Nat Rev Endocrinol doi: 10.1038/s41574-020-00426-5. .
Over the past three decades, the mainstay of treatment for osteoporosis has been antiresorptive agents (such as bisphosphonates), which have been effective with continued administration in lowering fracture risk. However, the clinical landscape has changed as adherence to these medications has declined due to perceived adverse effects. As a result, decreases in hip fracture rates that followed the introduction of bisphosphonates have now levelled off, which is coincident with a decline in the use of the antiresorptive agents. In the past two decades, two types of anabolic agents (including three new drugs), which represent a novel approach to improving bone quality by increasing bone formation, have been approved. These therapies are expected to lead to a new clinical paradigm in which anabolic agents will be used either alone or in combination with antiresorptive agents to build new bone and reduce fracture risk. This Review examines the mechanisms of action for these anabolic agents by detailing their receptor-activating properties for key cell types in the bone and marrow niches. Using these advances in bone biology as context, the comparative effectiveness of these anabolic agents is discussed in relation to other therapeutic options for osteoporosis to better guide their clinical application in the future.
It is important to note that anabolic agents have had disproportionately greater expectations attached to their development and subsequent introduction into the clinical arena than any of the antiresorptive agents. The reasons for this high expectation are not entirely clear, except that the rationale for their use is very straightforward and hence predictable (that is they primarily target the osteoblast to drive new bone formation). It is, however, never that simple, as exemplified by the anabolic effects of teriparatide and abaloparatide. Starting the remodelling cascade with PTH1R activation via the osteoblast or osteocyte inevitably leads to increases in bone resorption as well. While resorption is a key event in initiating remodelling, the continual stimulation of resorption limits the extent of the ‘formation window’ and therefore the magnitude of bone density increases. An improved understanding of the direct actions of an anabolic agent on each cell type in the bone remodeling unit, and thereby its effect on the processes of independent or coupled resorption and formation, could provide key insights for treatment and dosing strategies that maximize this window of anabolic effect. While the clinical efficacy of anabolic agents has been established, and the commercial introduction of romosozumab has been hailed by many as the new treatment for the future, the true effectiveness of such therapies will take time to ultimately ascertain. Further elucidating the basic mechanisms in bone that drive the anabolic action of these agents will be key, in parallel with continued evaluation of their safety and efficacy, to optimizing long-term treatment strategies for improved patient outcomes.