Extra-label bisphosphonate (BP) use in juvenile horses is anecdotally reported, primarily for analgesic effects, despite the limited scientific understanding of biologic impacts on skeletally immature horses undergoing exercise. The objective of this study was to determine the effects of clodronate disodium (CD), a form of BP, on endocrine regulators of calcium. Thus, 32 yearling Quarter Horses were stratified by age (500 +/- 13 d), body weight (BW; 336 +/- 26 kg), sex (n = 16 geldings, n = 16 fillies), and initial bone optical density into 1 of 4 treatment groups for a 168-d trial. The experimental period was divided into 2 exercise phases to model industry standards. Investigators were blinded to treatment, and all horses received iso-volumetric intramuscular injections of either 1.8 mg/kg BW CD (OSPHOS) or saline (placebo) on days 0, 42, 84, and 126. Treatments consisted of control (CON; n = 8), 1-dose (1X; n = 8; day 84), 2-dose (2X; n = 8; day 0, 84), and 4-dose groups (4X; n = 8; days 0, 42, 84, 126). Serum samples were collected, and physical measurements were recorded including BW, wither height, hip height, body length, and heart girth circumference (HG) every 42 d, prior to treatment administration. Serum samples were analyzed for growth hormone (GH), calcitonin, parathyroid hormone (PTH), and ionized calcium (Ca2+). Data were analyzed using MIXED and CORR procedures of SAS. All physical measurements increased over time (P <= 0.01) but were not affected by treatment (P >= 0.62). Similarly, there was no effect of treatment for GH (P = 0.44), but concentrations tended to decrease over time (P = 0.09). A treatment x day interaction was observed for PTH (P = 0.05) where concentrations increased following a second CD dose. Specifically, concentrations increased on day 84 in 4X and on day 126 in 2X following the second treatment with CD whereas 1X and CON remained unchanged. Despite the increase in PTH, there was no effect on calcitonin (P >= 0.33). Ionized calcium concentrations decreased over time (P < 0.01) with no effect of treatment (P = 0.26). Parathyroid hormone was negatively correlated with serum Ca2+ (r = -0.28, P < 0.01), whereas calcitonin was not correlated with serum Ca2+ (r = 0.06, P = 0.48) nor PTH (r = -0.13, P = 0.12). According to these results, CD has no effect on growth morphometrics, but its use transiently increases PTH concentrations after 2 doses.