The Young Investigator Series: Scrutinising testosterone, osteoarthritis, and osteonecrosis of the jaw

Thursday, 18 Apr 2019


Three young investigators from around Australia shared their research on testosterone, osteoarthritis, and medication-related osteonecrosis of the jaw (MRONJ) at the Amgen One conference in Melbourne.

Findings from the CHAMP study

Dr Ben Hsu, from the ANZAC Research Institute, School of Public Health, University of Sydney and Concord Hospital, presented findings from the Concord Health and Ageing in Men Project (CHAMP).1 “The CHAMP study aimed to determine if calculated free testosterone (cFT) provided additional prognostic information independent of serum testosterone in predicting morbidity in older men,” Dr Hsu said. “A range of morbidity outcomes including quality of life (SF-12), function (Katz ADL), and bone loss (DXA scan), were assessed in male patients 70 years and older”.

Patients were assessed at baseline (n=1705) between 2005 and 2007, 2 years follow-up (n=1367), and 5 years follow-up (n=958). “Our observations were consistent with previous studies,” said Dr Hsu. “Low testosterone or low cFT was associated with a variety of health outcomes such as frailty, falls, weight, or fat mass”.2 His research confirmed that cFT provides minimal additional clinical or biological information independent of accurate measurement of serum testosterone concentrations. However, Dr Hsu raised a question around the impact of survival bias “with 35% loss of follow-up due to death,” and potential diurnal variation in hormone concentration, which may have contributed to the study results.

Osteoarthritis: more than just cartilage

Dr Laura Laslett, epidemiologist and NHMRC Early Career Fellow, summarised the potential for bone-targeted therapies to treat osteoarthritis (OA). “New research suggests that OA is a disease which affects the entire joint, rather than just cartilage. Subchondral bone is significant in OA pathogenesis and increased turnover has been observed,” Dr Laslett began.3-6 Researchers have postulated targeting subchondral bone, in particular bone turnover and bone marrow lesions (BML) may benefit patients. “In knee OA, the presence and progression of bone marrow lesions seems to be a better predictor for knee pain,” said Dr Laslett.7-9 One study demonstrated treatment with bisphosphonates (alendronate) reduced the odds of a BML to 0.11 (95% CI; 0.01-0.89), which is an 89% reduction,10 “but in general bisphosphonates don’t seem to have a consistent effect on pain, radiographic change or BMLs,” she noted.

For example, while the ZAP1 trial demonstrated zoledronic acid (ZA) improves pain and BML size, ZAP2 did not.11 In ZAP2, ZA did not affect tibial cartilage loss over two years, and no difference in knee pain and BML size over 24 months when compared with placebo. “Surprisingly, subgroup analyses revealed ZA improved knee pain in patients without radiographic osteoarthritis, but had the opposite effect in patients with radiographic osteoarthritis,” Dr Laslett summarised.12

She then put the results in context with BMLs that have also been observed in the spine as Modic changes, and in the hands. Some antiresorptives have been shown to reduce low back pain associated with Modic changes.13 However, “that the results of these pilot trials have not come from larger trials is a major limitation,” she noted. Trials are underway to determine if denosumab may be used to treat hand and knee OA. Currently in Australia, ZA and denosumab are not indicated for pain control associated with Modic changes.

How teriparatide fits into the picture of osteonecrosis of the jaw

Dr Ie-Wen Sim, an endocrinologist practicing at Monash Health, Eastern Health, and Western Health, presented his findings on medication-related osteonecrosis of the jaw (MRONJ). “We observed a reduction in the incidence of MRONJ from 4.7% to 0.8% (p <0.01) with oral hygiene, and an odds ratio of 0.24 for developing MRONJ with active dental care,”14 Dr Sim told delegates.

Dr Sim commented on the American Dental Association Council on Scientific Affairs which stated “The highest reliable estimate of ONJ prevalence is approximately 0.10%… the benefit provided by antiresorptive medications outweighs the low risk of developing ONJ.”15 Importantly, he highlighted how this means the risk of ONJ should not deter clinicians from prescribing antiresorptives.

Teriparatide has been observed to resolve bone defects in chronic periodontitis and case reports have detailed MRONJ resolution with teriparatide therapy.16,17 “Patients with MRONJ were recruited and in a randomised double-blinded trial, patients were assigned teriparatide or placebo for eight weeks. At follow-up 12 months later, teriparatide showed a striking decrease in MRONJ sites,” Dr Sim remarked.18 Albeit teriparatide is not indicated for ONJ treatment in Australia, this looks like an interesting development to keep an eye on.”

 

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. Hsu, et al J Gerontol A Biol Sci Med Sci2017;72(4):520-527.
  2. Hsu, et alThe Journals of Gerontology: Series A, glx142 2017, https://doi.org/10.1093/gerona/glx142.
  3. Lane, et al Osteoarthritis Cartilage 2011;19(5):478-82.
  4. Castaneda, et al Biochemical Pharmacology 2012;83(3):315-23.
  5. Dieppe, et al Ann Rheum Dis 1993;52(8):557-63.
  6. Bailey, et al Age Ageing 2001;30(5):374-8.
  7. Davies-Tuck, et al Ann Rheum Dis 2009;68(6):904-8.
  8. Felson, et al Ann Intern Med 2003;139(5 Pt 1):330-6.
  9. Dore, et al Arthritis Res Ther 2010;12(6):R222.
  10. Carbone, et al Arthritis Rheum 2004;50(11):3516-25.
  11. Laslett, et al Ann Rheum Dis 2012;71(8):1322-8.
  12. Cai, et al Ann Rheum Dis 2018;77:57-58.
  13. Cai, et al J Bone Miner Res 2018;33(5):773-782.
  14. Sim I, et al J Clin Endocrinol Metab 2015;100(10):3887-93.
  15. Hellstein, et al J Am Dent Assoc 2011;142(11):1243-51.
  16. Bashutski, et al N Engl J Med 2010;363(25):2396-2405.
  17. Cheung & Seeman, N Engl J Med 2010;363:2473-74.
  18. Sim, et al. 2019 unpublished data.

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