Research Confirms Bisphosphonates Can Linger In Horses’ Bones For Years

Bisphosphonates continue to be a topic of concern in the racing world, most notably raised by a report of a positive test from John Salder trainee Flagstaff, but researchers are still learning about how to find and regulate the drugs in horses. Although two drugs, sold under the trade names Osphos and Tildren, were approved by the Food and Drug Administration for use in horses several years ago, research into the drugs' action in young horses and the length of its life inside the equine body is still catching up. (FDA-mandated testing is focused on safety and efficacy of a new drug, not necessarily the ability of a state racing commission to detect it in a post-race sample from a young racehorse.)

Read more about bisphosphonates in our archives here and here.

Dr. Heather Knych, renowned equine pharmacologist at the University of California-Davis, gave an overview of current research on bisphosphonates at the most recent, virtual convention of the American Association of Equine Practitioners (AAEP).

A few takeaways:

  • Bisphosphonates may be new to the horse world, where they are FDA-approved for the management of navicular syndrome in older horses, but the drug class has actually been in use in different settings for a couple of centuries. Knych explained that the substance was first used in the detergent industry in the 1800s as a water softener, anti-corrosive or anti-scaling agent. Their action on calcium carbonate made them effective in these settings. They were adapted as therapeutic drugs for human bone conditions in the 1970s.
  • While we've most often heard of bisphosphoantes in humans as part of osteoporosis treatment, they've also been used in metastatic bone disorders, and multiple myeloma.
  • We know that after an administration, bisphosphonates disappear from blood fairly quickly – their half life is one to two hours in plasma, but they can linger on bone surfaces for months or years.
  • Bisphosphonates seem to prefer settling in trabecular bone – bones like skulls and ribs that take less mechanical stress – over cortical bone, like the long bones in limbs. It withdraws from bones based on the amount of turnover in that bone, which can vary depending on age, exercise, and trauma.
  • Concentrations of bisphosphonates continues to increase as concentrations of it elsewhere decreases. It can also release from bone back into blood in small amounts and move into other bone surfaces, though we don't know a lot about why and when it does that.
  • Knych presented the results of a two-part study led by researchers across multiple universities to learn more about how long bisphosphonates linger in the skeleton. The first part of the project required administration of the two FDA-approved bisphosphonates – Osphos and Tildren – to a total of four horses in university research programs who were already slated for euthanasia for unrelated reasons. Bone samples were taken after euthanasia, which came four days or 30 days after administration in each drug group. Samples from the radial bones showed detectable amounts of both drugs four days after administration, with levels of Tildren being higher in both samples. Thirty days after administration, both drugs could be found in all bones sampled, even right and left molars. Concentrations of both drugs were highest in the tuber coxae (hips).
  • In the second phase of the study, researchers tested blood and fluid samples from four horses euthanized due to on-track injuries in California – three whose connections said they'd never had bisphosphonates, and one who had a treatment 18 months prior. The team could find no evidence of bisphosphonates in the three horses with no treatment history. The horse who had been treated 18 months before had no detectable amounts of the drug in serum, urine, or synovial fluid, but did have a detectable level in a sample from the radial bone.
  • These results suggest, in line with what veterinarians had expected based on human data, that the drug does linger on the surfaces of bone for considerable periods of time, and lives on different bones in different ways.
  • Knych acknowledged that both parts of the study came from extremely small sample sizes, as is often true in academic research with horses, and that further study is needed to better understand how bisphosphonates work in the equine body.

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Flagstaff Ordered Unplaced Over Bisphosphonate Positive; No Hearing Yet Scheduled For Sadler

A stewards' ruling released on Saturday ordered Flagstaff unplaced from the Grade 2 Santa Anita Sprint Championship Stakes Sept. 27, 2020, at Santa Anita Park in Arcadia, Calif., due to the presence of clodronic acid, a bisphosphonate sold under the brand name Osphos, in a post-race sample, reports the Daily Racing Form.

Flagstaff finished second in that race, and stewards have ordered the purse money to be redistributed.

The bisphosphonate positive was originally announced in late May and trainer John Sadler could still be facing Class 1 drug sanctions, but no hearings have yet been scheduled, according to the DRF report.

Because clodronic acid is not included on the CHRB's current list of prohibited substances, under the regulatory body's rules it automatically falls under the most severe drug category, Class 1. A medication classification proposal working its way through the CHRB's approval process recommends classifying clodronate (clodronic acid) as Class 3, but in the A penalty category.

Sadler referred questions to attorney Darrell Vienna, who said Flagstaff was legally treated with Osphos on an unspecified date “late in 2019” when Flagstaff was 5 years old.

Vienna cited the extended half life of Osphos as an explanation for the positive test, saying it can linger in a horse's system for many months or even longer than a year.

Read more at the Daily Racing Form.

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Bisphosphonate Use In Young Horses The Focus Of Texas A&M Study

Texas A&M researchers have created a study to evaluate off-label bisphosphonate use in horses. Originally meant to mitigate navicular pain in mature horses, off-label use of the drug in younger horses may promote bone degradation.

Though the number of equine fatalities from horse racing is decreasing, California, Kentucky, and New York have seen increased racing fatalities in 2018. Lead researcher Dr. Jessica Leatherwood says that a primary concern regarding these breakdowns is the off-label use of bisphosphonates; the study will assist in determining the effects of the drug on developing skeletons.

There is currently no scientific data exploring the effects of bisphosphonate use on young, exercising horses. The study, “Bisphosphonate Pharmacokinetics and Comprehensive Effects on Juvenile Cartilage, Bone Growth and Healing: Implications for Animal Welfare,” received a $500,000 grant from the U.S. Department of Agriculture's National Institute of Food and Agriculture. The particular bisphosphonate that will be studied is clodronate disodium, which is easy to administer and popular.

Racing commissions acknowledge the off-label use of bisphosphonates, but laboratories are unable to reliably test for the drug, limiting the ability to regulate off-label use.

Radiographs are often a key to racehorse sales, particularly in young horses where they expose skeletal health. Off-label use of bisphosphonates may mask potential flaws and cause microdamage accumulation, which could lead to breakdowns. The concern over bisphosphonate use isn't limited to racing; some sport horse disciplines are also limiting or restricting their use.

Horse and sheep models will be used in the study. As sheep are typically processed before they are two years old, they will offer insight into the potential changes in bone and biomechanical properties. The team hypothesizes that younger animals will clear the bisphosphonates more rapidly than older animals, that the drug alters bone in young, exercising horses, and that it will also have anti-inflammatory effects on the joint.

The findings could help shape new regulatory policies on bisphosphonate use in young horses.

Read more at Texas A&M AgriLife.

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Sadler Faces Class 1 Drug Complaint After Flagstaff Tests Positive For Bisphosphonate

The California Horse Racing Board has filed a complaint against trainer John Sadler after graded stakes winner Flagstaff tested positive for clodronic acid, a bisphosphonate sold under the brand name Osphos, following a second-place finish in the Grade 2 Santa Anita Sprint Championship Stakes Sept. 27, 2020, at Santa Anita Park in Arcadia, Calif. A split sample confirmed the presence of the drug.

Flagstaff, a now 7-year-old gelding by Speightstown, is owned by Lane's End Racing and Hronis Racing LLC. He recently scored his first G1 victory in the Churchill Downs Stakes on Kentucky Derby day at Churchill Downs.

Because clodronic acid is not included on the CHRB's current list of prohibited substances, under the regulatory body's rules it automatically falls under the most severe drug category, Class 1. A medication classification proposal working its way through the CHRB's approval process recommends classifying clodronate (clodronic acid) as Class 3, but in the A penalty category.

Proposed amendments for medication violations require a one-year suspension absent mitigating circumstances along with a minimum fine of $10,000 for Category A penalties. Owners face loss of purse and potential placement of a horse on the vet's list for up to 90 days.

Complicating Sadler's status is the fact he is on probation as part of a settlement agreement issued in June 2020 for three medication violations from April and May 2019. Sadler received a 60-day suspension, but 45 days of the ban were stayed provided he have no Class 1, 2 or 3 violations during a probationary period that ends June 28, 2021.

Bisphosphonates are a class of drug approved by the FDA in 2014 and prescribed to prevent bone loss in people and to treat navicular syndrome in horses, a common cause of forelimb lameness. The drug is not approved for horses less than four years old.

Equine surgeon Dr. Larry Bramlage of Rood & Riddle warned about the use of bisphosphonates Osphos and Tildren in young horses during a client education seminar in 2018, saying the drug can have unintended, detrimental side effects. Many racing states moved to ban the drugs.

The CHRB banned bisphosphonates effective July 1, 2020, saying that any horse administered the drug in the previous six months – effectively a cutoff date of Jan. 1, 2020 – was prohibited from stabling on CHRB regulated grounds.

Sadler referred questions to attorney Darrell Vienna, who said Flagstaff was legally treated with Osphos on an unspecified date “late in 2019” when Flagstaff was 5 years old.

Vienna cited the extended half life of Osphos as an explanation for the positive test, saying it can linger in a horse's system for many months or even longer than a year.

Sadler, whose best horses include 3-year-old filly champion Stellar Wind and Horse of the Year Accelerate, is the trainer of this year's G1 Santa Anita Derby winner Rock Your World, a prospective starter in the G1 Belmont Stakes on June 5.

The complaint against Sadler was ordered on April 28 but not published on the CHRB's website until Wednesday, May 26. No hearing date has been set at this time.

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