Bisphosphonates - Is their use worth the problems?

In the early to mid-noughties bisphosphonates (BPs) were hailed by many equine clinicians as a useful group of drugs that could treat or prevent a wide host of troublesome skeletal issues. In the intervening years sentiment has changed dramatically and use of these compounds is now considered contraindicated in all but older horses with specific degenerative conditions. Bans on their use have been imposed by many racing jurisdictions and severe penalties exist for violation of embargos. However, knowledge of the pharmacological and physiological effects of these drugs in the horse is wanting and there may be a call for a more rational, science-based review of their use in equine medicine.

Not all BPs are equal. Firstly, they can be classified into two broad groups: those that contain an amine group (so-called nitrogen-containing BPs) and those that do not. The effect of these different groups on the metabolism of cells is fundamentally different. This is mirrored in their pharmacological properties. Nitrogen-containing BPs (such as Pamidronate and Zoledronate) are many times more potent at inhibiting osteoclastic resorption of bone than non-nitrogen containing products (e.g. Tiludronate and Clodronate). Furthermore, the range of pharmacological effects varies between groups and there is some evidence that the analgesic properties of non-nitrogen-containing BPs may be the greater of the two. Secondly, the potency of BPs at inhibiting bone resorption and range of other effects varies greatly between different products, depending on molecular subgroup substitutions.

Much of the discussion about the effects of BPs in the horse and nearly all of the concerns regarding potential complications of these drugs in this species has been inferred from studies on laboratory animals and data from human clinical practice. In fact, only one study has demonstrated that one of the BPs licensed for use in horses (Tiludronate) inhibits bone resorption in the horse (as determined by serum concentrations of a marker of type I collagen degradation, CTX-1) and then only for a short duration [1]. More recently it was found that while Clodronate (the only other BP licensed for use in horses) administered to a group of Thoroughbreds at a standard clinical dose did not increase plasma concentration of CTX-1 above that of a saline placebo administered to a control group, it did decrease concentration of type 5 acid phosphatase, which may be a more sensitive indicator of osteoclastic activity [2]. Conversely, others have found that Tiludronate and Clodronate administered at clinical dose rates do not appear to impact bone structure or cellular activity in horses [3,4]. Only one study reports the effect of nitrogen-containing BPs in horses and this did demonstrate that Zolendronate resulted in a profound and prolonged inhibition of bone resorption [5]. These findings suggest that concerns over the clinical use of BPs currently licensed for use in the horse, namely that they may interfere with bone development and homeostatic repair mechanisms, may not be as significant as some claim. On the other hand, the off-label use of nitrogen-containing BPs is clearly a potential concern.

In the absence of profound inhibition of bone resorption, the beneficial clinical effects reported from the BPs licensed for use in horses may be due to their analgesic or anti-inflammatory properties. Bisphosphonates are used in human medicine to manage pain arising from tumours that have metastasised to bone.

The pharmacological mechanism by which BPs affect analgesia and whether this property is more profound in bone than other tissues remains undetermined. If these drugs do preferentially impact bone pain they may been beneficial in the management of pain associated with subchondral bone disease, which is prevalent in racehorses.

Several studies have documented prolonged detection times of BPs in horses, which are measured in times of months and years. While pragmatic measures can be used to manage evidence of BP administration in legitimate cases, clinicians considering clandestine use of these products should be aware of the fact that evidence of their administration to a horse can be detected for such protracted periods.