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Management of osteoporosis
1. Recent Advances in Diagnosis
&Management of Osteoporosis
Dr. Ashok Bhatt
Consultant Orthopedic Surgeon
2.
3. Osteoporosis
Osteoporosis is defined as a systemic skeletal disorder
characterized by reduced bone mass and compromised
micro architectural structure resulting into reduced bone
strength predisposing to an increased risk of Fragility
fracture.
OP is uncoupling of Osteclastic(bone resorption)
and Osteoblastic (bone formtation) acitivity
Normal Bone Osteoporotic Bone
4. Changes in Bone Density with Age
6/2/2021 4
Peak Bone is achieved at around age of 30 years
Peak Bone Mass(PBM) - Protein, Vitamin D and Calcium intake
during childhood has role in PBM
5. Risk Factors
Major
• History of fracture as an
adult
• Fragility fracture in first
degree relative
• Caucasian/Asian
postmenopausal woman
• Low body weight (< 127 lb)
• Current smoking
• Use of oral corticosteroids >
3 mo.
Additional
• Impaired vision
• Estrogen deficiency at early
age (< 45 YO)
• Dementia
• Poor health/frailty
• Recent falls
• Low calcium intake (lifelong)
• Low physical activity
• > 2 alcoholic drinks per day
6. Factors Associated with Bone Loss in Men
• Genetics
• Smoking/alcohol
• Calcium intake
• Physical
activity/strength
• Testosterone
production
• Estrogen production
7. Medical Conditions Associated with
Increased Risk of Osteoporosis
• COPD
• Cushing’s syndrome
• Eating disorders
• Hyperparathyroidism
• Hypophosphatasia
• IBS
• RA, other autoimmune
connective tissue
disorders
• Insulin dependent
diabetes
• Multiple sclerosis
• Multiple myeloma
• Stroke (CVA)
• Thyrotoxicosis
• Vitamin D deficiency
• Liver diseases
Not an inclusive list
8. Drugs Associated with
Reduced Bone Mass
• Aluminum
• Anticonvulsants
• Cytotoxic drugs
• Glucocorticosteroids
(oral/high dose inhaled)
• Immunosuppresants
• Gonadotropin-releasing
hormone (e.g. Lupron)
• Lithium
• Heparin (chronic use)
• Supraphysiologic
thyroxine doses
• Aromatase inhibitors
• Depo-Provera
Not an inclusive list
9. Risk Assessment/Diagnosis
• After menopause, all women should be evaluated
clinically for osteoporosis risk to determine need for BMD
testing
• 50-60% of men with osteoporosis have disorders known
to reduce bone mass, such as hyperparathyroidism,
intestinal disorders, malignancies, conditions resulting in
immobilization
• BMD recommended in men with known risk factors and
who have lost > 1.5 inches in height
• Diagnosis can be established in patients who have never
had a fragility fracture by BMD measurement
10. New Assessment Tools for
Fracture Risks & Treatment Decisions
• FRAX
The WHO developed a computer-generated algorithm.
Provides country- and ethnic-specific 10-year hip and major osteoporotic
fractures.
Obtained from simple questioning; it includes age, sex, weight, height,
personal and family history of fracture, current tobacco and alcohol
consumption, corticosteroid usage, previous conditions,& RA
• SOF
based only on BMD and age
• QFracture
Based on some enlisted risk factors
Does not need BMD
11. Who Should be Tested?
• Decision to test based on individual risk profile,
never indicated unless results influence
treatment decision
• BMD testing should be performed on:
1. All women 65 YOA and older regardless of risk
factors*
2. Younger postmenopausal women with one or more
risk factors (other than being white, postmenopausal
and female)
3. Postmenopausal women who present with fractures
(confirm diagnosis, determine disease severity)
*Medicare permits repeat BMD testing every 2 years.
12. Everything about BMD
• Gold standard for diagnosis of Osteopenia and
Osteoporosis & “ At risk “ patients.
• Gives clear picture about Bone density
• Machine specific, position specific, variable with
subjective factor.
• Repeat BMD should be done at least after 2 yrs.
• Compare BMD and not T score
• Does not reveal about quality & architecture of bone.
• Risk factors for low BMD are not the same as for
Fragility fracture.
• Researchers are developing tool based on CT of spine &
hip with 3D images and computer modeling, to study the
architecture of bone and predict fragility #s.
13. “THE CARE GAP”
IN OSTEOPOROSIS
Despite the introduction of methods to
identify those with osteoporosis and
despite effective treatment, a large
‘care gap’ continues to exist for
these patients.
14. Male Osteoporosis: Morbidity and
Mortality
As compared to women, while lifetime
fracture risk may be less,
– Men have higher rates of morbidity and
mortality due to fractures
– Men are twice as likely to die in hospital
after a hip fracture
– Men have a higher mortality rate than
women one year after a hip fracture
Cooper C, et al. Osteoporos Int 1992;2:285-9; Singer BR, et al. J Bone Joint Surg
Br 1998;80:243-8; Center JR, et al. The Lancet 1999;353:878-82; orsen L, et al.
Osteoporos Int 1999;10:73-8; Johnell O., et al. Calcif Tissue Int 2001;69:182-4;
Amin S. Curr Osteoporos Rep 2003;1:71-7; Campion JM, et al. Am Fam Phys
2003;67:1521-6.
15. HIP FRACTURES
MORBIDITY AND MORTALITY
“One-third of all hip fractures occur in men and are
associated with as much illness and increased risk
of death as those that occur in women .”
“The average 50-year-old Caucasian man has a 13
per cent chance of having a fracture related to
osteoporosis sometime in his remaining lifetime. A
60-year-old Caucasian man has a 29 per cent
chance.”
Dr. John Schousboe, Minneapolis 2007
18. Organizations involved in rationalization of
Osteoporosis Management :
IOF : International Osteoporosis Foundation
NOF : National Osteoporosis Foundation
ISCD : International Society for Clinical
Densitometry
ISBMR: Indian Society for Bone Mineral Research
IOM : Institute of Medicine
AACE American Association of Clinical
Endocrinologists
Prevention of Osteoporosis
Medical Management
Management during treatment of Fragility fractures
20. Prevention and Treatment Goals
Decrease fracture risk
Stabilize or increase bone mass
Maintain or improve bone quality
Prevent falls: Fall prevention strategies are not in place in India
Risk of fall can be evaluated by:
Patient can’t walk and talk simultaneously
Ask patient to sit, walk for 10 m, comeback and sit again. Slowness
in such patients is indicative of risk of fall
Fracture management
Relieve pain
Stabilize fracture and restore anatomy
Manage co-morbidities, Treat Osteoporosis aggressively
Restore level of function
Psychosocial support
21. Non-Pharmacological Therapy
NOF Recommendations
Adequate intake of dietary calcium and vitamin D
Calcium: at least 1200 mg/day in divided doses
Vitamin D: at least 800-1000 IU/day
Regular weight-bearing and muscle-strengthening
exercise including walking
Avoidance of smoking and excess alcohol
Fall prevention esp in Elderly
Cordless phone near bed at night, towel at floor of bathroom,
light in staircase, correct sights etc..
Hip Protectors (Hip Pelvis Arms useful, may not be in leg
and trunk )
22. Recommended Calcium Intake per
2010 IOM Report
RDA (mg) Upper limit (mg)
9-18 (boys/girls) 1300 3000
Women 19-50 1000 2500
Pregnancy No adjustments
Women over 50 1200 2000
Men 19-50 1000 2500
Men 50-70 1000 2000
Men over 70 1200 2000
23. Calcium Reduces Bone Loss and
Fracture Risk: A Meta-Analysis
Calcium or calcium with vitamin D
BMD: reduced rate of bone loss
23 trials (n = 41,419)
Hip: reduced loss 0.54% (0.35-0.73%, p < 0.0001)
Spine: reduced loss 1.19% (0.76-1.61%, p < 0.0001)
Fractures: reduced fracture risk
17 trials (n = 52,625)
RR 0.88 (CI 0.83-0.95, p = 0.0004)
Best results with calcium 1200 mg or more and vitamin D
800 IU or more
WHI study conclusion
24. Calcium Citrate Malate Vs
Calcium Carbonate
Calcium salt per
tablet
% of elemental
calcium
Elemental
calcium
% bioavailable
Mg of
elemental
calcium
absorbed
Calcium
carbonate
(500mg)
40% 200mg 26% 52
Calcium citrate
malate (1250
mg)
20% 250mg 40% 100
Other Benefits of CCM over Calcium Carbonate
•Does not increase the risk of kidney stones
•CCM can be consumed with or without food
•Does not interfere with Fe absorption and retention
25. 2010 Institute Of Medicine Report:
Vitamin D
Practically all persons are sufficient at 25-OH vitamin D levels of
20 ng/mL (50 nmol/L) or above
No consistent evidence for extra-skeletal benefits above a level of
20 ng/mL
Levels between 20-50 ng/mL appear to be safe
RDA to cover 97.5% of the population
0-12 months 400 IU daily
1-70 years old 600 IU daily
Over 70 years old 800 IU daily
AACE response to IOM report emphasis on clinical judgment
Dosage recommendation varies with different guidelines of
association/inst
26. D-hormone analogs vs.
Native vitamin D
One meta-analysis in 2008 showed that D-hormone analogs
(Calcitriol & Alfacalcidiol) may prevent falls and
fractures to a greater extent compared to their native
compound(Vitamin D)
Richy F et al. Differential effects of D-hormone analogs and native vitamin D on the risk of falls: a comparative
metaanalysis. Calcif Tissue Int 2008; 82: 102–7.
27. Summary: Calcium and Vitamin D
Low calcium intake and vitamin D deficiency should be corrected in all
patients
Hip fractures occur often in patients aged > 75-80 years and this population is
particularly prone to calcium and vitamin D deficiency
In patients with low calcium intake, calcium alone induces small increases in
bone mineral density and possibly reduces fracture incidence
Low-dose vitamin D (400 IU/d) alone did not reduce fracture incidence in a
free living population
Calcium and vitamin D supplementation in women living in nursing homes
decreases hip fracture incidence
Serum Vitamin D needs to be done in patients in whom
Bisphonates or Teriparatide has to be prescribed
28. Prevention of Falls
Correct visual and
hearing impairment
Optimize medications
Bathroom grab-bars
and nonskid mats
Avoid throw-rugs and
slippery mats
Keep electric and
telephone cords away
Reduce clutter from
walking areas
Nightlight in bedroom
and bathroom
Handrails on steps and
stairs
Walking aids, if needed
Exercise for strength
and balance (Tai Chi)
Michael, YL, et. al., AHRQ Publication # 11-05150-EF-1, Dec
2010
29. Pharmacologic Prevention
Calcium, Vitamin D supplementation
Treatment of co morbid conditions
Hormone Therapy
Estrogens
SERM, Raloxifen ( Selective Estrogen Receptor
Modulators)
Only indicated for Peri menopausal or post menopausal
women
30. Osteoporosis - Treatment
Ideal treatment:
Increase bone mass
Improve bone architecture and strength
Reduce the risk of fracture
31. Hormonal therapy
When No other rx available, or lot of toxicity with other drugs
then only preferred
Estrogen( .625 mg of oral conjugated equine estrogen or
equivalent taken daily) for prevention and not for treatment ,
Est fails to show reduces the #, can be taken 5 years after
menopause…taking longer than it would be weighed against
the risk,
SERM :
Tamoxifen : monitor uterine endothelium
Raloxifen :60 mg tablet daily adv. is inhibitory on uterine
endo, selective, little benefit for non vertebral #, reduces ER
positive breast cancer so start before 2 year of menopause to
take care of flushes.
34. How Do Osteoporosis Medications
Work?
Anti-resorptive
Alter quality
Anabolic
Extra-skeletal
e.g. reduce falls
As a result, Fracture Risk is
reduced
35. Bisphosphonates: Alendronate(70 mg/wkly,
Risedronate ( 35 mg /wkly : Ibandronate
(150mg/monthly : Zoledronic Acid ( 5mg
iv/yrly )
Class: antiresorptive
BMD: increases BMD at various skeletal sites
Bone turnover markers: decreased
Fractures: reduces risk of fractures
Extra-skeletal considerations
Specific dosing requirements
Interval and IV/oral dosing available
Occasional GI irritation
Infrequent – musculoskeletal pain
Very rare - hypocalcemia, osteonecrosis of jaw, atypical femoral fracture
Effect on bone resorption persists after discontinuation
Unique to bisphosphonates
36. B.L.Riggs and M.Parfitt J Bone Miner Res. 2005;20:177
Bisphosphonates
Mechanism of Antifracture Efficacy
Refilling
Remodeling space
Mineralization
Remodeling
balance positive
Prevents microstructural damage
• trabecular plate perforation
• loss of trabeculae
• resorption “stress risers“
Increase BMD
• trabecular + to ++
• cortical 0 to +
Preservation of
architecture
Fracture risk
Bone
remodeling
37. Bisphosphonate are Antiresorbers, Increase
BMD and Reduce Fracture Risk
Spine
Bone
Turnover
Bone
Mineral
Density
Time Time
Femur
BR
BF
Fracture
Rate
PreMP Range
Rapid decrease in bone
resorption (BR), followed by a
decrease in bone formation (BF)
Refill remodeling space +
secondary mineralisation
Increase in BMD spine > hip
Reduction in
fracture risk
HOWEVER: trabecular thickness does not increase
38. Efficacy (Relative Risk Reduction
in %)
Alendronate Risedronate Ibandronate
Efficacy (Relative Risk Reduction in %)
Vertebral # 47% 41% 62%
Non vertebral # 36% 40% 38-43%*
Hip # 51% 30%
decrease in bone
turnover markers
50-70 % 40-60 %
6/2/2021 38
Reginster J Y.Antifracture efficacy of currently available therapies for Postmenoapausal Osteoporosis. Drugs 2011; 71 (1): 65-78
* Cranney A et al. Ibandronate for the prevention of nonvertebral fractures:a pooled analysis of individual patient data.
Osteoporosis Int (2009) 20:291–297
39. Bisphosphonates – Side Effects
Oral
GI-Intolerance
Flu-like symptoms (myalgia, arthralgia,“fever“)
Intravenous
Flu-like symptoms (myalgia, arthralgia, “fever“)
In 12-48 hours after application
Lasts usually for 1-2 days, sometimes 1 week
Steroids reduce intensity and risk
Hypocalcemia
Ocular effects
Renal dysfunction
Segmental glomerulosclerosis (PAM)
Tubular dysfunction – interstitial nephritis (ZOL)
Osteonecrosis of the jaw
Atypical fractures
Check prior to IV Rx
- Calcium
- Creatinine
Serum Calcium & Serum Creatinine is mandatory with I.V. bisphosphonates
40. Calcitonin Nasal Spray
Class: anti resorptive, biologic agent
200 IU daily as nasal spray
BMD: slight increase
Bone turnover markers: decreased
Fractures: reduces risk of vertebral fractures, no proven
benefit for hip or non vertebral fractures
Extra-skeletal considerations
Possible analgesic effect
Occasional nasal irritation, rarely epistaxis
No known drug interactions
41. 5-year study of 1255 women, average age 68,
with 1-5 prevalent vertebral fractures
Nasal Calcitonin Reduces Spine Fracture
Risk
Adapted from Chesnut CH III, et al. Am J Med. 2000;109:267.
0
5
10
15
20
25
30
35
Placebo 100IU 200IU 400IU
%
Subjects
with
New
Vertebral
Fractures
No significant reduction in non-vertebral
fractures or hip fractures
36%
P<0.05
PROOF Trial: Prevent Recurrence of Osteoporotic Fractures
42. Calcitonin and Cancer Risk?
European Medicines Agency Committee for Medicinal
Products for Human Use recommended that calcitonin
should no longer be used for osteoporosis (July 2012)1
Meta-analysis finds increased overall cancer risk (2012
ASBMR abstract # 1234, Heep, et. al.)
Not yet published in peer-reviewed literature
Future of calcitonin unclear
1www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/referrals
/Calcitonin/human_referral_000319.jsp&mid=WC0b01ac0580024e99
43. Teriparatide: rhPTH (1-34)
Class: anabolic, hormone
20 mcg SC inj daily for at least 6 months. Maximum
period of treatment is two years with stringent monitoring.
BMD: increases at spine and hip
Bone turnover markers: increased
Fractures: decreases at spine and non vertebral, no
proven benefit for hip
Extra-skeletal considerations:
Osteosarcoma in rats, daily subcutaneous injection,
refrigeration, hypercalcemia, leg cramps, dizziness, high
cost, limit of 2 years of therapy
44. PTH Treatment
Mechanism of Antifracture Efficacy
B.L.Riggs and M.Parfitt J Bone Miner Res. 2005;20:177
Bone
Remodleing
(formation>resorption)
Renewed periosteal
remodeling
Positive remodeling
balance
Microstructure repair
Renewed trabecular
modeling
Improved bone geometry
Increase BMD
trabecular +++
cortical ++
Improved
architecture
Fx risk
stimulates osteoblast function, increases gastrointestinal calcium
absorption, increases renal tubular reabsorption of calcium
Enhances bone turnover by initiating greater bone formation
45. Teriparatide Increases BMD
Adapted from Neer RM, et al. N Engl J Med. 2001;344:1434.
RCT of 1637 women with postmenopausal osteoporosis and 1 vertebral fractures
treated an average of 18 months with placebo, 20 µg PTH (1-34)
-4
-2
0
2
4
6
8
10
12
Spine Total Hip Distal Radius Shaft Radius
%
Change
in
BMD
Placebo
PTH 20 mcg
NS
NS
P<0.001
P<0.001
46. RCT of 1637 women with postmenopausal osteoporosis and 1 vertebral fractures
treated an average of 18 months with placebo, 20 µg PTH (1-34)
Teriparatide Reduces Fracture Risk
Adapted from Neer RM, et al. N Engl J Med. 2001;344:1434.
65%**
53%*
*P<0.02
**P<0.001
47. Effects of PTH (1-84) on Bone Mineral Density
n=2532, age 64.5±7.9, T-score ≤ -3.0
-2
-1
0
1
2
3
4
5
6
7
0 6 12 18 0 6 12 18
%
Change
from
baseline
Months
Lumbar Spine Total Femur
PTH
Placebo
48. Recent Reports Do Not Find Increased
Osteosarcoma Risk With PTH/Teriparatide
No cases of teriparatide use among over 1400 cases
of osteosarcoma seen over a 7-year period.1
Extensive review of overall safety data with
teriparatide and PTH (1-84) did not reveal any risk of
osteosarcoma.
1Andrews EB, Gilsenan AW, Midkiff K, Sherrill B, Wu Y, Mann BH,
Masica D. The US postmarketing surveillance study of adult
osteosarcoma and teriparatide: study design and findings from the first 7
years. J Bone Miner Res, 2012, Sept. 2012 [Epub ahead of print]
2Cipriani C, Irani D, and Bilezikian JP. Safety of Osteoanabolic therapy: a
decade of experience. J Bone Miner Res (in press), 2012.
49. Strontium
Discovered in 1790 and isolated in 1808 (near
Scottish village Strontian)
Divalent cation
Resembles calcium and often mimics action of
calcium
Participates in bone mineralization
Anabolic properties
Uncoupling of BF and BR
Stimulates osteoblast proliferation
Inhibits osteoclast activity
Activation of signaling pathways through CaSR (?)
50. Denosumab
Class: anti resorptive, fully human monoclonal antibody,
binds and inhibits RANKL
BMD: increased at spine and hip
Indicated in PMO
Trials under way for its use in Men
60mg/ml Sc twice yearly
Bone turnover markers: decreased
Fracture: reduces spine, hip and non vertebral fractures
Extra-skeletal considerations
SQ injection every 6 months
Hypocalcemia, infection, ONJ likely adverse effect
51. Denosumab (RANK-Ligand
Antibody)
IgG2 immunoglobulin isotype
Its a bone metabolism regulator – a newer class
High affinity to human RANKL*
High specificity for RANKL
No neutralizing antibodies found in clinical trials
Effect on bone resorption = reversible
* does not bind to rat or mouse
54. Newer Molecules
• Cinacalcet
Calcium sensing receptor agonist, calcimimetics , Reduces PTH
• Ronacaleret
Calcium sensing receptor antagonist, calcilytics , Elevates PTH
• Ondanacatib
Anti resorptive molecule, Ondanacatib inhibits cathepsin K, acts on
osteoclasts
• Glucagon-like Peptide 2
intestinal polypeptide hormone , Bone resorption activity peaks
overnight; therefore, treatment with GLP-2 at bedtime will
achieve a substantial reduction in the bone resorption
• Monoclonal Antibodies
Regulates Bone cell pathophysiology
Drug action is monitored with C Telopeptide [CTx] a marker of bone resorption
And Osteocalcin a marker of bone formation
55. Osteoporosis – Treatment
How Long to Treat?
Optimal duration of treatment in women with
postmenopausal osteoporosis is unknown
Is prolonged treatment safe ?
Long term effects of chronically reduced bone
turnover: could skeletal health and repair mechanisms
be impaired?
Does long term beneficial antifracture efficacy require
long term use?
56. Effect of 3 vs. 6 Years of Annual
Zoledronic Acid Treatment
1233 postmenopausal women who received ZOL for 3 years
randomized to 3 additional years of ZOL or placebo (Z6 vs Z3P3)
In years 3-6 FN BMD remained constant with Z6 and dropped
slightly in Z3P3 (1.04%, p < 0.001)
Markers rose slightly in Z3P3 group but remained below
pretreatment levels
New morphometric vertebral fractures lower in Z6 vs Z3P3 but other
fractures were not different
Black, et. al., JBMR, 2012; 27, 243-254
“..after 3 years of annual ZOL, many patients may discontinue
therapy up to 3 years. However, vertebral fracture reductions
suggest that those at high fracture risk particular vertebral
fracture, may benefit by continued treatment.”
57. Bisphosphonates Have Been Reported
to Have Other Beneficial Effects
Decreased risk of breast cancer1-5
Decreased risk of colorectal cancer6
Decreased risk of stroke7
Reduced risk of gastric cancer8
Decreased overall mortality9,10
58. Bisphosphonate Summary
Bisphosphonates appear to be safe and effective when
used long-term
Prolonged reduction of bone remodeling may be
associated with atypical femur fractures
Osteonecrosis of the jaw associated with bisphosphonate
treatment is rare when BPs are used in osteoporotic
patients
“Further investigation into the benefits and risks of long-
term therapy, as well as surveillance of fracture risk after
discontinuation of bisphosphonate therapy, will be crucial
for determining the best regimen of treatment for
individual patients with osteoporosis.”1
1Whitaker, et. al, NEJM, 2012; 366:22, 2048-2051
60. Summary
The different therapeutic options include several anti-
resorptive drugs and more recently new anabolic compounds
Bisphosphonates reduce fracture risk for vertebral and non-
vertebral fractures
Anti-fracture efficacy is already evident after one year of
treatment
Raloxifene (SERM) has skeletal effects similar to those of
estrogen and reduces vertebral fracture risk
Parathyroid hormone treatment induces significant increases
in bone mass and decreases fracture risk. Used as last resort
and those extreme cases with advanced osteoporosis and
already with Fragility fractures
In postmenopausal women with low bone mass, denosumab
(RANKL-Ab) increases bone mass and decreases bone
resorption and reduces fracture risk