Equine Lameness and Laminitis Research Studies

This focus on recent research can help veterinarians help their patients.
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Researchers noted that rather than being thought of as a discrete disease caused by systemic inflammatory response syndrome (SIRS) events, laminitis should instead be viewed as a clinical syndrome occurring as a sequel to several systemic disease problems.

Historically, laminitis has been associated with a specific inflammatory condition that evokes changes in blood flow and associated injury to the lamellar components of the hoof.

Researchers at the University of Helsinki discuss a different vantage for understanding this crippling malady [Patterson-Kane, J.C.; Karikoski, N.P.; McGowan, C.M. Paradigm shifts in understanding equine laminitis. Veterinary Journal, Jan 2018, vol. 232; pp. 33- 40]. They noted that rather than being thought of as a discrete disease caused by systemic inflammatory response syndrome (SIRS) events, laminitis should instead be viewed as a clinical syndrome occurring as a sequel to several systemic disease problems. Occasionally, laminitis develops as a supporting limb problem related to severe lameness in the opposite leg.

Specifically, the authors suggested that multiple stimuli might elicit laminitis in horses affected with endocrine problems. This has significant implications for treatment that includes the need for dietary management in addition to treating hoof pathology.

The authors further remarked that endocrinopathic laminitis is “the most common form of naturally occurring laminitis in horses in the United States and Europe.” Evaluation of laminitis cases by a USDA study (2000) identified that carbohydrate overload, colic or diarrhea cause only 12% of laminitis cases, whereas the bulk of laminitis develops due to dietary imbalances and/or obesity.

The dominant endocrinological problems that cause laminitis include equine metabolic syndrome (EMS) and pituitary pars intermedia dysfunction (PPID). Insulin dysregulation is a primary feature of endocrinopathic disorders.

Another paradigm shift elucidated by the authors is that lamellar stretch and elongation might be a key “early and potentially crucial lesion.” SIRS events occur acutely and are associated with overt laminitis; however, chronic endocrine disease is often associated with a lengthy subclinical phase. The authors suggest that the term “laminopathy” might be more appropriate for cases of endocrinopathic laminitis, because histological exam of endocrine-elicited lamellar injury demonstrates minimal inflammation despite lamellar tearing. This is different from the histologic picture of SIRS-induced laminitis, which is associated with accumulation of inflammatory white blood cells in the lamellar tissue.

Injury and separation of the basement membrane (BM), particularly due to matrix metalloproteinases, has been the focus of SIRS-induced laminitis. By contrast, in the acute phase of hyperinsulinemic laminitis cases, the BM remains mostly intact and attached, with only subtle changes in the BM. Tearing of lamellae in chronic endocrinopathic lesions tends to be located abaxially (closest to the hoof wall), whereas SIRS lesions involve tearing axially and disruption to the BM.

Of noteworthy importance in this paradigm shift is that chronic endocrinopathic laminitis cases experience a preclinical stage witnessed by divergent growth rings in the hoof, which might provide “a window of opportunity for intervention.”

Nerve Block MRI Artifacts

It is not uncommon for a horse to be evaluated for lameness using diagnostic nerve blocks, then fairly quickly undergo an MRI examination. A recent study sought to determine whether recent diagnostic analgesia with mepivacaine—either perineural or intra-synovial—could cause artifacts that could confuse MRI interpretation [Nagy, A. and Dyson, S. Does Diagnostic Analgesia in the Distal Aspect of the Limb of Horses Performed in a Clinical Situation Less than 12 or 36 Hours Before MRI Result in Artifacts? Journal of Equine Veterinary Science, Mar 2018, vol 62; pp. 18-24].

The study looked at horses undergoing MRI that had diagnostic analgesia of the distal limb, either on the same day (i.e., less than 12 hours prior to imaging) or on the day before (i.e., less than 36 hours prior to imaging). Control horses had the same region of the limb examined but had not undergone any analgesic injections within the 36 hours prior to the MRI.

In conclusion, the study demonstrated that no artifacts resulted from diagnostic analgesia within 12 or 36 hours prior to examination with low-field or high-field MRI.

Use of Stem Cells and PRP in Laminitis Treatment

Efforts to stabilize the blood supply and to control pro-inflammatory enzymes within a laminitic foot could yield useful therapeutic applications. Stem cells and platelet-rich plasma have demonstrated the ability to positively improve inflammatory conditions.

One study sought to use both regenerative therapies in treating laminitis. The researchers theorized that bioactive factors in the platelets could reinforce stem cell biologic functions [Angelone, M.; Conti, V.; Biacca, C.; et al. The Contribution of Adipose-Derived Mesenchymal Stem Cells and Platelet-Rich Plasma in the Treatment of Chronic Equine Laminitis: A Proof of Concept. International Journal of Molecular Sciences, Oct 2017, vol. 18: 2122].

The study used nine laminitic horses that had not previously responded to conventional therapy and would otherwise have been euthanized. Ages ranged from 13-21 years of age. Instead of euthanasia, they were entered into a clinical trial. Adipose-derived mesenchymal stem cells were suspended in autologous platelet-rich plasma (PRP) and administered into a digital vein. Four horses with laminitis in one foot received three injections; five horses with bilateral laminitis received six treatments. Continual monitoring included clinical examination, radiography and venography.

The results are promising: All horses experienced anatomical and physiologic progress, including hoof quality, with steady improvement in mobility. All returned to an improved quality of life and/or activity by six months after the first treatment. Of the nine, seven remained active at a year post-treatment. Two horses were euthanized due to recurrence of laminitis; three horses died from unrelated causes, such as colic.

The authors admit to limitations to the study based on the small number of patients and the absence of controls. Further exploration is warranted into regenerative treatment modalities for equine laminitis.

Bisphosphonate

Bisphosphonate is a popular medication used to control osteoporosis in humans. This drug has become available for use in horses under the names of Tildren (tiludronate) and Osphos (clodronate). The intended application is for the treatment of navicular syndrome in mature horses. However, bisphosphonates are being used off-label for a variety of musculoskeletal disorders.

Known for its effects on osteoclasts specifically, there are unintended consequences when used inappropriately [McLellan, J. Science-in-brief: Bisphosphonate use in the racehorse: Safe or unsafe? Equine Veterinary Journal 49 (2017); pp. 404-407]. Osteoclasts are important for part of the natural process of bone repair, which is especially relevant for equine athletes such as racehorses that routinely undergo bone remodeling in response to training stresses on the skeleton.

In a normal situation, osteoblasts lay down immature woven bone to begin repair of micro-fissures in bone that occur with training. Then osteoclasts clean up the woven bone through resorption; this process allows the osteoblasts to finish the repair with strong, organized lamellar bone.

The bisphosphonates impair the osteoclasts such that woven bone remains for extended periods. Although on radiographs the bone appears OK, a bone crack is “patched” with layers of woven bone, but not actually repaired and remodeled with strong bone material. This subjects the weakened bone to risk from additional stresses and predisposes it to more significant stress fractures. In addition, bisphosphonates adversely affect cartilage, particularly if given at high doses via intra-articular injection or intravenous regional limb perfusion.

Due to its short half-life in serum and urine, it is difficult to detect bisphosphonate with conventional drug testing. However, the drug might remain in bone for at least six months.

“The drug stays ‘buried’ within the bone matrix until it is recruited in an area of active bone turnover” (McLellan, EVJ). This poses an ethical dilemma in regard to sale horses that might exchange hands with a new owner unaware of potential risks due to extended effects of this medication.

Bisphosphonates should only be used on mature horses that are likely to be rested for convalescence of an injury. The manufacturer label on bisphosphonate states that this drug should not be used on horses younger than four years old.

In summary, using these products according to label specifications is the most prudent and successful use of the drugs. Veterinarians should refrain from using the drugs on young horses. The longterm effects of using bisphosphonates in horses are not yet known and still need science-based scrutiny. 

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