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  • Osteoporosis is a disease that simply can’t be ignored. The statistics are mind boggling ! In USA alone there are 10 million ppl….. Out of which 80 % are women. Also about 10 % of US population ( 33 million) have weak bones i.e. osteopenia.
  • Here we can see the immense fracture risk ass. with the disease. More than 2 million fractures occur per year in patients with either osteo…or osteo… Out of which majority are vertebral # f/b hip # f/b pelvic #.
  • Out of these 3, maximum morbidity and mortality is assoc. with hip #. As you can see after sustaining hip #, half of the people loose their mobility and a quarter loose skills to live independently. A recent metaanalysis showed increase in rate of death by 5- 8 times after a hip #.
  • This graph shows the relevance of recognizing osteoporosis as a major disease. As you can clearly see it far out numbers the other 3 major illnesses.
  • Coming to the definition , This disease has three components: loss of mass and architecture and fragility . Who DEFINES OSTEOPOROSIS AS t SCORE OF -2.5 AS DIAGNOSTIC. Definition of t score and z score……?
  • Following are the risk factors which predispose to osteoporosis: elderly caucasian female, low BMI, h/o personal or parental fracture , rheumatoid arthritis, chronic alcoholic, smoking.
  • As per the NOF guidelines, the recommendations for screening are women ……
  • This is the WHO’s fracture risk assessment tool called FRAX which takes into account the prior mentioned risk factors and calculates their 10 year risk of fracture. This is used to guide management of patient's with osteopenia.
  • So, Who to treat ? As per the NOF guidelines …. For T score b/w -1 to – 2.5, we go by the FRAX risk score.
  • As we all know calcium and vitamin d are useful for prevention and treatment of osteoporosis. These are the sources rich in calcium and vitamin D. Weight bearing exercise plays an important part in management as well.
  • The mainstay of treatment is bisphosphonates. Alendronate was the first bisphosphonates approved in US f/b rise.., f/b iband…and the most recent one is zoledronate.
  • This slide gives an overview of different therapeutic strategies for osteoporosis. Bisphosphonates act by inhibiting bone resorption. Many other modalities including estrogen, serms, calcitonin, denosumab act by inhibiting bone resorption.Few of the treatment are aimed at stimulation of bone formation . PTH analog Teriparatide is the only FDA approoved agent which is an anabolic agent.
  • Now, I will be talking about 2 major trials looking at the efficacy of bisphosphonates. This is one of the earlier trials looking at the effect of alendronate on risk of # in women with existing vertebral #.
  • They found that the risk of morphometric as well as clinical vertebral fracture was significantly reduced in the alendronate group.
  • Also the incidence of hip and wrist # was also significantly reduced in the alendronate group.
  • This is one of the major trial on zoledronic acid infusion. It is given as once a year iv infusion for osteoporosis.. The advantages are 1. compliance is confirmed. And Gi side effects are less common.
  • The major findings in this trial were that there was significant reduction in the incidence of hip, vertebral or any clinical #.
  • Taking bisphophonate involves certain essential steps which have to be conveyed to the patient. Only 1 % of the drug ingested per dose is absorbed. The medication has to be taken empty stomach with 6- 8 ounces of water.Patient needs to stay upright for atleast 30 – 60 min after that Even with complete instructions, 25 – 50 % patients disregard at least one requirement. Coffee, juice, even calcium supplements can interfere if taken simultaneously..
  • The CI include….
  • There has been considerable discussion about how long to treat with bisphosphonates. This does not come up with other diseases such as HTN, hyperlipidemia. For these diseases, benefits of treatment disappear on stopping drugs. However, Bispho. Accumulate in the bone for years. There is no standard of care on this but numerous opinions exist.. As per one expert opinion, duration should be individualized and should be based on risk factors. Patient with high risk should be treated for 10 years , then a holi……….., Patients who deserve treatment should have min. duration of 5 years , then holiday and resumption of drug depends on risk factors.
  • ONJ is defined as Exposed necrotic bone in maxillofacial region, not healing > 6-8 weeks with no prior h/o cranio- facial radiation.60 % of the cases have been found to follow dental surgical procedure. Pain/swelling/suppuration/paresthesia/soft tissue ulceration/sinus tracts/loose teeth..The First report came in 2003. These are all post marketing trial . They looked retrospectively in patients in the HORIZON trial, they found one case each in placebo and ZA group.
  • This slide shows the difference in incidence of ONJ in patient with skeletal mets vs osteoporosis. The reporting rate has been 1 ……….. As compared to patients with malignancy and mets ,in whom incidence is much higher.The main reason behind the difference is that patients with sk mets require higher and more frequent doses/
  • The risk factors for ONJ are high dose frequent dosing of Iv bisphosphonates as in cancer patients ,patients on chemo/ chronic steroids, dental extraction/ dental surgical procedure , prior periodontal disease ,alcohol/smoking. LONG duration of treatment. poorly fitting dental appliances and intraoral trauma.
  • Patients should be informed about the risk of developing ONJ, good dental hygiene is recommended. Endodontic treatment is preferred to dental extraction or surgery.
  • ThThe usual osteoporotic hip # occurs at femoral neck or intertrochanteric site. This atypical fracture has been found to occur below the lesser trochanter and above the supracondylar flare. It may be assoc. with Prodromal groin or thigh pain for weeks to months. This # has characteristic radiological findings…transverse or short oblique, medial cortical spike and cortical hypertrophy
  • Prolonged tx with BPs decreased structural integrity at the femoral shaft. This corresponds with the occurrence of this type of transverse subtrochanteric fracture clinically. The published and unpublished data reviewed show these atypical fractures occur in less than 1 in 10000 pts and many more fractures are prevented by these medications. The risk-benefit ratio clearly favors treatment with bisphosphonates. ASBMR position statement : The published and unpublished data reviewed show these atypical fractures occur in less than 1 in 10000 pts and many more fractures are prevented by these medications. The risk-benefit ratio clearly favors treatment with bisphosphonates. Patients should be aware of this and report thigh pain and continue current medications as directed. Physicians should also be aware and follow prescribing instructions and report side effects to the FDA.
  • The HORIZON pivotal trial showed a significant increased incidence of serious a fib. 1.3 % vs 0.5 %. But no statistically sig. Increase in incidence was found in the HORIZON recurrent # trial (small/short study), or FIT or VERT trial. A recent meta analysis did show ass. With risk of serious A fib but no risk of stroke or CV mortality.
  • Esophageal cancer has been a concern in patients on oral bisphosphonates. Over the past 2 decades, FDA has received 23 case reports from USA. 31 cases from Japan/Europe. Current data do not support a causal ass. b/w oral bisphosphonates $ eso. Ca.
  • Adverse effects on kidneys after iv infusion depends on peak conc, dose and rate of infusion. Risk is lowered by decreasing rate of infusion and hydrating prior to infusion.
  • Treasure your and your patient’s bones !!!

Transcript

  • 1. Osteoporosis
  • 2. Learning objectives :
    • Burden of the disease.
    • Screening and treatment guidelines.
    • Bisphosphonates.
    • Controversial topics : Association of bisphosphonates with
      • ONJ
      • Atypical femoral fractures
      • Atrial fibrillation.
      • Esophageal cancer.
  • 3. Burden of Disease
    • 10 million people in US have Osteoporosis
    • 33 million people in US have Osteopenia.
    • Bone health and osteoporosis: Department of health & human services 2004.
  • 4. Burden of Disease
    • > 2 million fractures/year due to either.
      • 300,000 HIP fractures.
      • 547,000 vertebral fractures.
      • 135,000 pelvic factures.
      • Bone health and osteoporosis: Department of health & human services 2004.
  • 5. Burden of Disease :
    • Hip fractures :
    • 50 % Permanent impaired mobility.
    • 25 % Loose skills to live independently.
    • Increased all cause mortality : first 3 months after hip fracture.
      • 1.2010 position statement of the North American Menopause Society. Menopause 2010.
  • 6. Annual incidence
  • 7. Osteoporosis
  • 8. Risk factors
  • 9. Who to screen
    • Women > 65 years.
    • Men > 70 years.
    • Postmenopausal women /men >50 years with clinical risk factors.
    • H/o fracture at age > 50 years.
    • Chronic steroid use.
  • 10.  
  • 11. Who to treat ? Prior h/o hip/vertebral # or T Score < -2.5 or T Score -1 to -2.5 & 10 yr risk (FRAX) : HIP # > 3 % or major osteoporotic # > 20 % Postmenopausal women /men > 50 yrs with
  • 12. Calcium and vitamin D
  • 13. Mainstay of treatment :
    • Bisphosphonates
    • Approval in US for osteoporosis
    • Alendronate : 1995
    • Risedronate : 2000
    • Ibandronate : 2005
    • Zoledronate : 2007.
  • 14. Bone marrow precursors Osteoblasts Osteoclast Lining cells Stimulators of Bone Formation Fluoride PTH analogs Sr Ranelate (?) Inhibitors of Bone Resorption Estrogen, SERMs Bisphosphonates Calcitonin Inhibitors of RANKL Cathepsin K Therapeutic strategies
  • 15. THE LANCET Vol 348 • December 7, 1996 Clinical Evidence
  • 16.  
  • 17.  
  • 18.  
  • 19.  
  • 20. Taking Bisphosphonates
  • 21. Contraindications
  • 22. Duration of treatment
  • 23. Cost factor
    • Alendronate: $4 - $40/month
    • Risedronate : $60 - $120/month
    • Ibandronate (oral): $90 - $130/month
    • IV Ibandronate : $1300/year
    • IV Zoledronate : $1300/year
  • 24. Hot topics
  • 25. Osteonecrosis of jaw
  • 26. ONJ
    • Osteoporosis :
      • Reporting rate 1/100,000 - 1/250.000.
      • True incidence may be higher.
    • Malignancy/skeletal metastasis :
      • Estd. Incidence: btw 1- 10 %
  • 27. Risk factors
  • 28. Recommendations
  • 29. Atypical fractures
  • 30. Atypical fractures
    • ? Long term over suppression of bone turnover.
    • Incidence : 1 in 10,000.
    • Associated median treatment duration : 7 years.
    • Causality : long term bp/ atypical # unproven.
    • Further large scale studies needed.
  • 31. Recommendations
    • Educate physician/patient about Prodromal pain.
    • Evaluate with urgent X-Ray.
    • If negative, may consider MRI.
    • Stop BP’s if atypical fracture confirmed.
    • Shane et al. ASBMR task report. J Bone Miner Res. 2010
  • 32. Atrial fibrillation
    • FDA recommends physicians to not alter their prescribing patterns while it continues to monitor post marketing reports of AF in such patients.
    • In v/o above and absence of definitive data : Benefits of treatment outweigh risks.
  • 33. Esophageal cancer
    • 23 cases reported in last 2 decades. (Wysowski et al)
    • 31 cases from Europe/Japan.
    • Median time from use to diagnosis : 1-2 yr.
    • Time from exposure inconsistent w/ causal relation.
    • Further studies needed.
  • 34. Renal safety
    • Safe for creatinine clearance > 30 -35 ml/min.
    • Lack of experience < 30 ml/min.
    • No data for use in ESRD.
    • Exact bone disease unknown unless biopsy.
    • Expert opinion: half the dose could be used for 3 years in ESRD once bone biopsy confirms osteoporosis.
  • 35. Take home points
    • Osteoporosis : significant burden of disease.
    • Main stay treatment : bisphosphonates.
    • ? Duration of treatment : individualized.
    • More research needed to confirm association with ONJ, Subtrochanteric fracture.
    • Benefits of treatment outweigh risks in osteoporosis.
  • 36.