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Novel Strategy Identified for Treating Osteoporosis

Key findings

  • This study tested the efficacy of YKL-05–099, an oral drug that inhibits salt inducible kinases (SIKs), in a mouse model of postmenopausal osteoporosis
  • YKL-05–099 led to gains in bone formation and trabecular bone mass comparable to those with the currently-used osteoporosis treatment parathyroid hormone (PTH), and unlike PTH, it did not stimulate bone resorption. However, mild increases in glucose and blood urea nitrogen were noted
  • In contrast, mice with global Sik2/Sik3 deletion showed dramatic bone formation without hyperglycemia or nephrotoxicity—but increased bone resorption was observed
  • YKL-05–099 also potently inhibited CSF1R, the receptor for a cytokine (M-CSF) that plays a key role in bone resorption by osteoclasts
  • Oral medications that target both SIKs and CSF1R may overcome the limitations of current anabolic osteoporosis therapies, which can concomitantly stimulate bone resorption

Most patients with osteoporosis receive drugs that aim to slow down bone resorption (bisphosphonates and denosumab), but this approach usually fails to fully reverse bone loss. A more recent development is parathyroid hormone–based therapies that stimulate bone formation (teriparatide and abaloparatide), but patients must inject them and they can concomitantly stimulate bone resorption.

Researchers at Massachusetts General Hospital previously reported in Nature Communications that parathyroid hormone signaling in osteocytes works primarily by suppressing salt inducible kinases (SIKs). The paper also showed that an orally available SIK inhibitor, YKL-05–099, mimics many actions of the parathyroid hormone.

Now, Cheng-Chia Tang, PhD, research fellow, and Marc N. Wein, MD, PhD, clinician and researcher in the Mass General Endocrine Unit, and colleagues have documented both bone-stimulating and anti-resorptive effects of YKL-05–099. As they explain in eLife, this promising profile is due to inhibition of two distinct targets in bone, representing a novel treatment strategy for osteoporosis.

Efficacy and Safety of YKL-05–099

The researchers tested systemic YKL-05–099 in female mice following the removal of their ovaries. The drug led to gains in bone formation and trabecular bone mass comparable to those with parathyroid hormone, and unlike parathyroid hormone, it did not stimulate bone resorption.

After four weeks of YKL-05–099 treatment, though, the mice showed mild but significant increases in blood urea nitrogen (BUN) and fasting glucose.

Sik2/Sik3 Deletion

YKL-05–099 is a multi-kinase inhibitor, and the researchers investigated whether some of its effects are related to non-SIK targets. They bred mice to have adult-onset global Sik2/3 deletion.

Unlike YKL-05–099 treatment, Sik2/3 deletion was associated with dramatically increased bone formation and bone resorption. Another difference was that Sik2/3 deletion had no effect on BUN or glucose levels. Therefore, the mild toxicities of YKL-05–099 noted in the earlier experiments were probably due to SIK1 inhibition or off-target effects.

Dual Therapeutic Targets

To explore potential off-target effects, the team conducted protein modeling studies. YKL-05–099 bound similarly to SIK2 and CSF1R, the receptor for M-CSF, a cytokine that's key to generating osteoclasts (the cells that break down bone). In vitro, YKL-05–099 blocked M-CSF action in osteoclast lineage cells.

It seems YKL-05–099 uncouples bone formation and bone resorption by inhibiting both SIKs and CSF1R. Next-generation oral drugs that target CSF1R, as well as SIKs (probably SIK2 and SIK3), may overcome the limitations of many current anabolic osteoporosis therapies.

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