Review articleBone biology, signaling pathways, and therapeutic targets for osteoporosis
Introduction
Discovery of new therapeutic targets for treatment of osteoporosis is important because of the limited efficacy and variable toxicities of currently approved agents. These agents, while significantly more effective than estrogen, have a relatively moderate ability to reduce hip, vertebral, and non-vertebral fractures. Current treatments reduce vertebral fracture risk significantly more than hip or nonvertebral fracture risk.
Currently approved agents in the U.S. include bisphosphonates, hormone therapy, raloxifene, calcitonin, teriparatide, or denosumab. Calcitonin was recently removed from the market in several countries due to concerns regarding cancer risk with an oral formulation used in clinical trials, and the FDA recently recommended against long-term treatment of osteoporosis with calcitonin. Teriparatide (PTH 1–34) and PTH 1–84 remain the only approved agents for stimulating new bone formation in some countries.
This narrative review will briefly summarize the bone biology relevant for understanding osteoporosis, describe the critical signaling pathways involved in bone resorption and bone formation and discuss potential therapeutic targets, and review data available for some of the newer agents developed against these targets.
Section snippets
Bone modeling and remodeling
The skeleton undergoes longitudinal and radial growth, modeling, and remodeling during life. Longitudinal and radial growth occurs during childhood and adolescence. Growth plates cause longitudinal growth due to cartilage proliferation in the epiphyseal and metaphyseal regions of long bones. Newly-produced cartilage mineralizes to form primary new bone. Radial growth occurs due to periosteal apposition during and after puberty, and also later in life with normal aging.
Modeling results in bones
Signaling pathways
Signaling pathways are critical in regulation of how osteoclasts and osteoblasts control bone turnover leading to bone loss after menopause and during normal aging. Activation of pathways that stimulate osteoclast recruitment and activation lead to bone loss unless other factors prevent this, and those that stimulate osteoblast recruitment and activation lead to bone formation, unless other factors prevent this. Whereas currently available agents used to treat osteoporosis mostly inhibit bone
Antiresorptive pathways
Antiresorptive agents reduce bone turnover relatively rapidly, by reducing bone resorption initially, follow by a slower reduction in bone formation. These changes lead to an altered balance between bone resorption and formation at a lower rate of bone turnover that favors an increase in BMD, preservation or strengthening of structural and material properties of bone, increase in bone strength, and reduction in fractures [39].
Anabolic pathways
Anabolic agents stimulate bone turnover significantly and relatively rapidly by stimulating bone formation initially, followed by slower stimulation of bone resorption. These changes lead to an altered balance between bone formation and resorption, at a higher rate of bone turnover, which leads to an increase in BMD, preservation or strengthening of structural and material properties of bone, increase in bone strength, and reduction in fractures.
Therapeutic targets for osteoporosis
Newer therapies for osteoporosis are targeted to molecules discovered during elucidation of signaling pathways in osteoclasts and osteoblasts (Table 1). The limitations of new therapies are mostly related to their specificity of action and safety. Agents that also affect tissues other than bone may result in off-target effects, which cause adverse events in clinical trials.
Antiresorptive agents
Most currently approved therapeutic agents primarily prevent bone loss. There is continued interest in development of new antiresorptive agents that offer selective advantages over existing agents. Because newer antiresorptive agents do not markedly suppress bone formation, and may uncouple bone formation from resorption, these compounds offer the potential of creating anabolic windows of variable magnitude and duration to stimulate new bone formation.
Anabolic agents
Anabolic agents increase bone strength by directly stimulating new bone formation. A number of potential targets for anabolic agents have been identified [68]. New parathyroid hormone (PTH) and PTH-related protein (PTHrP) analogues remain under development. New anabolic targets being evaluated stimulate the Wnt-signaling pathway in osteoblasts. Monoclonal antibodies to these targets block inhibition of the pathway, leading to stimulation of new bone formation.
Conclusions
Major advances have occurred recently in the treatment of osteoporosis. Patients are most often treated currently with bisphosphonates, denosumab, raloxifene, or teriparatide, and in some countries, strontium ranelate. Calcitonin has been removed from the market in some countries, and its use restricted in others, due to risk of malignancy. Use of strontium ranelate has been reduced due to cardiovascular concerns. These agents have generally provided excellent options that effectively reduce
Practice points
- •
Until the newer anabolic or antiresorptive agents are approved, physicians should continue to prescribe the current best agent uniquely suited for each patient.
- •
Use of the currently available agents should not preclude the use of new agents when these become available.
- •
Physicians and patients should be aware that, unlike the longer-acting bisphosphonates, all the newer agents are relatively shorter-acting, and have reasonably rapid offset of action.
- •
Physicians should consider using longer-acting
Research agenda
- •
Continue clinical trials of the available new antiresorptive and anabolic agents.
- •
Continue development of newer therapeutic agents currently undergoing preclinical evaluation.
- •
Continue preclinical research on agents targeting anabolic pathways other than the Wnt/β-catenin signaling pathway to expand options for treatment.
Conflict of interest
The authors declare no conflict of interest.
Authors’ contribution
Both authors contributed equally to the design, writing, and editing of this narrative review, submitted at the invitation of the Editor-in-Chief, Dr. Margaret Rees.
Funding
The authors have received no funding for this article.
References (88)
- et al.
Trabecular minimodeling in human iliac bone
Bone
(2003) - et al.
Significance of minimodeling in dialysis patients with adynamic bone disease
Kidney Int.
(2005) - et al.
Histomorphometric features of bone in patients with primary and secondary hyperparathyroidism
Kidney Int.
(2003) Targeted and nontargeted remodeling
Bone
(2002)Targeted and nontargeted bone remodeling: relationship to basic multicellular unit origination and progression
Bone
(2002)Cell biology of the osteoclast
Exp. Hematol.
(1999)- et al.
Microelectrode studies on the acid microenvironment beneath adherent macrophages and osteoclasts
Exp. Cell Res.
(1988) - et al.
Effects of TGFbeta and bFGF on the differentiation of human bone marrow stromal fibroblasts
Cell Biol. Int.
(1999) - et al.
Osteoclast-derived activity in the coupling of bone formation to resorption
Trends Mol. Med.
(2005) - et al.
Epidemiology and outcomes of osteoporotic fractures
Lancet
(2002)
Novel approaches to the treatment of osteoporosis
Best Pract. Res. Clin. Endocrinol. Metab.
Bisphosphonates: the first 40 years
Bone
Biochemical properties and regulation of cathepsin K activity
Biochimie
Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling
J. Biol. Chem.
SOST is a ligand for LRP5/6 and a Wnt signaling inhibitor
J. Biol. Chem.
Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin
J. Biol. Chem.
Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib
J. Am. Acad. Dermatol.
The single dose pharmacokinetic profile of a novel oral human parathyroid hormone formulation in healthy postmenopausal women
Bone
JTT-305, an orally active calcium-sensing receptor antagonist, stimulates transient parathyroid hormone release and bone formation in ovariectomized rats
Eur. J. Pharmacol.
A novel tetracycline labeling schedule for longitudinal evaluation of the short-term effects of anabolic therapy with a single iliac crest biopsy: early actions of teriparatide
J. Bone Miner. Res.
Osteoclast differentiation and activation
Nature
Recent advances in osteoclast biology and pathological bone resorption
Histol. Histopathol.
Matrix metalloproteinases (MMP) and cathepsin K contribute differently to osteoclast activities
Microsc. Res. Tech.
Normal and pathological remodeling of human trabecular bone: three-dimensional reconstruction of the remodeling sequence in normals and metabolic bone disease
Endocr. Rev.
Regulatory mechanisms operative in osteoclasts
Crit. Rev. Eukaryot. Gene Expr.
Role of transforming growth factor beta in bone remodeling
Clin. Orthop. Relat. Res.
Insulin-like growth factor I (IGF-I) has independent effects on bone matrix formation and cell replication
Endocrinology
Is BMU-coupling a strain-regulated phenomenon? A finite element analysis
J. Bone Miner. Res.
A case for strain-induced fluid flow as a regulator of BMU-coupling and osteonal alignment
J. Bone Miner. Res.
Matrix vesicles and calcification
Curr. Rheumatol. Rep.
Strain-derived canalicular fluid flow regulates osteoclast activity in a remodeling osteon – a proposal
J. Biomech.
Evidence that intermittent treatment with parathyroid hormone increases bone formation in adult rats by activation of bone lining cells
Endocrinology
Cancellous bone remodeling occurs in specialized compartments lined by cells expressing osteoblastic markers
J. Bone Miner. Res.
Osteonal and hemiosteonal remodeling: the spatial and temporal framework for signal traffic in adult bone
J. Cell Biochem.
Osteoclast differentiation and activation
Nature
Genetic regulation of osteoclast development and function
Nat. Rev. Genet.
The new bone biology: pathologic, molecular, and clinical correlates
Am. J. Med. Genet. A
αvβ3 and macrophage colony-stimulating factor: partners in osteoclast biology
Immunol. Rev.
Molecular mechanisms of bone resorption
J. Cell Biochem.
The cell biology of osteoclast function
J. Cell Sci.
Multilineage potential of adult human mesenchymal stem cells
Science
Vascular pericytes express osteogenic potential in vitro and in vivo
J. Bone Miner. Res.
The Wnt signaling pathway in development and disease
Annu. Rev. Cell Dev. Biol.
High bone density due to a mutation in LDL receptor-related protein 5
N. Engl. J. Med.
Cited by (53)
A green, efficient and stable platform based on hyperbranched quaternized hydrothermal magnetic chitosan nanospheres integrated cytomembranes for screening drug candidates from natural products
2024, International Journal of Biological MacromoleculesBone repair and key signalling pathways for cell-based bone regenerative therapy: A review
2023, Journal of Taibah University Medical SciencesTransdermal formulations and strategies for the treatment of osteoporosis
2022, Journal of Drug Delivery Science and TechnologyCarfilzomib alleviated osteoporosis by targeting PSME1/2 to activate Wnt/β-catenin signaling
2022, Molecular and Cellular EndocrinologyCitation Excerpt :However, it should be mentioned that some drugs have side effects such as gastrointestinal adverse reactions and venous thrombosis. Recently, with the emergence of new antibodies such as romosozumab (Bandeira et al., 2017) and denosumab (Davis et al., 2020), it was seen that the application of signal pathway targets in the diagnosis and treatment of OP could have a very broad prospect (Iñiguez-Ariza and Clarke, 2015), and it became a research hotspot in the field of orthopedics. Carfilzomib (CFZ), formerly known as PR-171, is a novel epoxyketone-based irreversible proteasome inhibitor having well-tolerated secondary effects and is considered among the potential anti-multiple myeloma (MM) therapies (Khan and Stewart, 2011; Hu et al., 2013).
Employment of selective pharmacologically active natural compounds in treatment and management of osteoporosis
2022, Studies in Natural Products ChemistryCitation Excerpt :Anabolic agents include teriparatide parathyroid hormone (PTH) 1–34 and abaloparatide which is a parathyroid hormone-related protein (PTHrP) 1–34 analog. These peptides bind to the receptor expressed on osteoblast lineage cells to promote bone formation [13,14]. Most of the currently used chemical agents for the treatment of osteoporosis are either too costly or associated with adverse side effects when used for a longer period.