New hope for treatment of nonalcoholic fatty liver disease?

Current clinical testing has honed in on nonalcoholic steatohepatitis (NASH), yet no treatment exists for this deadly condition. In a recent article published in Medical Hypothesis, experts hypothesized that the antiosteoporotic denosumab, an inhibitor of nuclear factor kappa-B ligand (RANKL), could treat NASH. Denosumab is a human monoclonal IgG2 antibody that is indicated for the treatment of postmenopausal, male, and glucocorticoid-induced osteoporosis, as well as metastatic bone disease.

“Congenital or acquired aberrations in RANK/RANKL/osteoprotegerin axis have been associated with osteoporosis and other metabolic bone diseases,” wrote the authors. “We hypothesized that hepatic RANKL upregulation may be positively associated with hepatic steatosis and inflammation, thus playing a role in the pathogenesis of NAFLD [nonalcoholic fatty liver disease].” Of note, osteoprotegerin is a circulating decoy receptor of RANKL, and attenuates RANK stimulation.

To test this hypothesis, the authors recommended first evaluating the effect of denosumab on transgenic mice that overexpress human RANKL. Second, researchers would perform observational, case-control studies of hepatic RANK/RANKL/osteoprotegerin expression. Third, if results based on animal models and case-control studies are positive, a proof-of-concept clinical trial with NASH patients could be undertaken, eventually followed by randomized clinical trials. 

Limitations

One potential limitation cited by the authors involves discrepancies between circulating levels of RANKL in animals and humans. “It should be noted that commercially available kits for circulating RANKL levels do not always provide optimal results,” they noted. “[F]urthermore, circulating RANKL levels may originate from diverse tissues and may largely differ from those on distinct tissue level (eg, liver, bone).” 

In preclinical models, support of the RANK/RANKL/osteoprotegerin axis is apparent. Mice fed a high-fat diet demonstrated increased levels of RANKL and decreased levels of osteoprotegerin. Additionally, these high-fat diets increased circulating RANKL concentrations and decreased osteoprotegerin concentrations.

In mice, gradually ramping up hepatic and circulating RANKL levels placed them on a continuum of control to steatosis to NASH. This same research showed that RANKL expression was correlated with Runt-related transcription factor 2 (Runx2) in hepatic stellate cells, indicating that RANKL acts as a mediator of Runx2-induced macrophage migration. This finding jibed with earlier findings that blocking RANKL signaling—either by knockout or drugs—in mice fed high-fat diets enhanced hepatic insulin resistance; hepatic insulin resistance is integral to NAFLD pathogenesis. Moreover, this improvement was observed sans changes in body fat or weight. Notably, RANKL is  a prototypic activator of nuclear factor kappa-B (NF-κВ), which is key in the development and progression of NAFLD.

The authors stressed, however, that some clinical evidence supporting their hypothesis is nebulous. Specifically, decreased circulating levels of osteoprotegerin, as well as an inverse relationship between osteoprotegerin and NAFLD, were noted in diabetic patients with NAFLD. But, although lower in those with hepatic fibrosis, circulating RANKL levels were comparable in patients with and without steatosis.

Importantly, the authors wrote that administration of denosumab to a woman with osteoporosis and NASH improved her liver function tests. Furthermore, rates of NAFLD are higher in postmenopausal women, who also exhibit RANKL upregulation. 

NAFLD, which has recently been redubbed metabolic-associated fatty liver disease (MAFLD), is a worldwide scourge, occurring in a whopping 25% in the general population. It is directly linked to rises in obesity and type 2 diabetes mellitus. The most dangerous form of NAFLD is NASH, with NASH complicated by fibrosis predicting substantial morbidity and mortality. 

Some studies have demonstrated that maintaining a healthy diet is correlated with lower accumulation of fat in the liver and lower risk for developing hepatic steatosis. Observational studies have shown that exposure to ultraviolet radiation mitigates the development of NAFLD.

The bottom line

The authors of the Medical Hypothesis article concluded by highlighting potential idiosyncrasies in treatment with denosumab or other anti-RANKL drugs (eg, recombinant osteoprotegerin). They noted that it would be nearly impossible to effectively treat every NASH patient with the drug because of the multifactorial nature of NAFLD. Consequently, personalized management of NASH would require different drugs or combinations of drugs. Ultimately, the repurposing of denosumab or other anti-RANKL medications could prove helpful in only a subpopulation of NASH patients.