metabolism, structural integrity, and architecture might render the bone more susceptible to aberrant loading or even induce abnormal reactions to normal physiological load. OA-related changes in subchondral bone structure were long regarded as an adaptation of bone to the biomechanical changes observed in articular cartilage. Recently, several pre-clinical and clinical studies demonstrated that alterations in bone structure might even precede and instead mediate cartilage pathology 61, 62 and that OA progression is associated with temporal changes in bone structure 60. In early OA, accelerated bone turnover leads to bone plate thinning and increased porosity, whereas the trabecular compartment shows increased trabecular spacing and decreased bone volume fraction. Progression of OA is accompanied by subchondral bone plate thickening, increased trabecular thickness, and increased bone volume fraction 60. Bone marrow lesions (BMLs), a hallmark of OA, appear early on MRI and are associated with increased pain and cartilage degeneration 63. Therapies with bisphosphonates Bisphosphonates (BPs) effectively slow down bone turnover by inhibiting osteoclast activity in osteoporosis, but their usability in OA remains uncertain 18. There are indications that a specific patient subgroup might respond to BP use: intravenous zoledronic acid successfully reduced BML size and visual analogue scale (VAS) pain score after 6 months in a randomized controlled trial, though a second multicenter trial could not confirm the results 16, 17. Furthermore, a meta-analysis by Vaysbrot et al. identified similar effects in a trial using oral risedronate treatment in a patient subgroup with BMLs 18. An active phase III trial (NCT02746068) using AXS-02 (disodium zoledronate tetrahydrate) in knee OA with associated BMLs provided promising results in the reduction of pain supposedly by suppression of local acid and pro-inflammatory cytokine production 64. The ongoing phenotype debate in OA raised the question of whether the effectiveness of BPs has been confounded owing to the heterogeneity of the patient group enrolled in clinical trials so far 64. Indeed, BPs might be especially beneficial in patients with BML or high bone turnover in an early state of OA. Interestingly, pharmacologic agents like BPs that directly affect osteoclast activity effectively reduced pain. Recent research identified osteoclasts as the inducers of OA bone pain by induction of sensory innervation in a murine OA model 65. Determination of more of these connections and more precise categorization of patient subgroups (like bone pain due to BML development or increased osteoclast activity/bone turnover) might lead to the repurposing of already existing drugs for new targets. Drugs targeting bone cells New therapeutic approaches include neutralization of cathepsin K, the major osteolytic protease released by osteoclasts. The “small molecule” cathepsin K inhibitor MIV-711 effectively attenuated joint pathology in a rabbit OA model 66 and slowed bone and cartilage degeneration in a phase IIa multicenter trial of primary knee OA 20. With 26 weeks’ duration, the study was relatively short, and MIV-711 did not reduce pain during this time . Denosumab, a monoclonal antibody directed against RANKL and thereby inhibiting osteoclastogenesis, is currently tested in erosive OA of interphalangeal finger joints (NCT02771860) and in knee OA (DISKO, ISRCTN96920058), but results have not been published to date. Potential new targets to address subchondral bone include TGFβ, which is elevated in OA synovial fluid 67. Systemic blocking of TGF prevented bone and cartilage degeneration in a rodent OA model 68, but targeting this specific molecule needs to take into consideration the physiological role of TGFβ as a differentiation stimulus for chondrocyte precursor cells 67. Furthermore, OA bone is targeted by anabolic therapies. Teriparatide, a synthetic parathyroid hormone, effectively reduced chondrocyte apoptosis and attenuated OA progression after i.a.