Bone Formation Promoting Agents (Anabolics)
1. Parathyroid Hormone (PTH) Analogs
Fundamentally, parathyroid hormone (PTH) is a catabolic hormone that stimulates bone resorption to maintain blood calcium levels in conditions of calcium deficiency. Paradoxically, however, intermittent administration of PTH can induce mesenchymal stromal cells to proliferate and differentiate into osteoblasts, thereby increasing bone formation through an anabolic mechanism. This occurs primarily through the activation of the Wnt/β-catenin pathway by PTH, which promotes osteoblast differentiation, and through the inhibition of sclerostin (SOST) expression in osteocytes, a known antagonist of the Wnt/β-catenin pathway.
The key lies in the "intermittent" mode of administration. Prolonged exposure to elevated levels of PTH increases RANKL expression, leading to osteoclast activation and a predominance of bone resorption. To understand this in more detail, we will examine two representative synthetic PTH analogs that promote bone formation: teriparatide and abaloparatide. First, let’s explore the molecules PTH and PTH-related peptide (PTHrP), which are the active components of these drugs.
*See Wnt/β-catenin pathway reference.
PTH and PTH-related Peptide (PTHrP)
PTH is secreted from the parathyroid glands and mainly targets the kidneys and bones. In response to low calcium levels, PTH stimulates bone resorption to replenish blood calcium and promotes the activation of the 1α-hydroxylase enzyme in the kidneys, converting vitamin D to its active form and enhancing calcium reabsorption.
PTH-related peptide (PTHrP) is expressed in various tissues, including the cardiovascular system, kidneys, lungs, bladder, uterus, placenta, mammary glands, stomach, pancreas, bone, cartilage, and teeth. It is locally produced in osteoblast precursor cells and promotes the differentiation of mature osteoblasts and bone formation.
Both PTH and PTHrP bind to the parathyroid hormone type 1 receptor (PTH1R). PTH consists of 84 amino acids secreted from the parathyroid glands, with biological activity concentrated in the N-terminal 1-34 amino acids. PTHrP is a peptide with an N-terminal sequence highly similar to the 1-34 amino acid region of PTH and is locally synthesized in various tissues, mimicking the physiological functions of PTH. Despite their similarities, PTH and PTHrP differ significantly in their interactions with their common receptor, PTH1R.
G Protein-Coupled Receptors (GPCRs)
PTH1R is a transmembrane receptor belonging to class B of the G protein-coupled receptor (GPCR) family. Briefly, GPCR signaling operates as follows: when a ligand binds to the transmembrane domain receptor spanning the cell membrane 7 times, it induces a conformational rearrangement, activating the receptor. As the name implies, GPCRs couple with G proteins composed of three subunits: α, β, and γ. Upon activation, the Gα subunit exchanges GDP for GTP and dissociates from the Gβγ complex. The Gα subunit (classified into Gs, Gi, and Gq) then activates downstream effectors, and the Gβγ complex may also participate in signaling.
Main Signaling Pathway: cAMP/PKA Pathway
In bone, both PTH and PTHrP bind to the same receptor, PTH1R, initiating intracellular signaling mainly through the cAMP/PKA pathway. In some tissues, an auxiliary IP₃/DAG pathway is also involved. The cAMP/PKA pathway proceeds as follows: receptor binding activates the Gαs protein, which in turn activates adenylyl cyclase (AC). AC hydrolyzes ATP to form cAMP. cAMP then activates protein kinase A (PKA) by releasing its catalytic subunit, which translocates to the nucleus to phosphorylate and activate the transcription factor CREB (cAMP response element binding protein). Phosphorylated CREB binds to the CRE (cAMP response element) sequence in DNA, inducing transcription of target genes involved in osteoblast function and bone formation such as Runx2, osteocalcin, and collagen. This pathway also induces expression of 1α-hydroxylase, promoting vitamin D activation and calcium homeostasis.
In the auxiliary phosphatidylinositol (IP₃/DAG) pathway, receptor activation stimulates the Gαq protein, which activates phospholipase C (PLC). PLC hydrolyzes PIP₂ into IP₃ and DAG. IP₃ mobilizes intracellular Ca²⁺ from the endoplasmic reticulum, and DAG activates PKC in the presence of Ca²⁺, supporting osteoblast differentiation.
Signal Termination via β-Arrestin and Endosomal Internalization
After ligand binding and initiation of GPCR signaling, the receptor must be desensitized to prevent continuous activation. GRKs(G protein coupled receptor kinases) phosphorylate the receptor, enabling β-arrestin binding, which blocks G protein interaction. β-arrestin also facilitates receptor-ligand complex internalization through clathrin- and dynamin-mediated endocytosis. In the endosome, the ligand and phosphate groups are removed, and the receptor is either recycled to the membrane or degraded via lysosomes.[1] However, interestingly, some hormones, including PTH, continue to signal from the endosome. PTH1R remains active in the endosome, continuing to generate cAMP.[2] This sustained signaling mode is referred to as the R⁰ state, whereas classical membrane-bound activation is the Rᴳ state.
Two Receptor States of PTH1R: Rᴳ and R⁰
In the classical Rᴳ state, receptor activation is transient, producing short bursts of cAMP, which strongly stimulates osteoblasts while minimally activating osteoclasts. This favors bone formation over resorption. In contrast, sustained receptor activation in the R⁰ state leads to prolonged cAMP generation, stimulating both osteoblasts and osteoclasts, and potentially causing bone resorption and hypercalcemia.
Teriparatide vs. Abaloparatide
Among the two ligands, PTH shows a higher affinity for the R⁰ state, while PTHrP prefers the Rᴳ state. Teriparatide is a synthetic analog of human PTH, and abaloparatide is derived from human PTHrP. Due to its Rᴳ affinity, abaloparatide stimulates osteoblasts effectively with less osteoclast activation, resulting in a lower incidence of hip and non-vertebral fractures compared to teriparatide.[3] Of course, there are also reports indicating that there is no significant difference between the two drugs.[4]
In summary, PTH analogs increase osteoblast proliferation and activation, promoting bone formation. However, treatment is generally limited to 18-24 months due to the risk of dominant bone resorption. Intermittent administration is more effective. Abaloparatide is more commonly used due to its lower bone resorption profile. To preserve new bone mass, antiresorptive agents are often co-administered.
2. Sclerostin Inhibitors
Osteocytes are differentiated cells that originate from osteoblasts which, after completing bone formation, become embedded within the bone matrix they have produced. These cells act as sensory sensors that continuously monitor and assess the condition of bone through close communication with surrounding bone cells. When mechanical stimuli applied to bone tissue decrease due to factors such as lack of exercise, reduced gravity, or aging, osteocytes detect this change and respond by secreting a glycoprotein called sclerostin, which inhibits bone formation. This is considered an evolutionary mechanism to save energy and resources—there is no need to recruit various biological resources to unnecessarily reinforce bone in areas experiencing reduced mechanical load. Although exercise can cause micro-damage requiring bone resorption and subsequent bone formation for repair, when mechanical loading decreases, the necessity for such remodeling diminishes. As differentiation of osteoblasts declines, the differentiation of coupled osteoclasts is also expected to decrease.
Sclerostin suppresses bone formation by inhibiting the Wnt/β-catenin pathway, which is essential for promoting osteoblast differentiation. For the Wnt/β-catenin pathway to be activated, the Wnt ligand must bind to the LRP5/6 receptors on osteoprogenitor cells. Sclerostin interferes with this binding, ultimately leading to the degradation of β-catenin, preventing it from entering the nucleus. As a result, the differentiation, proliferation, and survival of osteoblasts are inhibited.
Therefore, inhibiting sclerostin can promote osteoblast differentiation and improve bone mineral density. Furthermore, since sclerostin also stimulates the production of RANKL and suppresses OPG expression in osteoblasts and their precursors—thus indirectly promoting osteoclastogenesis—inhibiting sclerostin can simultaneously enhance bone formation and suppress bone resorption, offering a dual therapeutic effect.
Romosozumab is a humanized monoclonal antibody that targets sclerostin and has received FDA approval. It is known to be effective in rapidly increasing bone mineral density in patients with severe osteoporosis, thanks to its dual mechanism of promoting bone formation while inhibiting bone resorption.
The various medications used to treat osteoporosis are classified into two groups—antiresorptives, which inhibit bone resorption, and anabolics, which stimulate bone formation—and are summarized in the table below.
[References]
[1] Endosomal generation of cAMP in GPCR signaling
doi: 10.1038/nchembio.1611
[2] Endosomal PTH Receptor Signaling Through cAMP and Its Consequence for Human Medicine
DOI:10.1007/7355_2017_1
[3] Comparative Effectiveness of Abaloparatide and Teriparatide in Women 50 Years of Age and Older: Update of a Real-World Retrospective Analysis
https://doi.org/10.3389/fendo.2021.628994
[4] Teriparatide and Abaloparatide Have a Similar Effect on Bone in Mice
https://www.endocrinepractice.org/article/S1530-891X(24)00827-9/fulltext
