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비스포스포네이트 장기 치료의 효과와 안정성. 서울아산병원 내분비내과 고 정 민. 골다공증 치료제. 칼슘 , 비타민 D 골흡수 억제제 : 에스트로겐 선택적 에스트로겐 수용체 변형체 비스포스포네이트 칼시토닌 골형성 촉진제 : Teriparatide (PTH1-34) 스트론튬 (Strontium Ranelate). 치료 제 비교 : 골절 감소 효과.
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비스포스포네이트 장기 치료의 효과와 안정성 서울아산병원 내분비내과 고 정 민
골다공증 치료제 • 칼슘, 비타민 D • 골흡수 억제제: 에스트로겐 • 선택적 에스트로겐 수용체 변형체 • 비스포스포네이트 • 칼시토닌 • 골형성 촉진제: Teriparatide (PTH1-34) • 스트론튬 (Strontium Ranelate)
비스포스포네이트 제재 결합력 O O-P O- R1 C R2 O-P O- O 효능
대사 및 분포 • 경구 투여 시 생체 이용률: 0.9 ~ 1.8% • 생체 내 대사가 없음 • 약제 분포: • 뼈에 특이적으로 결합 (흡수된 양의 40 ~ 60%) • 제거: 1. 소변으로 제거 • 2. 골 교체가 일어날 때 뼈로부터 제거 • 약제를 투여하여 제거할 방법이 없다.
Alendronate 20 mg Alendronate 5 mg Placebo Pharmacokinetics • Very little accumulation in bone • For 10 yrs, total 75 mg in whole skeleton • After stopping, 6 g/day release • After stopping, suppressed bone turnover for at least 5 yrs.
Another Mechanisms • 조골세포 표면의 RANKL 감소 • 파골세포 형성 억제 • 조골세포로의 분화 촉진 • 조골세포와 osteocyte의 세포자멸사 억제
골재형성 (Bone Remodeling) • 역할: 1) 복구 기전:새로운 뼈로 교체 골력의 유지 • 2) 칼슘 항상성 • High bone turnover rate in post-menopause • - 3 times for pre-menopause • - New bone remodeling before full mineralization • - Decreased BMD & deterioration of bone microarchitecture
Reduction of Fracture by Antiresorptives • Suppression of increase in bone resorption • Increased bone mass • - Time differences between resorption & formation • - Secondary mineralization
Resorption vs. Fracture Reduction • Not closely linked to the increase in bone density • No proven effects of combination of resorptive agents for fracture reduction • Risedronate hip study (McClung et al. N Engl J Med, 333) - 5.0 mg/day vs. 2.5 mg/day - Further increased BMD & decreased bone turnover - No further reduced fracture risk
Physiological Range Optimal Reduction of Bone Turnover • Insufficient turnover • Accumulation of microdamage • Increased brittleness due to excessive mineralization • Excessive turnover • Increase in stress risers (weak zones) • Increase in perforations • Loss of connectivity Bone Strength Bone Turnover
Adequacy of Suppressed bone resorption By bisphosphonates?
Raloxifene Risedronate Alendronate Zoledronate Reduction Bone Turnover
Preclinical Animal Studies • Marked reduction in • bone turnover • Increased bone • volume and density • Doubling of • mechanical strength • Fracture healing was • not impeded Risedronate Alendronate
In Human … Using bone biopsy, With usual doses of the bisphosphonates Suppression of bone-forming surface by 60-90%
How long Suppressed bone resorption By bisphosphonates?
No Accumulation of Bone Turnover Urinary NTx BSAP
Number of Fractures in 10 yrs (FLEX) FIT ALN for 5 years PBO (N=437) ALN 10mg (N=333) ALN 5 mg (N=329) Clinical spinal fractures RR 0.45 [0.23-0.84] Non-spine fractures RR 1.00 [0.76-1.32] Morphometric fracture RR 0.87 [0.61-1.25]
Delayed/Absent Fracture Healing Bishphosphonate therapy in osteoporotic patients should be stopped after 5 years, pending additional research
Normal Patients OB Osteoid OC Normal Patients
….it seems reasonable to suggest discontinuation for some indefinite period of time after 5 years of use in younger lower-risk postmenopausal women. Miller PD Expert Opin Pharmacother 2003 4:2253 • …bisphosphonate therapy in osteoporotic patients should be stopped after 5 years, pending additional research Ott SM J Clin Endocrinol Metab 2005 90:1897
Osteonecrosis of the Jaw (ONJ) • No universally accepted definition • of ONJ • Typically appears as an area of • exposed alveolar bone that can • occur in the mandible or maxilla. • It may or may not be painful. • It may or may not beassociated with infection or local • trauma. • First report: 2003 • In many, occurrence after recent dental pathology, trauma, • or oral surgery.
Osteonecrosis • Most were treated with IV bisphosphonate • had very poor oral health • had serious comorbidities such as cancer • Much smaller number of cases • of ONJ have been associated • with oral bisphosphonates used • at lower doses to treat • osteoporosis / Paget’s disease. • Millions of osteoporosis patients are estimated to • have taken oral bisphosphonates. Other 6% Prostate Ca. 5% Osteoporosis 13% MM 44% Breast Ca 32%
Figure 1. Time to the Onset of Osteonecrosis of the Jaw in Patients with Myeloma Receiving Zoledronic Acid or Pamidronate. Durie et al., N Engl J Med 353:99, 2005
Osteonecrosis • Many also had a medication history, such as • chemotherapy or corticosteroids. • No ONJ in RCT for osteoporosis • - > 60,000 patient-years of exposure • - Recently, ON of external auditory canal • By Council on Scientific Affairs of the American Dental • Association • - 170 ONJ with ALN, and 20 with RISE • ASBMR Task Force Team on ONJ …
Conclusions • Short-term reduction of bone turnover: no problem • Low risk of long-term reduction of bone turnover, such as brittle • bone and ONJ • No proven effects of additional 5 year treatment for • fracture reduction • Although it was very low, possible risk for delayed fracture • healing or ONJ • - Long-term medications (> 5 years?) • - According to co-morbidities or co-medications • Five years treatment Switch with another drugs, or • skipping?