Covering the field of osteoporosis morphology and treatments

Speaking at the Amgen One conference in Melbourne, Juliet Compston, Professor of Bone Medicine and Honorary Consultant Physician at Cambridge University, gave delegates a comprehensive review of the current understanding of bone morphology, and the effects of antiresorptive and anabolic drugs on bone.

Abnormal bone morphology

Professor Compston after outlining the accepted understanding of normal morphology, introduced the notions of bone remodelling rate and remodelling imbalance as they are currently understood. “As a result of an increased remodelling rate, the number of resorption cavities present at any point in time is increased. Remodelling imbalance describes how formation and resorption are no longer coupled together,” she remarked. She discussed how without coupling of bone formation to resorption, “resorption cavities might only be partially filled in by new bone. The implication of this is of course irreversible bone loss.”

In the context of postmenopausal bone loss, Prof. Compston told delegates that increased remodelling rate and remodelling imbalance were particularly problematic. In men, a low bone turnover rate predominates, while in women an increase in the rate and balance of remodelling is observed. Studying remodelling rates and bone turnover has been possible through histomorphometric bone assessments. “What we know is that bone modelling is fundamentally different from bone remodelling in that resorption and formation are not coupled in space or time. Distinguishing between the two is mainly based on the characteristics of the cement line which in remodelling-based formation is scalloped by the previously occurring resorption. Whereas in modelling bone formation there has been no prior resorption, so the cement line is smooth. It’s a nice visual clue,”¹ she summarised.

“Experiments with teriparatide treatment have also demonstrated overflow modelling adjacent to remodelling-based formation, which is where bone formation seems to produce a smooth cement line over a previously remodelled site,”¹ she added. “There’s also mechanisms of modelling-based bone gain, where bone is formed in the absence of resorption, but distinguishing this histomorphetrically is difficult as we cannot always be sure it isn’t due to overflow modelling.” She said the 2018 study by Dempster et al. confirmed that both remodelling and modelling bone formation contribute to the skeletal effects of parathyroid hormone (PTH) and teriparatide.¹

Despite the benefits that histomorphometric assessment of bone has yielded in terms of understanding both remodelling rates and balance, Prof. Compston outlined some disadvantages such as limitations to skeletal site assessment (often the iliac crest), likening it to a snapshot in time. “If a biopsy is performed early, then there is a possibility that the clinician will miss long-term changes. Conversely, if a biopsy is performed later, then the clinician may miss out on observing the early short-term changes,” she explained. This implies the importance of timing in relation to biopsies and potentially skewed observations which may impact clinical decisions.

It’s also important to keep in mind that a single site may not be representative of the entire skeleton explained Prof. Compston, “there is heterogeneity within single sites, as cortical thickness and porosity can vary within the same bone.” This could affect calculations based on steady-state remodelling and not accurately reflect inconsistencies that occur within the sampling site.

Current treatments

Prof. Compston then examined current treatments for osteoporosis and made the point that while bisphosphonates decrease remodelling rates, remodelling balance remains unchanged. What we don’t know at present is what’s going on with bisphosphonates and modelling bone formation.^2,3 In contrast, we know denosumab decreases remodelling rates; there are some animal data suggesting modelling bone formation may be maintained and potentially improves remodelling balance.^2,3 But both treatment options increase mineralisation. “The negative remodelling imbalance, uncorrected by antiresorptives should not be a concern,” she emphasised, “as the overall impact will be negligible since there are fewer remodelling units. This is especially the case with potent antiresorptive drugs,” she added.

Future treatments and directions

To put our understanding of bone modelling and remodelling in context, Prof. Compston discussed emerging data on abaloparatide, a PTH1 receptor activator not available in Australia.⁴ She commented that “the data on this treatment are sparse with respect to effects on bone remodelling, modelling and structure, but suggest similarities to teriparatide in terms of effects on cortical porosity, but less effects on the eroded surface. However, we need to consider that comparisons should be made with caution as dosages between treatments in the trial were different.”⁵ Another drug not currently registered in Australia is romosozumab, an anti-sclerostin antibody which shows promise as it has a unique mechanism of action that stimulates formation and inhibits resorption.⁶

Prof. Compston summarised that as our understanding of bone modelling and remodelling is enhanced, there is a need to now “fill in the gaps of our understanding of how current and future treatments affect bone.”

This article was sponsored by Amgen, which has no control over editorial content. The content is entirely independent and based on published studies and experts’ opinions, the views expressed are not necessarily those of Amgen.

References

1. Dempster DW, et al. J Bone Miner Res 2018;33(2):298-306.
2. Seeman E & Martin TJ, Nat Rev Rheumatol doi: 10.1038/s41584-019-0172-3. [Epub ahead of print].
3. Chavassieux P, et al. J Bone Miner Res doi: 10.1002/jbmr.3631. [Epub ahead of print].
4. Miller PD, et al. JAMA 2016;316(7):722-733.
5. Moreira CA, et al. Bone 2017;97:314-319.
6. Suen PK & Ling Q. J Orthapaed Transl 2016;4:1-13.