Osteoporosis and Bone Mineral Density

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Osteoporosis and Bone Mineral Density

• Netee Papneja
• PGY4 Endocrinology

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Objectives

• To review the basic of Osteoporosis definition,
  epidemiology, and risk factors
• To review the current Osteoporosis guidelines for
  women and men
• To review basics of BMD and it's interpretation

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What is Osteoporosis?

• A skeletal disorder - compromised bone strength
  (low bone mass and poor quality) increased risk
  for fragility fracture
• Fragility fracture occurs spontaneously or with
  low trauma from standing height or less

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Osteoporosis

• Fragility represent 80 of all fractures in
  menopausal women gt 50
• 1-year mortality after hip fracture ranges 8.6
  to 36 and only 25 return to baseline
  functioning
• Large care gap exists
• lt20 of women receive therapies to reduce future
  fracture within the year following fracture and
  lt10 of men!
• 60 of women with fragility fractures have
  non-osteoporotic bone mineral density(T-score
  gt-2.5)

Bessette L et al. The care gap in diagnosis and
treatment o f women with a fragility fracture.
Osteoporos Int 20081979-86. Abrahamsen B et al.
Excess mortality following hip fracture a
systematic epidemiological review. Osteoporos Int
2011201633-50.
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Pathogenesis

• Low peak bone mass
• Consequence of peak bone mass accrued in utero
  and during childhood and puberty
• Genetic factors account for up to 85 of peak
  bone mass determinant
• Other influences hormonal, nutritional, and
  environmental
• Increased bone re absorption (ex. Low Estrogen)
• Decreased bone formation (ex. Steroids)

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Secondary Osteoporosis

• Secondary osteoporosis (20 in women and 50
  cause in men)
• Genetic
• Hypogonadism
• Endocrine
• Nutritional and GI related
• Hematologic and neoplastic
• Medication Induced
• Miscellaneous

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Endocrine Causes
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Disorders strongly associated with osteoporosis
include

• Endocrine
• Primary hyperparathyroidism, Type I diabetes,
  Osteogenesis imperfecta in adults, Untreated
  long-standing hyperthyroidism, hypogonadism,
  Cushings disease
• menopause (lt45 years)
• Chronic malnutrition or malabsorption
• Chronic liver disease
• Chronic inflammatory conditions

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How is the diagnosis of Osteoporosis Made?

• Can be made or suspected if fragility
• In pre-fracture patient, the WHO recommends
  making the diagnosis based on BMD value at lowest
  skeletal site
• NORMAL T- score over -1
• OSTEOPENIA (Now replaced by LOW BONE MASS)
  T-score -1 TO -2.5
• OSTEOPOROSIS T-score over-2.5

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BMD basics

• Measures bone mass to establish diagnosis of
  osteoporosis, predict risk of subsequent
  fractures and to monitor changes in BMD during
  therapy
• Methods of measuring BMD
• Dual energy x-ray absorptiometry (DXA)
• Quantitative ultrasonography (QUS)
• Quantitative computed tomography (QCT)

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How does bone densitometry measure bone mass?

• Technique uses an ionizing radiation source (from
  a radionuclide or from x-rays) and a radiation
  detector to measure amount of calcium in bone.
• Principle bone will absorb radiation in
  proportion to its bone mineral content
• Bone mineral content then divided by measured area

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Dual energy x-ray absorptiometry (DXA)

• Preferred method of measuring bone mass
• DXA measures bone mineral content (BMC, in grams)
  and bone area (BA, cm2)
• "areal" BMD (aBMD) is calculated in g/cm2 by
  dividing BMC by BA

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Bone Mineral Density DXA
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• Patient on whole body scanner, with x-ray sources
  beneath a table and a detector overhead. Scanned
  with photons that are generated by 2 low-dose
  x-rays at different energy levels. The body's
  absorption of the photons at the two levels is
  measured. The ratios can be then used to predict
  total body fat, fat-free mass, and total body
  bone mineral.

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Advantages of DXA Scans

• precise, accurate, and reliable

PRECISION ERROR () ACCURACY ERROR () RADIATION DOSE (mSV)
Spine 1 5-8 1
Proximal femur 1-2 5-8 1
Total body 1 1-2 3

• Relatively short scanning times (few minutes)
• low radiation exposure
• DXA can also distinguish regional as well as
  whole body parameters of body composition.

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• Disadvantages
• Initial cost of the equipment
• Significant differences in the technologies used
  by different manufacturers
• Same centre
• Same machine and calibration
• Same technician
• Contraindicated in pregnancy
• Careful of falsely low or high results

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Factors modifying bone mineral density
INCREASED BMD DECREASED BMD
HIP Excessive or inadequate internal hip rotation rotation Osteoarthritis Metal artifactFocal skeletal sclerosis Artifact overlying soft tissue Lytic lesions
SPINE OsteophytesFocal skeletal pathology (i.e., sclerosis, metastasis) Vertebral compression Vascular calcificationMetal, radiology contrast, stones, calcium tablets or other artifact overlying spine Artifacts overlying soft tissues RotoscoliosisLaminectomyLytic lesions
CARJ Vol 56, No 3, June 2005 179
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What do results mean?

• What is a T score?
• Number of standard deviations above or below the
  mean bone mass of a normal young adult sex-match
  population
• A patient whose bone mass is 1 SD below that of
  the reference population has a T-score of -1.0
  and has lost about 10 of bone mass
• What is a Z score?
• of SD above/below the mean bone mass of an age-
  and sex- matched reference population

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Best bone to use?

• Hip is preferred because bone mass at hip site
  best correlates with risk of hip fractures
  (highest mortality and morbidity)
• Role of forearm bone mass?
• Useful in primary hyperparathyroidism, if patient
  overweight and cannot be scanned

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Main Focus.

• Manage the patient according to their absolute
  fracture risk and not their BMD
• 60 of women with fragility fractures have
  non-osteoporotic bone mineral density(T-score
  gt-2.5)
• Over-reliance on BMD missed opportunity to
  prevent future fractures

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Screening

• Individuals over the age of 50
• Anyone with a history of fragility fracture
• A detailed history and physical exam can help
  identify individuals at high risk of fractures

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How do I assess for osteoporosis and fracture
risk?

• History identify RF for low BMD, future ,
  falls
• History of fracture
• Parental hip fracture
• Steriod use (gt3months, 7.5mg)
• Smoker
• High alcohol intake (gt3units/day)
• Inflammatory disorders (ie RA)
• Falls in last 1 year
• Gait and balance issues

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Screening Examination
Parameter Positive Results
Weight Under 60 kg Weight loss 10 since age 25
Vertebralfracture assessment Height (measure annually) Prospective loss gt 2 cm Historical height loss gt 6 cm
Vertebralfracture assessment Rib-to-pelvis distance 2 fingers breadth
Vertebralfracture assessment Occiput-to-wall distance (kyphosis) gt 5 cm
Fall risk assessment Get-up-and-go test Inability or difficulty performing test Long time (gt 30 seconds) to complete2
If vertebral fracture assessment is positive,
screen for vertebral fracture using lateral spine
x-ray

1. Papaioannou A, et al CMAJ 2010.

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JAMA

• Does this woman have osteoporosis?
• Weight lt 51 kg LR7.3
• Tooth count lt20 LR 3.4
• Self-reported humpback LR 3.0
• Rib Pelvis lt 2 finger breadth LR3.8
• Wall to Occiput gt0cm LR4.6

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Next Steps BMD

• BMD for
• gt65
• Presence of fracture
• Individuals who have risk factors

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Osteoporosis Investigations

• Recommended tests for for people with
  osteoporosis, defined as T-score -2.5
• Calcium, corrected for albumin
• Complete blood count
• Creatinine
• Alkaline phosphatase
• Thyroid-stimulating hormone
• Serum protein electrophoresis (for patients with
  vertebral fractures)
• 25-Hydroxyvitamin D

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Osteoporosis Risk Assessment

• Two tools available
• Canadian Association of Radiologists and
  Osteoporosis Canada (CAROC)
• Fracture Risk Assessment tool (FRAX)

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Osteoporosis Risk Assessment

• CAROC
• Uses age, sex, and femoral neck T-score
• 10-year risk of major osteoporotic fracture is
  determined
• 2 Risk factors raise a patients risk level to
  next category
• Fragility fracture after age 40
• Prolonged systemic glucocorticoid use

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Osteoporosis CAROC
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Osteoporosis CAROC
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Osteoporosis Risk Assessment

• FRAX
• Developed and recommended by the WHO
• Uses sex, age, femoral neck T-score (optionally),
  and
• BMI
• Prior fracture
• Parental hip fracture
• Prolonged glucocorticoid use
• Rheumatoid arthritis (or secondary cause of
  osteoporosis)
• Current smoking
• Alcohol intake gt3/d
• 10-year probability of major osteoporotic
  fracture and hip fracture is calculated as a

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FRAX Tool On-line Calculator
www.shef.ac.uk/FRAX.
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CAROC Verses FRAX

• Both reflect risk assessment in treatment-naïve
  patients
• FRAX more complete, but complex to use, not
  available in BMD machines
• The CAROC tool is the only tool that can be
  applied nationally at the present time.
• 2010 CAROC tool is recommended for use in Canada
  by Osteoporosis Canada it is also available in
  an electronic format.

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Treatment- Non pharmacological For ALL Patients

• 1. Exercise Resistance, weight-bearing aerobic
  exercises, that enhance core stability and/or
  focus on balance (i.e. tai chi)
• 2. Hip protectors for LTC residents
• 3. Smoking cessation
• 4. Reduce alcohol
• 5. Fall-prevention strategies

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Osteoporosis Calcium Vit D

• New Osteoporosis Canada Guidelines
• Adults over age 50
• Total daily intake of elemental calcium (through
  diet and supplements) should be 1200 mg
• Healthy adults at low risk for vitamin D
  deficiency
• Vit D3 400-1000 IU daily
• Adults over age 50 at moderate risk of vitamin D
  deficiency
• Vit D3 800-1000 IU daily (up to 2000 IU may be
  required)

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Treatment
CAROC stratification guides treatment decisions
Women
Low risk (lt10)
Moderate risk (10-20)
High risk (gt 20)
Papaioannou A, et al CMAJ 2010.
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Pharmacological Treatment

• Low risk (10-year risk lt10)
• Treatment not recommended. Reassess risk in 5
  years
• Moderate risk (10-year risk 10-20)
• Consider treatment if additional risk factors or
  vertebral present
• High risk (10-year risk gt20)
• Should be offered pharmacologic therapy

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Factors to Consider in moderate risk patients

• Fracture
• vertebral fracture
• Previous wrist fracture in individuals either gt
  65yrs or with a T-score -2.5
• BMD
• Lumbar spine T-score ltlt femoral neck T-score
• Rapid bone loss
• Medications
• Aromatase-inhibitor or androgen deprivation
  therapy
• Long-term or repeated systemic glucocorticoid use
  not meeting conventional criteria for prolonged
  use
• Other
• Recurrent falls ( 2 times in the past 12 months)
• Disorders strongly associated with osteoporosis,
  rapid bone loss or fractures

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First-line therapies in post-menopausal women
Based on GRADE A evidence Based on GRADE A evidence Based on GRADE A evidence Based on GRADE A evidence Based on GRADE A evidence Based on GRADE A evidence Based on GRADE A evidence Based on GRADE A evidence
Type of Fracture Antiresorptive Therapy Antiresorptive Therapy Antiresorptive Therapy Antiresorptive Therapy Antiresorptive Therapy Antiresorptive Therapy Bone Formation Therapy
Type of Fracture Bisphosphonates Bisphosphonates Bisphosphonates Denosumab (Prolia) RANK ligand Inhibitor SERM Raloxifene Estrogen (Hormone Therapy) Teriparatide (Forteo) PTH analog
Type of Fracture Alendronate Risedronate Zoledronic Acid Denosumab (Prolia) RANK ligand Inhibitor SERM Raloxifene Estrogen (Hormone Therapy) Teriparatide (Forteo) PTH analog
Vertebral ? ? ? ? ? ? ?
Hip ? ? ? ? - ? -
Non-vertebral ? ? ? ? - ? ?
For menopausal women can be used as a first-line
for prevention of vertebral fractures For
menopausal women with vasomotor symptoms
Papaioannou A, et al CMAJ 2010. Papaioannou A,
Morin S. CMAJ. 2010.DOI10.1503/cmaj.100771.
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Osteoporosis Treatment

• Osteoporosis Canada Guidelines for Menopausal
  women
• Second line therapy calcitonin or etidronate for
  prevention of vertebral fractures grade B

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Treatment Bisphosphonates

• Osteonecrosis of the jaw (ONJ) 1/100,000 pts/ yr
• nonhealing area of exposed bone in the jaw
• Commonly after dental procedures
• Mostly with higher doses of IV BP use for cancer,
  in patients with co-factors like chemo,
  radiation, steroids
• Atypical Fracture subtrochanteric or shaft
  fracture
• 2/100,000 pts on 2yrs BP 78/100,000 pts on
  8yrs BP

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Treatment RANKL antibody60mg SC q6months

• Denosumab (Prolia) is a monoclonal antibody
  against Rank Ligand
• Inhibits Rank Ligand, a protein which activates
  osteoclasts. Denosumab blocks osteoclast
  differentiation and reduces osteoclast numbers
  and thereby inhibiting bone reabsorption.
• Long-term safety data not available
• Not studied in men
• Used in
• Patients who have failed, are intolerant of other
  therapies, poor adherence, patient preference
• Covered by OBD if 2/3 present gt75, BMD lt-2.5,
  fracture

Cummings SR et al. Denosumab for prevention of
fractures in postmenopausal women with
osteoporosis. N Engl J Med. 2009361(8)756
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Treatment Recombinant PTH

• FORTEO (teriparatide rDNA origin injection) 20
  microgram SC OD x 2years
• 800/month
• Vertebral and Non Vertebral prevention
• Consider using in
• Men and women with severe osteoporosis who
  continue to fracture after bisphosphonate therapy
• Intolerance to bisphosphonates

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SERM

• Selective estrogen receptor modulator-Raloxifene
  (Evista)
• Reduces only vertebral fractures
• Breast Ca protection/no endometrial hyperplasia
• Increases risk of venous thromboembolism/hot
  flashes

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HRT

• reduce overall fractures with a relative risk
  reduction of 30
• Risks associated with VTE, stroke and Breast
  Cancer
• Requires assessment of risks, benefits and
  patient preference
• Consider with intolerable menopausal symptoms

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Treatment Calcitonin

• Binds to osteoclasts and inhibits bone
  reabsorption
• Can be given IM, SC, or intranasal
• Less efficacious than other therapies
• Reduces only vertebral
• Can be considered in patients with back pain

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Duration of Bisphosphoates (BP) Treatment

• Large, RCTs show benefit of BP therapy for 3-4
  yrs
• Only two RCT looking at use of BP beyond 5 years
• Fracture Intervention Trial Long-Term Extension
  (FLEX)- 1099 postmenopausal women on avg 5yrs of
  Alendronate to continue it or placebo for
  additional 5 yrs
• Health Outcomes and Reduced Incidence with
  Zoledronic Acid Once Yearly (HORIZON) Extension
  trial- 3 years of treatment followed by 3 years
  of active extension (n 616) or placebo ( n
  617)
• n engl j med 36622 nejm.org may 31, 2012

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• FLEX and HORIZON trials
• modest bone loss after D/C of therapy as compared
  to continued therapy ?persistent effect of
  alendronate (5 years) and zoledronic acid (3
  years)
• Both showed significant reductions in the risk of
  vertebral with continuation of bisphosphonate
  treatment
• Neither trial showed an overall reduction in
  nonvertebral fractures.

n engl j med 36622 nejm.org may 31, 2012
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5-Yr Risk of Clinical Vertebral Fracture
FN T score at start Placebo Alendronate Risk Difference NNT
ALL BMD 23/437 (5.5) 16/662 (2.5) 2.9 (0.35.4) 34
lt-2.5 -2.5 to -2 gt-2 11/132 (9.3) 9/126 (5.8) 3/179 (2.3) 9/190 (4.5) 3/185 (2.8) 4/282 (1.1) 4.8 (0.89.2) 3.0 (0.36.7) 1.2 (0.22.8) 21 33 81

No Vertebral
lt-2.5 -2.5 to -2 gt-2 6/75 (8.0) 3/82 (3.0) 2/130 (1.8) 4/109 (3.8) 1/121 (1.4) 2/203 (0.9) 4.2 (0.69.1) 1.6 (0.25.0) 1.0 (0.12.6) 24 63 102

Vertebral
lt-2.5 -2.5 to -2 gt-2 5/57 (11.1) 6/44 (11.1) 1/49 (3.7) 5/81 (5.3) 2/64 (5.3) 2/79 (1.7) 5.8 (0.812.1) 5.8 (0.813.6) 2.0 (0.35.6) 17 17 51
Continuing Bisphosphonates for Osteoporosis
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Osteoporosis Treatment

• Monitoring
• Treatment initiation 1-3 years after
• Good response if BMD improves or stabilizes
• Poor response Decrease in BMD greater than the
  least significant change (LSC) of the measuring
  facility
• adherence issues, undiagnosed secondary causes
• Moderate risk repeat BMD testing in 1-3 years to
  assess for rapid decline in BMD
• Low risk individuals repeat at 5-10 year interval

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Bone Turnover Markers (BMT)

• Prospective studies increased levels of BTMs are
  associated with two-fold increased risk in
  women 65 and older
• In estimating the 10- year absolute risk of hip
  fracture, the combination of an elevated
  reabsorption marker (C-terminal telopeptide) with
  an osteoporotic BMD or a history of previous
  fracture resulted in a 70-100 higher risk than
  from BMD alone
• The value of BTMs still unclear, not integrated
  in any fracture risk assessment system.

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Monitoring Cross-linked
C-terminal telopeptides (CTX)

• proteolytic fragments of type 1 collagen formed
  during bone resorption
• high levels of CTX higher rate of bone
  remodeling (turnover)
• Menopause Low estrogen reduced osteoblasts
  and thus accelerating the rate of bone loss
  higher CTX
• antiresorptive therapy CTX back to
  pre-menopausal level

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• Interpretation
• drop in CTX concentration of 35 to 55 percent
  from baseline levels after three to six months
  indicates effective antiresorptive therapy.
• Ineffective therapy or lack of compliance
  absence of a decline
• Provides early indication of treatment response
• Changes in bone turnover can be detected in three
  months by measuring CTX
• testing for CTX is noninvasive and can be
  repeated often.

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Limitations

• variability of CTX due to diet, exercise, time of
  day, etc
• cannot replace BMD in diagnosing osteoporosis
• Although levels of CTX are associated with
  increased risk of fractures, the test cannot be
  used to predict fractures.
• Low GFR CTX concentrations may be higher than
  expected due to reduced excretion of CTX

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Treatment
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Osteoporosis Guidelines for Men 2012

• Evaluation with BMD
• gt70
• 50-69 yo if additional RF (ex. fragility ,
  steroids, hypogonadism, hyperparathyroidism, or
  COPD)
• Hyperparathyroidism or anti-androgen tx for
  prostate ca measure forearm dXa (1/3 or 33
  radius)

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Treatment- Lifestyle

• 10001200 mg calcium daily
• Obtain vitamin d levels gt 75 nmol/liter
• weight-bearing activities for 3040 min per
  session, 3-4/wk
• Etoh lt3/day
• cease smoking

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Pharmacological

• Treatment for
• hip or vertebral fragility fracture
• BMD below -2.5 at any site
• gt20 10yr risk of fracture
• Long term steroids
• Options
• alendronate, risedronate, zoledronic acid, and
  Forteo also Prolia for men receiving adT for
  prostate cancer

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Special Groups

• hypogonadal men
• High risk Testosterone bisphosphonate or
  Forteo
• Borderline high risk Testosterone if its
  lt6.9nmol/L and positive signs of symptoms low
  androgen or chronic hypogonadism (due to HPA
  problem)
• Men with prostate cancer receiving ADT
• High risk Recommend pharmacological treatment of
  OP

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Monitoring

• BMD q1-2 years until plateau reached, then reduce
  frequency
• consider measuring a bone turnover marker (CTX)
  at 36 months after initiation for anabolic
  therapy (Forteo)

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Summary

• Osteoporosis is prevalent and causes a great
  burden by increasing fractures
• Assessment of osteoporosis should include
  determination of risk factors and BMD
• Two validated tools (CAROC and FRAX) are
  available for fracture risk assessment in Canada
• Pharmacologic treatment is guided by risk level

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• Thank you!
• Special thanks to Dr. Paul and Ronen