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Osteoporosis Diagnosis and Therapy

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

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

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

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 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 X 700 mg 1200 mg 1000 mg 1300 mg Institute of Medicine 2010

6 Calcium: How much and what kind?
Do calcium supplements increase the risk of heart attack? Meta analysis:Medline, Embase, and Cochrane Central Register of Controlled Trials (1966-March 2010), 1-2 gms calcium no D in supplements Hazard ratio 1.31 p Dietary calcium no increased risk MI 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. 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 No increased incidence of CV disease mg/day Joshua R Lewis JBMR on line 2010 Look at the ASBMR website

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

9 CALCIUM SUPPLEMENTS Calcium carbonate 40% calcium
Acid is necessary to dissolve Patients on proton pump inhibitor Use calcium citrate Can’t swallow pills Chewables tasty!

10 Haney Calc Tissue 1998 Haney Cal Tissue 1998

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

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

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


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


17 THE 25(OH)D CONTINUUM “deficiency” “insufficiency” “normal” 10 20 30
? 10 20 30 40 50 60 (ng/ml) (ng/mL) 25 50 75 100 125 150 (nmol/L) PTH is elevated modified after Heaney CALCIUM ABSORPTION INCREASES

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

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

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

21 Replacing Vitamin D 1000 IU daily from the 25-30 range
Raises the level to about 40 ng/ml For significant deficiency 50,000 IU (D2) may give once a week for 8 weeks check 25OH D Holick et al 1998 lancet 351:805 May give 50,000 IU once a month safely for 5 years

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

23 Definition of Osteoporosis
A skeletal disorder characterized by… Excessive osteoclast-mediated bone resorption Compromised bone strength Increased risk of fracture at all skeletal sites Normal Osteoporosis According to the NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy, osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. In addition to the physical effects, osteoporosis has financial and psychosocial consequences, all of which significantly affect the individual, the family, and the community.1 The images show micro-computed tomography (microCT) scans of normal and osteoporotic paired iliac crest bone biopsies in a patient at 53 and then 58 years old. Note, the thinning and perforations of both the cortical and trabecular bone. 1. NIH Consensus Development Panel. JAMA. 2001;285: “Osteoporosis has financial, physical, and psychosocial consequences, all of which significantly affect the individual, the family, and the community.” –NIH Consensus Statement 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.

24 WHO Diagnostic Categories for Osteopenia
T-Score Osteopenia Osteoporosis Normal –2.5 –2 –1 WHO. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis; 1998. Guidelines established by the World Health Organization (WHO) in 1998 designated 4 diagnostic categories for osteoporosis in postmenopausal Caucasian women1: Normal: BMD representing a T-score ≥ –1.0 Osteopenia: BMD representing a T-score between –1.0 and –2.5 Osteoporosis: BMD representing a T-score < –2.5 Severe (established) osteoporosis: BMD representing a T-score < –2.5 and the presence of 1 or more fragility fractures In studies of populations, the lower the T-score, the higher the risk for fracture. These categories were established on the basis of data available at the time. The critical clinical question is, When should a physician intervene and begin treatment? Reference 1. World Health Organization. Guidelines for Preclinical Evaluation and Clinical Trials in Osteoporosis. Geneva, Switzerland: WHO; 1998:5-6. REMEMBER BONE STRENGTH ,DISEASE STATE WHO = World Health Organization.

25 BMD Testing Recommended by the Surgeon General’s report in 2004: US Preventive health task force 3/2011 Postmenopausal women with FRAX score 9.3% risk osteoporotic fracture Women>/=65 years of age with fractures - required by NCQA Younger women with risk factors Men and Women with fragility 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

27 No. of Women With Fractures
Population BMD Distribution, Fracture Rates, and Number of Women With Fractures Fracture rate 60 50 40 30 20 10 Fracture per 1000 Person-Years No. of women with fractures 450 350 300 250 200 100 150 50 400 No. of Women With Fractures BMD distribution The concept of fracture risk being a continuum is well demonstrated by looking at the frequency distribution of BMD T-scores in the population of women studied in NORA. The BMD T-score distribution displays a normal (Gaussian) distribution. If the WHO diagnostic categories for osteoporosis are considered as a diagnostic and fracture threshold, then this would imply that the majority of fractures would occur below a T-score of –2.5. This slide, drawn from the NORA study, shows the increasing incidence of fracture risk as a function of declining BMD status. (Note that these BMD measurements were made with peripheral rather than central dual-energy x-ray absorptiometry [DXA].)1 Approximately half of the fractures occur above a T-score of –2.5. Therefore, to prevent fractures, clinical consideration must be given as well to patients with T-scores above –2.5.1 Again, the concept here is that fracture risk is a continuum, not an absolute threshold. Reference 1. Siris ES, Chen Y-T, Abbott TA, et al. Bone mineral density thresholds for pharmacological intervention to prevent fractures. Arch Intern Med. 2004;164: BMD T-Scores (Peripheral) >1.0 1.0 to 0.5 0.5 to 0.0 0.0 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 Adapted from Siris ES, et al. Arch Intern Med. 2004;164:



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

31 Updated NOF Clinician’s Guide Incorporation of WHO Algorithm
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 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%

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

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

34 Risedronate and Ibandronate
Risedronate 150 mg Once a Month Minimum of 30-minute wait before eating Approved for prevention and therapy of Postmenopausal osteoporosis, male osteoporosis, steroid induced osteoporosis Enteric coated form now available Key Points: Additional less frequent dosing options are in development with 150 mg Once a Month 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 Only eliminate GI adverse events Adverse events and considerations Flu-like syndromes Injection-site reactions Renal toxicities (Check creatinine) Long-term use Osteonecrosis of the jaw Electrolyte abnormalities (hypocalcemia) Issues concerning the use of intravenous bisphosphonates Intravenous bisphosphonate administration usually occurs in a clinical setting, which significantly increases compliance. Adverse events associated with IV bisphosphonates: Flu-like syndromes Injection site reactions Renal toxicities (zoledronic acid) Adverse events associated with long-term use of bisphosphonates are osteonecrosis of the jaw and electrolyte abnormalities (hypocalcemia). Conte et al. Oncologist. 2004;9(suppl 4):28. Conte P, Guarneri V. Safety of intravenous and oral bisphosphonates and compliance with dosing regimens. Oncologist. 2004;9(suppl 4):28-37.

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

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

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

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



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 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 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 Warnings PI: Thigh or groin pain look for fracture – Plan film of the area may show sclerosis.


45 FDA opinion 3/10/10 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 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:

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 </= -2.5. Continuing alendronate for 10 years instead of stopping after 5 years reduces non-vertebral fracture risk in women without prevalent vertebral fracture whose FN T-score, achieved after 5 years of ALN, is </= -2.5, but does not reduce risk of NVF in women whose T-score is > -2 after 5 years could stop

47 Long Term Use– a Plan Drug holiday after 5-10 years
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) 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:

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 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. Don’t use orals in high risk patients BMJ Sep 1;341:c4444

49 Human Parathyroid Hormone
1-34 and 1-84 1 10 H2N- Ser Val Glu Ile Gln Leu Met His Asn Gly Lys Arg Trp Asp Phe 20 30 40 Parathyroid hormone (PTH) is secreted by the parathyroid glands and is an important regulator of blood calcium concentrations. Synthesis and secretion of PTH are stimulated by a decrease in blood calcium. PTH has three actions: 1) Increase the release of calcium from bone, 2) Reduce renal clearance of calcium, and 3) Stimulate the production of 1,25 (OH)2D3.. Human parathyroid hormone is a single chain polypeptide with 84 amino acids and a molecular weight of 9425 Da. The N-terminal region, 1-34, shown here in yellow, is biologically active and sufficient for regulation of mineral ion homeostasis. 50 70 60 80 - COOH

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

Kurland ES et al. Osteoporos Int. 2004;15:

52 Role of RANK Ligand in Bone Resorption
CFU-M Pre-Fusion Osteoclast RANKL RANK OPG Multinucleated Osteoclast Hormones Growth factors Cytokines Activated Osteoclast When RANK Ligand overwhelms OPG, bone resorption may become excessive leading to osteoporosis.1,2 1. Boyle WJ, et al. Nature. 2003;423: 2. Hofbauer LC, Schoppet M. JAMA. 2004;292: Osteoblasts Bone Formation In the presence of M-CSF CFU-M=colony forming unit macrophage M-CSF=macrophage colony stimulating factor Bone Resorption Adapted from Boyle WJ, et al. Nature. 2003;423: © 2007 Amgen. All rights reserved. Provided as an educational resource. Do not copy or distribute.

53 RANKL-Inhibitors: Mechanism of Action
OPG RANKL RANK Inhibitors CFU-M Cytokines Growth factors Hormones RANKL OPG Prefusion osteoclast Multinucleated osteoclast Denosumab, a RANKL inhibitor, blocks the binding of RANKL to RANK, resulting in the inhibition of osteoclast formation, function, and survival. Denosumab is a RANKL inhibitor that blocks the binding of RANKL to RANK and mimics the activities of the endogenous OPG (RANKL inhibitor).1 Blocking the activation of RANK results in the inhibition of osteoclast formation, function, and survival.2 By inhibiting osteoclast activity, bone loss is reduced.2 Active Osteoclast Osteoblast Stromal cells BONE Adapted from Boyle et al. Nature. 2003;423:337. 1. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354: 2. Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature. 2003;423:

54 Denosumab SC q6mo: Effect on Lumbar Spine BMD
-2 -1 1 2 3 4 5 6 Placebo (n=46) from baseline (%) Mean change Denosumab 14 mg (n=53) Denosumab 60 mg (n=46) Denosumab 100 mg (n=41) Denosumab 210 mg (n=46) Alendronate 70 mg/wk (n=46) Denosumab significantly increased lumbar spine BMD at 12 months; thus the primary end point of this study was achieved. The primary end point of this study was the mean percentage change from baseline in lumbar spine BMD at 12 months. The mean increase in lumbar spine BMD was 3.0% to 6.7% at 12 months across all denosumab dose groups (including the every-3-month doses), as compared with a 0.8% decrease for placebo (P<0.001). Significant changes in lumbar spine BMD were evident as early as 1 month in patients receiving 14 and 30 mg every 3 months and 60 mg every 6 months, compared with a 0.6% decrease with placebo (P<0.05). At 12 months, alendronate significantly increased BMD as compared with placebo. In exploratory comparisons, the mean change in lumbar spine BMD for alendronate (4.6%) was similar to denosumab. 2 4 6 8 10 12 60 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 Months Adapted from McClung et al. N Engl J Med. 2006;354:821. McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med. 2006;354:

55 Steven R. Cummings, M. D. , Javier San Martin, M. D. , Michael R
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)
Indication: postmenopausal osteoporosis With a high risk of fracture Sub q every 6 months (prefilled syringe) Contraindicated in hypocalcemia May use in renal insufficiency ( monitor calcium, phosphorus, magnesium)

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

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

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