Nick Boyd

Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases.

Denosumab (Amgen, Thousand Oaks, California, USA) is a new bone antiresorptive agent used in patients with osteoporosis or metastatic cancer to the bones. As with the bisphosphonates that are used as antiresorptive medications, denosumab has been associated with osteonecrosis of the jaws (ONJ). Over the past two years there has been an increase in the literature describing ONJ in patients receiving agents such as denosumab. Due to promising study results that demonstrate the effectiveness of denosumab in avoiding skeletal complications related to osteoporosis and metastatic bone disease, more patients will receive denosumab in the future. It is reported that this has the potential to become a comparable challenge to bisphosphonate related osteonecrosis of the jaws (BRONJ) for clinicians. This article describes the management of two patients that developed ONJ while receiving denosumab, reviews the incidence of ONJ associated with denosumab, and contrasts the pharmacokinetics of denosumab and the bisphosphonates. The importance of avoiding interventional dental treatment until denosumab has been withdrawn for six months cannot be overstated.

Oxygen distribution and consumption in rat lower incisor pulp

The aim was to determine the oxygen tension (P(O(2))) and rate of oxygen consumption in the pulp. Twelve rats were anaesthetised and artificially ventilated. Under an operating microscope, a recessed oxygen-sensitive microelectrode was inserted into the pulp through a small saline-covered cavity on the labial surface of the lower incisor. P(O(2)) was measured as a function of the transverse distance from the saline medium through to the middle of the pulp. Oxygen profiles were characterised by a decline of oxygen tension outside the pulp in the saline medium and a steeper gradient across the interface, before a localised oxygen consuming region corresponding to the odontoblasts. A plateau with some localised fluctuations was then followed by an increase in oxygen tension in the middle of the pulp. The average oxygen tension in the plateau region was 23.2 mmHg+/-2.1 mmHg (n=12). A mathematical model was used to extract oxygen consumption data from P(O(2)) profiles recorded from non-perfused pulp (created by reducing systemic blood pressure). The analysis revealed that there was a distinct oxygen consumption zone in the outer pulp, which anatomically corresponded to the odontoblast layer. The average oxygen consumption rate of the odontoblasts was 3.2+/-0.2 ml O(2)/min per 100g pulp tissue. The zone of high oxygen consumption was 68.7 micro m+/-6.9 micro m (n=24) thick. It is concluded that pulpal oxygen distribution is heterogeneous and that the odontoblast could be a major oxygen consumer within the rat incisor pulp.

An in vivo and in vitro comparison of the effects of vasoactive mediators on pulpal blood vessels in rat incisors

The effects of endogenous vasoactive substances were evaluated in anaesthetized rats using a laser Doppler flowmeter to monitor changes in pulpal blood flow, as well as directly in isolated pulpal arteriole preparations utilising a microperfusion and monitoring system to observe changes in vessel diameter. In anaesthetized rats, while systemic arterial blood pressure remained relatively stable, intra-arterial delivery of adrenaline (epinephrine) (A), noradrenaline (norepinephrine) (NA), phenylephrine (PHE), dopamine (DOPA), 5-hydroxytryptamine (5-HT), or endothelin-1 (ET-1) produced a dose-dependent reduction in pulpal blood flow (order of potency: ET-1>>A=NA>PHE=DOPA=5-HT); acetylcholine induced a dose-dependent increase in pulpal blood flow; histamine, isoproterenol and adenosine produced no significant changes. In isolated arteriole preparations, intraluminal delivery of A, NA, PHE, DOPA or 5-HT produced dose-dependent vasoconstriction (A=NA>PHE=DOPA=5-HT). Acetylcholine relaxed NA-precontracted vessels dose-dependently. Histamine and isoproterenol produced a small vasodilatation. Intraluminal ET-1 produced a small vasoconstriction at 10(-8)M, whereas extraluminal ET-1 produced a dose-dependent vasoconstriction from 10(-10)M and above. Intraluminal adenosine failed to dilate vessels precontracted with ET-1, whereas extraluminal adenosine caused a complete relaxation. These combined in vivo and in vitro data suggest that, in the rat incisor, the pulpal microcirculation is capable of functional regulation and that pulpal blood flow may be modulated by endothelium-related factors, metabolic (tissue-related) factors, as well as humoral (blood-borne) factors.

Agonist-induced vasoactive responses in isolated perfused porcine dental pulpal arterioles

A novel isolated perfused pulpal arteriole preparation and microperfusion system was used to evaluate the direct vasoactive responses of pulpal arterioles to selected agonists. Short lengths of porcine pulpal arterioles (101.7+/-2.2 microm o.d., n=105) were dissected out and placed in an environment-controlled bath on the stage of an inverted microscope. Both ends of the vessel were cannulated and perfused at a controlled rate through the lumen. The diameter of the vessel was measured online. Following equilibration, the vessel was challenged with various agonists: adrenaline (epinephrine), noradrenaline (norepinephrine), phenylephrine, dopamine, isoproterenol, 5-hydroxytryptamine, histamine and adenosine. The endothelium-dependent vasodilator acetylcholine was used to evaluate endothelial cell function. Adrenaline, noradrenaline, phenylephrine, 5-hydroxytryptamine and dopamine caused dose-dependent contractions (adrenaline=noradrenaline>phenylephrine>dopamine>5-hydroxytryptamine). Isoproterenol and histamine provoked a dose-dependent dilation. Adenosine produced pronounced vasodilatation in vessels precontracted with 10(-8)M endothelin-1. Functional adrenergic, histamine, 5-hydroxytryptamine and adenosine receptors are, therefore, present in porcine pulpal arterioles. The isolated perfused pulpal arteriole preparation may prove valuable in understanding local control mechanisms of pulpal microcirculation.

Acetylcholine-induced Vasodilation of Isolated Pulpal Arterioles

The presence of cholinergic mechanisms in the control of pulpal microcirculation has been a controversial issue. In this study, we aimed to determine the direct vasoactive responses of isolated pulpal arterioles to acetylcholine, and to investigate whether such responses are endothelium-dependent. Using an in vitro micro-perfusion system, we isolated pig pulpal arterioles, cannulated and perfused them intraluminally, and monitored the diameter. Following equilibration, the vessels were contracted with 10-5 M noradrenaline, and the effect of increasing doses of acetylcholine was determined. The influence of the muscarinic antagonist, atropine, or the loss of endothelial cell function following saponin treatment was also determined. Acetylcholine induced a dose-dependent vasodilation, reaching 94.6 ± 1.4% (n = 22) of the uncontracted diameter at 10-4 M. The vascular relaxation effect of acetylcholine was abolished in the presence of atropine, and by saponin treatment. Analysis of these data suggests that, in the pig, the acetylcholine-induced vasodilation of incisor pulpal arterioles is endothelium-dependent and mediated by muscarinic receptors.

Tissue oxygen tension and blood-flow changes in rat incisor pulp with graded systemic hyperoxia

The role of oxygen in the regulation of the pulpal microcirculation is unknown. This investigation is aimed to measure tissue oxygen tension and blood-flow changes in the pulp of rat lower incisors during graded systemic hyperoxia, and to determine the response of the pulpal vasculature to various oxygen tensions. Twenty-four Sprague-Dawley rats were anaesthetized and artificially ventilated with the appropriate gas mixture. Recessed oxygen-sensitive microelectrodes were used to measure pulpal tissue oxygen tension via a small access cavity filled with saline on the labial surface of the incisor. A laser Doppler flowmeter was used to record pulpal blood-flow. Inspired oxygen was increased stepwise from 20 to 100% in 20% steps. Systemic blood-gas concentrations were measured at each step. Systemic arterial oxygen tension at 100% oxygen ventilation reached 481.2 +/- 30.7% of the baseline at 20% oxygen breathing (n=21). Pulpal tissue oxygen tension did not change significantly whereas pulpal blood-flow fell dose-dependently to 74.6 +/- 5.0% at 100% oxygen ventilation (n=21). Systemic hyperoxia, therefore, induces a significant reduction in pulpal blood-flow whereas pulpal tissue oxygen tension remains relatively stable, indicating an oxygen-dependent local regulatory mechanism.

Vasoactive response of isolated pulpal arterioles to endothelin-1.

The vasoactive effect of endothelin-1 applied intraluminally or extraluminally was studied in vitro in isolated perfused porcine pulpal arterioles using a microperfusion system. Pulpal arterioles (outer diameter, 94.2 +/- 2.8 microm, n = 12) were cannulated and perfused at a constant flow rate in an environment-controlled bath on the stage of an inverted microscope. The vessel diameters were measured online. Both intraluminal and extraluminal application of endothelin-1 (10(-16) M to 10(-8) M) induced dose-dependent constrictions, reaching 82.3 +/- 1.7% (n = 12) and 70.5 +/- 1.3% (n = 12) at 10(-8) M, respectively. Nifedipine reversed endothelin-1-induced constriction dose-dependently at 10(-7) M and above. These data demonstrate that endothelin-1 induces calcium-dependent vasoconstriction in porcine pulpal arterioles, with extraluminal application more potent, which seems to reflect the possible modulation of vascular endothelium in the control of vascular tone.

Combined UV and IR laser ablation of dentine

OBJECTIVE The aim of this study was to increase the rate of removal of dentine tissue by a 213-nm laser through the introduction of an Er:YAG assisting laser. BACKGROUND DATA The rate of dentine removal is increased by using a CO2 laser to assist a XeCl excimer laser. METHODS Extracted human teeth were sliced parallel to the crown and exposed to 213-nm laser and Er:YAG laser beams that were spatially and temporally aligned. The 213-nm laser radiation was generated using a Q-switched Nd:YAG (5 nsec, 10 Hz) and three nonlinear crystals. The Er:YAG laser was free running with a pulse duration of 100 microsec and a pulse repetition rate of 10 Hz. A fluence range of 5-18.6 J/cm2 (213 nm) and 0.6-1.3 J/cm2 (Er:YAG) was used. Axial ablation rates were measured for different pulse energies and pulse overlaps. RESULTS The ablation rate of dentine increased in most cases by a factor of two. The highest ablation rate achieved was 18.3 microm/pulse +/- 2.51, which is more than twice the highest ablation rate previously published using a 213-nm laser. Changes in the pulse superpositions that were investigated did not present a significant change in the ablation rate. CONCLUSIONS The Er:YAG laser can be used to increase the removal rate of dentine by a short-pulse ultraviolet (UV) laser.