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Fracture healing

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Title: Fracture healing


1
Fracture healing
2
Fracture
  • Those of us who have experienced a significant
    fracture likely recall first the pain of the
    injury, then we often focus our attention on the
    prospect of time in a cast or other form of
    extended immobilization.
  • We imagine the discomfort and limitations that
    will ensue, and after all else settles down, we
    often wonder, How strong are my bones anyway,
    and will I fracture again?

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
3
Cont
  • Nature, on the other hand, has no such questions,
    but moves swiftly to initiate healing.
  • Guided by a complex intelligence that we do not
    yet fully understand, bone repairs itself and
    over a few months is made whole again.

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
4
Bone healing
  • Bone healing, or fracture healing, is a
    proliferative physiological process in which the
    body facilitates the repair of a bone fracture.
  • Generally bone fracture treatment consists of a
    doctor reducing (pushing) dislocated bones back
    into place via relocation with or without
    anaesthetic, stabilizing their position, and then
    waiting for the bone's natural healing process to
    occur.

Schiller AL (1988) Bones and joints. Rubin E,
Farber JL (eds), Pathology. Philadelphia
Lippincott, 13041393.
5
Physiology of fracture healing
  • Fracture healing shares many similarities with
    soft-tissue healing but its ability to be
    completed without the formation of a scar is
    unique.
  • Fracture healing involves complex processes of
    cell and tissue proliferation and
    differentiation.
  • Many players are involved, including growth
    factors, inflammatory cytokines, antioxidants,
    bone breakdown (osteoclast) and bone-building
    (osteoblast) cells, hormones, amino acids, and
    uncounted nutrients.

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
6
Cont
  • Fracture healing can be divided into three
    phases
  • Inflammatory phase
  • Repair phase
  • Remodeling phase

7
  • Inflammatory phase The defect is initially
    filled with hematoma and there is intense
    inflammation (1). Repair phase This is quickly
    replaced by granulation tissue (2). Remodeling
    phase Over the weeks a fibrocartilaginous callus
    is formed (3). Mineralization leads to formation
    of a hard callus, becoming fusiform and slowly
    disappearing as Haversian remodeling progresses
    (4).

Dominique J Griffon. Fracture healing
8
Cont
  • Schematic representation of inflammation and
    repair during fracture healing

Lutz Claes, Stefan Recknagel and Anita Ignatius.
Fracture healing under healthy and inflammatory
conditions. Nat. Rev. Rheumatol. 8, 133143
(2012)
9
Factors that affect fracture healing
  • Many risk factors for impaired fracture healing
    exist
  • Type of injury (fracture geometry, degree of open
    injury, mechanism of injury)
  • Fracture treatment (type of fixation, size of
    fracture gaps)

Bhandari, M. et al. Predictors of reoperation
following operative management of fractures of
the tibial shaft. J. Orthop. Trauma 17, 353361
(2003).
10
Cont
  • Gender, age
  • Comorbidities (diabetes mellitus, malnutrition,
    peripheral vascular disease, hypothyroidism,
    polytrauma)
  • Medications (NSAIDs, corticosteroids,
    antibiotics, anticoagulants) smoking and
    alcohol consumption.

Bhandari, M. et al. Predictors of reoperation
following operative management of fractures of
the tibial shaft. J. Orthop. Trauma 17, 353361
(2003).
11
Bone healing and excess inflammation
12
Systemic inflammation Chronic
  • The close relationship between systemic immunity
    and bone architecture is illustrated in chronic
    inflammatory diseases such as rheumatoid
    arthritis (RA), chronic obstructive pulmonary
    disease (COPD), diabetes mellitus and systemic
    lupus erythematosus (SLE).
  • These diseases display systemic inflammation that
    is closely associated with bone loss and
    secondary osteoporosis, and, consequently,
    increased fracture risk.

Lutz Claes, Stefan Recknagel and Anita Ignatius.
Fracture healing under healthy and inflammatory
conditions. Nat. Rev. Rheumatol. 8, 133143
(2012)
13
Cont
  • Clinical studies have shown impaired fracture
    healing in patients with diabetes mellitus,87 and
    the results of experiments in animal models
    suggest that disrupted repair is at least partly
    caused by inflammatory mediators.
  • In a retrospective study, fracture healing in
    patients with RA was associated with higher
    complication rates, including non-unions, but the
    underlying molecular mechanisms remain unknown.

Kayal, R. A. et al. TNF-a mediates
diabetes-enhanced chondrocyte apoptosis during
fracture healing and stimulates chondrocyte
apoptosis through FOXO1. J. Bone Miner. Res. 25,
16041615 (2010).
14
Systemic inflammation Acute
  • In comparison with chronic inflammatory diseases,
    the influence of acute systemic inflammations
    (polytrauma or sepsis) on fracture healing has
    been better characterized.
  • In this context, activation of a specific immune
    cell types (PMNs or macrophages) has considerable
    importance.
  • Systemic activation of PMNs was reported to
    impair rodent fracture healing.

Bhandari, M. et al. Predictors of reoperation
following operative management of fractures of
the tibial shaft. J. Orthop. Trauma 17, 353361
(2003).
15
Cont
  • The detrimental effect of PMNs on bone healing
    during systemic inflammation was confirmed by the
    observation of enhanced fracture repair in
    animals made systemically neutropenic.
  • Furthermore, longer fracture healing times were
    observed in patients with polytrauma.

Keel, M. Trentz, O. Pathophysiology of
polytrauma. Injury 36, 691709 (2005).
16
Local inflammation
  • Interesting insights into the effect of local
    inflammation on bone healing come from a rabbit
    model of inflammatory arthritisa disease
    characterized by a strong juxta-articular
    osteopenia.
  • Surprisingly, the fracture healing process was
    not disturbed by the inflammatory arthritis
    compared to healthy joints.

Bogoch, E., Gschwend, N., Rahn, B., Moran, E.
Perren, S. Healing of cancellous bone osteotomy
in rabbitsPart I regulation of bone volume and
the regional acceleratory phenomenon in normal
bone. J. Orthop. Res. 11, 285291 (1993).
17
Cont
  • This finding indicates that fracture repair
    processes can override the bone loss caused by
    inflammatory arthritis.
  • Therefore, a local proinflammatory milieu does
    not necessarily lead to impaired bone healing, a
    conclusion supported by evidence from a number of
    studies.

Bogoch, E., Gschwend, N., Rahn, B., Moran, E.
Perren, S. Healing of cancellous bone osteotomy
in rabbitsPart II l ocal reversal of
arthritis-induced osteopenia after osteotomy. J.
Orthop. Res. 11, 292298 (1993).
18
What is optimal fracture treatment?
  • The important outcome issues in fracture
    management are
  • First, do no harm avoid serious complications.
  • Second, assurance of healing achieving union
    when damage to the tissues makes this difficult.
  • Third, the speed of fracture healing.
  • Fourth, rehabilitation of soft tissues, function
    of the whole limb and the whole patient.

David R Marsh and Gang Li. The biology of
fracture healing optimising Outcome. British
Medical Bulletin 1999, 55 (No 4). 856-869
19
General measures
  • Though these are categorized as general, these
    are specifically important in morbid patients..
  • These are nutrition, energy medicine, exercise,
    pain relievers, etc.

20
The nutritional demands of healing
  • Each stage of the fracture healing process brings
    with it increased nutritional demands.
  • For starters, the whole process requires a great
    deal of energywhich is generally supplied
    through the intake of calories in food.
  • Next, healing requires the synthesis of new
    proteins, which is dependent upon an ample supply
    of amino acids derived from dietary proteins.

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
21
Nutritional steps to accelerate fracture healing
  • People who have had a fracture arent often told
    that they can do anything to make their bones
    heal faster at most, theyre told to limit the
    use of the injured bone or limb (not easy to do
    if the fracture is in your spine!).
  • But there are a number of methods you can employ
    to reduce your healing time

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
22
Provide the body with adequate energy
  • In traumatic fractures of the long bones, for
    example, there is an immediate increase in
    metabolic demands that can translate into a
    caloric demand three times that of normal.
  • While a normally active adult may require 2,500
    calories a day, a bedridden, injured patient with
    multiple fractures may need 6,000 calories per
    day!
  • If this demand is not met, the healing process is
    compromised.

Smith, TK. 1987. Prevention of complications in
orthopedic surgery secondary to nutritional
depletion, Clin Ortho and Related Research,
22291-97.
23
Check your protein intake
  • Bone can be imagined as being somewhat like a
    sponge made of living protein upon which mineral
    crystals are embedded.
  • By volume, roughly half of bone is comprised of
    protein.
  • Protein supplementation increases growth factors
    like insulin-like growth factor-1 (IGF-1), a
    polypeptide that exerts a positive effect on
    skeletal integrity, muscle strength, immune
    response, and bone renewal.

Schurch, MA, Rizzoli, R, Slosman, D, Vadas, L,
Vergnaud, P, and Bonjour, JP. 1998. Protein
supplements increase serum insulin-like growth
factor-I levels and attenuate proximal femur
bone loss in patients with recent hip fracture,
Ann Intern Med, 128(10)801-809
24
Cont
  • Protein malnutrition or under-nutrition leads to
    a rubbery callus, compared to the rigid
    calluses of those with adequate or high protein
    intake.
  • Numerous studies document the acceleration of
    fracture healing with even a modest 10- to
    20-gram increase in protein intake.

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
25
Cont
  • In fact, among elderly hip fracture patients,
    poor protein status at the time of fracture
    predicts fracture outcome.
  • Those with low protein status take longer to
    heal, and have more complications, including
    death.

Koval, KJ, Maurer, SG, Su, ET, Aharonoff, GB, and
Zuckerman, JD. 1999. The effects of nutritional
status on outcome after hip fracture, J Ortho
Trauma, 13(3)164-169
26
Cont
  • Specific amino acids of special importance
    include lysine, arginine, proline, glycine,
    cystine, and glutamine.
  • Lysine, for example, is known to enhance calcium
    absorption, increase the amount of calcium
    absorbed into the bone matrix, and aid in the
    regeneration of tissue.

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
27
Increase anti-inflammatory nutrients
  • When a bone fracture occurs, a remarkable yield
    of free radicals is generated by the damaged
    tissues.
  • In particular, this damage occurs as the tightly
    bound collagen strands running through the
    mineral phase of bone are forcefully broken.
  • These ruptured collagen strands interact with
    oxygen-yielding oxygen radical metabolites.

Sheweita, SA and Khoshhal, KI. 2007. Calcium
metabolism and oxidative stress in bone
fractures Role of antioxidants, Current Drug
Metabolism, 8519-525.
28
Cont
  • These free radicals are associated with
    inflammation, further breakdown of bone collagen,
    and excessive bone turnover.
  • In such cases, antioxidants including vitamins
    E and C, lycopene, and alpha-lipoic acid have
    been suggested to be beneficial in suppressing
    the destructive effect of oxidant free radicals
    on whole body systems and improving fracture
    healing in animal models and cultured human cell
    lines.

Sheweita, SA and Khoshhal, KI. 2007. Calcium
metabolism and oxidative stress in bone
fractures Role of antioxidants, Current Drug
Metabolism, 8519-525.
29
Boost your mineral intake
  • By weight, bone is roughly 70 minerals (calcium,
    phosphorus, magnesium, silicon, zinc, etc.) and
    fracture healing requires available minerals.
  • Most of us under-consume minerals on an everyday
    basis, so drawing minerals to the healing site
    can often involve a process of stealing from
    Peter to pay Paul.
  • Specific key minerals for fracture healing
    include the following

Dr. Susan E. Brown, PhD. How to Speed Fracture
Healing. www.betterbones.com
30
Cont
  • ZINC
  • Some 200 enzymes require zinc for their
    functioning.
  • Many of these functions involve cell
    proliferation.
  • Zinc supplementation aids in callus formation,
    enhances bone protein production, and thus
    stimulates fracture healing.
  • COPPER
  • Copper aids in the formation of bone collagen and
    is important to the healing process. The bodys
    demand for both copper and zinc rises according
    to the severity of the trauma.

Simsek, A, Senköylü, A, Cila, E, Ugurlu, M,
Bayar, A, Oztürk, AM, Isikli, S, Musdal, Y, and
Yetkin, H. 2006. Is there a correlation between
severity of trauma and serum trace element
levels?, Acta Orthop Traumatol Turc,
40(2)140-143.
31
Cont
  • CALCIUM AND PHOSPHORUS
  • The main minerals in bone are calcium and
    phosphorus, in the form of calcium hydroxyapatite
    crystals. This hydroxyapatite compound plays an
    important role in regulating the elastic
    stiffness and tensile strength of bone.
  • Early research suggested that fractures can heal
    normally independent of dietary calcium and
    indeed it has been found that during the first
    few weeks of healing, calcium is drawn from the
    skeleton for fracture healing. After that, the
    diet provides the calcium necessary for fracture
    repair.

Kakar, S and Einhorn, TA. 2004. Importance of
nutrition in fracture healing, In Nutrition and
Bone Health, ed. Holick, MF and Dawson-Hughes, B,
Totowa, NJHumana Press, Inc.
32
Cont
  • Human studies, in fact, suggest that for best
    fracture healing both calcium and vitamin D
    should be obtained in optimum daily levels.
  • Most of us consume plenty of phosphorus and often
    too much if the diet is high in processed foods
    and colas.
  • However, the elderly, dieters, and those on low
    protein diets often do not consume enough
    phosphorus to meet the needs of new bone
    formation.

Doetsch, A et al. 2004. The effect of calcium and
vitamin D3 supplementation on the healing of the
proximal humerus fractures A randomized
placebo-controlled study, Calcified Tissue
Internal, 75(3)183-188.
33
Cont
  • SILICON
  • It has long been known that bioactive silicon
    (silica) plays an important role in bone collagen
    synthesis.
  • A 2005 human study found bioactive silicon to
    enhance the effects of calcium and vitamin D3 on
    new bone formation

Spector, TD, et al. 2005. Effect on bone turnover
and BMD in low dose oral silicon as an adjunct to
calcium/vitamin D3 in a randomized
placebo-controlled trial. Abstract from the ASBMR
27th Annual Meeting, Nashville, TN.
34
Enhance vitamin intake
  • While protein and minerals may be the building
    blocks, vitamins are the catalysts for many
    biochemical reactions and are equally important.
  • VITAMIN C
  • It is essential for proper synthesis of the bone
    collagen protein matrix.
  • It is also one of the most important antioxidants
    and anti-inflammatory nutrients.
  • In severe vitamin C deficiency, collagen becomes
    too unstable to function properly.

Alcantara-Martos, T, Delgado-Martinez, D, Vega,
MV, Carrascal, MT, and Munuera-Martinez, L. 2007.
Effect of vitamin C on fracture healing in
elderly Osteogenic Disorder Shionogi rats, J Bone
Joint Surg Br, 89-B(3)402-407.
35
Cont
  • VITAMIN D
  • It is the primary regulator of calcium absorption
    and without adequate vitamin D calcium blood
    level drops making less calcium available for
    fracture healing.
  • Further, we now know that vitamin D, in
    conjunction with vitamin K, stimulates the
    transformation of fracture site stem cells to
    bone building osteoblasts.
  • Vitamin D status has been shown to be an
    independent predicator of functional recovery
    after a fracture.

Gigante, A, Torcianti, M, Boldrini, E, Manzotti,
S, Falcone, G, Greco, F, and Mattioli-Belmonte,
M. 2008. Vitamin K and D association stimulates
in vitro osteoblast differentiation of fracture
site derived human mesenchymal stem cells, J Biol
Regul Homeost Agents, 22(1)35-44.
36
Cont
  • VITAMIN K
  • It is an essential part of the biochemical
    processes that bind calcium to bone and it is
    required for proper formation of the osteocalcin
    bone protein.
  • In addition, vitamin K helps conserve calcium by
    reducing the loss of calcium in the urine.

Knapen, MHJ, Hamulyák, K, and Vermeer, C. 1989.
The effect of vitamin K supplementation on
circulating osteocalcin (bone Gla protein) and
urinary calcium excretion, Ann Inter Med,
1111001-1005.
37
Cont
  • VITAMIN B6
  • It is one of the B vitamins that has been linked
    to fracture healing.
  • Animals deficient in this vitamin fracture more
    frequently and experience reduced fracture
    healing. It appears that vitamin B6 modulates the
    effects of vitamin K on bone through complex
    biochemical pathways.

Reynolds, TM. 1998. Vitamin B6 deficiency may
also be important, Clin Chem, 442555-2556.
38
An Alkaline for Life eating program stimulates
bone repair
  • The Alkaline for Life eating program provides a
    diet rich in minerals, vitamins, and
    phytonutrients obtained from vegetables, fruits,
    nuts, and seeds.
  • This life-supporting eating pattern has been
    shown to create a health-promoting internal
    biochemical environment which, among other
    things, conserves bone building minerals and
    proteins.

Frassetto, L, et al. 2001. Diet, evolution and
aging, Eur J Nutr 40200-213.
39
Cont
  • Such a base-forming eating program also has been
    shown to increase growth hormones and growth
    factors such as IGF insulin-like growth factor.
  • These growth hormones are among the most
    important biochemical forces encouraging fracture
    repair and new bone formation

Sheweita, SA and Khoshhal, KI. 2007. Calcium
metabolism and oxidative stress in bone
fractures Role of antioxidants, Current Drug
Metabolism, 8519-525.
40
Exercise and fracture healing
  • In general, bone tissue responds to patterns of
    loading by increasing matrix synthesis, altering
    composition, organization, and mechanical
    properties.
  • Evidence indicates that the same holds true for
    bone under repair.
  • Further, fracture healing requires good
    circulation and an adequate flow of
    nutrient-replenishing blood to the fracture site
    both of which are enhanced by exercise.

41
Cont
  • To avoid stress on the broken bone, joint
    loading, range of motion, and specific
    tendon-gliding exercises are employed to
    accelerate healing and assure return of function
    post fracture.
  • For example, in the case of a broken forearm,
    exercises would involve movements of the fingers
    and hand, as well as the elbow and shoulder
    joints.

Zhang, P, Malacinski, GM, and Yokota, H. 2008.
Joint loading modality Its application to bone
formation and fracture healing, Br J Sports
Med,42(7)556-560.
42
Energy medicine for fracture healing
  • Energy medicine is described in a recent medical
    journal as, ...a field of complementary therapy
    based on the interactions of the human energy
    field with other energy fields (human or other).
  • Interestingly enough, pulsing electromagnetic
    field therapy is a form of energy medicine that
    has been used for many years by conventional
    doctors to heal fractures that have not healed on
    their own.
  • The use of electromagnetic bone stimulating
    devices has proven to speed healing.

www.ifess.org/Services/Consumer_Ed/References/bone
_healing_references.htm
43
Pain relievers and fracture healing
  • Cells damaged from the trauma of fracture release
    large amounts of inflammatory prostaglandins at
    the site of fracture.
  • In this case, non-steroidal anti-inflammatory
    drugs (COX-1 and COX-2 inhibitors) might be the
    medication we reach for to relieve the pain.

Nwadinigwe, CU and Anyaehie, UE. 2007. Effects of
cyclooxygenase inhibitors on bone and cartilage
metabolismA review, Niger J Med, 16(4)290-294
Murnaghan, M, Li, G, and Marsh, DR. 2006.
Nonsteroidal anti-inflammatory drug-induced
fracture nonunion An inhibition of
angiogenesis?, J Bone Joint Surg Am, 88 Suppl
3140-147.
44
Cont
  • The use of these COX-1 and COX-2 inhibitors,
    however, can delay fracture healing.
  • As it turns out, prostaglandin-induced
    inflammation is an essential component of the
    fracture healing process, and cyclooxygenase
    enzymes (COX-1 and COX-2) play important roles in
    fracture repair.

Nwadinigwe, CU and Anyaehie, UE. 2007. Effects of
cyclooxygenase inhibitors on bone and cartilage
metabolismA review, Niger J Med, 16(4)290-294
Murnaghan, M, Li, G, and Marsh, DR. 2006.
Nonsteroidal anti-inflammatory drug-induced
fracture nonunion An inhibition of
angiogenesis?, J Bone Joint Surg Am, 88 Suppl
3140-147.
45
Cont
  • Because of this, the use of non-steroidal
    anti-inflammatory pain killers (NSAIDs) is not
    recommended for fracture pain relief.
  • Among the NSAID COX-1 and COX-2 inhibitor drugs
    to be avoided are aspirin, ibuprofen,
    indomethacin, etodolac, meloxicam, nabumetone,
    and naproxen

Nwadinigwe, CU and Anyaehie, UE. 2007. Effects of
cyclooxygenase inhibitors on bone and cartilage
metabolismA review, Niger J Med, 16(4)290-294
Murnaghan, M, Li, G, and Marsh, DR. 2006.
Nonsteroidal anti-inflammatory drug-induced
fracture nonunion An inhibition of
angiogenesis?, J Bone Joint Surg Am, 88 Suppl
3140-147.
46
Cont
  • Acceptable alternatives to help reduce the pain
    of fracture include acetaminophen.
  • In severe cases, narcotics such as codeine are
    given along with the acetaminophen.
  • In a study of 328 wrist fracture patients, modest
    500 mg/day supplementation with vitamin C reduced
    by more than 4-fold the incidence of
    post-fracture complex regional pain syndrome.

Zollinger, P.E., Tuinebreijer, W.E., Breederveld,
R.S., and Kreis, R.W. 2007. Can vitamin C prevent
complex regional pain syndrome in patients with
wrist fractures? J Bone Joint Surg, 891424-1431.
47
Cont
  • The well-studied flavonoid, quercitin, used in
    doses of 23 g per day, has a synergistic effect
    with vitamin C, amplifying the pain-relief
    benefits.
  • European research has shown the value of
    proteolitic enzymes (protein digesting enzymes)
    such as bromelain and trypsin for reducing
    inflammation, edema, and pain in fracture
    patients.

Kamenicek, V., Holán, P., and Franek, P. 2001.
Systemic enzyme therapy in the treatment and
prevention of post-traumatic and postoperative
swelling. Acta Chir Orthop Traumatol Cech,
68(1)45-49.
48
Special cases
49
Fracture healing in the elderly patient
  • Osteoporosis is the result of progressive
    catabolic changes, mainly, but nor exclusively,
    occurring in the aging skeleton, that cause an
    increase in the risk of fracture.
  • In large part due to population demographics and
    to some extent as a consequence of the greater
    amount of physical activities available for the
    elderly, there is a compelling concern about the
    steady increase in the number of fractures each
    year.

Reinhard Gruber, Hannjorg Koch, et al. Fracture
healing in the elderly patient. Experimental
Gerontology 41 (2006) 10801093
50
Therapeutic considerations in the osteoporotic,
elderly patient
  • Potent pharmacologic substances such
    asbisphosphonates, parathyroid hormone, strontium
    ranelateand selective estrogen receptor
    modulators were developedthat will lower the
    fracture risk in elderly women and men.
  • Moreover, despite sophisticated therapeutics and
    diagnostics, osteoporoticchanges frequently
    remain undiagnosed and these patientsare at an
    even higher risk to incur atraumatic fractures.

Reinhard Gruber, Hannjorg Koch, et al. Fracture
healing in the elderly patient. Experimental
Gerontology 41 (2006) 10801093
51
Cont
  • Postfracture patient management can additionally
    require invasive treatments such as mechanical
    stabilization of the fracture ends and bridging
    of defects with bone grafts.
  • However, in neither of the post-fracture patient
    managements, the biology of the aged skeletal
    system has been adequately considered.

Reinhard Gruber, Hannjorg Koch, et al. Fracture
healing in the elderly patient. Experimental
Gerontology 41 (2006) 10801093
52
Cont
  • The strategy to address care and management of
    the elderly fracture patient will emphasize
    geriatric bone biology to guide design and
    development of a rational therapeutic protocol.

Reinhard Gruber, Hannjorg Koch, et al. Fracture
healing in the elderly patient. Experimental
Gerontology 41 (2006) 10801093
53
(No Transcript)
54
Changes in fracture healing caused by diabetes
  • Changes at the tissue level
  • Reduced bone formation
  • Reduced cartilage formation
  • Accelerated loss of cartilage
  • Reduced vascularity and reduced angiogenesis
  • Changes at the molecular level
  • Reduced expression of growth factors
  • Reduced expression of matrix proteins
  • Increased expression of proinflammatory genes
  • Increased expression of pro-osteoclastogenic
    factors
  • Increased expression of proapoptotic genes

Dana T. Graves, Jazia Alblowi. Impact of Diabetes
on Fracture Healing. J Exp Clin Med 20113(1)3e8
55
Treatment Influence on Bone and Cartilage
Formation
  • Controlled insulin therapy may reverse the
    impairment in fracture repair in diabetic
    patients with poor metabolic control.
  • Localized insulin therapy improved fracture
    healing in diabetic animal models in terms of
    chondrogenesis and cellular proliferation.

Dana T. Graves, Jazia Alblowi. Impact of Diabetes
on Fracture Healing. J Exp Clin Med 20113(1)3e8
56
Cont
  • Treatment of diabetic animals with subcutaneous,
    controlled-release insulin implants that
    normalized glucose homeostasis, resulted in
    normalization of fracture healing.
  • Application of basic fibroblast growth factor to
    the fracture site normalized healing in diabetic
    animals and enhanced repair in normoglycemic
    animals.

Dana T. Graves, Jazia Alblowi. Impact of Diabetes
on Fracture Healing. J Exp Clin Med 20113(1)3e8
57
Cont
  • Platelet-rich plasma (PRP) was investigated as a
    potential treatment agent for improving diabetic
    fracture repair because PRP contains high levels
    of mitogenic growth factors.
  • Percutaneous injection of PRP into the fracture
    site increased cellular proliferation in diabetic
    rat fracture calluses to a level that matched the
    level in nondiabetic animals

Dana T. Graves, Jazia Alblowi. Impact of Diabetes
on Fracture Healing. J Exp Clin Med 20113(1)3e8
58
Cont
  • Diabetic fracture healing is characterized by
    anabolic and catabolic changes that contribute to
    impaired healing.
  • A better understanding of how diabetes,
    hyperglycemia, hypoinsulinemia, or insulin
    resistance affect bone will provide insight into
    newtreatment modalities to enhance diabetic
    fracture healing.

Dana T. Graves, Jazia Alblowi. Impact of Diabetes
on Fracture Healing. J Exp Clin Med 20113(1)3e8
59
Conclusion
  • Rational therapeutic design requires a biological
    foundation as a guide.
  • Therapeutics that will enable patients with
    systemic disease to overcome the
    pathophysiological challenges of compromised bone
    healing must be based on biology.

60
Cont
  • The parameters that define bone quality with
    regard to bone regeneration are multiple and
    include the number, life time and responsiveness
    to local and systemic factors of mesenchymal
    progenitors and cells required for blood vessel
    formation.
  • It is not clear to which extent each parameter
    contributes to the regenerative cascade.

61
Cont
  • Future strategies should consider both, the
    osteogenic and the angiogenic requirements to
    overcome the compromised situation in the morbid
    patient.
  • More basic, fundamental research is needed to
    define the temporal, spatial, quantitative and
    qualitative cellular interrelationships of
    signaling molecules and extracellular matrix of
    fracture healing.

62
Thank you
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