Acute development of cortical porosity and endosteal naïve bone formation from the daily but not weekly short-term administration of PTH in rabbit

Abstract

Teriparatide [human parathyroid hormone (1–34)], which exerts an anabolic effect on bone, is used for the treatment of osteoporosis in patients who are at a high risk for fracture. That the once-daily administration of teriparatide causes an increase in cortical porosity in animal models and clinical studies has been a matter of concern. However, it is not well documented that the frequency of administration and/or the total dose of teriparatide affect the cortical porosity. The present study developed 4 teriparatide regimens [20 μg/kg/day (D20), 40 μg/kg/day (D40), 140 μg/kg/week (W140) and 280 μg/kg/week (W280)] in the rabbit as a model animal with a well-developed Haversian system and osteons. The total weekly doses were equivalent in the low-dose groups (D20 and W140) and in the high-dose groups (D40 and W280). After the short-term (1 month) administration of TPDT, micro-CT, histomorphometry and three-dimensional second harmonic generation (3D-SHG) imaging to visualize the bone collagen demonstrated that daily regimens but not weekly regimens were associated with the significant development of cortical porosity and endosteal naïve bone formation by marrow fibrosis. We concomitantly monitored the pharmacokinetics of the plasma teriparatide levels as well as the temporal changes in markers of bone formation and resorption. The analyses in the present study suggested that the daily repeated administration of teriparatide causes more deleterious changes in the cortical microarchitecture than the less frequent administration of higher doses. The findings of the present study may have some implications for use of teriparatide in clinical treatment.

Cortical Bone Porosity in Rabbit Models of Osteoporosis

“…Endosteal bone apposition induced by PTH administration has been well documented in animal (39)(40)(41)67,69) and human studies, (70,71) and it has been suggested that this bone formation may be compensating for the increase in intracortical porosity to limit negative biomechanical effects. (41,72) We observed extensive endosteal bone formation for PTH, which uniquely had a trabecular-like appearance in 2D and 3D (Fig.…”

“…The PTH dose used was intermediate to what has been utilized in recent studies analyzing the effects of PTH dosing regimens (10 μg/kg/d versus 40 μg/kg/d) on rabbit cortical bone. ( 39,42 ) The GC dose used was an intermediate‐to‐high dose (0.5 mg/kg/d versus 1.0 mg/kg/d versus 2.0 mg/kg/d) based on a previous study analyzing OVX and OVX + GC OP models in the rabbit. ( 44 ) SHAM and OVX received daily subcutaneous injections of 1 mL saline for the corresponding 4‐week dosing period.…”

“…( 34–36 ) Rabbits also have the advantage of a remodeling period that is shorter than larger animal models, a relatively rapid skeletal maturation (by 6 to 9 months), ( 37,38 ) and they are known to respond to parathyroid hormone (PTH) treatment with elevated remodeling and cortical porosity. ( 39–42 ) Taken together, these characteristics make the rabbit a promising platform for OP studies, which is well suited for potential in vivo imaging ( 43 ) in future studies.…”

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

“…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.…”

Optimal dosing and delivery of parathyroid hormone and its analogues for osteoporosis and hypoparathyroidism – translating the pharmacology

“…Analyses of the microstructure of the cortex of the tibia by micro‐ computed tomography or bone histomorphometry in rabbits show that the same total dose administered daily increased cortical porosity but not if administered weekly over 1 month. Newly deposited endosteal bone collagen fibres were well organized in the weekly regimen suggesting lamellar bone formation was normal but haphazard in the daily regimen . However, the mere demonstration of an increase in cortical porosity does not imply poorer bone quality, particularly since there are concomitant increases in periosteal and endosteal bone formation.…”