1. health and fitness
2. disease

E d u c a t i o n a l P ro g r a m s f o r 2014
Bone Health 2014
Saturday
March 29, 2014
UT Southwestern Medical Center
T. Boone Pickens Biomedical Building
6001 Forest Park Rd.
Dallas, Texas 75390
Sponsored by
UT Southwestern Department of Internal Medicine
and the Office of Continuing Medical Education
Office of Continuing Medical Education presents:
Bone Health 2014
March 29, 2014
T. Boone Pickens Biomedical Building Auditorium
University of Texas Southwestern Medical Center
Dallas, Texas
Course Director: Khashayar Sakhaee, MD
PROGRAM OVERVIEW
The aim of this symposium is to provide the latest knowledge in the diagnosis and treatment of primary as well
as secondary bone loss as a result of drug treatments, chronic kidney disease and bone disease after bariatric
surgery. The format of this symposium will be a series of lectures presented by experts in the field on a variety
of topics followed by panel discussions where the audience can directly interact with the speakers. The
highlighted talk will be given by Dr. Sundeep Khosla, M.D., a world-renowned expert in the field of osteoporosis.
TARGET AUDIENCE
This symposium is designed for family physicians, internists, geriatricians, endocrinologists, gynecologists,
rheumatologists, orthopedic surgeons, nephrologists, and other health care providers who are interested in the
care of patients with osteoporosis and bone-related diseases. Students and trainees are encouraged to attend.
EDUCATIONAL OBJECTIVES
Upon completion of this activity, participants should be able to link the educational objectives to Core
Competencies (New Knowledge and Performance) and be able to:




Review the pathophysiology and evaluation of primary and secondary osteoporosis
Understand and discuss information on the latest diagnostic tools to be used in patients with primary
and secondary osteoporosis
Distinguish and identify the optimal medical treatment for their patients
Discuss the latest controversies in the selection of treatment for the management of patients with
osteoporosis
EDUCATIONAL METHODS
Didactic presentations, Question and Answer Sessions, Presentation Handouts
ACCREDITATION AND DESIGNATION STATEMENTS
Physicians:
The University of Texas Southwestern Medical Center at Dallas is accredited by the Accreditation Council for
Continuing Medical Education to provide continuing medical education for physicians.
The University of Texas Southwestern Medical Center at Dallas designates this live activity for a maximum of
6.25 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their
participation in the activity.
Physical Therapists:
Awaiting approval from the Texas Physical Therapy Association for CCU’s
EVALUATION
Evaluation by online questionnaire will address program content, presentation, and possible bias.
GENERAL INFORMATION
Certificates
CME Certificates & Attendance Certificates
Keep the yellow copy for your permanent records (you are responsible for maintaining your own CME records).
Leave white copy at the registration desk. Credit will not be awarded unless the original white copy is on file.
Special Assistance and Dietary Needs
Americans With Disabilities Act
In compliance with the Americans with Disabilities Act, UTSW will make reasonable efforts to accommodate
persons with disabilities. Please see the Registration Desk with your special assistance needs.
Dietary Needs
Continental breakfast, refreshment breaks, and lunch are provided. Please see the Registration Desk with your
specific dietary needs.
Mobile Phones/Pagers
As a courtesy to the speakers and fellow participants, please turn silence all mobile phones/pagers.
Photography Policy
Any person attending may be photographed or videotaped, and by your attendance, you give permission to use
your image in possible future marketing publications including print, online, and video.
Syllabus/Slides
Handout materials may not directly coincide with the speakers’ presentations for the following reasons:
 Changes were made to the slides after handout materials were produced.
 The speaker excluded proprietary slides for inclusion in the handout materials.
COURSE DIRECTOR
Khashayar Sakhaee, MD
Professor
Laura Kim Pak Professorship in Mineral
Metabolism Research
BeautiControl Cosmetics Inc. Professorship in
Mineral Metabolism and Osteoporosis
Department of Internal Medicine
UT Southwestern Medical Center
Dallas, Texas
FACULTY
Ugis Gruntmanis, MD
Associate Program Director
Internal Medicine Residency Program
Associate Professor
Department of Internal Medicine
UT Southwestern Medical Center
Dallas, Texas
Orson Moe, MD
Professor
The Charles Pak Distinguished Chair in Mineral
Metabolism; Donald W. Seldin Professorship in
Clinical Investigation
Department of Internal Medicine, Physiology
UT Southwestern Medical Center
Dallas, Texas
Craig Rubin, MD
Professor
Margaret and Trammell Crow Distinguished
Chair in Alzheimer’s and Geriatric Research
Walsdorf Professorship in Geriatrics Research;
Seymour Eisenberg Distinguished Professorship in
Geriatric Medicine
Department of Internal Medicine
UT Southwestern Medical Center
Dallas, Texas
Naim Maalouf, MD
Associate Program Director
Endocrinology Fellowship Program
Associate Professor
Department of Internal Medicine
UT Southwestern Medical Center
Dallas, Texas
Ellen Wilson, MD
Associate Professor
Department of Obstetrics & Gynecology
UT Southwestern Medical Center
Dallas, Texas
Sydney Bonnick, MD
Medical Director
Institute for Women’s Health
Texas Woman’s University
Denton, Texas
Sundeep Khosla, MD
Dr. Francis Chucker and
Nathan Landow Professor of Medicine
Mayo Clinic
Rochester, Minnesota
DISCLOSURE OF FINANCIAL RELATIONSHIPS
The University of Texas Southwestern Medical Center (UTSW) Office of Continuing Medical Education (OCME)
makes every effort to develop CME activities that are scientifically based, accurate, current, and objectively
presented. In accordance with the Accreditation Council for Continuing Medical Education Standards for
Commercial Support, UTSW has implemented a mechanism requiring everyone in a position to control content
of an educational activity (e.g., directors, planning committee members, contributors, peer reviewers, CME staff)
to disclose any relevant financial relationships with commercial interests (drug/device companies) and
manage/resolve any conflicts of interest prior to the activity. Individuals must disclose to participants the
existence or non-existence of financial relationships: 1) at the time of the activity or 12 months prior; and 2) of
their spouses/partners.
The University of Texas Southwestern Medical Center does not view the existence of interests or relationships
with commercial entities as implying bias or decreasing the value of a presentation. It is up to the participants to
determine whether the interests or relationships influence the presenter with regard to exposition or conclusions.
In addition, contributors have been requested to use generic names for products (drugs/devices), and to include
various products within and across classes. If at any time during this activity you feel that there has been
commercial or promotional bias, please inform us by using the commercial bias comments box in the evaluation
form. Please answer the question about balance in the CME activity evaluation candidly.
Some drugs/devices identified during this activity may have United States Food and Drug Administration (FDA)
clearance for specific purposes only or for use in restricted research settings. The FDA has stated that it is the
responsibility of the individual physician to determine the FDA status of each drug or device that he/she wishes
to use in clinical practice and to use the products in compliance with applicable law.
To comply with ACCME policies, the University of Texas Southwestern Medical Center requires that all faculty
disclose any unlabeled use or investigational use (not yet approved for any purpose) of pharmaceutical and
medical device products, and provide adequate scientific and clinical justification for such use. Physicians are
urged to fully review all the available data on products or procedures before using them to treat patients.
FACULTY DISCLOSURES
Speaker Name
Sundeep Khosla
Name of Commercial Interest
Merck
Amgen, Bone Therapeutics
Nature of Relevant
Relationship
Research Activities
Formal Advisor
The following speakers and planning committee members have no relevant financial relationships to
disclose:
Ugis Gruntmanis, MD
Naim Maalouf, MD
Orson Moe, MD
Craig Rubin, MD
Khashayar Sakhaee, MD
Ellen Wilson, MD
Sydney Bonnick, MD
Tajuanekja Brown – CME Coordinator
Veronica Mason – CME Supervisor
DISCLAIMER
This symposium has been planned to be well-balanced and objective in discussion of comparative treatment
regimens, and the symposium format allows for the free scientific exchange of ideas. Information and opinions
offered by the speakers represent their viewpoints. Conclusions drawn by the audience should be derived from
careful consideration of all available scientific information.
Bone Health 2014
Saturday, March 29, 2014
T. Boone Pickens Biomedical Building Auditorium
AGENDA
8:00 am
Breakfast and Registration
8:25 am
Introduction – Khashayar Sakhaee, MD
SESSION I
Bone Health Building Blocks
8:30 am
Bone Biology for the Clinician – Naim Maalouf, MD
9:00 am
Estrogen and Bone – Ellen Wilson, MD
9:30 am
Lifestyle (diet and exercise) Management of Bone Disease – Naim Maalouf, MD
10:00 am
Bone Density and Bone Quality – Sydney Bonnick, MD
10:30 am
Case Study and Panel Discussion
10:50 am
Break and Exhibit Time
SESSION II
Pharmacological Management of Bone Disease
11:10 am
12:00 pm
Current and Evolving Pharmacological Options for the Treatment of Osteoporosis –
Sundeep Khosla, MD
Calcium and Vitamin D – Craig Rubin, MD
12:30 pm
Case Study and Panel Discussion
12:50 pm
Lunch
SESSION III
Bone Disease in Special Populations
1:50 pm
Renal Bone Disease (CKD) – Orson Moe, MD
2:20 pm
Bariatric Surgery and Bone Disease – Khashayar Sakhaee, MD
2:50 pm
Management of Patients with Prior Fracture – Ugis Gruntmanis, MD
3:20 pm
Case Study and Panel Discussion
4:00 pm
Adjourn
The University of Texas Southwestern Medical Center gratefully acknowledges educational
grants from the following companies in support of this CME activity:
Amgen, Inc.
The University of Texas Southwestern Medical Center gratefully acknowledges the exhibitors
from the following companies in support of this CME activity:
Lilly USA
Session I: Bone Health Building Blocks
Bone Biology for the Clinician
Naim Maalouf, MD
Bone Biology for Clinicians
Naim Maalouf, MD
Department of Internal Medicine
UT Southwestern Medical Center
Dallas, TX, USA
Disclosures
• I have no financial relationships with commercial interests
• I will be discussing non-FDA approved treatments
Outline
• Osteoporosis and Bone Strength
• Bone Turnover
• Bone Cells
Osteoclasts, Osteoblasts, Osteocytes
1
Osteoporotic Fractures are Common, Costly
2,000,000
800,000
others
1,500,000
380,000
forearm
1,000,000
280,000
hip
500,000
540,000
vertebral
0
Fractures from
Osteoporosis
ER Visits
Hospitalizations
Nursing Home
Placement
Risk factors for osteoporotic fractures
Female Gender
Early Menopause / Amenorrhea- Hypogonadism in Men
Older Age
Low body weight /BMI
White or Asian Race
Family history of hip fracture
or osteoporosis
Previous fragility fracture
Smoking
Excessive alcohol use
Low calcium intake
Vitamin D deficiency
Prolonged immobilization
Glucocorticoid Therapy
Poor visual acuity or other fall-related risk
Osteoporosis
A skeletal disorder characterized by compromised bone
strength predisposing to an increased risk of fracture
Bone strength reflects the integration of two main features:
bone density and bone quality.
NIH Consensus Panel on Osteoporosis, JAMA, 2001
2
Determinants of Bone Strength
Bone Mass
Bone Quality
Mass
• Density
• Geometry
• Size
Bone Remodeling
Micro-architecture
Tissue Properties
• Mineralization
• Collagen
structure,cross-links
• Microdamage
Bone Strength
FALL
FRACTURE
Determinants of Bone Strength
Kalkwarf HJ, Nutr Today, 2006
The Bone Remodeling Cycle
Lining cells Osteoclasts
Pre-osteoblasts
Osteoblasts
3 weeks
3 months
Resorption
Formation
Osteocytes
3
Osteoporosis: Imbalance in Bone Remodeling
Formation
Resorption
BMD, resorption markers and fracture risk
4.8
4
(odds ratio)
Risk of hip fracture
5
3
2.7
2.2
2
1
0
low hip BMD
low hip BMD
+ high CTX
high CTX
Garnero P, J Bone Miner Res, 1996
Bone turnover and bone strength
Evidence suggesting that elevated turnover is detrimental to bone strength
- Prospective trials in postmenopausal women
- African Americans have lower turnover and lower fracture risk
- Antiresorptives decrease turnover and lower fracture risk
Evidence suggesting that decreased turnover is detrimental to bone strength
- Osteopetrosis
- Local bone radiation increases fracture risk
- Long-term glucocorticoid administration
- Long-term bisphosphonates and Atypical Femoral Fractures
- Animal studies using high doses of bisphosphonates
4
Bone strength
Bone turnover and bone strength
Bone Turnover
Weinstein RS, JBMR, 2000
Changes in Bone Mass Throughout Life
Determinants of Peak Bone Mass
Genetics
Nutrition
PEAK BONE MASS
20-30 years of age
Hormones
Lifestyle
5
Postmenopausal Bone Loss
Estrogen Deficiency
Marrow Stromal Cells,
Monocytes, T-cells
Osteoblasts
Kidney
 TNF-, IL-1, IL-6, INF
 RANKL,  OPG
 Ca
Reabsorption
Osteoclast
Recruitment,
Activity
Negative Ca
Balance
 Bone
Resorption
Age-Related Bone Loss
Aging
 Sun
Exposure
 Renal
Function
 Calcium
Intake
Estrogen
Deficiency
 Vitamin D
Synthesis
 Calcium
Absorption
Osteoblast
 Bone
Formation
Secondary
Hyperparathyroidism
 Bone
Loss
Glucocorticoid-Induced Osteoporosis
Glucocorticoids
BONE
Neuroendocrine system
Calcium Metabolism
Muscle
Increased risk of
fracture
Canalis E, Osteoporosis Int, 2007
6
The Bone Remodeling Cycle
Lining cells Osteoclasts
Pre-osteoblasts
Osteoblasts
3 weeks
3 months
Resorption
Formation
Osteocytes
Origin of Bone Cells
HematopoieticSCs
MesenchymalSCs
Runx2
Growth Factors
M-CSF, RANKL
Monocytes
Macrophages
PreOsteoclasts
RANKL
Adipocytes
Chondrocytes
PreOsteoblasts
Wnt signaling
PTH
Osteoclast
Osteoblasts
Osteocytes
Bone
Intercellular Communication within the BMU
OPG
RANK
RANKL
Sclerostin
Wnt
lrp5
Ephrin-B2 EphB4
RANKL
IGF-1
TGF-β
Osteocytes
7
Osteoporosis Therapy: Targeting Remodeling
Formation
Resorption
Targeting Bone Resorption
RANK
Osteoclast
RANKL
αVβ3 Integrin
ClC7
V-ATPase
H+
Clcathepsin K
Bone
The RANK / RANKL / OPG System
Wild type
RANKL KO
OPG KO
RANK KO
Osteopetrosis Osteopetrosis Osteoporosis
Blair, Nature Clin Prac Onc, 2006
8
RANKL-inhibition
• Denosumab: Fully human monoclonal antibody that blocks RANKL
RANK
RANKL
Osteoclast
Osteoblast
Denosumab
Bone
Osteocytes
Cathepsin K
• Major protease involved in the degradation of type I collagen and
other noncollagenous proteins
• Mainly expressed in osteoclasts and secreted into resorption pits
Osteoclast
Osteoblast
cathepsin K
Bone
Osteocytes
Cathepsin K Inhibition
• Odanacatib: Orally available highly selective cathepsin K inhibitor
• Phase II trial: Significant improvement in lumbar and spine BMD
• Suppresses resorption markers without altering bone formation
Bone H, J Bone Miner Res, 2010
Rachner, Lancet, 2011
9
Targeting Bone Formation
Sclerostin as a Therapeutic Target
• Romosozumab: humanized monoclonal ab blocking sclerostin
• Romosozumab: ↑ bone formation and ↓ bone resorption
• Blosozumab: humanized anti-sclerostin monoclonal ab being
developed as an anabolic agent for treating osteoporosis
• Phase 1 study: Dose-dependent responses in bone turnover
markers, BMD: 3.4-7.7% increase in spine BMD at day 85
McClung M, N Engl J Med, 2014
McColm J, J Bone Miner Res, 2013 online
Bone Biology for Clinicians: Summary
-Osteoporosis: Compromised bone strength (density and quality)
-Osteoporosis results from dysregulated bone remodeling
-Medications that reduce fracture risk modulate bone remodeling
-Recent understanding of bone biology has resulted in new
pharmacological approaches targeting osteoporosis
-Newer agents may cause uncoupling of the processes of bone
formation and bone resorption
10
Estrogen and Bone
Ellen Wilson, MD
Estrogen and Bone
TLE
Ellen E. Wilson, M.D.
Department of Obstetrics and Gynecology
Division of Reproductive Endocrinology University of Texas Southwestern Medical Center
Dallas, Texas, USA
AGENDA
• Adolescent and young adult bones
• Menopause and bones
• Treatment options
Gabrielle Douglas
Gabby Douglas
Bones are important
Bone Mass by Age and Sex
Women
Women
Bone Mass
Bone Mass
Men
Men
Menopause-Associated
Menopause-Associated
Bone
Bone Loss
Loss
Age
Age(years)
(years)
Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999;1366-73.
Riggs BL, Melton LJ III. N Engl J Med. 1986;314:1676-86.
Estrogen and Bone Health
1) Childhood (0-12)
2) Adolescence (13-18)
Calcium requirements in females
•
•
•
•
•
Children - 800 mg/d
Adolescents – 1300 mg/d
Premenopausal – 1000 mg/d
Pregnant or lactating – 1500 mg/d
Postmenopausal – 1200 mg/d
The vast majority of young women at the
age of 13 have a calcium intake inadequate
to achieve peak bone mass.
Factors Influencing Peak Bone
Mass in Adolescence POSITIVELY
•
•
•
•
•
•
•
•
•
•
•
Race – African American
Heredity – NO family history of osteoporosis
Gender – be a male
Pubertal timing – at the normal age
Hormonal status – normal estrogen levels
Nutrition – adequate calcium, Vit D, protein, etc
Activity – some but not TOO much
Weight – normal to a little overweight
Strength – weight bearing exercise is good
Smoking/ETOH – NO and very little
Drugs – no steroids, etc
Title IX 1972
Female Athlete Triad - 1980
A- Amenorrhea
E- Eating disorders (low energy availability)
O- Osteoporosis
Estrogen-deficient states
Anorexia
HPO Axis
HPO Axis
Hypogonadism and Bones
Nature Reviews Endocrinol 8, 395-404 (July 2012)
Estrogen-deficient states
Turner’s Syndrome (45X)
Depo-Provera
‘The Shot’
Progesterone-only
Lowers estrogen levels
Depo-Provera
‘The Shot’
Is associated the short-term bone loss while on it
Berenson et al, Obstet Gynecol 103:899, 2004
Clark et al, Fertil Steril 82:1580, 2004
Kaunitz et al, Contraception 74:90,2006
Men and Estrogen
‘Males with mutations in the estrogen
receptor-alpha or who have aromatase
deficiency grow slowly and have markedly
reduced bone densities.’
‘In men, both androgens and estrogens are
necessary in order for males to reach optimal
bone.’
Smith et al, NEJM 331:1056, 1994
Carani et al NEJM 337: 91, 1997
Estrogen and Bone Health
1) Critical hormone in both males and females
2) Anti-resorption factor
3) Enhances availability of vitamin D
4) Increased efficiency of calcium absorption
5) Estrogen-dependent growth factors and cytokines
involved in bone remodeling
6) Mechanism of action for estrogen protection of
bones is not entirely understood
Estrogen and Bone Health
1) Childhood (0-12)
2) Adolescence (13-18)
3) Reproductive years (13-51)
4) Menopause (>51)
Bone Mass by Age and Sex
Women
Women
Bone Mass
Bone Mass
Men
Men
Menopause-Associated
Menopause-Associated
Bone
Bone Loss
Loss
Age
Age(years)
(years)
Adapted from Finkelstein JS. Cecil Textbook of Medicine. 21st ed. 1999;1366-73.
Riggs BL, Melton LJ III. N Engl J Med. 1986;314:1676-86.
Menopause
Cessation of menses for one year
Average age is 51.3 years
Life Expectancy and Menopause
Fritz and Speroff, Clinical Gynecologic Endocrinology and Infertility, Eighth Edition, Lippincott and
Williams 2011
‘The Change of Life”
#1 Vasomotor Symptoms
Hallmark of menopause
Hot flashes/night sweats
- twice a week to 20 times a day
Incidence: 75% of women
25% severely
HRT is effective in 92%
Cause: decline in estrogen
Women's HOPE Study
Number of Hot Flushes Over 12 Weeks
for EE Population (n = 241))
Placebo
0.625
0.45
0.3
Placebo
0.625/2.5
0.45/2.5
0.45/1.5
0.3/1.5
*Adjusted for baseline.
Mean hot flushes at baseline = 12.3 (range 11.3–13.8); Women’s HOPE = Women’s Health, Osteoporosis, Progestin,
Estrogen; EE = Efficacy-evaluable population included women who recorded taking study medication and had at least
7 moderate-to-severe flushes/week or at least 50 flushes per week at baseline.
Utian WH, et al. Fertil Steril. 2001;75:1065-79.
#2 Urogenital Atrophy
Vaginal dryness, thinning, atrophy
Itching, burning, minor bleeding
Dyspareunia (painful intercourse)
Up to 50% of women 3 years after
menopause
#2 Urogenital Atrophy
Estrogen vaginal therapy - is the most
effective therapy
1) 2 marketed creams
2) vaginal ring (3 month)
3) slow-release tablets
No need for added progesterone
#3 Osteoporosis
HRT is FDA approved for the prevention of
osteoporosis
Randomized controlled trial evidence shows
that HRT reduces postmenopausal
osteoporotic fractures, including hip, spine
and all non-spine fractures. ?
The Women’s HOPE Trial:
Changes in Spine BMD
CEE
CEE/MPA
Intent-to-treat population only; Women’s HOPE = Women’s Heart, Osteoporosis, Progestin, Estrogen;
CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate.
Intent-to-treat
population
only; Women’s
HOPE = Women’s Heart, Osteoporosis, Progestin, Estrogen;
Lindsay R,
et al. JAMA.
2002;287:2668-76.
CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate.
Lindsay R, et al. JAMA. 2002;287:2668-76.
Benefits of HRT
Vasomotor symptoms
Mood changes
 Cognitive function
 Sleep quality
 Urogenital symptoms
 Skin changes
Later:
 Osteoporosis
 Colon cancer


1980s-90s….
“estrogen for life” philosophy
To prevent heart disease, osteoporosis,
and dementia in women
Women’s Health Initiative
(WHI) - 2002
Randomized Controlled Trial by the NIH
instituted to address HRT as it relates
to:
1) Heart Disease
2) Cancer
3) Osteoporosis
Women’s Health Initiative
(WHI) - 2002
Randomized Controlled Trial by the NIH
instituted to address HRT as it relates
to:
1) Heart Disease - worse
2) Breast Cancer - worse
Colon Cancer - better
3) Osteoporosis - better
2012 Position Statement from
North American Menopause
Society (NAMS)
The primary indications for HRT remains:
1) vasomotor symptoms
2) urogenital atrophy (local therapy)
Low dose (HOPE data)
Short duration (<5 years)
Osteoporosis? (consider alternate therapy)
Case #1
19 yo white female complains of:
Primary amenorrhea
Competitive gymnast since the age of 5. Now college varsity
team but they will not let her compete. She is 5’1” and 93#.
No breast development until given low doses of premarin:
0.3 mg X 6 months, 0.625mg X 6 months, 0.09 mg X 6
months – followed by cyclic Provera. Calcium, Vitamin D
Then placed on oral contraceptive pill.
DEXA: osteopenia (spine -2.1), normal (hip)
NOW: 25 yo runner (8 miles/d), 5’1” and 86# - no periods
when she goes off the OCPs. Now seeing a counselor.
Case #2
54 yo white female complains of:
No periods for over a year, hot flashes and nights sweats,
vaginal dryness, and is miserable. She is healthy, and has no
family history of breast cancer or heart disease. Her mother
(80) has severe osteoporosis. DXA scan shows a T-score of 1.5 at the femoral neck and and -1.7 at the lumbar spine.
MENOPAUSAL
VASOMOTOR sxs
OSTEOPENIA and strong FH
Is she a candidate for HRT?
Case #2
1) Estrogen + Progesterone (HRT)


80-95% improved
Oral vs transdermal
2) SSRIs and SNRIs

50% improved
3) Behavioral therapy
4) Other Medications (gabapentin)
5) Black cohosh
6) Raloxifene - NO
Case #2
For her Bone Health:
a) Calcium
b) Vitamin D
c) Weight-bearing exercise
d) Avoid smoking/limit alcohol
e) Continue HRT for at least 5 years
Mammogram every year
Case #3
52 yo Asian female history:
Also complains of hot flashes, night sweats, no period for
over 6 months. Strong family history of breast cancer in her
mother and sister. Strong family history of heart disease in
her father and brother. She has hypertension and elevated
cholesterol. Mother (80) has severe osteoporosis. DXA scan
shows T score of -1.6 at the femoral neck and -2.0 at the
lumbar spine.
MENOPAUSAL
RISK FACTORS FOR BREAST CA, HEART DZ
OSTEOPENIA AND STRONG FH
Is she a candidate for HRT?
Case #3
1) Estrogen + Progesterone - NO


80-95% improved
Oral vs transdermal
2) Raloxifene - NO
2) SSRIs and SNRIs

50% improved
3) Behavioral therapy
4) Other Medications (gabapentin)
5) Black cohosh
Case #3
For her Bone Health:
a) Calcium
b) Vitamin D
c) Weight-bearing exercise
d) Avoid smoking/limit alcohol
e) Consider a bisphosphonate, proliaCOnsid
Case #4
54 yo female seen for her annual exam:
She has not had a period in 6 years. Very few hot flashes, not
bothered by them. She has no medical problems. Very
strong family history of breast cancer in her mother and
sister. Her DXA scan shows a T score of -2.5 at the lumbar
spine and -1.9 at the femoral neck.
MENOPAUSAL
RISK FOR BREAST CANCER AND OSTEOPOROSIS
FEW VASOMOTORS SYMPTOMS
What is an appropriate treatment for this patient?
Raloxifene
1) Selective estrogen receptor modulator (SERM)
2) FDA approved for the prevention and treatment of
menopausal bone loss
3) Inhibits bone resorption – 60 mg/day
4) Approved for the reduction in risk of breast
cancer in women at risk for osteoporosis and
breast cancer
5) Side effects:
Hot flashes, joint pains
Increased risk of thromboembolism including
deep vein thrombosis, pulmonary embolus
Raloxifene Improves BMD in Postmenopausal
Women With Osteoporosis
Femoral Neck
Mean % Change in BMD
Lumbar Spine
Months
Months
P < 0.001 for all comparisons
Ettinger B, et al. JAMA. 1999;282:637-45.
Summary and Conclusions
Final Summary
1) Adolescent and Young Adults years
Pay attention to risk factors:
1) Poor nutrition, excess exercise, too thin
2) What are menstrual cycles like??
2) Postmenopausal years
Bone loss is most rapid several years immediately
following menopause
Options: HRT, bisphosphonates, other
Lifestyle (diet and exercise) Management
of Bone Disease
Naim Maalouf, MD
Lifestyle and Bone Health
Naim Maalouf, MD
Department of Internal Medicine
UT Southwestern Medical Center
Dallas, TX, USA
Determinants of Bone Mass
• Osteoporosis: Multifactorial etiology
• In twin studies, environmental factors account for 40‐50 % of variance in BMD
• Nutrition and physical activity: – Bone Mass: Peak bone mass; Rate of bone loss
– Muscle Mass: Prevention of sarcopenia
Outline
• Diet
–
–
–
–
–
–
–
Dietary calcium and vitamin D
Dietary proteins
Sodium
Caffeine
Soft drinks
Fruits, vegetables
Others: Magnesium, Vitamin K, Strontium
• Exercise
• Other Lifestyle Factors
Dietary Calcium and Vitamin D
• Recommended Daily Allowance for Calcium:
– 1,000 mg/day in men 19‐70 yrs, non‐pregnant women 19‐50 yrs
– 1,200 mg/day in men > 70 years, women > 50 years
• Major Dietary Sources of Calcium:
– Dairy products: 300 mg/ 8 oz milk, ~150 mg/6 oz yogurt, cheese
– Fortified foods: almond milk, soy milk, rice milk, orange juice
– Fibers in vegetables reduce calcium absorption
• Limited Dietary Sources of Vitamin D:
– Fatty fish, shiitake mushrooms, cod liver oil
– Fortified food
Dietary Proteins and Bone Health
• Recommended Daily Allowance: 0.8 mg/Kg BW/ day
• Low protein intake common in elderly and hip fracture patients
• Protein supplementation post‐fracture: trend to attenuated bone
loss, better muscle strength (? IGF‐1), reduced complications
• Excessive protein intake (> 1.6 mg/Kg BW/day) associated with
hypercalciuria, and potentially negative calcium balance
• Impact of vegetable proteins and soy proteins on bone health is
inconclusive
Avenell A, Cochrane Database Syst Rev, 2010
Maalouf NM, J Clin Endocrinol Metab, 2011
Salt Intake and Bone Health
• Recommended intake: < 2,300 mg sodium/day (< 100 mEq/day)
• Recommended intake in DM, HTN, CKD, age >50: < 1,500 mg/day
• Average intake in U.S. population: 3,400 mg/d
• Higher salt intake associated with greater calcium excretion:
Urine Ca increases by 40 mg for each 100 mEq Na
• Sustained negative calcium balance leads to bone loss
40 mg/day x 365 days = 14.6 g calcium/year
Caffeine and Osteoporosis
• Caffeine: Negative calcium balance in rats (renal, fecal losses) and greater osteoclastic resorption
• Human: Higher caffeine intake associated with lower milk intake and slightly higher urine Ca loss (5 mg/day/6 oz coffee)
• > 330 mg caffeine/day (4 cups of coffee): modest increase in osteoporotic fractures, mostly in women with low Ca intake
Lee DR, Bone, 2014
Soft Drinks and Bone Mass
• Soda associated with lower BMD in adolescents and adults
• Mechanisms: Milk displacement; caffeine; phosphoric acid
Tucker KL, Am J Clin Nutr, 2006
Fruits, Vegetables and Osteoporosis
• Minerals such as potassium, magnesium, trace minerals, and vitamins B, K, and C may be important to bone health
• None individually proven to ↑ BMD or ↓ fracture • Fruits and vegetables are excellent sources of many of these nutrients, may create an alkali environment, and provide other potentially beneficial antioxidants and compounds
Magnesium and Bone Health
• 60% of body magnesium stored in bone
• Magnesium deficiency associated with osteoporosis, impaired mechanical properties in animals
• Direct vs. Indirect Effects
Castiglioni S, Nutrients, 2013
Magnesium and Bone Health
• Relating Mg intake to BMD confounded by coexisting intake of other nutrients (fruits)
• Some Mg supplements raise urine calcium excretion
• No evidence that Mg supplementation prevents osteoporosis in the general population
• Mg may prevent constipation from calcium supplements
Castiglioni S, Nutrients, 2013
Vitamin K and Bone Health
• Vitamin K is essential for ‐carboxylation of glutamic acid residues in osteocalcin, other components of bone matrix • Diets low in vit. K associated with lower BMD, higher risk of hip fractures in elderly
• RCTs with vitamin K1 or K2 did not increase BMD Binkley NK, J Bone Miner Res, 2009
Emaus N, Osteoporosis Int, 2010
Strontium and Bone Health
Strontium and Bone Health
• Strontium is incorporated into hydroxyapatite, replacing Ca, leading to dramatic BMD increases • Strontium ranelate: Approved in Europe for osteoporosis Rx‐
Reduces vertebral fractures and nonvertebral fractures. Common side effects: GI; small increased risks of venous thrombosis, seizures, and abnormal cognition
• Many Sr salts available on the Internet referencing data from strontium ranelate trials as proof of efficacy
Outline
• Diet
–
–
–
–
–
–
–
Dietary calcium and vitamin D
Dietary proteins
Sodium
Caffeine
Soft drinks
Fruits, vegetables
Supplements: Magnesium, Vitamin K, Strontium
• Exercise
• Other Lifestyle Factors
Exercise and Bone Mass
• Significant impact of physical activity in childhood and adolescence on peak bone mass
• Elite athletes and chronic exercisers have higher BMD than age‐matched, non‐exercising subjects
• Tennis players: BMD higher in playing vs. non‐playing arm
Exercise and Bone Mass
Sanchis‐Moysi, Eur J Appl Physiol , 2010
Exercise and Bone Mass
∆ Bone Density (% / year)
• Complete immobilization or lack of gravity: Rapid bone loss (30% decline in BMD per year)
• Impact of exercise on BMD, falls and fracture risk variable in adults with osteoporosis
Activity (hours / day)
Marcus R
Exercise and Osteoporosis
• 4,320 participants from 43 RCTs, mostly postmenopausal
• Variable type of exercises:
– Weight‐bearing: • Low‐force (walking, tai‐chi)
• High force (running, jogging, dancing, jumping)
– Non‐weight‐bearing:
• Low force (low‐load, high repetition strength training)
• High force (progressive resistance strength training)
– Combination of above
• Duration of intervention: 1 year in 26 studies, > 1 yr in 7
• Frequency of intervention: 2–3 times/wk in 33/43 studies
Howe TE, Cochrane Database Sys Rev, 2011
Exercise and BMD
• Spine BMD from 24 studies with 1,441 participants: Significant difference, +0.85% (95% CI: +0.62 to +1.07)
• Exercises associated with higher spine BMD:
‐ Low force weight‐bearing (tai‐chi, walking)
‐ High force non‐weight‐bearing (progressive resistance)
‐ Combination
• Fem neck BMD from 19 studies with 1,338 participants: No significant difference: ‐0.08% (95% CI: ‐1.08 to +0.92)
• Hip BMD from 13 studies with 863 participants: No significant difference: +0.41% (95% CI: ‐0.64 to +1.45)
• High force weight‐bearing (jogging, dancing), combination
Howe TE, Cochrane Database Sys Rev, 2011
Exercise and Fracture Risk
• Fractures examined in 4 studies enrolling 539 participants:
Study
Fractures/Total:
Exercise
17 / 312
Control
Odds Ratio, 95% CI
Odds Ratio, 95% CI
24 / 227
• Combination exercises associated with significantly lower fracture risk in 2 studies
Howe TE, Cochrane Database Sys Rev, 2011
Reducing Falls
• 1 in 3 adults > 65 falls each year
• 159 trials with 79,193 participants
• Tai Chi, multiple‐component home‐based and multiple‐
component group exercise significantly reduce fall risk • Exercise interventions reduced risk of fall‐related fracture (RR: 0.34, 95% CI 0.18‐0.63; 6 trials, 810 participants)
Gillespie LD, Cochrane Database Sys Rev, 2012
Exercise and Osteoporosis ‐ Summary
‐ Immobilization is associated with rapid bone loss
‐ Exercise: Improves peak bone mass in children/adolescents
Slows rate of bone loss in postmenopausal and older individuals to a small extent, best data for spine BMD
Reduces the risk of falls
‐ Exercise interventions with fracture data as endpoint are scant
Exercise and Bone Health
Patients without Osteoporosis
Moderate‐ to high‐intensity activities to load the bone:
‐ Jogging, running, jumping
‐ High impact aerobics
‐ High‐weight, low‐repetition resistance exercises
‐ Tennis, squash, basketball Patients with Osteoporosis
Low‐intensity activities to load the bone:
‐ Walking, stair climbing, Tai Chi
‐ Low‐impact or water aerobics
‐ Low‐weight, high‐repetition resistance exercises
‐ Standing on one leg, heel‐to‐
toe walking, stepping sideways
Reducing Falls
• Home hazards modification in community‐living elderly. Best in high risk groups, and when led by OT
• Vitamin D supplements in vitamin D deficient patients
• Adjustment of psychotropic meds, poly‐pharmacy • Outdoor anti‐slip shoe devices in elderly in icy weather
• Multifaceted podiatry to patients with specific foot disability • First eye cataract surgery • Pacemakers in patients with cardio‐inhibitory carotid sinus hypersensitivity
Gillespie LD, Cochrane Database Sys Rev, 2012
Smoking and Osteoporosis
‐ Independent risk factor for fractures
‐ Dose, duration‐dependent
‐ Nicotine vs. non‐nicotine effects
‐ Direct effects on bone cells ‐ Altered estrogen metabolism: Low estradiol, early menopause
‐ Lower intestinal Ca absorption
‐ Altered calciotropic hormones
‐ Impaired fracture healing
‐ Reversible impact with cessation
Yoon V, Maalouf NM, Sakhaee K, Osteoporosis Int, 2012
Trochanter BMD, g/cm2
Current smokers
Past smokers
Never smokers
Gerdhem P, Osteoporosis Int, 2002
Alcohol Consumption and Osteoporosis
‐ Independent risk factor for falls and fractures
‐ Deleterious at ≥ 3 drinks/day
‐ Direct effects: altered osteoblast/clast activity
increased osteocyte apoptosis fat accumulation in bone marrow changes in oxidative stress
altered wnt/DKK1 signaling
‐ Indirect effects: Hormonal changes, higher fall risk, drop in caloric intake, change in body composition
Maurel DB, Osteoporosis Int, 2012
Other Lifestyle Factors and Osteoporosis
How to Build Your Bones While You Sleep
• Sleep deprivation associated with lower BMD in children, adults and in rodents; possible involvement of melatonin
Casazza, J Clin Densitom, 2011; Fu X, Bone, 2011; Everson, Exp Biol Med, 2012; Ostrowska, Endo Reg, 2003
Whole Body Vibration:
Yes, No, or Maybe?
• Whole body vibration therapy: Variable design, protocols; scant evidence on the benefits /harms for osteoporosis
Torvinen, J Bone Miner Res. 2003 ; Verschueren, J Bone Miner Res 2004; Wysocki A, Ann Int Med, 2011 Lifestyle and Osteoporosis ‐ Summary
• Environmental factors account for 40‐50% of BMD variance
• For most healthy adults, supplementation with nutrients other than calcium and vitamin D is not required
• Protein intake in moderation is beneficial
• The impact of exercise on BMD in older adults is small
• Exercise interventions should be tailored to the patient, with a focus on weight‐bearing and balance exercises
• Fracture risk increases significantly with smoking and with ≥ 3 alcoholic drinks/d; increases slightly with ≥ 4 coffees/d
Lifestyle and Bone Health
QUESTIONS?
Bone Density and Bone Quality
Sydney Bonnick, MD
BMD and Bone Quality
Sydney Lou Bonnick, MD, FACP
Department of Kinesiology and Biological Sciences
University of North Texas
Denton, Texas, USA
2013 NOF Recommendations for BMD Testing
• Women age 65 and older and men age 70 and older
• Younger postmenopausal women, women in the menopausal transition and men age 50‐69 based on risk factors
• Adults who fracture after age 50
• Adults with a condition or taking a medication associated with bone loss
2013 ISCD Recommendations for BMD Testing
• Women age 65 and older and men age 70 and older
• Younger postmenopausal women, women in the menopausal transition and men age 50‐69 based on risk factors
• Adults who fracture after age 50
with a fragility fracture
• Adults with a condition or taking a medication associated with bone loss
• Anyone receiving or being considered for pharmacologic therapy
The Relationship Between Declining BMD and Increasing Vertebral Fracture Risk
Vertebral Fracture Incidence
(per 1,000 patient‐years)
60
Spine
Distal radius
Calcaneus
50
40
30
20
10
0
2 SD
1 SD
Mean
–1 SD
–2 SD
Bone Mass
Wasnich RD et al. J Nucl Med 1989;30:1166–1171.
Hip Fracture Rate by # of Risk Factors and Calcaneal BMD Tertile
27.3
30
14.7
20
9.4
5.6
4
10
1.9
2.6
1.1
1.1
0
Lowest
>5
3 ‐ 4
0 ‐ 2
Middle
Highest
BMD Tertile
Cummings SR, et al. N Engl J Med 1995;332:767‐773.
Bone Density and Fracture Risk by Age
10‐Year Hip Fracture Probability
Age
Kanis JA, et al. Osteoporos Int 2001;12:989‐995
80
70
60
50
FRAX and LS/FN Discordance
FRAX may underestimate or overestimate major osteoporotic fracture risk when the lumbar spine T‐score is much lower or higher (>1 Standard Deviation discrepancy) than the femoral neck T‐score.
2010 ISCD‐IOF Official Positions on FRAX
Adjustment of FRAX for LS/FN Discordance
Increase / decrease Increase
major osteoporotic fracture FRAX
estimate by one tenth for each rounded T‐score difference between the lumbar spine and femoral neck.
FN T‐score ‐1.7
MOFx Probability 18%
LS T‐score ‐3.5
Offset = 3.5 – 1.7
Offset = 1.8
Rounded offset = 2.0
2 x 0.1 MOFx Probability
2 x 0.1 x 18% = 3.6%
Adj MOFxProbability = 18% + 3.6%
Adj MOFxProbability = 21.6%
Leslie WD, et al. Osteoporos Int 2011;22:839‐847.
FRAX Predicted 10‐Year Hip Fracture Probability vs. Observed
12
% Observed
10
8
6
4
2
0
0%
2%
4%
Predicted
6%
8%
n=35764 women age ≥50; f/u mean 5.3 yrs; 12450 women untreated
Leslie WD, et al. J Bone Miner Res 2012;27:1243‐1251.
FRAX and Steroid Dose
There is a dose relationship between glucocorticoid
use of greater than 3 months and fracture
risk. The average dose exposure captured within
FRAX is likely to be a prednisone dose of 2.5—
7.5 mg/day or its equivalent. Fracture probability
is under‐estimated when prednisone dose is greater
than 7.5 mg/day and is over‐estimated when
prednisone dose is less than 2.5 mg/day.
2010 ISCD‐IOF Official Positions on FRAX
% Adjustment of FRAX for Steroid Dose
Dose
Prednisolone
Equivalent (mg/day)
Age (years)
40
50
60
70
80
90
All Ages
Hip Fx
Low
<2.5
‐40
‐40
‐40
‐40
‐30
‐30
‐35
High
>7.5
+25
+25
+25
+20
+10
+10
+20
Major Osteoporotic
Fx
Low
<2.5
‐20
‐20
‐15
‐20
‐20
‐20
‐20
High
>7.5
+20
+20
+15
+15
+10
+10
+15
Adapted from Kanis JA, et al. Osteoporos Int 2011;22:809‐816.
BMD Testing Intervals
• Re‐assess fracture risk in the untreated individual
• Re‐assess BMD
– Precision and the LSC
– Expected Rate of Change in BMD
• Therapy
• Disease State
Projected FRAX 10‐Year Hip Fracture Risk Over 15 Years in a 65‐Year‐Old Woman by Baseline T‐Score
10‐Year Hip Fracture Risk (%)
14
T = ‐2.0
12
10
T = ‐1.5
8
6
T = ‐1.0
4
X
2
X
3%
X
0
0
5
10
15
Time (years)
Adapted from Reid IR, Gamble GD. J Bone Miner Res 2014;29:389‐391.
1991 and 1993 Consensus Conference Definitions of Osteoporosis
“...a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.”
Consensus Development Conference. Am J Med 1991;90:107‐110.
Consensus Development Conference. Am J Med 1993;94:646‐650.
Osteoporotic Bone
Normal & Osteoporotic Bone
Courtesy of Dr. David Dempster
2005 David W. Dempster, PhD
Courtesy of Alan Boyde
The Trabecular Bone Score or TBS
TBS = 1.360
TBS = 1.115
Correlations Between DXA‐Based BMD TBS and CT‐Based Parameters of Bone Microarchitecture at the LS—Ex Vivo Study
BV/TV
TBS
0.528*
TbTh
TbSp
TbN
ConnD
‐0.553** ‐0.643*** 0.751*** 0.821***
*p=0.0033; **p=0.0015
***p<0.0001
Hans D, et al. J Clin Densitom 2011;14:302‐312.
Correlations Between DXA‐Based LS‐TBS and HRpQCT‐
Based Parameters of Bone Microarchitecture at the Radius & Tibia—In Vivo Study
BV/TV
TbTh
TbSp
TbN
TbSpSD
Radius
0.342***
0.266**
‐0.253**
0.207*
‐0.253**
Tibia
0.328***
0.135
‐0.244***
0.202*
‐0.254***
*p<0.05; **p<0.01; ***p<0.001
Silva B, et al. J Clin Densitom 2013;16:554‐561.
Fracture Incidence by Areal BMD and Lowest Quartile of LS‐TBS
Below TBS Threshold
At or Above TBS Threshold
Fracture Incidence (%) 35
p<0.01 p<0.05 p=0.06
30
25
20
15
10
5
0
Osteoporotic Non‐Osteoporotic Osteopenic
Normal
n=570 postmenopausal women; mean f/u 7.8 yrs; TBS threshold 1.209
Boutroy S, et al. Osteoporos Int 2013;24:77‐85.
OR’s for Measurement in Lowest vs. Highest Tertile of BMD or TBS in Diabetes
3.5
Adjusted OR
3
2.61
2.5
2
1.5
1
0.66
0.8
0.68
0.5
0
L1‐L4 BMD
Fem Neck BMD Total Hip BMD
Leslie WD, et al. J Clin Endocrinol Metab 2013;98:602‐609.
L1‐L4 TBS
Adjustment of FRAX Probability According to LS‐TBS
Change to FRAX
Major Osteoporotic Fracture Probability
Change to FRAX
Hip Fracture Probability
Lowest Tertile
Increase 25%*
Increase 30%*
Middle Tertile
No Change
No Change
Highest Tertile
Decrease 21%*
No Change
L1‐L4 TBS
*p<0.001
n=42,170 women age 50 and older; mean f/u 5.6 yrs
Leslie W, et al. J Clin Densitom 2013;16:267‐268.
Session II: Pharmacological Management
of Bone Disease
Current and Evolving Pharmacological
Options for the Treatment of
Osteoporosis
Sundeep Khosla, MD
CURRENT AND EVOLVING PHARMACOLOGICAL
OPTIONS FOR THE TREATMENT OF OSTEOPOROSIS
Sundeep Khosla, M.D.
Mayo Clinic
DISCLOSURES
Scientific Advisory Boards
Bone Therapeutics
Amgen
Investigator-Initiated Research Grant
Merck
CURRENTLY APPROVED (US FDA) THERAPIES
FOR OSTEOPORSIS
• Estrogen:
• SERM:
• Bisphosphonates:
• RANKL inhibitor:
• PTH:
Anti-resorptive
Oral, transdermal
Raloxifene
Alendronate, risedronate,
ibandronate, zoledronic acid
Denosumab
Anabolic
Teriparatide
EVOLVING AND NEW DIRECTIONS FOR
TREATING AGE-RELATED BONE LOSS
• Low dose PTH, PTHrP
• Sclerostin inhibition/modulating Wnt action
• Cathepsin K inhibition
EVOLVING AND NEW DIRECTIONS FOR
TREATING AGE-RELATED BONE LOSS
• Low dose PTH, PTHrP
• Sclerostin inhibition/modulating Wnt action
• Cathepsin K inhibition
Once Weekly PTH- aBMD end point
Telephone Screening N=348
Excluded=245
Screening Visit 1 N=103
Excluded=51
Screening Visit 2 N=52
Excluded=2
Randomization
PTH
Complete
N=25
N=25
N=50
Placebo
Complete
N=24
N=25
Discon (AE)
N=1
Black et al, 2008, JCEM
PTH 1-84 once Weekly Increases L-S BMD-2%
CTX TRANSIENTLY INCREASES AND THEN DECLINES,
P1NP INCREASES 80% THEN DECLINES
Rosen, Black et al, JCEM,2008
PTH once weekly Fracture Trial-56ug: 1-34
Nakumara, 2012
Spine and total hip BMD Changes with PTH
PTH reduced all fragility fractures
by six months
Vertebral Fractures Reduced by 80%
Turnover Markers with once weekly PTH
OC
P1NP
NTx
Calcium
PTHrp
PTHrp is produced by several cell types
Acts on the PTHr like PTH
Mobilizes calcium by stimulating resorption
Important during lactation for mobilization
of calcium, and during linear growth
NSCLC- 2/3 make this protein
Synthesized by tumor cells metastatic to bone
BA058-SC (aPTHrP): Phase 2 Clinical Trial Design
• Randomized, parallel-group, placebo-controlled, comparator-controlled, Phase 2
Dose-finding study
• Statistically powered for the major efficacy outcomes of BMD change
• Study sites in USA, Argentina, India and UK
• All patients received concomitant Vitamin D and Calcium (4 weeks prior to
treatment through treatment period)
Treatment
Regimen
Study Medication
Daily Dose (SC)
Number of
Patients
1
BA058-SC
20 µg
45
2
BA058-SC
40 µg
43
3
BA058-SC
80 µg
43
4
FORTEO
20 µg
45
5
Placebo
–
45
Total
221
Hattersley et al., Endo Soc, 2012
Phase 2 Results Show Faster and Greater
Improvement in Hip BMD
Total Hip BMD % Change from Baseline, Mean (SE), ITT Population (n=221)
Dose Selected for
Phase 3 Pivotal
Trial
Phase 2 Results Show Faster and Greater
Improvement in Spine BMD
Spine BMD, % Change from Baseline at 24 Weeks, Mean (SE), ITT Population (n=221)
Phase 2 Results Show Continued Strong
Improvement in Spine BMD at 48 Weeks
Spine BMD: % Change from Baseline, Mean (SE), Extended Population (n=55)
Phase 2 Results Show Faster and Greater BMD Improvements
Across Critical Vertebral and Non-Vertebral Sites
Results Demonstrate BA058-SC Safety Profile and Robust Anabolic Effect at 24 Weeks
BA058-SC
80 µg*
FORTEO
20 µg*
Spine BMD
6.7%
5.5%
Hip BMD
2.6%
0.5%
Mean % Change
*n=221
• Safe and well-tolerated
• 50% reduction in occurrence of hypercalcemia vs. Forteo at highest
dose
EVOLVING AND NEW DIRECTIONS FOR
TREATING AGE-RELATED BONE LOSS
• Low dose PTH, PTHrP
• Sclerostin inhibition/modulating Wnt action
• Cathepsin K inhibition
WNT SIGNALING IN BONE
Khosla, Westendorf, and Oursler JCI 118:421, 2008
WNT SIGNALING IN BONE
Khosla, Westendorf, and Oursler J Clin Invest 118:421, 2008
WNT SIGNALING IN BONE (Cont’d)
Khosla, Westendorf, and Oursler J Clin Invest 118:421, 2008
EFFECTS OF SCLEROSTIN Ab ON BONE MASS
AND STRUCTURE
Li et al. J Bone Miner Res 24:578, 2009
***
***
300
Tb. BV/TV, %
Tb. vBMD, mg/cm3
CHANGES IN BMD AND BONE VOLUME
FRACTION
200
100
30
***
***
20
10
0
0
SHAM Vehicle Scl-AbII
SHAM Vehicle Scl-AbII
OVX
OVX
***P<0.001 vs OVX + vehicle
Li et al. J Bone Miner Res 24:578, 2009
EFFECTS ON BONE FORMATION
OVX
BFR/BS (μm3/μm2/day)
MAR, μm/day
OVX
†††
*
2.0
1.5
1.0
0.5
0
SHAM Vehicle Scl-AbII
OVX
†††
***
1.2
0.8
0.4
0
SHAM Vehicle Scl-AbII
OVX
*P<0.05, ***P<0.001 vs OVX + vehicle
†††P<0.001
vs SHAM + vehicle
DUAL EFFECTS ON OSTEOBLASTS AND
OSTEOCLASTS
Li et al. J Bone Miner Res 24:578, 2009
EFFECTS OF A SINGLE DOSE OF AMG 785 ON
BONE TURNOVER IN WOMEN
Percent change from baseline
PINP
sCTx
200
60
160
40
20
120
0
80
-20
40
-40
0
-60
-40
0
8
15 22 29 36 43 50 57 64 71 78 85
Study Day
-80
0
8
15 22 29 36 43 50 57 64 71 78 85
Study Day
Padhi et al. J Bone Miner Res 26:19, 2011
AMG 785 (ROMOSOZUMAB): PHASE 2
TRIAL RESULTS - BMD
McClung et al., NEJM 370:412, 2014
AMG 785 (ROMOSOZUMAB): PHASE 2 TRIAL
RESULTS – BONE TURNOVER
EVOLVING AND NEW DIRECTIONS FOR
TREATING AGE-RELATED BONE LOSS
• Low dose PTH, PTHrP
• Sclerostin inhibition/modulating Wnt action
• Cathepsin K inhibition
BONE REMODELING AND THE BONE
REMODELING COMPARTMENT (BRC)
Khosla, Westendorf, and Oursler JCI 118:421, 2008
BONE REMODELING AND THE BONE
REMODELING COMPARTMENT (BRC)
ANTI-RESORPTIVE
Khosla, Westendorf, and Oursler JCI 118:421, 2008
BONE REMODELING AND THE BONE
REMODELING COMPARTMENT (BRC)
ANTI-RESORPTIVE
FORMATION-STIMULATING
Khosla, Westendorf, and Oursler JCI 118:421, 2008
BONE REMODELING AND THE BONE
REMODELING COMPARTMENT (BRC)
ANTI-RESORPTIVE
FORMATION-STIMULATING
Khosla, Westendorf, and Oursler JCI 118:421, 2008
CATHEPSIN K INHIBITORS
Background
• Cysteine protease expressed in osteoclasts which degrades the
bone matrix
• Mutations in the cathepsin K gene cause pycnodysostosis
(Toulouse-Lautrec syndrome): osteosclerosis, abnormalities of
the head, face, and spine
• Cathepsin K knock out mice have a similar phenotype (Saftig et
al. PNAS 95:13453, 1998)
CATHEPSIN K INHIBITORS
• Balicatib (AAE581)
- Development stopped because of morphea-like skin
reactions in 9/709 (1.3%) of the subjects
- Likely due to lack of specificity for cathepsin K and inhibition
of cathepsins B and L, which are expressed in the skin
CATHEPSIN K INHIBITORS
• Balicatib (AAE581)
- Development stopped because of morphea-like skin
reactions in 9/709 (1.3%) of the subjects
- Likely due to lack of specificity for cathepsin K and inhibition
of cathepsins B and L, which are expressed in the skin
• Odanacatib (ODN, MK-0822) has greater specificity for
cathepsin K and is in Phase III trials
PHASE II STUDY OF ODN: BMD
Bone et al. JBMR 25:937, 2010
Placebo
-2
Weighted LS mean
FN BMD
4
2
0
-2
01 3
6
N = 399
12
Month
18
N = 320
24
change from baseline
0
Weighted LS mean %
2
change from baseline
4
6
change from baseline
ODN 50 mg
6
LS BMD
Weighted LS mean %
change from baseline
Weighted LS mean %
6
Total hip BMD
4
2
0
-2
0
-2
-4
-6
one-third radius BMD
01 3
6
N = 399
12
Month
18
N = 320
24
PHASE II STUDY OF ODN: RESORPTION MARKERS
Bone et al. JBMR 25:937, 2010
Placebo
ODN 50 mg
sCTx, ng/mL
0
-20
-40
-60
-80
-100
01 3
6
12
Month
N = 399
18
80
change from baseline
Geometric weighted LS mean
change from baseline
Geometric weighted LS mean
uNTx, nmol/mmol
20
40
0
-40
-80
24
01 3
N = 320
6
12
Month
N = 399
18
24
N = 320
PHASE II STUDY OF ODN: FORMATION MARKERS
Bone et al. JBMR 25:937, 2010
Placebo
ODN 50 mg
sP1NP, ng/mL
60
40
20
0
-20
-40
01 3
6
N = 399
12
Month
18
80
change from baseline
Geometric weighted LS mean
80
change from baseline
Geometric weighted LS mean
sBSAP, ng/mL
60
40
20
0
-20
-40
24
N = 320
01 3
6
12
Month
N = 399
18
24
N = 320
ODN: PHASE II STUDY
• Increase in BMD at multiple sites
• Decrease in bone resorption
• Transient decrease in bone formation; at baseline by 24
months
• No significant skin reactions
ODANACATIB: 5 YEAR EXTENSION DATA
PBO/PBO
50 mg/PBO/PBO
50mg/50mg/50mg
Total Hip
12
11.9%
8
4
-0.4%
0
-2
0.8%
0 3 12
24
36
48
60
1 6
18
30
42
54
Mean % change
from baseline (SE)
Mean % change
from baseline (SE)
Lumbar Spine
12
8.5%
8
4
-0.1.8%
0
-2
0.7%
0 3 12
24
36
48
60
1 6
18
30
42
54
Month
Month
Langdahl et al. J Bone Miner Res 27:2251, 2012
SUMMARY OF ODN STUDIES IN OVX’D
MONKEYS
• Preservation of bone mass at multiple sites
• Increase in relatively normal appearing osteoclasts on
bone surfaces
• Decrease in bone resorption markers
• Decrease in trabecular bone formation rates
• Increase in periosteal bone formation rates
Cusick et al. J Bone Miner Res 27:524, 2012
SCHEMATIC OF THE BONE REMODELING
COMPARTMENT
PROPOSED MECHANISMS FOR OSTEOCLASTOSTEOBLAST COUPLING
Khosla S. J Bone Miner Res 27:506, 2012
EFFECTS OF BISPHOSPHONATES, DENOSUMAB ON
OSTEOCLAST-OSTEOBLAST COUPLING
Bisphosphonates, denosumab
Khosla S. J Bone Miner Res 27:506, 2012
EFFECTS OF BISPHOSPHONATES, DENOSUMAB
VERSUS ODN ON OSTEOCLAST-OSTEOBLAST
COUPLING
Bisphosphonates, denosumab
Khosla S. J Bone Miner Res 27:506, 2012
ODN
EFFECTS OF BISPHOSPHONATES, DENOSUMAB
VERSUS ODN ON OSTEOCLAST-OSTEOBLAST
COUPLING
Bisphosphonates, denosumab
ODN
EFFECTS OF BISPHOSPHONATES, DENOSUMAB
VERSUS ODN ON OSTEOCLAST-OSTEOBLAST
COUPLING
Bisphosphonates, denosumab
ODN
OSTEOCLAST CONDITIONED MEDIA
STIMULATES MINERALIZATION
600
Mature
Osteoclast
CM
ALIZARIN RED
Alizarin red units
Osteoclast
Precursor
CM
500
400
300
200
100
0
Pederson et al. PNAS 105:20764, 2008
OC Precursor Conditioned Media
Mature OC Conditioned Media
*
MARROW-DERIVED OSTEOCLAST
COUPLING FACTOR EXPRESSION
Pederson et al. PNAS 105:20764, 2008
S1P IS AN IMPORTANT “CLASTOKINE” UPREGULATED
FOLLOWING CAT K DEFICIENCY
Wild-type
Cat K KO
Lotinum et al.
JCI 123:666, 2013
APPROVED AND PENDING DRUGS
Anti-resorptive Drugs
Estrogen, SERMs
Bisphosphonates
Calcitonin
Strontium
RANKL antibody
Cathepsin K inhibitors
Formation Stimulating Drugs
• Teriparatide - Low dose PTH,
PTHrP
• Sclerostin antibody
•
•
•
•
•
•
•
•
•
•
Which drug, when?
Combinations?
What sequence?
Duration/drug holidays?
Calcium and Vitamin D
Craig Rubin, MD
Calcium and Vitamin D Craig D. Rubin MD Department of Internal Medicine
UT Southwestern
Dallas, TX, USA
Calcium Controversies •
•
•
•
Does supplementation prevent fractures?
Differing recommendations
Who is most likely to benefit, if any?
Is calcium supplementation harmful ? Outline • Calcium and vitamin D physiology • IOM recommendations • Evidence for primary or secondary prevention of osteoporosis • Calcium supplement controversy/concerns • Review USPSTF recommendations
Calcium Vitamin D and Bone • >98 % of calcium exists in bone • Key component of hydroxyapatite [Ca10 (PO4)6
(OH)2] which provides strength and rigidity to bone • Ca++ Intracellular messenger • Vitamin D essential for calcium metabolism
• Vitamin D effect on muscle and balance Factors that Influence Calcium
Metabolism with Aging
PTH
Serum Ca++
Concentration
Recommended Dietary Intake of Elemental Calcium for Healthy Persons.
Bauer DC. N Engl J Med 2013;369:1537-1543
Widely Available Calcium Supplements.
Bauer DC. N Engl J Med 2013;369:1537-1543
Effect of Calcium and Vitamin D Supplementation on Bone Density in Men and Women 65 Years of Age or Older
Bess Dawson‐Hughes, M.D., Susan S. Harris, D.Sc., Elizabeth A. Krall, Ph.D., and Gerard E. Dallal, Ph.D.
N Engl J Med 1997;337:670‐6
Cumulative Probability of Hip Fracture and Other Nonvertebral Fracture
Chapuy et al. NEJM 1992;327:1637
• 1460 Australian women 70 yrs and older
• Calcium carbonate 600 mg twice a day or placebo
• Fracture, vertebral deformity, adverse effects
Arch Intern Med. 2006;166:869‐875
Calcium and bone in older age
57% took tablets > 80% of time
Prince et al Arch Intern Med. 2006;166:869‐875
Zhu et al Clin Biochem 2012
Calcium and bone in older age
Prince et al Arch Intern Med. 2006;166:869‐875
Zhu et al Clin Biochem 2012
Oral vitamin D3 and calcium for secondary prevention of low‐trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo‐
controlled trial
• 5292 from UK aged 70 or older mobile with low trauma fracture* • 800 IU oral D3, 1000 mg Ca, D3 and Ca or placebo (24 to 62 months)
• Primary outcome subsequent low trauma fracture
*0.1 to 0.2% (n=8 of 5292) had baseline clinical vertebral fracture
Lancet 2005; 365: 1621–28
Cumulative Rates of all Fractures and of Hip Fractures by Group The RECORD Trial Group
55% taking tablets at 24 months
Lancet 2005; 365: 1621–28
• 12 weeks with 800 IU of vitamin D and 1200 mg of calcium versus 1200 mg of calcium
• The number of fallers did not differ between the treatment arms (RR 0.7; 95% CI, 0.3–1.5).
• Mean number of recurrent falls among fallers was lower in the CalD‐
group (p 0.045)
• Musculoskeletal function improved significantly in the CalD‐group compared with the Cal‐group (p 0.0094) (half completed testing)
• 50% of women had 25‐hydroxyvitamin D serum concentrations below 12 ng/ml and 90% below 31 ng/ml. JOURNAL OF BONE AND MINERAL RESEARCH
Volume 18, Number 2, 2003
Less than 3% of a subgroup of participants had 25-hydroxycholecalciferol levels lower than 25 nmol/L.
Sanders et al. JAMA. 2010;303
Summary of Cochrane Reviews
• Nursing home – Vitamin D was beneficial • Hospitals
– Vitamin D had no benefit in single acute care hospitalization
• Community
– Vitamin D did not reduce falls or fractures Cameron et al. Cochrane Database of systematic Reviews 2010
Gillespie et al. Cochrane Database of Systematic Reviews 2009
• 36,282 postmenopausal women 50 to 79 years enrolled in Women’s
Health Initiative
• Prevention study to test hypothesis pmo would have lower risk of hip
fracture
• 1000 mg of elemental calcium as calcium carbonate with 400 IU of
vitamin D3 or placebo
• Fractures were ascertained for average follow-up 7 years
Jackson RD et al NEJM 2006;357(4):669
Baseline Characteristics of the Participants According to Randomly Assigned Group
Jackson RD et al NEJM 2006;357(4):669
17%
Baseline Characteristics of the Participants According to Randomly Assigned Group
*6000 began taking osteoporosis medications after start of study
Jackson RD et al NEJM 2006;357(4):669
BMD and Relative Risk
Relative Risk
for Fracture
60%
37%
4%
Bone Density (T-score)
Jackson RD et al NEJM 2006;357(4):669
Results • During 7 years of the study there were 175 hip fractures among women assigned to calcium/vitamin D and 199 hip fractures among women assigned to placebo • Calcium/vitamin D group nonsignificant, 12 percent
lower risk of hip fracture than women assigned
to placebo • No significant reductions in clinical vertebral fracture,
fracture of the lower arm or wrist, or total fractures
WHI
• Study of relatively young women (50≠80yrs)
• Already following current government guideline for calcium intake. • Large number already taking antiresorptive
agents • Patient level data:
Risk of myocardial infarction 31 % (P=0.035)
Non-significant increases occurred in the incidence of stroke
(1.20, P=0.11)
Composite end point of myocardial infarction, stroke, or
sudden death (1.18, P=0.057)
Death (1.09, P=0.18)
• Trial level data:
Incidence of myocardial infarction in those allocated to
BMJ 2010:341:c3691
calcium (pooled relative risk 27%, P=0.038)
BMJ 2011;342:d2040
Effect of allocation to calcium and vitamin d supplementation on CV events among participants in the WHI CaD Study
BMJ 2011:342:d2040
Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, a finding obscured in the WHI CaD Study by the widespread use of personal calcium supplements. A reassessment of the role of calcium supplements in osteoporosis management is warranted
BMJ 2011;342:d2040
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
JR Lewis, J Calver, K Zhu,L Flicke, R L Prince CI 0.74‐1.15
Combined atherosclerotic vascular disease events CI 0.70‐1.3
J Bone Miner Res. 2011;26:35–41
JBMR 2014 29(3):534 ITT and Per‐Protocol ANCOVA for CCA Intimal Medial Thickness and Atherosclerosis, According to Calcium Supplementation at Baseline
Meta-analysis on effects of vitamin D on hip
fractures
Bischoff-Ferrari JAMA 2005
• Insufficient to assess the balance of the benefits and harms of
combined vitamin D and calcium supplementation for the primary
prevention of fractures in premenopausal women or in men. (I
statement)
• Insufficient to assess the balance of the benefits and harms of daily
supplementation with greater than 400 IU of vitamin D3 and greater
than 1000 mg of calcium for the primary prevention of fractures in
noninstitutionalized postmenopausal women
Ann Intern Med. 2013;158:691‐696.
• Recommends against daily supplementation with 400 IU or less of
vitamin D3 and 1000 mg or less of calcium for the primary
prevention of fractures in noninstitutionalized postmenopausal
women. (D recommendation). There is inadequate evidence for
higher dose.
• This recommendation does not apply to to persons with
osteoporosis or vitamin D deficiency
• Prior rec (B) vitamin D supplementation is effective in preventing
falls in community-dwelling adults aged 65 years or older who
are at increased risk for falls.
• Appropriate dose and dosing regimens require further study.
Ann Intern Med. 2013;158:691‐696.
Session III: Bone Disease in Special
Populations
Renal Bone Disease (CKD)
Orson Moe, MD
3/26/2014
Bone Disease in Renal Patients
Orson W. Moe, M.D.
Department of Internal Medicine and Physiology
Charles and Jane Pak Center of Mineral Metabolism
University of Texas Southwestern Medical Center
Dallas, TX USA
Agenda
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
•
•
•
•
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
Chronic Kidney Disease Mineral & Bone Disease
CKD‐MBD
Soft tissue vascular calcification
Biochemical abnormalities
Bone abnormalities
1
3/26/2014
1883
Lucas RC: On a form of late rickets associated with albuminuria. Lancet
1942
Liu SH, and Chu H: Treatment of renal osteodystrophy with dyhydrotachysterol and iron. Science
2006
KDIGO Group. Kidney International
Exper ts
CKD‐MBD
Abnormal calcium, phosphorus, PTH, vitamin D
Vascular or soft tissue calcification Pathophysiology
• Hyperphosphatemia
• Hypocalcemia
• High PTH
• Low 1,25(OH)2D3
• Metabolic acidosis
• Hypogonadism
• Deficiency of growth factors
• Resistance to growth factors
• High fibroblast growth factor 23
•Low Klotho
• Uremic toxins
• Underlying primary renal disease
Abnormal bone turnover, mineralization, volume, growth, strength
TMV classification of bone histomorphometry in CKD‐MBD
www. KDIGO.org Kidney Inter 2006
Turnover
Mineralization
Volume
Osteoid volume
Osteoid thickness
Mineralization lag time
Apposition time
Bone formation rate
Activation frequency
Resorption rate – not measured
Bone per unit volume
Cancellous bone
High
Bone volume
Osteitis
fibrosa
Mild HPT
Adynamic
bone
Low
Normal
Osteomalacia
Low
Osteoporosis
Mixed uremic osteodystrophy
Turnover
High
Abnormal
2
3/26/2014
Histopathology in CKD‐MBD
Hemodialysis
CKD
Osteitis Fibrosa
Mixed uremic osteodystrophy
Osteomalacia
Mild hyperparathyrodism
Adynamic
Peritoneal
Dialysis
Osteoporosis ?
KDIGO Kidney Internat 2009
In 1994 WHO says..
T score < ‐2.5
Does this work in the CKD population?
CKD‐MBD
Osteoporosis
What’s in a name?
Romeo and Juliet Act 2 Scene 2
Bill
3
3/26/2014
Agenda
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
•
•
•
•
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
Fractures in CKD
Dialysis Outcome & Practice Patterns Study (DOPPS)
Tentori et al. Kidney Internal 2013
4
3/26/2014
Tentori et al. Kidney Internal 2013
9704 women >65 yo
Ensrud et al . Arch Int Med 2007
Third National Health and Nutrition Examination Survey (NHANES III) Kidney disease prevalence %
Hip fracture prevalence %
participants with and without kidney disease.
eGFR > 60 eGFR < 60 ml/min
Hip fracture No Hip fracture No hip fracture
hip fracture
Age 50‐74
Age >75
Nickolas et al. J Am Soc Nephrology 2006
5
3/26/2014
Agenda
•
•
•
•
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
DEXA OK
Stage 1
>90
Stage 2
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
Estimated GFR ml/min
60‐89
Stage 3
A: 45‐59 B:30‐44
Stage 4
DEXA
Not OK
Why?
15‐29
Stage 5
<15
Not
useful !
Useful !
American Journal of Kidney Diseases, Vol 49, No 5 (May), 2007
6 cross‐sectional studies 683 subjects. 75 morphometric fractures
79 clinical fractures.
Study
n
Yamaguchi 1996
124
Fontaine 2000
88
Jamal 2002
104
Kaji 2002
183
Urena 2003
70
Inaba 2005
114
Lower Higher
BMD BMD
with fracture
Lower Higher
BMD BMD
with fracture
Lower Higher
BMD BMD
with fracture
‐4 ‐2 0 2 4 ‐4 ‐2 0 2 4 ‐4 ‐2 0 2 4
Lumbar Mid Radius
Femoral Neck
‐4 ‐2 0 2 4
1/3 Radius
‐4 ‐2 0 2 4
Distal radius
Lower Higher
BMD BMD
with fracture
Lower Higher
BMD BMD
with fracture
6
3/26/2014
Agenda
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
•
•
•
•
Concept of CKD‐MBD
Fractures in CKD
Is DEXA useful
What to do
• Diagnose
• Treat
CKD
CKD‐MBD
Vascular or soft tissue calcification Fracture
Abnormal calcium, phosphorus, PTH, vitamin D
Abnormal bone turnover, mineralization, volume, growth, strength
7
3/26/2014
DEXA OK
Stage 1
Estimated GFR ml/min
>90
Stage 2
60‐89
Stage 3
A: 45‐59 B:30‐44
Stage 4
Phosphate PTH
Vitamin D
FGF23
15‐29
Stage 5
DEXA
Not OK
•
•
•
•
<15
Osteoporosis
CKD‐MBD
Anti‐resorptive
Bisphosphonates
HRT/SERM
Calcitonin
 Calcium  Vitamin D
Osteo‐anabolic
PTH
Strontium
Calcilytic
IGF‐1
Anti‐RANKL MAb
Anti‐Sclerostin MAb
Cathepsin K Inhibitor
Osteoprotegerin
Tph1 inhibitor
GLP‐2 inhibitor
H+
Fluoride
transport Inhibitors
8
3/26/2014
Conventional Rx
DEXA OK
Stage 1
>90
Stage 2
Estimated GFR ml/min
60‐89
Stage 3
A: 45‐59 B:30‐44
Stage 4
15‐29
Stage 5
DEXA
Not OK
<15
Focus on CKD‐MBD
• Phosphate binder
• Vitamin D
• Calcimimetic
Bone Disease in Renal Patients
Orson W. Moe, M.D.
Department of Internal Medicine and Physiology
Charles and Jane Pak Center of Mineral Metabolism
University of Texas Southwestern Medical Center
Dallas, TX USA
Take Home
•
•
•
•
•
•
Fracture risk is increased in all stages of CKD
Bone lesion ‐ a mix of osteopathologies
Part of a broad range mineral metabolic derangements
BMD is useful
Conventional therapies acceptable in early CKD stages
Treat CKD‐MBD
9
Bariatric Surgery and Bone Disease
Khashayar Sakhaee, MD
Bariatric Surgery and Bone Disease
Khashayar Sakhaee, M.D.
Department of Internal Medicine
Charles and Jane Pak Center For Mineral Metabolism and Clinical Research
University of Texas Southwestern Medical Center
Dallas, TX, USA
Obesity Trends* Among U.S. Adults
(*BMI > 30, or about 30 lbs. overweight for 163cm person)
2000
1990
2010
No Data
<10%
10%–14%
15%–19%
20%–24%
25%–29%
≥30%
Number of Bariatric Surgery Procedures Performed Between 1990 and 2010, by Year and Type of Bariatric Surgery Lalmohamed, BMJ, 2012
Weight Change at 3 Years After Bariatric Surgery Among Individuals With Severe Obesity
Courcoulas, JAMA, 2013
Skeletal Impact of Bariatric Surgery
RR: 2.3 (95% CI: 1.8‐2.8)
Olmstead County, MN
1985‐2004
Bariatric Surgeries
N=258
Expected Incidence
Nakamura, Osteoporosis Int, 2013
Bariatric Surgery and Fracture Site
Nakamura, Osteoporosis Int, 2013
Normal Bone Remodelling
Resorption
Formation
Osteoporosis: An Imbalance in Bone Remodelling
 Estradiol
 GLP 1
 PTH
 Ghrelin
 GIP
Formation
 Adiponectin
 Leptin
Skeletal Unloading
Resorption
 Serotonin
Bone Strength = f (Bone mineral density and Bone Quality)
Bariatric Surgery and Bone Loss: Pathophysiologic Mechanism
 Gastric Acid
Dietary Changes
Duodenal Exclusion
 Calcium Absorption
 PTH
 Bone Loss
Fast Transit
Fat Malabsorption
and Vitamin D Deficiency
Changes in BMD 1 Year After RYGB
Fleischer, JCEM, 2008
Changes in BMD 1 Year After RYGB
Stein, JCEM, 2013
Changes in Microarchitecture by HR‐pQCT
1 Year after Bariatric Surgery
Tot = Total
Ct = Cortical
Tb = Trabecular
Ar = Area
D = Density
Th = Thickness
N = Number
Stein, JCEM, 2013
Association Between Serum PTH Levels and Cortical Microarchitecture
Stein, JCEM, 2013
Demographic and Calciotropic Profiles
Before and After Bariatric Surgery
Baseline
1 y
P Value
Body Composition
Weight, kg
115 ± 3
87 ± 3
< 0.0001
Lean Body Mass, %
52.11 ± 0.65
59.82 ± 1.54
< 0.0001
Truncal Fat, %
48.70 ± 0.70
38.99 ± 1.72
< 0.0001
< 0.0001
Fat, % (subtotal)
49.26 ± 0.68
41.36 ± 1.59
Lean Body Mass, g
57824 ± 1298
50399 ± 1303
< 0.0001
Truncal Fat, g
26795 ± 796
16359 ± 1243
< 0.0001
Fat (subtotal), g
52189 ± 1450
34084 ± 2392
< 0.0001
Calcium Intake, mg/d
875 ± 89
1443 ± 205
0.02
Vitamin D Intake, IU/d
5440 ± 1242
5852 ± 1810
0.80
Corrected Calcium (8.6‐10.2 mg/dL)
9.37 ± 0.01
9.17 ± 0.06
< 0.02
< 0.05
Calciotropic Indices
PTH (14‐66 pg/mL)
Serum 25OHD (30‐80 ng/mL)
Serum CTX (0.112‐0.738 ng/mL)
BSAP (11.6‐42.7 U/L)
37 ± 3
47 ± 5
33.0 ± 3.1
35.8 ± 3.6
0.07
0.236 ± 0.026
0.562 ± 0.071
< 0.0001
31.9 ± 2.1
35.9 ± 2.9
0.32
Stein, JCEM, 2013
Bariatric Surgery and Bone Mineral Density
7 BPD, 226 RYGB patients
Johnson, J Gastrointest Surg, 2005
Bone Turnover Markers Following Gastric Bypass Surgery
220%
82%
Yu, JBMR, 2014
BMD Changes Following Bariatric Surgery
Author
Number of Patients
Mean BMI
Type of Surgery
Duration of Study
Supplements Outcome BMD
Carrasco
42
45
RYGB
12 months
Calcium (640‐1000 mg/day)
Vitamin D (400‐800 units/day)
Spine (‐7.4%)* Total hip (‐10.5%)*
Pereira
16
33
RYGB
12 months
Calcium (250 mg/day)
Vitamin D (400 units/day)
Spine (‐6.2%)*
Forearm (‐5.1%)* Femoral neck (‐10.2%)*
Fleischer
23
47
RYGB
12 months
Calcium (1500‐1800 mg/day)
Vitamin D (658 units/day)
Femoral neck (‐9.2%)*
Coates
25
31
RYGB
11 months
Calcium (1200 mg/day)
Vitamin D (400‐800 units/day)
Spine (‐3.3%)*
Femoral neck (‐5.1%)*
Total hip (‐7.8%)*
Johnson
226
50
RYGB
36 months
Calcium (1200 mg/day)
3 multivitamins
Spine (‐4.5%)*
Radius (‐1.8%)*
Total hip (‐9.2%)*
Stein
14
44
RYGB
12 months
Calcium (1500‐1800 mg/day)
Vitamin D (400‐800 units/day)
Femoral neck (‐4.5%)* Total hip (‐5.2%)*
Cundy
18
43
VGB
24 months
Calciferol (75 mcg/day)
Ward’s triangle (‐3.9%)*
Trochanter (‐4.8%)*
Guney
16
46
VGB
12 months
None
Femoral neck (‐4.8%)*
RYGB=Roux‐en‐Y gastric bypass
VGB=Vertical banded gastroplasty
* =Significant reduction in Bone Mineral Density (BMD)
Sakhaee, Clin Rev in Bone and Min Metab, 2014
Serum Vitamin D Levels Following Vitamin D Intake After RYGB
What is the title?
Fleischer, JCEM, 2008
Changes in Dietary Calcium Intake, PTH Levels and 24‐hr Urine Calcium
Fleischer, JCEM, 2008
Impact of RYGB Surgery and Nephrolithiasis
• Blue Cross Blue Shield claims database from 2002‐06 (2.4
million pts)
• 4,639 patients who underwent RYGB surgery and a
control group of 4,639 obese patients (no surgery)
• All patients with ≥ 3 years of continuous claims data
• 7.65% (355 of 4,639) of RYGB patients diagnosed with
urolithiasis vs. 4.63% (215 of 4,639) of controls
(p<0.0001).
• Rates of urological interventions also significantly greater
in RYGB cases vs. controls.
Matlaga B, J Urol, 2009
Impact of Gastric Banding and Nephrolithiasis
• Blue Cross Blue Shield claims database from 2002‐2006
(2.4 million pts)
• 201 patients who underwent gastric banding and a
control group of 201 obese patients (no surgery)
• All patients with ≥ 2 years of continuous claims data
• 1.49% (3 of 201) of gastric band patients diagnosed with
stones vs. 5.97% (12 of 201) of controls (p=0.018)
• Gastric banding is not associated with an increased risk for
kidney stone disease
Semins MJ, Urology, 2009
Complications of Bariatric Surgery
Bariatric Surgery
Malabsorption
 PTH
Alkali Loss
 Acid Load
Kidney Stones
Bone Loss
Novel Actions of Potassium Calcium Citrate
Bariatric Surgery
Malabsorption
 PTH
Alkali Loss
Potassium Citrate
Calcium Citrate
 Acid Load
PCC
Calcium Citrate
Potassium Citrate
Kidney Stones
Bone Loss
Effect of Potassium Calcium Citrate Supplementation
Following Bariatric Surgery
Sakhaee, Surg Obesity Rel Dis, 2012
Conclusion
• Bariatric Surgery has emerged as the most effective and sustained treatment for weight reduction
• This treatment modality has been recognized to diminish the risk of cardiovascular morbidity and mortality and ameliorate diabetes mellitus
• The derangement in mineral metabolism has emerged as a major complication following bariatric surgery
• Despite a lack of presence of hard data on any specific treatment showing decrease incidence of fragility fractures or kidney stones, a novel treatment with effervescent potassium calcium citrate may potentially prevent complications of bone loss and risk of kidney stone formation
• Future studies are needed to support the effectiveness of this treatment in reduction of bone fracture of kidney stone incidence
Management of Patients with Prior
Fracture
Ugis Gruntmanis, MD
,20,3-,*-+.0'1-,- .,',%-,*2&>
T\[SHUSSZ
7000
%'106,2+,'1>AA
.02+,2- '',
-62&8120,
**1>>
5000
4000
14
12
10
8
3000
6
2000
4
1000
2
0
0
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
,%+,2- 3,21
8'2&0'-00260
6000
U.S.
Norway
Switzerland
Canada
Netherlands
France
Germany
Sweden
U.K.
Italy
New Zealand
Australia
Total expenditures on health
as percent of GDP
16
U.S.
France
Switzerland
Germany
Canada
Netherlands
New Zealand
Sweden
Norway
Italy
U.K.
Australia
1980
1981
1982
1983
1984
1985
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
Average spending on health
per capita ($US PPP)
8000
Source: OECD Health Data 2009 (June 2009).
Total Reimbursement
Rates for Noncapitated Medicare per Enrollee, 2006, and
Annual Growth in Medicare Reimbursements, 1992-2006, for the 25 Largest
U.S. Hospital-Referral Regions
Fisher E et al. N Engl J Med 2009;360:849-852
&0,2-6*'2:
,'2-01>-0',%2-
-,'3-,A
%2'',%7'!%
=;;>5>?C6=A>@8=A?@7
0-11',%2&6*'2:&1+
• 
• 
• 
• 
• 
• 
02601
•  U+'**'-,,8-12-.-0-3J+','+*206+K
02601:0*:',,'2221A
•  V\_',+,,YT_',8-+,A
•  TW_- &'.>US_- -00+>WT_- 7020*
,UX_- &6+061 02601A
•  XU+'**'-,&7*-8',,'2221
!37
3,2,20
'+*:
#',2
/6'2*
&5.@FF888A'-+A6F.-021FUSSTF0-11',%G2&G6*'2:G
&1+GG8G*2&G:12+G -0G2&GUT12G,260:A1.9
Johnell O, Kanis JA, Osteoporosis Int. 2006; 17:1726-33
'#'("*('##++6'
''/%#'#'((&&('#+++
YSS >S SS
XSS >S SS
•  '(,1(1(&'1#%%"0&#'#&%
,*/&*%,*,/*7
•  '#',"*1#%%"07
•  '#' 01#%%"0+,*($7
•  '#'#!",1#%%"0*+,'*7
WSS >S SS
VSS >S SS
USS >S SS
TSS >S SS
S
'#'("*('##++6(&'
6, %
,
0
0- 12 2 ,
0
*; &'+
0B1
'1 1 20- )
02
22 )
,-,>3-,*12-.-0-1'1-6,3-,F12 21-,-12-.-0-1'1>USS[
,-,>02'11,120-)123131GUSS\6.2A'06*3-,>USS\?TT\@UTGT[T
+0',,0-'2:>123131 -0USS\@888A,0A-0%F-0--2FFIA1.
12-.-0-3
0260
'.02601
'%&02- +-0''2:
– XS_- .3,21-,-20%',2&'0',.,,
– XS_- .3,21-,-20%',2&'0.07'-61
+-'*'2:
'%&02- +-02*'2:
– TZGUU_',8-+,,VTGVX_8'2&',T:0
'.02601
•  \S.0,2- .-.*8&--,-2,11'12,*'+',%12'01
-0&'. 0260>8'**,-2*2-*'+"712.1',2&
:0$02& 0260A
•  YY.0,28'**,-2*2-%2-,-0-!2-'*28'2&-62
11'12,A
•  XS.0,28-,M2*2-0'12&+1*71-62- &'0A
•  VT.0,28'**6,*2-%2-62- 8'2&-62&*. 0-+
0%'70A
•  US.0,28'**,-2*2-.62-,.'0- .,218'2&-62
11'12,A
&-1*>+',>08-**A,-0',7AUSS[?U\@WWTGYW
'#''('(&#/*'(+,()(*(+#+8
%,*,/*+#',"'#,,,+7
Fractures and morbidity.
*+,'*?#%%#('4
*(+,,'*<;#%%#('
Morbidity
attributable to
ageing alone
(/*'%((''#'*%+*"
-*6+UU>
116V>.%1WYXGWZX>WUSSY
Kanis JA & Johnell O. Osteoporosis Review. 2009;17(1):14-16
VFUVFTW
How many patients with hip fractures
have had previous fractures?
"*',(/%#,2'#,(*+4(*#'!,(
('#-('7
100.0
90.0
n=2038
n=632
n=704
80.0
Percentage
70.0
60.0
50.0
45.3
45.4
44.6
40.0
30.0
20.0
10.0
0.0
12
Lyles et al
13
Edwards et al
14
Mclellan et al
12. ASBMR 2006. 28th Annual Meeting in Philadelphia, Pennsylvania, USA. 2006. Abstract SA405. Lyles KW et al
13. Clin Orthop Rel Res 2007;461:226-230 Edwards BJ et al
Graph courtesy of Dr. JR Bayly
14. NHS Quality Improvement Scotland. Effectiveness of Strategies for the Secondary Prevention of Osteoporotic
Fractures in Scotland. 2004. McLellan AR et al
-8%--08>'0USSS=
2'1&0%>VYV.3,21$0&'. 0260>WAX_
+,,UZ_8-+,80%'7,-12-.-0-1'1
2&0.:A
2X:01>TT_- +,,UZ_- 8-+,&7
&-,A
';)2*A0&
,2AUSSU?TYU@UUTZGUU
%2'',%7'!%
=;;>5>?C6=A>@8=A?@7
-8%--08>'0USS[=
•  2&-1.'2*'1&0%>$0&'. 0260',[SW
.3,21>WAZ_80%'7,-12-.-0-1'12&0.:A
•  -00 -0V_- .3,21A
&5.@FF888A7A%-7F-'%FXWF0.-021F
GS\GSVTV[GT\TA. W
-8%--08>'0USTW=
•  2&-1.'2*'1&0%>$0&'. 0260',
\Y>[[Z.3,21> 0-+2&-18&-80,-2-,
-12-.-0-1'12&0.:>-,*:TYAX_80%'7,
-12-.-0-1'12&0.:A
•  -00 -0VA[_- .3,21A
-*-+-,2*AAUSTWA-'@LTSATSSUF(+0AUUSU
-8%--082=
TA&ZX&'. 02601',USTUJ2-,W\KA
UA,%ZU>TX&.07'-61 02601A
VA2&-1.'2*'1&0%>T[JVZ_K0'7
16..*+,21>TWJU\_K0'77'2+',,
,-,0'7'.&-1.&-,21A
-6021:- 01A*2,')>%6:,,*-6 Role of finding fracture in men with
prostate cancer.
Neubecker K et al. J Osteoporos. 2011
VFUVFTW
9'13,%020*0260',0'21
62600260
Bone Mineral (g/cm2)
!2- %-,-,',0*
,1'2:
=B=@)-',+,$#'!%#/&+,/#(*<2*
1
G
'#'
(1
*,*%
*,/*
#,"#'
<*
0.6
0.4
0.2
0
24
25
0.8
20
15
5
20
40
60
80
11.5
10
3.6
100
0
0
Age (yrs)
Riggs, et al. J Clin Invest. 1982;70:716-723.
Lindsay et al. JAMA. 2001.
1
2 or more
/&*(+%#'*,*%*,/*+
YS
026002
-A- 8-+,
8'2& 02601
WS
WXS
WSS
VXS
VSS
UXS
VS
USS
US
TXS
TSS
TS
S
&6'22*A
AUSSW
'120'63-,
XS
XS
aTAS
SAX2-SAS
HSAX2-HTAS HTAX2-HUAS HUAX2-HVAS
`HVAX
TAS2-SAX
SAS2-HSAX HTAS2-HTAX HUAS2-HUAX HVAS2-HVAX
-A- -+,'2&02601
0260.0TSSS01-,G01
-.6*3-,'120'63-,>026021>
,6+0- -+,'2&02601
S
G-01J0'.&0*K
'0'12*A
AUSSWA
Y
&:016*21',.3,218'2& 02601
01-'1..-',3,%=
TY
ZAW
•  -61-,*-8020.0-*+JKA
•  0'1'1(-',2J&1.'*2:
01.-,1'* -0.036*00.'1-KA
•  :+,2+-*1&7,-2,-60%
8-0)',%2-%2&0A
•  D&0)1,"9>'2C1:-60
&-*120-**7*2&2
+8-00'-62EA
NA7'**2@&5.@FF888A1& AA6)FF',9A&2+A
Risk of future fractures and
allocation of resources.
HiROC
service
-,0:
.07,3-,
-',+1#,"
*!#%#,2*,/*
50% of hip
fractures from
16% of the
population
-',+1#,"*!#%#,2*,/*
0'+0:
.07,3-,
-',+,*#+$(+/*#'!<+,*!#%#,2*,/*
-',+,
*#+$(+/*#'!<+,*!#%#,2*,/*
-',+,*#+$(+/*#'!<+,*!#%#,2*,/*
50% of hip
fractures from
84% of the
population
'107'','32
J12.TK
•  -0**.3,218'2&&'. 02601>'
107'62-+3**:8'**,-3"A
•  &:1'*'',2+11**.3,21
8'2&&'. 0260*0:A
•  3,2,20,101111>8-0)G
6.,202+,2','32A
•  '. 0260.3,21 -**-86.:'
107'YG[8)1$0'1&0%A
7. BOA-BGS 2007 Blue Book. http://www.nhfd.co.uk/
15. (Adapted from) Curr Med Res Opin 2005;21:4:475-482 Brankin E et al
#&,(*#&*2(*('*2'(#',7
01160 0-+.:01
,USTW>'00-.-1*','*6*'2:
160SSW[A
•  12-.-0-1'1,%+,2-**-8',%0260
-0,>-+,%XS,-*0A
•  &28'**+160@
G .0 -0+A
G &0+-*-%'*2&0.:.010'A
2%+,%7'!%
=;;B5>@B6<BDD8<C;D7
-+.*',
•  XY_'1-,3,68)*:'1.&-1.&-,21A
•  ZY_- .3,218&--,3,6
'1.&-1.&-,21>&',2006.3-,1A
•  VS_',-22)2&+1'02A
•  -126'11&-8',%2&2'7061
02601+-02&-0*1A
Papaioannou et al. Drugs Aging. 2007;24:37-55
-1 0260.07,3-,1202%'1
8-0)=
•  YUX>SSS','7'6*1-70%XS',*6',
126:A
•  07,2T>SY\&'. 02601-0WTAU_
063-,A
•  &&'. 0260-62PVZ>SSSA
•  7V\AX+'**'-,A
•  7UXZ*'71A
**2*A-,-',260%+A-7USS\?\T
','+
','+*06+02601>*:62
','
+**0
06
0
6+02601>*:62
%,-0A*6..0-&A
%,
%
%,-00A*6
..
..00-&A
%'106,2+,'1>A
%'
%
%%''11
10
06
006,
6,2+
22+
+,
+
,'1
,'
''11>>
>
AA
A