Search

Bisphosphonates are commonly used to treat and prevent bone loss, but their effects in active, juvenile populations are unknown. This study examined the effects of intramuscular clodronate disodium (CLO) on bone turnover, serum bone biomarkers (SBB), bone mineral density (BMD), bone microstructure, biomechanical testing (BT), and cartilage glycosaminoglycan content (GAG) over 165 days. Forty juvenile sheep (253 ± 6 days of age) were divided into four groups: Control (saline), T0 (0.6 mg/kg CLO on day 0), T84 (0.6 mg/kg CLO on day 84), and T0+84 (0.6 mg/kg CLO on days 0 and 84). Sheep were exercised 4 days/week and underwent physical and lameness examinations every 14 days. Blood samples were collected for SBB every 28 days. Microstructure and BMD were calculated from tuber coxae (TC) biopsies (days 84 and 165) and bone healing was assessed by examining the prior biopsy site. BT and GAG were evaluated postmortem. Data, except lameness data, were analyzed using a mixed-effects model; lameness data were analyzed as ordinal data using a cumulative logistic model. CLO did not have any measurable effects on the skeleton of sheep. SBB showed changes over time (p ≤ 0.03), with increases in bone formation and decreases in some bone resorption markers. TC biopsies showed increasing bone volume fraction, trabecular spacing and thickness, and reduced trabecular number on day 165 versus day 84 (p ≤ 0.04). These changes may be attributed to exercise or growth. The absence of a treatment effect may be explained by the lower CLO dose used in large animals compared to humans. Further research is needed to examine whether low doses of bisphosphonates may be used in active juvenile populations for analgesia without evidence of bone changes. [ABSTRACT FROM AUTHOR]

The non-nitrogenous bisphosphonate clodronate disodium (CD) inhibits bone resorption and is approved for horses ≥ 4 yr of age. Extra-label use in juvenile exercising horses is a concern due to potential interference with normal bone growth and development. The objective was to determine the effects of single and repeated doses of CD on bone optical density (radiographic bone aluminum equivalence; RBAE) and lameness score (LS) in juvenile, exercising horses. Quarter Horses [n = 32 (16 geldings, 16 fillies); 500 ± 13 d of age; body weight (BW) = 336 ± 26 kg]) were used to test the hypothesis that horses receiving CD would have greater RBAE and reduced LS, and additional doses of CD would accentuate these effects. In a 168-d trial, horses were housed in individual stalls, and fed 1% BW/d concentrate and ad libitum Coastal bermudagrass hay. Horses were exercised 5 d/wk following a phase-based progressive workload using a free stall exerciser; Phase I (d 0 to 84) mimicked sales preparation whereas Phase II (d 85 to 168) simulated early training. Horses were stratified by age, BW, sex, and initial RBAE into control (CON; n = 8), single dose CD (1X; d 84; n = 8), 2-doses CD (2X; d 0 and d 84; n = 8), and four-doses CD (4X; d 0, d 42, d 84, d 126; n = 8). On injection d (0, 42, 84, and 126), horses were administered either 1.8 mg/kg BW CD (OSPHOS) or isovolumetric saline. On d 0, 84, and 168, dorsalpalmar and lateral-medial radiographs of the left third metacarpus and metatarsus were captured. An aluminum step wedge was included in each image and raw images were analyzed (Quantity One Basic, BioRad) to determine total bone RBAE at 1 cm distal to the nutrient foramen. On d 0 and d 168, horses were evaluated by a veterinarian unaware of treatment group and assigned a LS according to the American Association of Equine Practitioners Lameness Scale. The RBAE and LS data were analyzed via PROC MIXED and PROC GENMOD, respectively, in SAS. For each view, RBAE increased from d 0 to d 84 and remained increased to d 168 (P ≤ 0.02), regardless of treatment, likely due to progressing exercise protocol. On d 0, 29 horses were LS 0, 1 horse was LS 1, and 2 horses were LS 2; LS did not differ among treatment groups (P = 0.61). On d 168, 5 horses were LS 0, 13 horses were LS 2, 11 horses were LS 3, and 1 horse was LS 4; LS did not differ among treatments (P = 0.16). Based on these results, the hypothesis that single or repeated CD administration would increase RBAE and decrease lameness in juvenile, exercised Quarter Horses was rejected. [ABSTRACT FROM AUTHOR]

Anecdotal assertions that bisphosphonates, such as clodronate disodium (CD), exhibit anti-inflammatory properties has led to extra-label use, despite a lack of scientific evidence of its efficacy. The objective of this study was to determine the effects of CD on intra-articular inflammation, hypothesizing that intra-muscular administration of CD would reduce intra-articular inflammation following an acute inflammatory challenge by lipopolysaccharide (LPS). To test this, 32 yearling Quarter horses were stratified by age (500 ± 13 d), BW (336 ± 26 kg), sex (n = 16 female; n = 16 male) and initial bone optical density into 4 treatment groups. The 140-d study consisted of two phases: Phase 1 (d 0 to 83) and Phase 2 (d 84 to 140) emulated sale preparation and early performance training, respectively. Horses were housed individually (3.6 m × 7.3 m) and fed to meet requirements of growing horses undergoing moderate training. Treatments consisted of control (CON; n = 8; no CD), single-dose (1X; n = 8; d 84), two-doses (2X; n = 8; d 0, 84), and four-doses (4X; n = 8; d 0, 42, 84, 126) of CD. All horses received isovolumetric intramuscular injections of 1.8mg/kg BW clodronate disodium (OSPHOS) or saline (placebo) on d 0, 42, 84, and 126. Following treatment administration on d 126, radial carpal joints of each horse were injected with 0.8 mL of either 0.5 ng sterile LPS derived from Escherichia coli O55:B5 or sterile lactated Ringer's solution as a contralateral control. Synovial fluid was collected before LPS injection (h 0) and at 6, 12, 24, and 336 h post injection. Synovial fluid was analyzed using an ELISA for prostaglandin E2 (PGE2), an indicator of joint inflammation. Data were log transformed and analyzed using the MIXED procedure of SAS. There was an h × LPS interaction (P < 0.01) confirming an acute, transient inflammatory response with increased PGE2 at 6, 12, and 24 h compared with the contralateral control joint, and resolved (P = 0.62) by h 336 post-injection. There was a treatment × h × LPS interaction (P = 0.02) in which 1X, 2X and 4X CD groups had greater synovial PGE2 concentrations at 6 h post-injection in the LPS joint compared with CON. In summary, intra-articular LPS induced localized inflammation, and the PGE2 response was greater in all horses treated with CD. The results of this study reject the hypothesis, suggesting clodronate disodium administration does not reduce intra-articular inflammation following acute induced synovitis. [ABSTRACT FROM AUTHOR]

Off-label bisphosphonate use in juvenile horses is widespread despite little scientific understanding of biological and welfare impacts on skeletally immature, exercising horses. Therefore, the objective was to determine the effects of clodronate disodium on growth parameters of young horses. Thirty-two yearling Quarter horses (335 ± 4 kg, 500 ± 13 d of age) were stratified by age, BW, sex, and initial bone density by aluminum equivalence into four treatment groups for a 168-d trial. The experimental period was divided into two phases mimicking common management practices in horses undergoing sales preparation (Phase I: d 0 to 83) and early performance training (Phase II: d 84 to 168). Horses were housed in individual stalls (3.6 m × 7.2 m). Diets were formulated to meet nutrient requirements including concentrate offered every 12 h and ad libitum access to coastal bermudagrass (Cynodon dactylon) hay and water. Treatments consisted of control (CON; n = 8), single-dose (1X; n = 8), two-dose (2X; n = 8), and four-dose groups (4X; n = 8). All horses received iso-volumetric intramuscular injections of either 1.8 mg/kg BW clodronate disodium (OSPHOSÒ) or saline (placebo) on d 0, 42, 84, and 126. Physical measurements including BW, wither height (WH), hip height (HH), body length (BL), and heart girth (HG) circumference were recorded every 42 d, beginning on d 0. Data were analyzed using PROC MIXED procedure of SAS. There were no treatment differences (P = 0.62) or treatment' time interactions (P = 0.25) for BW, WH, HH, BL, and HG, but all measurements increased over time (P = 0.01). These results indicate that clodronate does not impact physical growth parameters in juvenile horses undergoing forced exercise. Further work is ongoing to determine tissue-specific effects of clodronate on bone growth and development in yearling Quarter horses. [ABSTRACT FROM AUTHOR]