Osteoporosis: all you ever wanted to know

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Osteoporosisall you ever wanted to know

• Angela F. Hawk
• 12/6/06

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Background

• Definition multifactorial systemic skeletal
  disorder characterized by
• 1)decreased bone mass
• 2)deterioration of bony microarchitecture
• Result increased fragility of bones, increased
  risk of fracture with minimal trauma
• Presentation normally silent until fracture
  occurs

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Some statistics

• Frequency in the US approximately 10 million
  (another 14-18 are affected by osteopenia)
  internationally approximately 1 in 3 women and 1
  in 8 men
• Race caucasians and asians are at increased risk
  (african americans have 6 higher BMD)
• Sex types 1 and 2 women gt men, with
  female-to-male ratios of 62 and 21
  respectively. Type 3, women men.
• Age peak incidence of type 1 ages 50-70 y/o,
  peak incidence for type 2 gt70 y/o, type 3 occurs
  at any age

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Osteoporosis defined

• Low bone mass as defined by bone mineral density
  testing of axial skeleton (done by dual energy
  X-ray absorptiometry, aka DEXA)
• Standardized by Z and T-scores
• Z SD from mean bone density of reference
  population of same age, sex, and race
• T SD from mean of normal young adult population
• Can refer to spine or hip bone mass measurement

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Definitions (contd)

• WHO definitions
• Osteopenia bone density b/w 1 and 2.5 SDs below
  mean (T score)
• Osteoporosis 2.5 or more SDs below mean (T
  score)
• Other organizations define osteoporosis as gt2 SDs
• At spine and hip, a decrease of 1 SD below mean
  is associated with a 2-fold increase in fracture
  risk

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Bones

• Made of osseous tissue
  a hard and lightweight
  composite composed of calcium
  phosphate.
• Characteristics high compressive strength, poor
  tensile strength, significant elasticity due to
  presence of collagen
• Made of living cells in a mineralized organic
  matrix. Osteoblasts make bone, osteoclasts break
  down bone (living in resorption pits called
  Howships lacunae), and osteocytes are
  osteoblasts trapped in matrix they help produce
  (functions include formation of bone, matrix
  maintenance and calcium homeostasis)

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Life cycle of bone

• Bone remodeling unit site on surface of bone
  where osteoblasts and osteoclasts form/resorb
  bone
• Divided into 4 stages resting, resorption,
  reversal, formation
• Each cycle can take several months to complete

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Stages (in more detail)

• Resting stem cells from bone marrow attracted
  to bone surface and differentiate into
  osteoclasts
• Resorption oclasts remove bone with acid pH
  and proteolytic proteins
• Reversal oclasts stop above process,
  mesenchymal stem cells attracted to surface and
  differentiate into osteoblasts
• Formation oblasts make new bone by laying down
  protein matrix (osteoid) which is then mineralized

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Types of bone

• 2 major types cortical and trabecular
• Cortical outer shell, makes up 75 all bone
  mass
• Trabecular spongy, interlacing network forming
  internal support. Concentrated in vertebral
  bodies/bony pelvis. 25 all bone mass, however
  makes up most of volume of bone
• Trabecular bone larger surface area, thus higher
  turnover rate than cortical. Most likely to show
  bone loss, also most likely to show response to
  therapy

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Its all about balance

• Formation in balance with resorption
• Bone mass peaks at age 30 in??
• 0.4 bone lost per year in both sex, PLUS 2
  cortical and 5 of trabecular per year in women
  for first 5-8 years post menopause
• Immediately after menopause, most loss due to
  excess resorption. Later, most loss is due to
  decreased formation
• This difference can be used to guide treatment
  approaches
• Several different types of osteoporosis

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Type 1

• AKA postmenopausal osteoporosis
• Due to gonadal (ie, estrogen, testosterone)
  deficiency resulting in accelerated bone loss
• Post menopause, women experience an accelerated
  bone loss of 1-5 per year for the first 5-7
  years causing increased fractures
• Brief science behind type 1 increased
  recruitment and responsiveness of osteoclast
  precursors leading to increased bone resorption.
  Bone loss begins to occur faster than bone
  formation.

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More science

• Decreased estrogen ? increased sensitivity of
  bone to parathyroid hormone (PTH). Net effect
  increased calcium release from bone, decreased
  renal calcium excretion, and increased production
  of 1,25-dihydroxyvitamin D (1,25OH2 D3).
• Increased 1,25(OH)2 D3 ? increased calcium
  absorption from the gut, increased calcium
  resorption from bone, and increased renal tubular
  calcium resorption.
• PTH secretion decreases via negative feedback
  effect, causing the opposite effects.
• Osteoclasts are also influenced by cytokines,
  such as TNF-alpha and interleukins 1 and 6, whose
  production by mononuclear cells may be increased
  in the presence of gonadal deficiency.

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Types 2 and 3

• Type 2 - AKA senile osteoporosis.
  Due to decreased formation of bone and decreased
  renal production of 1,25(OH)2 D3 occurring late
  in life. Results in loss of cortical and
  trabecular bone and increased risk for fractures
  of the hip, long bones, and vertebrae.
• Type 3 - secondary to medications (ie
  glucocorticoids) or other conditions causing
  increased bone loss by various mechanisms.

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Factors affecting bone mass

• Biggest factor genetics (up to 80 of
  variability attributed to genetic factors alone)
• Other risk factors for osteoporotic fractures
  prior fracture, caucasian race, dementia, poor
  nutrition, smoking, low weight/BMI, estrogen
  deficiency (early menopause, long amenorrhea),
  low calcium, ETOH-ism, impaired eyesight, fall
  history, inadequate physical activity

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The truth about exercise

• Weight bearing exercise
  has positive effect on
  skeleton
• Insufficient to prevent bone
  loss in early menopause,
  but will slow the rate
• Impact loading (ie weight
  lifting) best osteogenic stimulus
• Exercise reduces risk of falls, /- reduces
  fracture risk in falls that do occur

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Medical conditions associated with oporosis

• AIDS/HIV
• Amyloidosis
• Ankylosing spondylitis
• COPD
• Congenital porphyoria
• Cushings
• Eating disorders
• Gastrectomy
• Gauchers
• Hemochromatosis
• Hemophilia
• Hyperparathyroidism
• Hypogonadism
• Hypophosphatasia
• Idiopathic scoliosis
• Inflammatory bowel disease
• IDDM

• Lymphoma/leukemia
• Malabsorption syndromes
• Mastocytosis
• Multiple myeloma
• Multiple sclerosis
• Pernicious anemia
• Rheumatoid arthritis
• Liver dz (esp PBC)
• Spinal cord transection
• Sprue
• Stroke
• Thalessemia
• Thyrotoxicosis
• PTH secretion due to malignancy
• Weight loss

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Drugs associated with increased oporosis risk

• Aluminum
• Anticonvulsants (phenobarb/phenytoin)
• Cytotoxic drugs
• Glucocorticosteroids and adrenocorticotropin (up
  to 10 bone loss in first year of tx with high
  doses)
• GNRH agonists
• Immunosuppressants
• Lithium
• Long term use of heparin (bone loss in 1/3 of
  women)
• Long acting parenteral progesterone
• Supraphysiologic thyroxine doses
• Premenopausal use of tamoxofen
• TPN

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Screening

• DEXA characteristics
  inexpensive, high precision
  and accuracy, modest radiation exposure
• Peripheral site testing (wrist, calcaneus) can
  identify low bone mass but results not as
  precise. T scores do not correlate with those of
  DEXA screening
• Should limit to when DEXA not available or with
  lower risk populations
• Can be useful to predict fracture, but should not
  be used for definitive diagnosis or to monitor
  therapy response

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When to screen

• Definite screening
• All postmenopausal women gt65 years old
• Postmenopausal women lt65 y/o with one or more
  risk factor
• All postmenopausal women with fractures
• Also consider screening pre- and post-menopausal
  women with certain diseases or conditions and
  taking certain meds
• Without new risk factors, subsequent screening
  should not be repeated more frequently than q2
  years. ?

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Monitoring options

• Repeat BMD testing after a year. Ensure
  compliance with therapy if declines, and either
  modify therapy or re-test in one year
• Repeat BMD testing after 2 years
• Check biochemical markers in 6 months and if
  falling appropriately, repeat BMD testing in 2
  years
• No monitoring necessary

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Other options

• Quantitative US ? low cost, lack of ionizing
  radiation. Measurements of heel may be able to
  predict hip/spine fractures.
• Peripheral Quantitative CT ? can distinguish
  cortical from trabecular bone at a particular
  site (b/c trab. bone changes faster, perhaps will
  provide earlier detection). More , more
  radiation.
• Biochemical markers ? cannot diagnose oporosis,
  predict bone density, or predict fracture risk.
  Useful for assessing response to therapy because
  change occurs faster than bone mineral density
  changes. Serum tests better than urine.

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Biochemical markers

• Of bone formation
• Serum bone specific alkaline phosphatase
• Serum osteocalcin
• Serum procollagen I extension peptides
• Of bone resorption
• Urinary N-telopeptide
• Urinary C-telopeptide
• Collagen cross links
• Urinary deoxypyridinoline
• Urinary hydroxyproline

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W/u for secondary causes of bone loss

• First tier
• Serum calcium
• Serum chemistry analysis
• 24-hour urine calcium/creatinine
• PTH levels
• TSH levels in women taking synthroid
• Second tier
• Renal profile
• Vit D and PTH levels
• Evaluation of thyroid function
• Serum protein electrophoresis (r/o myeloma)

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When to treat

• First lifestyle changes
  (details to follow)
• Next follow guidelines as stated by National
  Osteoporosis Foundation (NOF) recommend
  pharmacologic therapy to postmenopausal women
  with T-scores lt-2.0 as measured by central DEXA
  regardless of risk factors, and lt-1.5 if risk
  factors present

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Lifestyle changes as prevention

• Exercise, avoidance
  of certain meds,
  treatment of DM/ sensory
  impairment
• Adjustment of living environment
• Smoking cessation
• Increased protein intake
• Decreasing ETOH consumption (however, moderate
  alcohol consumption in women gt65 y/o associated
  with increased BMD and lower risk for hip
  fracture)

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Treatment options

• Bisphosphonates
• SERMs
• Calcium/Vitamin D
• Hormones
• Etc, etc, etc.

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Bisphosphonates

• Alendronate, risendronate, ibandronate
• Effective for tx and
  prevention of osteoporosis
• Increase bone mass, reduce
  incidence of fractures by
  
  inhibiting osteoclast activity
  
• Precautions avoidance of pill induced
  esophagitis (CI with reflux, GERD, other
  esophageal abnormalities) must take on empty
  stomach and remain upright for 30 min
• Complications osteonecrosis of the jaw (seen
  mostly in cancer pts getting IV bisphosphonates)

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SERMs

• Mixed estrogenic and antiestrogen
  properties depending on tissue
• Raloxifene
• AKA Evista. Besides increasing BMD, also lowers
  risk of breast Ca without stimulating endometrial
  hyperplasia. However can increase risk of DVTs
  and increase vasomotor symptoms (hot flashes,
  etc). Decreases LDL without noticeable effect on
  CAD.
• Tamoxifen
• Not typically rx for osteoporosis alone, but if
  already being used for breast cancer can provide
  effective bone protection

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Calcium/Vitamin D

• Should be considered adjuvant therapy for all
  individuals (esp gt65 y/o)
• WHI study modest benefit in bone health.
  Statistically significant only with FULL doses
  and in older population. Otherwise small
  increase in BMD with small decrease in hip
  fractures.
• NIH recs
• Premenopausal 1000 mg
• Postmenopausal lt65 y/o using estrogen 1000 mg
• Postmenopausal not using estrogen 1500 mg
• All women gt65 1500 mg

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Hormones

• Estrogen medroxyprogesterone reduced risk of
  hip and clinical vertebral fractures by 34, and
  overall fractures by 24
• Another study showed positive bone changes after
  unopposed estrogen for 24 months without
  induction of endometrial hyperplasia
• Initial recommendations start hormone therapy
  within 5-10 years after menopause

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Hormones contd

• However, as of recent WHI study,
  estrogen-progesterone therapy no
  longer first-line approach for osteoporosis
  treatment in postmenopausal women due to
  increased risk of breast cancer, stroke, VTEs,
  and possibly CAD.
• Indications persistent menopausal symptoms,
  inability to tolerate other options, failure to
  respond to other options.

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Why not try

• PTH daily subcutaneous injections can favor
  bone formation over resorption. Use should be
  limited to high risk/refractory patients. Should
  not be combined with bisphosphonates.
• Calcitonin nasal formulation, concern over
  tachyphylasis, less effective use suggested in
  pts with painful osteoporotic fractures for
  analgesic action
• Calcitrol must monitor for hypercalcemia,
  hypercalciuria, renal insufficiency. Lack of
  consistent benefit.
• Vitamin K required for carboxylation of
  osteocalcin (needed in mineralization). Perhaps
  only beneficial when Vit K deficiency present.
• Sodium fluoride not recommended hardens
  teeth but increased bone brittleness.

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Continued.

• Combination therapy use of bisphosphonates with
  estrogen, etc, may have additive effects.
• Isoflavones phytoestrogens, micronutrients with
  properties similar to estrogen OTC in many
  countries. Risk of lymphocytopenia.
• Thiazides Hypocalciuric effect, use with
  coexisting HTN.
• Tibolone synthetic steroid whose metabolite
  have estrogenic, androgenic, and progestagenic
  properties. Possible increased endometrial
  hyperplasia and CAD.
• Folate/B12 may help elderly patients after
  stroke, studies only in patients with elevated
  homocysteine levels

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Medical interventions after fracture

• Majority of patients who have had an osteoporotic
  fracture do not receive subsequent antiresorptive
  therapy.
• One study showed lt50 of 300 women who had had
  fractures were receiving any tx for osteoporosis.
  Another showed only 13 receiving adequate
  treatment.
• The older the patient with an osteoporotic
  fracture, the lower the likelihood of receiving
  drug therapy.
• Men less likely than women to be treated
  pharmacologically after an osteoporotic fracture
  (4.5 vs 49 respectively)

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On the horizon?

• Denosumab monoclonal antibody against RANKL, a
  member of TNF family essential for osteoclast
  function. Immune/infectious concerns?
• Androgens men with higher BMD than women.
  Virulizing conerns?
• Statins conflicting data
• Strontium ranelate meta-analysis has shown
  reduction in vertebral and non-vertebral
  fractures. Not yet commercially available.

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References

• Rosen H and Drezner M. Overview of management of
  osteoporosis in women. UpToDate. September 12,
  2006.
• Osteoporosis. ACOG Practice Bulletin, Number 50,
  January 2004.
• Hobar, C. Osteoporosis. Emedicine article,
  December 16 2005.
• Bone. From Wikepedia. http//en.wikipedia.org/wiki
  /Bone
• WHI Study Results Calcium and Vitamin D
  Supplements Offer Modest Bone Improvements, No
  Benefits for Colorectal Cancer. From NEJM. 15
  February 06.
• Rosen, H. Epidemiology and Causes of
  Osteoporosis. UpToDate. Augusta 29, 2006.

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The end!

• Yippee!
• (now go drink
  your milk)