Impact of CDK4/6 Inhibitors on Aromatase Inhibitor-Associated Musculoskeletal Syndrome (AIMSS) in the Adjuvant Setting

Breast J. 2023 May 31:2023:3614296. doi: 10.1155/2023/3614296. eCollection 2023.


Background: Third-generation aromatase inhibitors (AIs) are the mainstay of treatment in hormone receptor (HR)-positive breast cancer. Even though it is considered to be a well-tolerated therapy, AI-induced musculoskeletal symptoms are common and may be accused for treatment discontinuation. Recently, selective cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors changed the therapeutic setting, and currently, ribociclib, palbociclib, and abemaciclib are all approved in combination with nonsteroidal AIs in patients with ER-positive, HER2-negative advanced or metastatic breast cancer. This systematic review aims to identify the frequency of aromatase inhibitor-associated musculoskeletal syndrome (AIMSS) in the adjuvant setting in patients under AI monotherapy compared to patients under combination therapy with AIs and CDK4/6 inhibitors and demonstrate the underlying mechanism of action.

Methods: This study was performed in accordance with PRISMA guidelines. The literature search and data extraction from all randomized clinical trials (RCTs) were done by two independent investigators. Eligible articles were identified by a search of MEDLINE and database concerning the period 2000/01/01-2021/05/01.

Results: Arthralgia was reported in 13.2 to 68.7% of patients receiving AIs for early-stage breast cancer, while arthralgia induced by CDK4/6 inhibitors occurred in a much lower rate [20.5-41.2%]. Bone pain (5-28.7% vs. 2.2-17.2%), back pain (2-13.4% vs. 8-11.2%), and arthritis (3.6-33.6% vs. 0.32%) were reported less frequently in patients receiving the combination of CDK4/6 inhibitors with ET.

Conclusions: CDK4/6 inhibitors might have a protective effect against joint inflammation and arthralgia occurrence. Further studies are warranted to investigate arthralgia incidence in this population.

Publication types

  • Systematic Review
  • Review

MeSH terms

  • Aromatase Inhibitors* / adverse effects
  • Arthralgia / chemically induced
  • Arthralgia / drug therapy
  • Breast Neoplasms* / pathology
  • Cyclin-Dependent Kinase 4
  • Female
  • Humans


  • Aromatase Inhibitors
  • Cyclin-Dependent Kinase 4
  • CDK4 protein, human