Browsing by Author "Iwata, Ken"

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    Alterations in Canine Vertebral Bone Turnover, Microdamage Accumulation, and Biomechanical Properties following 1-year Treatment with Clinical Treatment Doses of Risedronate or Alendronate
    (2006-10) Allen, Matthew R.; Iwata, Ken; Phipps, Roger; Burr, David B.
    One year of treatment with bisphosphonates at 5x the dose used for post-menopausal osteoporosis significantly increases failure load and microdamage, and decreases toughness at multiple skeletal sites in intact female beagles. The goal of this study was to determine if similar changes occur with doses equivalent to those used for post-menopausal osteoporosis treatment. Skeletally-mature female beagles were treated daily for 1 year with vehicle (VEH) or one of three doses of risedronate (RIS; 0.05, 0.10, 0.50 mg/kg/day) or alendronate (ALN; 0.10, 0.20, 1.00 mg/kg/day). Doses of ALN corresponded to treatment dose for PMO, 1/2 that dose, and 5x that dose on a mg/kg basis; RIS was given at a dose-equivalent to ALN. Vertebral density, geometry, percent ash, static/dynamic histology, microdamage, and biomechanical parameters were quantified. Trabecular bone activation frequency (Ac.f) was dose-dependently lower in RIS-treated groups (-40%, -66%, -84%, P < 0.05 vs. VEH) while the three ALN groups were all similarly lower compared to VEH (-65%, -71%, -76%; P <0.05). Crack surface density (Cr.S.Dn) was significantly higher than VEH for all doses of RIS and ALN (+2.9 to 5.4-fold vs. VEH). Stiffness was significantly increased with both agents while there were no significant changes in any other structural or estimated material properties. Cr.S.Dn and Ac.f exhibited a significant non-linear correlation (r(2) = 0.21; P < 0.001) while there was no relationship between Cr.S.Dn and any mechanical properties. These results document that 1 year of bisphosphonate treatment at clinical doses allows significant accumulation of microdamage in the vertebra but this is offset by increases in bone volume and mineralization such that there is no significant impairment of mechanical properties.
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    Bisphosphonates suppress periosteal osteoblast activity independently of resorption in rat femur and tibia
    (2006-05) Iwata, Ken; Li, Jiliang; Follet, Helene; Phipps, Roger J; Burr, David B.
    Recent studies demonstrate that bisphosphonates suppress bone resorption by leading to apoptosis of the osteoclast and inhibiting the differentiation to mature osteoclasts. The influence of bisphosphonates on bone formation is unknown, although it has been hypothesized that bisphosphonates inhibit osteoblast apoptosis and stimulate osteoblast proliferation and differentiation in vitro, leading to increased bone formation. The purpose of this study was to investigate the effect of bisphosphonates on bone formation. We administered risedronate at 0.05, 0.5 or 5.0 μg/kg/day or alendronate at 0.1, 1.0 or 10 μg/kg/day subcutaneously for 17 days to 6-month-old female Sprague–Dawley rats. Control rats were given a daily subcutaneous injection of saline. Following sacrifice, the femoral and tibial mid-diaphyses were harvested and mineralizing surface (MS/BS), mineral apposition rate (MAR) and bone formation rate (BFR/BS) were measured on periosteal and endocortical surfaces. In the femur, periosteal MAR was significantly lower in all treatment groups (22–29% for risedronate, 26–36% for alendronate) than in control. In the tibia, periosteal MAR and BFR of all treatment groups were significantly lower (41–50% for risedronate, 43–52% for alendronate) than in the control group. Because the periosteal surfaces of these bones are only undergoing bone formation in modeling mode, our results show that bisphosphonates suppress bone formation independently of bone resorption. Because this effect is seen on periosteal MAR rather than on periosteal MS/BS, we hypothesize that bisphosphonates affect the activity of individual osteoblasts at the cell level. This may help to explain the reason that the anabolic effects of teriparatide are blunted when administered concurrently with or following a course of bisphosphonates in humans.
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    Raloxifene Enhances Vertebral Mechanical Properties Independent of Bone Density
    (2006-11) Allen, Matthew R.; Iwata, Ken; Sato, Masahiko; Burr, David B.
    Anti-remodeling agents produce similar reductions in vertebral fracture risk despite large differences in BMD changes suggesting the mechanism of fracture risk reduction may differ among these agents. Forty-eight intact (non-ovariectomized) skeletally mature female beagle dogs were treated orally for 12 months with clinically relevant doses of risedronate (RIS, 0.10 mg/kg/day), alendronate (ALN, 0.2 mg/kg/day), raloxifene (RAL, 0.50 mg/kg/day), or saline (VEH, 1 ml/kg/day). After sacrifice, the following measurements were made on vertebral bone: areal (aBMD) and volumetric (vBMD) bone mineral densities, tissue mineralization by ash content, static and dynamic histomorphometric parameters, microdamage, and extrinsic and intrinsic measures of biomechanical strength, stiffness and energy to fracture. At these doses, RAL suppressed bone turnover (-20%) significantly less than the bisphosphonates (-66 and -71%) and did not produce significant differences in aBMD, vBMD, BV/TV or percent ash compared to VEH-treated animals. Microdamage accumulation in RAL-treated animals was not significantly different than VEH; both RIS and ALN had significantly higher crack surface density compared to VEH. Stiffness was significantly higher than VEH in all treatment groups. Ultimate load divided by aBMD, a measure of strength independent of BMD, was significantly higher only in RAL-treated animals compared to VEH (+16%, P = 0.015). Based on these data, we conclude that raloxifene produces improvements in bone mechanical properties in ways that do not involve increases in BMD.