Advances in macrophages research in postmenopausal osteoporosis_West China Medical Journal

Authors：

LI Xin ¹ , CHENG Jie ¹ , ZHAO Haiyan ² ,  WANG Wenji ²

1. Department of Orthopedics, First People’s Hospital of Tianshui, Tianshui, Gansu 741000, P. R. China;
2. Department of Orthopedics, the First Hospital of Lanzhou University, Lanzhou, Gansu 730000, P. R. China;

Corresponding author：

WANG Wenji, Email: ldyygjwwj@163.com

Keywords：

Macrophage; postmenopausal osteoporosis; macropha polarization; bone metabolism; diagnosis and treatment

DOI：

10.7507/1002-0179.202502150

Video：

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Abstract Full text Figures/Tables Video References Cited by

Postmenopausal osteoporosis (PMOP) is a significant metabolic bone disease triggered by estrogen deficiency. Macrophages, as pivotal cells in bone metabolism regulation, participate in bone remodeling and inflammatory modulation through differentiation into osteoclasts and polarization phenotype switching. This article systematically reviews the mechanistic roles of macrophages in PMOP, encompassing their interactions with osteoclasts, polarization effects, immune-inflammatory responses, and impacts of oxidative stress. Furthermore, it explores the potential applications of macrophages in molecular diagnosis and pharmacological interventions for PMOP, while proposing future research directions.

Citation： LI Xin, CHENG Jie, ZHAO Haiyan, WANG Wenji. Advances in macrophages research in postmenopausal osteoporosis. West China Medical Journal, 2025, 40(6): 1003-1007. doi: 10.7507/1002-0179.202502150 Copy

1.	Walker MD, Shane E. Postmenopausal osteoporosis. N Engl J Med, 2023, 389(21): 1979-1991.
2.	Guilliams M, Thierry GR, Bonnardel J, et al. Establishment and maintenance of the macrophage niche. Immunity, 2020, 52(3): 434-451.
3.	McClung MR, O’Donoghue ML, Papapoulos SE, et al. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT extension study. Lancet Diabetes Endocrinol, 2019, 7(12): 899-911.
4.	Paschalis EP, Gamsjaeger S, Hassler N, et al. Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality. Bone, 2017, 95: 41-46.
5.	Weivoda MM, Bradley EW. Macrophages and bone remodeling. J Bone Miner Res, 2023, 38(3): 359-369.
6.	McDonald MM, Khoo WH, Ng PY, et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, 2021, 184(5): 1940.
7.	Batoon L, Millard SM, Raggatt LJ, et al. Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model. J Bone Miner Res, 2021, 36(11): 2214-2228.
8.	Guo M, Liu N, Guo Z. MiR-221-5p/Smad3 axis in osteoclastogenesis and its function: potential therapeutic target for osteoporosis. Steroids, 2022, 185: 109063.
9.	Allison H, McNamara LM. Inhibition of osteoclastogenesis by mechanically stimulated osteoblasts is attenuated during estrogen deficiency. Am J Physiol Cell Physiol, 2019, 317(5): C969-C982.
10.	Yu L, Hu M, Cui X, et al. M1 macrophage-derived exosomes aggravate bone loss in postmenopausal osteoporosis via a microRNA-98/DUSP1/JNK axis. Cell Biol Int, 2021, 45(12): 2452-2463.
11.	Dou C, Ding N, Zhao C, et al. Estrogen deficiency-mediated M2 macrophage osteoclastogenesis contributes to M1/M2 ratio alteration in ovariectomized osteoporotic mice. J Bone Miner Res, 2018, 33(5): 899-908.
12.	Fischer V, Haffner-Luntzer M. Interaction between bone and immune cells: implications for postmenopausal osteoporosis. Semin Cell Dev Biol, 2022, 123: 14-21.
13.	Cline-Smith A, Axelbaum A, Shashkova E, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T cells, which promotes osteoporosis in mice. J Bone Miner Res, 2020, 35(6): 1174-1187.
14.	Ma'arif B, Mirza DM, Hasanah M, et al. Antineuroinflammation activity of n-butanol fraction of Marsilea crenata Presl. in microglia HMC3 cell line. J Basic Clin Physiol Pharmacol, 2020, 30(6): 20190255.
15.	Brunetti G, Storlino G, Oranger A, et al. LIGHT/TNFSF14 regulates estrogen deficiency-induced bone loss. J Pathol, 2020, 250(4): 440-451.
16.	Mohamad NV, Ima-Nirwana S, Chin KY. Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? A review of current evidence. Endocr Metab Immune Disord Drug Targets, 2020, 20(9): 1478-1487.
17.	Zhou X, Yuan W, Xiong X, et al. HO-1 in bone biology: potential therapeutic strategies for osteoporosis. Front Cell Dev Biol, 2021, 9: 791585.
18.	Nishida Y, Terkawi MA, Matsumae G, et al. Dynamic transcriptome analysis of osteal macrophages identifies a distinct subset with senescence features in experimental osteoporosis. JCI Insight, 2024, 9(23): e182418.
19.	Wang X, Chen B, Sun J, et al. Iron-induced oxidative stress stimulates osteoclast differentiation via NF-κB signaling pathway in mouse model. Metabolism, 2018, 83: 167-176.
20.	Fang S, Ni H, Zhang Q, et al. Integrated single-cell and bulk RNA sequencing analysis reveal immune-related biomarkers in postmenopausal osteoporosis. Heliyon, 2024, 10(18): e38022.
21.	Liu D, Wang K, Wang J, et al. Identification of the molecular link: STAT3 is a shared key gene linking postmenopausal osteoporosis and sarcopenia. Bone Joint Res, 2024, 13(8): 411-426.
22.	Yang XW, Wang F, Qin RZ, et al. Elevated serum CCL4/MIP-1β levels in postmenopausal osteoporosis patients are linked with disease severity. Biomark Med, 2019, 13(1): 17-25.
23.	Wang Y, Xiao H, Chen Y, et al. PGRMC2 influences the onset of postmenopausal osteoporosis through disulfidptosis in monocytes: evidence from experimental validation and Mendelian randomization. Heliyon, 2024, 10(17): e36570.
24.	Huang X, Ni B, Li Q, et al. Association between postmenopausal osteoporosis and IL-6、TNF-α: a systematic review and a Meta-analysis. Comb Chem High Throughput Screen, 2024, 27(15): 2260-2266.
25.	Yokota S, Matsumae G, Shimizu T, et al. Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway. Bone, 2021, 153: 116140.
26.	Shen G, Ren H, Shang Q, et al. miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss. Theranostics, 2020, 10(10): 4334-4348.
27.	Ayers C, Kansagara D, Lazur B, et al. Effectiveness and safety of treatments to prevent fractures in people with low bone mass or primary osteoporosis: a living systematic review and network Meta-analysis for the American College of Physicians. Ann Intern Med, 2023, 176(2): 182-195.
28.	Anastasilakis AD, Makras P, Yavropoulou MP, et al. Denosumab discontinuation and the rebound phenomenon: a narrative review. J Clin Med, 2021, 10(1): 152.
29.	Reid IR, Billington EO. Drug therapy for osteoporosis in older adults. Lancet, 2022, 399(10329): 1080-1092.
30.	Yang X, Xu X, Chen J, et al. Zoledronic acid regulates the synthesis and secretion of IL-1β through histone methylation in macrophages. Cell Death Discov, 2020, 6: 47.
31.	Keum BR, Kim HJ, Lee J, et al. Heterogeneous osteoimmune profiles via single-cell transcriptomics in osteoporotic patients who fail bisphosphonate treatment. Proc Natl Acad Sci U S A, 2024, 121(8): e2316871121.
32.	Kendler DL, Marin F, Zerbini CAF, et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet, 2018, 391(10117): 230-240.
33.	He J, Zhao D, Peng B, et al. A novel mechanism of vildagliptin in regulating bone metabolism and mitigating osteoporosis. Int Immunopharmacol, 2024, 130: 111671.
34.	Son HS, Lee J, Lee HI, et al. Benzydamine inhibits osteoclast differentiation and bone resorption via down-regulation of interleukin-1 β expression. Acta Pharm Sin B, 2020, 10(3): 462-474.
35.	Ihn HJ, Lim J, Kim K, et al. Protective effect of ciclopirox against ovariectomy-induced bone loss in mice by suppressing osteoclast formation and function. Int J Mol Sci, 2021, 22(15): 8299.
36.	姜俊杰, 刘峘, 谢雁鸣, 等. 绝经后骨质疏松症中医临床实践指南编制要点解读. 中国骨质疏松杂志, 2022, 28(7): 998-1001, 1023.
37.	Hu R, Chen L, Chen X, et al. Aloperine improves osteoporosis in ovariectomized mice by inhibiting RANKL-induced NF-κB, ERK and JNK approaches. Int Immunopharmacol, 2021, 97: 107720.
38.	Wang K, Chen Y, Gao S, et al. Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER α to inhibit RANKL signaling. Acta Pharm Sin B, 2021, 11(2): 442-455.
39.	Shim KS, Hwang YH, Jang SA, et al. Water extract of Lysimachia christinae inhibits trabecular bone loss and fat accumulation in ovariectomized mice. Nutrients, 2020, 12(7): 1927.
40.	Jang SA, Hwang YH, Kim T, et al. Anti-osteoporotic and anti-adipogenic effects of the water extract of Drynaria roosii nakaike in ovariectomized mice fed a high-fat diet. Molecules, 2019, 24(17): 3051.
41.	Li Y, Yuan J, Deng W, et al. Buqi-tongluo decoction inhibits osteoclastogenesis and alleviates bone loss in ovariectomized rats by attenuating NFATc1, MAPK, NF-κB signaling. Chin J Nat Med, 2025, 23(1): 90-101.

1. Walker MD, Shane E. Postmenopausal osteoporosis. N Engl J Med, 2023, 389(21): 1979-1991.
2. Guilliams M, Thierry GR, Bonnardel J, et al. Establishment and maintenance of the macrophage niche. Immunity, 2020, 52(3): 434-451.
3. McClung MR, O’Donoghue ML, Papapoulos SE, et al. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT extension study. Lancet Diabetes Endocrinol, 2019, 7(12): 899-911.
4. Paschalis EP, Gamsjaeger S, Hassler N, et al. Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality. Bone, 2017, 95: 41-46.
5. Weivoda MM, Bradley EW. Macrophages and bone remodeling. J Bone Miner Res, 2023, 38(3): 359-369.
6. McDonald MM, Khoo WH, Ng PY, et al. Osteoclasts recycle via osteomorphs during RANKL-stimulated bone resorption. Cell, 2021, 184(5): 1940.
7. Batoon L, Millard SM, Raggatt LJ, et al. Osteal macrophages support osteoclast-mediated resorption and contribute to bone pathology in a postmenopausal osteoporosis mouse model. J Bone Miner Res, 2021, 36(11): 2214-2228.
8. Guo M, Liu N, Guo Z. MiR-221-5p/Smad3 axis in osteoclastogenesis and its function: potential therapeutic target for osteoporosis. Steroids, 2022, 185: 109063.
9. Allison H, McNamara LM. Inhibition of osteoclastogenesis by mechanically stimulated osteoblasts is attenuated during estrogen deficiency. Am J Physiol Cell Physiol, 2019, 317(5): C969-C982.
10. Yu L, Hu M, Cui X, et al. M1 macrophage-derived exosomes aggravate bone loss in postmenopausal osteoporosis via a microRNA-98/DUSP1/JNK axis. Cell Biol Int, 2021, 45(12): 2452-2463.
11. Dou C, Ding N, Zhao C, et al. Estrogen deficiency-mediated M2 macrophage osteoclastogenesis contributes to M1/M2 ratio alteration in ovariectomized osteoporotic mice. J Bone Miner Res, 2018, 33(5): 899-908.
12. Fischer V, Haffner-Luntzer M. Interaction between bone and immune cells: implications for postmenopausal osteoporosis. Semin Cell Dev Biol, 2022, 123: 14-21.
13. Cline-Smith A, Axelbaum A, Shashkova E, et al. Ovariectomy activates chronic low-grade inflammation mediated by memory T cells, which promotes osteoporosis in mice. J Bone Miner Res, 2020, 35(6): 1174-1187.
14. Ma'arif B, Mirza DM, Hasanah M, et al. Antineuroinflammation activity of n-butanol fraction of Marsilea crenata Presl. in microglia HMC3 cell line. J Basic Clin Physiol Pharmacol, 2020, 30(6): 20190255.
15. Brunetti G, Storlino G, Oranger A, et al. LIGHT/TNFSF14 regulates estrogen deficiency-induced bone loss. J Pathol, 2020, 250(4): 440-451.
16. Mohamad NV, Ima-Nirwana S, Chin KY. Are oxidative stress and inflammation mediators of bone loss due to estrogen deficiency? A review of current evidence. Endocr Metab Immune Disord Drug Targets, 2020, 20(9): 1478-1487.
17. Zhou X, Yuan W, Xiong X, et al. HO-1 in bone biology: potential therapeutic strategies for osteoporosis. Front Cell Dev Biol, 2021, 9: 791585.
18. Nishida Y, Terkawi MA, Matsumae G, et al. Dynamic transcriptome analysis of osteal macrophages identifies a distinct subset with senescence features in experimental osteoporosis. JCI Insight, 2024, 9(23): e182418.
19. Wang X, Chen B, Sun J, et al. Iron-induced oxidative stress stimulates osteoclast differentiation via NF-κB signaling pathway in mouse model. Metabolism, 2018, 83: 167-176.
20. Fang S, Ni H, Zhang Q, et al. Integrated single-cell and bulk RNA sequencing analysis reveal immune-related biomarkers in postmenopausal osteoporosis. Heliyon, 2024, 10(18): e38022.
21. Liu D, Wang K, Wang J, et al. Identification of the molecular link: STAT3 is a shared key gene linking postmenopausal osteoporosis and sarcopenia. Bone Joint Res, 2024, 13(8): 411-426.
22. Yang XW, Wang F, Qin RZ, et al. Elevated serum CCL4/MIP-1β levels in postmenopausal osteoporosis patients are linked with disease severity. Biomark Med, 2019, 13(1): 17-25.
23. Wang Y, Xiao H, Chen Y, et al. PGRMC2 influences the onset of postmenopausal osteoporosis through disulfidptosis in monocytes: evidence from experimental validation and Mendelian randomization. Heliyon, 2024, 10(17): e36570.
24. Huang X, Ni B, Li Q, et al. Association between postmenopausal osteoporosis and IL-6、TNF-α: a systematic review and a Meta-analysis. Comb Chem High Throughput Screen, 2024, 27(15): 2260-2266.
25. Yokota S, Matsumae G, Shimizu T, et al. Cardiotrophin Like Cytokine Factor 1 (CLCF1) alleviates bone loss in osteoporosis mouse models by suppressing osteoclast differentiation through activating interferon signaling and repressing the nuclear factor-κB signaling pathway. Bone, 2021, 153: 116140.
26. Shen G, Ren H, Shang Q, et al. miR-128 plays a critical role in murine osteoclastogenesis and estrogen deficiency-induced bone loss. Theranostics, 2020, 10(10): 4334-4348.
27. Ayers C, Kansagara D, Lazur B, et al. Effectiveness and safety of treatments to prevent fractures in people with low bone mass or primary osteoporosis: a living systematic review and network Meta-analysis for the American College of Physicians. Ann Intern Med, 2023, 176(2): 182-195.
28. Anastasilakis AD, Makras P, Yavropoulou MP, et al. Denosumab discontinuation and the rebound phenomenon: a narrative review. J Clin Med, 2021, 10(1): 152.
29. Reid IR, Billington EO. Drug therapy for osteoporosis in older adults. Lancet, 2022, 399(10329): 1080-1092.
30. Yang X, Xu X, Chen J, et al. Zoledronic acid regulates the synthesis and secretion of IL-1β through histone methylation in macrophages. Cell Death Discov, 2020, 6: 47.
31. Keum BR, Kim HJ, Lee J, et al. Heterogeneous osteoimmune profiles via single-cell transcriptomics in osteoporotic patients who fail bisphosphonate treatment. Proc Natl Acad Sci U S A, 2024, 121(8): e2316871121.
32. Kendler DL, Marin F, Zerbini CAF, et al. Effects of teriparatide and risedronate on new fractures in post-menopausal women with severe osteoporosis (VERO): a multicentre, double-blind, double-dummy, randomised controlled trial. Lancet, 2018, 391(10117): 230-240.
33. He J, Zhao D, Peng B, et al. A novel mechanism of vildagliptin in regulating bone metabolism and mitigating osteoporosis. Int Immunopharmacol, 2024, 130: 111671.
34. Son HS, Lee J, Lee HI, et al. Benzydamine inhibits osteoclast differentiation and bone resorption via down-regulation of interleukin-1 β expression. Acta Pharm Sin B, 2020, 10(3): 462-474.
35. Ihn HJ, Lim J, Kim K, et al. Protective effect of ciclopirox against ovariectomy-induced bone loss in mice by suppressing osteoclast formation and function. Int J Mol Sci, 2021, 22(15): 8299.
36. 姜俊杰, 刘峘, 谢雁鸣, 等. 绝经后骨质疏松症中医临床实践指南编制要点解读. 中国骨质疏松杂志, 2022, 28(7): 998-1001, 1023.
37. Hu R, Chen L, Chen X, et al. Aloperine improves osteoporosis in ovariectomized mice by inhibiting RANKL-induced NF-κB, ERK and JNK approaches. Int Immunopharmacol, 2021, 97: 107720.
38. Wang K, Chen Y, Gao S, et al. Norlichexanthone purified from plant endophyte prevents postmenopausal osteoporosis by targeting ER α to inhibit RANKL signaling. Acta Pharm Sin B, 2021, 11(2): 442-455.
39. Shim KS, Hwang YH, Jang SA, et al. Water extract of Lysimachia christinae inhibits trabecular bone loss and fat accumulation in ovariectomized mice. Nutrients, 2020, 12(7): 1927.
40. Jang SA, Hwang YH, Kim T, et al. Anti-osteoporotic and anti-adipogenic effects of the water extract of Drynaria roosii nakaike in ovariectomized mice fed a high-fat diet. Molecules, 2019, 24(17): 3051.
41. Li Y, Yuan J, Deng W, et al. Buqi-tongluo decoction inhibits osteoclastogenesis and alleviates bone loss in ovariectomized rats by attenuating NFATc1, MAPK, NF-κB signaling. Chin J Nat Med, 2025, 23(1): 90-101.

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