News from the World: Future New Kids on the Block for the treatment of osteoporosis? By Elena Tsourdi

Dual antibodies against Dickkopf-related protein 1 (DKK1) and sclerostin

Dual antibody therapy targeting both Dickkopf-related protein 1 (DKK1) and sclerostin is supported by robust preclinical evidence for synergistic anabolic effects on bone mass and fracture healing. In multiple animal models, including rodents and non-human primates, dual inhibition of DKK1 and sclerostin—either via bispecific antibodies or combination therapy—results in greater increases in bone mineral density, bone strength, and fracture repair compared to monotherapy with either agent alone [1-3]. Mechanistically, sclerostin inhibition upregulates DKK1, which can limit the anabolic response; thus, co-inhibition overcomes this compensatory feedback and enhances Wnt signaling-driven bone formation.

Recent studies in non-human primates demonstrate that combination therapy not only improves systemic bone mass but also augments local bone healing, with DKK1 inhibition preferentially enhancing fracture repair and sclerostin inhibition driving systemic bone accrual [2]. Unique skeletal effects, such as pronounced skull thickening, have been observed with dual inhibition, indicating distinct biological consequences compared to sclerostin inhibition alone [4].

Salt-inducible kinase inhibitors

Salt-inducible kinase inhibitors (SIKs) are key regulators of bone metabolism, acting downstream of parathyroid hormone receptor signaling to modulate osteoblast and osteocyte function. Small molecule SIK inhibitors, such as YKL-05-099, have been shown in murine models to increase bone formation and bone mass, mimicking the anabolic effects of intermittent parathyroid hormone (PTH) therapy [5]. Importantly, SIK inhibition can uncouple bone formation from bone resorption. YKL-05-099 increases bone formation without a concomitant increase in bone resorption, partly due to dual inhibition of SIKs and CSF1R, the latter suppressing osteoclastogenesis [5]. SIK inhibitors also stimulate fracture mineralization and accelerate callus formation in animal models, further supporting their anabolic potential [6].

References

1. Florio M, Gunasekaran K, Stolina M, et al. A bispecific antibody targeting sclerostin and DKK1 promotes bone mass accrual and fracture repair. Nat Commun. 2016;7:11505.
2. Florio M, Kostenuik PJ, Stolina M, et al. Dual inhibition of the WNT inhibitors DKK1 and sclerostin promotes fracture healing and increases the density and strength of uninjured bone: An experimental study in nonhuman primates. J Bone Joint Surg Am. 2023;105:1145-1155.
3. Choi RB, Hoggatt AM, Horan DJ, et al. Targeting sclerostin and DKK1 at optimized proportions of low-dose antibody achieves similar skeletal benefits to higher-dose sclerostin targeting in the mature adult and aged skeleton. Aging Dis. 2022;13:1891-1900.
4. Bienvenu JG, Chouinard L, Felx M, et al. Inhibition of both sclerostin and DKK1 results in novel skull findings in the rat and non-human primate that is not observed with inhibition of sclerostin alone. Bone. 2024;179:116985.
5. Tang CC, Castro Andrade CD, O’Meara MJ, et al. Dual targeting of salt inducible kinases and CSF1R uncouples bone formation and bone resorption. eLife. 2021;10:e67772.
6. Momenzadeh K, Yeritsyan D, Abbasian M, et al. Stimulation of fracture mineralization by salt-inducible kinase inhibitors. Front Bioeng Biotechnol. 2024;12:1450611.