Jamal, Sophie

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Western UniversityScholarship@WesternCanadian Centre for Activity and AgingPresentations Canadian Centre for Activity and Aging2011Nitric Oxide and Osteoporosis: What a Gas!Sophie JamalUniversity of TorontoFollow this and additional works at: https://ir.lib.uwo.ca/ccaapresPart of the Geriatrics CommonsCitation of this paper:Jamal, Sophie, "Nitric Oxide and Osteoporosis: What a Gas!" (2011). Canadian Centre for Activity and Aging Presentations. 2.https://ir.lib.uwo.ca/ccaapres/2Nitric Oxide and Osteoporosis:What a Gas!Sophie Jamal, MD, PhD, FRCPCAssociate Professor of MedicineUniversity of TorontoOutline? Pathophysiology of osteoporosis? Nitric oxide and bone turnover? The effects of isosorbide mononitrate on markers of bone turnover? The effects of nitroglycerin on bone turnover geometry and strengthEffect of estrogen and transdermal NTG on BMD (Wimalawansa et al Bone 1996)Treatment group Percent increase in BMD (L2-L4) over 6 weeksSham operated 25% ? 2%Ovariectomized rats 8% ? 3%Ovariectomized + Estrogen 27% ? 5%*Ovariectomized + NTG 20% ? 3%**Ovariectomized + E + NTG 22% ? 2%**different than ovariectomized rats at p<0.005** different than ovariectomized rats at p<0.02Low bone mineral density (BMD): a risk factor for osteoporotic fractures? Relationship between hip fracture and hip BMD: 2.6 RR/SD? BMD = bone formation - bone resorption? Increased bone resorption at menopause ? Nitric oxide may contribute to postmenopausal bone lossSources of nitric oxideL-arginine + O2 Nitric OxideNitric Oxide Synthase(NOS)EndogenousIsosorbide MononitrateIsosorbide DinitrateNitroglycerinNitrate & NitriteExogenousBone cells make nitric oxide? Two cell types involved in bone remodeling:?Osteoclasts ? bone resorption?Osteoblasts ? bone formation? Osteoblasts produce enitric oxide synthase? Estrogen and mechanical strain produceinitric oxide synthaseNO influences osteoclasts?Nitric oxide has a biphasic effect on osteoclasts?Low levels enhance osteoclast activity and differentiation?High levels inhibit osteoclast activity and differentiationNO may mediate effects via OPG?High levels of nitric oxide activate OPG? Low levels of nitric oxide activate OPGLBONEBone resorption depends on the balance of OPG and OPGLOPGL OPGOPGOsteoclast PrecursorBoneOsteoblastsOsteoclastRANKRANKHormones OPG LigandThe OPG/OPGL/RANK axisOPGNOWhat about osteoblasts?? Limited data?Biphasic activity:?High levels of NO stimulate osteoblast activity?Low levels of NO inhibit osteoblast activityIn vitro data: a summary? Nitric oxide stimulates OPG ?OPG binds to OPGL?Prevents binding of OPGL to RANK?Decreased osteoclast activity (bone resorption)? Issues? Is the effect similar with nitric oxide donors??Does the decrease in bone resorption lead to increased bone mineral density?Effect of estrogen and transdermal NTG on BMD (Wimalawansa et al Bone 1996)Treatment group Percent increase in BMD (L2-L4) over 6 weeksSham operated 25% ? 2%Ovariectomized rats 8% ? 3%Ovariectomized + Estrogen 27% ? 5%*Ovariectomized + NTG 20% ? 3%**Ovariectomized + E + NTG 22% ? 2%**different than ovariectomized rats at p<0.005** different than ovariectomized rats at p<0.02Effect of frequency of administrationTreatment Group (n = 5) Change in Spine BMDSham operated 6.3 % ? 5.3 *Ovariectomy (OVX) – 2.5 % ? 2.0OVX + estrogen 5.9 % ? 3.4*OVX + 0.2 mg  NTG once a day 6.2 % ? 2.8*OVX + 0.2 mg  NTG twice a day 1.9 % ? 2.1OVX + 0.2 mg  NTG  three times a day – 0.2 % ? 3.3Wimalawansa SJ et al.  JBMR 2000Does NO play a role in menopause?? Menopause is characterized by:?Increased bone resorption?Low circulating estrogen?Low levels of nitric oxide? Treatment with HRT increases nitric oxide and decreases bone resorptionNitrates and bone mineral density -1996? SOF study (n = 6201) (Jamal SA et al JBMR 1998)?BMD at heel and spine?Daily users = nonusers? Intermittent users higher? Open label trial (n = 16) (Wimalawansa SJ, JBMR 2000).? Conjugated estrogen or transdermal nitroglycerin? Equal BMD at one yearPercent difference in BMD, nitrate     users compared with nonusersDaily vs.Nonusers(n = 317, 5810)(95% CI)Intermittent vs. Nonusers(n=74,5810)(95% CI)Hip BMDUnadjusted  0 (-2.7 to 1.4) 0 (-4.1 to 4.1)Adjusted 1.3 (0.14 to 4.1) 2.6 (0.4 to 6.8)Heel BMDUnadjusted -2.6 (-5.3 to 0) 0 (-5.3 to 7.9)Adjusted 0 (-2.6 to 2.6) 5.3 (2.6 to 11)Jamal SA, et al.  JBMR 1998Nitrates and Fractures? 124,655 subjects with fractures (cases)? 373,962 controls? Self-reported nitrate use 1995-200? Nitrate use associated with decreased fracture risk:?Any fracture: OR = 0.89 (0.86 to 0.92)?Hip fracture: OR = 0. 85 (0.79 to 0.92)Rejnmark L et al, JBMR 2006Findings so far...?Use of nitrates may be associated with increases in BMD?Use of nitrates may decrease risk of fractures? Tolerance to nitrates might existThe second study- 1998? To determine the effects of isosorbide on markers of bone turnover? To assess if there is a dose response?Applied for funding 1998, received funding 1999?Completed study 2002?Published 2004Study designMonthsPhase I0 1 2 3Vitamin D 400 IUCalcium 500 mgBloodUrineISMO 5 mg or ISMO 20 mgor Placebo4 5 6BloodUrinePhase IIStudy subjects? Inclusion Criteria:?Postmenopausal women, 50 to 80 yrs?Osteopenia or normal BMD at femoral neck? Exclusion Criteria:?Low trauma fracture (hip, wrist, spine)?Active bone disease?Treatment for osteoporosis?Treatment with steroids?Heart diseaseMarkers of bone turnover? 2 classes of biochemical markers: ?Bone formation (osteoblast activity)?Bone resorption (osteoclast activity)? Resorption and formation are coupled ?May be different with ISMOWhy biochemical markers??Markers of bone turnover are correlated with bone mineral density?Substantial changes in markers can be seen within 3 months of treatment?Minimizes costs?Minimizes adverse events 451 women screened245 eligible146 women : calcium and vitamin D 144 women randomized48 : placebo4 drop outsno samples 44 : placebo49 : 5 mg ISMO11 drop outs6 samples44 : 5 mg ISMO206  ineligible47 : 20 mg ISMO10 drop outs5 samples42 : 20 mg ISMO99 did not participate2 did not returnSubject characteristics22 ? 6.623 ? 6.325 ? 6.9BSAP (IU/L)82 ? 71.579 ? 61.862 ? 65.9NTX (nmol BCE/mmol Cr)10 ? 612 ? 1013 ? 8Years since menopause7 (15%)5 (10%)5 (10%)Current smoker44 (94%)44 (90%)45 (94%)Caucasian 74 ? 1570 ? 1574 ? 16Weight  (kg)59 ? 5.559 ? 7.562 ? 7.0Age (yrs)20 mg ISMO(n = 47)5 mg ISMO(n = 49)Placebo (n = 48)Jamal SA et al, JBMR 2004ISMO decreased bone resorption markers20 mg -36.3-45.4-60-40-2002040NTXPercentchangevs. placebo5 mgp = 0.0002           p = 0.0001ISMO increased bone formation markers20 mg 15.9 23.3-60-40-2002040BSAPPercentchangevs. placebo5 mgp = 0. 005      p = 0.001Headaches were commonPlacebo(n = 48) 5 mg ISMO(n = 49)20 mg ISMO(n = 47)Discontinued study 4 11 10D/C due to  headache 2 7 9Limitations?Generalizability?Study population healthy Caucasians?Duration of study was 12 weeks?Studies with BMD and fracture end points are neededImplications of our findings? Decrease in NTx similar to bisphosphonates? 40% decrease in NTx: 30% decrease in fracture risk? We also found an increase in formation markers-? ?greater fracture reduction than with antiresorptives? Headache may limit the use of this drug:? 10% of women had headaches, 75% of drop outs? 4X more common in women randomized to ISMO? Higher than reported in CV literature? ?Less headaches with transdermal NTGThe third study? Applied for funding March 2004- rejected? Reapplied for funding March 2005? Funded October 2005? Completed Trial March 2010? 2 part randomized controlled trial:?3 week cross over study to compare tolerability of NTG and ISMO?2 year study of best tolerated nitrate? Outcomes in 2 year study:?Change in lumbar spine and hip BMD?Change in bone turnover markers?Changes in trabecular bone with pQCTStudy Hypothesis15 mg of Nitroglycerin, applied once daily, will lead to uncoupling of bone turnover, increases in bone mineral density and bone geometry, compared with placebo.Study Design?One week run in phase?24 month duration?End points:?Bone turnover markers?Bone mineral density?pQCT Study Subjects?Inclusion: ?Postmenopausal ? 50 years ?L spine T score between 0 and -2.0?Exclusion:?Migraine headaches?Already taking nitrates?SBP ? 100 mm Hg, DBP ?110 mm HgStatistical Analyses?Primary Endpoint:?Lumbar spine BMD?Secondary Endpoints:?Hip BMD ?pQCT at radius and tibia?B-ALP, NTX (log transformed data)- L -Assessed for eligibility (n=1526)Enrolled in 1 week run inphase (n = 400)-Discontinued study (n= 157)Headaches (93)Headaches and nausea (11)Randomized (n = 243)Nitroglycerin ( n =126)Analysed:Data on 116 at 24 mDiscontinued intervention ( n = 30)Headaches ( n =7)No follow up data ( n = 8)Analysed:Data on 109 at 24mPlacebo ( n = 117)Discontinued intervention ( n =15)Headaches ( n = 2)Lost to follow up ( n = 6)Excluded (n = 1283)Did not meet inclusion criteria (541)Declined to participate (585)NTG OintmentN = 126PlaceboN = 117Age (yrs) 61.3 61.9 Weight (kg) 70.3 70.9 Vitamin D (IU/day) 783. 2 753.2Calcium (mg/day) 1548.8 1565.6 L Spine T-score -0.9 -1.1 Nitrate=126Placebo=11735.9%(34.4 to 37.4)6.7% (5.2 to 8.2)7.0%(5.5-8.5)6.2%(5.2 to 7.3)PQCT of the RadiusMeasurement % Difference (95%CI)Trabecular density 11.9 (8.1 to 15.7)Cortical thickness 13.9 (6.0 to 21.7)Cortical density 2.2 (0.6 to 3.7)Cortical area 10.6 (6.9 to 14.3)Periosteal circumference 7.4 (4.3 to 10.4)Indices of Radial Bone StrengthMeasurement % difference (95%CI)Polar Section Modulus 10.7 (7.5 to 13.8)Polar Moment of Inertia7.3 (4.6 to 10.1)PQCT of the TibiaMeasurement % Difference (95%CI)Trabecular density 8.5 (4.3 to 12.7)Cortical thickness 24.6 (18.9 to 30.4)Cortical density 1.5 (0.8 to 2.3)Cortical area 10.0 (5.2 to 15.0)Periosteal circumference 2.9 (1.0 to 6.8)Indices of Tibial Bone StrengthMeasurement % difference (95%CI)Polar Section Modulus 9.8 (0.2 to 19.4)Polar Moment of Inertia14.5 (3.2 to 25.8)HeadachesRun In Phase400 enrolled, 104 did not continueTreatment Nitroglycerin Placebod/c at 12 months7 (23.3%) 2 (13.3%)1 month 35% 5.4%12 months 5.3% 0.9%24 months 2% 0NitroglycerinPlaceboSerious Adverse events 5 (4.2%) 5 (4.3%)-Death 1 (1%) 0Fractures 2 (1.6%) 2 (1.7%)Conclusions?Nitroglycerin uncouples bone turnover?Improves BMD, geometry, indices of strength?Inexpensive and widely available?Initiation of treatment limited by headache?The efficacy of nitroglycerin to reduce fracture risk should be tested in a clinical trial

Nitric Oxide and Osteoporosis: What a Gas!

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Nitric Oxide and Osteoporosis: What a Gas!

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