Transcript Vitamin D Deficiency 25 OH Vitamin D

Osteoporosis 2008
Compromised bone strength
predisposing to increased risk of
FRAGILITY FRACTURES
Michael T. McDermott MD
Director, Endocrinology and Diabetes Practice
University of Colorado Hospital
Disclosure
Speakers Bureau:

Eli Lilly

Novartis

Sanofi Aventis

Procter and Gamble
Objectives

Explain the new guidelines for the evaluation
of osteoporosis.

Review the treatment options for osteoporosis.

Discuss efficacy and safety issues related to
osteoporosis therapy.
Osteoporosis
Fragility Fractures (Low Trauma)
 Spine ~ 700,000/year in US
 Hip ~ 300,000/year in US
 Wrist ~ 250,000/year in US
Total Fragility Fractures: 1.5 million
Osteoporosis Pre-fracture Diagnosis
Bone Densitometry
 Normal
T-score > -1.0
 Osteopenia
T-score = -1.0 to -2.5
 Osteoporosis
T-score < -2.5
Diagnosis made at lowest site
Who to Treat in 2008?
Anyone with a Fragility Fracture
Vertebral Fracture
Hip Fracture
Less than 20% of patients with fractures
are treated
WHO Absolute Fracture Risk
Weighted Probability Calculation
Age
Sex
Previous
Fractures
Parental
Hip Fracture
Rheumatoid
Arthritis
Secondary
Osteoporosis
Height
Current
Smoking
Weight
Glucocorticoid
Use
Alcohol >
3 unit/day
Femoral
Neck BMD
Treat when probability of:
Hip Fracture > 3%
Major Osteoporosis Fracture > 20%
www.shef.ac.uk/FRAX
WHO Absolute Fracture Risk
Treat when probability of:
Hip Fracture > 3%
Major Osteoporosis Fracture > 20%
www.shef.ac.uk/FRAX
Who to Treat in 2008?
T-Score*
< -2.5
-1.0 to -2.5
> -1.0
Therapy Decision
High Risk: Treat All
Moderate Risk: Treat
a) Prior fracture
b) 2o cause of bone loss
c) FRAX > 3% hip fracture
> 20% major fracture
Low Risk:
Recheck in 1-2 years
* Based on DXA
Spine, Hip or FN
National Osteoporosis Foundation 2008.
Low Bone Mass
is not always
Osteoporosis
Differential Diagnosis of Low Bone Mass
 Osteoporosis
 Inflammatory Bowel Dz
 Osteomalacia
 Primary Biliary Cirrhosis
 Osteogenesis Imperfecta  Eating/exercise disorders
 Hyperparathyroidism
 Multiple Myeloma
 Hyperthyroidism
 Rheumatoid Arthritis
 Hyperprolactinemia
 Renal Failure
 Hypogonadism
 Idiopathic Hypercalciuria
 Cushing’s Syndrome
 Renal Tubular Acidosis
 Celiac Disease
 Mastocytosis
Evaluation of Low Bone Mass
 History and Physical Examination
 Routine laboratory
 Calcium, Phosphorus, Alkaline Phosphatase
 25 OH vitamin D
 eGFR (creatinine clearance)
 Testosterone (men)
 Urine (24 hour): calcium, creatinine
 Consider
 Tissue transglutaminase antibodies
 TSH
Non-Pharmacological
Therapy
Osteoporosis
Prevention and Treatment
 Calcium: 1000-1500 mg/day
 Vitamin D: 800-1200 units/day
 Exercise: aerobic and resistance
 Fall prevention
Calcium Supplements
Which are best?
Solubility
Calcium carbonate 0.14 mmol/L
Calcium citrate
7.3 mmol/L
40%
30%
Absorption
30% 30%
24% 24%
20%
10%
0%
Conclusions:
1. Calcium carbonate +
Calcium citrate are
both well absorbed
2. Calcium is absorbed
better with meals
Without
Food
Heaney R, Calc Tissue Int
1990; 46:300-304
With
Food
Proton Pump Inhibitors:
Reduce calcium carbonate
absorption by 60%
Increased Hip Fracture Risk
O’Connell M, Am J Med 2005; 118:778
Yang Y, JAMA 2006: 296:2947
Calcium Nutrition
 Dairy products (CaPO4) best calcium source
 Calcium: 300 mg/serving
 Calcium carbonate and calcium citrate both
well absorbed with meals
 Gastric acid needed for calcium absorption
 PPI: i calcium carbonate absorption 60%
 PPI: may h risk of hip fractures
 Ca citrate or higher dose of Ca carbonate if PPI
is used; keep urine calcium 150-300 mg/24 h
Heaney R, Calc Tissue Int 1990; 46:300
O’Connell M, Am J Med 2005; 118:778
Yang Y, JAMA 2006: 296:2947
Vitamin D Metabolism
Skin
Diet
Vitamin D
D3 Cholecalciferol
25 OH Vitamin D
D2 Ergocalciferol
D3 Cholecalciferol
Major storage form
of Vitamin D
ng/ml quantities
PTH
1,25 (OH)2 Vitamin D
Active form of
Vitamin D
pg/ml quantities
Vitamin D Nutrition
Maintenance
 Optimal intake: 800-1200 U/day
 Safe intake: up to 2000 U/day
 Goal 25 Vitamin D level: 30-100 ng/ml
Vitamin D Deficiency
 25 OH Vitamin D < 10 ng/ml: 50,000* U D BIW x 3 mos.
 25 OH Vitamin D 10-20 ng/ml: 50,000* U D QW x 3 mos.
 25 OH Vitamin D 20-30 ng/ml: 1000-2000 U D3 QD x 3 mos.
*50,000 U caps now
available as D2 or D3
Thomas M, N Engl J Med 1998; 338:777
Armas L, J Clin Endocrinol Metab 2004; 89:5387
Dawson Hughes B, Osteoporosis Int 2005, epub
Dawson Hughes B, Am J Clin Nutr 2004; 80:1763-6S
Pharmacological
Therapy
Bone Remodeling
OC
Old
Bone
Bone Remodeling
OB
Old
Bone
OC
OB
OB
Bone Remodeling
Ca P04
Old
Bone
Calcifying Osteoid
New
Bone
Bone Remodeling
RANK-L Signaling
OPG
RANK-L
Ca P04
RANK
Old
Bone
OB
OC
OB
OB
RANK: Receptor Activator of Nuclear Factor kb
RANK-L: Rank Ligand
OPG: Osteoprogeterin (decoy receptor for RANK-L)
New
Bone
RANK-L
h Bone resorption
OPG
i Bone resorption
Osteoporosis Treatment
Anti-Resorptive Agents
Bisphosphonates
Raloxifene
Calcitonin
Estrogens
Rank-L Inhibitors
Anabolic Agents
Teriparatide
Strontium
Growth hormone
Fluoride
OB
Old
Bone
OC
OB
OB
New
Bone
Anti-Resorptive
Therapy
Osteoporosis Treatment
Anti-Resorptive Agents
Bisphosphonates
Raloxifene
Calcitonin
Estrogens
Rank-L Inhibitors
OB
Old
Bone
OC
OB
OB
New
Bone
Oral Bisphosphonates

Risedronate [Actonel]




Alendronate [Fosamax]




5 mg q day
35 mg q week
150 mg q month
10 mg q day
70 mg q week (+ Vit D3 2800 U)
70 mg q week (+ Vit D3 5600 U)
Ibandronate [Boniva]

150 mg q month
Oral Bisphosphonates all approved for treatment of Osteoporosis
Intravenous Bisphosphonates

Zoledronic Acid [Reclast]*



Ibandronate [Boniva]*



5 mg in 100 ml NS, IV over 15-30 min.
Once a year
3 mg in NS, IV over 15-30 sec.
Every 3 months
Pamidronate [Aredia]


30 mg in 250-500 ml NS, IV over 2-4 hrs.
Every 3 months
*FDA approved for treatment of Osteoporosis
Anabolic Therapy
Osteoporosis Treatment
Anabolic Agents
Teriparatide
Strontium
Growth hormone
Fluoride
OB
Old
Bone
OC
OB
OB
New
Bone
Teriparatide Effects on Bone Matrix
Micro CT Studies: Baseline and After 20 Months
Before Teriparatide Treatment
After Teriparatide Treatment
Jiang et al, J Bone Miner Res.
2002;17(Suppl 1):S135
Fracture Reduction Demonstrated
Women with Postmenopausal Osteoporosis
Agent
Vertebral Fx Hip Fx Nonvertebral Fx
Alendronate
Yes
Yes
Yes
Risedronate
Yes
Yes
Yes
Zoledronate
Yes
Yes
Yes
Ibandronate
Yes
No
No
Raloxifene
Yes
No
No
Calcitonin
Yes
No
No
Teriparatide
Yes
No
Yes
Chesnut C, AM J Med 2000, 109:267
Ettinger B, JAMA 1999, 282:637
Writing Group, JAMA 2002, 288:321
Black DM, NEJM 2007, 365:1809
Harris S, JAMA 1999, 282:1344
Black D, Lancet 1996, 348:1535
Delmas P, Osteo Int 2004, 15:792
Black D, NEJM 2007, 365:1809
Osteoporosis Treatment Decisions
Non-Fracture Patient
Normal
Osteopenia
T-score -1.0
Osteoporosis
-2.5
-3.0
20 cause of bone loss, or
FRAX > 3% hip fx, or
> 20% major fx
Calcium
Vitamin D
Exercise
Bisphosphonates
Raloxifene
Fracture Patients
Bisphosphonates
Teriparatide
Bisphosphonates
Raloxifene
Bisphosphonates
Teriparatide
Osteonecrosis of the Jaw
Osteonecrosis of the Jaw
Non-healing exposed bone in oral cavity for > 8 weeks
Osteonecrosis of the Jaw
Primary Diagnosis
Multiple myeloma
Metastatic breast cancer
Metastatic prostate cancer
Metastatic disease (other)
Osteoporosis
Paget’s disease
Cases
47%
39%
6%
4%
4%
1%
Literature Review:
368 cases of ONJ
Woo S, Ann Intern Med 2006; 144:753
Osteonecrosis of the Jaw
Medication
Cases
Zoledronic acid
35%
Pamidronate
31%
Zoledronic acid and pamidronate 28%
Alendronate (oral)
4%
Risedronate (oral)
.3%
Ibandronate (oral)
.3%
Literature Review:
368 cases of ONJ
Woo S, Ann Intern Med 2006; 144:753
Osteonecrosis of the Jaw

Highest Risk:
High dose IV BP; Cancer; Chemotherapy;
Radiation; Steroids; Trauma; Poor oral
hygiene; Periodontal disease

Bisphosphonate causality not validated

Discuss; follow appropriate dental guidelines

DC bisphosphonate x 3 mos reasonable; no data
Atypical Fractures
of the
Femoral Diaphysis
Atypical Fractures of Femoral Diaphysis
FIG. 3. Case 3
Copyright ©2008 The Endocrine Society
Visekruna, J Clin Endocrinol Metab 2008;93:2948-2952
Atypical Fractures of Femoral Diaphysis

Thigh pain, discomfort, weakness

Transverse fractures of the femoral shaft

Bilateral in 2/3 of patients

Delayed healing or non-healing

Prolonged use (> 5 years) of alendronate +/-
other anti-resorptive medications

Severely suppressed bone turnover
Atrial Fibrillation
and Bisphosphonates
Atrial Fibrillation and Bisphosphonates
FDA Press Release Oct 1, 2007

Conducting ongoing safety review of atrial
fibrillation with all bisphosphonates.

No population currently identified at being at
increased risk of atrial fibrillation.

Do not suggest healthcare providers alter
bisphosphonate prescribing practices.
http://www.fda.gov/medwatch/safety/2007/safety07.htm#bisphosphonates
Osteoporosis Medications
and
Renal Disease
Renal Failure and Bisphosphonates

FDA: Bisphosphonates not recommended if
eGFR < 30 ml/min (Stage 4 and 5 CKD)

Limited published experience with
eGFR 15-30 ml/min - appears safe and effective

No experience with eGFR < 15 ml/min: may be
toxic to kidneys +/or bone (adynamic bone)
Monitoring Therapy
Monitoring Treatment Response
Least Significant Change

Minimum serial change that is a true change

LSC must be established for each instrument

Serial changes only valid on same instrument

Calculate for absolute BMD (g/cm2), not T-score
LSC in Clinical Trials
Spine 2.7%
Hip 5.7%
Cummings S, JAMA 2000; 283:1318
Bonnick S, J Clin Densitom 2001; 4:1
Lenchik L, J Clin Densitom 2002; 5:S1
Monitoring Treatment Response
Response
BMD
> 50% fracture
reduction
Response
Therapy
Started
~ 20-25% fracture
reduction
> LSC
Cummings S, JAMA 2000; 283:1318
Chapurlat R, Osteo Int 2005; 16:842
Wasnich R, J Clin Endocrinol Metab 2000; 85:231
On Same
Machine
Response
Failure
Monitoring Treatment Response
ISCD Recommendations
Response
No Therapy Change
BMD
Therapy
Started
Response
No Therapy Change
Response
Failure
Evaluation
Therapy Change
Failure to Respond to Therapy
Common Causes
 Poor compliance
 Calcium / Vitamin D deficiency
 Co-morbid conditions
 Medications
 Wrong dose or dose interval
 Lack of efficacy
Lewiecki M, J Clin Densitom 2003; 6:307-14
Failure to Respond to Therapy
Management
 Poor compliance g Education
 Calcium / Vitamin D deficiency g Correct
 Co-morbid conditions g Correct
 Medications g Adjust
 Wrong dose or dose interval g Correct
 Lack of efficacy g Change therapy
Lewiecki M, J Clin Densitom 2003; 6:307-14
Thank You