Perceptions of using lithium in fracture management: a survey of orthopaedic surgeons, fracture patients and the general public

Fracture healing is a proliferative physiologic process that can fail in up to 10% of cases despite appropriate and timely orthopaedic care [1, 2]. Fracture management, particularly in cases of delayed healing, results in significant costs to the healthcare and the individual in loss of function and work productivity. An inexpensive, non-invasive strategy to predictably increase bone healing and provide earlier mobility and independence is currently not available.

Lithium therapy is well known for the treatment of bipolar disorder. Under proper clinical monitoring, psychiatrists have widely prescribed lithium demonstrating its safe and effective administration over prolonged periods [3]. Recently, a positive link has been established between lithium and enhanced bone repair. Lithium is a glycogen synthase kinase-3β (GSK-3β) inhibitor which activates the canonical Wingless (Wnt)/β-catenin signaling pathway that is of significance in bone biology and as a mechanism of increasing bone formation [4]. Preclinical models have been used to identify the optimal administration parameters for lithium in the context of fracture healing. It was shown that a low dose of oral lithium administered during the transition from soft to hard callus stages of fracture healing demonstrated a 46% increase in strength of healing femoral fractures compared to untreated controls [5, 6].

The strength of these preclinical findings has led to the initiation of a Phase II clinical trial evaluating the effect of lithium treatment (300 mg daily from week 2 to week 4 post fracture injury) on long bone fracture healing by relative stability in otherwise healthy patients (LiFT trial, NCT02999022). This represents a simple regimen at a very low dose of 300 mg, with little risk of systemic side effects such as diarrhea, weight gain and increased thirst that are typically experienced with chronic intake of 900–1800 mg. This is different from the therapeutic dosing range of lithium indicated for its psychotropic benefits where dose dependent side effects occur at a much higher dosing range from 900 to 1800 mg/day with long term use.

In working towards future adoption of lithium for fracture treatment, it is important to understand potential barriers that may hinder its clinical uptake. As such, it is critical to understand the current perceptions of lithium as a psychiatric drug and in its other non-medical uses. The objective of this study was to understand perceptions of the general public, patients, and orthopaedic surgeons towards the use of lithium in the context of fracture treatment and factors affecting the perceptions of these three cohorts.

Three questionnaires were designed to evaluate the level of knowledge about lithium and the willingness to consider an alternative use of lithium in fracture healing among three distinct populations: the general population, fracture patients eligible to participate in the LiFT trial and orthopaedic surgeons across Canada. The survey questions fell under three broad categories: background information, knowledge about lithium in fracture repair and opinion on the use of lithium for fracture treatment (Additional file 1). Descriptive statistics are presented separately for the three cohorts. Data has been reported as percentages of the respective group size. Given the exploratory nature of this study, qualitative analysis was performed to identify trends in knowledge and opinions about lithium and its adoption in orthopaedics.

In considering future adoption of lithium for fracture treatment, current knowledge and perceptions of this drug highlight potential barriers to its uptake (Table 3). Knowledge about lithium may be limited in the general public, fracture patients, and orthopaedic surgeons, which impact their openness to consider its use in the context of fracture healing. Yet, there is a clear desire for new therapies to improve fracture healing.

Improving fracture healing through therapeutics was seen as acceptable by the majority (84%) of the general population. A stigma was found to exist with respect to taking a psychiatric drug in this context lowering the willingness to take such a medication to improve fracture healing to only 54% of respondents. Concerns about side effects, trust in psychiatric medications and lack of knowledge can all be addressed through appropriate education via clinical materials and information provided verbally by treating practitioners. Equivalent responses were found in the general public independent of whether they had previously suffered a fracture.

Those who were willing to consider taking a drug with a psychiatric indication expressed some similar concern with potential for side effects (15–17%) as well as the desire for prescription by a physician (9%). The willingness to take lithium specifically for fracture healing was lower than a non-identified psychiatric drug, primarily due to concerns over side effects or effects on the brain. Lack of a need for a medication for bone healing, insufficient knowledge about lithium and skepticism about lithium’s efficacy in the context of fracture healing were also identified. These concerns could be readily addressed through appropriate education.

The majority of long bone fracture patients seen at Sunnybrook Health Science Centre (69%) had heard of lithium, with 38% aware of its clinical use in psychiatry (as compared to the 22% in the general population survey). Of the 20 patients completing the survey, 40% were willing to take lithium for fracture healing. Low dose and/or short duration of use increased those willing by 10%. Half the patients acknowledged that lithium has side effects; education as to possible side effects at the lower dose for fracture healing would be critical information for patients considering this therapeutic. Social stigma related to lithium was identified with concerns about submitting insurance claims (33%) and others knowing about a lithium prescription (20%) among those who declined to participate in the LiFT trial. If lithium therapy for fracture healing becomes a standard of care, such barriers may shrink, but remain substantial in considering early adoption.

New treatments for fracture healing are clearly desired by orthopaedic surgeons, specifically those that may reduce the number of cases of delayed healing or non-unions. The acceleration of fracture healing in otherwise healthy patients was also deemed important by ~ 90% of the responding surgeons. As such there is an opportunity for new therapeutics in both contexts from a clinical perspective, suggesting a potential for widespread utilization of a new or repurposed drug or therapy to enhance fracture healing.

There is a lack of knowledge about lithium in the orthopaedic surgeon community, despite most respondents knowing of its use in psychiatric medicine (88%). Dissemination of accurate knowledge about lithium including dose dependent side effects and precautions for use in patients with diabetes or impaired renal function is needed if lithium is to be considered for clinical use in the context of fracture healing. Initial uptake may be improved if another experienced physician can be involved in the prescription of the lithium. A standard protocol would likely only have a modest initial effect in improving some surgeons’ willingness to prescribe lithium but may be worthwhile to ensure proper and consistent implementation. While drug interactions may pose less of a barrier in the treatment of otherwise healthy individuals with a long bone fracture, the use of lithium in the context of osteoporotic fracture healing may require more detailed knowledge and the dissemination of this knowledge to multiple practitioners involved in a patient’s circle of care. Adoption planning must consider the current limited knowledge state and address this gap through information dissemination and training, perhaps initially with interdisciplinary mentorship support (i.e. from psychiatry). Overcoming such adoption barriers in the context of lithium for fracture healing may provide an important broader context to enable uptake of this and other repurposed drugs/psychiatric drugs for new indications.

Surprisingly, 17% of orthopaedic surgeon respondents who had heard of lithium were unsure or unwilling to consider its use in the context of fracture healing even if there were scientific evidence demonstrating its benefit. While this could be due to the perception that in the short term most fractures will heal, the unanimously identified need for new treatments for fracture healing suggest that perhaps this is not the case. Differences in early vs. late adopters of new therapeutics may explain some of the variability in the responses of surgeons. As such, uptake in lithium usage for fracture healing may initially follow a limited incremental adoption model. Randomized controlled data (level 1 evidence) followed by longer term clinical experience from early adopters may be required before it can be more widely accepted as a possible standard of care.

Although this study provides crucial information for secondary adoption of lithium, it has limitations. Firstly, the group sizes for patient and surgeon surveys were small. While the volume of trauma patients with fractures received at the site hospital was considerable, only a small proportion of these patients were eligible for the LiFT trial, and hence for the survey due to the strict inclusion and exclusion criteria intended for a more homogenous healthy patient cohort. For the surgeon survey, the low recruitment was attributed to the voluntary nature of their participation. Secondly, those patients who accepted to participate in the trial took the survey at their final visit (6–10 weeks post-acceptance) as opposed to those patients who declined to participate in the trial and took the survey immediately after making this decision. The difference in timing was mainly for logistical reasons for the trial recruitment team. However, regardless of the timing, all the patients were asked to fill the questionnaire based on their knowledge and perception of lithium prior to learning about the trial to minimize the bias in their responses.

This study identified a lack of knowledge about indications, side effects and dosage of lithium in the general population, patients with long bone fractures and orthopaedic surgeons that have the potential to delay early adoption, even with strong clinical evidence. Development of a robust educational framework for orthopaedic surgeons, their patients and the members of their clinical care teams will be essential to translation. Ultimately, the success of lithium in the context of fracture healing with early adopters will be needed to drive widespread acceptance of repurposing of this drug into orthopaedic fracture care.