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Endocrine Abstracts (2022) 81 OC8.6 | DOI: 10.1530/endoabs.81.OC8.6

ECE2022 Oral Communications Oral Communications 8: Calcium and Bone (6 abstracts)

Dose-range analysis of the effects of the long-acting parathyroid hormone analog AZP-3601 versus PTH(1-34) delivered by daily injection or continuous infusion on blood calcium levels and bone metabolism in thyroparathyroidectomized (TPTX) rats

Cagri Aksu 1,2 , Michael D Culler 3 & Thomas Gardella 1,2


1Massachusetts General Hospital, Boston, United States; 2Harvard Medical School, Boston, United States; 3Amolyt Pharma, Écully, France


AZP-3601, a long-acting PTH/PTHrP(1-36) analog, is a candidate new treatment option for hypoparathyroidism (HP). As compared to conventional PTH(1-34), AZP-3601 binds with higher affinity to the R0 conformation of the PTH-1 receptor, resulting in prolonged signaling and sustained elevations in blood calcium (Ca++) in vivo, despite a very short circulating half-life. We assessed whether repeated injection of AZP-3601 into TPTX rats at doses aimed to normalize serum Ca++ levels would produce different effects on bone than PTH(1-34) administered either intermittently or continuously.

Methods: Male S-D rats at age 9 weeks and 2 weeks after TPTX surgery received either a daily sc injection of AZP-3601 at doses of 1.0, 2.0 or 4.0 nmol/kg, daily sc injection of PTH(1-34) at 50, 100 or 150 nmol/kg, or continuous infusion of PTH(1-34) via ALZET mini pump at 1.5, 2.0 or 3.0 nmol/kg/day (n=8/group) for 16 days. TPTX controls received vehicle injections or infusion. Tail vein blood Ca++ was analyzed on days 7 and 14 at 6 h post-injection. Rats were euthanized on day16 (24 h post injection) and blood and femurs collected for analysis.

Results: Each treatment modality resulted in dose-dependent increases in blood Ca++ levels. Optimal doses for raising blood Ca++ to normal range (1.2-1.4 mM vs 0.9-1.1 mM in TPTX-vehicle controls, P<0.001) on days 7 and 14 were identified as 1.0 nmol/kg for AZP-3601 daily injection, 50 nmol/kg for PTH(1-34) daily injection and 3.0 nmol/kg/day for PTH(1-34) continuous infusion. Effects on bone markers and uCT parameters at these optimal doses were as follows: Continuous infusion of PTH(1-34) significantly increased serum levels of the bone formation marker P1NP (P=0.03) and the bone resorption markers CTX1 (P=0.02) and TRAP-5b (P=0.03), and decreased distal femur trabecular (Tb) bone volume relative to tissue volume (BV/TV, P=0.002), as well as mid-femur cortical thickness (Ct.Th P=0.01). Daily injection of PTH(1-34) significantly increased serum P1NP (P<0.001) and TRAP-5b (P=0.001), and increased distal femur trabecular BV/TV (P=0.01) as well as mid-femur cortical thickness(P=0.02). Daily injection of AZP-3601 caused no significant change in these bone turnover and structural parameters.

Conclusion: At doses that similarly normalized blood Ca++ levels in TPTX rats, continuous infusion of PTH(1-34) was bone-catabolic, daily injection of PTH(1-34) was bone-anabolic and daily injection of AZP-3601 was bone-neutral. The distinct mechanism used by AZP-3601 may lead to less impact on bone, as compared to either daily injection or sustained, continuous delivery of PTH(1-34), when used as chronic treatments for HP.

Volume 81

European Congress of Endocrinology 2022

Milan, Italy
21 May 2022 - 24 May 2022

European Society of Endocrinology 

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