DENTAL PBL III-Faculty
Mrs. Jones, a 59-year-old patient, lost her first and second molars (#18, 19, 30, and 31)
six years ago and has been using a mandibular removable partial denture since then. She
decided and had implant surgery 5 months ago. When implants were uncovered, clinical
inspection revealed that implants replacing #18, 19 and 30 had failed to osteointegrate.
The implants were mobile and had a fibrous connective tissue encapsulating them. She
had fractured her left wrist 4 months ago; it is still not fully healed according to the
orthopedic surgeon. She had a regular physical check up two years ago but has not seen
her physician lately. Recently, she has been an experiencing back pain and headache
localized in the temple region; OTC medication seems to help. You suggest that Mrs.
Jones go to her internist and have complete physical examination including serology.
Mrs. Jones was suspected of suffering from either osteomalacia or osteoporosis.
Serology tests showed: Blood glucose (>150 mg %); Lower than normal serum calcium;
Lower than normal serum phosphorus; Elevated PTH levels; Elevated alkaline
phosphatase levels.
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What conditions might lead to loss of molars at such a young age?
What is the process and mechanism of osteointegration?
What types of collagens are present in the bone and what is the process of bone
formation?
Is a 4-month too short an interval for bone to heal and if so what might be the
problem with this repair process?
Are symptoms of headaches in the temple region an indication of lack of
osteointegration? If so what type of OTC medications might help and what is the
mechanism of their action at the biochemical level?
Is there any significance to the plasma glucose of 150 mg%?
What can be deduced from observed lower than normal plasma calcium and
phosphate levels in this patient?
Under what conditions is the level of serum PTH elevated and what is the
biochemical mechanism of PTH release?
Why would the plasma levels of alkaline phosphatase go up in this patient and
what is the function of alkaline phosphatase in the process of bone formation?
What are distinguishing features of osteoporosis and Osteomalacia?
What procedures/tests should have been performed before the implantation
procedure?
Reading Material
http://courses.washington.edu/bonephys/hypercalU/opmal2.html
http://chorus.rad.mcw.edu/doc/00906.html
http://new.wheelessonline.com/ortho/osteomalacia
http://www.osteo.org/osteo.html
http://courses.washington.edu/bonephys/
In addition get information from your text book.
Faculty handout
1.
Premature loss of teeth can be due to a variety of causes:
 Accidents
 Diabetes
 Radiation therapy: When malignancies of the orofacial region are treated
by means of radiation one of the most common sequelae is xerostomia
(dry mouth) due to salivary gland destruction. Xerostomia is responsible
for the development of cervical caries. Another complication is
osteonecrosis, which in many instances is initiated by severe periodontal
involvement. Loss of teeth is the end result of these radiation secondary
effects.
 Hereditary diseases like Acatalasia (an autosomal recessive peroxisomal
disorder caused by a complete lack of catalase. It causes periodontal
infections. , Chediak-Higashi syndrome (is a rare autosomal recessive
disorder that arises from a microtubule polymerization defect which leads
to a decrease in phagocytosis) , cyclic neutropenia (is a form of
neutropenia that tends to occur every three weeks and lasting three to six
days at a time due to changing rates of cell production by the bone
marrow)[1], Dentin dysplasia (is a genetic disorder of teeth, commonly
exhibiting an autosomal dominant inheritance. It is characterized by
presence of normal enamel but atypical dentin with abnormal pulpal
morphology), hypophosphatasia (is a rare, and sometimes fatal metabolic
bone disease) vitamin D resistant rickets, Lesch-Nyhan syndrome.
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2.
Lymphomas and leukemias; soft and hard tissue, benign and malignant
neoplasms either primary or metastatic.
Other abnormalities like Acrodynia (mercury poisoning), Odontodysplasia
deficient formation of enamel) (ghost teeth), Osteomyelitis, Periodontitis
and Vit. C deficiency.
Osteointegration:
In general, the implant site is filled with blood clot characterized by the presence of high
proportion of erythrocytes entrapped in a fibrin network. This is followed by proliferation
of vascular structures and migration of fibroblast-like mesenchymal cells into the wound
chamber. Osteoblasts then migrate to the implant site within a week and within 4 weeks
primary bone spongiosa is formed. This is then replaced by lamellar and/or parallel fibred
bone.
Osteointegration was defined as a "direct structural and functional connection between
ordered living bone and the surface of a load-carrying implant." Although
osteointegration was meant originally to describe a biologic fixation of the titanium
dental implants, it is now used to describe the attachment of other materials used for
dental and orthopedic applications as well. Analyses of material-bone interface show that
osteointegrated implants can have an intervening fibrous layer or direct bone apposition
characterized by bone bonding depending on the composition and surface properties of
the biomaterial. Biologic factors include the quality of bone. Biomaterial factors include
the effect of material composition on the bone-material interface. Areas that need to be
considered include determining the correlation between oral bone status and osteoporosis,
the effect of gender, age, and endocrine status (e.g., osteoporosis) on implant success or
failure, the effect of calcium phosphate coating composition and crystallinity on in vivo
performance of implants, the factors contributing to accelerated osteointegration, and
development of osteoinductive implants.
3. Bone collagen and process of bone formation
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There are more than 19 collagens known. The main collagen in bone is type 1but
small amounts of collagen type III may also be present.
Collagens are synthesized and secreted by a variety of cells. For bone the
osteoblasts are the most important cell types.
a. Bone Formation
The process of bone formation (osteogenesis) involves three main steps:
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production of the extracellular organic matrix (osteoid);
mineralization of the matrix to form bone;
and bone remodeling by resorption and reformation.
The cellular activities of osteoblasts, osteocytes, and osteoclasts are essential to the
process. Osteoblasts synthesize the collagenous precursors of bone matrix and also
regulate its mineralization. As the process of bone formation progresses, the osteoblasts
come to lie in tiny spaces (lacunae) within the surrounding mineralized matrix and are
then called osteocytes. The cell processes of osteocytes occupy minute canals
(canaliculi), which permit the circulation of tissue fluids. To meet the requirements of
skeletal growth and mechanical function, bone undergoes dynamic remodeling by a
coupled process of bone resorption by osteoclasts and reformation by osteoblasts.
b.
Osteoblasts and Bone Matrix
Osteoblasts are derived from mesenchymal stem cells of the bone marrow stroma.
They possess a single nucleus; have a shape that varies from flat to plump, reflecting their
level of cellular activity, and in later stages of maturity line up along bone-forming
surfaces. Osteoblasts synthesize and lay down collagen 1, which comprises 90-95% of
the organic matrix of bone. Osteoblasts also produce osteocalcin -the most abundant noncollagenous protein of bone matrix- and the proteoglycans of ground substance and are
rich in alkaline phosphatase, an organic phosphate-splitting enzyme. Osteoblasts have
receptors for parathyroid hormone and apparently for estrogen. Hormones, growth
factors, physical activity, and other stimuli act mainly through osteoblasts to bring about
their effects on bone.
The collagen 1 formed by osteoblasts is typically deposited in parallel or concentric
layers to produce mature (lamellar) bone. But when bone is rapidly formed, as in the
fetus or certain pathological conditions (fracture callus, fibrous dysplasia,
hyperparathyroidism), the collagen is not deposited in a parallel array but in a basket-like
weave and is called woven, immature, or primitive bone.
In fully decalcified bone sections, the extracellular matrix stains pink with H+E, similar
to collagen elsewhere but with a more homogeneous than fibrillar structure, which latter
is easily observed by polarizing microscopy.
c.
Bone Mineralization
The main mineral component of bone is an imperfectly crystalline hydroxyapatite [Ca10
(PO4)6(OH) 2], which comprises about ¼ the volume and ½ the mass of normal adult
bone. The mineral crystals, as shown by electron microscopy, are deposited along, and in
close relation to, the bone collagen fibrils. Calcium and phosphorus (Pi, inorganic
phosphate) are, of course, derived from the blood plasma and ultimately from nutritional
sources. Vitamin D metabolites and parathyroid hormone (PTH) are important mediators
of calcium regulation, and lack of the former or excess of the latter leads to bone mineral
depletion.
Undercalcified bone sections, such as those stained with the von Kossa stain, are best
used for the histological study of bone mineral distribution. The extracellular matrix of
bone is mineralized soon after its deposition, but a very thin layer of unmineralized
matrix is seen on the bone surface, and this is called the osteoid layer or osteoid seam. In
some pathological conditions, the thickness and extent of the osteoid layer may be
increased (hyperosteoidosis) or decreased. Hyperosteoidosis may be caused by conditions
of delayed bone mineralization (as in osteomalacia/rickets resulting from vitamin D
deficiency) or of increased bone formation (as in fracture callus, Paget’s disease of bone,
etc.).
4.
Clinical observations demonstrate high failure rates of implant fixation in
osteoporosis. The reduced healing capacity, including impaired bone formation, in
osteoporotic humans might be due to defects in mesenchymal stem cells that lead
to reduced proliferation and osteoblastic differentiation. Growth factors show
remarkable promise as agents that can improve the healing of bone or increase the
proliferation and differentiation capacities of mesenchymal stem cells. The
attraction of gene-transfer approaches is the unique ability to deliver authentically
processed gene products to precise anatomical locations at therapeutic levels for
sustained periods of time.
Bisphosphonates (BPs) are used in the treatment of osteoporosis. However, their
effects, especially long-term effects, on bone and bone healing are not fully
known. Clodronate (dichloromethylene bisphosphonic acid) is a first-generation
BP.
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Headaches in the temple region may be due to lack of integration and
inflammation caused by secreted cytokines. Over the counter medications like
aspirin inhibit COX-1 and COX-2 (induced due to inflammation) irreversibly and
inhibit the production of PGE2.
Plasma glucose of 150 mg% (8.3 mM) is indicative of mild form of diabetes.
Diabetic individuals are susceptible to slow healing fractures and exhibit high
incidence of periodontal disease.
It seems that this individual is suffering from osteomalacia (soft bones). In
osteomalacia, the osteoid does not mineralize properly and becomes wide and
irregular. This causes a decrease in plasma Ca and phosphate levels. To
compensate for low plasma Ca, PTH is released from the chief cells of
parathyroid gland.
PTH level increased in response to low plasma Ca levels. PTH is synthesized as
115 amino acid pre-pro PTH by membrane bound polysomes and processed first
to 90 AA pro PTH (- signal peptide) and then to 85 AA PTH which is stored in
the secretory granules and then released as needed.
Alkaline phosphatase (ALKP) is an enzyme that hydrolyzes
X-P
X + Pi; the identity of X is not known.
There are a number of isoenzymes; bone ALKP is relevant one here. It is
associated with the calcification of organic matrix. During process of active bone growth,
the level of ALKP goes up. This is consistent with osteomalacia where the process of
calcification is active.
10.
Osteomalacia, Osteoporosis: Osteomalacia: soft bones; Osteoporosis: Low bone
mass
Bone stores 99% of body calcium and calcium salts, laid down in a soft protein matrix,
are responsible for the hardness of bones. Long-term calcium deficiency leads to bone
thinning or osteomalacia. Osteomalacia refers to the reduction of the mineralization of
bone.
The problem of demineralization of bone is confused with loss of whole bone tissue
(osteoporosis). A high calcium intake and adequate Vitamin D will promote optimal
bone mineralization in youth and decrease the rate of bone-mineral loss in the later
postmenopausal period. Lack of Vitamin D in children leads to Rickets-soft, poorly
mineralized bone that bends easily. In older women, a high plasma level of vitamin D
enhances calcium absorption, whereas high sodium, protein, alcohol and caffeine intakes
will cause increased urinary losses and negative calcium balance. Other regulatory
changes and/or vitamin D deficiency may alter the balance between calcium absorption
from the bowel and excretion from the kidney.
The term "Osteoporosis" refers to a loss of total bone mass and not just bone thinning due
to calcium deficiency. Bone loss in adults increases the risk of bone fractures and may
contribute to the loss of teeth in healthy postmenopausal women. Low bone mass in
women is attributed to heredity, estrogen deficiency and lack of regular physical activity.
Osteoporosis is more a problem of disuse atrophy, with age-related reduction of bone
growth factors than of calcium deficiency itself. Women, fearing the stooped posture of
old age, are eager to take milk or calcium supplements. TV ads, promoting calcium
ingestion, show the degenerating profiles of an aging woman and are deceptive. Women
over 50 years of age show the most bone thinning because of deficiency of anabolic sex
hormone production, especially estrogen and declining physical activity. In early
menopause, estrogen replacement is effective therapy for conserving bone mass in
women. Daily, weight-bearing exercise is the best method of maintaining bone-growth
at any age.
The best answer to the problem of bone tissue loss, if you rule out daily exercise, would
be preventive treatment with hormone replacement, taken from age 45 onward. Cyclic
estrogen and progesterone supplementation in post-menopausal women is the currently
recommended strategy. Progesterone acts in concert with estrogen to increase bone
formation, and decrease bone resorption, with a net increase in bone mass and strength.
Low dosage estrogen (0.3 mg/d - day 1 to 25 of arbitrary cycle month), a progestin (day
16-25), with 1000 mg of calcium plus other minerals - manganese, copper, zinc - are
recommended as part of a treatment program for post-menopausal osteoporosis.
Postmenopausal women given calcium alone show progressive bone de-mineralization.
Vitamin D is added and doses up to 4000 i.u. per day have been useful postmenopausal
women.
Bisphosphonates
Bisphosphonates are a family of drugs used to prevent and treat osteoporosis. There are
three bisphosphonates currently approved for use: alendronate (Fosamax ®), etidronate
and risedronate.
Bisphosphonates bind permanently to the surfaces of the bones and slow down the
osteoclasts (bone-eroding cells). This allows the osteoblasts (bone-building cells) to work
more effectively.
All three bisphosphonates increase bone density and prevent fractures of the spine
(vertebral fractures). Alendronate and risedronate have also been shown to prevent hip
fractures. Studies show alendronate and risedronate to be more effective in treating
osteoporosis than etidronate.
Alendronate (Fosamax) 5.0 to 10.0 mg per day prevents osteoporosis in younger
postmenopausal women, an alternative therapy for women who cannot take hormone
replacement therapy (HRT) and an adjunctive therapy for women on HRT. The drug also
prevents steroid induced osteoporosis should be considered for use in all patients who
require long-term steroid therapy.
Calcitonin (salmon hormone nasal spray) has also been effective in reducing spinal
fracture rate in women over a 4-year period.
Raloxifene (Evista 60-120 mg/day), an estrogen hormone receptor modulator reduced
spinal fracture rates by 38% in a group of postmenopausal women who had one fracture.
Osteoporosis is a reduction in osseous tissue with unchanged skeletal structure. Two
distinct forms are recognized:
 Primary osteoporosis – Here, the regulatory mechanism between the plasma
calcium level and parathyroid hormone secretion is disturbed; generally, the entire
skeleton is affected. The juvenile form occurs during pregnancy; the senile form
appears during menopause (involution osteoporosis).
 Secondary osteoporosis – It usually starts in the central skeleton and proceeds
centrifugally. There are a number of possible triggers: inactivity, e.g. due to
paralysis or immobilization, malnutrition (malabsorption, alcoholism),
hyperthyroidism, long-term cortisone therapy. Bone density and strength are
highest between the ages of 25 and 35: bone buildup and breakdown are roughly
in equilibrium, but buildup predominates during the growing years, breakdown
after the age of 35 – if the dietary supply and enteric resorption, or hormonal
regulation, is inadequate. In advanced age, furthermore, the food’s calcium supply
can no longer be utilized fully, while decreasing physical activity and diminished
exposure to fresh air (and sunlight!) accelerate bone breakdown.
11.
Take the medical and oral history of the patient. All serology tests should be done
to determine bone health prior to initiating the implant procedure.
Osteoinduction is the process by which osteogenesis is induced. It is a phenomenon
regularly seen in any type of bone healing process. Osteoinduction implies the
recruitment of immature cells and the stimulation of these cells to develop into
preosteoblasts. In a bone healing situation such as a fracture, the majority of bone
healing is dependent on osteoinduction. Osteoconduction means that bone grows
on a surface. This phenomenon is regularly seen in the case of bone implants.
Implant materials of low biocompatibility such as copper, silver and bone cement
shows little or no osteoconduction. Osseointegration is the stable anchorage of
an implant achieved by direct bone-to-implant contact. In craniofacial
implantology, this mode of anchorage is the only one for which high success rates
have been reported. Osseointegration is possible in other parts of the body, but
its importance for the anchorage of major arthroplasties is under debate.
Ingrowths of bone in a porous-coated prosthesis may or may not represent
osseointegration.
OSTEOMALACIA
Classification of the Main Osteomalacias
MAIN ETOLOGIC DEFECT
CAUSES
MAIN CLINICAL
FORMS
Vitamin D deficiency
Dietary deficiency
(Asian
(Elderly
(Small-bowel disease
25-hydroxyvitamin D2
deficiency
25-hydroxylase abnormality
(Liver disease
Drugs
1.25 - dihydroxyvitamin D3
deficiency
1-alpha-hydroxylase failure
Renal failure
1-alpha-hydroxylase deficiency
Pseudo-vitamin D
deficiency
Decreased tubular phosphate
reabsorption
(Familial
(Sporadic
(Tumoral
Phosphate depletion
Use of oral phosphate
binds
Hypophosphataemia
(Nordin BEC, Peacock M. Aaron J et al: Osteoporosis and osteomalacia. Clin.
Endocrinal Metab 9:177-205, 1980)
Usual Biochemical Abnormalities in Various Types of Osteomalacia
FASTING PLASMA
VITAMIN-DDEFICIENT
RENAL
FAILURE
Decreased calcium
X
X
Decreased phosphorus
X
X
Decreased calcium x
phosphorous
X
X
Increased alkaline
phosphatase
X
X
Increased parathyroid
hormone
X
X
Decreased 25hydroxyvitamin D3
X
X
HYPOPHOSPHATAEMIA
(Modified from Nordin BEC, Peacock M. Aaron J et al: Osteoporosis and
osteomalacia. Clin. Endocrinol Metab 9:177-205, 1980)
Table 1. Characteristics of Patients with Osteomalacia Due to Vitamin D
Depletion
*
The time interval between the diagnosis of underlying gastrointestinal disease
and the development of symptoms due to osteomalacia.
Table 2. Clinical Manifestations of Osteomalacia in 17 Patients
Table 3. Biochemical Measurements in 15 Patients with Osteomalacia Due to
Vitamin D Depletion*
*
Two patients were not included because they had received vitamin D and
calcium supplementation for 1 to 2 months. All measurements made in serum
unless otherwise indicated.
Data from Parfitt et al [5] and Kleerekoper et al [6] from Michigan population.
Adjusted for serum albumin [5].
§
Ratio in urine.
Table 4. Bone Mineral Density before Treatment in Patients with Osteomalacia
Due to Vitamin D Depletion
Table 5: Bone Histomorphometric Findings in 17 Patients with Osteomalacia Due
to Vitamin D Depletion
*
Data from 66 white postmenopausal healthy women [10, 11 and 12].