measured by quantitative microradiography on transiliac bone biopsies taken from 53 postmenopausal osteoporotic women who had been treated with ALN (10 mg/day) during 2 (9 patients) or 3 years (16 patients) or with PLA (15 and 13 patients, respectively). In the same patients, BMD values were obtained by dual-energy X-ray absorptiometry on lumbar spine at the beginning and end of treatment. Histomorphometric parameters and activation frequency of new remodeling units were also measured on the biopsies. After 2 years of ALN, mean DMB in compact bone was 9.3% (p=0.0035) and in cancellous bone was 7.3% (p=0.0009) higher, respectively, versus PLA. After 3 years of ALN, mean DMB in compact bone was 11.6% (p=0.0002) and in cancellous bone was 11.4% (p=0.0001) higher, respectively, versus PLA. After 2 and 3 years of ALN and compared to the corresponding PLA, the distribution of the DMB clearly showed a shift towards the highest mineralization values and a decrease of the number of bone structure units having low values of mineralization. The between group differences in mean DMB were similar to those of BMD at the lumbar spine level (+8.7% after 2 years +9.6% after 3 years, respectively), suggesting that mean DMB augmentation probably accounts for the major part of the increase in BMD seen with ALN. These results support our model that the reduction in the activation frequency caused by the antiresorptive effect of ALN is followed by a prolonged secondary mineralization which increases the percentage of bone structure units having reached a maximum degree of secondary mineralization and, through this mechanism, mean DMB. That these effects contribute to improved bone strength is demonstrated by the reduction in fracture incidence previously demonstrated in these patients. In conclusion, quantitative microradiography gives access to the mineral dimension of bone tissue which has been insufficiently taken into account until now as an important determinant of bone strength and quality of bone.