The anabolic action of intermittent parathyroid hormone on cortical bone depends partly on its ability to induce nitric oxide‐mediated vasorelaxation in BALB/c mice

Abstract

There is strong evidence that vasodilatory nitric oxide (NO) donors have anabolic effects on bone in humans. Parathyroid hormone (PTH), the only osteoanabolic drug currently approved, is also a vasodilator. We investigated whether the NO synthase inhibitor L‐NAME might alter the effect of PTH on bone by blocking its vasodilatory effect. BALB/c mice received 28 daily injections of PTH[1–34] (80 µg/kg/day) or L‐NAME (30 mg/kg/day), alone or in combination. Hindlimb blood perfusion was measured by laser Doppler imaging. Bone architecture, turnover and mechanical properties in the femur were analysed respectively by micro‐CT, histomorphometry and three‐point bending. PTH increased hindlimb blood flow by >30% within 10 min of injection (P < 0.001). Co‐treatment with L‐NAME blocked the action of PTH on blood flow, whereas L‐NAME alone had no effect. PTH treatment increased femoral cortical bone volume and formation rate by 20% and 110%, respectively (P < 0.001). PTH had no effect on trabecular bone volume in the femoral metaphysis although trabecular thickness and number were increased and decreased by 25%, respectively. Co‐treatment with L‐NAME restricted the PTH‐stimulated increase in cortical bone formation but had no clear‐cut effects in trabecular bone. Co‐treatment with L‐NAME did not affect the mechanical strength in femurs induced by iPTH. These results suggest that NO‐mediated vasorelaxation plays partly a role in the anabolic action of PTH on cortical bone. © 2016 The Authors. Cell Biochemistry and Function published by John Wiley & Sons, Ltd.

Mechanical, hormonal and metabolic influences on blood vessels, blood flow and bone

“…Vasodilation of bone blood vessels occurs in the presence of PTH; e.g., vasodilation in isolated rat femoral PNAs was observed to increasing concentrations of PTH 1–84, PTH 1–34 and PTHrP 1–34 (Benson et al 2016). Additionally, bolus doses of PTH have produced a rise (Kapitola & Zák 2003; Gohin et al 2016), a biphasic response (Boelkins et al 1976) and no change (Driessens & Vanhoutte 1981) in blood flow to various hind limb bones. In regards to the chronic influences of intermittent PTH administration on bone blood vessels, the picture becomes more complex.…”

“…The presence of 99m Tc-MDP in the skeleton serves as a clinical indicator of bone blood flow (Blake et al 2001). In a mouse model, trabecular bone volume in the distal femoral metaphysis and L5 vertebra and hind limb tissue perfusion were not altered following 4 weeks of intermittent PTH 1–34 administration (Gohin et al 2016). Caution must be used in the interpretation of these data since the hind limb tissue perfusion measurements were not limited to the skeleton.…”

“…Caution must be used in the interpretation of these data since the hind limb tissue perfusion measurements were not limited to the skeleton. Acute rises in bone perfusion (i.e., within 5–15 minutes) were observed in the whole hind limb as measured by laser Doppler imaging and in the cortical diaphysis as assessed by the augmented presence of procion red fluorescence following an injection of PTH (Gohin et al 2016). Unfortunately, this measure was not obtained following the 4 week protocol when cortical bone volume and bone formation rate were enhanced (Gohin et al 2016).…”

“…Acute rises in bone perfusion (i.e., within 5–15 minutes) were observed in the whole hind limb as measured by laser Doppler imaging and in the cortical diaphysis as assessed by the augmented presence of procion red fluorescence following an injection of PTH (Gohin et al 2016). Unfortunately, this measure was not obtained following the 4 week protocol when cortical bone volume and bone formation rate were enhanced (Gohin et al 2016). The PTH-induced rise in hind limb tissue perfusion and enhanced cortical bone volume were blocked and blunted, respectively, with NO inhibition, highlighting the importance of this signaling cascade (Gohin et al 2016).…”

“…Unfortunately, this measure was not obtained following the 4 week protocol when cortical bone volume and bone formation rate were enhanced (Gohin et al 2016). The PTH-induced rise in hind limb tissue perfusion and enhanced cortical bone volume were blocked and blunted, respectively, with NO inhibition, highlighting the importance of this signaling cascade (Gohin et al 2016). These data coincide with previous descriptions of the reliance on NO signaling for bone blood vessels (Prisby et al 2013), bone blood flow (Kapitola & Zák 2003) and bone (Prisby et al 2013) with PTH treatment.…”