Despite there being many factors identified that regulate osteoblast-osteoclast interactions, currently very few of these pathways have resulted in approved therapeutics for the treatment of skeletal disorders. However, osteoblast–osteoclast interactions have played a powerful role in shaping the action of all currently approved drugs acting on the skeleton, including often imposing limitations on the activities of these agents. Most anti-resorptive agents inhibiting osteoclast formation and activity simultaneously suppress bone formation, whereas the activity of anabolic agents inducing bone formation are similarly tempered by simultaneously increasing bone resorption.

Denosumab is a humanized monoclonal antibody that binds RANKL and acts as an OPG-like RANK decoy receptor, disrupting the RANKL-RANK interaction and osteoclast differentiation, function, and survival, leading to a decrease in bone resorption. In patients, biannual administration of Denosumab increases bone density, and reduces the risk of vertebral, nonvertebral, and hip fractures [82]. However, as expected, inhibiting osteoclast formation by blocking RANKL-RANK signaling pathway results in reduction of osteoclast-derived coupling factors that induce osteoblast-mediated bone formation. Denosumab leads to an immediate and sustained decrease in markers of bone resorption such as urinary N-telopeptide (NTX) along with a delayed reduction in markers of bone formation, such as serum bone specific alkaline phosphatase (BSAP) [83,84].

Odanacatib, a selective cathepsin K (CTSK) inhibitor, suppresses osteoclast-mediated bone resorption [85,86]. CTSK is a cysteine proteinase, abundantly expressed in activated osteoclasts and secreted to extracellular space that cleaves the N-telopeptide of collagen [87]. CTSK mutation in humans causes pycnodysostosis, a rare skeletal dysplasia, characterized by short stature, an increase in the bone density of long bones, acroosteolysis of distal phalangers and skull deformities [88]. Despite the high bone mass phenotype, patients with pycnodysostosis suffer from bone fragility with a high incidence of pathological fractures [89]. Odanacatib has received a lot of attention as a potential osteoporosis drug since it inhibits osteoclast activity and function, rather than osteoclast generation, resulting in prevention of bone resorption with more modest overall effects on the ability of osteoblasts to form bone than most other anti-resorptive agents. It still remains unclear whether these effects reflect functional blockade of osteoclast-driven coupling processes or whether CTSK inhibition may have direct effects on CTSK-expressing periosteal mesenchymal progenitors [90,91]. Although odanacatib was highly effective in reducing fractures of postmenopausal women in clinical phase-3, its further development was discontinued due to concerns regarding risk of cerebrovascular events [92].

Parathyroid hormone (PTH), a bone anabolic agent, is normally secreted by the parathyroid glands and contributes to the maintenance of calcium homeostasis through its direct actions on bone cells. Intermittent PTH administration increases bone mass by recruiting mesenchymal stromal cells into osteoblast lineage and promoting the differentiation of osteoprogenitors into mature osteoblast [93,94]. Also, PTH downregulates sclerostin (SOST) expression from osteocytes, leading to a favorable environment for osteoblast differentiation and function through enhanced WNT signaling pathway [95,96]. However, continuous treatment results in an increase in net bone resorption due to increases in RANKL and decreases in the RANKL decoy receptor, OPG, in osteoblasts and osteocytes [97]. As seen in each of these examples, one of the most fundamental and enduring challenges in developing increasingly effective skeletal therapeutics is overcoming the osteoblast/osteoclast interaction effects that often blunt the activity of both anti-resorptive and anabolic drugs.