Recent osteoporosis guidelines increasingly recommend osteoanabolic treatments as preferred initial therapy for patients at very high risk of fracture. Established osteoanabolic agents include injectable drugs like abaloparatide, teriparatide, and romosozumab, which have been have been shown to significantly increase bone mineral density (BMD) and reduce fracture risk more effectively than traditional antiresorptives (e.g., bisphosphonates or denosumab) when used as initial treatment. The latest trends in oral osteoanabolic therapy are toward developing effective oral small molecule or peptide-based anabolic agents to complement or replace injectable options, improving patient convenience and adherence while continuing to focus on maximizing bone density gains and fracture prevention in severe osteoporosis.
One promising compound is a small molecule salt inducible kinase (SIK) inhibitor named SK-124, developed by a research team led by Dr. Marc Wein at Massachusetts General Hospital. The oral osteoanabolic agent SK-124 is a novel small molecule that inhibits salt-inducible kinases (SIK2 and SIK3), enzymes involved in the parathyroid hormone (PTH) signaling pathway that regulates bone formation. SK-124 mimics PTH-like effects and has demonstrated osteoanabolic activity when given orally to mice, significantly increasing bone formation and bone mass without short-term toxicity (1). The next steps in the clinical development of SK-124 for osteoporosis treatment primarily involve further preclinical and early-stage clinical work. Concrete focus areas include a) conducting longer-term preclinical studies to determine whether the bone anabolic effects of SK-124 persist over time and to monitor for any potential side effects or toxicity with extended use, b) evaluating the metabolic and cardiovascular impacts of SIK2/SIK3 inhibition, since salt-inducible kinases have roles beyond bone, such as in adipose tissue metabolism, glucose homeostasis, and other physiological systems and c) investigating new small-molecule “degrader” technologies that might allow tissue-specific degradation of SIK2/SIK3, improving the safety profile. Ultimately, once preclinical evaluation supporting safety has been established, first-in-human clinical trials focusing initially on dose ranging, pharmacodynamics, and safety assessments are awaited.
Reference:
Sato T et al. Proc Natl Acad Sci U S A. 2022;119(50):e2214396119.