From bone biology to better treatments

Origin

Humans are born with 270 bones which during development fuse to create an adult skeleton comprised of 206 bones.¹ These bones are dynamic, growing and changing over our lifespan. The changing nature of bones with age presents problems such as osteoporosis, a condition where bones are weak and prone to fracture, defined clinically by a low bone mineral density scan.

Age-related osteoporosis is caused by new bone generation not keeping pace with bone breakdown. In 2022, around 3.4% of the Australian population (853,600 people) was estimated to be living with osteoporosis or low bone mineral density.² However, the prevalence is likely higher as it often remains undiagnosed until a fracture occurs. The disease disproportionately affects older individuals and women and has increased in prevalence since 2001.

Individuals with osteoporosis are particularly predisposed to trauma fractures, which occur from a fall or impact that would not normally cause a bone to break in a healthy person. Such fractures remain a major cause of morbidity in Australia, affecting one in two women and one in four men over the age of 60 years.³ Mortality is increased after all minimal trauma fractures, even when these fractures are minor. Hip fractures are particularly devastating, leading to decreased quality of life, increased mortality and loss of functional independence.

Bone structure is maintained primarily by three key cell types: osteoblasts, which build new bone; osteoclasts, which break down old bone; and osteocytes, which help regulate bone maintenance and mineral balance. These three cell types were first described in the 19th and early 20th centuries, leading bone to be considered as a ‘living tissue’, however these cellular components remained poorly understood because of the inability of researchers to isolate the cells. This was until NHMRC funded researcher Thomas ‘Jack’ Martin and colleagues at the University of Melbourne turned to studying a tumour to solve this problem.

Investment

The research of Martin and his colleagues was initially supported by NHMRC Project Grants and subsequently received multiple NHMRC Program Grant support from 1984 to 2009. Additional NHMRC Project Grants followed, enabling sustained investigation over decades. The long-term investment for researchers working in the University of Melbourne and SVI facilitated the development of new models, cell lines, and collaborations that were critical to the field’s advancement.

Research was also supported by project grants from the Cancer Council Victoria (then known as The Anti-Cancer Council of Victoria).

The PDF poster version of this case study includes a graphical timeline showing NHMRC grants provided and other events described in the case study.

Research

Using radioactive phosphorous (P32), Martin and colleagues were able to induce a tumour in the femur (the thigh bone) of a rat. This tumour – called an osteogenic sarcoma – was made up of cells that produced bone. The bone cells produced by these sarcomas were able to be isolated and were found to be very responsive to the hormone parathyroid hormone (PTH).⁴ From these cells, researchers in collaboration with Dr Ray Bradley were able to develop the UMR106 cell line ^{5, 6} which behaved similarly to what would be expected of osteoblasts ^{6, 7, 8, 9}

These cells enabled further study of the communication between osteoblasts and osteoclasts. Researchers found that when certain substances acted on osteoblasts (eg PTH and prostaglandins), this regulated the activity and formation of osteoclasts. This led to the hypothesis that the formation and activity of osteoclasts are determined by activity produced by osteoblasts.^{10, 11} The chemical responsible for these interactions was identified in the late 1990s as RANK Ligand (RANKL).^{12, 13} This molecule was made by osteoblasts and promoted the formation of osteoclasts and when its actions were inhibited, bone breakdown was stopped.¹⁴

Researchers went on to investigate other proteins that facilitated communication between bone cells. Here they looked to lung cancer which can be associated with high levels of blood calcium (hypercalcemia) as calcium is leeched from the bones. Using a cell line from a lung cancer patient they isolated a protein similar to PTH which was produced by these cancer cells and acted on bones.^{16, 17, 18, 19} This protein, which they called PTH related protein (PTHrP) increased osteoclast formation and activity, facilitating increased bone breakdown. When produced by cells locally in bone marrow, it facilitated the growth of cancer metastases in the bone itself by promoting bone breakdown, explaining how these cancers can grow in what would otherwise be thought of as a hard tissue that would be a poor supporter of cell growth.¹⁹

PTHrP was also found to be produced in many other tissues, where various physiological effects were exerted. These included actions on the placenta to allow calcium to be provided to the foetus, and upon smooth muscle cells of the vasculature to relax blood vessels.^{20, 21}

Translation

The UMR106 cell line isolated from osteogenic sarcoma was from the outset made available to scientists who had reasons to study the cells. In the late 1980s, for convenience, the UMR106 cells were given to the American Type Culture Collection, a cell repository for the distribution of cell lines. Since that time, the UMR106 cells have become a fundamental research tool internationally and have been referred to within thousands of publications. 

The discovery of how RANKL stimulated osteoclast activity and increased bone breakdown led to the development of a drug by Amgen against this target and an effective treatment for osteoporosis. This monoclonal antibody therapy (Denosumab) acts by binding to RANKL produced by osteoblasts rendering it unable to promote the development of osteoclasts, reducing the breakdown of bone by these cells. Denosumab was first registered for the treatment of osteoporosis in Australia in 2010.²² In a review of 27 studies of osteoporosis treated worldwide, it was concluded that Denosumab was a cost effective and dominant option when compared with oral bisphosphonate therapy.²³

PTHrP expression in breast cancer was linked to improved survival, suggesting its use as a prognostic marker and potential tumour suppressor. Understanding PTHrP’s role in bone metastases informed the use of bone resorption inhibitors in cancer patient¹⁹, improving management of skeletal complications.  

Outcomes and impacts

The UMR106 osteoblast cell line played a significant role in the establishment of the field of bone biology. These cells have been adopted widely and used in more than 400 peer-reviewed publications in bone biology, cancer, and pharmacology.

Targeted therapies such as denosumab and emerging anti-PTHrP agents have improved treatment options for osteoporosis and cancer-related bone disease, transforming patient outcomes. Denosumab significantly reduces the decline in bone mineral density and reduces vertebral, non-vertebral, and hip fractures in people with osteoporosis, while in cancer patients with bone metastases, it delays skeletal-related events, lowers fracture risk, and improves quality of life compared to bisphosphonates (a class of drugs used for osteoporosis treatment).^{24, 25, 26} In Australia, more than one million prescriptions for denosumab were dispensed between 2023 and 2024.²⁷ Globally, over 26 million people are estimated to have received treatment with denosumab.²⁸

Research on RANKL inhibition and denosumab has been fully integrated into national osteoporosis clinical guidelines shaping recommendations for clinical practice. In 2024, the Royal Australian College of General Practitioners and Healthy Bones Australia endorsed denosumab as a first-line option for postmenopausal women at high fracture risk and as an alternative to bisphosphonates for men at increased risk.²⁹ International guidelines including the UK National Osteoporosis Guideline Group, International Osteoporosis Foundation and Endocrine Society guidelines recognise denosumab as an effective antiresorptive therapy for osteoporosis, particularly in patients at high or very high fracture risk.

However, all guidelines place emphasis on continuity of therapy. Treatment should not be stopped or delayed without specialist advice, and if discontinued, transition to another antiresorptive agent is required to prevent rebound fractures.

Researchers

Professor T John Martin AO

Jack Martin studied medicine at the University of Melbourne (UoM), graduating in 1960. After holding a position as Professor of Chemical Pathology at the University of Sheffield, UK, he returned to the University of Melbourne as Foundation Professor of Medicine at the Heidelberg and Repatriation General Hospital. He then became Director of SVI in 1988, holding the position until 2002. He was instrumental in establishing SVI as a leading centre for bone and cancer research. Martin was elected Fellow of the Australian Academy of Science in 1998. He was appointed Officer of the Order of Australia in 1996 for his contributions to medical research, particularly in bone biology and cancer, and was elected as a Fellow of the Royal Society (London) in 2000.  He was named 2013 Victorian Senior Australian of the year.

Professor Natalie Sims

Natalie Sims received her PhD from the University of Adelaide in 1994. She joined SVI in 2006 before becoming Associate Director (2009) then Deputy Director of SVI in 2018. She has held editorial roles in journals including Bone, Journal of Biological Chemistry, Journal of Bone and Mineral Research and Endocrine Reviews. She has received multiple awards for her work including the Paula Stern Achievement Award (2020), Herbert A Fleisch Award (2013) and Fuller-Albright Award (2010).  

Other researchers

Other researchers that contributed to the impacts described in this case study include, Associate Professor Jane Moseley, Professor Bruce Kemp, Professor Richard Wettenhall, Associate Professor Matthew Gillespie, Associate Professor Kong Wah Ng, Professor David Findlay, Associate Professor Janine Danks, Professor Hong Zhou, Dr Stephen Livesey, Dr Nicola Partridge, Dr Maryann Rakopoulos, Dr Larry Suva, Ms Patricia Ho, Dr Valdo Michelangeli and Dr Nobuyuki Udagawa.

Partner

This case study was developed in partnership with St Vincent’s Institute of Medical Research.

Under NHMRC’s Funding Agreement, Administering Institutions must comply, and require their Participating Institutions, Research Activities and applications to comply, with relevant legislation. At the time of writing, relevant legislation governing the use of animals for research includes state and territory animal welfare legislation. NHMRC also requires compliance with NHMRC approved Standards and Guidelines and any applicable NHMRC policies. At the time of writing, and with respect to animals, these include the:

• Australian Code for the Responsible Conduct of Research (2018)
• Australian code for the care and use of animals for scientific purposes 8th edition (2013, updated 2021)
• Best practice methodology in the use of animals for scientific purposes (2017).
• Principles and guidelines on the care and use of non-human primates for scientific purposes (2016)
• A guide to the care and use of Australian native mammals in research and teaching (2014).

Ethical, scientific, veterinary and medical standards and practices related to animal research change over time. NHMRC-funded research activities that occurred before the present time were subject to the legislation and NHMRC’s Standards, Guidelines and policies in force at the time that they occurred.

References

The information and images from which impact case studies are produced may be obtained from a number of sources including our case study partner, NHMRC’s internal records and publicly available materials. Key sources of information consulted for this case study include:

¹Marshall Cavendish Corporation. Mammal anatomy: an illustrated guide. New York: Marshall Cavendish; 2010. p. 129. ISBN: 9780761478829
²Australian Institute of Health and Welfare. Osteoporosis and minimal trauma fractures [Internet]. Canberra: Australian Institute of Health and Welfare; 2024 [cited 2025 Jul 2]. Available from: https://www.aihw.gov.au/reports/chronic-musculoskeletal-conditions/osteoporosis
³Nguyen ND, Ahlborg HG, Center JR, et al. Residual lifetime risk of fractures in women and men. J Bone Miner Res 2007; 22: 781-788.
⁴Martin TJ, Ingleton PM, Underwood JC, Michelangeli VP, Hunt NH, Melick RA. Parathyroid hormone-responsive adenylate cyclase in induced transplantable osteogenic rat sarcoma. Nature 1976; 260(5550): 436-8.
⁵Partridge NC, Frampton RJ, Eisman JA, et al. Receptors for 1,25(OH)2-vitamin D3 enriched in cloned osteoblast-like rat osteogenic sarcoma cells. FEBS Lett 1980; 115(1): 139-42.
⁶Partridge NC, Alcorn D, Michelangeli VP, Ryan G, Martin TJ. Morphological and biochemical characterization of four clonal osteogenic sarcoma cell lines of rat origin. Cancer Res 1983; 43(9): 4308-14.
⁷Partridge NC, Kemp BE, Veroni MC, Martin TJ. Activation of adenosine 3',5'-monophosphate-dependent protein kinase in normal and malignant bone cells by parathyroid hormone, prostaglandin E2, and prostacyclin. Endocrinology 1981; 108(1): 220-5.
⁸ Partridge NC, Kemp BE, Livesey SA, Martin TJ. Activity ratio measurements reflect intracellular activation of adenosine 3',5'-monophosphate-dependent protein kinase in osteoblasts. Endocrinology 1982; 111(1): 178-83.
⁹Livesey SA, Kemp BE, Re CA, Partridge NC, Martin TJ. Selective hormonal activation of cyclic AMP-dependent protein kinase isoenzymes in normal and malignant osteoblasts. J Biol Chem 1982; 257(24): 14983-7.
¹⁰Rodan GA, Martin TJ. Role of osteoblasts in hormonal control of bone resorption--a hypothesis. Calcif Tissue Int 1981; 33(4): 349-51.
¹¹Martin TJ. Drug and hormone effects on calcium release from bone. Pharmacol Ther 1983; 21(2): 209-28.
¹²Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell 1998; 93(2): 165-76.
¹³Yasuda H, Shima N, Nakagawa N, et al. Osteoclast differentiation factor is a ligand for osteoprotegerin/osteoclastogenesis-inhibitory factor and is identical to TRANCE/RANKL. Proc Natl Acad Sci U S A 1998; 95(7): 3597-602.
¹⁴Seeman E, Martin TJ. Antiresorptive and anabolic agents in the prevention and reversal of bone fragility. Nat Rev Rheumatol 2019; 15(4): 225-36.
¹⁵Melick RA, Martin TJ, Hicks JD. Parathyroid hormone production and malignancy. Br Med J 1972; 2(5807): 204-5.
¹⁶Moseley JM, Kubota M, Diefenbach-Jagger H, et al. Parathyroid hormone-related protein purified from a human lung cancer cell line. Proc Natl Acad Sci U S A 1987; 84(14): 5048-52.
¹⁷Suva LJ, Winslow GA, Wettenhall RE, et al. A parathyroid hormone-related protein implicated in malignant hypercalcemia: cloning and expression. Science 1987; 237(4817): 893-6.
¹⁸Kemp BE, Moseley JM, Rodda CP, et al. Parathyroid hormone-related protein of malignancy: active synthetic fragments. Science 1987; 238(4833): 1568-70.
¹⁹Powell GJ, Southby J, Danks JA, et al. Localization of parathyroid hormone-related protein in breast cancer metastases: increased incidence in bone compared with other sites. Cancer Res 1991; 51(11): 3059-61.
²⁰Rodda CP, Kubota M, Heath JA, et al. Evidence for a novel parathyroid hormone-related protein in fetal lamb parathyroid glands and sheep placenta: comparisons with a similar protein implicated in humoral hypercalcaemia of malignancy. The Journal of endocrinology 1988; 117(2): 261-71.
²¹ Kovacs CS, Manley NR, Moseley JM, Martin TJ, Kronenberg HM. Fetal parathyroids are not required to maintain placental calcium transport. J Clin Invest 2001; 107(8): 1007-15.
²²The Royal Australian College of General Practitioners. Denosumab. In: Osteoporosis: Pharmacologic approaches to prevention and treatment. East Melbourne, Vic: RACGP; 2024 [cited 2025 Jul 4]. Available from: https://www.racgp.org.au/clinical-resources/clinical-guidelines/key-racgp-guidelines/view-all-racgp-guidelines/osteoporosis/pharmacologic-approaches-to-prevention/denosumab
²³Li N, Cornelissen D, Silverman S, Pinto D, Si L, Kremer I, Bours S, de Bot R, Boonen A, Evers S, van den Bergh J, Reginster JY, Hiligsmann M. An updated systematic review of cost-effectiveness analyses of drugs for osteoporosis. Pharmacoeconomics. 2021 Feb;39(2):181-209. doi:10.1007/s40273-020-00965-9. PMID: 33026634; PMCID: PMC7867562.
²⁴Bone HG, et al. Ten years of denosumab treatment in postmenopausal women with osteoporosis: results from the FREEDOM extension trial. J Bone Miner Res. 2017;32(3):448-455. doi: 10.1016/S2213-8587(17)30138-9
²⁵Ha J, Lee YJ, Kim J, Jeong C, Lim Y, Lee J, et al. Long-term efficacy and safety of denosumab: insights beyond 10 years of use. Endocrinol Metab (Seoul). 2025;40(1):47-56. doi:10.3803/EnM.2024.2125.
²⁶Lu J, Hu D, Zhang Y, Ma C, Shen L, Shuai B. Current comprehensive understanding of denosumab (the RANKL neutralizing antibody) in the treatment of bone metastasis of malignant tumors, including pharmacological mechanism and clinical trials. Front Oncol. 2023;13:1133828. doi:10.3389/fonc.2023.1133828.
²⁷Top 10 drugs 2023–24. Aust Prescr. 2024;47(6):194. doi:10.18773/austprescr.2024.048. Available from: https://australianprescriber.tg.org.au/articles/top-10-drugs-2023%E2%80%9324.html
²⁸Prolia® (denosumab). Postmenopausal osteoporosis [Internet]. Thousand Oaks (CA): Amgen Inc.; [cited 2025 Dec 11]. Available from: https://www.prolia.com/taking-prolia/postmenopausal-osteoporosis
²⁹The Royal Australian College of General Practitioners and Healthy Bones Australia.
Osteoporosis management and fracture prevention in postmenopausal women and men over 50 years of age. 3rd ed. East Melbourne, Vic: RACGP; 2024. Available from: https://healthybonesaustralia.org.au/wp-content/uploads/2024/03/hba-racgp-guidelines-2024.pdf