Treatment of Osteoporosis รศ.นพ.ศุภศิลป์ สุนทราภา ภาควิชาออร์โธปิดิกส์ คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น 20 สิงหาคม 2547

Secondary Prevention and Treatment of Osteoporosis Menopause PEAK BONE MASS MEN WOMEN BONE MASS SECONDARY PREVENTION FRACTURE THRESHOLD FRACTURE 20 30 40 50 60 70 80 90 AGE

Secondary Prevention and Treatment of Osteoporosis Menopause PEAK BONE MASS MEN WOMEN BONE MASS SECONDARY PREVENTION FRACTURE THRESHOLD FRACTURE 20 30 40 50 60 70 80 90 AGE

Secondary Prevention and Treatment of Osteoporosis HRT STEAR (Selective Tissue Estrogenic Activity Regulator: tibolone) Calcitonin Bisphosphonate

Secondary Prevention and Treatment of Osteoporosis HRT STEAR (Selective Tissue Estrogenic Activity Regulator: tibolone) Calcitonin Bisphosphonate

WHI (Women’s Health Initiative) Objective ต้องการดูผลของ อาหารไขมันต่ำ HRT Ca+vit.D ต่อสุขภาพของสตรีวัยหมดประจำเดือน (50-70 ปี) โดยดูในประเด็น การเกิดมะเร็ง เช่น breast cancer, colorectal cancer endometrial cancer. Cardiovascular disease, Alzheimer’s disease Fracture rate

WHI (Women’s Health Initiative) Subjects and Methods Multicenter studies: 40 centers in USA Total subjects in clinical trial 64,500 cases Total subjects in observational study 100,000 cases เริ่มต้นรวบรวมผู้ป่วยตั้งแต่พ.ศ. 2535 ระยะเวลาติดตามผลเฉลี่ย 9 ปี ต้นเดือน ก.ค. 2545 มีรายงานผลบางส่วนของ WHI

WHI (Women’s Health Initiative) Results HRT: CEE 0.625 mg + MPA 2.5 mg P.O. เทียบกับ placebo จำนวนทั้งหมด 16,608 cases ติดตามผลเฉลี่ย 5.2 ปี พบความเสี่ยงต่อการเกิดโรคต่อไปนี้ CHD (R.R. 1.29; 95%CI: 1.02-1.63) Strokes (R.R. 1.41; 95%CI 1.07-1.85) P.E. (R.R. 2.13; 95%CI 1.39-3.25) CA breast (R.R. 1.26; 95%CI 1.00-1.59)

WHI (Women’s Health Initiative) Results: HRT สามารถลดความเสี่ยงต่อการเกิดโรคต่อไปนี้ Hip fractures ลดลงได้ 34 %, absolute risk reduction 5/10,000/yr. Vertebral fracture ลดลงได้ 34 % Other osteoporotic fractures ลดลงได้ 23 % Total fractures ลดลงได้ 24% Colorectal cancer ลดลงได้ 37% Global risk excess benefit in > 5 years of Rx

สรุปผลจาก WHI ควรใช้ HRT เฉพาะในสตรีวัยหมดประจำเดือนที่มีข้อบ่งชี้ในการใช้อย่างชัดเจน ได้แก่ มีอาการของ postmenopausal syndrome (ออกร้อนวูบวาบตามตัว ขี้หงุดหงิด เป็นต้น) Low bone mass ไม่ควรใช้ HRT เกินกว่า 5 ปี

Secondary Prevention and Treatment of Osteoporosis HRT STEAR (Selective Tissue Estrogenic Activity Regulator: tibolone) Calcitonin Bisphosphonate

10th IMS World Congress Berlin, Germany,10-14 June, 2002 Livial ไม่เพิ่มความหนาแน่นของเต้านมและไม่ก่อให้เกิด breast proliferation หรือผลข้างเคียงต่อเต้านม Livial มี abnormal vaginal bleeding ต่ำกว่า HRT (15%/26.9%) Livial เพิ่ม BMD ของกระดูกได้ แต่ไม่มีหลักฐานว่าสามารถลดอัตราการเกิดกระดูกหักได้หรือไม่ Livial ไม่เพิ่มอุบัติการณ์ของ CA endometrium Livial สามารถป้องกัน post-menopause syndrome ได้เท่ากับ HRT IMS = International Menopause Society

Secondary Prevention and Treatment of Osteoporosis HRT STEAR (Selective Tissue Estrogenic Activity Regulator: tibolone) Calcitonin Bisphosphonate

Calcitonin and The Treatment of Ostoeporosis

Introduction Calcitonin 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.

Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosis Reduce fracture rate Improve bone quality Relieve pain Increase fracture union rate

Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosis Reduce fracture rate Improve bone quality Relieve pain Increase fracture union rate

PROOF 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. 2000 Sep; 109(4):267-76.

TREATMENT PROTOCOLS/FOLLOW-UP

Bone mineral density of lumbar spine Precision error ranged from 0.3-2.0% over 5 yr. N=274 N=280 N=273 N=226

The 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%)

Adverse Effects Rhinitis occurred in active-treated groups higher than in placebo group (p<0.01). Most of them were mild to moderate severity.

Discussion 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.

จุดอ่อนของ PROOF study High dropout rate อาจมีผลกระทบต่อผลการศึกษาที่ได้ (dropout rate (12%/yr) รวม 59% ใน 5 ปี). ค่า BMD ตลอด 5 ปีมีการเปลี่ยนแปลงน้อยมาก (ประมาณ 1-2%) ไม่มี clinical significance. ค่า relative risk ถึงแม้จะพบว่าสามารถลดความเสี่ยงลงได้ แต่ค่า 95%CI ใกล้กับ 1 มาก (0.96-0.99)

“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 University Reprinted with permission from McClung MR. JAMA. 1999;282:687-689.

Question Raised……. Is there a mechanism of action, other than a substantiated effect on BMD, through which calcitonin is able to reduce vertebral fracture risk?

Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosis Reduce fracture rate Improve bone quality Relieve pain Increase fracture union rate

The QUEST study (Qualitative Effects of Salmon Calcitonin Therapy)

QUEST: STUDY OBJECTIVES Evaluate the effect of calcitonin-salmon nasal spray on bone quality 15

QUEST: STUDY DESIGN 2-year, double-blind, randomized, calcium-controlled study

QUEST: STUDY DESIGN 91 postmenopausal women At least 5 years postmenopause 1 to 5 wedged and/or compressed vertebrae at baseline

QUEST: STUDY PARAMETERS Bone quantity DXA: spine Bone quality (in vitro) Iliac crest bone biopsy Microcomputed tomography of biopsy specimen Bone quality (in vivo) : baseline, 12 and 24 months MRI: wrist, hip BSAP = bone-specific alkaline phosphatase; CTx = C-telopeptide; DXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging; NTx = N-telopeptide. 17

QUEST: STUDY PARAMETERS Bone quantity DXA: spine Bone quality (in vitro) Iliac crest bone biopsy Microcomputed tomography of biopsy specimen Bone quality (in vivo) : baseline, 12 and 24 months MRI: wrist, hip BSAP = bone-specific alkaline phosphatase; CTx = C-telopeptide; DXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging; NTx = N-telopeptide. 17

QUEST STUDY: BMD-DXA RESULTS, SPINE No significant change in lumbar spine BMD between or within calcitonin-salmon nasal spray–treated and placebo-control groups

QUEST: STUDY PARAMETERS Bone quantity DXA: spine Bone quality (in vitro) Iliac crest bone biopsy Microcomputed tomography of biopsy specimen Bone quality (in vivo) : baseline, 12 and 24 months MRI: wrist, hip 17

QUEST:Bone Quality, Microarchitesture Bone biopsies วัดที่ baseline และ 24 months ภายหลังย้อมและตัด section แล้ว 3 slides ใช้กับ 2-D histomorphometry ที่เหลือใช้กับ 3-D micro-CT 3-D micro-CT

QUEST:Results of Bone Biopsies 2-D Histomorphometry No statistical significant changes in trabecular parameters Micro-CT No statistical significant changes in trabecular parameters Conclusion No mineralization defects No woven bone

QUEST: STUDY PARAMETERS Bone quantity DXA: spine Bone quality (in vitro) Iliac crest bone biopsy Microcomputed tomography of biopsy specimen Bone quality (in vivo) : baseline, 12 and 24 months MRI: wrist, hip DXA = dual x-ray absorptiometry; MRI = magnetic resonance imaging. 17

QUEST:Bone Quality, Microarchitesture MRI scans were conducted at baseline, 12 and 24 months High resoluation MRI scan of the radius was assessed for Apparent bone volume Apparent trabecular number Apparent trabecular spacing Apparent trabecular thickness MRI at the hip was assessed by MRI based T2* relaxation times

Chesnut CH III et al. J Bone Miner Res 2001; Difference in the architecture of vertebra between normal and osteoporotic women Osteoporotic Woman Normal Woman This 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):101-10. -Bone volume/total volume -Trabecular number -Trabecular thickness -Trabecular spacing Chesnut CH III et al. J Bone Miner Res 2001;

Results 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 radius Improvements 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)

QUEST Conclusions 1 Treatment 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

QUEST Conclusions 2 Treatment 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 vivo Improvements in bone quality (relative to placebo) expressed by T2* at the hip (femoral neck, upper and lower trochanter)

Conclusions 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 BMD Miacalcic is an effective treatment of osteoporosis, convenient for patients and with proven long-term safety.

Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosis Reduce fracture rate Improve bone quality Relieve pain Increase fracture union rate

Analgesic Mechanism of Calcitonin Megumu Yoshimura J Bone Miner Metab (2000) 18:230-233.

The 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; 44:712-722.

Involvement of serotonergic system in calcitonin antinociception It was postulated that the antinociceptive effect of peripherally injected calcitonin via serotonergic system.

Effect of Menopause on Pain In the animal model Ovariectomized 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;60:371-376.

Plan 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.

Inhibitor of serotonin biosynthesis

Plan 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.

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Conclusion การที่ calcitonin สามารถลดอาการปวดในผู้ป่วยโรคกระดูกพรุนได้ กระทำโดยผ่าน serotonin pathway โดยการเพิ่ม receptor ต่อ serotonin ให้กลับมาเป็นปกติ

Calcitonin สามารถใช้ได้ในกรณี Treatment of osteoporosis Reduce fracture rate Improve bone quality Relieve pain Increase fracture union rate

Huusko TM, et al. Calcif Tissue Int (2002) 71:478-84. Randomized, Double-Blind, Clinically Controlled Trial of Intranasal Calcitonin Treatment in Patients with Hip Fracture Huusko TM, et al. Calcif Tissue Int (2002) 71:478-84.

Objective To evaluate the short-term outcome of intranasal calcitonin treatment of elderly hip fracture patients on Pain Bone loss Functional recovery Length of hospital stay Compare the effect of calcitonin with placebo on bone healing of hip fractures treated with internal fixation using a screw or a nail.

Patients and Methods 260 independently living patients (aged >65 years) Randomly assigned to intranasal calcitonin 200 IU daily for 3 months or matching placebo nasal spray.

Results No 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

Conclusion Miacalcic 200 IU intranasal daily improves bone quality and reduce fracture risk. Analgesic mechanism of calcitonin via serotonergic system Miacalcic 200 IU intranasal daily improves bony union rate of hip fracture treated with internal fixation.

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