Osteoporosis

1. Osteoporosis ACOG 2004; 50: 203-16. 부산백병원 산부인과 R4 김 성 용

2. Osteoporosis • Systemic skeletal disease • Microarchitectural deterioration of bone tissue with a resultant increase in fragility. • 13-18 % of U.S. women over 50 years • Another 37-50% have osteopenia • Increase the risk of fracture • Hip Fx. • Morbidity and mortality 15-20% • Thoracic spine Fx. • Morbidity, including pain • Deformity • Loss of indepandence • Reduce of cardiovascular, respiratory, digestive function. • Osteoporosis is a largely preventable complication of menopause.

3. Background • Definition • Pathophysiology • Factors Affecting Bone Mass • Screening Methods

4. Definitions • Axial skeleton measurement of bone mineral density. • Z score or T scores of DXA of lumbar spine or hip. • Z score • Based of standard deviation from the bone mineral density of a same sex, race, and age. • T score • Based on the mean peak bone mineral density of a normal young adult population.

5. Definitions • 1 SD decrease = 2 fold increase of Fx. Risk • Peripheral bone T score • Cannot used WHO classification. • Used predict of fracture. • Osteoporosis screening. • In development.

6. Pathophysiology • Bone remodeling • unit : osteoblast, osteoclast • Cycle is divided into 4 phase • Take several months to complete • Resting • Stem cell from BM are attracted to bone surface and differentiate into osteoclasts. • Resorption • Acid pH 로 mineral 을 dissolve , proteolytic enzymes 으로 digest the bone proteins. • Reversal • Osteoclast cease removing bone. • Stem cell attracted to the bone surface, and differentiated into osteoblast. • Formation • Make new bone with protein matrix(osteoid). • Protein matrix accounts for much of tensile strength. • Mineral component provides compressional strength. • Cytokine (interleukin 1, 3, 6, 11), growth factor, platelet derived GF, IGF-I,II modulate osteoclast and osteoblast function.

7. Pathophysiology • Bone can be divided into 2 major type • Cortical bone • Outer shall • 75% of total bone mass • Trabecular bone • Internal support • Spongy, interlacing network. • 25% of total bone mass • Most of the volume in bone. • Because of it’s larger surface and higher rate of turnover, it shows early bone loss, and first response to therapy.

8. Pathophysiology • Bone mass • peaks at age 30 years • 0.4% lost per year after peak. • 2% of cortical bone, 5% of trabecular bone loss per year for the 5-8 years after menopause. • In recently menopause, excess bone loss is commonly caused by excessive osteoclast-mediated resorption. • Later poatmenopausal, suppression of osteoblast activity and inadequate formation of bone play a major role of osteoporosis

9. Factors Affecting Bone Mass • Single largest factor is Genetic factor. • Family history • Caucasian and Asian women > Mexican-American > African-American • Weight-bearing exercise stimulate osteoblastic activity. • High dose of corticosteroid(>7.5mg) chronic heparin thrapy(12,000-50,000) is associated with bone loss. • Hyperthyroidism

10. Factors Affecting Bone Mass

11. Clinical Considerations and Recommendations • When should screening for osteoporosis be initiated? • Under what circumstances are screening tests other than DXA useful? • Can lifestyle changes prevent osteoporosis and osteoporosis related fracture? • Is there a role for estrogen and progestin for the prevention or treatment of osteoporosis? • When estrogen therapy is discontinued, how should a woman be monitored for osteoporosis risk? • Is other pharmacotherapy beneficial for the prevention and treatment of osteoporosis? • Are complementary and alternative therapies beneficial for the prevention of osteoporosis? • When should treatment for osteoporosis begin and how should patients be followed?

12. When should screening for osteoporosis be initiated? • Guidelines of testing bone mineral density • All postmenopausal women aged 65yrs or older. • Post menopausal women younger than 65yrs who have 1 or more risk factor • All postmenopausal women with fracture to confirm the diagnosis of osteoporosis and determine disease severity. • National Osteoporosis Foundation : postmenopausal women aged 50-60 with risk factors or 60-65yrs with or without R/F. • Premenopausal women with certain disease or medical conditions • For making decision about prevention therapy of early menopausal women. • Without new risk factor, not be performed more frequently than every 2 years. • Vertebral Fx. 가 있는 order, menopausal women 에게는 bone mineral density test 없이도 치료를 시작해야 하지만 nonvertebral Fx.(hip or wrist) 의 경우는 반드시 검사를 시행하고 적응증에 맞을때 치료를 시작해야 한다.

13. Under what circumstances are screening tests other than DXA useful? • Peripheral bone densinometry • Less expensive, portable, reasonable precision, and low radiation exposure. • Screening tools in the evaluation of bone loss, but cannot replace DXA scan for prediction of hip Fx. And the diagnosis of osteoporosis. • Quantitative Ultrasonography • Provides information on bone elasticity and structure in peripheral sites. • Advantage : low cost and lack of radiation. • Peripheral Quantitative Computed Tomography • Ability to distinguish cortical form trabecular bone. • Early and more precise assessment of skeletal change, due to quick change of trabecular bone • More expensive and more radiation • Less data

14. Under what circumstances are screening tests other than DXA useful? • Biochemical Makers of Bone Turnover • Cannot diagnose osteoporosis, predict bone density or fracture risk. • Useful to help identify women with high bone turnover. • Assessment of theraputic response (earlier than bone mineral density change) • Very expensive.

15. Can lifestyle changes prevent osteoporosis and osteoporosis-related fracture? • Weight-bearing exercise stimulate osteoblast to form new bone. • Persist only when exercise is continued. • For 22 months, 6.1% of bone density of lumbar vertebrae increase observed in postmenopausal women. • Disease and sensory impairments that can cause falling should be treated. • Medications, living environment should be monitored. • Cessation of smoking, reducing alcohol intake • Alcohol(7 oz or more per week) increase the risk for both fall and hip fracture and has detrimental effect on bone mineral density. • Moderate alcohol is associated with increased mineral bone density. (it is not clear why this occur)

16. Is there a role for estrogen and progestin for the prevention or treatment of osteoporosis? • Conjugated equine estrogen(0.625 mg/d) with medroxyprogesterone acetate(2.5 mg/d) reduced the risk of hip and vertebral Fx by 34%, overall Fx by 24%. • Lower dose combinations of conjugated equine estrogen(0.3 mg/d) with medroxyprogesterone acetate(2.5 mg/d) increased bone density 3.5-5.2% in postmenopausal(order than 65 yrs). • Other study • 0.3mg of oral esterified estrogens • Transdermal 17B-estradiol 0.025-0.1 mg per day • Optimal time to initiate therapy • Not determined • Believed work best in the first 5-10 years after menopause. • A study shows order (mean 76 yrs old) women therapy increased bone density. • Therapy discontinued, bone turn over and bone loss accelerated, then approaches that of not treated. • Risk of long-term use • Increase the risk of cardiovascular and breast cancer.

17. When estrogen therapy is discontinued, how should a woman be monitored for osteoporosis risk? • Same as early stage of menopause. • Based on age and other risk factor

18. Is other pharmacotherapy beneficial for the prevention and treatment of osteoporosis? • 2 categories • Bisphosphonates (ie, alendronate, risendronate) • Inhibit osteoclast activity • Both spine and hip • Reduce Fx. 30-50% • Upper G-I S/E and very poor absorption(less then 1%) • Take on empty stomach • With only water • Remain upright at least 30 min. • No additional food or drink during this period. • Used when established disease.

19. Is other pharmacotherapy beneficial for the prevention and treatment of osteoporosis? • Selective estrogen receptor modulators (SERMs) (ie, raloxifene, tibolone, tamoxifen) • Mixed estrogenic and antiestrogenic property depending on tissue. • Estrogen like effect on skeleton bone density and to reduce fracture without stimulating endometrial and breast tissue. • Raloxifene • Reduce 35-50% vertebral Fx. • S/E – vasomotor symptoms (hot flush, night sweat) - DVT • Tibolone • Reduce Fx risk • Androgenic effect on sexual function • Progestational effect on the endometrium. • Tamoxifen • Used as estrogen receptor positive breast ca. and for chemo prevention of breast ca. • Reduce Fx risk . • Increase vasomotor Sx. • Stimulate endometrium. • Incerase venous thrombosis

20. Is other pharmacotherapy beneficial for the prevention and treatment of osteoporosis? • Salmon calcitonin is available for osteoporosis treatment. • S.C. inj. or nasal spray • Reduce lumbar spine Fx(36%) at a dose 200U per day, but did not reduce hip Fx. • Reduce bone turnover, but bone density change are small(1 %). • Reduce bone pain of osteoporotic compression Fx. • S/E : nausea, local inflammation(inj.), flush of face and hands, nasal irritation. • Recombinant human PTH • Increase trabecular bone density and connentivity. • Use in case of failed response to other therapy or very severe disease. • Reduce vertebral Fx 53-54%. • Expensive and needs daily injection. • PTH is significantly reduced when co-administration with bisphosphonates; therefore, they should not be combined. • Fluoride increase bone brittleness and propensity to fracture. • Testosterone effect is not clear.

21. Is other pharmacotherapy beneficial for the prevention and treatment of osteoporosis? • Combinations of Antiresorptive Therapies • Addition of progesterones, addition of androgens can have additive effect on bone mineral density. • Risedronate, alendronate and raloxifen 은 실험으로 병용 시 bone mineral density 증강(1-3%)의 효과가 있음이 입증됨. • 이 결과가 fracture protection 에도 효과적인지는 아직 밝혀진 바 없음. • Calcium and vit.D should be considered adjuvant therapy for individual.

22. Are complementary and alternative therapies beneficial for the prevention of osteoporosis? • Isoflavones (a class of phytoestrogens found in rich supply in soybeans and red clover) studies has not demonstrated a reliable positive effect on bone density, bone turnover marker, or fracture risk in woman with osteoporosis

23. When should treatment for osteoporosis begin and how should patients be followed? • T score 1 SD decrease = 10-12% change in bone mineral density. • Low risk of fracture in young women with osteopenia • High cost long term side effect led to suggest withholding treatment until certain theraputic threshold have been reached. • The National Osteoporosis Foundation • T score -2 without risk factor • T score -1.5 with risk factor

24. When should treatment for osteoporosis begin and how should patients be followed? • Monitoring of treatment requires central bone densinometry. • Precision : 2-3% • Repeat DXA testing • untreated post menopausal 은 per 3-5 years • Treatment 받는 동안은 치료의 효과를 monitor 하기 위해 2년 마다 한번씩 시행한다. • 4-5% 의 mineral density loss 가 있을 때는 치료의 방법을 변화하는 것이 필요하다.

25. Summary of Recommendations • Recommendations based on good and consistent scientific evidence (Level A) • Treatment should be initiated to reduce fracture risk in postmenopausal women who have experienced a fragility or low-impact fracture. • T scores less than -2 by central DXA in the absence of risk factor and less than -1.5 with 1 or more risk factor. • First-line pharmacologic options determined by the FDA to be safe and effective for osteoporosis prevention (bisphosphonate [alendronate and risedronate], raloxifene, and estrogen) should be used. • First-line pharmacologic options determined by the FDA to be safe and effective for osteoporosis treatment (bisphosphonate [alendronate and risedronate], raloxifene, calcitonin, and PTH) should be used.

26. Summary of Recommendations • Recommendations based on limited or inconsistent evidence (Level B) • Women should be counseled about the following prevention measures • Adequate calcium consumption, using diatary supplements if dietary sources are not adequate • Adequate vit.D consumption(400-800 IU per day) • Regular weight-bearing and muscle-strengthening exercises • Smoking cessation • Moderation of alcohol intake • Fall prevention strategies • Bone mineral density testing should be recommended • to all postmenopausal women over 65 yrs • To younger than 65 yrs with risk factor • To all menopausal women with fracture to confirm the diagnosis of osteoporosis and determine disease activity • Screening should not be performed more frequently than every 2 yrs without new risk factors.