Use of bisphosphonates for the treatment of stress fractures in athletes

Knee Surg Sports Traumatol Arthroscstrengthen itself when subjected to high strains or strainrates, or new strain patterns. Milgrom et al. [49] haveshown in their in vivo human bone strain gauge study thattibial stress fractures are likely due to bone remodeling,while metatarsal stress fractures are caused by cyclicoverloading alone.Over the past decade, bisphosphonates have been widelyused to treat a variety of bone diseases and have beenshown to increase bone mass and decrease fracture risk inpostmenopausal, osteoporotic women. The marked inhibitoryaction of bisphosphonates on osteoclast-mediated boneresorption has also led to successful treatment of pathologicprocesses associated with increased bone remodelingsuch as Paget’s disease, bone tumors, and metastases.Given their inhibitory action on osteoclast activity, shorttermsuppression of bone remodeling using bisphosphonatescould prevent the initial bone loss observed duringthe remodeling response to high bone strains and potentiallyprevent stress fractures [19]. This concept is not new.Physicians have empirically treated athletes who sufferfrom stress fractures with bisphosphonates, but this iscontroversial and has not been well investigated [3, 24].The present review summarizes and discusses thecurrent understanding and the potential role of bisphosphonatesfor the treatment and prevention of stressfractures in athletes.remodeling, which prevents the increased porosity associatedwith remodeling and maintains lower strains on thebone, can prevent stress fractures.One would expect that an increase in bone remodelingwould be accompanied by an elevation of serum or urinebiochemical markers that reflect the remodeling process. Intheir prospective study, Murguia et al. [53] detected asignificant increase in plasma hydroxyproline during thefirst week of military training in a group of recruits whosubsequently presented with stress fractures, compared tothose who did not. This showed that an initially higherbone remodeling rate is a risk factor for subsequent stressfractures. According to this result, preventive bisphosphonatetreatment may be feasible for those who haveincreased bone remodeling at baseline. However, Bennellet al. [8] reported that bone remodeling in athletes whodeveloped stress fractures was not different from those whodid not develop stress fractures at baseline, or immediatelyprior or subsequent to the start of bone pain. The resultsfrom military recruits may not generalize to athletes as theyrepresent a different population. Failure to detect increasedbone remodeling, either prior to or following the onset ofstress fractures in athletes, may reflect overall total bodybone remodeling and the tests may not be sufficientlysensitive enough to detect locally accelerated boneremodeling.Pathogenesis of stress fractures and the relationshipto bisphosphonatesAs stated above, stress fractures occur when a bone fails toremodel adequately following the application of repetitivesub-threshold stress. The first stage of bone remodelinginvolves bone resorption, which further weakens thealready compromised bone [19]. A mathematical modelproposes that the porosity introduced by remodeling contributesto an unstable situation in which a stress fracturewill occur [44]. Experimental studies with a rabbit impulsiveloading model [17] also suggested that a positivefeedback between loading and remodeling might be afeature of stress fracture pathogenesis. By 6 weeks ofloading, activation of new bone remodeling had increasedfurther still and there was a tenfold increase in bone microdamage.The incidence of overt stress fractures in theseanimals had increased to 68% after 6 weeks. These datasuggest that overloading first creates a biological remodelingresponse, which is associated with the early signs of astress fracture. Continued loading causes acceleration ofbone microdamage accumulation, which further increasesthe incidence of stress fractures, perhaps through a positivefeedback mechanism [19]. Taken together, these experimentshave suggested that the suppression of boneEffect of bisphosphonates on fracture healingOver the years, there have been concerns about whether ornot bisphosphonates interfere with the fracture healing.Because they suppress bone remodeling, one might expectthat bisphosphonates interfere with fracture repair. Li et al.[37] have reported in a growing rat model using incadronatethat bisphosphonate treatment resulted in a largerfracture callus and delayed maturation of the fracture.Alendronate treatment also suppressed remodeling of thefracture callus in ovariectomized rats [20]. These changesmay be secondary to inhibition of bone resorption becausebone formation and resorption are intimately linked. Conversely,there are reassuring reports on this topic that showfracture callus remodeling is not a problem in severalanimal models unless very high doses of bisphosphonatesare used [7, 25].In contrast to these concerns, there are now severalreports suggesting that bisphosphonates may actuallyenhance fracture repair, probably by stabilizing the fracturecallus [42]. Other studies relevant to this problem includethe improved osseointegration of metal implants in ovariectomizedrats treated with ibandronate [34]. There are alsopotential applications of bisphosphonates in orthopedics,including improved healing in distraction osteogenesis [39,123