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Joan Parambi January 14th 2009 Antiresorptive

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Title: Joan Parambi January 14th 2009 Antiresorptive


1
Advances in osteoporosis
  • Joan Parambi
  • January 14th 2009

2
Objectives
  • -New findings regarding the pathophysiology of
    osteoporosis.
  • -Identifying who needs to be treated.
  • -Current treatment guidelines.
  • -Monitoring therapy.
  • -Areas of future development.

3
Impact of osteoporosis
4
Epidemiology
  • In 2002 NOF(National Osteoporosis Foundation)
  • published the projected prevalence of those aged
    50 and older based on yr 2000 census3
  • 2002 2010
    2020
  • Women with osteoporosis 7.8 9.1
    10.5
  • Women with low bone mass 21.8 26
    30.4
  • Men with osteoporosis 2.3 2.8
    3.3
  • Men with low bone mass 11.8 14.4
    17.1

  • (number in millions)

5
Osteoporosis fracture incidence
Incidence and Economic Burden of
Osteoporosis-Related Fractures in the United
States, 20052025.Russel Burge,, Bess Dawson
Hughes, Daniel H Solomon, John B Wong, Alison King
,Anna Tosteson.
6
Cost of osteoporosis
  • Projected annual direct costs of osteoporosis
    25.3billion by 202541
  • Osteoporotic fractures accounted for
  • 17 billion in direct medical costs. 41
  • gt400,000 hospital admissions.42
  • 2.5million physician visits. 42
  • gt180,000 nursing home admissions42

7
Pathogenesis of osteoporosis
8
Bone Architecture
  • Bone is comprised of 2 components
  • 40 organic collagenous 60
    inorganic (mineral)
  • matrix providing tensile mostly in
    the form of
  • strength.
    Calcium hydroxyapetite

  • providing compressive

  • strength.

9
Definition
  • Metabolic bone disease categorized by histology
  • Osteoporosis
    Osteomalacia
  • Decrease in matrix Bone
    matrix intact
  • and mineral. reduced
    mineral.
  • Osteoporosis defintion by NIH Consensus
  • Conference, 2000 Skeletal disorder characterized
    by compromised bone strength predisposing to an
    increased risk of fracture.
  • Bone strength Bone density Bone
    quality1

10
Regulation of bone remodeling.
Signals that determine the differentiation,
function, and death of these cells and their
progenitors determine how many units are
activated over time, how active and well-balanced
the basic multicellular unit is, and whether, at
the end of the cycle, bone mass will be gained,
lost, or stable4
Canalis E et al. N Engl J Med 2007357905-916
11
Local growth factors that regulate bone formation
Bone morphogenetic proteins members of TGF
beta superfamily of polypeptides, which includes
activins and inhibins.5 These proteins bind to
and activate specific receptors to initiate
signal transduction and influence intracellular
events leading to osteoblastogenesis 6, 7
Wnt uses a Wnt beta-catenin signaling pathway.8
Wnt binds to specific receptors, and to
low-density lipoprotein receptorrelated proteins
5 and 6 (LRP5 and LRP6). This stabilizes the
beta-catenin which translocates into the nucleus
and regulates gene expression.
IGF-I made in the liver and other tissues,
including the skeleton, mediates the effects of
growth hormone on longitudinal bone growth.9
IGF-I exerts direct actions in bone and is
necessary for skeletal development and the
maintenance of bone mass.9 It acts both as a
circulating growth hormonedependent hormone and
as a local skeletal growth factor influenced by
PTH.10,11,12 IGF-I primarily influences the
differentiated function of the osteoblast and
prevents osteoblast apoptosis
Canalis E et al. N Engl J Med 2007357905-916
12
Local growth factors continued
  • PTH-related protein produced by bone and
    cartilage cells has developmental and local
    regulatory function.13,14 Its secretion by
    lactating mammary glands may play a role in the
    increased rate of bone resorption and rapid bone
    loss that occurs in lactating women.15
  • Fibroblast growth factor produced by bone and
    connective tissue. Regulated by PTH,
    prostaglandin E2, TGF-beta. It decreases collagen
    synthesis in vitro but can stimulate bone
    formation in vivo. 16,17

13
Local cytokines and prostaglandins
Uptodate Pathogenesis of osteoporosis 18
14
RANKL a member of the TNF superfamily of ligands
and receptors, is essential for the
differentiation, activation, and survival of
bone-resorbing osteoclasts.19 It is expressed on
the surface of marrow stromal cells, activated T
cells, and precursors of bone-forming osteoblasts
. 19 RANKL accelerates osteoclastogenesis when it
binds to its receptor, RANK, on osteoclast
precursor cells to enhance nuclear factor- B and
other signaling pathways.19 Osteoprotegerin that
is produced by osteoblasts, the key modulator of
RANKL, acts as a soluble decoy receptor for RANKL
and blocks its effects
Whyte M. N Engl J Med 2006354860-863
15
Systemic hormones involved
  • Parathyroid hormone - is the most important
    regulator of calcium homeostasis. It maintains
    serum calcium concentrations by
  • Stimulating bone resorption
  • Increasing renal tubular calcium reabsorption
  • Increasing renal calcitriol production.
  • PTH stimulates bone formation when given
    intermittently, but inhibits collagen synthesis
    at high concentrations 26,27. It stimulates
    osteoclast mediated bone resorption when given
    (or secreted) continuously. It also stimulates
    gene expression and increases the production of
    several local factors, including IL-6, IGF-1 and
    an IGF-binding protein, IGF-BP-5, and
    prostaglandins. 28,37.

Canalis E et al. N Engl J Med 2007357905-916
16
  • Calcitriol  increases intestinal calcium and
    phosphorus absorption, thereby promoting bone
    mineralization. At high concentrations, under
    conditions of calcium and phosphate deficiency,
    it also stimulates bone resorption, thereby
    helping to maintain the supply of these ions to
    other tissues.
  • Calcitonin  inhibits osteoclasts and therefore
    bone resorption in pharmacologic doses. However,
    its physiologic role is minimal in the adult
    skeleton. Its effects are transient, probably
    because of receptor downregulation.
  • Growth hormone and IGFs  The GH/IGF-1 system and
    IGF-2 are important for skeletal growth,
    especially growth at the cartilaginous end plates
    and endochondral bone formation.

17
  • Glucocorticoids 
  •  Have both stimulatory and inhibitory effects on
    bone cells.
  • Essential for differentiation of osteoblasts and
    sensitize bone cells to regulators of bone
    remodeling.
  • Inhibition of bone formation is the major cause
    of glucocorticoid-induced osteoporosis and may be
    due to accelerated apoptosis of osteoblasts and
    osteocytes 38
  • Thyroid hormones stimulate both bone resorption
    and formation. Thus, bone turnover is increased
    in hyperthyroidism, and bone loss can occur. 39
  • Estrogen and Androgen reduces rate of bone loss
    by many local effects like
  • Reducing the number and depth of resorption
    cavities.44
  • Promoting osteoclast apoptosis.40
  • Increasing TGF-beta release from osteoblasts
  • Inhibiting release of TNF-alpha

18
Osteoporotic bone showing loss of bone with
larger spaces decreasing its strength .2
19
Diagnosis and evaluation
20
Fracture risk assessment
  • Is based on
  • Clinical risk factors
  • BMD measurement.
  • Using the above data a FRAX score can be
    calculated.

21
Clinical risk factors
Ebeling P. N Engl J Med 20083581474-1482
22
Identifying who needs imaging
Raisz L. N Engl J Med 2005353164-171
23
BMD measurement
  • Dual-Energy X-Ray Absorptiometry
  • Results expressed as
  • T-SCORE is the number of SD the measurement is
    above or below the YOUNG-NORMAL MEAN BMD.
  • Z-SCORE is the number of SD the measurement is
    above or below the AGE-MATCHED MEAN BMD.
  • Sites used for measurement per WHO criteria
  • Total proximal femur
  • Femoral neck
  • Lumbar spine
  • 33percent(1/3rd)radius if e/o OA or surgery at
    other 3 sites.
  • Peripheral skeletal sites predict global risk,
    however not used in WHO/FRAX criteria therefore
    limited value. Changes to therapy at these sites
    are slow.
  • Raisz L. N Engl J Med 2005353164-171

24
WHO diagnostic categories of BMD
Ebeling P. N Engl J Med 20083581474-1482
25
Other imaging techniques
  • Quantitative ultrasonography (QUS)   does not
    measure BMD, but instead measures the
    transmission of ultrasound through accessible
    limb bones or the reflectance of the ultrasound
    waves from the bone surface.
  • Quantitative computed tomography  (QCT) measures
    volumetric BMD (vBMD) in mg/cm3, most often at
    the spine. Unlike DXA, QCT can isolate trabecular
    bone from its envelope of cortical bone. The
    studies are split regarding its superiority to
    DXA.
  • Emerging technologies 
  • High resolution microCT and microMRI allow
    noninvasive three-dimensional evaluation of bone
    microarchitecture. These techniques are used
    primarily in research settings.

26
FRAX score
  •  In 2008, a WHO task force introduced a Fracture
    Risk Assessment Tool (FRAX), which estimates the
    10-year probability of hip fracture or major
    osteoporotic fractures combined (hip, spine,
    shoulder, or wrist) for an untreated patient
    using femoral neck T-score or Z-score and easily
    obtainable clinical risk factors for fracture 50.
  • FRAX is based upon data collected from large
    prospective observational studies of men and
    women of different ethnicities and from different
    world regions in which clinical risk factors,
    BMD, and fractures were evaluated 51,52 . FRAX
    has been validated in 11 independent cohorts,
    mainly comprised of women 53. The statistical
    power of this large dataset allows estimation of
    fracture probability from an individual's set of
    risk factors.
  • The country-specific FRAX prediction algorithm is
    available online at (http//www.shef.ac.uk/FRAX/).
    54
  • In the United States, cost-effectiveness modeling
    suggests that the 10-year hip fracture
    probability at which treatment becomes
    cost-effective (intervention threshold) ranges
    from 2.5 to 4.7 percent for women and from 2.4 to
    4.9 percent in men, depending upon age and
    assuming annual treatment costs of 600 and a
    willingness-to-pay threshold of 60,000 . 55

27
Markers of Bone turnover
  • Uses
  • They can give some indication about the future
    risk for bone loss and fractures.
  • Useful in monitoring the efficacy of
    antiresorptive therapy in patients with
    osteoporosis
  • Markers indicating rate of bone formation
  • Serum bone-specific ALP reflects the cellular
    activity of osteoblasts 56,57,58
  • Serum osteocalcin reflects its rate of synthesis
    by osteoblasts.
  • Serum concentration of the carboxy-terminal and
    amino terminal propeptides of type I collagen
    (PICP and PINP, respectively) reflects changes in
    synthesis of new collagen. 59
  • Markers indicating rate of bone resorption
  • Serum skeletal acid phosphatase .
  • Urinary excretion of collagen crosslinks
    deoxypyridinoline (DPD) and the peptide-bound
    alpha-1 to alpha-2 N-telopeptide crosslinks
    (NTX), and the c-telopeptide crosslink (CTX)
    reflects bone resorption and not dietary intake.
    60

28
Other lab tests
  • Initial laboratory tests
  • Complete chemistry profile (including alkaline
    phosphatase)
  • CBC
  • Calcium, phosphorus
  • 25 hydroxyvitamin D
  • Urinary calcium excretion
  • Additional laboratory tests if indicated(clinical
    features/ low Z-score)
  • 24 hour urine for free cortisol
  • Estradiol, FSH, LH, Prolactin , TSH
  • Magnesium
  • 1,25 dihydroxyvitamin D ,Intact PTH
  • Celiac screen
  • SPEP/UPEP
  • ESR, Rheumatoid Factor
  • Serum tryptase and histamine levels
  • Homocysteine
  • Skin biopsy for connective tissue disorders
  • COL1A genetic testing for osteogenesis imperfecta

29
Management of osteoporosis
30
National Osteoporosis Foundation guidelines for
pharmacologic intervention in postmenopausal
women and men 50 years of age
31
Guidelines by other organizations
Rosen C. N Engl J Med 2005353595-603
32
Non-pharmacological therapy
Ebeling P. N Engl J Med 20083581474-1482
33
Approved pharmacological therapies
Rosen C. N Engl J Med 2005353595-603
34
Other therapies
  • Antiresorptive agents
  • Zoledronic acid 5 mg administered intravenously
    once yearly.
  • Calcitriol effective in preventing
    glucocorticoid-induced and posttransplant-related
    bone loss.
  • Strontium ranelate is an orally active drug
    consisting of two atoms of stable strontium and
    an organic moiety (ranelic acid). In animal
    studies, strontium appears to inhibit bone
    resorption and increase bone formation . Its
    mechanism of action in humans is less certain.
    Approved for use in Europe only.
  • Anabolic agents
  • Denosumab  investigational humanized monoclonal
    antibody against RANKL . Encouraging Phase 2
    trial results.
  • Tibolone  a synthetic steroid whose metabolites
    have estrogenic, androgenic, and progestagenic
    properties used in some countries.

35
Monitoring therapy
  • ISCD   recommends follow-up BMD testing (DXA
    spine and hip) when the expected change in BMD
    equals or exceeds the least significant change
    (LSC), which is typically one year after
    initiation or change of therapy, with longer
    intervals once therapeutic effect is established.
    In conditions associated with rapid bone loss,
    such as glucocorticoid therapy, testing more
    frequently is appropriate 43
  • AACE  recommends annual DXA of the LS and
    proximal femur until stability is achieved, and
    every two years thereafter. 44
  • NAMS  recommends DXA of the total hip every two
    years. 45
  • Others
  • Conservative approach - takes the position that
    monitoring for efficacy of antiresorptive therapy
    is unnecessary, as only a minority of patients
    continue to lose bone on therapy. 46,47,48
  • Bone turnover markers- if DXA cannot be performed
    at one year then measure fasting urinary NTX or
    serum CTX before and three to six months after
    starting antiresorptive therapy. 48,49 If the
    marker has fallen significantly (by 50 percent),
    the patient can be reassured that the next BMD
    measurement will likely be stable or improved .
    Repeat DXA can be done in 2 yrs.

36
Emerging Therapies
  • 12/15-lipoxygenase inhibitors coded by the
    Alox15 gene which is up regulated in IL4 mediated
    bone resorption.20
  • Oral calcium sensing receptor antagonists
    Administration leads to a transient rise in
    endogenous parathyroid hormone, similar to
    intermittently administered exogenous parathyroid
    hormone 21
  • Sclerostin inhibitors Sclerostin is produced by
    osteocytes and inhibits bone formation 22.
    Antagonism of sclerostin might be associated with
    anabolic effects on bone. Monoclonal antibodies
    against sclerostin, for example, prevent its
    binding to Wnt coreceptors, enhancing Wnt
    signaling and increasing bone mass in rodents and
    nonhuman primates.23
  • Integrin antagonists Integrins mediate the
    adhesion of osteoclasts to the bone surface, an
    important initial step for bone resorption 24
  • Cathepsin-K inhibitors Cathepsin K is a
    protease that may play a role in
    osteoclast-mediated bone resorption .25

37
  • Antagonists of Dkk-1 Mutations of LRP5 and LRP6
    (wnt coreceptor) that lead to impaired binding
    of Dkk-1 are associated with increased bone
    mass.29 . Dkk-1 antibodies increased BMD,
    trabecular bone volume, and bone formation in
    rodents, suggesting that Dkk-1 inhibitors
    targeted specifically to bone might have
    potential as an anabolic approach in the
    treatment of osteoporosis.30
  • Soluble Activin Receptors Activin enhances
    osteoclastogenesis, and its effects on bone
    formation are controversial.31,32 A soluble
    activin receptor II, which binds activin and
    possibly bone morphogenetic protein 3, decreases
    bone resorption and enhances bone formation in
    rodents.33,34
  • The Osteoblast Proteasome and Its Inhibitors
    Inhibitors of proteolytic processing systems
    might unmask or enhance anabolic pathways.35,36
    The use of proteasome inhibitors will depend on
    their skeletal specificity and their safety
    profile, since such inhibitors can induce
    cellular toxic effects and the intracellular
    accumulation of misfolded proteins.35

38
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41
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