Risedronate Slows or Partly Reverses Cortical and Trabecular Microarchitectural Deterioration in Postmenopausal Women

Abstract

During early menopause, steady-state bone remodeling is perturbed; the number of basic multicellular units (BMUs) excavating cavities upon the endosteal surface exceeds the number (generated before menopause) concurrently refilling. Later in menopause, steady-state is restored; the many BMUs generated in early menopause refill as similarly large numbers of BMUs concurrently excavate new cavities. We hypothesized that risedronate reduces the number of cavities excavated. However, in younger postmenopausal women, the fewer cavities excavated will still exceed the fewer BMUs now refilling, so net porosity increases, but less than in controls. In older postmenopausal women, the fewer cavities excavated during treatment will be less than the many (generated during early menopause) now refilling, so net porosity decreases and trabecular volumetric bone mineral density (vBMD) increases. We recruited 324 postmenopausal women in two similarly designed double-blind placebo-controlled studies that included 161 younger (Group 1, 55 years) and 163 older (Group 2, ! 55 years) women randomized 2:1 to risedronate 35 mg/week or placebo. High-resolution peripheral computed tomography was used to image the distal radius and tibia. Cortical porosity was quantified using the StrAx1.0 software. Risedronate reduced serum carboxyterminal cross-linking telopeptide of type 1 bone collagen (CTX-1) and serum aminoterminal propeptide of type 1 procollagen (P1NP) by $50%. In the younger group, distal radius compact-appearing cortex porosity increased by 4.2% AE 1.6% (p ¼ 0.01) in controls. This was prevented by risedronate. Trabecular vBMD decreased by 3.6% AE 1.4% (p ¼ 0.02) in controls and decreased by 1.6% AE 0.6% (p ¼ 0.005) in the risedronate-treated group. In the older group, changes did not achieve significance apart from a reduction in compact-appearing cortex porosity in the risedronate-treated group (0.9% AE 0.4%, p ¼ 0.047). No between-group differences reached significance. Results were comparable at the distal tibia. Between-group differences were significant for compact-appearing cortex porosity (p ¼ 0.005). Risedronate slows microstructural deterioration in younger and partly reverses it in older postmenopausal women, features likely to contribute to antifracture efficacy.

Osteoporosis drug effects on cortical and trabecular bone microstructure: a review of HR-pQCT analyses

“…Our search found 12 published articles describing the treatment-related effects on bone parameters assessed by HRpQCT imaging: Bisphosphonates (BPs) were tested in eight of these studies, [20][21][22][23][24][25][26][27] strontium ranelate (SR) in two, 22,23 denosumab (DMAB) in two, 21,27 teriparatide (TPTD) in four, 25,[28][29][30] PTH 1-84 in two 25,27 and odanacatib in one study, 31 sometimes in head-to-head comparisons, sometimes in combination. Most of these studies included postmenopausal women with some level of low BMD, with one exception concerning a TPTD study where premenopausal women with idiopathic osteoporosis were enrolled.…”

“…29 The number of patients and the design of these studies varied quite substantially ( Table 1). Some of these clinical trials were multicentric; [21][22][23][24]26,31 other studies were performed in a single center. 20,25,[27][28][29] None of these studies considered fracture incidence as an end point due to their relatively short duration and limited size.…”

“…26 In the first group, women were in their early phase of menopause with age p55 years; in group 2, women were older with age 455 years. All these women were randomly allocated to receive either risedronate or placebo once a week, for 1 year.…”

“…Tibia was more responsive than radius to BPs in particular for the cortical bone parameters. 20,[24][25][26] The weight-bearing nature of the distal tibia as compared with the distal radius suggests a possible interaction between BP treatment and the mechanical stimulus. Synergetic or additive effects between exercise and osteoporosis drugs have been clearly demonstrated in 2 Â 2 factorial design trials in ovariectomized rats.…”

The clinical contribution of cortical porosity to fragility fractures

“…25,26 Increasing porosity increases odds for fracture, 14,24,25 and treatment reduces porosity at the distal radius and at the proximal femoral shaft in postmenopausal women. [27][28][29] It is therefore reasonable to conclude that porosity is a substantial determinant of the bone fragility that underlies risk of fractures.…”