Original Full Length Article Undercarboxylated osteocalcin, muscle strength and indices of bone health in older women ☆ Itamar Levinger a,b, ⁎, David Scott b , Geoffrey C. Nicholson b,c , Amanda L. Stuart d , Gustavo Duque e , Thomas McCorquodale e , Markus Herrmann f , Peter R. Ebeling b , Kerrie M. Sanders b a Institute of Sport, Exercise and Active Living (ISEAL), College of Sport and Exercise Science, Victoria University, Melbourne, Australia b Australian Institute of Musculoskeletal Science, NorthWest Academic Centre, The University of Melbourne, Western Health, St Albans, Australia c Rural Clinical School, The University of Queensland, Toowoomba, Australia d School of Medicine, Deakin University, Geelong, Australia e Ageing Bone Research Program, Sydney Medical School Nepean, The University of Sydney, Sydney, Australia f Central Clinical School, Royal Prince Alfred Hospital, The University of Sydney, Sydney, Australia abstract article info Article history: Received 11 January 2014 Revised 13 March 2014 Accepted 15 March 2014 Available online 21 March 2014 Edited by: Nuria Guanabens Keywords: Osteocalcin Undercarboxylated osteocalcin Muscle strength Bone remodelling Older-adults We investigated the association between undercarboxylated osteocalcin (ucOC) and lower-limb muscle strength in women over the age of 70 years. The study also aims to confirm the association between bone turnover markers and heel ultrasound measures. A post-hoc analysis using data collected as part of a randomized placebo-controlled trial of vitamin D supplementation.An immunoassay was used to quantify total OC (tOC), with hydroxyapatite pre-treatment for ucOC. We determined associations of absolute and relative (ucOC/tOC; ucOC%) measures of ucOC with lower-limb muscle strength, heel ultrasound measures of speed of sound (SOS) and broadband ultrasound attenuation (BUA), bone turnover markers (BTMs; P1NP and CTx) and the acute phase protein alpha-1-antichymotrypsin (α-ACT). ucOC%, but not absolute ucOC concentration, was posi- tively associated with hip flexor, hip abductor and quadriceps muscle strength (all p b 0.05). ucOC% was nega- tively associated with α-ACT (β-coefficient = -0.24, p = 0.02). tOC was positively associated with both P1NP and CTx (p b 0.001). For each per unit increase in tOC (μg/L) there was a corresponding lower BUA, SOS and SI (β-coefficient = -0.28; -0.23 and -0.23, respectively; all p b 0.04). In conclusion, ucOC% is positively associ- ated with muscle strength and negatively associated with α-ACT. These data support a role for ucOC in muscu- loskeletal interactions in humans. Whilst tOC is associated with bone health, ucOC% and ucOC may also be linked to falls and fracture risk by influencing muscle function. © 2014 Elsevier Inc. All rights reserved. Introduction Osteocalcin (OC) is an osteoblast-specific secreted protein. Its syn- thesis is exclusive to bone and serum levels reflect bone remodelling and, in particular, bone formation [1]. Recently novel metabolic roles of OC have been identified in preclinical studies, including increasing in- sulin secretion and sensitivity [2–4]. In humans, epidemiological studies which demonstrate serum levels of total OC (tOC) are, in general, in- versely associated with metabolic syndrome, measures of adiposity and glycaemia, and cardiovascular mortality [5]. The regulation of insu- lin sensitivity by OC may be either direct or indirect, via the adipocyte- derived hormone, adiponectin [1,6]. In addition, increased bone fragility is common among adults with type 2 diabetes mellitus and may be re- lated to changes in the material properties of bone. Sarcopenia, a reduction in muscle mass, strength and function, is common in older adults and contributes to a reduction in the ca- pacity to perform activities of daily living, and an increased risk of falls and fractures in the elderly [7,8]. Sarcopenia has been associ- ated with high levels of inflammatory markers, interleukin-6 and tumour necrosis alpha (TNF-α), and with low levels of the acute phase reactive protein, alpha-1-antichymotrypsin (α-ACT) [9]. Muscle strength is important for preventing and managing chronic metabolic, cardiovascular and musculoskeletal diseases, and is also associated with tOC [10]. In bone and serum, OC is incompletely carboxylated (undercarboxylated OC) (ucOC) and it is the uncarboxylated form that has been linked to glucose homeostasis in mice. In the few human studies that have measured ucOC results have been equivocal [1]. Previously it was reported that exercise in- creases circulating levels of ucOC and that increases in ucOC correlated with the post-exercise reductions in serum glucose levels [11]. As skeletal muscle is a major site for glucose dis- posal [12,13] it suggests that the ucOC may have a link, Bone 64 (2014) 8–12 ☆ Trial registration: ISRCTN83409867 and ACTR12605000658617. ⁎ Corresponding author at: Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, PO Box 14428, Melbourne, VIC 8001, Australia. Fax: +61 3 9919 5532. E-mail address: itamar.levinger@vu.edu.au (I. Levinger). http://dx.doi.org/10.1016/j.bone.2014.03.008 8756-3282/© 2014 Elsevier Inc. All rights reserved. Contents lists available at ScienceDirect Bone journal homepage: www.elsevier.com/locate/bone