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

11. HISTORY OF RENAL STONES
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:

12. DOES CALCIUM PREVENT FRACTURES?
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

14. DECREASES PTH SYNTHESIS
CA x P
INCREASES PHOSPHORUS ABSORPTION
DECREASES PTH SYNTHESIS

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

22. VITAMIN D AND FRACTURES
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

40. ALENDRONATE OVER 10 YEARS BONE AND LIBERMAN ET AL NEJM 2004;350:1189-1199

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

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

51. PTH 1-34 2 YEARS FOLLOWED BY BISPHOSPHONATE IN MEN
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