Reply to Letter to the Editor by Hind et al.

Dear Editors,

We appreciate the substantive body of evidence-based research that definitely supports low energy availability as the primary driver of athletic osteopenia, as pointed out by Hind et al. in their letter [1]. However, we wish to emphasize that prolonged endurance exercise represents an accelerated physiological model for which short-range (nongenomic) regulatory circuits likely become more operative [2] [3] [4] [5]. Heightened physiological and mental stress necessitates moment-to-moment short-loop homeostatic responses that serve to complement the more classic genomic model of steroid activation, which takes hours to days to fully initiate [2]. As such, the metabolic demands of running a 161 km footrace in less than 30 h are 10-fold higher (13 000–16 000 kcal/day [6]) than the estimated basal metabolic rate of our 6 race finishers (1 531 kcal/day, using the Harris-Benedict Equation [7]). Thus, our data do not in any way undermine the classic physiological processes that contribute to low bone mineral density chronically in endurance athletes, but seek to build upon existing data to further determine whether or not: 1) pituitary-bone short-range homeostatic circuits exist and if so, 2) does repetitive stimulation of such short-range circuits have long-term pathological consequences related to low energy and serum mineral availability?

Short-range regulatory circuits linking sodium and bone metabolism have been previously demonstrated, but in isolated contexts. For example, the nongenomic effects of aldosterone have been shown to activate the epithelial sodium channel in animal models [8]. Additionally, rapid increases in plasma aldosterone concentrations have been confirmed after only 10 min of high intensity exercise in humans, presumably from a nongenomic source [9]. Arginine vasopressin receptors type 1α (AVPR1α) and type 2 (AVPR2) have also been shown to exist on osteoblasts and osteoclasts, with short-circuit AVP stimulation favoring overall bone resorption in mouse models [3]. Similarly, exercise-induced nonosmotic plasma AVP concentrations have been verified in humans and could hypothetically translate into acute bone remodeling if exercise duration and elevated plasma AVP levels were sustained [9]. Lastly, the heteroionic exchange of ions within the hydration shell of bone – and across the 80% of quiescent osteoblasts present in the skeleton – can liberate 50–100 mmol of calcium daily from the skeleton to acutely regulate serum calcium levels without activation of the classic remodeling mechanisms [4]. Thus, the ability of hydroxyapatite crystals to dynamically mirror the composition of the surrounding extracellular fluid has been shown to be physicochemically plausible [4]. Whether or not these short-circuit homeostatic responses could potentially lead to irreversible pathology over time (such as in the osteoporosis case documented in a middle aged male with chronic inappropriate AVP secretion) [10], remains uncertain. Systematic investigations aimed at verifying the existence of short-circuit regulatory loops within the pituitary-bone axis are suggested based on our reported results, using endurance exercise as a model to (possibly) accentuate both sodium and bone metabolism.

With regards to the potential precision errors in our dual energy X-ray absorptiometry (DEXA) scan measurements, we recognize that the small sampling sizes (cohort and %CV) represent our greatest limitation towards scientific acceptance of these preliminary findings. Nana et al. [11] recently reported a typical error range of 1–3% in total bone mineral content (BMC) in a repeated measurement study of 31 subjects undergoing 5 DEXA scans within a 2 day period. This variation was well above our %CV of 0.39, reported in one subject repositioned 6 times. However, we reiterate that the strength of our data lie in the robust linear relationships seen between variables, which were not reflected by absolute changes in mean values. Of additional note, it is not clear whether or not the changes seen in our DEXA scans represent: 1) actual changes in sodium ions within either the hydration shell or crystal surface [4]; 2) sodium-mediated displacement of calcium ions [12]; or 3) exercise-induced alterations in interstitial fluid pressure [13]. Despite these limitations and uncertainties, we feel that our results provide insights into the intersection of sodium balance, bone metabolism, and exercise physiology, particularly with regard to the potential importance of short-range homeostatic circuits. Only additional studies employing larger numbers of subjects and sufficiently sensitive technologies will resolve the issues raised by Hind et al. [1].

• References

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