Clodronate disodium reduced TRAP5b independent of affecting other systemic biomarkers of bone resorption or formation in yearling, exercising Quarter Horses.

Research Overview

• This study investigated how clodronate disodium (CD), a bisphosphonate drug, affects bone metabolism markers in young, exercising Quarter Horses.
• The main finding was that CD reduced a specific biomarker linked to osteoclast activity (bone resorption cells) without changing other markers of bone formation or resorption.

Background and Purpose

• Clodronate disodium is a bisphosphonate used to influence bone metabolism and is approved for horses aged ≥ 4 years.
• Anecdotally, CD is used off-label in juvenile horses to mask bone abnormalities, promote bone growth, or reduce pain, but effects on developing skeletons are unclear.
• Young exercising horses experience high bone turnover, which raises concerns about potential impacts of off-label bisphosphonate use.
• The study aimed to determine how CD influences systemic biomarkers of bone formation and resorption in yearling horses under an exercise regimen.
• The hypothesis was that bone resorption markers would decrease after CD treatment, while bone formation markers would remain unchanged, with repeated treatments having a greater effect.

Experimental Design

• Subjects: 32 yearling Quarter Horses, balanced by age (~500 days), body weight (~336 kg), sex (16 geldings, 16 fillies), and bone density.
• Randomized into 4 groups (n = 8 each):
  • Control (CON): placebo saline injections
  • Single-dose CD (1X): CD on day 84
  • Two doses CD (2X): CD on days 0 and 84
  • Four doses CD (4X): CD on days 0, 42, 84, and 126
• Exercise Protocol:
  • 5 days per week using a free stall exerciser
  • Phase I (days 0-84) simulated sales preparation
  • Phase II (days 85-168) simulated early training
• Blood samples collected on days 0, 42, 84, 126, and 168 before treatments when applicable.
• Analyzed serum biomarkers included:
  • TRAP5b (tartrate-resistant acid phosphatase 5b) – osteoclast activity
  • RANKL (receptor activator of nuclear factor κB ligand) – osteoclast differentiation
  • CTX-1 (C-terminal crosslinks of type I collagen) – bone resorption marker
  • BAP (bone-specific alkaline phosphatase) – bone formation marker
  • PINP (procollagen type I N-terminal propeptide) – bone formation marker
• Statistical analysis used a mixed model with baseline covariate adjustment for BAP.

Key Findings

• TRAP5b levels showed a treatment×time interaction:
  • 4X group: TRAP5b decreased from day 0 to 126, then returned to baseline by day 168.
  • 2X group: TRAP5b decreased until day 84.
  • CON and 1X groups: TRAP5b either increased or remained stable over time.
• This indicates reduced osteoclast number/activity after repeated CD doses.
• CTX-1 increased over time across all groups, indicating ongoing collagen degradation associated with bone resorption during exercise.
• BAP, a marker of bone formation, increased from day 42 to 84 and remained elevated, but was unaffected by CD treatment.
• PINP and RANKL levels did not significantly change with treatment.

Interpretation and Implications

• CD administration selectively reduced TRAP5b, a biomarker reflecting osteoclastic activity, in exercising yearling horses.
• This suggests CD lowers osteoclast number or activity without broadly affecting other bone resorption or formation biomarkers systemically.
• The standard dosing approved for adult horses might be insufficient to cause systemic changes in bone turnover in yearlings undergoing low-intensity exercise.
• The absence of changes in other biomarkers indicates a limited systemic effect of CD on overall bone remodeling at the molecular level under these conditions.
• Further research is necessary to:
  • Investigate local effects on weight-bearing bones, which may not be reflected by systemic biomarkers.
  • Determine optimal dosing and potential developmental impacts in juvenile horses.
  • Evaluate safety and efficacy of off-label CD use during skeletal maturation.

Summary

• This controlled study provides new scientific data on the effects of clodronate disodium in young, exercising horses, quantifying its impact on bone metabolism markers.
• Findings support that while CD reduces osteoclast activity marker TRAP5b, it does not significantly alter other systemic bone turnover markers during low-intensity exercise, raising questions about dose sufficiency and localized bone effects.
• These insights are valuable for veterinarians considering bisphosphonate use in juvenile horses and underscore the need for additional targeted research before endorsing extra-label CD use for skeletal modulation or analgesia in yearlings.