148 EFFECT OF DENOSUMAB IN IMPROVING ORTHOSTATIC HYPOTENSION

Abstract

Background: Denosumab is widely used for the treatment of postmenopausal women with osteoporosis at high/increased risk for fracture. It is a fully human monoclonal antibody to RANKL that blocks its binding to RANK, inhibiting the development and activity of osteoclast, decreasing bone resorption, and increasing bone density1. RANKL leads to the activation of antiapoptotic kinase and nitric oxide synthase and to nitric oxide (NO) production in endothelial cells. Moreover RANKL acts as a potent vasodilator2. Objective(s): This is a pilot observational study for further longitudinal work on an interesting hypothesis. The aim is to determine if denosumab improves orthostatic hypotension (OH) by inhibition of RANKL leading to vasoconstriction and reduction of NO production. Method(s): Data of 30 patients with head-up-tilt (HUT) test prior to denosumab treatment (T0) at 3(T3), 6(T6) and 12 months (T12) were analysed. 8 were excluded due to incomplete participation. Result(s): 16 patients had OH prior to treatment and only two were on midodrine. Drop in systolic blood pressure varied between 20 mmHg to 101 mmHg and diastolic drop between 10 mmHg to 34 mmHg prior to treatment. Following denosumab treatment, 5 of 16 patients had completely resolved OH. Magnitude of the blood pressure drop improved in 8 patients. 3 patients had worsened OH; Among them 2 had Parkinson's disease and one was on antihypertensive treatment. Of 6 patients who did not have OH pretreatment, 5 developed OH, in which 3 were on antihypertensive medications. 2 of 5 patients who developed OH at 6 months had resolution of OH after 12 months of treatment. Mean age of the participants was 76.09 with standard deviation (SD) of 7.38. Age range was between 65 to 88. 15 people (68.2 %) had OH prior to treatment. T0 median DELTASBP (Systolic Blood Pressure) was 27.5, minimum DELTASBP was -6 and maximum was 101, IQR of 25. 16 people had HUT at 6 months and 13 of them had OH. 4/5 people with no OH at T0 had OH at T6. 2/11 people with no OH at T0 do not have OH at T6. There was a mean reduction of DELTASBP of 11.8, SD 11.9 at T6 compared to T0 (p value of 0.52). In those with OH at T0, there was mean reduction in DELTASBP of 12.54, SD 21.87 (p value of 0.09). There was no significant difference in DELTADBP (Diastolic Blood Pressure) at T6 compared to T0 (p value of 0.6). 16 people had HUT at 12 months and 11 of them had OH. 1/4 people who did not have OH at T0 had OH at T12. 10/12 people who had OH at T0 still have OH at T12. T12 mean DELTASBP 16.36, SD 20.54, T12 mean DELTADBP 6.07, SD 7.96. There was no significant difference in mean DELTASBP between T0 and T12 (p value of 0/075). There was no significant difference in mean DELTADBP between T0 and t12 (p value of 0/6). In those who had OH at T0 there was a significant reduction in DELTASBP at T12 compared to T0 (p value of 0.003) with mean reduction in systolic postural blood pressure drop of 17.9 and SD of 21.6 Conclusion(s): HUT test results after a year of denosumab treatment showed improvement in orthostatic hypotension. Deterioration of orthostatic hypotension in several patients was probably due to underlying Parkinson disease and anti-hypertensive medications. Thus, improvement in OH is expected in patients on longstanding denosumab treatment. Discussion(s): Freedom trial study on denosumab for prevention of fractures in postmenopausal women with osteoporosis published in New England Journal of Medicine. 2009;361(8):756-765 reported falling as an adverse event. Number of people who had falls on denosumab among was 175 (4.5) among 3886 with p value of 0.02. In this study, denosumab improves orthostatic hypotension (OH) by inhibition of RANKL leading to vasoconstriction and by reduction of NO production. Thus, improvement in OH is expected to reduce the risk of falls in patients who receives denosumab treatment. Limitations of this study include small number of participants and multiple confounding factors. A further study is planned with strict protocols and also to do a HUT at 36 months in order to compare the falls risk results with freedom trial study on denosumab.