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Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Is Bisphosphonates Road To Block Osteoporosis Saf...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
PHARMACOKINETICS

Inverse relation between pharma...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
TYPES OF BISPHOSPHONATES

NON-NITROGENOUS
Olpadro...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
5
Bisphosphonates – Antiresorptive Agents
FDA-app...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
6
6
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
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Bisphosphonates – Dosing
Alendronate*
Preventio...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
High attraction for hydroxyapatite crystals
and t...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Anti-resorptive
Anabolic
‘Dual action’
!
Alendron...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
10
Osteoporotic bone remodelling
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
!
Hwang and Wang, 2007
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
12
Bone Remodelling With Alendronate
Gets prefere...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
OVERALL EFFECT:!
!
Less trabecular thinning
!
Dec...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
MECHANISM OF ACTION

Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Bone marrow precursors
Osteoblasts
Osteoclast
Lin...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
19
Bisphosphonates – Administration
Must be taken...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
20
Bisphosphonates – Missed Dose
Once weekly alen...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
21
Bisphosphonates – Adverse Effects
Hypocalcemia...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
22
Contraindications/Precautions
!
Abnormalities ...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Contraindications
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24
Zolendronic Acid
Approved for osteoporosis tre...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
25
Bisphosphonates – Clinical Efficacy
Controlled ...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
26
Bisphosphonate Therapy - Risks
Initial studies...
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27
Osteonecrosis Of Jaw
Exposed necrotic bone in ...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
BISPHOSPHONATE RELATED

OSTEONECROSIS OF THE JAW ...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
WHY DOES BONJ ONLY AFFECT THE MAXILLOFACIAL
SKELE...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
31
Femoral Shaft Fractures
In 2005, Odvina et al ...
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32
Atypical Fractures of the Femoral Diaphysis in...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
33
Femoral Shaft Fractures
Usually occur in the p...
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34
Atypical Femoral Fracture
Shane et al, JBMR 25...
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35
Bisphosphonate Use and the Risk of
Subtrochant...
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36
Summary
716 (0.35%) suffered a subtrochanteric...
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Bisphosphonates for Osteoporosis
— Where Do We...
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38
How Long to Treat With
Bisphosphonates?
1.Pati...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!39
Whom to treat ?
Prior h/o hip/vertebral #
or
T ...
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40
Proposed Guidelines for Use of
Bisphosphonates...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
THE “DRUG HOLIDAY”
Suggested that cessation of th...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
42
*
*Use FRAX to estimate risk
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
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NOF’s Clinician’s Guide
Applies the recently r...
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When Should the Holiday End?*

Arbitrary* - Lo...
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45
Hot topics
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46
Bisphosphonates for Osteoporosis
- Summary
Ris...
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47
www.hormone.org
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No known Metabolism of the drug in Vivo!
!
Rem...
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49
Bisphosphonate Therapy Benefits
Decreased risk...
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50
A single infusion of ZOLENDRONATE 5 mg reduced...
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51
Safety:
Five most common Post-Dose Symptoms (≤...
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Reduce frequent dosing with bisphosphonates may
i...
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•Herbert Fleisch. Bisphosphonates: Mechanisms of ...
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Thank you
Keep your bone healthy
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
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Bisphosphonates for osteoporosis where do we go from here? is bisphosphonates road to block osteoporosis safe dr.sandeep c agrawal agrasen hospital gondia india www.agrasenortho.com

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Bone Loss Trabeculae,Wedging,BMD,T score,Z Score,Vitamin D3,Calcium Deficiency,Osteomalacia,Hip Fracture Osteoporotic compression fracture,Serum Calcium,Serum Phosphorus,Serum Vitamin D,Serum 1,25 dihydroxry cholecalcirol,Urine pH,Urine Calcium,Avascular Necrosis of femoral Head,Zolendronic acid,Alendronic acid,Risedronate,Osteoporosis,OSTEOPOROSIS - Silent Bone Disease -Hidden Facts,Red Flags,Prevention & Treatment http://www.slideshare.net/sandeepcagrawal/silent-bone-disease-osteoporosis-hidden-factsred-flagsprevention-treatment-drsandeep-c-agrawal-agrasen-hospital-gondia-india


CALCIUM METABOLISM:VITAMIN D-PARATHYROID-CALCITONIN ROLE(Rickets,Osteoporosis,Renal Osteodystrophy) Prevention.
http://www.slideshare.net/sandeepcagrawal/calcium-homeostasis-vitamin-dparathyroidcalcitonin-role-ricketshypercalcemiahyperparathyroidismosteoporosisrenal-osteodystrophy-prevention-drsandeep-c-agrawal-agrasen-hospital-gondia-india
APPROACH TO CHILD WITH RICKETS Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com

http://www.slideshare.net/sandeepcagrawal/approach-to-child-with-rickets-drsandeep-c-agrawal-agrasen-hospital-gondia-india-wwwagrasenorthocom

Understanding Rickets-Types,Diagnosis,Prevention & Treatment

http://www.slideshare.net/sandeepcagrawal/understanding-rickets-typesdiagnosisprevention-treatment-drsandeep-c-agrawal-agrasen-hospital-gondia-india

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  • Bone Loss Trabeculae,Wedging,BMD,T score,Z Score,Vitamin D3,Calcium Deficiency,Osteomalacia,Hip Fracture Osteoporotic compression fracture,Serum Calcium,Serum Phosphorus,Serum Vitamin D,Serum 1,25 dihydroxry cholecalcirol,Urine pH,Urine Calcium,Avascular Necrosis of femoral Head,Zolendronic acid,Alendronic acid,Risedronate,Osteoporosis OSTEOPOROSIS - Silent Bone Disease -Hidden Facts,Red Flags,Prevention & Treatment http://www.slideshare.net/sandeepcagrawal/silent-bone-disease-osteoporosis-hidden-factsred-flagsprevention-treatment-drsandeep-c-agrawal-agrasen-hospital-gondia-india Percutaneous Vertebroplasty and Osteoporotic Spinal Compression Fracture Treatment. http://www.slideshare.net/sandeepcagrawal/osteoporotic-compression-fracture-and-percutaneous-vertrebroplasty-drsandeep-c-agrawal-agrasen-hospital-gondia-maharashtra-india CALCIUM METABOLISM:VITAMIN D-PARATHYROID-CALCITONIN ROLE(Rickets,Osteoporosis,Renal Osteodystrophy) Prevention. http://www.slideshare.net/sandeepcagrawal/calcium-homeostasis-vitamin-dparathyroidcalcitonin-role-ricketshypercalcemiahyperparathyroidismosteoporosisrenal-osteodystrophy-prevention-drsandeep-c-agrawal-agrasen-hospital-gondia-india APPROACH TO CHILD WITH RICKETS Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com http://www.slideshare.net/sandeepcagrawal/approach-to-child-with-rickets-drsandeep-c-agrawal-agrasen-hospital-gondia-india-wwwagrasenorthocom Understanding Rickets-Types,Diagnosis,Prevention & Treatment http://www.slideshare.net/sandeepcagrawal/understanding-rickets-typesdiagnosisprevention-treatment-drsandeep-c-agrawal-agrasen-hospital-gondia-india
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Bisphosphonates for osteoporosis where do we go from here? is bisphosphonates road to block osteoporosis safe dr.sandeep c agrawal agrasen hospital gondia india www.agrasenortho.com

  1. 1. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! Is Bisphosphonates Road To Block Osteoporosis Safe ? Bisphosphonates for Osteoporosis — Where Do We Go from Here? Dr.Sandeep Agrawal Consultant Orthopedic Surgeon MS,DNB Agrasen Hospital Gondia Maharashtra India drsandeep123@gmail.com www.agrasenortho.com 09960122234 Osteoblasts Osteoclast Lining cells Inhibitors of RANKL Cathepsin K THE BISPHOSPHONATES “DRUG HOLIDAY”
  2. 2. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! PHARMACOKINETICS
 Inverse relation between pharmacologic activity & oral bioavailability! ! Absorption by passive diffusion from gut! ! Milk & dairy products, orange juice, coffee and calcium and iron products reduce absorption (Form insoluble complexes)! ! Bound to plasma proteins! ! 20-80% of the absorbed dose is rapidly taken up by bone. ! Remainder is rapidly excreted in urine! ! Long skeletal retention (half life up to 10 years)
  3. 3. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! TYPES OF BISPHOSPHONATES
 NON-NITROGENOUS Olpadronate  NITROGENOUS Tiludronate Clodronate  Etidronate  Alendronate  Neridronate  Pamidronate  Risedronate  Ibandronate  Zoledronate
  4. 4. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
  5. 5. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 5 Bisphosphonates – Antiresorptive Agents FDA-approved for: Prevention and treatment of osteoporosis in postmenopausal women ! Treatment to increase bone mass in men with osteoporosis ! Treatment of glucocorticoid-induced osteoporosis in men and women receiving glucocorticoids ! Treatment of Paget’s disease of bone in men and women
  6. 6. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 6 6
  7. 7. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 7 Bisphosphonates – Dosing Alendronate* Prevention 5 mg PO daily 35 mg PO weekly Treatment 10 mg PO daily 70 mg PO weekly 70 mg/2,800 IU vitamin D PO weekly Risedronate Prevention/Treatment 5 mg PO daily 35 mg PO weekly Ibandronate Prevention/Treatment 2.5 mg PO daily 150 mg PO monthly Treatment 3 mg IV every 3 months
  8. 8. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! High attraction for hydroxyapatite crystals and thus rapidly included into all parts of skeleton ! Used as inhibitors of osteoclastic activity to alleviate bone pain that results from release of biochemical mediators in metastatic bone disease
  9. 9. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! Anti-resorptive Anabolic ‘Dual action’ ! Alendronate inhibits the osteoclastic bone resorption! without inhibiting the osteoblastic bone formation –! increase in bone mass Mode Of Action
  10. 10. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 10 Osteoporotic bone remodelling
  11. 11. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! ! Hwang and Wang, 2007
  12. 12. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 12 Bone Remodelling With Alendronate Gets preferentially bound under osteoclasts. ! Osteoclasts ingest the attached alendronate. Released alendronate inactivates the osteoclasts. ! Bone resorption inhibited. Alendronate may reduce the number of remodelling sites
  13. 13. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
  14. 14. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
  15. 15. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
  16. 16. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! OVERALL EFFECT:! ! Less trabecular thinning ! Decreased number of trabecular perforations ! Smaller erosion of cortex ! Slowing down decrease in bone strength and occurrence of fractures
  17. 17. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! MECHANISM OF ACTION

  18. 18. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 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
  19. 19. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 19 Bisphosphonates – Administration Must be taken at least one-half hour before the first food, beverage, or medication of the day with plain water only (1 hour prior for monthly ibandronate) ! Should only be taken upon arising for the day ! Tablet should be swallowed with a full glass of water (8 oz) and patients should remain upright, walking, standing, or sitting for at least 30 minutes (60 minutes for monthly ibandronate) ! Should supplement with calcium/vitamin D if dietary intake inadequate
  20. 20. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 20 Bisphosphonates – Missed Dose Once weekly alendronate, risedronate Take on morning after remembering, then resume once weekly on regularly chosen day ! Once monthly ibandronate If next dose > 7 days away, take dose the morning following the date remembered Then return to original schedule If next dose < 7 days away, wait until next scheduled dose Must not take two 150 mg tablets within the same week
  21. 21. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 21 Bisphosphonates – Adverse Effects Hypocalcemia (18%) ! Hypophosphatemia (10%) ! Musculoskeletal pain, cramps – recent FDA warning Gastrointestinal Abdominal pain Acid reflux Dypepsia Esophageal ulcer Gastritis ! Osteonecrosis of the jaw (IV bisphosphonates) Visual disturbances (rare)
  22. 22. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 22 Contraindications/Precautions ! Abnormalities of the esophagus which delay esophageal emptying, such as stricture or achalasia ! Inability to stand or sit upright for at least 30 minutes ! Patients at increased risk of aspiration ! Hypocalcemia: Should be corrected prior to initiating therapy ! Renal insufficiency (Not recommended if CrCl < 30-35 ml/min)
  23. 23. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! Contraindications
  24. 24. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 24 Zolendronic Acid Approved for osteoporosis treatment in postmenopausal women in August 2007 ! Single 5 mg infusion given IV over > 15 minutes, once yearly ! Should still supplement with calcium/vitamin D ! May be ideal for those with GI contraindications to the oral formulations
  25. 25. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 25 Bisphosphonates – Clinical Efficacy Controlled clinical trials indicate over 3-4 year period, alendronate ↑ bone mass and ↓ incidence of vertebral, hip, and all non- vertebral fractures by 50%! ! Controlled clinical trials indicate risedronate ↑ bone mass and ↓ risk of vertebral fractures by 40% and non-vertebral fractures by 30% over 3-year period! ! Ibandronate has been shown in controlled clinical trials to ↑ BMD and reduce the risk of vertebral fracture by 50% over 3-year period! ! Alendronate appears to be well tolerated and effective for at least ten years
  26. 26. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 26 Bisphosphonate Therapy - Risks Initial studies taken to the FDA to gain approval for these drugs identified a lower than expected risk of GI side effects No unexpected side effects were seen in these studies However, about 15 years ago, cases of osteonecrosis of the jaw which dentists had not seen for a least a century, began to appear Subsequently, the possibility of an increased risk of atypical femur fractures in patients treated with these drugs was proposed.
  27. 27. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 27 Osteonecrosis Of Jaw Exposed necrotic bone in the maxillo-facial region Not healing after 6-8 weeks in patients with no hx of craniofacial radiation Exposed yellow-white hard bone with smooth or ragged borders, often in the site of dental extraction or other invasive dental procedure with poorly fitting dentures Over 90% of reported cases in cancer patients receiving BP doses 10X higher than used to treat osteoporosis Estimated incidence in OP: 1:10,000-1:100,000 Khosla et al. ASBMR Rask Force, JBMR 2008;23:159. Woo S-B et al, Ann Intern Med 2006;144:753-761.
  28. 28. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! BISPHOSPHONATE RELATED
 OSTEONECROSIS OF THE JAW (BRONJ) ! Patients may be considered to have BONJ if they have exposed bone in the maxillofacial region for at least 8 weeks, are currently on or have taken bisphosphonates and have no history of radiotherapy to the jaws (AAOMS )
  29. 29. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! WHY DOES BONJ ONLY AFFECT THE MAXILLOFACIAL SKELETON BPs accumulate in high turnover areas like mandible than elsewhere.! ! As a result of trauma or infection bone cannot respond adequately.! ! Masticatory Forces! Chronic Low Grade Trauma! Unable to repair micro-fractures! Necrotic Bone! Bony sequestrum
  30. 30. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
  31. 31. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 31 Femoral Shaft Fractures In 2005, Odvina et al reported a series of nine patients with spontaneous, atypical fractures, all on bisphosphonate therapy for a period of time ranging from 3 to 8 years. Four with fractures in the subtrochanteric region and one each with fractures of the sacrum, rib, ischium, pubic rami and lumbar spine. 6/9 had delayed or absent healing during management. Histology revealed over suppression of bone turnover, possibly linked to bisphosphonate usage, but other factors, i.e.. estrogens and glucocorticoid use left much room for debate. Odvina et al JCEM2005;90:1294–1301
  32. 32. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 32 Atypical Fractures of the Femoral Diaphysis in Postmenopausal Women Taking Alendronate. Lenart, Brett; Lorich, Dean; Lane, Joseph ! New England Journal of Medicine. 358(12):1304-1306, March 20, 2008. Radiographs of Fractures of the Femoral Shaft Showing the"Simple with Thick Cortices” ! Pattern Panel A shows a fracture of the femoral shaft in an 83-year-old woman with a 9-year history of alendronate use. Panel B shows a similar fracture in a 77-year-old woman with a 5-year history of alendronate use.
  33. 33. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 33 Femoral Shaft Fractures Usually occur in the proximal third of the femoral shaft ! May have a prodrome of thigh pain ! Often bilateral or sequential ! X-rays prior to fracture may reveal some beaking of the cortex and cortical thickening of the proximal femoral shaft ! Early identification may require intervention – but exactly what is unclear
  34. 34. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 34 Atypical Femoral Fracture Shane et al, JBMR 25:2010;25:2267–2294. Conventional AP radiograph of the pelvis (A) shows bilateral focal cortical thickening from periosteal new bone formation (arrows). Corresponding bone scintigraphy (B) demonstrates focal increased radionuclide uptake in the proximal lateral femoral cortices (arrows). MRI images of the femurs (C) demonstrate subtle decreased signal on T1-weighted and increased signal on T2-weighted images only of the right femur on! this section. Similar findings on AP DXA hip images (D) show focal bilateral cortical thickening consistent with early, evolving femoral insufficiency fractures. A B DC
  35. 35. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 35 Bisphosphonate Use and the Risk of Subtrochanteric or Femoral Shaft Fractures in Older Women L. Park-Wyllie, PharmD, MS, M. Mamdani, PharmD, MA, MPH, D. Juurlink, MD, PhD, G. Hawker, MD, MSc, N. Gunraj, MPH, P. Austin, PhD, D. Whelan, MD, MSc, P. Weiler, MD, MASc, P Eng. Laupacis, MD, MSc JAMA. 2011;305(8):783-789 Population-based, nested case-control study in a cohort of women aged 68 years or older from Ontario, Canada treated with oral bisphosphonate between April 1, 2002, and March 31, 2008. Primary analysis - association between hospitalization for a subtrochanteric or femoral shaft fracture and duration of bisphosphonate exposure Secondary analysis - association of bisphosphonate use and classic intertrochanteric or femoral neck fractures
  36. 36. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 36 Summary 716 (0.35%) suffered a subtrochanteric or femoral shaft fracture after receiving bisphosphonate therapy. Cases were matched with 3580 controls Bisphosphonate treatment to prevent typical femoral fractures should last at least 5 years. Bisphosphonate treatment for more than 5 years begins to increase the risk for atypical femoral shaft fractures which are still extremely rare. JAMA. 2011;305(8):783-789
  37. 37. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 37 Bisphosphonates for Osteoporosis — Where Do We Go from Here? Available data do not identify patients likely to benefit from treatment beyond 3-5 years. ! ! ! … decisions to continue treatment must be based on individual assessment of risks and benefits and on patient preference. NEJM 366:2048, 2012
  38. 38. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 38 How Long to Treat With Bisphosphonates? 1.Patients who did not need treatment in the first place Discontinue Treatment ! 2.Lower risk patients, if DXA is stable/increasing Consider a drug holiday after 3-5 years of treatment ! 3.Higher risk patients (fractures, corticosteroid Rx, very low BMD) Consider a drug holiday after 10 years of therapy ! 4.May use teriparatide or raloxifene (but not another potent antiresorptive agent – ie. denosumab) during the holiday from bisphosphonates Watts and Diab JCEM, 2010 95:1555.
  39. 39. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!39 Whom 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
  40. 40. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 40 Proposed Guidelines for Use of Bisphosphonates 1.Patients with bone density T-scores of -2.5 or lower at femoral neck after 3 to 5 years of treatment at highest risk for vertebral fractures and appear to benefit most from continued therapy (for up to 10 years). ! 2.Patients with an existing vertebral fracture and T-scores up to −2.0 may also benefit from continued therapy. ! 3.Patients with femoral neck T-scores above −2.0 have low risk of vertebral fractures and are unlikely to benefit from continued treatment after 3-5 years. Black et al. 2012, NEJM 366:2051
  41. 41. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! THE “DRUG HOLIDAY” Suggested that cessation of the BPs allows regeneration of osteoclasts and some improvement in bone turnover.! ! For patient who has been taking an oral BP longer than 3years, it should be discontinued, 3 months before and 3 months after the surgical procedure, if approved by the patient’s physician.! ! Serum C-telopeptide (CTx) levels should be greater than 150 pg/mL before any surgical procedure, and rechecked at the time of surgery. ! (Lam DK, Sandor GKB 2007)
  42. 42. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 42 * *Use FRAX to estimate risk
  43. 43. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 43 NOF’s Clinician’s Guide Applies the recently released algorithm on absolute fracture risk call FRAX® by the WHO! ! Also called 10-year fracture risk model and 10-year fracture probability! ! Estimates the likelihood of a person to break a bone due to low bone mass over a period of 10 years! ! Most useful to determine if treatment needed for those with low bone mass or osteopenia! ! http://www.shef.ac.uk/FRAX/tool.jsp?locationValue=2 43
  44. 44. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 44 When Should the Holiday End?*
 Arbitrary* - Longer for drugs with highest skeletal affinity (zoledronic acid), shorter for drugs with lowest skeletal affinity (risedronate)? ! Many patients will have been on more than one - complicating matters. ! Some use bone turnover markers (measure degree of active bone resorption) – but which ones and what cut off values to use is unclear. ! There is no good evidence here. BMD – If significant decrease seen with annual testing Watts and Diab JCEM, 2010 95:1555. * To quote Dr. Watts himself, this is an evidence free zone.
  45. 45. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 45 Hot topics
  46. 46. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 46 Bisphosphonates for Osteoporosis - Summary Risk/Benefit Ratio – favorable for most high risk patients ! Length of treatment depends upon fracture risk ! Risks of ONJ and AFF (Atypical Femoral Fracture) may increase after 5 years but risk is low ! What to do about ONJ and AFF? ONJ: Look in the mouth ! AFF: Instruct patient to report thigh/groin pain and investigate if clinically indicated. Review films of any reported femur fracture
  47. 47. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 47 www.hormone.org
  48. 48. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 48 No known Metabolism of the drug in Vivo! ! Remains in body for ever and goes for recycling?! ! Insufficiency fractures! ! Immediate Osteoclasts apoptosis! ! Osteoblastic activity continues! ! Mineralization and maturation take long time! ! Increased BMD is due to non absorption of hydroxyapatite and continued mineralization! ! Increased mineral content with diminished elasticity, increased brittleness Hidden Truth Of Alendronate
  49. 49. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 49 Bisphosphonate Therapy Benefits Decreased risk of breast cancer ! Decreased risk of colorectal cancer ! Decreased risk of stroke ! Decreased risk of gastric cancer ! Decreased overall mortality Nelson Watts – Endocrine Society National Meeting - 2012
  50. 50. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 50 A single infusion of ZOLENDRONATE 5 mg reduced bone resorption marker rapidly than weekly oral ALN 70 mg (Urine NTX) (Serum β-CTX ) * P<0.0001; †P<0.05, for relative change from baseline, ZOL vs ALN; NTX: urine N-telopeptide; β-CTX: Serum β-C-telopeptide of type I collagen
  51. 51. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! 51 Safety: Five most common Post-Dose Symptoms (≤ 3 Days After Infusion) and declined markedly with subsequent infusions 0 2 4 6 8 10 12 14 16 Annual Infusion Pyrexia Myalgia Flu-like illness Headache Arthralgia 1 2 3 1 2 3 1 2 3 1 2 3 1 2 3 Incidence(%) 15% 2% 1% 1% 2% 1% 2% 1% 2% 1% 8% 7% 6% 5% Placebo values cross-hatched 1% Treatment with antipyretic analgesics appeared to mitigate these symptoms2 Acetaminophen four times/day for 3 days significantly reduced the incidence and severity of post-dose symptoms following ZOL infusion3
  52. 52. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! Reduce frequent dosing with bisphosphonates may improve compliance as an important thing for the success of osteoporosis treatment.! ! Six years of annual ZOL 5 mg infusion preserves bone mass and discontinuation after 3 years still provided residual benefit of fracture protection.! ! It may be beneficial for some women, particularly those at high vertebral fracture risk, to continue ZOL for an additional 3 years 1Black DM, et al. N Engl J Med. 2007;356:1809-1822 2Black DM, et al. J Bone Miner Res. 2012;27:240–242
  53. 53. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! •Herbert Fleisch. Bisphosphonates: Mechanisms of Action. Endocrine Reviews 19(1): 80–100. •M.D. Francis,D.J. Valent J. Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases. Musculoskelet Neuronal Interact 2007; 7(1):2-8. •Angelo Mariotti. Bisphosphonates and Osteonecrosis of the Jaws. •Carol Tekavec, CDA, RDH. Bisphosphonates. Journal of the American Dental Association in August 2006. •Howard C Tenenbaum et al .Bisphosphonates and periodontics : potential applications for regulation of bone mass in the periodontium and other therapeutic/ diagnostic uses. JOP 2002;73:813-822. •R. G. G. Russell, N. B. Watts, F. H. Ebetino, M. J. Rogers. Mechanisms of action of bisphosphonates: similarities and differences and their potential influence on clinical efficacy. Osteoporos Int (2008) 19:733–759. •American Association of Oral and Maxillofacial Surgeons. Position Paper on Bisphosphonate-Related Osteonecrosis of the Jaw—2009 Update. ! REFERENCES
  54. 54. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! Thank you Keep your bone healthy
  55. 55. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com!
  56. 56. Dr.Sandeep C Agrawal Agrasen Hospital Gondia India www.agrasenortho.com! This presentation is for  doctors and students in general. . Graphics,Images and jpeg files are taken from Google and yahoo  Image  to heighten the specific points in this presentation.  • If there is any objection/or copyright violation, please inform drsandeep123@gmail.com for prompt deletion.  • It is intended for use only by the doctors of orthopaedic surgery. . Views expressed in this presentation are personal. • .For any confusion please contact the sole author for clarification.  • Every body is allowed to copy or download and use the material best suited to him.  There is no financial involvement.  • For any correction or suggestion please contact drsandeep123@gmail.com or www.agrasenortho.com

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