Definition. Consensus Development Conference: Diagnosis, prophylaxis, and treatment of osteoporosi (1993) Am J Med 94:

Transcription

1 OSTEOPOROSIS

2 Definition Osteoporosis is a disease characterized by low bone mass and microar-chitectural deterioration of bone tissue, leading to enhanced bone fragilityand a consequent increase in fracture risk. Consensus Development Conference: Diagnosis, prophylaxis, and treatment of osteoporosi (1993) Am J Med 94: Osteoporosis as a skeletal disordercharacterized by compromised bone strength predisposing a person to an increased risk offracture. Bone strength primarily reflects the integration of bone density and bone quality. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy Mar 7-29, 2000: highlights of the conference. (2001) South Med J 94:

3 Pathophysiology Osteoblasts and osteoclasts. Osteoporosis results from loss of bonemass when the rate of bone resorption exceeds that of bone formation. Clinically, osteoporosis can be classified as primaryand secondary. Primary osteoporosis includes postmenopausal osteoporosis and senile osteoporosis.

4 J Korean Soc Endocrinol Dec;20(6): Kore

5 Type 1 primary osteoporosis Postmenopausal osteoporosis Postmenopausal women, especially those who have been menopausal for years. Estrogen level drops drastically, and increased activity ofosteoclasts to promote the resorption of the trabecular bone, weakening of bone strength. Compression spine fracture, wrist fracture and intertrochantericfracture of the femur.

6 Type 2 primary osteoporosis Senile osteoporosis Women aged 70 years or men aged 80 years. Decreased bone formation caused by diminished function of osteoblasts, insufficient intake of calcium and vitamin D, and poor intestinal absorption. Multiple vertebral wedge fracture, and fracture of humerus, tibia and femoral neck (hip).

7 Secondary osteoporosis Secondary osteoporosis is usually related to bone mass loss from certain conditions Steroid use Hyperparathyroidism Thyroid disease Hypogonadism Rheumatoid arthritis Kidney disorders Liver disorders Diabetes mellitus Smoking, alcohol abuse Organ transplantation Fracture Insufficient intestinal absorption

8 Epidemiology Age Male Female All 50 ~ 64 years old 8.4% 16.7 % 12.6 % 65 ~ 74 years old 13.2 % 29.6 % 21.9 % Over 75 years old 17.4 % 32.7 % 24.1 % Incidence of hip fracture in Taiwan, women were twice as likely to experience bone fracture as men. Patient increases the number of cases by 3~5% annually, and the gross one-year death rate of men is 22% and 15% for women.

9 Epidemiology In Taiwan, the incidence rate of vertebral body fracture in women aged 65~70 was 14% and 30% for the group of 80 The prevalence in men is about sixty percent of that in women. The incidence of hip fracture or spine fracture of the middle-aged and aged patient is higher than the world average.

10 Diagnosis Difference between present height and height at youth A 3-cm difference between the present height and the height at youthstrongly suggests the possibility of osteoporosis. Weight Body weight is inversely proportional to bone density, indicating that low body weight is arisk factor of osteoporosis, and this is especially true when body mass index is lower than 18.5 kg/m 2.

11 Diagnosis Wall-Occiput Distance (WOD) This is a quick method for screening subclinical compression fracture of the thoracic spine. A gap of <1 cm(or no gap) is considered normal. When a gap of >3 cm is found, a problem is strongly suggested, and it is confirmed when it is >6 cm

12 Diagnosis Rib-pelvis distance (RPD) This is a quick method for screening subclinical compression fracture of the lumbar spine. In normal individuals, it shouldbe 2-3 fingerbreadths or >5 cm. A distance of <2 cm is highly confirmative for a spinal problem.

13 Diagnosis Quantitative Ultrasound (QUS) Ultrasound can be used to obtain more information about bones to define the resilience and stiffness of bone mass. Calcaneus or tibia is the most frequently used for measurement QUS can be used for the effective evaluation of bone fracture risk in postmenopausal women and aged men

14 Diagnosis Dual energy X-ray Absorptiometry (DXA) It uses X-ray emitters of two different levels for scanning, and BMD value (g/cm2) is calculated with the amount of absorption by dorsal bone and soft tissue, and the scanned area. It is usually used on the lumbar spine and hip bone. It can be used for estimation of the risk of bone fracture, the response and efficacy of treatment

15 Diagnosis Bone mineral density (BMD) World Health Organization Definitions Based on Bone Density Levels Level Definition Normal +1 Tscore 1 Low bone mass 1 T score 2.5 Osteoporosis Severe (established) osteoporosis 2.5 T score 2.5 T score, and there have been one or more osteoporotic fractures. NIH Osteoporosis and Related Bone Diseases ~ National Resource

16 Diagnosis The Fracture Risk Assessment Tool (FRAX) published by the International Osteoporosis Foundation (IOF) in 2008 provides effective prediction of fracture risk in the following decade. For high risk patients (defined as individuals with a major fracture risk of 20% or hip fracture risk of 3%), active preventive intervention is recommended.

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18 Prevention and Treatment of Osteoporosis without Medication Diet- Calcium bone formation blood calcium level 100 mg / L bone resorption

19 Prevention and Treatment of Osteoporosis without Medication In Taiwan, the dietary reference intake (DRI) of calcium for adults aged 19 is 1000 (the adequate intake) 2500 (upper limit) mg/d. 含鈣量 (mg) 食物 份量 > 350 mg 高鈣奶粉 25 g mg 起司 補體素 40 g 25 g mg 鮮乳 保久乳 240 ml mg mg 黑芝麻 小魚乾 芥蘭菜 魚鬆 莧菜 紅鳳菜 15 g 10 g 100 g 35 g 100 g 行政院衛生署食品工業研究所

20 Prevention and Treatment of Osteoporosis without Medication Diet- Vitamin D Vitamin D maintains the balance of calcium and phosphorus in thehuman body and regulates active calcium absorption in the intestines. Its limited supply in natural foods, sun exposure is the main source of vitamin D other than fortified foods and supplements. The recommended dietary allowance (RDA) of vitamin D for adults aged in Taiwan is 200 IU/d (5 μg/d), and 400 IU/d (10 μg/d) for those aged The limit is 2000 IU/d (50 μg/d).

21 Prevention and Treatment of Osteoporosis without Medication Exercise Low to Moderate Intensity Weight-Bearing Impact Exercise Walking -femoral neck lumb spin High Intensity Weight-Bearing Impact Exercise Jogging - lumbar spine, femoral neck Mixed Weight-Bearing Impact Exercise Walking, Jogging and Stair Climbing -lumbar spine, femoral neck, calcaneus femoral neck calcaneu

22 Prevention and Treatment of Osteoporosis without Medication Lifestyle The bone density of somkers at the femoral neck, radius and calcaneus is lower. Alcoholics have lower bone density and bone formation, and a higher risk of bone fracture

23 Prevention and Treatment of Osteoporosis with Medication Mechanisms 1.anti-osteoclast/anti-resorptive activities calcium supplements, vitamin D, bisphosphates, sex hormones, selective estrogen receptor modulators (SERMs), and RANKL monoclonal antibodies 2.osteoblast and bone formation activators parathyroid hormone and its active fragments 3.Mixed activities strontium salts

24 Calcium supplements According to the International Osteoporosis Foundation, the recommended calcium intake of postmenopausal women and elders aged >65 is 1300 mg/day. Calcium carbonate is the most common and cheapest form of calcium supplement. calcium citrate is recommended for individuals with inadequate gastric acid secretion, constipation, bloating or a history of kidney stones

25 Vitamin D Adequate vitamin D (at least 800 IU/day) and calcium intake is abasic and important element in the prevention of osteoporosis. All clinical trials of medication with proven efficacy for treating osteoporosis and reducing bone fractures are must provided with critically sufficient vitamin D and calcium nutrition.

26 Bisphosphates When entering the human body, its high plasma clearance is associated with rapid elimination through urine, but still allows about 50% of the administered dose to accumulate in bone, where the half-life in bone is much longer. The mechanism of bisphosphates involves the inhibition of osteoclast activity and bone resorption. Bisphosphates include Alendronic acid Ibandronic acid Zoledronic acid

27 Bisphosphates Alendronic acid (Alendronate Sandoz ) : 70mg F.C. tablet oral QW Alendronic acid (Fosamax Plus ): 70mg + Colecalciferol 5600IU tablet oral QW It have an extremely low bioavailability and should be taken with 200ml water. When taken with food, calcium supplements, iron supplements, coffee, tea or orange juice, its absorption is likely to be affected. Not lie down for at least 30 minutes after taking alendronate and until after food. It is not recommended for patients with creatinine clearance less than 35 ml/min.

28 Bisphosphates Ibandronic acid (Bonviva ) : 3mg/3mL IV Q3M For the treatment of post-menopausal women with osteoporosis to reduce spine fractures. Intravenous injection 3 mg over 15 to 30 seconds. The missed dose should be given as soon as it can be rescheduled. After you receive the missed dose, your next injection should be scheduled 3 months from the date of your last injection.

29 Bisphosphates Zoledronic acid (Aclasta ) : 5mg/ 100ml IVF over 15 mins once of year Zolendronic acid is the only effective bisphosphate molecule against spinal, nonspinal and hip fractures, but long-term (>3 years) safety data is lacking. When patient receive zoledronic acid, be sure to drink at least 500 c.c. of water before and after the treatment.

30 Bisphosphates neric Name Alendronic acid Ibandronic acid Zoledronic acid and Name dications Fosamax plus Alendronate Sandoz Postmenopausal osteoporosis Senile osteoporosis Boniva Aclasta Postmenopausal osteoporosis Postmenopausal osteoporosis Senile osteoporosis osage and inistration 70 mg PO QW 3mg/3mL IV Q3M 5mg/100mL IVF once of year l Impairment Clcr less than 35 ml/min Clcr less than 30 ml/min Clcr less than 35 ml/min ower risk spinal, hip fractures spinal fractures spinal, non-spinal and hip fracture erse Events Osteonecrosis of the jaw The risk of ONJ may increase with duration of exposure to bisphosphonates. For patients requiring invasive dental procedures, discontinuation of bisphosphonate treatment may reduce the risk for ONJ.

31 Bisphosphates Suggested duration of bisphosphonate treatment and drug holidays Patient s fracture risk Suggested duration of treatment Suggested duration of drug holiday Low Treatment rarely indicated NA Mildly increased Moderately increased Treat for approximately 5 yr Treat for 5 10 yr Stay off bisphosphonate until BMD decreases significantly or fracture occurs Stay off bisphosphonate for 2 3 yr (or less if BMD decreases or fracture occurs) High Treat for 10 yr Stay off bisphosphonate for 1 2 yr (or less if BMD decreases or fracture occurs); alternate medication (e.g. raloxifene, teriparatide) may be given during the holiday from bisphosphonates Watts NB, Diab DL: Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 2010; 95:

32 Selective Tissue Estrogenic Activity Regulator Tibolone (Livial ) : 2.5mg tablet oral QD It is metabolized in the liver and intestines, and themetabolites from different enzymatic activities act as estrogen analogs and/or antagonists andprogesterone in various tissues Tibolone may be used in the prevention of osteoporosis because of its estrogenic effect of improving bone density. Tibolone can be used for postmenopausal syndrome because its actions are similar to estrogen andprogesterone, and it is associated with a lower risk of uterine bleeding than the hormone therapy with progesterone

33 Selective estrogen receptor modulator (SERM) Raloxifene (Evista ) : 60mg tablet oral QD SERM is a non-estrogenic medication that induces estrogenic or anti-estrogenic activity by binding with estrogen receptors on the cells. It can be taken with food, drinks, vitamin D and calcium supplements. VTEis a more serious side effect, And mainly occurs in the first two years of use.

34 RANKL monoclonal antibodies In the cell differentiation process of bone remodeling, receptoractivator of NF-kB (RANK) binds with RANK ligand (RANKL) to activate the differentiation of osteoclasts. RANKL monoclonal antibodies act on RANKL to block activation, which inhibits osteoclastic activity, and is followed by decreased bone loss, increased bone density and a decreased risk of bone fractures

35 RANKL mature and active osteoclasts

36 RANKL monoclonal antibodies blocks RANKL and activation of osteoclasts RANKL monoclonal antibodies

37 RANKL monoclonal antibodies Denosumab (Prolia ): 60 mg subcutaneous injection every 6 months. It s bioavailability of 61% and a half-life of 26 days, peak blood level is reached 10 days after administration. Side effects identified include infection, constipation, sore throat and rash that are usually mild. When you remove Prolia from the refrigerator, Prolia must be kept at room temperature [up to 77 F (25 C)] in the original carton and must be used within 14 days.

38 Parathyroid hormone It s regulates calcium homeostasis by promoting bone metabolism, renal calcium reabsorption and intestinal calcium absorption. When chronic or continuous exposure as seen in hyperparathyroidism, which causes higher osteoclastic activity and rapid progression of osteoporosis. When exogenous administered once a day, the risk of bone fractures is lower because intermittent use is associated with higher osteoblastic activity, which reinforces bone microstructure, mass and strength.

39 Parathyroid hormone Teriparatide (Forteo ): 20μg subcutaneous injection QD. It is bioavailability of 95% and a plasma half-life of 1 hour, peak blood level is reached 30 minutes after injection and became undetectable 3 hours after injection. Indications include postmenopausal osteoporosis and senile osteoporosis

40 Parathyroid hormone Adverse reactions include hypercalcemia, hypercalciuria, nausea,headache, leg cramps and orthostatic hypotension, and usually temporary and mild Teriparatide is not recommended for patients with history of metastatic bone tumors or bone malignancy because its long-term use at high doses has been associated with a higher risk of osteosarcoma in the animal model. PTH should not exceed 24 months. The bone density decline after the cessation of teriparatide, which means that other medications should be followed when the regimen is discontinous.

41 Strontium salts Stimulate promotes bone formation through the stimulation of calcium sensing receptors (CaSRs) that activates pre-osteoblasts to osteoblasts, while the inhibition of bone resorption is achieved by interfering with the binding of the receptor activator of NF-kB (RANK) with RANK ligand (RANKL) that strontium ranelate stimulate to secrete osteoprotegerin (OPG).

42 Strontium salts Strontium ranelate (Protos ): one package (2 grams) QD or HS One package (2 grams) of strontium ranelate added to water to prepare oral suspension taken once a day. For adequate absorption, at least two hours should be kept between strontium ranelate and the use of calcium, antacids and antibiotics (e.g. tetracycline, quinolone). Precaution is advised in patients, e.g. phenylketouria (PKU) and venous thromboembolism (VTE) Cessation is recommended for patients experiencing drug rash with eosinophilia

43 CONCLUSION

44 藥物種類 / 作用 抗破骨類藥物 Conclusion Bisphosphonates Raloxifene Denosumab 健保規範 1. 停經後婦女因骨質疏鬆症 ( 須附 DXA BMD 之 T score - 2.5SD) 引起脊椎或髖部骨折 2. 停經後婦女因骨質疏少症 ( 經 DXA 檢測 BMD 之 -2.5SD <T score <-1.0SD) 引起脊椎或髖部 2 處 / 次或以上之骨折 3. alendronate zoledronate denosumab 亦可使用於男性 副作用 腹痛 噁心 消化不良 骨頭痛 關節痛 肌肉痛 長期可能導致下顎骨壞死 (ONJ) 口服劑型 : 食道炎 胸灼熱 噁心 注射劑型 : 感冒樣症狀 熱潮紅 噁心 深層靜脈栓塞 中風 腿部痙攣 腫脹 感冒樣症狀 低血鈣 顎骨壞死 及因免疫調節而造成的嚴重感染, 如皮膚 膀胱 耳感染或 禁忌症 1. 不建議用於嚴重腎功能不全 (Clcr < 35 ml/min) 的或血鈣過低的病人 2. 口服劑型若發生胸痛, 胸灼熱感, 吞嚥困難或疼痛時應停藥 3. 發生顎骨壞死及非典型骨折時應停藥 不可用於會增加中風危險之婦女, 包含先前有過中風 短暫性缺血性發作 (transient ischemic attacks, TIAs) 心房顫動 無法控制的高血壓 免疫功能受抑制者或服用影響免疫系統藥物者

45 Reference Taiwan osteoporosis practice guidelines. Taiwan (ROC): Bureau ofhealth Promotion, Department of Health, Taiwan; 2011 Dec. Consensus Development Conference: Diagnosis, prophylaxis, and treatment of osteoporosis. (1993) Am J Med 94: NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy March7-29, 2000: highlights of the conference. (2001) South Med J 94: 國民健康署 103 年國民健康訪問調查 NIH Osteoporosis and Related Bone Diseases ~ National Resource Center; FRAX, Prolia (denosumab) prescribing information, Amgen

46 行政院衛生署 : 台灣地區食品營養成分資料庫 2010, RAO WHO (2002) Human Vitamin and Mineral Requirements Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P (2007) Need for additional calcium to reduce the risk of hip fracture with vitamin D supplementation: evidence from a comparative meta-analysis of randomized controlled trials. J Clin Endocrinol Metab 92: Sidney M. Wolfe, Kidney Damage Due to Osteoporosis Treatment, WorstPills.org, 12 Mar 于振東 : 治療骨質疏鬆的新利器 間歇式注射副甲狀腺素 台灣醫界 2008: 51: Hwang JS, Chen JF, Yang TS, Wu DJ, Tsai KS, Ho C, Wu CH, Su SL, Wang CJ, Tu ST (2008) The effects of strontium ranelate in Asian women with postmenopausal osteoporosis.[erratum appears in Calcif Tissue Int Apr;84(4):334]. Calcified Tissue International 83: 余傑明 : 骨質疏鬆症的藥物治療 臺灣老年醫學暨老年學雜誌 2012;7(2): 77-90

47 Thanks for your attention