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Osteosarcopenia: the Path Beyond Controversy

Zanker J1,2,3, Duque G4,5,6.

Curr Osteoporos Rep. 2020 Mar 4. doi: 10.1007/s11914-020-00567-6. [Epub ahead of print]

Osteosarcopenia is commonly accepted as the presence of low muscle mass and function (sarcopenia) and low bone mineral density (osteopenia and osteoporosis). Osteosarcopenia remains a topic of controversy as researchers worldwide seek to elucidate whether osteosarcopenia is associated with greater risk of negative outcomes than its component parts. This review examines the latest research and controversies, and charts a path forward.

Osteosarcopenia may occur in 5-37% of community-dwelling adults over the age of 65. This wide range is driven by variation in population, setting, and definitions applied. These differences in study design have resulted in mixed findings in associations with adverse outcomes for older adults living with osteosarcopenia. Research into interventions to prevent or treat osteosarcopenia, such as exercise, protein supplementation, and pharmacotherapy, is in its infancy but examined herein. The absence of a consensus operational definition of sarcopenia, and inaccurate measures of muscle mass, has hampered global progress in the field. We present a case for the path forward by reflecting on our recent history.

Back to the Future

Recent research examining the role of a direct measure of muscle mass – the D3 creatine dilution method (D3Cr muscle mass) – is having a game-changing effect on our understanding of the impact of low muscle mass on negative outcomes [18, 28]. In longitudinal studies of older men, low D3Cr muscle mass has shown strong relation with falls [29], fractures [30], and mortality [31] risk. These striking findings in older men with low D3Cr muscle mass contrasts the mixed associations of DXA ALM with the same outcomes [20], and demands that we reflect on the original concept of sarcopenia proposed by Rosenberg 30 years ago [15]; “no decline with age is more dramatic or potentially more functionally significant than the decline in lean body mass…perhaps it deserves a name from the Greek.” There is great appeal from a practical and clinical perspective at the prospect of treating disorders of muscle bone simultaneously. It is therefore unsurprising that osteosarcopenia has received attention from pharmaceutical companies globally.

Current targets of interest include the myostatin, androgen, fatty acid synthesis, and receptor activator of nuclear kB (RANK) pathways. Myostatin is an important factor in the regulation ofmuscle and bone. The myostatin decoy receptor, ACVR2B-Fc, has been shown to increase lean body mass and bone formation [32]. However, myostatin is expressed in cardiac tissue and concerns remain as to its safety profile. Clinical studies using Selective Androgen Receptor Modulators (SARMs) have demonstrated an increase in muscle mass and strength in hypogonadal men and post-menopausal women [33]. One trial has been undertaken on women over 65 years with sarcopenia. No difference was observed between treatment groups in terms of strength and physical performance measures [34]. Denosumab, a RANK ligand inhibitor, is a commonly used anti-resorptive for treatment of osteoporosis. A recent trial delivered either denosumab or a bisphosphonate to women with osteosarcopenia [35]. Those treated with denosumab had increased ALM and handgrip strength, but no change was observed in those treated with bisphosphonates [35]. These are exciting findings that may have wide and significant implications for those living with osteosarcopenia. Further research is required to determine whether alteration of the myostatin, androgen, or RANK pathways reduce the risk of falls, fractures, and mortality in older adults with or at-risk of developing osteosarcopenia. Resistance to change is an inherent human characteristic. In the history of both osteoporosis and sarcopenia, great resistance has preceded acceptance. Criticism of whether osteosarcopenia is an independent entity posing greater risk of falls, fractures, and mortality than its component parts are the necessary course to truth. In addition, attempts to link osteosarcopenia with obesity, which is unrelated to intra- and inter-muscular and marrow fat [36], have created additional confusion [4]. Accurate measures of muscle mass coupled with a consensus on the operational definition of sarcopenia will bring us closer to judicious acceptance or rejection of osteosarcopenia as a distinct entity. At present, the prospect of a unique pathophysiological mechanism and possible treatment for osteosarcopenia remains possible, appealing, and unanswered.