Pretreatment with Anticatabolic Agents Blunts But Does Not Eliminate the Skeletal Anabolic Response to Parathyroid Hormone in Oophorectomized Mice

Abstract

Previous studies have indicated that bisphosphonate pretreatment can inhibit the anabolic actions of PTH. We examined the capacity of two anticatabolic agents with different mechanisms of action, alendronate and osteoprotegerin (OPG), to influence the anabolic activity of PTH. Oophorectomized mice were pretreated for 30 d with alendronate or OPG and then treated for 30 d with the respective anticatabolic alone or the respective anticatabolic plus PTH(1-34). Bones were analyzed by bone mineral density (BMD), microcomputed tomography, histology and histomorphometry, and biochemical bone markers. OPG pretreatment produced a greater inhibition of bone turnover and a greater increase in bone than alendronate. Increases in bone were sustained during subsequent treatment with vehicle or continued administration of the anticatabolic. Pretreatment with each anticatabolic blunted the capacity of PTH to increase BMD and bone volume and continued treatment with each anticatabolic agent also reduced the effectiveness of PTH. Although both anticatabolics decreased the maximal PTH effect, BMD and bone volume increased more when PTH was added than when only anticatabolics were used. These results demonstrate that mechanistically distinct anticatabolics may reduce PTH efficacy, that the characteristics of this inhibition may reflect the different modes of action of the anticatabolics, but that the addition of PTH still provides a skeletal benefit even if the anabolic effect is submaximal.

Short-term intermittent PTH 1-34 administration enhances bone formation in SCID/Beige mice

“…Together, these data suggest inTo our knowledge, the skeleton of SCID/Beige mice has not been previously characterized regarding its response to exogenous intermittent PTH 1-34. However, the SCID/Beige mouse was developed on a C57BL/6J background [31]; arguably the most widely employed mouse strain in studies of PTH action on bone [12,13,17,19,32,33]. Our observations of increased serum osteocalcin, number of osteoblasts, and trabecular thickness are consistent with reports describing PTH 1-34 induced bone remodeling in C57BL/6J mice [12,32].…”

“…This discrepancy may be attributed to the lower dose of PTH 1-34 and/ or the timing of end stage analysis of bone turnover markers employed in this study. Elevations in bone resorptive parameters (osteoclast number and activity) have been reported when PTH 1-34 is administered intermittently, at doses of 40 µg/kg and higher, over a time course similar to the present investigation [12,19,26]. Herein the highest dose of PTH 1-34 administered was 2-4 times less than those typically administered; a dose that may be insufficient to increase osteoclast number or activity.…”

“…Studies employing murine models suggest the skeletal response to exogenous PTH 1-34 varies depending on the dose and duration of administration, as well as the mouse strain, age, and skeletal site investigated. Investigations of PTH 1-34 action on bone have employed doses ranging from 3-800 μg/ kg of body weight [10,11,[13][14][15][17][18][19] and durations lasting a couple of weeks to several months [14,[18][19][20][21][22]. In general, low dose (≤ 40 µg/kg), short term (≤ 3 weeks) intermittent PTH 1-34 administration enhances bone formation without altering bone resorp-Enzyme-linked immunosorbent assay kits for serum osteocalcin, mouse specific tartrate resistant acid phosphatase 5b (TRACP-5b), and type I collagen teleopeptides were purchased from Biomedical Technologies Inc. (Stoughton, MA), Immunodiagnostics Systems Inc. (Fountain Hills, AZ), and Nordic Bioscience Diagnostics (Herlev, Denmark), respectively.…”

Parathyroid hormone mediates bone growth through the regulation of osteoblast proliferation and differentiation

“…Although it has been shown that bisphosphonates may clinically impair the anabolic actions of PTH, this is not always the case in rodent models. Studies have shown that co-treatment with PTH and alendronate increased its anabolic effect [37], whereas pre-treatment with bisphosphonates blunted but did not abolish the anabolic response to PTH on the skeleton of oophorectomized mice [38]. In the present study, the concurrent initiation of PTH therapy and therapy with ZA increased percent bone volume in comparison to ossicles treated with PTH or ZA alone.…”

Regulation of beta catenin signaling and parathyroid hormone anabolic effects in bone by the matricellular protein periostin

“…Consequently, PTH exerts greater effects on endosteal surfaces than on the periosteum, where remodeling is virtually absent, at least in adults. In turn, RANKL inhibitors may restrict PTH anabolic effects on endosteal surfaces, without affecting bone formation at the periosteum (7)(8)(9). PTH has also been shown to inhibit sclerostin (Sost) expression (10), and this effect is mediated by MEF2C (11,12).…”