9WHI (Women’s Health Initiative) Objective ต้องการดูผลของอาหารไขมันต่ำHRTCa+vit.Dต่อสุขภาพของสตรีวัยหมดประจำเดือน (50-70 ปี) โดยดูในประเด็นการเกิดมะเร็ง เช่น breast cancer, colorectal cancer endometrial cancer.Cardiovascular disease, Alzheimer’s diseaseFracture rate
10WHI (Women’s Health Initiative) Subjects and MethodsMulticenter studies: 40 centers in USATotal subjects in clinical trial 64,500 casesTotal subjects in observational study 100,000 casesเริ่มต้นรวบรวมผู้ป่วยตั้งแต่พ.ศ ระยะเวลาติดตามผลเฉลี่ย 9 ปีต้นเดือน ก.ค มีรายงานผลบางส่วนของ WHI
18IntroductionCalcitonin is a 32-amino acid polypeptide hormone of thyroid origin discovered by Copp in 1961.Calcitonin secretion is stimulated by high plasma calcium levels.Calcitonin’s ability to lower serum calcium concentrations is associated with an inhibition of osteoclastic activity.
19Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosisReduce fracture rateImprove bone qualityRelieve painIncrease fracture union rate
20Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosisReduce fracture rateImprove bone qualityRelieve painIncrease fracture union rate
21PROOF Study (the prevent recurrence of osteoporotic fractures study) Objective: to determine the long-term efficacy and safety of salmon calcitonin nasal spray in the prevention of vertebral fractures in postmenopausal women with osteoporosis.Chesnut CH 3rd, et al. Am J Med Sep; 109(4):
23Bone mineral density of lumbar spine Precision error ranged from % over 5 yr.N=274N=280N=273N=226
24The cumulative percentage of incident vertebral fracture per year of entire study Placebo=270 (87%)100 IU=273 (87.5%)200 IU =287 (92%)400 IU=278(89.4%)RRR (95%CI)=33% (3%-53%)
25Adverse EffectsRhinitis occurred in active-treated groups higher than in placebo group (p<0.01). Most of them were mild to moderate severity.
26Discussion and conclusion 200 IU of salmon calcitonin nasal spray per day significantly reduces the risk of new vertebral fracture by 33% to 36% in postmenopausal women with low bone mass or prevalent vertebral fractures.
28“The reduction in fracture incidence is greater than expected on the basis of the change in BMD . . .BMD is not the only determinant of fracture risk, even in women with osteoporosis.”Michael R. McClung, MD Associate Professor, Department of Medicine Oregon Health Sciences UniversityReprinted with permission from McClung MR. JAMA.1999;282:
29Question Raised…….Is there a mechanism of action, other than a substantiated effect on BMD, through which calcitonin is able to reduce vertebral fracture risk?
30Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosisReduce fracture rateImprove bone qualityRelieve painIncrease fracture union rate
31The QUEST study(Qualitative Effects of Salmon Calcitonin Therapy)
32QUEST: STUDY OBJECTIVES Evaluate the effect of calcitonin-salmon nasal spray on bone quality15
33QUEST: STUDY DESIGN2-year, double-blind, randomized, calcium-controlled study
34QUEST: STUDY DESIGN 91 postmenopausal women At least 5 years postmenopause1 to 5 wedged and/or compressed vertebrae at baseline
35QUEST: STUDY PARAMETERS Bone quantityDXA: spineBone quality (in vitro)Iliac crest bone biopsyMicrocomputed tomography of biopsy specimenBone quality (in vivo) : baseline, 12 and 24 monthsMRI: wrist, hipBSAP = bone-specific alkaline phosphatase; CTx = C-telopeptide; DXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging; NTx = N-telopeptide.17
36QUEST: STUDY PARAMETERS Bone quantityDXA: spineBone quality (in vitro)Iliac crest bone biopsyMicrocomputed tomography of biopsy specimenBone quality (in vivo) : baseline, 12 and 24 monthsMRI: wrist, hipBSAP = bone-specific alkaline phosphatase; CTx = C-telopeptide; DXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging; NTx = N-telopeptide.17
37QUEST STUDY: BMD-DXA RESULTS, SPINE No significant change in lumbar spine BMD between or within calcitonin-salmon nasal spray–treated and placebo-control groups
38QUEST: STUDY PARAMETERS Bone quantityDXA: spineBone quality (in vitro)Iliac crest bone biopsyMicrocomputed tomography of biopsy specimenBone quality (in vivo) : baseline, 12 and 24 monthsMRI: wrist, hip17
40QUEST:Results of Bone Biopsies 2-D HistomorphometryNo statistical significant changes in trabecular parametersMicro-CTNo statistical significant changes in trabecular parametersConclusionNo mineralization defectsNo woven bone
41QUEST: STUDY PARAMETERS Bone quantityDXA: spineBone quality (in vitro)Iliac crest bone biopsyMicrocomputed tomography of biopsy specimenBone quality (in vivo) : baseline, 12 and 24 monthsMRI: wrist, hipDXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging.17
42QUEST:Bone Quality, Microarchitesture MRI scans were conducted at baseline, 12 and 24 monthsHigh resoluation MRI scan of the radius was assessed forApparent bone volumeApparent trabecular numberApparent trabecular spacingApparent trabecular thicknessMRI at the hip was assessed by MRI based T2* relaxation times
43Chesnut CH III et al. J Bone Miner Res 2001; Difference in the architecture of vertebra between normal and osteoporotic womenOsteoporotic WomanNormal WomanThis slide is a 3-D rendering of the trabecular architecture of vertebral bone from human cadavers. It was created using 3-D micro computed tomography by P&GP scientists.On the left is the trabecular architecture from a 52 years-old women without osteoporosis. You can see the dense matrix of vertical and horizontal trabeculae. It is easy to imagine the strength provided by this highly interconnected matrix.On the right is the trabecular architecture from a 84 years-old osteoporotic women. This woman has suffered a vertebral fracture, which is further evidence of the relative severity of her osteoporosis. You can see the preservation of trabeculae in the vertical plane. However, there is a substantial loss of trabeculae in the horizontal plane. This women has not only lost significant bone mass, but she has also lost a large amount of the connectivity of the trabeculae.Reference:Borah et al., Three-dimensional microimaging (MRmicroI and microCT), finite element modeling, and rapid prototyping provide unique insights into bone architecture in osteoporosis, Anat Rec 2001, Apr15;265(2):-Bone volume/total volume Trabecular number-Trabecular thickness Trabecular spacingChesnut CH III et al. J Bone Miner Res 2001;
44Results MRI at the hip MRI at the distal radius Improvements in microarchitecture of femoral neck, wards triangle, upper and lower trochater, statistically significant at the lower trochanter.MRI at the distal radiusImprovements in bone quality, i.e. increased BV/TV, increased trabecular number and decreased in trabecular spacing, in the wrist as measured by MRI. (no significant change in trabecular thickness)
45QUEST Conclusions 1Treatment with Miacalcic 200 IU NS for 2 years result in :BMD increase of 0.8% at lumbar spine (NS)Histomorphomatry confirmed the bone safety of Miacalcic, bone had normal appearance with no signs of woven bone or mineralization defects
46QUEST Conclusions 2Treatment with Miacalcic 200 IU NS for 2 years result in :Improvements(relative to placebo) in bone quality, i.e. BV/TV, trabecular number and spacing, in the wrist as measured by MRI in vivoImprovements in bone quality (relative to placebo) expressed by T2* at the hip (femoral neck, upper and lower trochanter)
47Conclusions of QUEST and PROOF Miacalcic 200 IU nasal spray reduces vertebral fracture risk (33%-36%)Miacalcic improves bone quality (as measured by MRI) regardless of the changes in BMDMiacalcic is an effective treatment of osteoporosis, convenient for patients and with proven long-term safety.
48Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosisReduce fracture rateImprove bone qualityRelieve painIncrease fracture union rate
49Analgesic Mechanism of Calcitonin Megumu YoshimuraJ Bone Miner Metab (2000) 18:
50The Antinociceptive Effects of calcitonin Calcitonin is administered to patients intramuscularly under clinical conditions and a period of about a month is required for efficacy to appear in relieving the pain accompanying osteoporosis.Gennari C, et al., Calcitonin in bone pain management. Curr Ther Res 1998; 44:
52Involvement of serotonergic system in calcitonin antinociception It was postulated that the antinociceptive effect of peripherally injected calcitonin via serotonergic system.
53Effect of Menopause on Pain In the animal modelOvariectomized rat produces a significant reduction in the latencies for tail withdrawal, inducing hyperalgesia.If osteoporosis and hyperalgesia are simultaneously induced by OVX, then the OVX rat becomes an ideal model to investigate the clinical analgesic effect of calcitonin.Shibata K, et al., Ovariectomy-induced hyperalgesia and antinociceptive effect of elcatonin, a synthetic eel calcitonin. Pharmacol Biochem Behav 1998;60:
54Plan of experimental study First part: to study antinociceptive effect of subcutaneously-and repeatedly-administered ECT was examined behaviorally in OVX rats using the tail-withdrawal nociceptive test, and an involvement of the serotonergic system in the effect was further investigated.
61Plan of experimental study Second part: using spinal cord slices that retained an attached dorsal root and blind whole-cell recordings.A relation between the effect of the serotonergic system was examined electrophysiologically in sham and OVX rats.Influence of ECT admintration on the effects of serotonin was also examined.
85Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosisReduce fracture rateImprove bone qualityRelieve painIncrease fracture union rate
86Huusko TM, et al. Calcif Tissue Int (2002) 71:478-84. Randomized, Double-Blind, Clinically Controlled Trial of Intranasal Calcitonin Treatment in Patients with Hip FractureHuusko TM, et al.Calcif Tissue Int (2002) 71:
87ObjectiveTo evaluate the short-term outcome of intranasal calcitonin treatment of elderly hip fracture patients onPainBone lossFunctional recoveryLength of hospital stayCompare the effect of calcitonin with placebo on bone healing of hip fractures treated with internal fixation using a screw or a nail.
88Patients and Methods260 independently living patients (aged >65 years)Randomly assigned to intranasal calcitonin 200 IU daily for 3 months or matching placebo nasal spray.
89ResultsNo significant difference on pain intensity between two groups (p=0.15)No significant change of calcaneal BMD from baseline and 3 months in both groups (p=0.28)No significant differences in mortality, side effects, length of hospital stay, and functional recovery.Bone union rate in calcitonin group (83%) > placebo group (63%) p=0.029
90ConclusionMiacalcic 200 IU intranasal daily improves bone quality and reduce fracture risk.Analgesic mechanism of calcitonin via serotonergic systemMiacalcic 200 IU intranasal daily improves bony union rate of hip fracture treated with internal fixation.