INTRODUCTION

It has recently been suggested that the term “subchondral insufficiency fracture of the knee” (SIFK) should replace the historical “spontaneous necrosis of the knee” (SONK) nomenclature due to evidence that SONK usually does not manifest spontaneously nor present with necrotic bone on histologic entities (Hussain et al. 2017). Rather, SIFK has been described as sequela of mechanical overloading of the knee, which is often attributable to meniscal lesions and extrusion (Hussain et al. 2017; Pareek et al. 2020). Despite the revised nomenclature, the optimal management of these lesions at initial presentation remains challenging. Patients with SIFK have demonstrated high rates of pain, chondral thinning, and progression to arthroplasty (Pareek et al. 2020; Filardo et al. 2015; Meier et al. 2013; Pareek et al. 2019; Strauss et al. 2011). It is necessary for orthopedic surgeons to understand pharmacologic treatment options in order to improve outcomes and ideally prevent arthroplasty in this patient population.

The goal of pharmacologic management of SIFK is to delay the progression of bone resorption while allowing for sufficient revascularization and mineralization of new bone to maintain the structural integrity of the subchondral bone (Meier et al. 2013). The two most commonly proposed drug classes for the treatment of SIFK, prostaglandins and bisphosphonates, target this pathway to improve blood supply, suppress extensive bone remodeling, and reduce pain (Kon et al. 2016). Prostaglandins cause vasodilation of the microvasculature and act as an anti-inflammatory agent, essentially decreasing local leukotriene concentration (Aktan et al. 1994; Erlansson et al. 1991; Erlansson, Svensjö, and Bergqvist 1989; Grant and Goa 1992). Bisphosphonates decrease bone resorption in metabolically active remodeling sites through osteoclast inhibition and reduce pain by inhibiting the local release of neuromediators (Meier et al. 2013; Buma et al. 1992; Cornish et al. 2011).

Recent studies have suggested that administration of pharmacologic agents may help improve clinical outcomes in animal models and in the clinical treatment of insufficiency fractures of the femoral head and talus (Bhatnagar et al. 2018; Breer et al. 2012; Jureus et al. 2012; Kraenzlin et al. 2010; Meier et al. 2013). As a result, bisphosphonates and prostaglandins have been proposed as possible treatment options for SIFK. However, limited data exist on the proposed treatment protocols, adverse effects, and clinical efficacy. Therefore, the purpose of this evidence-based opinion was to report on the clinical efficacy of pharmacologic treatment in patients with SIFK and to report on the adverse effects of pharmacologic treatment.

CLINICAL SAFETY & EFFICACY

The antiresorptive and analgesic properties of bisphosphonates have been reported to be effective in eleven prior studies. Although the exact mechanism of action for SIFK management is unclear, bisphosphonates can improve clinical symptomology by reducing subchondral lesion size (Bhatnagar et al. 2018; Kraenzlin et al. 2010; Agarwala, Sharoff, and Jagani 2019; Bartl, Imhoff, and Bartl 2012; Müller et al. 2019; Zippelius et al. 2018; Vasiliadis et al. 2021), reducing pain (Bhatnagar et al. 2018; Breer et al. 2012; Kraenzlin et al. 2010; Agarwala, Sharoff, and Jagani 2019; Bartl, Imhoff, and Bartl 2012; Müller et al. 2019; Vasiliadis et al. 2021; Kchler, Fehr, and Jeker 2020), and improving subjective function (Bhatnagar et al. 2018; Bartl, Imhoff, and Bartl 2012; Zippelius et al. 2018; Vasiliadis et al. 2021; Kchler, Fehr, and Jeker 2020; Baier et al. 2012). Similarly, iloprost has shown to be effective in reducing lesion size (Zippelius et al. 2018; Baier et al. 2012; Mayerhoefer et al. 2008, 2007) and pain (Baier et al. 2012; Mayerhoefer et al. 2008; Aigner et al. 2008), while also demonstrating accelerated healing rates as compared to analgesics (Mayerhoefer et al. 2008, 2007) and ibandronate (Baier et al. 2012) interventions. Oral iloprost has also demonstrated a lower incidence of adverse effects than intravenous and oral bisphosphonate treatment, suggesting that it may be a safe and effective treatment option among the currently investigated agents (Mayerhoefer et al. 2008, 2007). Furthermore, while prostaglandin and bisphosphonate treatments have been shown to have no significant differences in outcomes when directly compared, prostaglandins may offer additional therapeutic benefit by decreasing the duration of treatment and recovery time (Baier et al. 2012). Overall, these data highlight the early potential of such pharmacologic agents for the conservative treatment of patients using SIFK, with the majority of current bisphosphonate studies and all current prostaglandin studies describing beneficial effects including regression of radiographic lesion size, reduction in pain, acceleration of healing, or functional improvements from baseline after treatment. Therefore, these effects may demonstrate their possible role in protecting the structural integrity of the overlying knee cartilage. However, future placebo-controlled studies with consistent protocols and clinical reporting are needed to further elucidate the optimal pharmacologic treatment options before definitive clinical recommendations for SIFK management can be made.

Adverse reactions have been reported with the clinical use of bisphosphonates and prostaglandins for the treatment of SIFK. Among specific drugs, zoledronic acid has the highest rate of reported adverse effects (33%) among all agents (Müller et al. 2019), while oral iloprost has the lowest rate of reported adverse effects (0%) (Mayerhoefer et al. 2008, 2007). The most common adverse effects reported in patients include headache, fever, flu-like symptoms, and myalgia which are highly associated with intravenous protocols. Overall, there is a low incidence of adverse effects with prostaglandin administration and, to date, all reported reactions are solely limited to intravenous prostaglandin infusions (Baier et al. 2012; Gao et al. 2015). While no studies have directly compared the outcomes and side effect profiles between routes of administration for either prostaglandins or bisphosphonates, oral administration may be a promising alternative to infusions as oral agents appear to have lower rates of adverse reactions while providing clinical feasibility for the treatment of SIFK.

TREATMENT PROTOCOLS

When evaluating different treatment protocols reported in the literature, there is a high rate of heterogeneity in treatment protocols for both prostaglandin and bisphosphonate classes to treat SIFK including route of administration, dosage, frequency, and duration of treatment. Bisphosphonates have been administered either in isolation (Jureus et al. 2012; Bartl, Imhoff, and Bartl 2012; Baier et al. 2012) or as a part of a combination therapy regimen with vitamin D supplementation (Meier et al. 2013; Breer et al. 2012; Kraenzlin et al. 2010; Müller et al. 2019), NSAIDs (Meier et al. 2013; Bhatnagar et al. 2018), or alprostadil (Gao et al. 2015). Prostaglandin therapy has been described either in isolation (iloprost) (Zippelius et al. 2018; Baier et al. 2012; Mayerhoefer et al. 2008, 2007; Aigner et al. 2008) or in combination therapy (alprostadil with alendronate) (Gao et al. 2015). There is also heterogeneity among study designs and between comparison groups in Level-I and II clinical trials, which further limits the ability to provide a definitive clinical recommendation for the use of pharmacologic agents in treating SIFK. Therefore, as the inconsistency in reported treatment protocols and the heterogeneity of study designs and comparison groups of Level-I and II studies may provide an explanation for conflicting evidence for pharmacologic efficacy, future studies should focus on optimizing currently reported treatment protocols by conducting long-term, controlled investigations with analgesic or placebo comparison groups. Treatment protocols of bisphosphonates and prostaglandins reported for the treatment of SIFK are summarized in Table 1.

Table 1.Summary table of reported treatment regimens for subchondral insufficiency fractures of the knee (SIFK).
Medication
and ROA		 Number of Reported Protocols Sample Size (n) Dosage Frequency Duration Adverse Reactions (rate) Final Follow Up (mean, range)
Intravenous iloprost N=3 32 20-50 mcg or 0.5mg/kg/min over 5-6 hours 5 total infusions 5 days Headache (6.25%), increasing pain (12.5%), flush-like symptom (9.4%), facial rash (18.8%), all occurring during first 30 min of infusion
All symptoms except headache dissipated with slowing infusion rate		 17.7 months (8-33)
Intravenous ibandronate N=3 48 3-6 mg 1-3 total infusions 3 months Mild acute-phase reactions with flu-like symptoms (20%).
Musculoskeletal pain (4.1%)		 21.8 months (12-64)
Oral iloprost N=2 35 Days 1-3: 50 mcg
After day 3: 50 – 100 microg		 Days 1-3: 3x daily
After day 3: Range: 50 microg 2x daily up to 2x50 microg 3x daily		 4 weeks 0% 7.5 months (3-12)
Oral alendronate and intravenous alprostadil N=1 20 alendronate – 70 mg
Alprostadil – 10 mcg		 1x/week
1x/day		 NR Alprostadil – headache (15%), facial rash (10%) during first 1 hr. of transfusion
alendronate – 0%		 13 months
Intravenous Ibandronate + oral vitamin D N=3 19 ibandronate - 3-13.5 mg
vitamin D – 400-20,000		 2-5 total infusions
1x/day to 1x/week		 1 year ibandronate – myalgia, flu-like symptoms, exhaustion, fever (3.67%) 7.5 months (4-12)
Oral ibandronate + NSAID (etoricoxib) N=1 8 ibandronate – 150 mg
etoricoxib – 120 mg		 ibandronate – 1x per month
etoricoxib – 1x per day		 ibandronate – 1 year
etoricoxib – 2 weeks		 Adverse reactions were not reported 12 months
Oral alendronate N=1 17 70 mg 1x/week Minimum 6 mo. (range, 6-21) Gastrointestinal symptoms (5.9%)
Unspecified (5.9%)		 12 months
Intravenous pamidronate/oral alendronate
+ vitamin D		 N=1 28 pamidronate – 120 mg
alendronate – 70 mg
vitamin D – 400 – 800 IU		 3 - 4 infusions
1x/week
1x/day		 First two weeks
4 – 6 months after first two weeks
6 months		 pamidronate acute phase reaction (14.3%) with arthralgias and myalgias
alendronate – 0%
vitamin D – 0%		 6-12 months
IV zoledronic acid + oral alendronate with calcium, vitamin D, and NSAIDs N=1 11 zoledronic acid – 5 mg/100ml
alendronate – 70 mg		 Single infusion of ZA
2 doses of 35 mg/day		 First week
16 weeks		 0% 16 weeks
IV zoledronic acid N=1 32 zoledronic acid – 5 mg/100ml Single infusion First week Myalgias – 0.07% 6 months

mcg; micrograms, mg; milligrams, OA; osteoarthritis. BME; bone marrow edema. ROA; route of administration. NR; not reported.

The authors acknowledge limitations that are inherent to an evidence-based opinion article as well as the heterogeneity among presented research studies and complexity of the pathological condition. The clinical outcomes of SIFK may be influenced by the management of the underlying etiology of SIFK (Hussain et al. 2017). Furthermore, failure to address meniscal root pathology or iatrogenic cartilage damage secondary to arthroscopy may negatively affect the outcomes of patients receiving pharmacologic treatment for SIFK. Due to an historical lack of clarity in the definition of SIFK, there are several overlapping etiologies which may influence the efficacy of bisphosphonates and prostaglandins.

CONCLUSION

This evidence-based opinion article highlights the preliminary evidence that both bisphosphonates and prostaglandins may be safe and beneficial agents for the treatment of SIFK. Further placebo-controlled trials with consistent treatment protocols and long-term clinical outcomes are necessary before definitive clinical recommendations can be made.