Sex differences in pharmacokinetic and pharmacodynamic responses to a single injection of teriparatide

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Abstract

Background: Teriparatide, the bioactive 1-34 amino acids of parathyroid hormone (PTH1-34), is an anabolic agent used to treat osteoporosis in men and women. This study investigated sex differences in the pharmacokinetics and pharmacodynamics of teriparatide in young, trained, adult men and women as part of a wider project to understand its potential use as a treatment for bone stress injuries.

Methods: 35 healthy men and women (n 15:20; age 24.0±4.7 years; BMI 24.0±2.6 kg/m2) received a single subcutaneous injection of teriparatide (20 µg Terrosa, Gedeon Richter Plc) at 0800 h following an overnight fast. Venous blood was collected at 0 min and at regular intervals up to 720 min post injection (19 timepoints). Urine was collected at 0, 4, 8, 12 and 24 h post injection. Plasma PTH1-34 and urinary cAMP were measured by LCMS/MS; serum Ca, albumin (adjusted Ca [AdjCa]), PO4, and creatinine by standard methods (Roche Diagnostics Ltd). Pharmacokinetic parameters of PTH1-34 and statistics were performed on R. A repeated measures mixed model was employed using first order auto- regressive covariance adjusted for age and BMI. Differences between adjusted means were tested using a t-test. Graphical representation used GraphPad PRISM. Results are given as median [95%CI].

Results: PTH1-34 increased from 0 to 20 min and remained elevated to 240min (p>0.05). After adjusting for age and BMI, there was a sex difference (p=0.0296) in mean AUC for PTH1-34 but no difference for Tmax or Cmax. After adjusting for age and BMI, there was a sex difference (p<0.0001) in mean cAMP:creatinine concentration, with women having a higher adjusted mean cAMP:creatinine ratio of 444 (95% CI: 399 to 489) compared to males (253(95%CI: 202 to 305)). After adjusting for age and BMI, there was a sex difference (p=0.0251) in adjusted Ca.
After 30mins, PO4 concentration in men increased linearly until 600 mins post injection. Thereafter, it plateaued around 1.2mmol/L. In women, PO4 concentration increased until 240 mins post injection, followed by a steep decline from 1.17 mmol/L to 0.7mmol/L at 360 mins, then a linear increase to a maximum of 1.75mmol/L at 720mins. There were no sex differences in PO4 concentration when adjusted for age and BMI.

Conclusion: The response of PTH1-34 to a single injection of teriparatide was immediate and persisted for up to 240 min with a significantly higher AUC in men. When adjusted for age and BMI, pharmacodynamic sex differences were apparent in AdjCa and cAMP responses with women having a higher adjusted urinary cAMP:creatinine ratio and lower adjusted AdjCa concentration. Whether these differences impact the rate or quality of bone repair remains to be studied, and analysis of bone turnover markers may elucidate this further. Sex differences in the serum calcium response may have implications for hypoparathyroid patients. Further analysis of urinary calcium and phosphate is necessary to make a definitive hypothesis.
Original languageEnglish
Publication statusPublished - Sep 2022
EventASBMR 2022 annual meeting: American Society for Bone and Mineral Research - Austin, United States
Duration: 9 Sep 202212 Sep 2022

Conference

ConferenceASBMR 2022 annual meeting
Country/TerritoryUnited States
CityAustin
Period9/09/2212/09/22

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