Bisphosphonates and navicular syndrome in horses

Getty Images/Nash PhotosNavicular syndrome has long been considered one of the most common causes of forelimb lameness in horses. It has been researched and discussed for more than 260 years-and frustrating veterinarians and horse owners for even longer. The correlation between navicular bone pathology and clinical lameness was first established in 1752.1 Much has been learned about this condition since then, and numerous drugs, treatments and therapies have all been used with variable success.

But frustration with the condition continues principally because horses continue to be affected by navicular problems, no treatment to date has been found to be universally effective, and the veterinary community is still searching for a better solution. It has been estimated that one-third of all chronic lameness cases in horses are related to navicular issues. So it is no surprise that the approval and release of new drugs aimed at the treatment of navicular syndrome is being greeted with much interest and enthusiasm.

New treatment options

In May 2014, the U.S. Federal Drug Administration's Center for Veterinary Medicine approved two new equine drugs: Tildren (tiludronate disodium), manufactured by Ceva Sante Animale, and Osphos (clodronate disodium), manufactured by Dechra. These drugs became licensed in the United States and are “intended to control the clinical signs of navicular syndrome.”

Before last summer, Tildren had been enjoying heavy use in Europe and was being used in the United States under a limited license that required veterinarians to request importation of individual doses on a horse-by-horse basis. Tildren has been used as a treatment for lameness originating from multiple locations in horses, but its recent current licensure restricts its use to cases of navicular syndrome.

Osphos is a new product and has no past performance history. Both drugs are bisphosphonates and, though the exact mechanism of action in horses with navicular syndrome is unknown, there is enough science and recent testing to make owners and veterinarians cautiously optimistic about their potential use.

Navicular syndrome and the role of bisphosphonates

Navicular syndrome refers to a number of conditions that can cause chronic, progressive lameness localized to the structures in the caudal part of a horse's hoof. Because there are so many different parts to this area of a horse's anatomy-navicular bone, coffin joint, navicular bursa, collateral ligaments, deep digital flexor tendon and more-it is often difficult to determine the exact cause of a horse's pain and lameness. Degeneration of the navicular bone itself and the resultant arthritis produced, which is truly navicular disease, is the condition that may be best treated by these newly approved medications because of their mechanism of action.

Bisphosphonates are a class of drugs originally used to treat problems with bone loss in people. Bone is a constantly changing structure, and older bone is always being removed and remodeled into newer bone based on the stresses and pressures put upon it. The response of bones to strain, called Wolff's Law, was described by Wolff in 1892. For horses, this law can be restated to say that as increased loading or weight-bearing occurs in regularly worked horses, bone remodeling or “turnover” also occurs in response to that stress.

In other words, certain parts of bones become thicker and more dense to respond to an increased load and other parts may become thinner without load pressure. This remodeling of bone is accomplished by the action of osteoblasts and osteoclasts. Osteoblasts work more slowly and produce new bone. Faster-working osteoclasts resorb and remove bone.

Marcin Komosa is a bone researcher in the Department of Animal Anatomy and Institute of Zoology at the University of Life Sciences in Poland. In a recent paper in Biological Rhythm Research, Komosa and other scientists looked at navicular syndrome in sport horses from a bone remodeling and turnover prospective. “In properly performed remodeling,” they wrote, “a coupling mechanism must exist between resorption and formation of bone and in healthy individuals, the two processes remain in equilibrium.”2 In such situations osteoblasts and osteoclasts work evenly together. These researchers found, however, that in cases of navicular disease in horses, there is a disruption to this even remodeling process and “lost balance of the osteoclast-osteoblast relationship occurs.”2

There are many causes for this imbalance, including differences in the proportions of spongy (cancellous) and denser cortical bone within the navicular bones of different types of horses. Each type of bone will respond differently to weight-bearing stress. Differing hoof conformations (height ratio and heel-to-toe length) will also lead to different loading forces and altered bone remodeling responses. Work schedules, shoeing practices and ground surfaces can all alter this delicate remodeling process and lead to individual changes in the navicular bone, according to these researchers.

The principle problem that results in these situations of lost remodeling equilibrium is the increased action of osteoclasts relative to osteoblasts. Certain portions of the navicular bone degenerate, resulting in erosive cavities on the flexor surface of the bone, because osteoclasts are more active than osteoblasts in such situations. Progressive bone loss leads to recurring and worsening disease.

This is where the bisphosphonates offer some hope. Tildren and Osphos inhibit the action of osteoclasts. These drugs decrease the rate of bone digestion by causing apoptosis (cell destruction), specifically of osteoclasts, which then slows bone breakdown and preserves bone density. This science made Tildren and Osphos reasonable candidates to help treat navicular problems, which led researchers to progress to clinical trials.

What the studies say

The Tildren study evaluated 181 horses.3 Eight hundred horses were initially enrolled, but the selection criteria were very strict-only horses with navicular disease and no other concurrent problems were eventually used for the results. Horses were examined two months after treatment, and the drug was deemed successful if there was an improvement of at least one grade in lameness assessment. Results showed that 48 percent of the placebo-treated horses were better and that 64 percent of the treated horses improved.

While the results are encouraging, the differences between the two groups were barely significant statistically. Skeptics also point to the fact that most of the horses studied had a history of navicular disease of six months or less. It is unclear as to how some of these horses might have improved with standard treatments only for a longer period. The highly subjective assessment of a one-grade lameness improvement has also been seen as a weakness in this study. And some critics wonder what happens over time-is the noted improvement sustainable past the two-month evaluation period?

The Osphos trial was conducted in a similar manner.4 Researchers evaluated 149 horses and deemed treatment a success if there was, again, an improvement of one grade in the lameness assessment at 56 days. More than 70 percent of the Osphos-treated horses were better on day 56 as compared with just 3 percent of the placebo-treated horses.

At first glance, this trial seems much more successful. But it is worth noting that some of the horses that were better at day 56 were no longer improved on day 180. This is important because these drugs are being looked to as treatment options for chronically lame navicular horses, but the initial research seems to show that they work best in newly diagnosed cases of navicular disease and that beneficial results are best early on in the course of treatment.

Contraindications

Clearly these drugs have the science to be effective and researchers have garnered some encouraging clinical data, but there is much more work to be done. More trials are currently underway, and additional information should help confirm the equine community's initial optimism or temper overly hopeful expectations.

There are some concerns surrounding the use of these drugs and precautions that have been well-documented by the FDA during the approval process. Tildren has been shown to cause gastrointestinal irritation and renal toxicity. This drug is excreted by the kidneys, so it should not be used in horses with compromised renal function. It should also not be used along with nonsteroidal anti-inflammatory drugs, which can also stress the kidneys.

Bisphosphonates affect the blood plasma concentrations of minerals and electrolytes such as calcium, magnesium and potassium, so their use in horses with hypocalcemia or hyperkalemic periodic paralysis (HYPP) is not recommended. Mild colic-like signs can occur with the use of these drugs. They have not been investigated and are not approved for use in young horses or pregnant mares.

Conclusion

Owners of horses suffering from navicular disease and the veterinarians treating these cases will be more than ready to embrace any new potentially useful treatments for this condition. When anti-inflammatories, corrective shoeing, bursal injections, joint therapy and all other previous treatment options have been tried and navicular problems persist, even partially proven drugs such as Tildren and Osphos will likely be considered. Hopefully as greater numbers of horses are treated and observed over time and as more controlled clinical trials are done, a more complete understanding of these products and their place in the treatment of navicular syndrome in the horse will emerge.

References

1. Turner TA. Navicular disease management and shoeing principles, in Proceedings. Am Assoc Equine Pract 1984;625-633.

2. Komosa M, Purzyc H, Wojnar M, et al. Navicular syndrome in sport horses as a result of the disorder of biological bone tissue turnover rhythm: a review. Biologic Rhythm Res 2013;44(3):339-351.

3. Freedom of Information Summary. Original new account drug application Ceva Sante-Animale. The clinical effectiveness of Tiludronate disodium in equine navicular syndrome characterized by predominantly boney lesions. Study # ST-CLI/145RI/0611 July2007-Jan 2009.

4. Freedom of Information Summary. Original new account drug application Dechra LTD. An evaluation of the clinical efficiency of OSPHOS for the control of the clinical signs associated with navicular syndrome in horses. Study # CLR001 Jan 2010-June 2011.

Dr. Kenneth Marcella is an equine practitioner in Canton, Georgia.