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Summary

El Miedany et al. [1] recently published data of a study aimed at assessing if denosumab has a unique dual effect on both, bone and muscle, in comparison to other anti-resorptive agents and also its effectiveness during the follow-up period after completing treatment when compared to other anti-resorptive agents. For this, the authors looked at 135 patients diagnosed as having postmenopausal osteoporosis and who were prescribed denosumab compared to a control group of 272 patients stratified into 2 subgroups – 136 prescribed alendronate and 136 prescribed zoledronate. All patients were assessed for: bone mineral density (BMD) (DXA), falls risk (FRAS), fracture risk (FRAX), and sarcopenia measures. All patients were assessed after 5 years of denosumab/alendronate therapy and 3 years of zoledronate and 1 year after stopping the osteoporosis therapy. There were no significant baseline demographic differences between the 3 groups. After completing the 5-year denosumab therapy, there was a significant decrease in falls risk and significant improvements in all sarcopenia measures. One-year post-discontinuation of denosumab, a significant worsening of both falls risk and sarcopenia measures were noticed. The researchers finally conclude that denosumab displayed a positive impact and significant improvements in BMD and sarcopenia measures, suggesting that denosumab may be considered as a first osteoporosis therapeutic option in this group of patients presenting with osteosarcopenia manifestations.

Commentary

Most healthcare providers know that osteoporosis and osteopenia are well defined conditions with known risks associated with fracture. A recent review of PubMed found that the first article published with the keyword ‘osteoporosis’ was in 1894; through May 2020 there were a total of 93,335 articles utilizing that keyword. It is derived from the Greek osteon (bone), and poros (little hole). Thus, osteoporosis means ‘porous bone’. Sarcopenia is a condition characterized by a progressive and generalized loss of skeletal muscle mass, function and strength, with a risk of adverse outcomes such as physical disabilities, poor quality of life and even death [2,3]. The Greek roots for the word are sarx for flesh and penia for loss and it was coined in 1989 [4]. The same review of PubMed with ‘sarcopenia’ as the keyword revealed the first article in 1993, with a total through May 2020 of 12,068 articles. Muscle accounts for 60% of the body’s protein. Muscle mass decreases with age, although younger patients with malnutrition, cachexia or inflammatory diseases are also prone. However, unlike osteoporosis, with a well-accepted definition based on DXA measurements, there is no universally accepted definition of sarcopenia, consensus diagnostic criteria or treatment guidelines. In 2016, in the ICD-10-CM, sarcopenia was finally recognized as a disease entity. Currently the most widely accepted definition comes from the European Working Group on Sarcopenia in Older People (EWGSOP) who labeled pre-sarcopenia as low muscle mass without impact on muscle strength or performance, sarcopenia as low muscle mass with either low muscle strength or low physical performance, and severe sarcopenia as all three criteria being present [5].

Osteosarcopenia, the combination of osteoporosis/osteopenia and sarcopenia has been shown to increase the overall rate of falls and fractures when compared to those women with osteopenia or osteoporosis alone [6]. The paper being commented of El Miedany et al. [1] entitled: “Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia?” provides interesting data highlighting the positive effect that denosumab had on BMD and sarcopenia measurements, decreasing the risk of falls significantly as measured with the FRAS (falls risk assessment score) [7]. This FRAS uses the clinical variables of history of falls in the last 12 months, impaired sight, weak hand grip, history of loss of balance in the last 12 months, and slowing of the walking speed/change in gait to yield a percent chance of sustaining a fall. Sarcopenic measures included grip strength, TUG (timed up and go) as well as gait speed. Despite the positive impact that denosumab had on falls risk and sarcopenia measures, after one year of discontinuation, there was a worsening of these indices. This was in contrast to both control groups, alendronate and zoledronic acid, where there was an improvement, although less robust in gait speed and TUG but no improvement in risk of falls. Thus, the results of this study showed that denosumab not only improved bone mass, but also it reduced falls risk. In comparison to bisphosphonates, denosumab showed the highest significant positive effect on both the physical performance and skeletal muscle strength. This is evidenced by improvement of the gait speed, TUG and 4-m walk test in the denosumab group, versus 0.05 in the alendronate and zoledronate group. These results agree with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis 6 months) trial which revealed that not only did denosumab treatment reduce the risk of vertebral, non-vertebral, and hip fracture over 36 months, but also the denosumab treated group had fewer falls (4.5%) compared to the other groups (5.7%) (p=0.02) [8].

Recently, the National Osteoporosis Foundation (NOF) changed its name to Bone Health and Osteoporosis Foundation (BHOF). Localized breast cancer carries a five-year survival of 99% [9]. Most of my patients are keenly aware of periodic competent breast imaging as the key to the earliest possible diagnosis. Yet in this country a hip fracture carries a mortality in the first year of 21%! [10]. Furthermore, approximately one third of women who fracture their hip do not have osteoporosis [11]. Yes, if present, the risk of hip fracture is greatest in osteoporotic women, but not absent in those without.

In summary, increasingly the importance of muscle mass, strength, and performance is an essential component of bone health. Some bone specific agents like denosumab may not only improve bone mass, measures of sarcopenia but even reduce risk of falls.

Steven R. Goldstein, MD, CCD, NCMP, FAGCOG, FRCOG (H)
Professor of Obstetrics and Gynecology at New York University School of Medicine and Director of Gynecologic Ultrasound and Co-Director of Bone Densitometry at New York University Medical Center

References

  1. El Miedany Y, El Gaafary M, Toth M, et al. Is there a potential dual effect of denosumab for treatment of osteoporosis and sarcopenia? Clin Rheumatol. 2021 Oct;40(10):4225-4232.
    https://pubmed.ncbi.nlm.nih.gov/34008069/
  2. Goodpaster BH, Park SW, Harris TB, et al. The loss of skeletal muscle strength, mass, and quality in older adults: The health, aging and body composition study. J Gerontol A Biol Sci Med Sci. 2006;61(10):1059–1064.
    https://pubmed.ncbi.nlm.nih.gov/17077199/
  3. Santilli V, Bernetti A, Mangone M, Paoloni M. Clinical definition of sarcopenia. Clin Cases Miner Bone Metab. 2014;11(3):177–180.
    https://pubmed.ncbi.nlm.nih.gov/25568649/
  4. Rosenberg IH. Summary comments: Epidemiological and methodological problems in determining nutritional status of older persons. Am J Clin Nutr. 1989;50(5):1231–1233.
    https://academic.oup.com/ajcn/article-abstract/50/5/1231/4695358
  5. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al.; European Working Group on Sarcopenia in Older People. Sarcopenia: European consensus on definition and diagnosis: Report of the European Working Group on Sarcopenia in Older People. Age Ageing. 2010;39(4):412-23.
    https://pubmed.ncbi.nlm.nih.gov/20392703/
  6. Sepúlveda-Loyola W, Phu S, Bani Hassan E, et al. The joint occurrence of osteoporosis and sarcopenia (osteosarcopenia): Definitions and characteristics. J Am Med Dir Assoc. 2020;21(2):220–225.
    https://pubmed.ncbi.nlm.nih.gov/31669290/
  7. El Miedany Y, El Gaafary M, Toth M, Palmer D, Ahmed I. Falls Risk Assessment Score (FRAS). J Clin Gerontology and Geriatrics. 2011;2(1):21-26.
    https://www.sciencedirect.com/science/article/pii/S2210833511000037
  8. Cummings SR, Martin JS, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756-765.
    https://pubmed.ncbi.nlm.nih.gov/19671655/
  9. American Cancer Society. Cancer Facts & Figures 2020. Atlanta, Ga: American Cancer Society; 2020.
    https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2020/cancer-facts-and-figures-2020.pdf Accessed November 17, 2020.
  10. Downey C, Kelly M, Quinlan JF. Changing trends in the mortality rate at 1-year post hip fracture—a systematic review. World J Orthop. 2019;10(3):166-175.
    https://pubmed.ncbi.nlm.nih.gov/30918799/
  11. Schuit S, van der Klift M, Weel AE, et al. Fracture incidence in association with bone mineral density in elderly men and women: the Rotterdam Study. Bone. 2004;34(1):195-202.
    https://pubmed.ncbi.nlm.nih.gov/14751578/


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