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Abaloparatide at the Same Dose Has the Same Effects on Bone as PTH (1-34) in Mice.

ABSTRACT: Abaloparatide, a novel analog of parathyroid hormone-related protein (PTHrP 1-34), became in 2017 the second osteoanabolic therapy for the treatment of osteoporosis. This study aims to compare the effects of PTH (1-34), PTHrP (1-36), and abaloparatide on bone remodeling in male mice. Intermittent daily subcutaneous injections of 80 μg/kg/d were administered to 4-month-old C57Bl/6J male mice for 6 weeks. During treatment, mice were followed by DXA-Piximus to assess changes in bone mineral density (BMD) in the whole body, femur, and tibia. At either 4 or 18 hours after the final injection, femurs were harvested for μCT analyses and histomorphometry, sera were assayed for bone turnover marker levels, and tibias were separated into cortical, trabecular, and bone marrow fractions for gene expression analyses. Our results showed that, compared with PTH (1-34), abaloparatide resulted in a similar increase in BMD at all sites, whereas no changes were found with PTHrP (1-36). With both PTH (1-34) and abaloparatide, μCT and histomorphometry analyses revealed similar increases in bone volume associated with an increased trabecular thickness, in bone formation rate as shown by P1NP serum level and in vivo double labeling, and in bone resorption as shown by CTX levels and osteoclast number. Gene expression analyses of trabecular and cortical bone showed that PTH (1-34) and abaloparatide led to different actions in osteoblast differentiation and activity, with increased Runx2, Col1A1, Alpl, Bsp, Ocn, Sost, Rankl/Opg, and c-fos at different time points. Abaloparatide seems to generate a faster response on osteoblastic gene expression than PTH (1-34). Taken together, abaloparatide at the same dose is as effective as PTH (1-34) as an osteoanabolic, with an increase in bone formation but also an increase in bone resorption in male mice. © 2019 American Society for Bone and Mineral Research.

SUBMITTER: Le Henaff C

PROVIDER: S-EPMC7145759 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Abaloparatide, a novel PTH1 receptor agonist, increased bone formation in osteopenic ovariectomized cynomolgus monkeys while increasing cortical and trabecular bone mass. Abaloparatide increased bone strength and maintained or enhanced bone mass-strength relationships, indicating preserved or improved bone quality. INTRODUCTION:Abaloparatide is a selective PTH1R activator that is approved for the treatment of postmenopausal osteoporosis. The effects of 16 months of abaloparatide administration on bone formation, resorption, density, and strength were assessed in adult ovariectomized (OVX) cynomolgus monkeys (cynos). METHODS:Sixty-five 9-18-year-old female cynos underwent OVX surgery, and 15 similar cynos underwent sham surgery. After a 9-month period without treatments, OVX cynos were allocated to four groups that received 16 months of daily s.c. injections with either vehicle (n?=?17) or abaloparatide (0.2, 1, or 5 ?g/kg/day; n?=?16/dose level), while Sham controls received s.c. vehicle (n?=?15). Bone densitometry (DXA, pQCT, micro-CT), qualitative bone histology, serum calcium, bone turnover markers, bone histomorphometry, and bone strength were among the key measures assessed. RESULTS:At the end of the 9-month post-surgical bone depletion period, just prior to the treatment phase, the OVX groups exhibited increased bone turnover markers and decreased bone mass compared with sham controls. Abaloparatide administration to OVX cynos led to increased bone formation parameters, including serum P1NP and endocortical bone formation rate. Abaloparatide administration did not influence serum calcium levels, bone resorption markers, cortical porosity, or eroded surfaces. Abaloparatide increased bone mass at the whole body, lumbar spine, tibial diaphysis, femoral neck, and femoral trochanter. Abaloparatide administration was associated with greater lumbar vertebral strength, and had no adverse effects on bone mass-strength relationships for the vertebrae, femoral neck, femoral diaphysis, or humeral cortical beams. CONCLUSIONS:Abaloparatide administration was associated with increases in bone formation, bone mass and bone strength, and with maintenance of bone quality in OVX cynos, without increases in serum calcium or bone resorption parameters.

Project description:Intermittent parathyroid hormone (PTH) administration augments bone and progressive bone marrow blood vessel (BMBV) ossification occurs with advancing age. Since intermittent PTH administration augments bone, it may also serve to increase BMBV ossification. We assessed the influence of 5- and 10-days of intermittent PTH 1-34 administration on trabecular and cortical bone and BMBV ossification in mature (6-8 mon; n?=?30) and middle-aged (10-12 mon; n?=?30) male and female C57BL/6 mice. Mice were divided accordingly: control (CON) and 5-days (5dPTH) and 10-days (10dPTH) of PTH. Mice were given PBS (50??l) or PTH 1-34 (43??g/kg/d) for 5- and 10-consecutive days. Trabecular bone microarchitecture (i.e., BV/TV [%], Tb.Th [?m], Tb.N [/mm], and Tb.Sp [?m]) was assessed in the distal femoral metaphysis and cortical bone parameters (i.e., Ct.Th [?m] and CSMI [mm4]) at the femoral mid-shaft. BMBV ossification (i.e., ossified vessel volume [OsVV, %] and ossified vessel thickness [OsV.Th, ?m]) was assessed in the medullary cavity of the femoral shaft. All parameters were determined by ?CT. At this sample size, no gender-related differences were observed so female and male data were pooled. There were no main effects nor interactions for trabecular microarchitecture and Ct.Th. However, CSMI was larger (p?<?0.05) in Middle-Age vs. Mature and larger (p?<?0.05) in CON and 10dPTH vs. 5dPTH. OsVV tended (p?=?0.057) to be higher (0.18?±?0.04% vs. 0.09?±?0.02%, respectively) and OsV.Th was higher (p?<?0.05; 17.4?±?1.6??m vs. 12.1?±?1.4??m, respectively) in Middle-Aged vs. Mature mice. OsVV was not altered, but ossified vessels tended (p?=?0.08) to be thicker in 10dPTH (17.6?±?2.0??m) vs. CON (12.5?±?1.7??m). No interactions were observed for OsVV and OsV.Th. In conclusion, this is the first report of ossified BMBV in C57BL/6 mice. The increased OsV.Th in Middle-Aged mice coincides with previous reports of increased OsVV in aged rats. The tendency of augmented OsV.Th in 10dPTH suggests that this treatment may ultimately impair the patency of bone marrow blood vessels.

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Abaloparatide at the Same Dose Has the Same Effects on Bone as PTH (1-34) in Mice.

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