Update in Prevention and Treatment of Osteoporosis รศ.นพ.ศุภศิลป์ สุนทราภา ภาควิชาออร์โธปิดิกส์ คณะแพทยศาสตร์ มหาวิทยาลัยขอนแก่น 13 Aug 2004

อาการแสดงของโรคกระดูกพรุน โดยทั่วไปโรคกระดูกพรุนจะไม่มีอาการ ผู้ป่วยจะมีอาการต่อเมื่อ 1. มีกระดูกหักจากอุบัติเหตุเพียงเล็กน้อย 2. ปวดหลังโดยไม่ทราบสาเหตุ ส่วนใหญ่มักเกิดจากมีกระดูกสันหลังหักหรือทรุดลง 3. หลังโก่งหรือตัวเตี้ยลง

หากไม่มีอาการแสดงใดๆ จะรู้ว่าเป็นโรคกระดูกพรุนได้อย่างไร?

Definition of Osteoporosis (1991) Osteoporosis is a disease characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. Concensus development conference: Am J Med 1991; 90(1):107-10. Consensus Conference in Copenhagen, 1990

Definition of Osteoporosis (1993) Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. Concensus development conference: Am J Med 1993; 94:646-50.

Osteoporosis is not just a problem of low BMD “Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. ”1 The textbook definition of osteoporosis is of a disease which decreases bone strength and therefore increases the risk of fracture. As you look at these visuals, you can see that the healthy (normal) bone is comprised of thick, inter-linking trabeculae, while the osteoporotic bone is thin and some of the connectors are broken. Importantly, the disease is no longer considered as just a low bone mineral density problem. There are multiple factors affecting the strength of bone and therefore fracture risk – including BMD and bone architecture. You can relate this to a steel bridge. A high quality bridge is not one with just a lot of steel. Both the steel and the way in which it is structured combine to make a bridge strong. The same could be said about bone mineral density and bone architecture. One of the first thing you have to consider in osteoporosis is its consequences, mainly due to the fractures that can occur quickly with the time. The typical physical image of osteoporosis spiral is the cascade of fractures from the first, very early peripheral fracture to the first vertebral fracture and then, to the hip fracture. The progression of the disease from the first vertebral fracture to many subsequent vertebral fractures can be a fast one. References: 1. Consensus Development Conference: Osteoporosis prevention, diagnosis, and therapy, JAMA 2001; 285: 785-95. 2. Dempster DW et al., A simple method for correlative light and scanning electron microscopy of human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects, JBMR 1986; 1: 15-21. Normal2 Osteoporosis2 1. Consensus Development Conference, JAMA 2001; 285: 785-95; 2. Dempster DW et al, JBMR 1986; 1: 15-21.

Osteoporosis is not just a problem of low BMD “Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality. ”1 The textbook definition of osteoporosis is of a disease which decreases bone strength and therefore increases the risk of fracture. As you look at these visuals, you can see that the healthy (normal) bone is comprised of thick, inter-linking trabeculae, while the osteoporotic bone is thin and some of the connectors are broken. Importantly, the disease is no longer considered as just a low bone mineral density problem. There are multiple factors affecting the strength of bone and therefore fracture risk – including BMD and bone architecture. You can relate this to a steel bridge. A high quality bridge is not one with just a lot of steel. Both the steel and the way in which it is structured combine to make a bridge strong. The same could be said about bone mineral density and bone architecture. One of the first thing you have to consider in osteoporosis is its consequences, mainly due to the fractures that can occur quickly with the time. The typical physical image of osteoporosis spiral is the cascade of fractures from the first, very early peripheral fracture to the first vertebral fracture and then, to the hip fracture. The progression of the disease from the first vertebral fracture to many subsequent vertebral fractures can be a fast one. References: 1. Consensus Development Conference: Osteoporosis prevention, diagnosis, and therapy, JAMA 2001; 285: 785-95. 2. Dempster DW et al., A simple method for correlative light and scanning electron microscopy of human iliac crest bone biopsies: qualitative observations in normal and osteoporotic subjects, JBMR 1986; 1: 15-21. Normal2 Osteoporosis2 1. Consensus Development Conference, JAMA 2001; 285: 785-95; 2. Dempster DW et al, JBMR 1986; 1: 15-21.

clinical application osteoporosis นามธรรม รูปธรรม

Dual Energy X-Ray Absorptiometry (DEXA) Precision errors 1%-2% DPX-IQ, Lunar Corp, USA

ค่าเฉลี่ยของมวลกระดูกในแต่ละกลุ่มอายุ Peak bone mass (young adult reference mean)

Diagnostic criteria of skeletal osteoporosis 1. Normal : BMD within 1 SD of the young adult reference mean (T-score> -1) 2. Low bone mass (osteopenia) : BMD <-1 SD of the young adult mean but > -2.5 SD (-1< T-score>-2.5) 3. Osteoporosis : BMD < -2.5 SD (T-score<-2.5) 4. Severe osteoporosis : BMD< -2.5 SD with bony fracture Assessment of fracture risk and its application to screening for postmenopausal osteoporosis (WHO 1994) WHO 1994

Normal : BMD within 1 SD of the young adult reference mean (T-score> -1)

Low bone mass (osteopenia) : BMD <-1 SD of the young adult mean but > -2.5 SD (-1< T-score>-2.5) Normal -1 Osteopenia -2.5

Osteoporosis : BMD < -2.5 SD (T-score<-2.5) Normal Osteopenia Osteoporosis

Severe osteoporosis : BMD< -2.5 SD with bony fracture

Femoral neck fracture with complete displacement Femoral neck fracture with partial displacement Femoral neck fracture with complete displacement

Unstable intertrochanteric fracture

จากกราฟที่เห็นพบว่ายิ่งมีอายุมากขึ้น จำนวนคนที่จะถูกจัดอยู่ในกลุ่มโรคกระดูกพรุนจะยิ่งเพิ่มขึ้น โดยเฉพาะในกลุ่มอายุมากกว่า 80 ปี ประมาณครึ่งหนึ่งจะถูกจัดอยู่ในกลุ่มของโรคกระดูกพรุน

Bone mineral density is a good indicator for increased fracture risk 2 x Low BMD has been shown in numerous studies to be a good predictor of an increased vertebral fracture risk. As shown on this graph, low BMD is a good indicator of increased risk for a future vertebral fracture. A decrease of 1SD in BMD reflects a 2-fold increase in fracture risk. Reference: Watts et al., ASBMR 2001, symposium session. –1SD T–score Watts, ASBMR 2001

Relative Risk of Femoral Neck Fracture in Elderly Women (> 65 years) Z-score <-1 Low BMD has been shown in numerous studies to be a good predictor of an increased vertebral fracture risk. As shown on this graph, low BMD is a good indicator of increased risk for a future vertebral fracture. A decrease of 1SD in BMD reflects a 2-fold increase in fracture risk. Reference: Watts et al., ASBMR 2001, symposium session. -1 Z-score of femoral neck BMD Cumming SR Lancet 1993

Osteoporotic fractures are common Age-specific rates of specific fractures Over 50% of women over the age of 50 will experience an osteoporotic fracture1 Hip Incidence/100,000 person-yr Vertebrae Osteoporotic fractures are very common events: 1 out of 2 women over the age of 50 will experience an osteoporotic fracture during her lifetime (Chrischilles). This slide shows the incidence at specific fracture sites in women related to their age: Over 50-years old, hip and vertebral fractures increase with age, while wrist fractures remain fairly constant. It is important to note that the vertebral fractures reported here only represent clinically diagnosed vertebral fractures. Literature has shown that only 1 in 3 vertebral fractures come to clinical attention. Therefore, the vertebral fracture incidence is likely to be approximately 3 times higher than what is shown here. References: 1. Chrischilles EA et al., A model of lifetime osteoporosis impact, Arch Intern Med 1991; 151: 2026-32. 2. Cooper et al. Trends Endocrinol Metab 1992; 3: 224-229 Colles’ Age in Years 1.Chrischilles et al. Arch Intern Med 1991; 151: 2026-32; 2. Cooper et al. Trends Endocrinol Metab 1992; 3: 224-229

Osteoporotic vertebral fractures are often unrecognized Only 1 in 5 women with a fracture will receive a treatment (14.13%) Only 1 in 2 women with a fracture was diagnosed 20 40 60 80 100 120 140 Patients (n) Fracture Identified by study radiologists noted in radiology report medical record Received osteoporosis treatment 132 65 23 25 (100%) Moderate to severe vertebral fracture (49.24%) (18.94%) (17.42%) However, Osteoporosis is still unrecognized. In this study, Gehlbach shows that radiologists have identified 132 vertebral fractures and only 50% were noted in the radiologist report. Only 15% were noted in the medical record and eventually, only 20% of these patients received an anti-osteoporotic treatment. Thus, only 1 osteoporotic patient in 5 received an adapted treatment. So, how to recognize a vertebral fracture? Reference: Gehlbach SH et al., Recognition of vertebral fracture in a clinical setting, Osteoporosis Int. 2000, 11:577-582. n=934 white women >60 years old, Lateral CXR Baystate Medical Center, USA Oct 1,95 – Mar 31,97 Gehlbach et al. Osteoporosis Int 2000; 11: 577-582.

Fracture risk increases in just 1 year 1 in 5 postmenopausal women who have suffered a vertebral fracture, will suffer another one within 1 year 5 10 15 20 25 30 Overall 20% 5 10 15 20 25 30 1+ 2+ * Percent (%) of Patients “Why vertebral fracture diagnosis is so important?” This graph on the right, published by Lindsay, shows that after 1 vertebral fracture, your patient has a 5-fold increased risk of suffering another vertebral fracture, and after the 2nd one she has a 12-fold increased risk. Now, once a patient has suffered a vertebral fracture, she has an increased risk of suffering another one. Moreover, once a patient has suffered a vertebral fracture, she is at immediate risk of fracturing again. Indeed, Lindsay also showed that 1 in 5 patient who has suffered a vertebral fracture will suffer another one within just 1 year, which is really a short time. Therefore, one can conclude that vertebral fractures require quick diagnosis followed by treatment with a therapy that can quickly reduce the risk of another vertebral fracture. These figures clearly demonstrate that once a patient has suffered a vertebral fracture, she needs a rapid acting treatment. Reference: Lindsay R et al., Risk of new vertebral fracture in the year following a fracture, JAMA. 2001 Jan 17;285(3):320-3. *p<0.05, vs. patients with no prevalent vertebral fractures (12-Fold Increased Risk) Lindsay et al. JAMA 2001; 285: 320-23.

The presence of vertebral fractures increases the risk for hip fractures over 3-4 Years clinically diagnosed vertebral fracture radiologically diagnosed vertebral fracture The presence of prevalent vertebral fractures also significantly increase the risk of future hip fracture. However, while vertebral fractures may quickly lead to subsequent vertebral fractures (within 1 year), these studies show an increase hip fracture risk over 3 to 4 years. Several studies, as shown in this graph, have demonstrated a 2-4 fold increase in the relative risk of hip fracture for those osteoporosis patients with a prevalent vertebral fracture versus those with no previous vertebral fracture. Therefore, vertebral fractures lead to further spinal fractures and to hip fractures. One important way to reduce the risk for hip fractures is to reduce the risk for vertebral fractures. Additional information: The most recent of these studies was published by Ismail and colleagues. In this study, 6788 women aged 50 years and over were recruited from 31 European centers and followed for a median of 3 years. All subjects had a baseline radiograph. Vertebral fractures were a strong predictor of hip fractures over 3 years (relative risk= 4.5). References: Melton et al., Vertebral fractures predict subsequent fractures, Osteoporos Int 1999; 10: 214-221. Gunnes et al., How well can a previous fracture indicate a new fracture? A questionnaire study of 29,802 postmenopausal women, Acta Orthop Scand 1998; 69(5): 508-512. Black et al., Prevalent vertebral deformities predict hip fractures and new vertebral deformities but not wrist fractures. Study of Osteoporotic Fractures Research Group, JBMR 1999; 14: 821-828. Ismail et al., Prevalent vertebral deformity predicts incident hip though not distal forearm fracture: results from the European Prospective Osteoporosis Study, Osteoporosis Int 2001; 12: 85-90. Melton '99 Gunnes '98 Black '99 Ismail ‘01 Melton et al. Osteoporos Int 1999; 10: 214-221; Gunnes et al. Acta Orthop Scand 1998; 69: 508-512; Black et al. JBMR1999; 14: 821-828; Ismail et al. Osteoporosis Int 2001; 12: 85-90.

Conclusion Osteoporotic fractures are common in aging population After a vertebral fracture, 1 in 5 women will suffer another one within 1 year After a vertebral fracture, the relative risk of hip fracture will increase about 2.5-5 times over 3-4 years Osteoporotic patients need early diagnosis and early treatment

The Prevention of Osteoporosis

Risk Factor of Osteoporosis 1. old age 2. history of maternal hip fracture 3. menopause 4. Oophorectomy 5. Low calcium and vitamin D intake 6. small body frame 7.being sedentary, no regular physical activity and exercise 8. on long term steroid medications 9. drinking excessive alcohol and smoking

Primary prevention Menopause PEAK BONE MASS MEN WOMEN BONE MASS 20 30 FRACTURE THRESHOLD 20 30 40 50 60 70 80 90 AGE

Primary prevention High calcium diet Adequate vitamin D Weight bearing exercise

Primary prevention High calcium diet Adequate vitamin D Weight bearing exercise

คนไทยได้รับแคลเซียมไม่เพียงพอ จริงหรือ ?

Optimal calcium requirements recommended by the National Institutes of Health Concensus Panel (JAMA 272:1942-8;1994)

Optimal calcium requirements recommended by the National Institutes of Health Concensus Panel (JAMA 272:1942-8)

Status of Calcium Ingestion of U.S. 50% of U.S. women between the ages of 18 and 70 years ingest less than 500 mg of calcium per day. Suggestion of calcium-rich foods (mainly dairy products) or calcium supplements. Abraham s, et al. Dietary intake source data, United States. 1971-74. Hyattsville, Md.: National Center for Health Statistics, 1977. (DHEW publication no. (PHS) 77-1221.)

1500 1500 (ค.ศ. 1989)

Calcium requirement estimated by balance study in elderly Japanese people (K. Uenishi, et al. Osteoporos Int (2001) 12:858-863. Subject: 10 men (age 65-72 yrs.) and 10 women (age 62-77 yrs). From the balance study Daily Ca requirement was 702 mg in the men Daily Ca requirement was 788 mg in women RDA = 1.2x Ca requirement RDA for Ca was 842 mg/day for men RDA for Ca was 946 mg/day for women

842 1000 946

Calcium intake in Thais Ministry of Public Health Survey (2529) method : Family food-consumption data n : 208 families, 1770 family members (301 mg/day) Chitchumroonchokchai C (2536) method : Duplicated meal analysis n : 15 (7 M, 8 F), 25 - 45 years (456 mg/day) Suphiphat V,et al. (2537) method: Duplicated meal analysis n : 34 (19 M, 15 F), 6 - 16 years (261 mg/day)

ปริมาณแคลเซียมที่รับประทานในคนกรุงเทพและปริมณฑล รศ ปริมาณแคลเซียมที่รับประทานในคนกรุงเทพและปริมณฑล รศ. สุรัตน์ โคมินทร์ 2537 ศึกษาในคนที่มีสุขภาพแข็งแรงอายุ 20-80 ปี จำนวน 400 ราย แคลเซียมที่รับประทานโดยเฉลี่ยต่อวันประมาณ 361 มก. มากกว่าร้อยละ 65 รับประทานแคลเซียมน้อยกว่า 400 มก./วัน มีเพียงร้อยละ 2 ที่รับประทานแคลเซียมมากกว่า 800 มก./วัน

สรุปปริมาณแคลเซียมที่รับประทานต่อวันของคนไทย ส่วนใหญ่รับประทานแคลเซียมไม่เกิน 400 mg/day RDA ของคนไทยประมาณ 800-1200 mg/day คนไทยขาดแคลเซียมประมาณ 400-600 mg/day เชื่อหรือยัง !

หากเพิ่มปริมาณแคลเซียมต่อวันจะมีผลต่อมวลกระดูกจริงหรือไม่ ?

Percentage of increments (%) Percentage of increment in BMD and BMC between groups after 1 year of 500 mg Ca supplementation in males P = .030 P = .031 P = .007 P = .045 Percentage of increments (%) Charoenkiatkul, et al. 2542

Percentage of increments (%) Percentage of increment in BMD and BMC between groups after 1 year of 500 mg Ca supplementation in females P = .038 P = .033 Percentage of increments (%) Charoenkiatkul, et al. 2542

BMD AND QUARTILES OF CALCIUM INTAKE IN LATE POSTMENOPAUSAL WOMEN 1.1 .82 P < 0.05 .80 P < 0.05 1.0 .78 SPBMD (g/cm 2) FNBMD (g/cm 2) .76 .9 .74 .72 .8 .70 Q1 (157-278) Q2 (279-308) Q3 (309-372) Q4 (373-810) Q1 (157-278) Q2 (279-308) Q3 (309-372) Q4 (373-810) Quartiles of calcium intake (mg/d)

สรุป คนไทยรับประทานแคลเซียมไม่เพียงพอ การเสริมแคลเซียมในปริมาณ 500 mg/day เป็นเวลา 1 ปีสามารถเพิ่มค่ามวลกระดูกได้อย่างมีนัยสำคัญ ทั้งในบุรุษและสตรี คนที่รับประทานแคลเซียมน้อย (<280 mg/day)จะมีค่ามวลกระดูกต่ำกว่าคนที่กินแคลเซียมมาก (>370 mg/day)อย่างมีนัยสำคัญ

องค์ประกอบของแคลเซียม Soluble at all pH

ตัวอย่างองค์ประกอบแคลเซียมของยาบางชนิด Calcium-D-Redoxon Calcium carbonate- 625 mg Pure calcium = 250 mg (625*0.4) Cal-D-Vita Calcium carbonate - 1500 mg Pure calcium = 600 mg (1500*0.4)

การดูดซึมยาแคลเซียมจะมากน้อยเพียงใดขึ้นกับ 2 ปัจจัยใหญ่ๆคือ 1. การแตกตัวของเม็ดยา (disintegration) 2. การละลายตัวของยาในกระเพาะและลำไส้ (dissolotion)

Stomach 1-2 Duodenum 3-4 Jejunum proximal 6 middle 7.6 Ileum >7

Primary prevention High calcium diet Adequate vitamin D Weight bearing exercise

แหล่งสำคัญของวิตามินดีได้มาจาก 1. อาหาร 2. ได้จากการสังเคราะห์วิตามินดีที่ผิวหนัง โดยแสงแดด

แหล่งอาหารที่มีวิตามินดีสูง 1. ปลาไหล มีปริมาณ vit. D 1,814 IU/1 oz. 2. น้ำมันตับปลา มี vit. D 400 IU/1 tsp. 3. ปลา Salmon มี vit. D 142 IU/1 oz. 4. ปลา Sardines มี vit. D 85 IU/1 oz.

ที่ Boston (ละติจูด 42 องศาเหนือ) เพียงแค่หน้าและแขนรับแสงอาทิตย์ช่วงเที่ยงวัน ประมาณ 15-20 นาที ผิวหนังจะสร้างวิตามินดีประมาณ 200 IU ซึ่งเพียงพอต่อความต้องการในแต่ละวัน

ปัจจัยที่ควบคุมการสังเคราะห์ไวตามินดีที่ผิวหนัง 1. อายุ 2. สีผิว 3. ครีมกันแดด 4. ความเข้มของ UV-B ที่ส่องกระทบผิวหนัง (ขึ้นกับละติจูดที่ผู้นั้นอาศัยอยู่, เวลาและฤดูกาล)

กราฟแสดงความเข้มข้นของไวตามินดีในเลือดของผู้สูงอายุและผู้อายุน้อย ภายหลังได้รับแสงแดดระยะเวลาเท่ากัน

รูป A: ระดับ vit. D ในเลือดของคนผิวขาวภายหลังได้รับแสงในขนาด 1.5 MED รูป B: ระดับ vit. D ในเลือดคนผิวดำที่ได้รับแสง 1.5 MED รูป C: ระดับ vit. D ในเลือดคนผิวดำที่ได้รับแสง 6 MED ผิวขาว 1.5 MED ผิวดำ 1.5 MED ผิวดำ 6 MED

กราฟแสดงความเข้มข้นของไวตามินดีในกระแสเลือดในอาสาสมัครที่ทาครีมกันแดดที่มีค่า SPF 8 และคนที่ไม่ได้ทาครีมกันแดด ที่ได้รับแสงแดดในปริมาณเท่ากัน

ส่วนใหญ่ของวิตามินดีที่มนุษย์ได้รับมาจากการสังเคราะห์ทางผิวหนังโดยแสงแดด

ผู้สูงอายุไทยขาดวิตามินดี เป็นไปได้หรือ ?

ประเทศไทยตั้งอยู่ในช่วงเส้นรุ้งที่ 4-20 องศาเหนือ ซึ่งเป็นบริเวณที่ได้รับแสงแดดจ้าทั้งปี แพทย์ส่วนใหญ่จึงเชื่อว่าคนไทยควรจะได้รับแสงแดดเพียงพอ ด้วยเหตุนี้จึงเชื่อว่าคนไทยไม่ควรจะขาดวิตามินดี การเสริมวิตามินดีไม่มีความจำเป็นในผู้ป่วยโรคกระดูกพรุน ความเชื่อนี้มีความเป็นจริงมากน้อยเพียงใด ?

Soontrapa Sp. Srinagarind Med J 2002; 17(4) ความชุกและระดับของ 25(OH)D ในสตรีสูงอายุที่ขาดวิตามินดี ซึ่งอาศัยอยู่ในเขตเทศบาลเมือง จ.ขอนแก่น Soontrapa Sp. Srinagarind Med J 2002; 17(4) 78

Scatter plot แสดงความสัมพันธ์ระหว่างระดับวิตามินดีและระดับ PTH ในกระแสเลือด (r = - 0.421, p < 0.001, N = 105)

Prevalence 78.2% Hypovitaminosis D Hypovitaminosis D หรือ Subclinical vitamin D deficiency คือระดับของ 25(OH)D ที่เริ่มมีการเพิ่มขึ้นของ PTH (McKenna MJ Osteoporos Int 1998; Scharla SH Osteoporos Int 1998.)

Prevalence 65.35% Vitamin D deficiency Vitamin D deficiency คือระดับของ 25(OH)D ที่ทำให้ระดับของ PTH เพิ่มขึ้นอย่างมีนัยสำคัญ ผู้สูงอายุที่ผลการตรวจ BMD เป็น osteoporosis มีค่าเฉลี่ยของ 25(OH)D = 30.5 (SD=6.4) (McKenna MJ Osteoporos Int 1998)

unpaired T-test of the mean of 25(OH)D between non-osteoporotic group and osteoporotic group showed highly significant difference (p=0.004)

การขาดวิตามินดีและความเสี่ยงต่อการเกิดโรคกระดูกพรุนในสตรีสูงอายุ Soontrapa Sp. Srinagarind Med J 2002; 17(3):p153-158

ระดับ vitamin D deficiency < 35 ng/ml Prevalence 65.35% Vitamin D deficiency 66 ราย 35 ราย ระดับ vitamin D deficiency < 35 ng/ml

Results Lumbar spine (l2-4) Femoral neck Wards triangle Trochanter Site Odds ratio (95%CI) Chi-square (p-value) Lumbar spine (l2-4) Femoral neck Wards triangle Trochanter Total femur Radius UD Distal 1/3 of radius 1.38(0.6-3.19) 2.87(1.15-7.15) 1.15(0.46-2.86) 2.03 (0.64-6.4) 0.75(0.28-2.01) 0.42(0.12-1.51) 1.32(0.54-3.24) 0.58 (p=0.44) 5.10 (p<0.03) 0.09 (p=0.76) 1.37 (p=0.24) 0.31 (p=0.58) 1.69 (p=0.19) 0.36 (p=0.55)

Odds ratio (95%CI) ของ femoral neck= 2.2 (0.75-6.40) p-value=0.16 Prevalence 78.2% Hypovitaminosis D 79 ราย 22 ราย Hypovitaminosis D หรือ Subclinical vitamin D deficiency คือระดับของ 25(OH)D ที่เริ่มมีการเพิ่มขึ้นของ PTH < 40 ng/ml Odds ratio (95%CI) ของ femoral neck= 2.2 (0.75-6.40) p-value=0.16

ไม่เชื่อก็ช่วยไม่ได้ สรุป ระดับของ vitamin D deficiency <= 35 ng/ml Vitamin D deficiency เพิ่มความเสี่ยงต่อโรคกระดูกพรุนของ femoral neck (RR 2.87; p<0.03) Prevalence of vitamin D deficiency of urban elderly = 65.35% ไม่เชื่อก็ช่วยไม่ได้

Gillespie WJ, Avenell A, Henry Da, O’Connell DL, Robertson J Vitamin D and Vitamin D Analogues for Preventing Fractures Associated With Involutional and Post-menopausal Osteoporosis Systematic review Gillespie WJ, Avenell A, Henry Da, O’Connell DL, Robertson J 12 Nov. 2001

Objective To determine the effects of supplementation with Vitamin D or a Vitamin D analogue in the prevention of fractures of the axial and appendicular skeleton in elderly men or women with involutional or post-menopausal osteoporosis

Main Results Vitamin D3 alone was not associated with any reduction in incidence of hip fracture (RR 1.20, 95%CI 0.83, 1.75) or other non-vertebral fracture. Vitamin D3 with calcium co-supplementation to frail elderly people in sheltered showed a reduction in incidence of hip fracture (RR 0.74, 95%CI 0.60, 0.91).

Main Results Vitamin D3 with calcium co-supplementation in healthy younger, ambulant participants showed no risk reduction of hip fracture (RR 0.36, 95%CI 0.01, 8.78), but had a significant reduction on non-vertebral fracture incidence (RR 0.46, 95%CI 0.23, 0.90).

Main Results Calcitriol was effective in reducing the incidence of vertebral deformity (RR 0.49, 95%CI 0.25, 0.95). Calcitriol was more effective than calcium in reducing the frequency of new vertebral deformities during the third year of treatment (RR 0.28, 95%CI 0.15,0.52).

Main Results One-alpha D reduced the incidence of non-vertebral fractures in impaired mobility by neurological disease (RR 0.12, 95%CI 0.02, 0.95). No Statistically significant effects were found for other comparisons of vitamin D or its analogues against each other, with and without calcium supplementation.

Conclusions Uncertainty remains about the efficacy of regimens which include vitamin D or its analogues in fracture prevention. Further large randomized trials are currently being conducted to clarify the effectiveness of community fracture prevention programmes employing vitamin D supplementation

Primary prevention High calcium diet Adequate vitamin D Weight bearing exercise

Exercise Swimming - not increase bone mass Increase muscle strength increase bone mass weight bearing exercise : walking jogging jumping Swimming - not increase bone mass - increase strength & flexibility

The effect of exercise training programs on bone mass: a meta-analysis of published controlled trials in pre- and postmenopausal women Objective: the effect of exercise programs on BMC of LS spine and femoral neck in Pre- and postmenopausal women Result: Exercise programs can prevent or increase bone mass 1%/yr of both LS and FN in both pre- and postmenopausal women Endurance training programs had significantly increase bone mass of both LS and FN Strength training programs had no significantly increase bone mass of both LS and FN Wolff I., et al. Osteoporos Int 1999: 9(1) 1-12.

Treatment of Osteoporosis

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 Bisphosphonate Calcitonin

Secondary Prevention and Treatment of Osteoporosis HRT Bisphosphonate (Alendronate, Risedronate) Calcitonin

Pharmacological Properties of Bisphosphonates Low bioavailability (<1%) Food interaction (bioavailability further reduced by ~40%) Rapid distribution from plasma Specific affinity for bone Not metabolized, excreted renally Minimal systemic toxicity Adverse experiences predominantly limited to upper GI tract Bisphosphonates have a low bioavailability and when absorbed are cleared rapidly from the plasma with a specific affinity for bone. Thus, there is little systemic exposure and any observed toxicity is likely related to direct contact between the agent and the gastrointestinal mucosa (vs nonsteroidal anti-inflammatory drugs’ [NSAIDs’] systemic effect on tissue prostaglandins).

Evidence-based Review of FOSAMAX Trials Efficacy Studies FIT study (Fracture Intervention Trial study) FOSIT study (The FOSAMAX International Trial) 10 yrs. Fosamax Efficacy and Safty 2-yr O/W data Male osteoporosis

Evidence-based Review of FOSAMAX Trials Tolerability Endoscopy study 10 mg alendronate vs 5 mg risedronate 40 mg alendronate vs 30 mg risedronate Long term GI Safety (FIT) Alendronate :Once Weekly dosing

Evidence-based Review of FOSAMAX Trials Efficacy Studies FIT study (Fracture Intervention Trial study) FOSIT study (The FOSAMAX International Trial) 10 yrs. Fosamax Efficacy and Safty 2-yr O/W data Male osteoporosis

The Fracture Intervention Trial (FIT) FIT I1 FIT II2 Vertebral Fracture Arm Clinical Fracture Arm Number of patients 2027 4438 Fracture status With vertebral fracture Without vertebral fracture Mean age (yrs) 70.8 67.7 Entry criteria Femoral neck BMD < -1.6 Femoral neck BMD <-1.6 Existing vertebral fracture No vertebral fracture Duration 36 months 48 months Follow-up rate 4% lost to follow-up 4% lost to follow-up Study design Randomized, blinded, placebo-controlled Treatment groups Placebo or alendronate 5 mg for 2 years then 10 mg End points Vertebral and nonvertebral fracture (including hip), BMD 1Black DM. Lancet. 1996;348:1535-1541. 2Cummings SR. JAMA. 1998;280:2077–2082.

Fracture Risk Reduction Alendronate: Reductions in Vertebral Fractures Results from 3-Year Fracture End Point Trial FIT Vertebral Fracture Arm (FIT1) Vertebral Fractures ALN (2.3%) PBO (5.0%) ALN (8.0%) PBO (15%) ALN (0.5%) PBO (4.9%) Clinical Vertebral Fracture New Morphometric Fractures Multiple Morphometric Fractures 10 20 30 40 Fracture Risk Reduction 50 47* N = 2027 women, 55 to 81 years of age with at least one vertebral fracture. Randomly assigned to placebo or alendronate and followed for 36 months. The primary end point was new vertebral fractures. The most impressive reduction in fracture rate in the vertebral spine (90%) was in patients having multiple prior vertebral fractures. All reductions are statistically significant. The relative risk for wrist fracture for alendronate vs placebo was 0.52 (0.31–0.87). 60 N=2027 cases Age =55-81 years At least one vertebral fx. 55* 70 80 90 100 90* *Statistically significant. RR of wrist fx.=0.52 (0.31-0.87) Black DM et al. Lancet. 1996;348:1535-1541.

Early Efficacy of Alendronate: Combined Analysis of FIT N=3658 cases Age=55-80 years Inclusion BMD T-score<-2.5 with or without vert. fx. 1 2 3 4 5 6 12 18 24 30 36 59% Reduction at 12 Months P < 0.030 PBO ALN Study Time in Months Cumulative Incidence Clinical Vertebral Fracture 3 Hip Fracture 63% Reduction was Observed at 18 Months P < 0.014 PBO 2 Cumulative Incidence 1 ALN 3658 women, 55 to 80 years of age from the FIT were studied. Women had an existing vertebral fracture or no vertebral fracture. BMD T score less than –2.5 at the femoral neck. Fractures were defined as those reported by patients and evaluated by physicians. At 12 months of therapy, alendronate decreased the incidence of clinical vertebral fractures by 59%. At 18 months of therapy, alendronate decreased the incidence of hip fracture by 63%. There was a significant 51% reduction in fracture risk at the hip after 3 years of therapy and a risk reduction of 54% during 4 years of therapy. 6 12 18 24 30 36 Study Time in Months Black DM et al. Lancet. 1996;348:1535-1541.

Efficacy of Alendronate: Combined Analysis of FIT N=3658 cases Age=55-80 years Inclusion BMD T-score<-2.5 with or without vert. fx. 3 Hip Fracture PBO 2 51% Reduction was Observed at 36 Months And 54% Reduction was Observed at 48 Months Cumulative Incidence 1 ALN 3658 women, 55 to 80 years of age from the FIT were studied. Women had an existing vertebral fracture or no vertebral fracture. BMD T score less than –2.5 at the femoral neck. Fractures were defined as those reported by patients and evaluated by physicians. At 12 months of therapy, alendronate decreased the incidence of clinical vertebral fractures by 59%. At 18 months of therapy, alendronate decreased the incidence of hip fracture by 63%. There was a significant 51% reduction in fracture risk at the hip after 3 years of therapy and a risk reduction of 54% during 4 years of therapy. 6 12 18 24 30 36 Study Time in Months Black DM et al. Lancet. 1996;348:1535-1541.

Evidence-based Review of FOSAMAX Trials Efficacy Studies FIT study (Fracture Intervention Trial study) FOSIT study (The FOSAMAX International Trial) 10 yrs. Fosamax Efficacy and Safty 2-yr O/W data Male osteoporosis

The FOSAMAX International Trial (FOSIT) Number of patients 1908 Enrollment criteria PMP > 3 years LS BMD T-score < -2.0 Mean age (yrs) 63 Study design 12 month, randomized, blinded, placebo-controlled Drug Placebo vs. alendronate 10 mg daily End points Spine and hip BMD Clinical fractures Dropout rate 11% lost to follow-up Pols HA et al. Osteoporos Int. 1999;9:461–468.

Early Efficacy at Nonvertebral Sites FOSIT Nonvertebral Fractures 47% Reduction % of Patients With Fractures Alendronate 10 mg Placebo * 5 4 3 2 1 9 12 6 *P = 0.021 Months Pols HA, et al. Osteoporosis Int. 1999; 9:461–468.

Evidence-based Review of FOSAMAX Trials Efficacy Studies FIT study (Fracture Intervention Trial study) FOSIT study (The FOSAMAX International Trial) 10 yrs. Fosamax Efficacy and Safety 2-yr O/W data Male osteoporosis

Henry G. Bone, et al. N Engl J Med 2004;350:1189-99. Ten years’ Experience with Alendronate for Osteoporosis in Postmenopausal Women Henry G. Bone, et al. N Engl J Med 2004;350:1189-99.

Methods First (5 yrs.):Two-Year Double-Blind Extension (n = 788) 994 Postmenopausal Osteoporotic Women (3 Years) First (5 yrs.):Two-Year Double-Blind Extension (n = 788) Second (7 yrs): Two-Year Double-Blind Extension (n = 335) Third (10 yrs): Three-Year Double-Blind Extension (n= 247) Bone Mineral Density (BMD): DXA Lumbar Spine (Primary), Hip, Total Body, Forearm Biochemical Markers of Bone Turnover (BSAP, NTx) Stature (Stadiometer) Clinical and Laboratory Safety Evaluations

Phase III Osteoporosis Treatment Studies Alendronate Treatment Schedule* *Alendronate manufactured by Merck & Co., Inc., Whitehouse Station, NJ

Lumbar Spine BMD Mean Percent Change (± SE) 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 24 36 48 60 72 84 96 108 120 Mean Percent Change Month ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo 3 yrs. 5 yrs. 7 yrs. 10 yrs.

Total Body BMD Mean Percent Change (± SE) 1 2 3 4 12 24 36 48 60 72 84 96 108 120 Mean Percent Change Month ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo 3 yrs. 5 yrs. 7 yrs. 10 yrs.

Femoral Neck BMD Mean Percent Change (± SE) 1 2 3 4 5 6 7 12 24 36 48 60 72 84 96 108 120 ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo Month Mean Percent Change 3 yrs. 5 yrs. 7 yrs. 10 yrs.

Trochanter BMD Mean Percent Change (± SE) 1 2 3 4 5 6 7 8 9 10 11 12 24 36 48 60 72 84 96 108 120 Mean Percent Change Month ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo 3 yrs. 5 yrs. 7 yrs. 10 yrs.

Total Hip BMD Mean Percent Change (± SE) 1 2 3 4 5 6 7 8 9 12 24 36 48 60 72 84 96 108 120 Mean Percent Change Month ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo 3 yrs. 5 yrs. 7 yrs. 10 yrs.

Bone Specific Alkaline Phosphatase Mean Percent Change (± SE) -70 -60 -50 -40 -30 -20 -10 12 24 36 48 60 72 84 96 108 120 Placebo* ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo 3 yrs. 5 yrs. 7 yrs. 10 yrs. Month *Patients enrolled in the original, 3 year study

Urine NTx Mean Percent Change (± SE) Month Placebo* ALN 5 mg ALN 10 mg ALN 20 mg/ALN 5 mg/Placebo -90 -80 -70 -60 -50 -40 -30 -20 -10 12 24 36 48 60 72 84 96 108 120 3 yrs. 5 yrs. 7 yrs. 10 yrs. *Patients enrolled in the original, 3 year study

Alendronate 10 Year Data Non-vertebral Fractures Years 1 to 3* Years 8 to 10 * Liberman et al. N Engl J Med. 1995;333(22):1437

GI Adverse Experiences (AE) Years 8-10 (ALN 20/5/PBO) Placebo ALN 5 mg ALN 10 mg (N=83) (N=78) (N=86) % of women with adverse experiences: Any Upper GI 24.1 14.1 27.9 Drug-related† 7.2 3.8 9.3 Serious 1.2 1.3 0 Withdrawn 2.4 1.3 2.3 Esophageal 7.2 1.3 2.3 PUBs* 0 1.3 0 *Perforations, Ulcers or Bleeds †Rated by the investigator as possibly, probably or definitely drug-related

Conclusions Effects of long-term (10-year) treatment of postmenopausal women with alendronate: Progressive increases in spine BMD for 10 years Progressive increases in total hip, trochanter and total body BMD for 3-5 years, and prevention of loss, thereafter Prevention of loss of forearm BMD for 10 years Stable reduction of bone turnover to premenopausal level Discontinuation of therapy does not lead to accelerated bone loss, but continuous therapy yields optimum skeletal benefits Safety and tolerability are similar during all years of treatment

Evidence-based Review of FOSAMAX Trials Efficacy Studies FIT study (Fracture Intervention Trial study) FOSIT study (The FOSAMAX International Trial) 10 yrs. Fosamax Efficacy and Safty 2-yr O/W data Male osteoporosis

Once-Weekly Dosing With Bisphosphonates: Rationale Half-life in bone several weeks (therefore, weekly dosing should affect bone resorption to a similar extent as daily dosing) Once-weekly dosing more convenient ? Better tolerability Once-weekly dosing with a bisphosphonate is possible because of the long tissue half-life of the agent. Less frequent dosing would enhance convenience and compliance as patients must be fasting and in an upright position after ingesting the drug. Additionally, less frequent dosing may decrease any dyspepsia associated with use of these agents.

Comparability of Alendronate 70 mg Once-weekly to 10 mg Daily Across Studies: Spine BMD Mean change from baseline in spine BMD (%) 5.4 5.1 4.9 5.2 7 Daily 10 mg Once-weekly 70 mg FOSIT Pooled Treatment Once-weekly study Other osteoporosis treatment studies Increases in lumbar spine BMD were consistent across studies and no different between 70 mg once-weekly and 10 mg daily alendronate FOSIT = FOSAMAX® International Trial Schnitzer et al, Aging Clin Exp Res 2000;12:1. Pols et al. Osteoporosis Int 1999;9:461.

Gastrointestinal Injury With Alendronate 70 mg Once Weekly: A 10-Week Study 3.09 Mean Erosion Score 1.22 0.35 0.32 0.14 0.26 0.12 0.17 0.17 Patients randomized to alendronate 70 mg once weekly or placebo. From day 64, the 21 aspirin patients received aspirin 650 mg qid or matching placebo. Lanza et al. Am J Gastroenterol. 2001

Gastroduodenal Ulcers With Once-Weekly Alendronate Dosing 23.8% Incidence of Ulcers % 1.7% 0.0% Lanza et al. Am J Gastroenterol. 2001

Once-Weekly Dosing With Bisphosphonates: Conclusions Gastrointestinal mucosal injury comparable to placebo No ulcers in the alendronate arm GI AEs comparable to placebo No relationship between AEs and endoscopic findings In summary, once-weekly dosing appears to be as safe as daily dosing and side effects and adverse events also appear to be equivalent. Given the widespread use of once-weekly dosing, there does not appear to be any reason to be concerned about increased gastrointestinal toxicity with the higher doses of bisphosphonates used in this fashion.

Conclusions Bisphosphonates are effective and safe agents for managing osteoporosis Bisphosphonates are well tolerated and have symptom and ulcer rates comparable to placebo Endoscopic lesions do not correlate with meaningful clinical outcomes Bisphosphonates are effective agents used to manage osteoporosis and are well tolerated. Gastrointestinal mucosal injury of any clinical relevance rarely occurs and any differences in mucosal injury between agents within this class are inconsistent and clinically irrelevant. Outcomes studies have shown equivalent ulcer and symptom rates between placebo and these agents.

Evidence-based Review of FOSAMAX Trials Efficacy Studies FIT study (Fracture Intervention Trial study) FOSIT study (The FOSAMAX International Trial) 10 yrs. Fosamax Efficacy and Safty 2-yr O/W data Male osteoporosis

Alendronate for the Treatment of Male Osteoporosis 2-year, double-blind trial Primary end point: lumbar spine BMD 241 men ages 31–87 years (mean = 63) with osteoporosis; BMD at least 2 SD below young adult mean Patients randomly assigned to receive 10 mg alendronate or placebo daily All patients received calcium and vitamin D supplements daily Orwoll et al. N Engl J Med. 2000;343:604-610.

Effect of Alendronate on BMD and Fracture Risk in Men with Osteoporosis Lumbar spine BMD P = 0.02 Alendronate Placebo Incidence of vertebral fracture Orwoll E et al. N Engl J Med. 2000;343:604-610.

Effect of Alendronate on BMD in Male Osteoporosis 3.1 2.5 Increase in BMD (%) 2.0 0.6 P<0.001 0.4 -0.1 Orwoll et al. N Engl J Med. 2000;343:604-610.

Bisphosphonates: Benefits and Risks Fracture reduction BMD increase Non-hormonal Risks Nausea Upper gastrointestinal irritation Myalgias and arthralgias

Secondary Prevention and Treatment of Osteoporosis HRT Bisphosphonate Calcitonin

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

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Therapeutic Options Antiresorptive Therapy Anabolic Therapy Hormone replacement therapy (HRT) Raloxifene Bisphosphonates Alendronate Risedronate Calcitonin Anabolic Therapy Parathyroid hormone (PTH) During the past decade, these therapeutic agents have a place in the osteoporosis treatment protocol. Efficacy data about increasing BMD, controlling bone turnover, and reducing fracture risk is included in this slide presentation. Interpreting the data through an analytical approach is important. Anabolic therapy for osteoporosis is also under investigation. Parathyroid hormone (PTH) stimulates bone formation and resorption, and its use in women and men with osteoporosis has been studied.1,2 More research needs to be done on this possible therapeutic choice, however. 1Neer et al. N Engl J Med. 2001;344:1434-1441. 2Kurland E et al. J Clin Endocrinol Metab. 2000;85:3069-3076.

Parathyroid Hormone (PTH) Treatment for Osteoporosis Study of 1637 postmenopausal women with prior vertebral fractures Randomly assigned to one of 3 groups: 20 µg PTH injection daily 40 µg PTH injection daily Placebo injection daily Duration of observation: 21 months (median) Vertebral radiographs at baseline and at end of study Serum calcium measured before and 4-6 hours after injection at baseline and at 1, 3, 6, 12, 18, and 24 months of treatment Robert Neer and colleagues studied the effect of PTH therapy on 1637 postmenopausal women, and the results of the study were published in May 2001. The patients were randomly assigned to receive either 20 µg PTH (541 women), 40 µg PTH (552 women), or placebo (544 women) daily for the duration of the study (mean period of observation=21 months). The patients self-injected the agent. Patients were excluded if post-injection serum calcium was high or urinary calcium excretion exceeded 350. Neer et al. N Engl J Med. 2001;344:1434-1441.

Effect of PTH on the Risk of New Vertebral Fractures *P<0.001 vs. Placebo RR 0.31* RR 0.35† 0% 14 12 25% 10 % of Women 8 Risk Reduction (RR) 50% 65% 69% 6 The large BMD increments translated into very significant reductions in risk of fracture. There was a 65% to 69% reduction in risk of new incident vertebral fracture with no suggestion of a difference between the two PTH doses. 4 75% 2 64 22 19 100% Placebo (n=448) rhPTH 20 (n=444) rhPTH 40 (n=434) No. of women who had > 1 fracture *95% CI, 0.19-0.50 †95% CI, 0.22-0.55 Neer R et al. N Engl J Med. 2001;344:1434-1441.

Osteoporosis Therapies Overview BMD Spine BMD Hip Spine Fx Hip Fx Wrist Fx Biochemical Markers HRT Raloxifene Alendronate Risedronate Nasal Calcitonin PTH ( ) The chart gives an overview of each of the therapies discussed in this presentation.