Recent results from the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial and its extension regarding bone histology, histomorphometry, and matrix mineralization (1), as well as areal bone mineral density (BMD), fracture incidence, and adverse events (2), showed efficacy and safety of long-term denosumab treatment of osteoporosis in postmenopausal women. Interestingly, areal BMD at the lumbar spine, total hip, and femoral neck but not the one-third radius continuously increased for up to 10 years (2). Based on data from iliac bone biopsy specimens that the mean degree of mineralization and the heterogeneity index were similar at 5 and 10 years (1), the authors suggested that modeling-based bone formation shown in adult monkeys treated with denosumab would be one possible mechanism, as previously discussed (2–4). Here I would like to provide further mechanistic insights into the authors’ suggestion. The above-mentioned continuous but site-specific effects of denosumab treatment on areal BMD (2) indicate that long-term efficacy of denosumab treatment can be expected in both trabecular and cortical bone compartments at the weight-bearing sites. This is likely to support modeling-based bone formation uncoupled with bone resorption because the primary determinant of bone modeling is elastic deformation (strain) of the skeleton engendered by physical activity (5). The noncontinuous effect on areal BMD at the non-weight-bearing radius (2) agrees with the similar bone mineralization characteristics at 5 and 10 years (1), which could further support that long-term efficacy of denosumab treatment is independent of remodeling-based coupled bone resorption and formation, although iliac crest analyzed is also a non-weight-bearing bone as the authors pointed out. Here it is important to note that modeling-based bone formation in the adult skeleton would generally require an increase in the level of mechanical strain itself and/or the resultant skeletal response, whereas an increase in the degree of bone mineralization caused by denosumab treatment of up to 5 years (1) acts to decrease the level of mechanical strain, and denosumab treatment is unlikely to directly enhance skeletal response to mechanical strain. We previously suggested that the increased level of mechanical strain might be expected through an increase in physical activity (6); the incidence of falls that did not cause fractures in the denosumab group (4.5%) was significantly lower than that in the placebo group (5.7%) in the FREEDOM trial. However, even if an increase in physical activity after denosumab treatment is possible, the increased level of mechanical strain alone is difficult to fully explain the long-term continuous increases in areal BMD because skeletal adaptation to change in mechanical strain is relatively rapid. The homeostatic system to maintain the level of mechanical strain in the skeleton indicates the negative feedback control against the decreased level of bone strain resulting from an increase in bone strength associated with osteoporosis therapy (7). Consequently, long-term continuous modeling-based bone formation could be theoretically realized if denosumab treatment can indirectly and gradually increase the skeletal response to mechanical strain during habitual physical activity. Considering the osteocyte lacunocanalicular system (8), long-term denosumab treatment might enhance mechanical strain–related stimuli by narrowing the lacunocanalicular space and increasing fluid flow. Abbreviation: Abbreviation: BMD bone mineral density Acknowledgments Disclosure Summary: The author has nothing to disclose. References 1. Dempster DW , Brown JP , Fahrleitner-Pammer A , Kendler D , Rizzo S , Valter I , Wagman RB , Yin X , Yue SV , Boivin G . Effects of long-term denosumab on bone histomorphometry and mineralization in women with postmenopausal osteoporosis . J Clin Endocrinol Metab . 2018 ; 103 ( 7 ): 2498 – 2509 . 2. Bone HG , Wagman RB , Brandi ML , Brown JP , Chapurlat R , Cummings SR , Czerwiński E , Fahrleitner-Pammer A , Kendler DL , Lippuner K , Reginster JY , Roux C , Malouf J , Bradley MN , Daizadeh NS , Wang A , Dakin P , Pannacciulli N , Dempster DW , Papapoulos S . 10 Years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension . Lancet Diabetes Endocrinol . 2017 ; 5 ( 7 ): 513 – 523 . 3. Portal-Núñez S , Mediero A , Esbrit P , Sánchez-Pernaute O , Largo R , Herrero-Beaumont G . Unexpected bone formation produced by RANKL blockade . Trends Endocrinol Metab . 2017 ; 28 ( 10 ): 695 – 704 . 4. Dempster DW , Zhou H , Recker RR , Brown JP , Recknor CP , Lewiecki EM , Miller PD , Rao SD , Kendler DL , Lindsay R , Krege JH , Alam J , Taylor KA , Melby TE , Ruff VA . Remodeling- and modeling-based bone formation with teriparatide versus denosumab: a longitudinal analysis from baseline to 3 months in the AVA study . J Bone Miner Res . 2018 ; 33 ( 2 ): 298 – 306 . 5. Sugiyama T , Oda H . Osteoporosis therapy: bone modeling during growth and aging . Front Endocrinol (Lausanne) . 2017 ; 8 : 46 . 6. Sugiyama T , Kim YT , Oda H . A possible mechanism of denosumab treatment for fracture prevention . J Clin Endocrinol Metab . 2016 ; 101 ( 2 ): L15 – L16 . 7. Sugiyama T . Treatment of low bone density or osteoporosis to prevent fractures in men and women . Ann Intern Med . 2017 ; 167 ( 12 ): 899 – 900 . 8. Dallas SL , Prideaux M , Bonewald LF . The osteocyte: an endocrine cell ... and more . Endocr Rev . 2013 ; 34 ( 5 ): 658 – 690 . Copyright © 2018 Endocrine Society
Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: May 15, 2018
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