Correlations Between Changes in Undercarboxylated Osteocalcin and Muscle Function in Hypoparathyroidism

Abstract

BackgroundMuscles and bones are interconnected. Recent studies suggest that undercarboxylated osteocalcin from bone may affect muscle mass and strength. There are, however, no prospective human data on this relationship.MethodsWe previously treated patients with hypoparathyroidism with intact Parathyroid Hormone (PTH) or placebo in a six-month randomized, placebo-controlled trial and demonstrated a marked increase in undercarboxylated osteocalcin (ucOC) in the PTH-treated group. We therefore investigated if this increase correlated with changes in muscle mass, strength or function. Primarily, the muscle mass using Dual energy X-ray Absorptiometry (DXA) was measured and the maximal voluntary isometric muscle strength at the upper and lower extremities, using dynamometry, was assessed. Furthermore, repeated chair stands test, Timed Up and Go test were performed and postural stability using a stadiometer was assessed. Finally, the relationship between change in ucOC or the ratio of the changes in ucOC and total OC (ucOC%/OC%) and different measures of muscle function were analyzed, using regression analyses.ResultsThe findings indicated that ucOC%/OC% was positively and significantly associated with percentage change in max force production during elbow extension (β = 0.28, P = 0.034), however, all other associations were non-significant.ConclusionsGiven the number of statistical tests that were carried out, our one significant finding may represent a false positive. Thus the results do not support the role of ucOC in muscle function in humans with hypoparathyroidism. Our results are inconsistent with previous data from a human cross-sectional study; however, cross-sectional studies, do not allow for inference of causality. The analyses should be repeated in larger, randomized trials including healthy individuals.

Osteocalcin Induces Proliferation via Positive Activation of the PI3K/Akt, P38 MAPK Pathways and Promotes Differentiation Through Activation of the GPRC6A-ERK1/2 Pathway in C2C12 Myoblast Cells

“…Our data identify ucOC as a potential therapeutic target for alleviating the reduction in muscle mass associated with muscle disorders and ageing. To the best of our knowledge, only a few human studies have investigated osteocalcin in relation to muscle mass and function, and these studies have led to inconsistent conclusions [48][49][50]; thus, the role of ucOC in muscle mass and physical function in humans is still unknown. Further research in humans is needed to confirm the data obtained inanimal studies.…”

Bone and Muscle Crosstalk in Aging

“…Enhance C2C12 myoblast cell proliferation and myogenic differentiation thorough activation of the PI3K/Akt, p38 and GPRC6A-ERK1/2 signaling pathway separately . Positive associated with muscle mass or function (Levinger et al, 2014;Harslof et al, 2016;.…”

“…Later, Liu S. et al (2017) illustrated and confirmed that under-carboxylated OCN enhances C2C12 myoblast cell proliferation and myogenic differentiation thorough activation of the PI3K/Akt, p38, and GPRC6A-ERK1/2 signaling pathways, respectively. Moreover, several investigations on rats, healthy volunteers, or patients with hypoparathyroidism revealed that under-carboxylated OCN is positively associated with muscle mass or function ( Levinger et al, 2014 ; Harslof et al, 2016 ; Lin et al, 2016 ). However, this experiment should be repeated in a large healthy population.…”

Undercarboxylated Osteocalcin: Experimental and Human Evidence for a Role in Glucose Homeostasis and Muscle Regulation of Insulin Sensitivity

“…In a cross-sectional study of women aged ≥70 years in which ucOC was assayed using a HAP-binding assay, a positive correlation was found between % ucOC and quadriceps muscle strength [ 120 ]. In an interventional study of 62 patients with hypoparathyroidism, treatment with recombinant parathyroid hormone (rPTH) resulted in an increase in % ucOC which was not associated with energy metabolism [ 121 ], but was positively associated with the change of maximum force generated in elbow extension [ 122 ]. However, in that study, the increase in ucOC was not associated with other tests of muscle and physical performance [ 122 ].…”

“…In an interventional study of 62 patients with hypoparathyroidism, treatment with recombinant parathyroid hormone (rPTH) resulted in an increase in % ucOC which was not associated with energy metabolism [ 121 ], but was positively associated with the change of maximum force generated in elbow extension [ 122 ]. However, in that study, the increase in ucOC was not associated with other tests of muscle and physical performance [ 122 ]. Therefore, while there is some data to support a role for ucOC in the regulation of muscle strength and function, in addition to its role in muscle glucose uptake and metabolism, interventional studies are needed to determine if there is a causative effect and whether there is scope for novel therapeutic approaches to enhance both glucose metabolism and muscle function.…”