Advances and unmet needs in the therapeutics of bone fragility

Journal article


Ramchand, S. K. and Seeman, Ego. (2018). Advances and unmet needs in the therapeutics of bone fragility. Frontiers in Endocrinology. 9, pp. 1 - 10. https://doi.org/10.3389/fendo.2018.00505
AuthorsRamchand, S. K. and Seeman, Ego
Abstract

The prevalence of fragility fractures increases as longevity increases the proportion of the elderly in the community. Until recently, the majority of studies have targeted women with osteoporosis defined as a bone mineral density (BMD) T score of < −2.5 SD, despite evidence that the population burden of fractures arises from women with osteopenia. Antiresorptive agents reduce vertebral and hip fracture risk by ~50 percent during 3 years but efficacy against non-vertebral fractures, 80% of all fractures in the community, is reported in few studies, and of those, the risk reduction is only 20–30%. Recent advances in the use of antiresorptives and anabolic agents has addressed some of these unmet needs. Zoledronic acid is now reported to reduce vertebral and non-vertebral fractures rates in women with osteopenia. Studies using teriparatide demonstrate better vertebral and clinical (symptomatic vertebral and non-vertebral) antifracture efficacy than risedronate. Abaloparatide, a peptide sharing amino acid sequences with teriparatide, reduces vertebral and non-vertebral fractures. Romosozumab, a monoclonal antibody suppressing sclerostin, reduces vertebral and non-vertebral fractures within a year of starting treatment, and does so more greatly than alendronate. Some recent studies signal undesirable effects of therapy but provide essential cautionary insights into long term management. Cessation of denosumab is associated with a rapid increase in bone remodeling and the uncommon but clinically important observation of increased multiple vertebral fractures suggesting the need to start alternative anti-resorptive therapy around the time of stopping denosumab. Antiresorptives like bisphosphonates and denosumab suppress remodeling but not completely. Antifracture efficacy may be limited, in part, as a consequence of continued unsuppressed remodeling, particularly in cortical bone. Bisphosphonates may not distribute in deeper cortical bone, so unbalanced intracortical remodeling continues to cause microstructural deterioration. In addition, suppressed remodeling may compromise the material composition by increasing matrix mineral density and glycosylation of collagen. As antiresorptive agents do not restore microstructural deterioration existing at the time of starting treatment, under some circumstances, anabolic therapy may be more appropriate first line treatment. Combining antiresorptive and anabolic therapy is an alternative but whether anti-fracture efficacy is greater than that achieved by either treatment alone is not known.

Keywordsanabolic agents; antiresorptive agents; bone fragility; fractures; microstructure; osteoporosis; osteopenia
Year2018
JournalFrontiers in Endocrinology
Journal citation9, pp. 1 - 10
PublisherFrontiers Research Foundation
ISSN1664-2392
Digital Object Identifier (DOI)https://doi.org/10.3389/fendo.2018.00505
Scopus EID2-s2.0-85055136458
Open accessOpen access
Page range1 - 10
Research GroupMary MacKillop Institute for Health Research
Publisher's version
License
Place of publicationSwitzerland
EditorsJ. M. P. Holly and D. LeRoith
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Abimanyi-Ochom, J., Watts, Jennifer, Borgstrom, F., Nicholson, Geoffrey, Shore-Lorenti, Catherine, Stuart, Amanda, Zhang, Y., Luliano, S., Seeman, Ego, Prince, Richard, March, Lyn, Winzenberg, T., Laslett, Laura, Duque, Gustavo, Ebeling, P. and Sanders, K. M.. (2015). Changes in quality of life associated with fragility fractures : Australian arm of the International Cost and Utility Related to Osteoporotic Fractures Study (AusICUROS). Osteoporosis International. 26(6), pp. 1781 - 1790. https://doi.org/10.1007/s00198-015-3088-z
Genetic and environmental variances of bone microarchitecture and bone remodeling markers: A twin study
Bjornerem, Ashild, Bui, Q Minh, Wang, Xiaofang, Ghasem-Zadeh, Ali, Hopper, John L., Zebaze, Roger M. and Seeman, Ego. (2015). Genetic and environmental variances of bone microarchitecture and bone remodeling markers: A twin study. Journal of Bone and Mineral Research. 30(3), pp. 516 - 524. https://doi.org/10.1002/jbmr.2365
Bones material constituents and their contribution to bone strength in health, disease, and treatment
Bala, Y. and Seeman, Ego. (2015). Bones material constituents and their contribution to bone strength in health, disease, and treatment. Calcified Tissue International. 97(3), pp. 308 - 326. https://doi.org/10.1007/s00223-015-9971-y
A. Michael Parfitt: Enlightened scholar and revered mentor: May 10, 1930-May 18, 2015
Manolagas, Stavros C., Compston, Juliet, Rao, Sudhaker and Seeman, Ego. (2015). A. Michael Parfitt: Enlightened scholar and revered mentor: May 10, 1930-May 18, 2015. Journal of Bone and Mineral Research. 30(8), pp. 1349 - 1355. https://doi.org/10.1002/jbmr.2576
Co-administration of antiresorptive and anabolic agents: A missed opportunity
Seeman, Ego and Martin, T. John. (2015). Co-administration of antiresorptive and anabolic agents: A missed opportunity. Journal of Bone and Mineral Research. 30(5), pp. 753 - 764. https://doi.org/10.1002/jbmr.2496
The ABC of writing a grant proposal
Seeman, Ego. (2015). The ABC of writing a grant proposal. Osteoporosis International. 26(6), pp. 1665 - 1666. https://doi.org/10.1007/s00198-015-3085-2
Growth and age-related abnormalities in cortical structure and fracture risk
Seeman, Ego. (2015). Growth and age-related abnormalities in cortical structure and fracture risk. Endocrinology and Metabolism. 30(4), pp. 419 - 428. https://doi.org/10.3803/EnM.2015.30.4.419
High-resolution in vivo imaging of bone and joints: a window to microarchitecture
Geusens, P., Geusens, P., Chapurlat, Roland D., Chapurlat, Roland D., Schett, G., Ghasem-Zadeh, Ali, Ghasem-Zadeh, Ali, Seeman, Ego, De Jong, J. and Van Den Bergh, J.. (2014). High-resolution in vivo imaging of bone and joints: a window to microarchitecture. Nature Reviews Rheumatology. 10(5), pp. 304 - 313. https://doi.org/10.1038/nrrheum.2014.23
A new method of segmentation of compact-appearing, transitional and trabecular compartments and quantification of cortical porosity from high resolution peripheral quantitative computed tomographic images
Zebaze, Roger M., Ghasem-Zadeh, Ali, Mbala, A. and Seeman, Ego. (2013). A new method of segmentation of compact-appearing, transitional and trabecular compartments and quantification of cortical porosity from high resolution peripheral quantitative computed tomographic images. Bone. 54(1), pp. 8 - 20. https://doi.org/10.1016/j.bone.2013.01.007
Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy
Chiang, Cherie Ying, Zebaze, Roger M.D., Ghasem-Zadeh, Ali, Iuliano-Burns, Sandra, Hardidge, Andrew and Seeman, Ego. (2013). Teriparatide improves bone quality and healing of atypical femoral fractures associated with bisphosphonate therapy. Bone. 52(1), pp. 360 - 365. https://doi.org/10.1016/j.bone.2012.10.006
Predictors of new and severe vertebral fractures: Results from the HoRIZoN Pivotal Fracture Trial
Wustrack, R., Seeman, Ego, Bucci-Rechtweg, C. and Burch, S.. (2012). Predictors of new and severe vertebral fractures: Results from the HoRIZoN Pivotal Fracture Trial. Osteoporosis International. 23(1), pp. 53 - 58. https://doi.org/10.1007/s00198-011-1664-4
The effect of acute exercise on undercarboxylated osteocalcin in obese men
Levinger, Itamar, Zebaze, Roger M., Jeru, G., Hare, David L., Selig, Steve and Seeman, Ego. (2011). The effect of acute exercise on undercarboxylated osteocalcin in obese men. Osteoporosis International. 22(5), pp. 1621 - 1626. https://doi.org/10.1007/s00198-010-1370-7
Teriparatide therapy for osteonecrosis of the jaw REPLY
Cheung, Ada S. and Seeman, Ego. (2011). Teriparatide therapy for osteonecrosis of the jaw REPLY. New England Journal of Medicine. 364, pp. 1081 - 1082. https://doi.org/10.1056/NEJMc1100730
Festschrift to honor Professor Pierre D. Delmas
Seeman, E., Lindsay, R. and Kanis, J. A.. (2009). Festschrift to honor Professor Pierre D. Delmas. Osteoporosis International. 20(Supplement 3), pp. S231 - S233. https://doi.org/10.1007/s00198-008-0811-z
Bone fragility in men - Where are we?
Seeman, Ego, Bianchi, Georges, Khosla, Sundeep, Kanis, John and Orwoll, E. (2006). Bone fragility in men - Where are we? Osteoporosis International. 17(11), pp. 1577 - 1583. https://doi.org/10.1007/s00198-006-0160-8