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美 FDA, 'PPI 제제 골절 위험 높일 수 있다' 주의




지난 5월 17일자 Research Trends Sharing 8호에서 다룬 PPI(Proton pump inhibitor, 양자 펌프 억제제) 사용과 골절 관련 논문 발표 이후 FDA에서 PPI와 골절 위험에 대해 공식적으로 언급했습니다.

관련링크 : FDA Drug Safety Communication: Possible increased risk of fractures of the hip, wrist, and spine with the use of proton pump inhibitors

FDA는 25일 웹사이트와 이메일을 통해 '여러 역학조사를 검토한 결과 위궤양 치료에 사용하는 양자 펌프 억제제 (PPI 제제, eg. 오메프라졸 등)가 고관절, 팔목, 척추 골절 위험을 높인다고 발표했습니다. 특히 고용량 PPI 처방을 받을 경우 그 위험이 높아진다는 역학조사가 있었다고도 밝혔습니다.

이에따라 의사들은 PPI 사용에 따른 골절 위험에 대해 숙지하고 사용 전 약물 사용에 따른 환자의 득과 실에 대해 검토할 것을 권했습니다.

PPI는 위궤양이나 위식도 역류, 식도염 치료 및 약물로 인한 위장 손상 예방을 위해서 사용되고 있으며 현재 PPI 제제를 복용 중인 환자라고 하더라도 이 소식을 듣고 약물을 중단할 필요는 없습니다. 골절 위험이 매우 높아진 경우는 수년간 고용량으로 복용한 일부 환자들이었습니다만, 관련하여 걱정이 된다면 주치의와 상담을 먼저 하시길 당부드립니다.

FDA가 리뷰한 논문들 정보는 아래 표에서 확인하실 수 있습니다.

Table of epidemiological studies evaluating fracture risk with proton pump inhibitors
Study  
Study Time Period
Study Population
Findings related to Proton Pump Inhibitors (PPIs)
Vestergaard 20061/1/2000 12/31/2000
  • 124,655 cases with fractures
  • 373,962 matched controls
  • All ages Data source: Denmark health database1

PPI use within the last year

  • Overall fracture risk, Odds Ratio (OR) = 1.18 (95% CI, 1.121.43)
  • Risk of hip fracture, OR = 1.45 (95% CI, 1.281.65)
  • Risk of spine fracture, OR = 1.60 (95% CI, 1.252.04)
  • Risk of forearm fracture, OR = 0.95 (0.82-1.11)
  • No dose-response relationship seen with PPIs and fracture risk:
    (DDD [defined daily doses] were the number of doses in a year)
Yang 20061987 - 2003
  • 13,556 cases with fractures
  • 135,386 matched controls
  • Ages ≥ 50 years
  • Data source: U.K./GPRD2
  • Risk of hip fracture, PPI use > 1 year
    adjusted Odds Ratio (aOR)± = 1.44 (95% CI, 1.301.59)
  • Risk of hip fracture increased with high-dose PPI use > 1 year:
    (dose defined as dose/day, >1.75 doses/day)
    aOR = 2.65 (95% CI, 1.80-3.90)
  • Risk of hip fracture increased with longer duration of PPI use
    • 1 yr, aOR = 1.22 (95% CI, 1.15-1.30)
    • 4 yr, aOR = 1.59 (95% CI, 1.39-1.80)
Targownik 20081996 - 2004
  • 15,792 cases with fractures
  • 47,289 matched controls
  • Ages ≥ 50 years
  • Data source: PHRDR/3Manitoba, Canada
  • Risk of hip, wrist, spine fractures with PPI use ≥ 7 years
    adjusted Odds Ratio (aOR) = 1.92 (95% CI, 1.163.18)
  • Risk of hip fracture increased with longer duration of use
    • PPI use ≥ 5 years, aOR = 1.62 (95% CI, 1.022.58)
    • PPI use ≥ 6 years, aOR = 2.49 (95% CI, 1.33-4.67)
    • PPI use ≥ 7 years, aOR = 4.55 (95% CI, 1.6812.29)
Kaye
2008  
1995 - 2005
  • 1,098 cases with fractures
  • 10,923 matched controls
  • Ages 50 70 years
  • Data source: U.K/GPRD2
  • Estimated Relative Risk (RR) of hip fracture = 0.9 (95% CI, 0.71.11) (Patients at risk for fracture were excluded from the analysis) 
  • Risk of hip fracture not detected with increased number of PPI prescriptions
Corley
2010
1995-2007
  • 33,752 cases with fractures
  • 130,471 matched controls
  • Ages ≥ 18 years
  • Data source: KPNC/4California, USA
  • Risk of fracture with ≥ 2 years of PPI use and 1 other risk factor
    Odds Ratio (OR) = 1.30 (95% CI, 1.211.39)
    • Risk factors: alcohol abuse, arthritis, diabetes, kidney disease, glucocorticoids, cerebrovascular disease, dementia, epilepsy, gait disorder, hemiplegia, psychoses, smoking, visual impairment, anxiolytic use
  • Risk of fracture increased with higher PPI dose:
    (dose = number of pills per day >1.5)
    OR = 1.41 (95% CI, 1.21-1.64)
  • Risk of fracture did not consistently increase with longer duration of use
Yu
2008

Women: 7.6 years mean follow-up  

Men: 5.6 years mean follow-up  

  • Women (4,574 non-PPI users and 234 PPI users)
  • Men (4,920 non-PPI users and 487 PPI users) Ages ≥ 65 years
  • Data source: MrOS/SOF5
  • Risk of hip fracture
    • Women: adjusted Relative Hazard (aRH) = 1.16 (95% CI, 0.80-1.67)
    • Men: aRH = 0.62 (95% CI, 0.26-1.44)
  • Risk of nonspine fracture
    • Women: aRH = 1.34 (95% CI, 1.10-1.64)
    • Men: aRH = 1.21 (95% CI, 0.91-1.62)
Gray
2010
7.8 years, mean follow-up
  • 2,831 PPIs users
  • 127,756 non-PPIs users
  • Post-menopausal women ages 50 79 years
  • Data source: WHI OS/WHI CT6
  • Risk of total fractures
    adjusted Hazard Ratio (aHR) ≠ = 1.25 (95% CI, 1.15-1.36)
  • Risk of hip fracture, aHR = 1.00 (95% CI, 0.71-1.40)
  • Risk of spine fracture, aHR = 1.47 (95% CI, 1.18-1.82)
  • Risk of wrist fracture, aHR = 1.26 (95% CI, 1.05-1.51)
  • No consistent trend for fracture risk with duration of use

Data Source: 1. Denmark Health Database; 2. United Kingdom, General Practice Research Database; 3. Population Health Research Data Repository (Manitoba, Canada); 4. Kaiser Permanente Northern California; 5. Osteoporosis fractures in Men Study/Study of Osteoporotic Fractures; 6. Women's Health Initiative Observation Study/Women's Health Initiative Clinical Trials

± Adjusted for sex, age, body mass index, medication use (anxiolytics, antidepressants, NSAID/aspirin, thiazide diuretic, antipsychotic, antiparkinsonian, antiseizure, hormone therapy, corticosteroid, thyroxine), health condition (alcoholism, arthritis, stroke, asthma or COPD, dementia, diabetes mellitus, congestive heart failure, impaired mobility, myocardial infarction, peptic ulcer disease, seizure disorder, peripheral vascular disease, visual impairment, current smoker, prior fractures).

Adjusted for income, region of residence, diagnoses (short or long-term diabetes, epilepsy, ischemic heart disease, myocardial infarction, hypertension, arthritis, solid organ transplant, chronic obstructive pulmonary disease, substance use, depression, schizophrenia, dementia), home care use and multiple medications.

Adjusted for age, clinic, race, body mass index, alcohol use, exercise, oral or inhaled corticosteroid use, NSAID use, calcium supplement use, osteoporosis medication use, and self-reported health, concurrent weight change, and initial total hip bone mineral density. SOF group is also adjusted for caffeine intake and estrogen use. MrOS group is also adjusted for smoking and history of stomach surgery.

≠Adjusted for age, race/ethnicity, body mass index, enrollment in clinical trial status, indicator for cohort, smoking, physical activity (metabolic equivalent tasks), self-reported health, having a parent who broke a hip after age 40 years, treated diabetes mellitus, history of fracture at 55 years or older, and corticosteroid use, physical function score, history of myocardial infarction or angina, asthma or emphysema, arthritis, stomach or duodenal ulcer, moderate or severe heartburn, osteoporosis, number of psychoactive medications, and use of hormone therapy and bisphosphonates. 

   

References:

1. Vestergaard P, Rejnmark L, Mosekilde L. Proton pump inhibitors, histamine H2

receptor antagonists, and other antacid medications and the risk of fracture. Calcif Tissue

Int. 2006;79:76-83.

2. Yang YX, Lewis JD, Epstein S, Metz DC. Long-term proton pump inhibitor therapy

and risk of hip fracture. JAMA 2006;296:2947-53.

3. Targownik LE, Lix LM, Metge CJ, Prior HJ, Leung S, Leslie WD. Use of proton pump

inhibitors and risk of osteoporosis-related fractures. CMAJ 2008 Aug 12;179(4):319-26.

4. Kaye JA, Jick H. Proton pump inhibitor use and risk of hip fractures in patients

without major risk factors. Pharmacotherapy 2008;28:951-59.

5. Corley, D.A., Kubo, A., Zhao, W., Quesenberry, C., Proton Pump Inhibitors and Histamine-2 Receptor Antagonists are Associated with Hip Fractures among At-Risk Patients,Gastroenterology (2009), doi:10.1053/j.gastro.2010.03.055.

6. Gray SL, LaCroix AZ, Larson J, Robbins J, Cauley JA, Manson JE, Chen Z. Proton Pump Inhibitor Use, Hip Fracture, and Change in Bone Mineral Density in Postmenopausal Women. Arch Intern Med 2010;170 (9):765-771.

7. Yu EW, Blackwell T, Ensrud KE, Hillier TA, Lane NE, Orwoll E, Bauer DC, et al. Acid-Suppressive Medications and Risk of Bone Loss and Fracture in Older Adults. Calcif Tissue Int. 2008;83(4):251-259.

8. Targownik LE, Lix LM, Leung S, Leslie WD. Proton-pump inhibitor use is not associated with osteoporosis or accelerated bone mineral density loss. Gastroenterology 2010;138:896-90


양광모  editor@healthlog.kr

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