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Osteoporosis Diagnosis and Therapy Veronica Piziak MD, PhD Scott & White Professor of Endocrinology Texas A&M HSC.

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Presentation on theme: "Osteoporosis Diagnosis and Therapy Veronica Piziak MD, PhD Scott & White Professor of Endocrinology Texas A&M HSC."— Presentation transcript:

1 Osteoporosis Diagnosis and Therapy Veronica Piziak MD, PhD Scott & White Professor of Endocrinology Texas A&M HSC

2 Objectives Discuss: Discuss: Diagnosis of osteoporosis Diagnosis of osteoporosis Dosages of calcium and vitamin D and their role in bone disease Dosages of calcium and vitamin D and their role in bone disease Risks and benefits of bisphosphonates Risks and benefits of bisphosphonates Role of Denosumab Role of Denosumab Disclosures : Warner Chilcott- speaker Disclosures : Warner Chilcott- speaker Novartis, P+G research support Novartis, P+G research support

3 Bone loss accelerates with menopause (~1%-2% per year) Age-related bone loss (~0.5%-1.0% per year) AGE in YEARS HIGHER PEAK BONE MASS MANOPAUSE

4 How much calcium? What kind? Patients with renal insufficiency may not be able to clear usual doses of calcium and coronary artery calcification may progress Patients with renal insufficiency may not be able to clear usual doses of calcium and coronary artery calcification may progress Russo D, Miranda I, Ruocco C, Battaglia Y, Buonanno E, Manzi S,et al. The progression of coronary artery calcification in predialysis patients on calcium carbonate. Kidney Int 2007;72:

5 700 mg 1200 mg 1000 mg1300 mg X Institute of Medicine 2010

6 Calcium: How much and what kind? Do calcium supplements increase the risk of heart attack? Do calcium supplements increase the risk of heart attack? Meta analysis: Meta analysis:Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), 1-2 gms calcium no D in supplements 1-2 gms calcium no D in supplements Hazard ratio 1.31 p Hazard ratio 1.31 p Dietary calcium no increased risk MI Dietary calcium no increased risk MI Boland et al BMJ 2010; 341 Boland et al BMJ 2010; 341:c3691

7 Calcium intake and vascular calcification No correlation of coronary artery calcification or abdominal aortic calculations with dietary calcium or calcium intake in healthy men and women. No correlation of coronary artery calcification or abdominal aortic calculations with dietary calcium or calcium intake in healthy men and women. Wang TK et al JBMR Jul 2010 Wang TK et al JBMR Jul 2010 Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5 year RCT and a 4.5 year follow up Calcium supplementation and the risks of atherosclerotic vascular disease in older women: results of a 5 year RCT and a 4.5 year follow up No increased incidence of CV disease mg/day No increased incidence of CV disease mg/day Joshua R Lewis JBMR on line 2010 Joshua R Lewis JBMR on line 2010 Look at the ASBMR website Look at the ASBMR website

8 DIETARY CALCIUM 1200 mg very possible 1200 mg very possible Remember fortified foods Remember fortified foods Total, OJ, pasta, granola bars, yogurt Total, OJ, pasta, granola bars, yogurt Bread, raisins Bread, raisins Cheese 300 mg/ slice (Borden) Cheese 300 mg/ slice (Borden)

9 CALCIUM SUPPLEMENTS Calcium carbonate Calcium carbonate 40% calcium 40% calcium Acid is necessary to dissolve Acid is necessary to dissolve Patients on proton pump inhibitor Patients on proton pump inhibitor Use calcium citrate Use calcium citrate Cant swallow pills Cant swallow pills Chewables tasty! Chewables tasty!

10 Haney Cal Tissue 1998Haney Calc Tissue 1998

11 HISTORY OF RENAL STONES 1000 mg calcium citrate 1000 mg calcium citrate Measure urine calcium Measure urine calcium If > 3.5mg/kg/day If > 3.5mg/kg/day Use HCTZ 12.5mg/day Use HCTZ 12.5mg/day Encourage hydration Encourage hydration Dietary calcium Dietary calcium Inversely related to the risk of renal stones in >8000 women Inversely related to the risk of renal stones in >8000 women CURHAN ANN INT MED;97: CURHAN ANN INT MED;97:

12 DOES CALCIUM PREVENT FRACTURES? Review of 14 trials Review of 14 trials Calcium + D vs control Calcium + D vs control 7 trials studied hip fracture 7 trials studied hip fracture 7 trials studied nonvertebral 7 trials studied nonvertebral Calcium reduces fractures Calcium reduces fractures Calcium + D (400 IU) Calcium + D (400 IU) No better than calcium alone No better than calcium alone Gillespie AA et al Cochrane Database System Rev 2005 Gillespie AA et al Cochrane Database System Rev 2005

13 Vitamin D Metabolism Vitamin D Dehydrocholecalciferol (diet, skin) 25-hydroxylase 1 -hydroxylase 25-hydroxyvitamin D 1,25-dihydroxyvitamin D increased GI calcium absorption increased available calcium

14 INCREASES PHOSPHORUS ABSORPTION DECREASES PTH SYNTHESIS CA x P

15 How much Vitamin D? 600 IU /day everyone thru age IU /day everyone thru age IU for people > age IU for people > age 70 More then 4000 IU / day is not recommended More then 4000 IU / day is not recommended

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17 THE 25(OH)D CONTINUUM (ng/mL) (nmol/L) deficiency insufficiency normal (ng/ml) modified after Heaney PTH is elevated CALCIUM ABSORPTION INCREASES ?

18 Who to Screen for Deficiency Patients who do not increase BMD on bisphosphonates Patients who do not increase BMD on bisphosphonates Patients with hip fracture, nonunion fractures Patients with hip fracture, nonunion fractures Young patients with fracture at any site Young patients with fracture at any site Patients with hyperparathyroidism Patients with hyperparathyroidism

19 Who to Screen for Deficiency Breast fed infants not given vitamin D supplementation Breast fed infants not given vitamin D supplementation Institutionalized elderly- decreased sunshine exposure Institutionalized elderly- decreased sunshine exposure Obese individuals – decreased production Obese individuals – decreased production Fibromyalgia patients ? Fibromyalgia patients ? Pagets disease – Rapid bone turnover Pagets disease – Rapid bone turnover Medications that interfere with vitamin D absorption or metabolism. Medications that interfere with vitamin D absorption or metabolism.

20 Who to Screen for Deficiency Malabsorption Malabsorption Pancreatic insufficiency Pancreatic insufficiency Inflammatory bowel disease Inflammatory bowel disease Gastric bypass Gastric bypass Severe Liver dysfunction - Severe Liver dysfunction - decreased 25 hydroxylation decreased 25 hydroxylation

21 Replacing Vitamin D 1000 IU daily from the range 1000 IU daily from the range Raises the level to about 40 ng/ml Raises the level to about 40 ng/ml For significant deficiency For significant deficiency 50,000 IU (D2) may give once a week for 8 weeks check 25OH D 50,000 IU (D2) may give once a week for 8 weeks check 25OH D Holick et al 1998 lancet 351:805 Holick et al 1998 lancet 351:805 May give 50,000 IU once a month safely for 5 years May give 50,000 IU once a month safely for 5 years

22 VITAMIN D AND FRACTURES Meta analysis Meta analysis trials 9820 women 7 trials 9820 women Mean age 79 Mean age 79 Vitamin D doses IU were necessary to reduce fracture 25% Vitamin D doses IU were necessary to reduce fracture 25% Calcium intake variable Calcium intake variable Baseline vitamin D unknown Baseline vitamin D unknown BISCHOFF-FERRARI ET AL JAMA 2005;293: BISCHOFF-FERRARI ET AL JAMA 2005;293:

23 Definition of Osteoporosis A skeletal disorder characterized by… Excessive osteoclast-mediated bone resorption Excessive osteoclast-mediated bone resorption Compromised bone strength Compromised bone strength Increased risk of fracture at all skeletal sites Increased risk of fracture at all skeletal sites Boyle WJ, et al. Nature. 2003;423: NIH Consensus Development Panel. JAMA. 2001;285: Images are of a paired iliac crest biopsy and courtesy of Yebin Jiang MD, PhD. Osteoporosis & Arthritis Lab, University of Michigan. Normal Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the family, and the community. –NIH Consensus Statement Osteoporosis

24 WHO. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis; T-Score OsteopeniaOsteoporosis Normal –2.5–2–10 WHO = World Health Organization. WHO Diagnostic Categories for Osteopenia REMEMBER BONE STRENGTH,DISEASE STATE

25 BMD Testing Recommended by the Surgeon Generals report in 2004: US Preventive health task force 3/2011 Recommended by the Surgeon Generals report in 2004: US Preventive health task force 3/2011 Postmenopausal women with FRAX score 9.3% risk osteoporotic fracture Postmenopausal women with FRAX score 9.3% risk osteoporotic fracture Women>/=65 years of age with fractures - required by NCQA Women>/=65 years of age with fractures - required by NCQA Younger women with risk factors Younger women with risk factors Men and Women with fragility fractures Men and Women with fragility fractures People on medications or with diseases that can increase the risk of fractures People on medications or with diseases that can increase the risk of fractures

26 Who to treat? Goal - prevent fractures Patients at significant risk Who to treat? Goal - prevent fractures Patients at significant risk

27 Fracture rate Fracture per 1000 Person-Years Adapted from Siris ES, et al. Arch Intern Med. 2004;164: BMD distribution BMD T-Scores (Peripheral) > to to to –0.5 –0.5 to –1.0 –1.0 to –1.5 –1.5 to –2.0 –2.0 to –2.5 –2.5 to –3.0 –3.0 to –3.5 < –3.5 No. of women with fractures No. of Women With Fractures Population BMD Distribution, Fracture Rates, and Number of Women With Fractures

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30 Problems with FRAX Under estimates fracture risk in healthy women under 56 – 60 Use hip BMD Under estimates fracture risk in healthy women under 56 – 60 Use hip BMD Excellent for women 60 plus Excellent for women 60 plus Not accurate if patient has been on bone active agents Not accurate if patient has been on bone active agents Tremollieres FA et al JBMR 25: Tremollieres FA et al JBMR 25:

31 Updated NOF Clinicians Guide Incorporation of WHO Algorithm New NOF Guide (2008) Initiate Treatment in PM women and men age 50 with: Hip or vertebral fracture Other prior fracture and low bone mass (T-score -1.0 to -2.5) T-score <-2.5 (2º causes excl.) Low bone mass and 2º causes associated with high risk of fracture Low bone mass AND 10-yr hip fracture probability 3% or 10-yr major OP- related fracture probability of 20% Previous NOF Guide (2003) Initiate Treatment in those with : T-score <-2.0 & no risk factors T-score <-1.5 & risk factors Hip or Vertebral Fracture

32 OSTEOPOROSIS How to Treat? Approved medications Approved medications Raloxifene Raloxifene Bisphosphonates Bisphosphonates PTH 1-34 PTH 1-34 Denosumab Denosumab

33 ALENDRONATE Approved for: Approved for: Prevention and therapy Prevention and therapy Postmenopausal osteoporosis Postmenopausal osteoporosis Steroid induced osteoporosis Steroid induced osteoporosis 70mg/week 70mg/week Generic available! Generic available! Long life in bone, most commonly associated with bone suppression Long life in bone, most commonly associated with bone suppression

34 Risedronate and Ibandronate Risedronate 150 mg Once a Month Risedronate 150 mg Once a Month Minimum of 30-minute wait before eating Minimum of 30-minute wait before eating Approved for prevention and therapy of Approved for prevention and therapy of Postmenopausal osteoporosis, male osteoporosis, steroid induced osteoporosis Postmenopausal osteoporosis, male osteoporosis, steroid induced osteoporosis Enteric coated form now available Enteric coated form now available Ibandronate 150 mg Once a Month Minimum of 60 minute wait before eating Approved for prevention of vertebral fractures

35 IV Bisphosphonates: Considerations Potentially increased compliance Potentially increased compliance Only eliminate GI adverse events Only eliminate GI adverse events Adverse events and considerations Adverse events and considerations Flu-like syndromes Flu-like syndromes Injection-site reactions Injection-site reactions Renal toxicities (Check creatinine) Renal toxicities (Check creatinine) Long-term use Long-term use Osteonecrosis of the jaw Osteonecrosis of the jaw Electrolyte abnormalities (hypocalcemia) Electrolyte abnormalities (hypocalcemia) Conte et al. Oncologist. 2004;9(suppl 4):28.

36 IV Ibandronate 15 second IV push 15 second IV push Store at room temperature Store at room temperature 3 mg/every three months 3 mg/every three months Creatinine clearance at least 37 ml/min Creatinine clearance at least 37 ml/min

37 Zoledronic acid/ Reclast Approved as a once / year IV therapy for postmenopausal and male osteoporosis, Approved as a once / year IV therapy for postmenopausal and male osteoporosis, 15 minute infusion 5 mg/100 ml 15 minute infusion 5 mg/100 ml Side effects – hypocalcemia, fever, muscle pain, flu-like symptoms and headache Side effects – hypocalcemia, fever, muscle pain, flu-like symptoms and headache Not for use in pregnancy or with creatinine clearance < 35ml/min Not for use in pregnancy or with creatinine clearance < 35ml/min MAKE SURE PATIENTS TAKE CALCIUM! MAKE SURE PATIENTS TAKE CALCIUM! MAKE SURE THEY ARE WELL HYDRATED MAKE SURE THEY ARE WELL HYDRATED Consider obtaining 25 OH Vitamin D Consider obtaining 25 OH Vitamin D

38 Code properly Billed under Medicare Part B Billed under Medicare Part B Must have senile/postmenopausal osteoporosis T- score -2.5 Must have senile/postmenopausal osteoporosis T- score Unspecified adverse effect of other drug Unspecified adverse effect of other drug V12.79 Personal Hx of digestive system disease V12.79 Personal Hx of digestive system disease V49.84 bed confined status V49.84 bed confined status = payment = payment

39 RISEDRONATE CONTROL P < 0.01 VS CONTROL Hip fracture reduction by 9 months

40 ALENDRONATE OVER 10 YEARS BONE AND LIBERMAN ET AL NEJM 2004;350:

41 FLEX – FIT EXTENSION SAFE FOR 10 YEARS SAFE FOR 10 YEARS NO ONJ NO ONJ OVERSUPRESSION OF BONE WAS NOT SEEN OVERSUPRESSION OF BONE WAS NOT SEEN WHAT HAPPENS WHEN YOU STOP ALENDRONATE AFTER 5 YEARS? WHAT HAPPENS WHEN YOU STOP ALENDRONATE AFTER 5 YEARS? NO EXCESS IN ALL CLINICAL FRACTURES IN THE UNTREATED GROUP NO EXCESS IN ALL CLINICAL FRACTURES IN THE UNTREATED GROUP THERE WAS A 2.9% INCREASE IN CLINICALLY DETECTED VERTEBRAL FRACTURES. THERE WAS A 2.9% INCREASE IN CLINICALLY DETECTED VERTEBRAL FRACTURES.

42 BUT does over suppression result in fractures? In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures In the past 4 years, reports have been published implying that long-term bisphosphonate therapy could be linked to atraumatic femoral diaphyseal fractures Long-term alendronate therapy 8+ years ? Associated with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients. Long-term alendronate therapy 8+ years ? Associated with unilateral low-energy subtrochanteric and diaphyseal femoral fractures in a small number of patients.

43 JBMR Publishes ASBMR Task Force Report on Atypical Femoral Fractures Who is at risk? Date: September 14, 2010 Date: September 14, 2010 In the most comprehensive scientific report to date on the topic, the task force reviewed 310 cases of "atypical femur fractures," and found that 94 percent (291) of patients had taken the drugs, most for more than five years. The task force members emphasized that atypical femur fractures represent less than one percent of hip and thigh fractures overall and therefore are very uncommon. They MAY be related to long term use. In the most comprehensive scientific report to date on the topic, the task force reviewed 310 cases of "atypical femur fractures," and found that 94 percent (291) of patients had taken the drugs, most for more than five years. The task force members emphasized that atypical femur fractures represent less than one percent of hip and thigh fractures overall and therefore are very uncommon. They MAY be related to long term use. More than half of patients with atypical femur fractures reported groin or thigh pain for a period of weeks or months before fractures occurred, according to the report. More than a quarter of patients who experienced atypical femur fractures in one leg experienced a fracture in the other leg as well More than half of patients with atypical femur fractures reported groin or thigh pain for a period of weeks or months before fractures occurred, according to the report. More than a quarter of patients who experienced atypical femur fractures in one leg experienced a fracture in the other leg as well Warnings PI: Thigh or groin pain look for fracture – Warnings PI: Thigh or groin pain look for fracture – Plan film of the area may show sclerosis. Plan film of the area may show sclerosis.

44 FLEX – FIT EXTENSION WHO SHOULD NOT STOP? WHO SHOULD NOT STOP? PREVIOUS VERTEBRAL OR NONVETEBRAL FRACTURE PREVIOUS VERTEBRAL OR NONVETEBRAL FRACTURE VERY LOW BMD <- 2.5 VERY LOW BMD <- 2.5 BLACK ET AL JAMA 2006;296: BLACK ET AL JAMA 2006;296: EDITORIAL JAMA 2006;296: EDITORIAL JAMA 2006;296: FDA agrees 2010 FDA agrees 2010

45 FDA opinion 3/10/10 FDA reviewed Abrahamsen et al, that analyzed data from two large observational studies in patients with osteoporosis. FDA reviewed Abrahamsen et al, that analyzed data from two large observational studies in patients with osteoporosis. The authors concluded that atypical subtrochanteric femur fractures had many similar features in common with classical osteoporotic hip fractures, including patient age, gender, and trauma mechanism. The authors concluded that atypical subtrochanteric femur fractures had many similar features in common with classical osteoporotic hip fractures, including patient age, gender, and trauma mechanism. The data showed that patients taking bisphosphonates and those not taking bisphosphonates had similar numbers of atypical subtrochanteric femur fractures relative to classical osteoporotic hip fractures. More adherence fewer fractures The data showed that patients taking bisphosphonates and those not taking bisphosphonates had similar numbers of atypical subtrochanteric femur fractures relative to classical osteoporotic hip fractures. More adherence fewer fractures J Bone Miner Res. 2009;24: J Bone Miner Res. 2009;24:

46 Reanalysis of FLEX/FIT who could stop? In previous studies, ALN efficacy for NVF prevention in women without prevalent vertebral fracture was limited to those with femoral neck (FN) T-score -2 after 5 years could stop

47 Long Term Use– a Plan Drug holiday after 5-10 years Drug holiday after 5-10 years Duration of the treatment and holiday depend on fracture risk. Duration of the treatment and holiday depend on fracture risk. Continue for 10 years if osteoporosis or if holiday use another agent (? PTH 1-34) Continue for 10 years if osteoporosis or if holiday use another agent (? PTH 1-34) Low fracture risk then stop at 5 years and monitor the DXA stay off if stable and no fractures. Low fracture risk then stop at 5 years and monitor the DXA stay off if stable and no fractures. Watts et al JCE&M 95: Watts et al JCE&M 95:

48 Bisphosphonates and esophageal cancer Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort Oral bisphosphonates and risk of cancer of oesophagus, stomach, and colorectum: case-control analysis within a UK primary care cohort Data from patients using medications for three or more years. Risk of esophageal cancer doubled in users. 1/1000 to 2/1000. Data from patients using medications for three or more years. Risk of esophageal cancer doubled in users. 1/1000 to 2/1000. Looked at age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, and corticosteroids. Looked at age, sex, smoking, alcohol intake, or body mass index; by diagnosis of osteoporosis, fracture, or upper gastrointestinal disease; or by prescription of acid suppressants, non-steroidal anti-inflammatory drugs, and corticosteroids. Dont use orals in high risk patients Dont use orals in high risk patients BMJ Sep 1;341:c4444 BMJ Sep 1;341:c4444

49 Human Parathyroid Hormone 1-34 and SerValSer Glu IleGlnLeuMetHis Asn Leu Gly Lys His Leu Asn Ser Met GluArg Val Glu Trp Leu ArgLys LeuGlnAsp Val His Asn Phe COOH H 2 N-

50 When to use Severe osteoporosis Severe osteoporosis T score – 3, previous fractures T score – 3, previous fractures Fractures on bisphosphonate Fractures on bisphosphonate Unresponsive to bisphosphonates Unresponsive to bisphosphonates Few side effects Few side effects Very expensive Very expensive

51 PTH YEARS FOLLOWED BY BISPHOSPHONATE IN MEN Kurland ES et al. Osteoporos Int. 2004;15:

52 Role of RANK Ligand in Bone Resorption Hormones Growth factors Cytokines RANKL RANK OPG Bone Formation Adapted from Boyle WJ, et al. Nature. 2003;423: Bone Resorption Activated Osteoclast CFU-M Pre-Fusion Osteoclast Multinucleated Osteoclast In the presence of M-CSF CFU-M=colony forming unit macrophage M-CSF=macrophage colony stimulating factor Provided as an educational resource. Do not copy or distribute. © 2007 Amgen. All rights reserved. Osteoblasts

53 Cytokines Growth factors Hormones Prefusion osteoclast RANKL-Inhibitors: Mechanism of Action Adapted from Boyle et al. Nature. 2003;423:337. CFU-M Multinucleated osteoclast RANKL OPG BONE OPG RANKL Stromal cells InhibitorsRANK Active Osteoclast Osteoblast

54 Denosumab SC q6mo: Effect on Lumbar Spine BMD Placebo (n=46) Denosumab 60 mg (n=46) Denosumab 100 mg (n=41) Alendronate 70 mg/wk (n=46) Denosumab 14 mg (n=53) Denosumab 210 mg (n=46) Months Mean change from baseline (%) Adapted from McClung et al. N Engl J Med. 2006;354: mg dose sub q every 6 months Spine 6.5% 2 years, Hip 3.4%, Radius 1.4% (cortical bone) 96% responder rate 4/1/08 Endo Soc

55 Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., NEJM 2009;361 Aug 19th

56 Approved by the FDA! Denosumab (Prolia) Denosumab (Prolia) Indication: postmenopausal osteoporosis Indication: postmenopausal osteoporosis With a high risk of fracture With a high risk of fracture Sub q every 6 months (prefilled syringe) Sub q every 6 months (prefilled syringe) Contraindicated in hypocalcemia Contraindicated in hypocalcemia May use in renal insufficiency ( monitor calcium, phosphorus, magnesium) May use in renal insufficiency ( monitor calcium, phosphorus, magnesium)

57 Side Effects Side effects: dermatitis, significant infections, pancreatitis Side effects: dermatitis, significant infections, pancreatitis ONJ has been reported ONJ has been reported Examine the mouth Examine the mouth If patient has an infection they need to call If patient has an infection they need to call

58 TREAT OSTEOPOROSIS 10 million Americans with osteoporosis and it is treatable 10 million Americans with osteoporosis and it is treatable Yet Yet Calcium intake is low in the US Calcium intake is low in the US After hip fracture After hip fracture <25% given calcium and vitamin d <25% given calcium and vitamin d <10% treated with bone active agents <10% treated with bone active agents 50% no longer take medications at 1 year 50% no longer take medications at 1 year Keep trying Keep trying


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