Exercise for Postmenopausal Bone Health - Can We Raise the Bar?

Abstract

Purpose of review: This review summarises the latest evidence on effects of exercise on falls prevention, bone mineral density (BMD) and fragility fracture risk in postmenopausal women, explores hypotheses underpinning exercise-mediated effects on BMD and sheds light on innovative concepts to better understand and harness the skeletal benefits of exercise.

Recent findings: Multimodal exercise programs incorporating challenging balance exercises can prevent falls. Emerging clinical trial evidence indicates supervised progressive high-intensity resistance and impact training (HiRIT) is efficacious in increasing lumbar spine BMD and is safe and well-tolerated in postmenopausal women with osteoporosis/osteopenia. There remains uncertainty regarding durability of this load-induced osteogenic response and safety in patients with recent fractures. Muscle-derived myokines and small circulating extracellular vesicles have emerged as potential sources of exercise-induced muscle-bone crosstalk but require validation in postmenopausal women. Exercise has the potential for multi-modal skeletal benefits with i) HiRIT to build bone, and ii) challenging balance exercises to prevent falls, and ultimately fractures. The therapeutic effect of such exercise in combination with osteoporosis pharmacotherapy should be considered in future trials.

Keywords: Exercise; Fragility fractures; Osteopenia; Osteoporosis; Postmenopausal; Resistance exercise; Weightbearing exercise.

Fig. 1

Osteocytic changes in sclerostin expression mediate bone mechanotransduction to skeletal loading. MSC = mesenchymal stem/stromal cell; LRP = low-density lipoprotein receptor-related protein; GSK-3β = glycogen synthase kinase-3 beta; CKIα = casein kinase 1 alpha; APC = adenomatous polyposis coli; TCF/LEF = T cell factor/lymphoid enhancer factor family of transcription factors. Figure created with BioRender.com. Figure 2A represents a skeletally ‘unloaded’ model, for example during sedentary activity. Minimal strain is detected by the mechanosensitive osteocytes resulting in upregulation of SOST expression. Increased sclerostin inhibits the canonical Wnt signalling pathway in mesenchymal stem/stromal cells by preventing binding of Wnt proteins to the LRP/frizzled receptor complex, ultimately resulting in ubiquitin-mediated proteolysis of cytosolic β-catenin and hence inhibition of β-catenin mediated changes in osteogenic gene expression. Figure 2B represents a skeletally ‘loaded’ model, for example during HiRIT. Increased strain is detected by the mechanosensitive osteocytes resulting in downregulation of SOST expression. Reduced sclerostin allows Wnt to active LRP/frizzled receptor complex, ultimately resulting in protection of β-catenin against proteolysis, β-catenin nuclear translocation and modulation of transcription factors involved in gene expression promoting osteogenic differentiation

Fig. 2

Conceptual representation of potential mechanisms for osteogenic effects of exercise. HiRIT = high-intensity resistance and impact training; IL-6 = interleukin-6; sEVs = small extracellular vesicles; SOST = sclerostin gene; MSC = mesenchymal stem/stromal cell. Figure created with BioRender.com. HiRIT in a postmenopausal woman may exert positive effects on bone tissue through various musculoskeletal pathways. The increased skeletal load (strain) is detected by mechanosensitive osteocytes embedded in the bone matrix. Osteocytes then downregulate SOST expression which results in increased osteogenic differentiation (mesenchymal stem/stromal cells undergo differentiation into bone-forming osteoblasts). Activation of skeletal muscle tissue may also trigger release of myokines known to modulate bone metabolism (IL-6, irisin, myostatin) or other myokines/mediators travelling in muscle-derived small extracellular vesicles