Selective Modification of Bone Quality by PTH, Pamidronate, or Raloxifene

Abstract

Bone strength, a determinant of resistance to fracture, depends on BMD, geometry, microarchitecture, bone turnover rates, and properties of the bone at the material level. Despite comparable antifracture efficacy, anti-catabolics and bone anabolic agents are likely to modify the various determinants of bone strength in very different ways. Eight weeks after ovariectomy (OVX), 8-mo-old osteoporotic rats received pamidronate (APD; 0.6 mg/kg, 5 days/mo, SC), raloxifene (3 mg/kg, 5/7 days, tube feeding), PTH(1-34) (10 mg/kg, 5/7 days, SC), or vehicle for 16 wk, and we measured vertebral BMD, maximal load, stiffness and energy, microarchitecture, and material properties by nanoindentation, which allows the calculation of the elastic modulus, tissue hardness, and working energy. Markers of bone turnover, plasma osteocalcin, and urinary deoxypyridinoline (Dpd) were also determined. PTH induced greater maximal load than APD or raloxifene, as well as greater absorbed energy, BMD, and increased bone turnover markers. PTH markedly increased trabecular bone volume and connectivity to values higher than sham. Animals treated with APD had BV/TV values significantly higher than OVX but lower than sham, whereas raloxifene had no effect. Tissue hardness was identical in PTH-treated and OVX untreated controls. In contrast, APD reversed the decline in strength to levels not significantly different to sham, reduced bone turnover, and increased hardness. Raloxifene markedly increased material level cortical hardness and elastic modulus. These results show the different mechanisms by which anti-catabolics and bone anabolics reduce fracture risk. PTH influences microarchitecture, whereas bisphosphonates alter material-level bone properties, with probable opposite effects on remodeling space. Raloxifene primarily improved the material stiffness at the cortical level.

Modifications of bone material properties in postmenopausal osteoporotic women long-term treated with alendronate

“…These data were obtained exclusively in animal models. In ovariectomized (OVX) rats treated with pamidronate (0.6 mg/kg, 5 day per month) for 16 weeks, a significant decrease in the indentation modulus was found, while hardness was not changed compared with OVX receiving the vehicle (34). In dogs receiving ALN (6 mg daily) for 23 weeks, there was no modification of microhardness (35).…”

Low-dose PTH increases osteoblast activity via decreased Mef2c/Sost in senescent osteopenic mice

“…To date, only a few studies have analysed the anabolic effect of PTH in the ageing skeleton (Knopp et al 2005, Brennan et al 2009, Jilka et al 2010. Moreover, the effect of PTH 1-34 in osteopenic mice has been tested at standard doses ranging from 80 to 100 mg/kg per day, and it is not known whether PTH at a much lower dose (i.e.…”

Antifracture Efficacy of Currently Available Therapies for Postmenopausal Osteoporosis

“…Interpretation of comparative data for these properties is complex. For example, raloxifene has the most pronounced effects on tissue quality, [58,59] while teriparatide reduces tissue hardness in trabecular bone but has the greatest effect on bone volume. [58,60] Bisphosphonates increase stiffness but not hardness, and do not alter bone volume significantly.…”

“…For example, raloxifene has the most pronounced effects on tissue quality, [58,59] while teriparatide reduces tissue hardness in trabecular bone but has the greatest effect on bone volume. [58,60] Bisphosphonates increase stiffness but not hardness, and do not alter bone volume significantly. [58,59] Finally, bone biopsies performed in patients treated with denosumab show a strong downregulation of the bone remodelling induced by this agent, without any effect on bone architecture.…”