Use of bisphosphonates in equine practice in the UK

Bisphosphonates have been used in horses with bone disorders in the UK for nearly two decades. Recent additions in available bisphosphonates in horses, as well as industry-conducted interviews with UK-based practitioners and questionnaires around Europe that illustrated the disparity in usage and molecule understanding, prompted a literature review.

Many practitioners are not aware of differences between the molecules available, as well as recent changes in doping regulations. As with most veterinary medicines side effects can occur, and practitioners should be aware of the several ways to minimise risks.

About bisphosphonates

Bisphosphonates consist of two phosphonate (PO[OH]₂) groups, attached to a C atom. The other two side chains on the C atom, R1 and R2 vary from one bisphosphonate molecule to another. These have a marked influence on pharmacokinetics mostly via the R1 chain and different therapeutic effect mostly via the R2 chain.

A very well-known, but not much thought about, use of bisphosphonates in horses is their diagnostic use in scintigraphy. As an example, one of the “older” molecules with a very short half-life, medronate, is linked with radioactive technetium 99mTc. After injection, the complex finds its way to “areas of increased bone turnover” as the bisphosphonate has a high affinity for hydroxapatite crystals. These crystals are the calcium-containing part of the bone structure that has become exposed in areas of increased remodelling.

The gamma camera captures where in the body the bisphosphonate has taken the radioactive substance, and the clinician therefore sees these areas as areas of increased radiopharmaceutical uptake. This illustrates the selectivity of areas of interest for bisphosphonates in therapeutic use in general, but it is worth remembering that differences in pharmacodynamics and pharmacokinetics exist for the different molecules.

In therapy molecules with a longer half-life are selected, and instead of a radioactive link the R2 side chain now plays a role in the therapeutic effect. There are two classes of bisphosphonates: nitrogenous compounds as now often used in human medicine and non-nitrogenous compounds – two of which are licensed for use in horses (tiludronate and clodronate).

After binding to the hydroxapatite crystals the bisphosphonate molecule gets taken up selectively into osteoclasts by endocytosis. The osteoclast then either has its adenosine triphosphate pathway disrupted in the case of non-nitrogen-containing bisphosphonates or the cytoskeleton is disrupted in the case of nitrogenous bisphosphonates. Both mechanisms lead to apoptosis of the osteoclast.

In human medicine, indications for use of bisphosphonates include increased risk of fractures caused by osteoporosis in geriatrics, Paget’s disease, metastatic bone disease and bone density loss by lack of gravity experienced by astronauts in space.

In humans, diet and exercise regime play a significant role in the management of these diseases. Furthermore, bisphosphonates are rarely used in athletes with decreases in bone density. A much earlier recognition of risk existed, because most human athletes are better at communicating early signs of pain than their equine counterparts and, therefore, upstream management plays a more key role.

Nitrogenous bisphosphonates are administered to humans with a very high time interval; in some cases, a single administration is not repeated for up to 10 years. Injection is preferred over oral administration due to low compliance with daily oral administration required and oesophageal irritation described.

Humans receiving these nitrogenous bisphosphonates are closely monitored for side effects including risk of renal compromise and osteonecrosis of the jaw at older age (Pazianas, 2007). On balance, the benefits of administration of bisphosphonates are considered to outweigh the risk in humans for the indications described (Pazianas and Abrahamsen, 2016).

Based on the aforementioned human indications it is difficult to imagine reliably comparing cross-species indications. For horses, bisphosphonates are licensed for use in spavin and navicular disease, and research of efficacy have included these indications and other potential reasons for use as discussed later.

Only two non-nitrogenous bisphosphonate molecules are licensed, and the author does not recommend use of nitrogenous bisphosphonates until much more about the safety in horses is known and considers the extremely long treatment intervals a drawback for use in the equine athlete.

Literature available of bisphosphonates used in horses

Tiludronate efficacy was evaluated in 73 horses with navicular disease, and found a positive effect in lameness scores up to six months (Denoix, 2003). The main critique on this study is low statistical significance due to the patients being split into too many groups, which decreased the power of the study. However, from a practical point of view this is very interesting because Denoix found a much stronger positive effect in horses with lameness present less than six months.

Tiludronate efficacy was evaluated in 29 horses with thoracolumbar pain and found dorsal flexibility significantly improved up to four months after administration (Coudry, 2007). Critiques include a small number of horses, difficult case selection and difficulties monitoring “back pain” objectively.

Using advanced imaging techniques and bone markers, it was reliably shown that tiludronate decreased bone resorption during and because of cast immobilisation for eight weeks in 16 horses (Delguste, 2007). Besides the small numbers, the practical implications are questionable as not many sports horses will be cast immobilised for other reasons than a fracture, in which case bisphosphonates are not recommended during the earlier phases of fracture repair.

A significant improvement in lameness score was found in 108 horses with spavin treated with tiludronate. Not many changes in the x-rays were seen during the monitoring period (Gough, 2010). This study experienced difficulties, in part due to horses lost to evaluation when study protocol was not adhered to.

Tiludronate efficacy was compared when administered IV versus IV regional perfusion (IVRP) in 12 horses with navicular syndrome (Whitfield, 2016). None of the horses went completely sound. Interestingly, a force plate was used to objectively evaluate improvement, and significant improvement in lameness was found in horses where IV-only tiludronate was administered.

IVRP administration resulted in variable efficacy, aligning with other studies evaluating IVRP use (Hunter, 2015). Intra-articular use was found damaging to cartilage and is not recommended, as safe concentrations in the joint are likely to be exceeded (Duesterdieck-Zellmer, 2012; Duesterdieck-Zellmer, 2014).

A Freedom of Information request produced the studies done and used during licensing of tiludronate, which (at time of writing) are not yet available in peer-reviewed literature, but available online. Tiludronate was evaluated in a double-blinded placebo-controlled study with 204 horses with navicular disease diagnosed on radiography and MRI, and significant positive effect on lameness scores was found (Ceva, 2014).

It is worth noting that shoeing regime was also adapted to benefit the horses, as you would do in practice, for both the horses that received tiludronate or a placebo.

The safety study is the only study the author could find evaluating renal histology following bisphosphonate administration in horses, and no changes were found in 12 healthy horses that received up to 3× recommended dose at three separate administrations with a 10-day interval.

Clodronate effect was evaluated in 146 horses with navicular disease, and found a positive effect on lameness scores in 75% of horses for up to two months; this sustained for up to six months in 66% of improved horses, so 50% of all horses receiving clodronate; (Frevel, 2014).

A more recent study evaluating bone histology changes in young (two to four-year-old) horses after administration of clodronate did not find a negative effect on bone remodelling in young horses, but did also not find a reduction in remodelling of the previous bone biopsy sites two months after initial administration and first biopsy (Richbourg, 2017).

Zoledronate is an extremely potent nitrogenous bisphosphonate and is not licensed for use in horses. Its efficacy in horses is evaluated in 10 horses and an improvement in pain/lameness was found for up to six months after administration (Katzman, 2012). However, case selection is vague and numbers are low in this study.

Safety of zoledronate was evaluated in eight healthy horses, at an administration dose lower than the dose used in the efficacy study. Low calcium values were reported at seven days after administration, no clinical side effects were seen and urea/creatinine values were normal (Nieto, 2013). The author does not consider this sufficient safety data, as a normal urea/creatinine value does not imply no renal damage exists in the horse.

No adverse effects were found with tiludronate immediately after scintigraphy. However, the follow-up period was short and possibility of renal damage despite normal urea/creatinine values was not considered (Dörner, 2016). Hence the current recommendation is to not use bisphosphonates immediately after scintigraphy in the absence of reliable safety studies.

It is possible that the medronate used in scintigraphy occupies the binding sites at the hydroxapatite crystals, increasing the relative percentage of the therapeutic bisphosphonate carried in the blood and therefore theoretically increasing risk of side effects.

Interviews and questionnaire

The main findings of interviews at UK practices and a Europe-wide questionnaire was that most vets with much equine work use bisphosphonates approximately 10 times per year, value efficacy over cost and use the molecules for a very wide variety of indications.

A large proportion of UK equine practitioners indicated they routinely administer an NSAID alongside the bisphosphonate to prevent anticipated signs of colic, without consideration of potential renal effects.

Side effects and reducing risk

Side effects in horses are similar for the licensed drugs clodronate and tiludronate, and little is known about side effects of nitrogenous bisphosphonates in horses. Clodronate and tiludronate commonly induce transient signs of colic during or shortly after administration. Additionally, reported renal problems are rare (19 cases reported in 70,000 horses over a three-year period for tiludronate), but have been observed with both drugs.

It is pertinent for the veterinarian to be aware of the possibilities of these side effects to correctly inform the owner of potential side effects and to consider the potential ways to reduce the risk of side effects:

Risk of side effects is strongly linked to the C_max – the maximum concentration achieved in the blood (Miller, 2011). A slower administration lowers the C_max and therefore markedly lowers the risk of side effects. Speed of uptake into blood cannot be controlled after IM administration, so a slow IV drip is preferable, where the rate of administration can be decreased when horses are deemed at risk or when side effects are observed.

It is not advisable to use NSAIDs routinely alongside bisphosphonates to prevent the appearance of signs of colic, as this may increase the risk of renal damage. Colic is usually transient and alleviated by hand walking. If symptoms occur, the use of a sedative alone or in combination with an opioid would be the preferred method. Alternatively, a spasmolytic can be administered, but duration of action of these drugs is considerably shorter than the time frame during which colic signs may develop.

The author advises evaluating renal parameters prior to administration of bisphosphonates. However, it is important to bear in mind that a substantial proportion of kidneys are lost in the horse before blood values of urea/creatinine increase, and therefore relying on these parameters alone can lead to a false sense of security. An increase in urea/creatinine is always a contra-indication for use of bisphosphonates. Additionally, monitoring hydration status can prove very useful, and administration of bisphosphonates is not recommended for horses that may be dehydrated (including those that may not have drunk much during a day of lameness evaluation at a clinic or travel – these horses should be allowed to “settle” first).

Select a bisphosphonate molecule with a high bone affinity where possible, as a high proportion of unbound bisphosphonates in the blood leads to an increase of exposure of gut and kidneys to these molecules (Leu, 2006).

Avoid the use of bisphosphonates for a couple of weeks after scintigraphy where possible.

Doping

Bisphosphonates can be tested for in doping tests in race and other sports horses (Wong, 2015). Detection methods are published and show extremely low concentrations of bisphosphonates can be found in blood during doping tests.

The nature of these drugs with binding to bone and then gradual displacement back into blood, combined with these detection methods, means that bisphosphonates can be found in the blood for a very long time after administration. The European Horserace Scientific Liaison Committee has evaluated tiludronate and set an “acceptable threshold” below which tiludronate in blood is permissible (Popot, 2014).

The acceptation of this threshold resulted in a detection time applied by Fédération Equestre Internationale (FEI) of 28 days, the treating vet is expected to make a clinical judgement into the individual circumstances and apply a suitable withdrawal time (detection time plus safety margin) before FEI events. No acceptable threshold is set for other bisphosphonates and therefore the FEI operates a zero tolerance for other bisphosphonates than tiludronate. A similar policy is now operated by most European equestrian sports authorities.

Additionally, the British Horseracing Authority has published a 30 day stand-down time for bisphosphonates used in racing horses.

Take-home points

The different bisphosphonates are different molecular structures, each with their own pharmacokinetic properties.

When pondering the use of a bisphosphonate for a certain condition it is first worth considering if the diagnosed condition is likely to show up on a scintigraphy examination – if it is not then bisphosphonates are unlikely to focus their effect on the intended area and are less suitable. Secondly, the clinician should consider if osteoclast inhibition and decreased remodelling is likely to be beneficial in the condition – that is, if the remodelling is of a pathological nature. These are the cases where bisphosphonates are most beneficial.

Use during the early onset of disease might be more beneficial than “second intention” use.

Bisphosphonates are primarily used in more complex conditions of the horse that require further veterinary treatment and management, and not as a standalone.

Colic is a common side effect and renal problems are very rare. Communication to the client and informed consent is key, alongside the five ways to reduce risk of side effects discussed previously.