Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide

Zebaze, Roger; Takao-Kawabata, Ryoko; Peng, Yu; Zadeh, A Ghasem; Hirano, Kyoko; Yamane, Hiroshi; Takakura, Aya; Isogai, Yukihiro; Ishizuya, Toshinori; Seeman, Ego

doi:10.1016/j.bone.2017.03.042

Cited by 45 publications

(35 citation statements)

References 16 publications

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“…Bone formation by modeling involves little increase in bone resorption, thus resulting in no increase in cortical porosity, while daily treatment, which increases bone formation predominantly by remodeling, has been reported to increase the porosity of the radius in association with the activation of remodeling [16]. Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide in rabbits [17]. The fact that the daily formulation markedly decreases the BMD of the radius shaft, which consists of more cortical bone than the distal end, suggests that the difference in effect on the porosity of cortical bone may be related to the difference in changes of radial BMD.…”

Section: Discussionmentioning

confidence: 99%

24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk

et al. 2017

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IntroductionTo clarify the additional efficacy and safety benefits of 24 months’ treatment with the once-weekly formulation of teriparatide, which is currently used for 72 weeks.MethodsThis was a multicenter, open-label, single-arm study conducted in Japan. Subjects who were 65 years or older with prevalent vertebral fractures received once-weekly subcutaneous injection of 56.5 μg teriparatide for 24 months. The main outcome measure was percentage change from baseline in lumbar (L2–L4) BMD measured by dual-energy X-ray absorptiometry.ResultsA total of 189 subjects received at least one dose of the once-weekly formulation of teriparatide. Lumbar, femoral neck, and total hip BMD increased significantly compared with baseline at Weeks 24, 48, 72, and 104. In addition, significant increases in lumbar (+1.5%) and femoral neck (+0.8%) BMD were noted at Week 104 compared with Week 72. Significant increases from baseline in BMD for radius 1/10 were noted at Weeks 24 and 104. No substantial increases were noted in the cumulative incidences of new vertebral fracture and other types of fracture after Week 72. The safety profile seen in the first 72 weeks remained unchanged until 104 weeks.ConclusionThe once-weekly formulation of teriparatide is effective and safe for the treatment of osteoporosis over 24 months. The limitation of this study is that this was an open-label, single-arm study. Funding: Asahi Kasei Pharma Corporation. Clinical Trial Registration: JapicCTI-132276.

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Section: Discussionmentioning

confidence: 99%

24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk

et al. 2017

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“…provides an observation that contrasts to the increased intracortical resorption and porosity reported in PTH-treated rabbits [34], and monkeys [15,33]. It should be noted that the PTH-induced increase in cortical porosity is not uniform, and occurs preferentially near the endocortical surface, in a way that limits negative hardness and indentation modulus at the nanomechanical level [38].…”

Section: This Increase In Bone Formation In Intracortical Osteons In mentioning

confidence: 86%

Effects of Parathyroid Hormone, Alendronate and Odanacatib on the mineralisation process in intracortical and endocortical Haversian bone of ovariectomized rabbits

Vrahnas

Buenzli

Pearson

et al. 2018

Preprint

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Although cortical bone strength depends on optimal bone composition, the influences of standard therapeutic agents for osteoporosis on bone mineral accrual in cortical bone are not understood. This study compared effects on cortical bone composition of two current therapeutic approaches for osteoporosis: the antiresorptive bisphosphonate alendronate (ALN), and anabolic intermittent parathyroid hormone (PTH). The experimental anti-resorptive cathepsin K inhibitor, odanacatib (ODN) which inhibits resorption without inhibiting bone formation, was also tested.To determine effects of these agents on Haversian remodeling and mineral accrual, we compared ALN (100µg/kg/2xweek), PTH(1-34) (15µg/kg, 5x/week) and ODN (7.5µM/day) administered for 10 months commencing 6 months after ovariectomy (OVX) in skeletally mature rabbits by histomorphometry. We used synchrotron-based Fourier-transform infrared microspectroscopy (sFTIRM), coupled to fluorochrome labelling, to measure maturation of the cortical matrix in situ at both endocortical and intracortical sites of bone formation.PTH and ODN, but not ALN, treatment increased bone toughness, and PTH treatment stimulated bone formation, not only on endocortical and periosteal bone, but also in intracortical pores. In Sham and OVX rabbits, normal matrix maturation was observed at both endocortical and intracortical sites including: mineral accrual (increasing mineral:matrix), carbonate substitution (carbonate:mineral) and collagen molecular compaction (amide I:II) in situ in endocortical and intracortical bone. ALN treatment reduced bone formation on these surfaces. In ALN-treated bone, while intracortical bone matured normally, endocortical bone did not show a significant increase in mineral:matrix. ODN treatment resulted in slower mineral accrual and limited carbonate substitution. While PTH-treatment did not modify matrix maturation in endocortical bone, the initial stages of mineral accrual were slower in intracortical bone.In conclusion, these three classes of therapy have differing effects on both bone formation, and the process of bone matrix maturation. ALN suppresses bone formation, and the normal process of matrix maturation in endocortical bone. ODN does not suppress bone formation, but limits mineral accrual. PTH stimulates bone formation, and the matrix formed matures normally in endocortical bone. The ability of PTH treatment to stimulate bone formation in intracortical bone may provide a novel additional mechanism by which PTH increases bone strength.

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“…It was also reported in rabbits that the once-daily administration of teriparatide induced a marked increase in the cortical porosity, which was not observed following the once-weekly administration of equivalent total weekly doses. 26,27 Based on these previous studies, the shortening of dosing intervals to more than twice-weekly 28.2-μg injections in humans might induce the elevation of bone resorption markers, resulting in cortical porosity.…”

Section: Discussionmentioning

confidence: 99%

Safety Profiles, Pharmacokinetics, and Changes in Bone Turnover Markers After Twice‐Weekly Subcutaneous Administration of Teriparatide in Healthy Japanese Postmenopausal Women: A Single‐Blind Randomized Study

Kumagai

Ose

Tanaka

et al. 2019

Clinical Pharm in Drug Dev

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Once-weekly injection of 56.5-μg teriparatide formulation is a potent therapeutic agent for osteoporosis treatment. However, this treatment has an issue of difficulty in continuing the treatment by its adverse side effects including nausea, vomiting, and headaches. To reduce these adverse side effects, we conducted a randomized, single-blind, placebocontrolled study to examine the pharmacokinetics, changes in bone turnover markers, and safety profiles of twice-weekly 28.2-μg teriparatide injections. Different dosing intervals of the twice-weekly 28.2-μg injections were also studied. A total of 100 healthy Japanese postmenopausal women were enrolled in this multiple-dosing study. The systemic exposure of teriparatide acetate in the twice-weekly 28.2-μg injection was half that of the once-weekly 56.5-μg injection. Changes in bone turnover markers in the twice-weekly 28.2-μg injection were comparable to those in the once-weekly 56.5-μg injection. Incidences of adverse events including nausea, vomiting, and headaches were lower in the twice-weekly 28.2-μg injections than those in the once-weekly 56.5-μg injection. Findings were similar in the twice-weekly 28.2-μg injections regardless of the dosing interval. Thus, the new dosing regimen using twice-weekly 28.2-μg injections maintained comparable efficacy to the once-weekly 56.5-μg injections; however, it improved the safety profile and contributed to better continuity of care with teriparatide.

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Increased cortical porosity is associated with daily, not weekly, administration of equivalent doses of teriparatide

Abstract: Effects of intermittent teriparatide depend on the dose and frequency of administration. Daily dosing, particularly the higher dose, but not weekly dosing, increased cortical porosity. Work is needed to investigate the effects of the regimens on bone formation.

Cited by 45 publications

References 16 publications

24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk

24-Month Open-Label Teriparatide Once-Weekly Efficacy Research Trial Examining Bone Mineral Density in Subjects with Primary Osteoporosis and High Fracture Risk

Effects of Parathyroid Hormone, Alendronate and Odanacatib on the mineralisation process in intracortical and endocortical Haversian bone of ovariectomized rabbits

Safety Profiles, Pharmacokinetics, and Changes in Bone Turnover Markers After Twice‐Weekly Subcutaneous Administration of Teriparatide in Healthy Japanese Postmenopausal Women: A Single‐Blind Randomized Study

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