Osteoporos Int (2014) 25:1633–1642 DOI 10.1007/s00198-014-2673-x
ORIGINAL ARTICLE
Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months A. D. Anastasilakis & S. A. Polyzos & P. Makras & A. Gkiomisi & I. Bisbinas & A. Katsarou & A. Filippaios & C. S. Mantzoros
Received: 5 December 2013 / Accepted: 19 February 2014 / Published online: 6 March 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. Introduction This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass
A. D. Anastasilakis (*) Department of Endocrinology, 424 General Military Hospital, Ring Road, 564 29 N. Efkarpia, Thessaloniki, Greece e-mail: [email protected] S. A. Polyzos Department of Medicine, Second Medical Clinic, Ippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece P. Makras Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece A. Gkiomisi Department of Obstetrics and Gynaecology, 424 General Military Hospital, Thessaloniki, Greece I. Bisbinas 2nd Department of Orthopaedics, 424 General Military Hospital, Thessaloniki, Greece A. Katsarou Hellenic Military School of Medicine, Thessaloniki, Greece A. Filippaios : C. S. Mantzoros Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
and to assess a potential effect of denosumab or teriparatide treatment for 3 months. Methods Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤−2.0) and their agematched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n=50; Dmab control group, n=25) and (b) women with more severe disease (LS or FN BMD T-score ≤−2.8) and their agematched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n=25; TPTD control group, n=25). Results At baseline, irisin levels were inversely correlated with age (partial coefficient (rp)=−0.24; p=0.009), parathyroid hormone (PTH) (rp =−0.30; p=0.001), and creatinine (rp =−0.23; p=0.016) in univariate analysis, and were lower in women with (n=26; 41.6±2.7 ng/dL) than without previous osteoporotic fracture(s) (n=99; 51.0±1.6 ng/dL; p= 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p=0.04, CI −16.1 to −0.4 and p=0.002, CI −0.3 to −0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. Conclusions Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified. Keywords Bonemetabolism . Denosumab . Fracture . Irisin . Osteoporosis . Teriparatide
1634
Introduction Postmenopausal osteoporosis is the most common skeletal disease, resulting from increased bone resorption by the osteoclasts and/or decreased bone formation by the osteoblasts, and its complications represent a major cause of morbidity and mortality in the aging population [1]. Denosumab (Dmab) [2], which suppresses osteoclastogenesis through receptor activator of nuclear factor kappa-B ligand (RANKL) inhibition, and teriparatide (TPTD–recombinant human parathyroid hormone [rhPTH] 1-34) [3], which directly stimulates osteoblast activity and inhibits osteoblast apoptosis, represent two of the most potent anti-osteoporotic treatments available. The molecular mechanisms regulating the antiresorptive effect of Dmab and the anabolic effect of TPTD on the skeleton are not fully elucidated. Bones and skeletal muscles are often considered as one entity, referred to as musculoskeletal system, and muscles weaken along with bone loss with advancing age. Recently, skeletal muscle has been identified as an endocrine organ, which communicates with other tissues through myokines released into the circulation, especially during physical activity [4]. Irisin, a newly discovered myokine [5], induced in exercise, has potential effects in stimulating adipose tissue browning, thereby having a potentially favorable effect on obesity and diabetes [6–8]. Brown adipose tissue has been recently reported to be anabolic for the skeleton, through increased phospho-Akt and β-catenin expression by osteoblastic cells and decreased sclerostin gene (SOST) expression by the osteocytes [9]. Furthermore, in a recent in vitro study, irisin promoted osteoblast differentiation, partly through the bone morphogenetic protein (BMP) pathway, and inhibited osteoclast differentiation by suppressing the RANKL-Akt1/ MITF/PU1-NFATc1 pathway [10]. Thus, irisin could mediate the positive effects of exercise on the skeleton, and represent a therapeutic target for bone diseases, including osteoporosis [11]. The main aims of this study were (1) to evaluate predictors of circulating irisin levels in postmenopausal women with and without low bone mass and (2) to investigate the 3-month effect on irisin levels of therapeutic agents, namely Dmab and TPTD, exerting opposite effects on bone turnover.
Osteoporos Int (2014) 25:1633–1642
femoral neck (FN) T-score ≤−2.0 served as patients and were divided into (a) those with LS or FN T-score ≤−2.0 but >−2.8, who were assigned to a single subcutaneous injection of denosumab 60 mg (Dmab group); the women of the Dmab group were further subdivided into women that had not received any anti-osteoporotic treatment in the past (Dmab/naïve subgroup) and those previously treated with treatments other than Dmab (Dmab/non-naïve subgroup) and (b) those with T-score ≤−2.8, who were assigned to daily subcutaneous injections of teriparatide 20 μg (TPTD group). Women with LS and FN T-score >−2.0 and no previous diagnosis of or treatment for osteoporosis served as controls and were divided into two groups, so as to be age-, age at menopause-, and body mass index (BMI)-matched (±2 kg/m2) to (a) Dmab subgroups (Dmab control) or (b) TPTD group (TPTD control). Women in all groups/subgroups were supplemented with 1,000 mg/day calcium and 800 IU/day vitamin D throughout the study. Exclusion criteria for all groups were: (a) age
ORIGINAL ARTICLE
Circulating irisin is associated with osteoporotic fractures in postmenopausal women with low bone mass but is not affected by either teriparatide or denosumab treatment for 3 months A. D. Anastasilakis & S. A. Polyzos & P. Makras & A. Gkiomisi & I. Bisbinas & A. Katsarou & A. Filippaios & C. S. Mantzoros
Received: 5 December 2013 / Accepted: 19 February 2014 / Published online: 6 March 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary In vitro data suggest that myokine irisin may affect bone metabolism by promoting osteoblast differentiation while inhibiting osteoclast differentiation. In this study, circulating irisin levels were associated with previous osteoporotic fractures but not with bone mass and were not affected by denosumab or teriparatide treatment for 3 months. Introduction This study aimed to evaluate predictors of circulating irisin in postmenopausal women with low bone mass
A. D. Anastasilakis (*) Department of Endocrinology, 424 General Military Hospital, Ring Road, 564 29 N. Efkarpia, Thessaloniki, Greece e-mail: [email protected] S. A. Polyzos Department of Medicine, Second Medical Clinic, Ippokration General Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece P. Makras Department of Endocrinology and Diabetes, 251 Hellenic Air Force & VA General Hospital, Athens, Greece A. Gkiomisi Department of Obstetrics and Gynaecology, 424 General Military Hospital, Thessaloniki, Greece I. Bisbinas 2nd Department of Orthopaedics, 424 General Military Hospital, Thessaloniki, Greece A. Katsarou Hellenic Military School of Medicine, Thessaloniki, Greece A. Filippaios : C. S. Mantzoros Department of Internal Medicine, Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
and to assess a potential effect of denosumab or teriparatide treatment for 3 months. Methods Serum samples for irisin measurement were obtained from (a) postmenopausal women with low bone mass (lumbar spinal [LS] or femoral neck [FN] bone mineral density [BMD] T-score ≤−2.0) and their agematched controls at baseline and 3 months after denosumab (Dmab) injection (Dmab group, n=50; Dmab control group, n=25) and (b) women with more severe disease (LS or FN BMD T-score ≤−2.8) and their agematched controls at the above-mentioned time points after teriparatide (TPTD) initiation (TPTD group, n=25; TPTD control group, n=25). Results At baseline, irisin levels were inversely correlated with age (partial coefficient (rp)=−0.24; p=0.009), parathyroid hormone (PTH) (rp =−0.30; p=0.001), and creatinine (rp =−0.23; p=0.016) in univariate analysis, and were lower in women with (n=26; 41.6±2.7 ng/dL) than without previous osteoporotic fracture(s) (n=99; 51.0±1.6 ng/dL; p= 0.007). In multiple linear regression, previous osteoporotic fracture(s) and PTH were independently negatively associated with irisin [p=0.04, CI −16.1 to −0.4 and p=0.002, CI −0.3 to −0.07, respectively], but only the association with PTH remained after controlling for creatinine levels. Serum irisin levels were not different between women with or without low bone mass and were not affected by either Dmab or TPTD treatment for 3 months. Conclusions Circulating irisin levels were associated with previous osteoporotic fracture(s); whether this association is independent or is due to confounding by lower muscle mass, potentially reflected by lower creatinine levels, remains to be fully clarified. Keywords Bonemetabolism . Denosumab . Fracture . Irisin . Osteoporosis . Teriparatide
1634
Introduction Postmenopausal osteoporosis is the most common skeletal disease, resulting from increased bone resorption by the osteoclasts and/or decreased bone formation by the osteoblasts, and its complications represent a major cause of morbidity and mortality in the aging population [1]. Denosumab (Dmab) [2], which suppresses osteoclastogenesis through receptor activator of nuclear factor kappa-B ligand (RANKL) inhibition, and teriparatide (TPTD–recombinant human parathyroid hormone [rhPTH] 1-34) [3], which directly stimulates osteoblast activity and inhibits osteoblast apoptosis, represent two of the most potent anti-osteoporotic treatments available. The molecular mechanisms regulating the antiresorptive effect of Dmab and the anabolic effect of TPTD on the skeleton are not fully elucidated. Bones and skeletal muscles are often considered as one entity, referred to as musculoskeletal system, and muscles weaken along with bone loss with advancing age. Recently, skeletal muscle has been identified as an endocrine organ, which communicates with other tissues through myokines released into the circulation, especially during physical activity [4]. Irisin, a newly discovered myokine [5], induced in exercise, has potential effects in stimulating adipose tissue browning, thereby having a potentially favorable effect on obesity and diabetes [6–8]. Brown adipose tissue has been recently reported to be anabolic for the skeleton, through increased phospho-Akt and β-catenin expression by osteoblastic cells and decreased sclerostin gene (SOST) expression by the osteocytes [9]. Furthermore, in a recent in vitro study, irisin promoted osteoblast differentiation, partly through the bone morphogenetic protein (BMP) pathway, and inhibited osteoclast differentiation by suppressing the RANKL-Akt1/ MITF/PU1-NFATc1 pathway [10]. Thus, irisin could mediate the positive effects of exercise on the skeleton, and represent a therapeutic target for bone diseases, including osteoporosis [11]. The main aims of this study were (1) to evaluate predictors of circulating irisin levels in postmenopausal women with and without low bone mass and (2) to investigate the 3-month effect on irisin levels of therapeutic agents, namely Dmab and TPTD, exerting opposite effects on bone turnover.
Osteoporos Int (2014) 25:1633–1642
femoral neck (FN) T-score ≤−2.0 served as patients and were divided into (a) those with LS or FN T-score ≤−2.0 but >−2.8, who were assigned to a single subcutaneous injection of denosumab 60 mg (Dmab group); the women of the Dmab group were further subdivided into women that had not received any anti-osteoporotic treatment in the past (Dmab/naïve subgroup) and those previously treated with treatments other than Dmab (Dmab/non-naïve subgroup) and (b) those with T-score ≤−2.8, who were assigned to daily subcutaneous injections of teriparatide 20 μg (TPTD group). Women with LS and FN T-score >−2.0 and no previous diagnosis of or treatment for osteoporosis served as controls and were divided into two groups, so as to be age-, age at menopause-, and body mass index (BMI)-matched (±2 kg/m2) to (a) Dmab subgroups (Dmab control) or (b) TPTD group (TPTD control). Women in all groups/subgroups were supplemented with 1,000 mg/day calcium and 800 IU/day vitamin D throughout the study. Exclusion criteria for all groups were: (a) age
