osteoporosis and osteopenia- implications for periodontal and implant therapy
TRANSCRIPT
Osteoporosis and osteopenia:implications for periodontal andimplant therapy
JO A N OT O M O-CO R G E L
According to the National Osteoporosis Foundation,
osteoporosis is a major public health threat for an
estimated 44 million of the US population (55% of
people ‡50 years of age) (163). In the USA, 10 million
individuals are estimated to already have the disease
and almost 34 million more are estimated to have low
bone mass and thus are at risk for osteoporosis. In
Europe, the USA and Japan, osteoporosis is estimated
to affect 75 million people (64). One third of women
and one-fifth of men over 50 years of age will
experience osteoporotic fractures, (103, 147). The
combined lifetime risk for hip, forearm and vertebral
fractures is approximately 40%, equivalent to the risk
for cardiovascular disease (147).
Bone mineral density is quantified using dual-en-
ergy X-ray absorptiometry scans to define a T score.
The T score compares bone mineral density with the
mean peak bone density for an individual of the same
gender and is reported as the number of standard
deviations below that average. A T score of )2.5 or less
is diagnostic for osteoporosis. Scores of )1.0 to )2.5
indicate osteopenia, and scores of 0 to )1.0 are con-
sidered normal (61). T scores are used to determine
an individual�s fracture risk primarily at the lumbar
spine, total hip, femoral neck or trochanter. Some
clinicians evaluate Z scores, which are also deter-
mined by a dual-energy X-ray absorptiometry scan,
but compare the bone mineral density results with
persons of the same age, weight, ethnicity and gender.
Z scores are used to determine if there is an unusual
reason for the alteration in bone mineral density (e.g.
a systemic etiology such as thyrotoxicosis).
The incidence of osteoporosis is higher in women
(80%) than in men (20%). Women have a lower
total bone mass than men, and peak bone levels
occur at an earlier age in women (�25 years of age,
with 98% of the skeletal mass built by age 20) than
in men (�30 years of age). Women reach meno-
pause at a mean age of 50–51 years, and a decrease
in estrogen perimenopausally (3–5 years before
menopause) and a few years after menopause
(1 year without a menstrual cycle) causes acceler-
ated bone loss (Table 1). In women, two stages of
primary bone loss occur. The first stage is rapid
trabecular bone loss as a result of estrogen defi-
ciency initiated with the onset of menopause that
occurs for a duration of approximately 4–8 years
and is characterized by high bone resorption and
reduced bone formation. The second stage involves
slower trabecular and cortical bone loss that occurs
as a result of decreased bone formation. In men,
bone loss generally occurs at a slower rate, as a
result of lower levels of bioavailable testosterone
and estrogen.
Among white women, the lifetime risk of hip
fracture is one in six (compared with, for example, a
one in nine risk of a diagnosis of breast cancer) (45).
The greatest morbidity associated with osteoporosis
is related to hip fractures, with 20–24% mortality
within the first year after a hip fracture (120). Of
those who survive, 40–60% are unable to walk
unassisted 1 year later. Although osteoporosis is
more prevalent in women, the mortality rate for men
with a hip fracture is double that in women of a
similar age (104). Men acquire osteoporosis at a later
age with a sharp increase in incidence observed at
70 years of age and older, and therefore complica-
tions of the hip fracture that result from immobility,
for example thrombophlebitis, are more likely to
occur in men.
Risk factors for osteoporosis can be classed as
nonmodifiable or modifiable (Table 2). Gender
(female), hereditary factors, ethnicity, small body
frame (<127 lbs), and early or surgical menopause are
111
Periodontology 2000, Vol. 59, 2012, 111–139
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� 2012 John Wiley & Sons A/S
PERIODONTOLOGY 2000
nonmodifiable risk factors for osteoporosis. Exercise,
diet, alcohol intake, smoking, hormone replacement
therapy, immobility and lack of weight-bearing
exercise are modifiable risk factors. Medications
(Table 3) used routinely in clinical medicine may
have detrimental effects on bone remodeling.
Recently, a �prescriptiome� analysis of 62,865 men of
50+ years of age with a fracture indicated that the
largest impact on fracture risk at a population level
was exerted by loop diuretics and analgesics (1). A
multitude of systemic diseases are also associated
with an increased risk of osteoporosis, including
hypogonadal states (anorexia nervosa, female athletic
triad, Turner�s syndrome and Klinefelter�s syndrome),
endocrine disorders (Cushing�s syndrome, hyper-
parathyroidism, thyrotoxicosis, diabetes mellitus,
adrenal insufficiency and acromegaly), gastrointesti-
nal disorders (severe hepatic disease, malabsorption,
pernicious anemia, malnutrition and gastrectomy),
rheumatologic disorders (rheumatoid arthritis),
certain inherited diseases (osteogenesis imperfecta,
Table 1. Effects of estrogen on bone remodeling
• Enhanced numbers of remodeling sites as a result of enhanced bone formation of osteoclasts and decreased formation of
new bone in the resorption lacunae, eventually causing decreased bone mass and increased risk for osteoporosis
• Increased bone resorption is caused by decreased inhibition of estrogen on osteoclastogenesis and osteoclastic activity
• Estrogen receptors may be present in osteoclast progenitor cell and multinucleated osteoclasts. Note that marrow cells
(macrophages, monocytes, osteoclast precursors and mast cells) and bone cells (osteoblasts, osteocytes and osteoclasts)
have estrogen receptors a and b. Estrogen receptor-a is the dominant estrogen receptor in cortical bone and estrogen
receptor-b is the dominant receptor in cancellous bone
• Estrogen suppresses the synthesis of cytokines responsible for stimulating osteoblast apoptosis and reducing osteoclast
cell death.
• Stimulatory effect of estrogen on bone formation may be mediated by estrogen receptor-responsive elements on
promoters in genes involved in bone matrix biosynthesis, including type I collagen or cytokine genetics
• Estrogen may play a role in the longevity of bone cells by controlling the rate of apoptosis and reducing osteoclast cell
death
Table 2. Risk factors for osteoporosis
Nonmodifiable
Female
Thin skeletal frame
Family history
History of fracture in first relative
Caucasian or Asian
Advanced age
Adult fracture
Early menopause (<45 years of age) or bilateral
ovariectomy
Modifiable
Cigarette smoking
Low body weight (<57.6 kg)
Estrogen deficiency
Premenstrual amenorrhea (for >1 year)
Inadequate calcium intake
Alcoholism
Physical inactivity
Imbalance or vertigo
Lactose intolerance
Table 3. Medications ⁄ drugs associated with secondaryosteoporosis
Glucocorticoids
Anticonvulsants (i.e. phenytoin)
Ciclosporin
Cytotoxic drugs (i.e. methotrexate)
Lithium
Coumadin
Heparin therapy (long term)
Aluminum
Gonadotropin-releasing hormone agonists
Thyroid hormone (in excess)
Excessive alcohol
Proton pump inhibitors
112
Otomo-Corgel
hemochromatosis, hypophosphatasia and porphy-
ria), hematologic ⁄ malignant disorders (multiple
myeloma, leukemia, lymphoma, hemophilia and
thalassemia), and other disorders such as lactose
intolerance, chronic obstructive pulmonary disease,
breastfeeding, pregnancy and sarcoidosis.
Osteoporosis and osteopenia:physiology
Osteoporosis is a systemic skeletal disease charac-
terized by loss of bone mass and micro-architectural
deterioration with a consequent increase in bone
fragility and susceptibility to fracture (61). It results
from bone loss as a result of changes in remodeling
during normal aging, but may be accelerated by
extrinsic and intrinsic factors. Although bone appears
inert, it is a dynamic tissue that receives about 10% of
the cardiac output and remodels throughout life
(129). Bone consists of both compact and trabecular
bone. The extracellular bone components include a
solid mineral phase associated with an organic type I
(90–95%) collagen matrix. This part of the organic
matrix, which is noncollagenous, contains serum
proteins such as albumin, cell attachment ⁄ signaling
proteins (thrombospondin, osteopontin and fibro-
nectin), calcium-binding proteins (matrix gla protein
and osteocalcin) and proteoglycans (biglycan and
decorin). The serum proteins are responsible for the
organization of collagen fibrils, initiation of miner-
alization and ⁄ or bonding of the mineral phase to the
matrix.
The mineral phase contains calcium and phos-
phate in the form of a poorly crystalline hydroxyap-
atite. Sodium, potassium and magnesium are also
present in small amounts. The skeleton contains over
99% of the calcium in the adult human body. The
remaining 1% is in the extracellular fluid and serum,
and calcium homeostasis is imperative for critical
functions such as neurologic activity, clotting and
muscular contraction. Skeletal calcium accretion
accelerates throughout childhood and adolescence,
reaches a peak in early adulthood and gradually
declines thereafter at rates that rarely exceed 1–2%
per year (129). In contrast, there are high daily rates
of calcium flux into and out of bone, mediated by
coupled osteoblastic and osteoclastic activity, of the
0.5–1.0% of freely exchangeable skeletal calcium
within the extracellular fluid. Calcium channels can
be activated by hormones, metabolites or neuro-
transmitters affecting the 50% of total serum calcium
that is ionized. The concentration of ionized calcium
in the extracellular fluid is usually controlled by
adjusting the rates of calcium movement across
intestinal and renal epithelia, mediated primarily by
changes in the levels of parathyroid hormone,
1,25(OH)2D-vitamin D3 and calcitonin. Current
studies seek to understand vitamin D-mediated
activation and to identify vitamin D-regulated genes
that mediate osteoblast and osteoclast functions
(179). Proteins, either uncomplexed (albumin and
immunoglobulins) or loosely complexed with phos-
phate, citrate, sulfate or other anions, are bound to
the remaining nonionized calcium. Therefore, serum
proteins also directly affect the total blood calcium
concentration.
Bone tissues are dynamic, and healthy bone
models and remodels throughout life. Modeling is a
process in which the skeleton increases in size in a
linear manner in response to the stresses placed
upon it. This involves new bone formation that is
independent of prior bone resorption, and the skel-
eton can thus assume a new shape or cortical thick-
ening. On the other hand, remodeling is initiated by
resorption and is followed by new bone formation at
the same resorptive site. Bone remodeling repairs
micro-damage in the skeleton to preserve strength
and supplies serum calcium from the skeleton for
mineral homeostasis. Signals from mechanical
stresses are sensed by osteocytes and are then
transmitted to osteoclasts or osteoblasts, or to their
precursors. Bone resorption reflects the sum of
osteoclast recruitment and death, and the rate at
which the average cell degrades matrix (171).
When remodeling becomes unbalanced, osteoporo-
sis (a loss of bone) or osteopetrosis (a gain of bone)
occurs (Fig. 1) (34). This remodeling occurs at bone
multicellular units. Riggs & Parfitt (195) estimated that
the human skeleton has 1–2 · 106 of these units. In
postmenopausal osteoporosis, the number of activated
multicellular units is increased, leading to increased
numbers of osteoclasts and resorption lacunae in the
skeleton. There are also increased numbers of forma-
tion sites and osteoblasts, but as a result of estrogen
deficiency, the osteoblasts do not function effectively.
There are estrogen receptors on osteoblasts and oste-
oclasts, and therefore estrogen can inhibit osteoclast
formation, may indirectly affect receptor activator of
nuclear factor-jB ligand (RANKL) expression by
cytokine regulation and may influence osteoclast
formation by decreasing the expression of macrophage
colony-stimulating factor. Decreased estrogen also
results in reduced inhibition of osteoclastogenesis and
more osteoclastic activity (226). The net result is
decreased bone mass and reduced strength.
113
Osteoporosis and osteopenia: implications for periodontal and implant therapy
Current clinical therapies
Clinical therapy for osteoporosis is a lifelong inter-
vention. It is therefore important to understand not
only what medications the patient is currently taking,
but what medications they have previously taken, the
side effects, compliance, duration and how effective
the therapies have been. The current medications
approved for osteoporosis include calcium, vitamin
D, bisphosphonates, parathyroid hormone, selective
estrogen receptor modulators, calcitonin, hormone
therapy, denosumab and strontium ranelate (Ta-
ble 4). Controversies exist regarding the optimal cal-
cium dose and calcium sources.
With increasing longevity, it is important to
remember that osteoporosis is not only a female
disease. Owing to the increase of US veterans suf-
fering from osteoporosis, the Veterans Administra-
tion has developed an algorithm for the treatment of
male osteoporosis (Fig. 2) (53).
Calcium
Calcium intake in the USA is inadequate according to
the Harvard Medical Report, which identified that
only 45% of adult men and 22% of adult women
receive the recommended intake of calcium (216).
Among 9- to 17-year-old subjects, just 25% of boys
and 10% of girls receive sufficient calcium. Calcium
alone may be partially effective in preventing bone
loss, especially in elderly women with an inadequate
calcium intake (185, 190). In a 2002 review, 68 of 70
�investigator controlled� studies found that calcium
supplementation resulted in greater gains in bone
during growth, less loss of bone with age, and ⁄ or
reduced fracture risk (88). The National Academy of
Sciences, National Institutes of Health and the Na-
tional Osteoporosis Foundation support the recom-
mendations in Table 5. The best sources of calcium
are foods, especially dairy products (milk, yogurt,
cheese and ice cream), nuts ⁄ seed (peanuts, sesame
paste and almonds), legumes (soy and baked beans,
tofu), vegetables (spinach, broccoli, artichokes and
A
OsteoblastsOsteoclast
progen.
Initiation Resorption
2–4 weeks 4–6 months
Reversal Boneformation
Remodelingcompleted
“cleaningcells”
Osteoblastprogen.
OsteoblastsCouplingfactors?
B C D E
Fig. 1. Normal bone remodeling. (A) Bone remodeling is
initiated by osteoclastic resorption, but osteoclast formation
and activation are controlled by osteoblasts on the bone
surface. Next, the inactive osteoblasts or pre-osteoblasts
cover the surfaces of bone tissues where activation leads to
osteoblastic degradation of unmineralized osteoid sand-
wiched between the mineralized bone. (B) Osteoblasts now
increase their expression of receptor activator of nuclear
factor-jB ligand (RANKL) and macrophage colony-stimu-
lating factor, while decreasing osteoprotegerin (the inhibitor
of RANK). This process creates an increase in the osteoclast
progenitor pool and initiates the differentiation that allows
the development of latent multinucleated osteoclasts. Once
the surface osteoblasts retract from the surface, multinu-
cleated osteoclasts have access to the mineralized bone.
Here the osteoclasts develop a ruffled border and dissolve
hydroxyapatite crystals forming resorption lacunae. (C)
When osteoclasts leave the lacunae, mononuclear cells ap-
pear and they remove the organic matrix debris. (D) Osteo-
blast precursors are differentiated into active osteoblasts that
fill the lacunae with new bone. (E) Remodeling is complete.
Permission granted from U. H. Lerner (123).
Table 4. Medications approved for the treatment ofosteoporosis
Calcium supplementation
Vitamin D supplementation
Bisphosphonates*
Selective estrogen receptor modulators
Tamoxifen
Raloxifen
Calcitonin
Hormone therapy
Parathyroid hormone (teriparatide)
Denosumab
Strontium ranelate
*See Table 6.
114
Otomo-Corgel
snow peas), fruits ⁄ fortified fruit juices (fortified
orange juice, rhubarb and dried fruit), fish (salmon
with bones, sardines with bones, bass and ocean
perch) and shellfish (steamed clams, lobster and
shrimp). Some food constituents may affect the
absorption of calcium. For example, oxalic acid in
spinach and rhubarb may combine with the calcium
in these plants so that it is not readily absorbed.
The other sources of calcium are supplements. They
are usually administered as calcium carbonate or
calcium citrate; however, phosphate, lactate and
gluconate forms may also be found. Calcium pills are
compounds in which the actual amount of calcium is
�elemental calcium�. For example, calcium carbonate
contains 40% calcium by weight; thus, a 500-mg pill of
calcium carbonate contains 200 mg of calcium, and
therefore the labeling will indicate that each pill con-
tains 200 mg of elemental calcium. Calcium citrate
contains 21% calcium by weight. Calcium carbonate
is best taken with food because it requires stomach
acid for absorption. Although it is usually tolerated by
most people, it has been reported to cause bloating
and constipation in some. Calcium citrate is easier to
absorb, especially in the elderly, and can be taken with
food or on an empty stomach. One must remember
that approximately 500 mg of calcium can be
absorbed at one time, so if supplementing, the dose
should be spread throughout the day. Also, recom-
Glucocorticoid therapy (5 mg daily for 3 months)Low trauma fracture after age 45 yearsRadiographic evidence of vertebral osteopenia or fractureAndrogen deprivation therapy or other hypogonadismAnticonvulsant therapy (2 years or more)Gastrectomy, malabsorption, celiac disease, bariatric surgeryExcess alcohol consumptionOther conditions and medications
Indications present?
Reassess in 2 yearsDual-energy X-ray absorptiometry (spineand hip ♦)
T-score –2.5 or lessin spine or hip⁺
T-score between –1and –2.5
T-score –1 or higherin spine or hip
History, examination basic laboratory
analyses, serum and urine calcium, 25
hydroxyvitamin D
Secondary causesConsider evaluation and
treatmentRepeat bone mineral
density scan at 1–2 years
Low trauma fractureEvaluate and consider
treatment
No secondary causes or effectsRe-evaluate in 2 yearsLifestyle counselingEnsure adequate calcium/vitamin D
No osteoporosisLifestyle counselingEnsure adequate calcium/vitamin D
Treat abnormalities and/or refer patient
Re-evaluate fortreatment
Ensure adequate calcium:1.2 g dailyEnsure adequate vitamin D:800+ units dailyNonpharmacologic interventions to reducefracture riskOral bisphosphonates
Refer to metabolic bone specialist if bisphosphonates are contraindicated or patientintolerant or not responsive
YesNo
NormalAbnormal
⁺ For T-score less than –2.5 and multiple fracture or T-scoreless than –3.5, consider referral to a Metabolic Bone Specialist.♦ Do a forearm bone mineral density if spine or hip cannot beinterpreted.
Fig. 2. 2011 Veterans Administration algorithm for treat-
ing male osteoporosis. Owing to the increasing incidence
of osteoporosis among patients at the Veteran�s Adminis-
tration Hospitals, this algorithm was developed through
the office of the Under Secretary for Health (53). It is to be
used as a guide when selecting which men need to be
screened for osteoporosis, treatment recommendations
and management of complications.
Table 5. Calcium recommendations
Age National Academy of
Sciences
Calcium intake
recommendations
(mg ⁄ day)
Birth to 6 months 210
7 months to 1 year 270
1–3 years 500
4–8 years 800
9–18 years 1,300
19–50 years 1,000
51 years or older 1,200
Pregnant ⁄ lactating 14–18 years 1,300
Pregnant ⁄ lactating 19–50 years 1,000
115
Osteoporosis and osteopenia: implications for periodontal and implant therapy
mended doses should not exceed 2,500 mg ⁄ day
because of the possible increased risk for kidney stones.
Vitamin D
Vitamin D plays a vital role in calcium absorption in
the gastrointestinal tract. Vitamin D levels have been
shown to be inadequate in over half of the women
treated for osteoporosis in the USA and Europe (183).
7-Dehydrocholesterol is absorbed into the systemic
circulation via the skin or from the diet. It is then
hydroxylated in the liver to form 25-hydroxy vitamin D
or calcidiol. In order to be metabolically active, 25-
hydroxy vitamin D is hydroxylated in the kidney to
form the active hormone calcitriol or 1,25-hydroxy
vitamin. Calcitriol is responsible for maintaining
serum calcium and phosphate concentrations by
controlling absorption in the small intestine (52).
Parathyroid hormone is secreted when serum calcium
levels fall in order to increase 1,25-hydroxy vitamin D
synthesis and, as a result, calcium absorption from the
intestine increases. Although most studies show a
strong effect of vitamin D on reducing fracture risk
when supplemented in conjunction with calcium,
there are reports of increased bone density or reduced
fracture with vitamin D alone (26, 167, 176).
The recommended amount of vitamin D supple-
ment is under constant revision. The 2006 recom-
mended daily allowance (RDA) was 200 IU ⁄ day
(5.0 lg) for adults 19–50 years of age, 400 IU ⁄ day
(10.0 lg) for those 50–70 years of age and 600 IU ⁄ day
(15.0 lg) for those over 70 years of age. Most refer-
ences at that time indicated that the current vitamin D
intake was not optimal and recommendations were
made to increase the guidelines. Accordingly, in 2010
the US Institute of Medicine (IOM) revised the guide-
lines to the following: 1–3 years of age, 600 IU ⁄ day
with an upper limit of 2,500 IU ⁄ day; 4–8 years of age,
600 IU ⁄ day with an upper limit of 3000 IU ⁄ day; 9–
69 years of age, 600 IU ⁄ day with an upper limit of
4,000 IU ⁄ day; and>70 years of age, 800 IU ⁄ day with
an upper limit of 4,000 IU ⁄ day (204). End-points
associated with improved bone mineral density, such
as lower-extremity function, dental health, risk of
fractures and reduction in colorectal cancer, require
1,000 IU ⁄ day of vitamin D (20, 90). Also, a recent re-
view found that the safe upper limit for vitamin D
consumption by adults was 10,000 IU ⁄ day or >10
times any current recommended intakes (87, 230). It is
difficult to obtain an adequate intake of vitamin D from
the human diet; exposure of skin to ultraviolet light
provides the greatest effect. This means that geogra-
phy, season, skin color and sun-related behavior are
the main predictors of vitamin D nutritional status
(143, 225, 233). Vitamin D supplementation should
therefore be adjusted according to these factors.
Bisphosphonates
Bisphosphonates are analogs of inorganic pyrophos-
phates. They have low intestinal absorption, are ex-
creted via the kidneys without metabolic alteration and
have a high affinity for hydroxyapatite crystals (71, 217).
They are powerful inhibitors of osteoclastic activity,
have a high affinity to bone and are preferentially
delivered to sites of increased bone formation or
resorption. Clinical trials have shown that oral alendr-
onate, risedronate and, recently, ibandronate, reduce
hip fracture and increase bone mineral density in the
hip, spine and wrist (30, 31, 202). Despite data that
indicate good tolerance of oral bisphosphonates for up
to 10 years, it is unclear as to which patients need to
stay on medication in the long term. Pharmacokinetic
studies in humans and animal studies have demon-
strated that the tight binding of bisphosphonates to
hydroxyapatite results in the retention of bisphospho-
nates for prolonged periods in the bone, and they be-
come locally active again when that bone packet is
resorbed (128). This property raises the possibility of
both prolonged clinical effectiveness and prolonged
risk of harm (44). The Fracture Intervention Trial Long-
term Extension (FLEX) indicated that women who have
had a good response to 5 years of bisphosphonate
therapy (a 3–5% increase in hip bone mineral density,
an 8–10% increase in spine bone mineral density and a
T score of >)3.5) and who are not otherwise at in-
creased risk of vertebral fracture can consider a �holi-
day� off the drug for up to 5 years (28). In experimental
animals, alendronate has been shown to inhibit repair
of normal microdamage, so microdamage accumula-
tion may occur (125, 140). Note also that several bis-
phosphonates were approved by the US Food and Drug
Administration after 2001, and the long-term effects of
these drugs on bone suppression are not yet known.
There are differences in the physical and chemical
structure of available bisphosphonates that may
explain variations in clinical observations. Potency at
the enzyme level, binding affinity, distribution
accumulation and release vary among the different
bisphosphonates (Table 6). Low-affinity bisphospho-
nates do not bind as tightly and are available on the
surface of the bone for removal by osteoclasts; thus,
the drug �comes off� the bone more easily and its
effects may be shorter in duration. The chemical
differences between the bisphosphonates result in
differences in: uptake and retention by the skeleton;
116
Otomo-Corgel
diffusion of the drug within bone; release of the
adsorbed drug from bone; potential recycling of the
desorbed drug back onto bone surfaces; and on min-
eral dynamics and cellular functions (161). To date, in
bisphosphonate trials, specific gains in bone quality
(architecture, turnover, damage accumulation and
mineralization) have not been reported in the human
maxilla or mandible. Further research regarding the
distribution of the medication in individual patients
and distribution to oral bone is needed.
The term �bisphosphonate� is derived from the base
of the drug, namely two phosphate (PO3) groups
covalently linked to a central carbon. The carbon
atom confers resistance to hydrolysis and allows two
R side-chains to attach. The short side-chain, R1,
influences the chemical properties and pharmacoki-
netics of the drug.
R1O
P
R2
CP
O
O-
O- O-
O-
This chain usually has a hydroxyl moiety, which pro-
vides a strong affinity for calcium crystals and bone
mineral. The long side-chain, R2, determines the
chemical properties, the mode of action and the
strength of the bisphosphonate. Bisphosphonates in-
hibit osteoclasts by two mechanisms, depending on
whether the R2 side chain contains nitrogen side
groups. The nonaminobisphosphonates (etidronate,
clodronate and tiludronate) lack a �nitrogen� in their side
chains and are metabolized by osteoclasts to inactive
nonhydrolyzable ATP analogs that interfere with
osteoclast cellular energy and thus induce apoptosis.
The more potent aminobisphosphonates (pamidronate,
alendronate, ibandronate, risedronate and zoledronate),
with �nitrogen�-containing side groups, have four activ-
ities: inactivation of ATP; inhibition of farnesyl diph-
osphonate synthase (part of the mevalonate pathway in
cholesterol synthesis) resulting in osteoclast cytoskeletal
disruption, dysregulation of intracellular transport and
inhibition of cell proliferation; reduction of osteoclast
recruitment; and induction of osteoblasts to produce an
osteoclast-inhibiting factor.
Over 750,000 prescriptions for bisphosphonates
were written each week in 2006 in the USA. In 2010
the number of prescriptions had dropped to
approximately 702,000 per week, although this still
equates to 36.5 million per year. Bisphosphonates are
available in oral doses (daily, weekly, monthly and
quarterly) and in intravenous yearly doses. The long-
term effects of the newer medications are unknown.
Table 6. Dosage and US Food and Drug Administration approval dates of bisphosphonates for use in the USA
Agent Dosage forms Approved Potency
Etidronate (Didronel�; Warner-Chilcott
Laboratories, Rockaway, NY, USA)
200 ⁄ 400 mg tablets 1977 1·
Clodronate (Bonefos�; Bayer Healthcare,
Morristown, NJ, USA)
400 ⁄ 800 mg tablets
60 mg ⁄ ml ampules
Not approved in USA
(Canada only)
10·
Tiludronate (Skelid�; Sanofi-aventis,
Bridgewater, NJ, USA)
200 mg tablets 1977 10·
Pamidronate (Aredia�; Novartis
Cambridge, MA, USA)
20 ⁄ 60 ⁄ 90 mg vials 1991 100·
Alendronate (Fosamax�; Merck & Co.,
Whitehouse Station, NJ, USA)
5 ⁄ 10 ⁄ 35 ⁄ 40 ⁄ 70 mg tablets
70 mg ⁄ 75 ml oral solution
1995 100·
Alendronate + D 70 mg and 2800 U cholecalciferol tablets 2005
Ibandronate (Boniva�; Roche
Laboratories, Burlington, NC, USA)
2.5 mg tablets
150 mg tablets
3 mg ⁄ 3 ml vials
2003
2005
2006
500·
Risedronate (Actonel�; Procter & Gamble,
Cincinnati, OH, USA)
5 ⁄ 30 ⁄ 35 mg tablets
35 mg and 500 calcium
1998
2005
2,000·
Risedronate + (Actonel + calcium�) 35 mg ⁄ 1,250 mg calcium carbonate 2005
Zoledronate (Zometa�; Novartis
Cambridge, MA, USA)
Reclast�
4 mg vials
5 mg vial
2001
2007
10,000·
117
Osteoporosis and osteopenia: implications for periodontal and implant therapy
The oral doses have been associated with gastroin-
testinal side effects such as dysphagia, esophagitis,
esophageal ulcers and gastric ulcers. Bisphospho-
nates are recommended to be taken on an empty
stomach with a full glass of water while remaining
upright for 30 min afterwards. For this reason, com-
pliance has been a consistent problem.
In August 2007, the US Food and Drug
Administration approved once-per-year intravenous
zoledronic acid for the treatment of osteoporosis. In a
36-month trial, atrial fibrillation and arrhythmia were
observed among more patients on once-per-year
zoledronic acid (1.3%) than those on placebo (0.5%),
but the overall incidence was not significant (38).
Also, a growing number of atypical femur fractures in
patients taking oral bisphosphonates are a new con-
cern (208). Intravenous doses of pamidronate and
zolendronate for the treatment of multiple myeloma
and metastatic breast ⁄ prostate cancer that has
metastasized to bone have also been associated with
osteonecrosis of the jaw.
Parathyroid hormone
Human parathyroid hormone has shown significant
reductions in both vertebral and appendicular fracture
rates. Parathyroid hormone was approved by the US
Food and Drug Administration in 2002 as a re-
combinant parathyroid hormone 1–34 with the name
teriparatide. It is delivered as a 20 lg subcutaneous
injection indicated daily for postmenopausal women
and men with osteoporosis. Most osteoporosis thera-
pies act to primarily inhibit bone resorption and
reduce bone remodeling; however, parathyroid hor-
mone has the potential to enhance skeletal microar-
chitecture. The initial animal study showed that daily
injection of parathyroid hormone for several weeks or
months increased bone mass and strength (158).
Human studies indicate that parathyroid hormone
increases bone mineral density and decreases the risk
of vertebral and nonvertebral fractures (130, 164, 169,
213). The current recommendation is that, to avoid
decreases in bone density (27, 107), patients should be
treated with an antiresorptive medication (e.g. a bi-
sphosphonate) only after intermittent parathyroid
hormone therapy has been discontinued, and that bi-
sphosphonates should not be used concomitantly with
parathyroid hormone (70).
Selective estrogen receptor modulators
There are two classes of selective estrogen receptor
modulators: triphenylethylenes and benzothioph-
enes. Tamoxifen is a triphenylethylene known to have
estrogen antagonist activity in the breast and has
demonstrated activity consistent with estrogen ag-
onism in bone. Other triphenylethylene selective
estrogen receptor modulators are clomiphene (used
to induce ovulation) and toremifene (used for breast
cancer treatment). The benzothiophene selective
estrogen receptor modulator in clinical use is ra-
loxifene. It was developed specifically to avoid the
uterotrophic effects of the other selective estrogen
receptor modulators and has been approved for the
treatment and prevention of postmenopausal osteo-
porosis (142). It has been studied extensively and acts
as an antiresorptive agent, preserving both bone
mineral density and bone strength in a manner
identical to that of ethinyl estradiol (160), while
reducing the incidence of breast cancer in a targeted
population of women (67, 178). It has the following
effects on bone physiology: decreased bone forma-
tion and resorption, and fracture risk reduction re-
lated to decreased biochemical markers of turnover,
but no changes in bone density, no significant
change in bone volume, slight increase in minerali-
zation density and no evidence of osteomalacia or
bone toxicity (131). Note that selective estrogen
receptor modulators have not shown effectiveness in
reducing the vasomotor problems (i.e. hot flushes)
that are associated with menopause. Droloxifine,
idoxifene and toremifene are similar selective estro-
gen receptor modulator agents, but are still consid-
ered experimental (209).
Calcitonin
Calcitonin is a naturally occurring 32-amino-acid
polypeptide hormone produced by the C cells of the
thyroid. It is involved in calcium and phosphate
metabolism by decreasing calcium absorption by the
intestines, decreasing osteoclastic activity in bones
and decreasing calcium and phosphate reabsorption
by the kidney tubules. Osteoclasts have calcitonin
receptors, and calcitonin inhibits osteoclastic activ-
ity. Calcitonin is also associated with vitamin D reg-
ulation and enhanced bone mineral metabolism.
Studies evaluated bone loss in women after meno-
pause and found that calcitonin stopped bone loss,
normalized bone turnover without subjective or
objective side effects (42, 174, 188), reduced sub-
sequent vertebral fractures in patients with estab-
lished postmenopausal osteoporosis (40) and its
mechanism of action appears to be related to the
inhibition of bone resorption and preservation of
microarchitecture without a significant increase in
118
Otomo-Corgel
bone mineral density (41, 106). Calcitonin results in
reduced vertebral fracture risk, but has not been
demonstrated to reduce nonvertebral or hip fracture
risk. Calcitonin is unique for its analgesic effect on
vertebral fracture as a result of salmon calcitonin-
binding sites in the central nervous system (215).
Currently, research is underway to evaluate an oral
type of calcitonin, as well as a form of rectal sup-
pository. Further studies are needed to evaluate the
effects of intermittent administration (1 month on
and 1 month off) of calcitonin vs. daily doses, as well
as the possibilities of combination therapy with other
antiresorptive medications. Calcitonin-salmon is a
US Food and Drug Administration-approved daily
metered dose (200 IU) administered via intranasal
spray or an intramuscular or subcutaneous injection.
Estrogen ⁄ hormone replacement therapy
Estrogen, progesterone and androgen receptors are
present in all bone cell types. Both estrogen
replacement therapy and hormone replacement
therapy have been shown to reduce the risk of hip
and spine fractures and to reduce bone loss in
postmenopausal women. For women who require
drug therapy to reduce the risk for osteoporosis,
including women at high risk of fracture during
the next 5–10 years, estrogen replacement therapy ⁄hormone replacement therapy can be considered
an option (29). Owing to the results of the Women�sHealth Initiative, many women elected to treat
osteoporosis with alternative methods (241). Recent
data concluded that the incidence of fractures
among perimenopausal women and postmeno-
pausal women increased significantly in the 3 years
after publication of the Women�s Health Initiative
and Heart and Estrogen ⁄ Progestin Replacement
Study II, following a decline in the use of hormone
therapy, concurrent with an increase in the use of
other bone-modifying agents (94). The findings
using conjugated equine estrogens and progesterone
indicated an increase in the risk of venous throm-
boembolism, ischemic stroke, cardiovascular com-
plications and breast cancer when receiving estrogen
replacement therapy and ⁄ or hormone replacement
therapy. Note that these findings are contrary to
decades of previous clinical and observational trials
and clinical experience that validated the rationale
for hormone therapy. Current recommendations are
for short-term use and the early prevention of
osteoporosis. Wulf Utian, Director of the North
American Menopausal Society, noted that although
the North American Menopausal Society was the
first professional body to recommend stopping the
estrogen replacement therapy ⁄ hormone replace-
ment therapy group of the Women�s Health Initia-
tive, there are benefits of hormone replacement
therapy (241). For example, the hormone replace-
ment therapy group showed a significant reduction
in colon cancer (127). The beneficial effect was more
marked in women who began therapy within 5 years
after menopause (39). The net clinical effect of
estrogen is that it is primarily an antiresorptive
agent and therapeutically prevents osteoporosis by
inhibiting bone resorption and bone turnover. It has
been shown that estrogen deficiency led to fragility
of the trabecular structure of molar alveolar bone
that was inversely correlated with lumbar bone
mineral density in ovariectomized monkeys (14).
Currently, low-dose estrogen therapy for prevention
of bone loss in postmenopausal women as a
monotherapy is seen as a viable option in clinical
medical practice (194). Note that treatment with
androgens stimulates new bone formation and
results in higher bone mineral density than estrogen
therapy alone (166).
Alternative estrogens need further research. The
effect of phytoestrogen on bone and menopausal
vasomotor symptoms has yet to be confirmed (196).
The risk ⁄ benefit ratio of hormone replacement
therapy needs to be assessed with greater knowledge
of the effects of other treatments that exist for men-
opausal symptoms.
Denosumab
Denosumab is a human monoclonal antibody that
binds RANKL. It therefore blocks interaction with the
RANK receptor on osteoclasts and osteoclast pre-
cursors. Data also indicate that it is similarly effective
in various stages of renal function impairment: it
does not impair fracture healing processes or con-
tribute to atherosclerosis progression in patients with
high cardiovascular risks (72). The result is inhibition
of osteoclast-mediated bone resorption. Clinical tri-
als indicate that subcutaneous administration of
60 mg of denosumab every 6 months for 36 months
reduces bone turnover and increases bone mineral
density significantly more than alendronate at the
lumbar spine and hip in osteoporotic female patients
(46). Clinical data also indicate that it inhibits
structural damage in patients with rheumatoid
arthritis when added to methotrexate (124). Near-
maximal reductions in the mean levels of serum
C-telopeptide from baseline were evident 3 days after
administration of denosumab, and suppression of
119
Osteoporosis and osteopenia: implications for periodontal and implant therapy
bone turnover appeared to be dose-dependent (141).
This is a promising new treatment for osteoporosis
and rheumatoid arthritis that reduced bone resorp-
tion by a median of 86% at 1 month, which is greater
than that seen when using other antiresorptive drugs
(45). Note that Aghaloo et al. (4) have reported ONJ
associated with denosumab.
Strontium ranelate
Strontium ranelate is a new oral drug that reduced
the risk of all nonvertebral fractures and, in a high-
risk subgroup, of hip fractures over a 3-year period
(189). It is well tolerated and is a possible alternative
to current bisphosphonates. It acts by dissociating
bone remodeling by increasing bone formation and
decreasing bone resorption and in a Phase 3 trial led
to early and sustained reductions in the risk of
vertebral fractures (149, 189).
Periodontal implications
The evidence supporting the relationship between
osteoporosis and periodontitis is increasing. How-
ever, confounding factors play a significant role as
a result of the chronicity of both problems. Studies
on tooth loss, alveolar crestal height and clinical
attachment loss have been performed; however,
problems in extrapolation and application of data
arise owing to small sample sizes, study design vari-
ations and inadequately controlled confounding
factors, which have limited our understanding of the
relationship between the two diseases.
There are data which relate bone mineral density of
the spine, trochanter and other skeletal bones with
that of the maxilla and mandible. The preponderance
of evidence shows an association between systemic
measures of osteoporosis (such as dual-energy X-ray
absorptiometry) and oral bone mineral density (98).
Animal models indicated fragility of the trabecular
structure of molar alveolar bone (222), as well as
increased vertical loss of mandibular alveolar bone
(168, 224). In one study, the fragility of the monkey
alveolar bone trabecular structure inversely
correlated with lumbar bone mineral density when
ovariectomized (14). In a 28-month longitudinal
study of postmenopausal women, mandibular bone
loss, assessed by dual-energy X-ray absorptiometry,
was much higher than in other skeletal sites (56).
Also, Inagaki et al. (92) found that periodontitis and
tooth loss may be a useful indicator of metacarpal
bone mineral density loss in Japanese women. It has
been suggested that radiographic examination of the
facial skeleton may lead to early detection of osteo-
porosis (115). Although there are no current standard
methodologies to evaluate maxillary and mandibular
bone mineral density, research with newer technol-
ogies may permit dental practitioners to assess oral
bone quality.
Evaluation of dental panoramic radiographs for
identification of osteoporotic changes has yielded
mixed results. In an evaluation of mandibular pano-
ramic radiographs, it was found that osteoporotic
patients were more likely to have altered inferior cor-
tex morphology, but no statistically significant differ-
ences in cortical width, degree of alveolar crest
resorption, fractal dimension or number of mandib-
ular teeth were identified compared with nonosteo-
porotic patients. The authors recommended training
practitioners to use specific evaluation techniques to
detect significant radiographic changes, especially at
the inferior mandibular cortex, to help identify post-
menopausal women with currently undetected low
bone mineral density, as well as undetected spinal
fractures (220). Dental panoramic radiographs may be
useful for identifying women under the age of 65 with
osteoporosis by observation of a thin cortical width
and ⁄ or a severely eroded cortex (66, 221). Panoramic
studies indicate that the relative bone density of the
mandible is statistically significantly lower in patients
with osteoporosis (32, 170). However, when pano-
ramic-based indices were used to correlate bone
mineral density of the mandible and hip, it was found
that they were not able to distinguish normal from
osteopenic ⁄ osteoporotic mandibles (58).
Four different dental radiographic techniques were
compared for detecting osteoporosis: fractal dimen-
sion (measuring loss of trabecular continuity and
dimensions of space); microdensitometry (light
transmission through a selected area on a radio-
graph); pixel intensity (blackness or whiteness); and
panoramic analysis (cortical bone thickness at the
gonial angle). They were compared with standard
bone density measurement techniques used to
diagnose osteoporosis in bones other than the jaws:
quantitative computed tomography, and single- and
dual-photon absorptiometry. Pixel intensity was the
most effective dental method, and only panoramic
analysis was ineffective (119). Digitized bitewings
may be a more reliable method of monitoring chan-
ges in bone density. Jonasson et al. (100) found that
subjects with sparse mandibular trabeculation on
digitized radiographs had an increased risk of frac-
ture. Therefore, high-risk subjects may be identifiable
prior to fracture.
120
Otomo-Corgel
A study using a novel computed tomography ⁄micro-computed tomography-based hard-normal-
soft classification system proposed a formula to
convert ordinary computed tomography values,
expressed in Hounsfield units, into bone volume
percentages for objective measurements of bone
density (184). Computed tomography scanners can
determine the percentage of calcification in localized
sites, and this could be used in treatment planning
and may predict periodontal disease progression
before clinical attachment loss. This determination
would also enhance dental implant therapy.
Standardization of radiographic methods would be
needed to permit chairside determination of bone
mineral density, and although there is potential for
dentists to identify signs of osteoporosis in dental
radiographs, clear methodologies and criteria for
assessing bone have not yet been defined.
Tooth loss and alveolar crestal loss
Studies show the greatest associations between tooth
loss ⁄ alveolar ridge atrophy and osteoporosis (47, 57,
66, 85, 154, 246). There is also less risk of tooth loss
when postmenopausal women are placed on hor-
mone replacement therapy (84, 219). Krall et al. (114)
found that the odds of being edentulous were re-
duced by 6% for each 1-year increase in duration of
hormone replacement therapy use. It is also apparent
that there is increased alveolar ridge resorption in
edentulous patients with osteoporosis (54), and
greater alveolar crestal height loss is noted with
osteoporosis and osteopenia (155, 228, 236).
Periodontal disease
Current knowledge regarding the effects of osteopo-
rosis ⁄ osteopenia on periodontal diseases and alveolar
bone loss is inconclusive. The association of osteo-
porosis in postmenopausal women with periodontitis,
attachment loss and gingival recession has been re-
ported (33, 80, 93, 112, 228, 237). Several studies have
indicated that reduced bone mineral density was
associated with increased clinical attachment loss
(156, 201, 245). Others have found weak or no signifi-
cant associations between systemic bone mineral
density and clinical attachment loss (68, 180, 239).
However, recent studies provide stronger evidence of
an association between osteoporosis and clinical
attachment loss in humans (6, 135, 214, 218, 219, 221).
The relationship between periodontal disease and
plasma cytokines, vitamin D and bone mineral density
in postmenopausal women, with and without osteo-
porosis, has been investigated, and it was found that
periodontal disease was more common in women with
osteoporosis and was associated with lower vitamin D
and higher concentrations of RANKL and osteoprote-
gerin (95). Sub-antimicrobial doses of doxycycline in
postmenopausal women have shown a possible benefit
in reducing the progression of attachment loss with an
effect on serum biomarkers of bone loss (79, 177, 192).
Most studies indicate improved periodontal status in
women on hormone replacement therapy ⁄ estrogen
replacement therapy (43, 193, 219), characterized by
increased alveolar bone mass and improved alveolar
crest height, reduced clinical attachment loss and re-
duced periodontal inflammation. Also, estrogen
receptor-alpha gene polymorphism was shown to be a
possible indicator for bone mineral density variation of
lumbar spine L2–L4 and Ward�s triangle in both pre-
menopausal and postmenopausal Chinese women
with periodontitis (248). The lipoxygenase gene Alox 15
is shown to be a negative regulator of peak bone mineral
density in mice (111) suggesting future therapeutic
approaches to reduce periodontal disease may impact
osteoporosis. A recent study found that hypergonado-
tropic hypogonadism in men contributed to the pro-
gression of periodontal disease (229). The effect of daily
administration of teriparatide vs. placebo was studied
in conjunction with periodontal regeneration in pa-
tients with severe periodontal disease. Radiographic
linear resolution of osseous defects was significantly
greater after teriparatide therapy than after placebo at
6 months, with a mean linear gain in bone of 29% at
1 year vs. 3% in those receiving placebo (P < 0.001)
(21). A recent review suggested that reduced bone
mineral density is a shared risk factor for periodontitis
rather than a causal factor, but more prospective
studies are required to fully determine what, if any,
relationship truly exists between periodontal disease
and reduced bone mineral density (144).
Bisphosphonates: patientmanagement and their effect onthe periodontium
Thus far, animal studies have shown resistance-
conferring benefits of oral bisphosphonates in
experimentally induced periodontitis models (7, 8, 9,
35, 173, 187, 212, 238, 243). Topical (25, 81, 148, 243)
and systemic (108) alendronate applied during peri-
odontal flap elevation reduced alveolar bone loss in
rats. In contrast, a recent study, in which aggressive
periodontal disease was induced in conjunction with
potent bisphosphonate therapy (zoledronic acid),
121
Osteoporosis and osteopenia: implications for periodontal and implant therapy
induced osteonecrosis of the jaws in rats (5). Recent
studies on rats suggest that alendronate and ⁄ or doxy-
cycline may inhibit the expression of matrix metallo-
proteinase-8, increase the levels of tissue inhibitors of
matrix metalloproteinases in gingiva (37), increase ser-
um osteocalcin and provide slight inhibition of lipo-
polysaccharide-induced alveolar bone resorption (36).
A 2003 systematic review stated that preliminary
data on patients taking bisphosphonates reported
impacts on periodontitis management (186). Human
studies also showed a positive effect of bisphospho-
nates on the progression of periodontal disease (222,
223). Lane et al. (117), in a randomized, double-
masked, placebo-controlled 12-month study, and
Rocha et al. (199), in a controlled, double-masked,
prospective 6-month study, showed that bisphosph-
onate treatment improved the clinical outcome of
nonsurgical periodontal therapy and may be an
appropriate adjunctive treatment to preserve peri-
odontal bone mass. Jeffcoat et al. (97) also showed a
significant gain, over 2 years, in baseline alveolar
bone height in a group with low mandibular bone
mineral density treated weekly with alendronate rel-
ative to a placebo group receiving nonsurgical ther-
apy. Other investigators also showed positive gains
on alveolar bone density and height with weekly
alendronate therapy; however, these gains did not
last for longer than 6 months (65, 198, 200).
Given the potential for bisphosphonate-induced
osteonecrosis of the jaw, the use of bisphosphonates
as an adjunctive treatment for periodontal disease is
not indicated.
Further research on comparisons of long-term
bisphosphonates and the possible effect on the
periodontium and periodontal therapies are war-
ranted. There are no studies evaluating bisphos-
phonate therapy to improve surgical outcomes. In
clinical practice, the therapist should:
• Identify patients at risk for osteoporosis if not
diagnosed.
• Review medications, including length of time on
the medication(s), compliance, method of delivery
and dosages if the patient has been diagnosed with
osteoporosis.
• Evaluate lifestyle (i.e. exercise and diet).
• Explain to the patient the possible impact of
bisphosphonates on periodontal and implant
therapies.
• Institute a comprehensive oral hygiene program.
• Eliminate periodontal ⁄ dental inflammation.
• Consult with the physician if there is a question
regarding recommended periodontal ⁄ implant
treatment and bisphosphonates.
Figure 3 presents an algorithm to help dental
clinicians make the right decisions about how to
manage their patients who are taking bisphospho-
nates, and to provide advice on when to consult with
medical colleagues.
Bisphosphonates: dental implantimplications
There is currently an assumption that osteoporosis
will affect successful integration of dental implants
in the maxilla or mandible, and it is not clear
whether successful implant therapy can be ex-
pected in patients with osteoporosis. There are no
reliable data showing that systemic bone dual-
energy X-ray absorptiometry scans accurately
reflect the bone mineral density of the maxilla or
mandible (96, 235). Becker et al. (22) found no
association between peripheral dual-energy X-ray
absorptiometry scores and the risk of implant
failure. This exploratory study suggested that a
simple visual assessment of bone quality at the site
of implant placement may be more informative
regarding implant failure than peripheral bone
mineral density dual-energy X-ray absorptiometry
(22). In a review by Mombelli et al. (157), data from
17 papers showed low evidence for an association
between osteoporosis and implant failure. Most
published studies are case reports or cross-
sectional, have biased sampling, or used varying
criteria for measuring osteoporosis. However, most
show implant success despite skeletal osteoporosis
(24, 48, 51, 62, 73–76, 82, 132).
Animal studies provide mixed results in this re-
gard. The compact layer of bone in the rabbit tibia
was 28% thicker in controls than in animals in
which osteoporosis had been induced, and this
could potentially affect implant placement (132).
Ovariectomized rats had significant osteoporosis
around implants, but no difference in the extent of
implant–bone contact (175). In rabbits with steroid-
induced osteoporosis, significant correlations were
demonstrated between the bone density of the fe-
mur and the torque required to remove implants
placed in the tibia. However, there was no signifi-
cant difference in the torque required to remove
the implants placed in the mandible, suggesting
that steroid administration, which results in lower
bone mineral density, could have less effect on the
osseointegration of titanium implants in the
mandible than in skeletal bone (77). Most data,
however, do not suggest increased risk of implant
122
Otomo-Corgel
failure as a result of decreased bone mineral
density, although the long-term biomechanical sta-
bility of implants under masticatory forces is as yet
unknown (109).
Only a few studies have evaluated the effect of
hormone replacement therapy or oral bisphospho-
nates on implant success in humans, but most of
these noted minimal complications. Qi et al. (182)
found that estrogen therapy may promote bone
healing around titanium implants. Minsk et al. (153)
showed that hormone therapy did not improve out-
comes of implant therapy, while Moy et al. (159)
indicated that women on hormone replacement
therapy had an increased relative risk for implant
failure of 2.55. August et al. (15) found that post-
menopausal estrogen status could have an impact on
implant healing in the maxilla, but not in the
mandible. A recent animal study showed that
alendronate may prevent the negative influence of
estrogen deficiency on bone healing around titanium
implants (59). Jeffcoat (97) also showed 3-year results
of a single-blind controlled study with oral alendro-
nate or risedronate on implant placement. Implants
were >99% successful in both groups and no
occurrences of osteonecrosis of the jaw were noted. A
recent study showed that estrogen replacement
therapy and alendronate were effective in preventing
bone mass loss around integrated implants in ovari-
ectomized rats (78). Studies with adjunctive systemic
alendronate have also shown reduced vertical bone
resorption postextraction and suppression of free
bone graft resorption in Wistar rats (7–9) and in hu-
man wisdom teeth extraction sites (83).
Currently, many patients may have taken oral bis-
phosphonates for approximately 3 years and hence
may have experienced significant impacts on the
quality of oral and alveolar bone. The clinician must
evaluate the length of the time the patient has been
Intravenous bisphosphonates Oral bisphosphonatesIntravenous bisphosphonate for multiple myeloma, metastatic cancer and/or severe osteoporosis (once a month pamidronate or zoledronic acid)
Thorough oral examination, and consultation with prescribing physician
Prior to initiation of bisphosphonate
�Comprehensive periodontal examination and treatment toachieve optimal periodontal health
�Periodontal therapy needed to enhance control of disease
�Extraction of poor tohopeless teeth with reductionof irregular osseous contours
� Bisphosphonate therapy (ifsystemic conditions permit)should be delayed 14–21 days
� Assess restorative needs: �Removable appliances
should be stable with no rough areas that could traumatize mucosa�Caries control� Complete all invasive dental
procedures�Frequent periodontal/dental
maintenance visits andmonitoring
Bisphosphonate therapy already initiated
Intravenouszoledronic acid 5
mg once a year for up to 2 years
Follow guidelines for oral route
No ONJ
>65 year old woman>2–3 years on oral bisphosphonate History of steroid therapy Other medical risks*
�Non-surgical periodontal therapy�Close periodontal
maintenance�Antimicrobial
mouthrinse and antibiotics as needed�Prevent osseous injury�No extractions�No dental implants�Nonrestorable teeth
require endodontictherapy of theremaining roots�Good oral hygiene
practices
*Medical risksCancerSmokerDialysis
Low hemoglobinDiabetesObesity
Chemotherapeutic agentsHead/neck radiation therapy
>65 year old woman
No steroid therapyNo medical risks*
<65 year old woman<2–3 years on oral bisphosphonate No steroid therapyNo medical risks*
�Consult with prescribing physicianregarding proposed treatment, drug holiday, antibiotic regimen
�Antibiotic therapy � Pain reduction as needed�Antimicrobial mouthrinses�Gentle debridement of loose or
sharp bone segments�Follow Box 2 AAOMS
�Comprehensive periodontal examination � Clear treatment
plan with the physician, if extensive �Initiate treatment in
a single site or sextant to assesshealing potential�Close periodontal
maintenance�Sound oral hygiene
Consultation with prescribing physicianAdvise patients of risks of ONJ
�Comprehensive periodontal examination�Currently, no contraindications to
periodontal or implant therapy�Close periodontal maintenance�Sound oral hygiene practices
ONJ
Follow guidelines in Box 2 (AAOMS Staging and Treatment Strategies for ONJ)
Collaborate with prescribing physician
Close periodontal maintenance with gentle debridement
�Treat periodontal disease/periapical pathoses as soon aspossible�Treat in sextants if
assessing bone healing –nonsurgically if possible�Discuss options to avoid
extractions�Extractions should be
conservative with primary closure �Systemic antibiotics to
avoid risk of infections�Antimicrobial rinses�Sound oral hygiene �Close periodontal
monitoring
NB No validated diagnostictechnique to currently assess increased riskfor developing ONJ
NB Discontinuingbisphosphonates (time-outs) should bethrough the prescribingphysician
ONJ
>2–3 years on oral bisphosphonate
Fig. 3. Decision tree for managing patients who are taking
bisphosphonates. According to the medical and medi-
cation history, the dental clinical treatment can follow
pathways for the dental and periodontal treatment of pa-
tients who are taking bisphosphonates, including the
management requirements if bisphosphonate-induced
osteonecrosis of the jaws is identified. All patients pre-
scribed bisphosphonates should be informed of the risks
and possible effects of the bisphosphonate on oral bone
and treatment outcomes. Discussions should be docu-
mented, the options reviewed and consent obtained for
the elected course of treatment. Please note that this
algorithm does not apply to all patients in all situations.
The clinician must base decisions on their best clinical
judgment for individual patients at the time of treatment.
AAOMS, American Association of Oral & Maxillofacial
Surgeons; ONJ, Osteonecrosis of the jaw.
123
Osteoporosis and osteopenia: implications for periodontal and implant therapy
on an oral bisphosphonate, together with assessment
of case complexity, the patient�s overall systemic
health and risk factors (231). Currently, the American
Association of Oral and Maxillofacial Surgeons rec-
ommends that patients should be informed of the
small risk of compromised bone healing following
implant placement after oral bisphosphonate ther-
apy, especially if the implant is placed within 3 years
of bisphosphonate therapy. The American Associa-
tion of Oral and Maxillofacial Surgeons recommen-
dations for implant placement are (3):
• If the patient has been taking an oral bis-
phosphonate for less than 3 years without any
other clinical risk factors (e.g. steroids, chemo-
therapy, thalidomides, or genetic perturbations)
then no alteration or delay in the planned
implant surgery is necessary. It is important to
note that:
s Informed consent should be provided regarding
possible future implant failure and possible
osteonecrosis of the jaws if the patient continues
taking oral bisphosphonates and
s The prescriber of the oral bisphosphonates
should be contacted to suggest monitoring,
alternate dosing of the bisphosphonates, drug
holidays, or an alternative to the bisphosphonate
therapy.
• If the patient has been taking an oral bisphos-
phonate for less than 3 years and is also taking
concomitant corticosteroids then the prescriber
should be contacted and asked to consider dis-
continuing the oral bisphosphonates for at least
3 months prior to implant placement (or oral ⁄periodontal surgery). If systemic conditions permit,
bisphosphonates should not be restarted until
osseous healing has occurred.
• If the patient has been taking oral bisphosphonates
for more than 3 years, with or without concomitant
corticosteroids, the prescriber should be contacted
to discontinue the bisphosphonates for 3 months
prior to the oral surgery, if systemic conditions
permit. The oral bisphosphonate should not be
restarted until osseous healing is complete.
Note that dental implants are contraindicated in
patients taking monthly intravenous bisphospho-
nates for multiple myeloma, metastatic breast or
prostatic cancer of the bone, severe osteoporosis or
Paget�s disease.
There are many questions yet to be answered with
respect to osteoporosis and dental implants. Cur-
rently, there are no convincing data to contraindicate
dental implant placement in the osteoporotic patient.
However, limited case reports have shown osteone-
crosis of the jaws after implant therapy (23). One
study compared a control group of female patients
with dental implants taking no oral bisphosphonates
with a test group who were taking a bisphosphonate.
The bisphosphonate group had an 86% success rate
vs. a 95% success rate in the group not taking the
medication (105). In contrast, a recent animal study
showed that single-dose zoledronic acid improved
osseointegration in estrogen-deficient rabbits (244). A
second animal study showed that strontium ranelate
increased mechanical fixation of the implant in rats
(134).
Controlled studies are required to assess implant
outcomes in varying bone densities, in people taking
different bisphosphonates, in atrophic alveolar rid-
ges, in two-stage vs. early-loading vs. immediate-
loading situations, and in different implant systems
and implant surfaces. It has been noted that in-
creased function of the mandible 2 years after im-
plant overdentures were placed seemed to cause a
load-related bone formation that minimized, or in
some cases counteracted, the physiologic age-related
bone mineral density loss leading to osteoporosis
(234).
Osteonecrosis of the jaw
Bisphosphonate-induced osteonecrosis of the jaw
(Osteonecrosis of the jaw [ONJ], Bisphosphonate
osteonecrosis [BON], Bisphosphonate-related osteo-
necrosis of the jaw [BRONJ], Antiresorptive osteo-
necrosis of the jaw [ARONJ]) was described by Marx
in 1983 (136). It may, however, be the same disease
that was described in 1899 as an industrial disease
seen in phosphate miners and match factory work-
ers and referred to as phossy jaw (49, 50, 89). This
condition refers to exposure of bone in the mandible
or maxilla persisting for more than 8 weeks in a
patient who has previously, or is currently receiving,
treatment with a bisphosphonate and who has no
history of radiation therapy to the jaws (152).
Osteonecrosis of the jaw originates in the alveolar
bone, but may spread to the basal bone. Early
radiographic findings include sclerosis or loss of the
lamina dura, and ⁄ or widening of the periodontal
ligament space (136).
Osteonecrosis of the jaw is frequently observed in
the jaw as a result of the rapid rate of bone
remodeling. The alveolar crest remodels at 10 times
the rate of the tibia, at five times the rate of the
mandible at the level of the mandibular canal and at
3.5 times the rate of the mandible at the inferior
124
Otomo-Corgel
border (55). Thus, there is a higher uptake and
concentration of bisphosphonates in the alveolar
bone compared with other sites. It appears that
alveolar bone depends more on osteoclastic bone
resorption-remodeling and renewal than any other
bone in the adult skeleton. Sedghizadeh et al. (210)
also see the unique nature of the oral biofilm as a
potential source of osteonecrosis of the jaw. Histo-
pathologic and scanning electron microscopy
examination of osteonecrosis of the jaw vs. osteo-
myelitis specimens revealed that subjects with
osteonecrosis of the jaw had a greater diversity of
bacteria, in addition to fungal organisms not seen in
osteomyelitis of the jaws (210).
Bisphosphonates are used to prevent and reduce
the bone resorption that occurs in metabolic bone
diseases, such as osteoporosis, osteitis deformans
(Paget�s disease), metastatic bone diseases (i.e. mul-
tiple myeloma, metastatic breast cancer, metastatic
prostatic cancer and other metastatic cancers), or
other diseases that can reduce bone mineral density
secondarily (hyperthyroidism and diabetes mellitus).
It has become apparent that the intravenous nitrog-
enous bisphosphonates are implicated in osteone-
crosis of the jaw. Their potent anti-osteoclastic and ⁄or antiresorptive effects occur via inhibition or cell
death of the osteoclast, which resorbs bone and in-
gests the bisphosphonates. They become bound to
the mineral crystals on bone surfaces and, with in-
creased doses, accumulate in the bone matrix. When
bone resorption is inhibited, old bone is not removed
and new osteoid is not formed. The osteocyte that acts
as a mechanoreceptor to maintain the mineral matrix
of the bone outlives normal bone remodeling (44).
The result is hypermineralization or a hypodynamic
bone that has a reduced biomechanical competency.
Some authors warn that prolonged oral bisphospho-
nate use needs to be weighed against such long-term
suppression of bone metabolism (126, 171, 172).
Others say that long-term use may retard fracture
healing, but not affect bone mineralization or bone
mechanics (126). According to Marx, repeated bis-
phosphonate dosing is a �biologic catch-22�, in that
the drug accumulates in bone matrix and can be re-
moved only by osteoclast-mediated resorption as part
of the bone turnover cycle. The problem is that
bisphosphonates are toxic to osteoclasts and prevent
bone turnover. Bisphosphonates are also anti-
angiogenic (150), may be comorbid medications in
immunocompromised patients and may indirectly
modulate the osteoblast–osteoclast balance (122, 205).
Numerous reports in recent years have raised
concern about the serious nature of osteonecrosis of
the jaw (17, 18, 60, 86, 99, 101, 137, 145, 146, 181, 206,
207, 247). A systematic review reported on 368 cases
of osteonecrosis of the jaw. The primary medical
diagnoses were multiple myeloma (162 cases), met-
astatic breast cancer (134 cases) and metastatic
prostatic cancer (23 cases), which together consti-
tuted 91.5% of the reported cases. Over 94% of pa-
tients were taking intravenous zoledronic acid,
pamidronate, or both (240). Sixty per cent of patients
with osteonecrosis of the jaw had received dentoal-
veolar surgery, but 40% of the cases of osteonecrosis
of the jaw appeared spontaneously, often in denture
wearers, in which 39% were associated with exosto-
ses. Osteonecrosis of the jaw was more frequently
located in the mandible (65%) than in the maxilla
(26%) or both the mandible and maxilla (9%). Mul-
tifocal or bilateral involvement was more common in
the maxilla than in the mandible (31% vs. 23%,
respectively). There were 17 cases reported in pa-
tients using oral bisphosphonates. Of those, 15 were
taking alendronate (4.2%), one was taking rise-
dronate (0.3%) and one was taking ibandronate
(0.3%). The most important predisposing factor for
development of osteonecrosis of the jaw was the type
and dose of the bisphosphonates, followed by a his-
tory of trauma, dental surgery or dental infection.
Badros et al. (16) retrospectively reviewed 90 mul-
tiple myeloma patients with osteonecrosis of the jaw
and found it to be time-dependent, with a higher risk
in older multiple myeloma patients after long-term
use of bisphosphonates, often after dental extrac-
tions. Bamias et al. (18) found that the duration of
exposure to bisphosphonates was strongly related to
development of osteonecrosis of the jaw. Those who
developed osteonecrosis of the jaw received a median
of 35 (range, 13–68) infusions of bisphosphonates vs.
15 (range, 6–74) infusions for patients without
osteonecrosis of the jaw. Also the median time for
exposure to bisphosphonates was 39.3 (range, 11–86)
months for patients with osteonecrosis of the jaw
compared with 19 (range, 4–84.7) months for patients
without osteonecrosis of the jaw (18). Note that bis-
phosphonate doses for oncologic purposes are often
12 times higher than doses for treating osteoporosis
(191). It is becoming increasingly evident that the
cumulative dose of the bisphosphonate, its potency,
the stereochemistry of the nitrogen side chain
(monthly intravenous zolendronate and pamidro-
nate), patient�s age, medical status, history of dental
trauma, pre-existing dental disease and other phar-
macologic agents (corticosteroids, cytotoxic drugs
and multimodal antiretroviral therapies) all increase
the risk for osteonecrosis of the jaw.
125
Osteoporosis and osteopenia: implications for periodontal and implant therapy
Clinically, osteonecrosis of the jaw may present as
exposed alveolar bone occurring spontaneously or
after dental surgery. The sites usually are painful,
have soft tissue swelling or ulceration, mobile teeth
and induration with drainage (Fig. 4). Radiographi-
cally, if teeth are present, there may be sclerosis of
the alveolar lamina dura, loss of the alveolar lamina
dura and ⁄ or widening of the periodontal ligament
space, particularly at molars (138).
Intravenous bisphosphonates andosteonecrosis of the jaw:prevention and therapy
Before placing patients on intravenous bisphospho-
nates, the oncologist and dental team need to develop
management protocols similar to those developed by
the radiation therapist ⁄ oncologist before initiation of
full-course irradiation therapy to the head and ⁄ or
neck. Although osteochemonecrosis and osteoradi-
onecrosis are different, because of a lack of blood
supply in the latter, pre-oncologic therapy should be
aggressive in order to prevent postcancer therapy
sequelae. However, once intravenous bisphospho-
nates have been given to the patient, it is imperative
that meticulous monitoring and home care are
implemented and that periodontal maintenance is
provided at frequent intervals. Surgical therapy
should be avoided if possible. Even extractions should
ideally not be performed unless teeth are extremely
mobile (12) or there is spreading infection that cannot
be controlled by conservative therapy. However,
Adornato et al. (2) have reported successful treatment
of osteonecrosis of the jaw with bone resection and
autologous platelet-derived growth factors. A recent
review states that laser application at low intensity
may improve the reparative osteonecrosis of the jaw
process and can be used for conservative surgery,
whereby necrotic bone is vaporized until healthy
bone is reached (232). Ozone therapy was also
discussed for treatment of osteonecrosis of the jaw
during and after oral surgery to stimulate cell prolif-
eration and soft tissue healing. Marx et al. (138) rec-
ommends the treatments in Box 1 for therapy with
intravenous bisphosphonates specific to the stage of
osteonecrosis, in which effective control to a pain-free
state without resolution of the exposed bone was
90.1%. The American Association of Oral and Maxil-
lofacial Surgeons has revised their �Staging and
Treatment Strategies� for osteonecrosis of the jaw, as
shown in Box 2 (12).
Medical researchers have been actively engaged in
trying to identify ways to manage the sequelae of
osteonecrosis of the jaw (69, 91, 102, 110, 197). A re-
cent consensus statement recommended that intra-
venous bisphosphonates should be discontinued after
2 years of therapy for multiple myeloma patients who
achieve a complete response and ⁄ or plateau. If their
disease is still active, they have not achieved a re-
sponse, or have threatening bone disease beyond
2 years of therapy, the frequency of treatment can be
decreased to every 3 months. The consensus state-
ment recommended dental evaluation, good dental
hygiene, attention to reducing periodontal and peri-
apical infections, extracting teeth as necessary, but
withholding bisphosphonate treatment for at least
1 month before the procedure, and resuming treat-
ment when the patient has fully recovered and the
wound fully healed (116). It was recently noted that
surgery is more successful in patients with osteopo-
rosis or multiple myeloma than in those with solid
tumors, and that discontinuation of bisphosphonate
therapy favored the surgical outcome (242).
A B C
Fig. 4. Bisphosphonate-induced osteonecrosis of the jaw
in a 73-year-old woman with multiple myeloma, type II
diabetes, myocardial infarction and total hip replace-
ment. The patient had been taking intravenous zolendr-
onate for 1 year, and there was a history of extraction
1 year before this clinical presentation of bisphospho-
nate-induced osteonecrosis of the jaw. (A) Clinical
appearance. (B) Radiographic appearance. (C) Surgical
exposure to reveal the extensive necrosis and alveolar
bone defect.
126
Otomo-Corgel
Oral bisphosphonates andosteonecrosis of the jaw:prevention and therapy
Most osteoporotic patients who present in dental
practice are taking oral bisphosphonates, such as
alendronate, risedronate or ibandronate (as opposed to
an intravenous infusion of zolendronate or pamidro-
nate). Recently, intravenous zoledronate, 5 mg once a
year for 2 years, has increased in use as a result of ease
of compliance. It is now 18 years since alendronate
(Fosamax�) was approved by the US Food and Drug
Administration, 8 years since risedronate (Actonel�)
was approved and just 3 years since ibandronate
(Boniva�) was approved. Currently, alendronate poses
a higher risk for osteonecrosis of the jaw than risedr-
onate as a result of the numbers of patients who have
been prescribed alendronate over the years, whereas
ibandronate has been available only for a short period
of time. Some alternatives to bisphosphonates may not
be a safe option in light of new reports of osteonecrosis
of the jaw in patients taking denosumab (4).
Patients with, or at high risk of, osteopenia should
be counseled regarding the importance of weight-
bearing exercise, dietary vitamin D, calcium and
Box 1. Recommendations fordental treatment of patientsreceiving intravenousbisphosphonates (monthly),specific to the stage ofosteonecrosis
Stage 0 – Patients at risk (osteoclast
hypocellularity, apoptosis with a reduction in
endosteal osteoblasts and their osteoid
production) (12)
• Eliminate existing inflammatory dental
pathologies
• Withhold intravenous bisphosphonate ther-
apy for 2–3 months, if systemic conditions
permit, to allow dental providers to obtain
optimum dental health:
s Remove abscessed, nonrestorable or peri-
odontally unsalvageable teeth
s Perform caries control, restorative, root canal
and periodontal therapy (including peri-
odontal surgery)
s Provide fixed or removable partial dentures
s Leave impacted teeth undisturbed unless they
have oral communication
s Leave small single tori undisturbed; remove
large, multilobular lingual tori and large
midline palatal tori
s Prophylactic antibiotic coverage is recom-
mended for invasive dental procedures in
cancer patients
Stages 1a and 1b (Stage 1a, bone exposure
<1 cm and painless; Stage 1b, largest area of
exposure is >1 cm and painless)
Asymptomatic exposed bone requires either
no treatment or maintenance with a 0.12%
chlorhexidine oral rinse three times daily
Stages 2a, 2b and 3a (Stage 2a, a single ex-
posed area of bone measures <2 cm and is
accompanied by pain and ⁄ or clinical infection;
Stage 2b, exposure area is >2 cm; and Stage 3a,
exposed bone >3 cm in area or showing sig-
nificant osteolysis or an orocutaneous fistula)
These scenarios require an antibiotic regimen
and 0.12% chlorhexidine rinses administered
through one of three regimens:
• Rinse three times daily, plus penicillin VK
500 mg four times per day ongoing
• Rinse three times daily, plus penicillin VK
500 mg four times per day until pain is con-
trolled (for those concerned about long-term
penicillin problems)
• Rinse three times daily plus an alternative to
penicillin because of allergy or nonrespon-
siveness: doxycycline 100 mg once daily,
levofloxacin 500 mg once daily or erythro-
mycin ethylsuccinate 400 mg three times
daily
Note: metronidazole 500 mg three times daily
in addition to penicillin, doxycycline or levo-
floxacin has been shown to control pain and
infection in cases refractory to any of the anti-
biotics alone, but is recommended for only
10 days on an intermittent basis because of
toxicity
Stage 3b (Stage 3a plus a pathologic fracture)
The clinician may duplicate Stage 3a, but to
choose a more interventional approach: alveo-
lar resection or a continuity resection may be
performed. Titanium reconstruction plates
should not be placed immediately and deferred
until 3 months or when infection is resolved
127
Osteoporosis and osteopenia: implications for periodontal and implant therapy
magnesium, and therapies to improve the balance of
the body, before taking oral bisphosphonates. The
medical histories taken by clinicians should include
questions on lactose intolerance, hormone replace-
ment therapy, hysterectomy (date of), menstrual
history, menopause (at what age and if hormone
replacement therapy was prescribed), medications
that alter the calcium balance (especially corticos-
teroids or chemotherapy), diet and exercise ⁄ balance
histories. If a patient is taking oral bisphosphonates,
they need to be questioned regarding the type of
bisphosphonate, length of time they have been taking
it, compliance and side effects. There are many new
therapies available that may be better alternatives to
fit the individual patient to their individual needs at
that particular time, but current data do support oral
bisphosphonates as being effective in preventing hip
and spine fractures.
The risks for osteonecrosis of the jaw when the
patient is taking oral bisphosphonates have been
reported to be as low as 0.7 ⁄ 100,000 (202) and as
high as 4% (211). However, a new study by Barasch
et al. (19) found that oral bisphosphonates were a
potent risk factor for osteonecrosis of the jaw with
an odds ratio of 12.2 (95% CI: 4.3–35.0).
Currently, there are no clear guidelines to
determine precisely which patients on oral
bisphosphonates are at risk for osteonecrosis (a
variety of guidance documents and Web resources
are indicated in Box 3). There are recommendations
indicating increased risk of osteonecrosis of the jaw
in patients treated with oral bisphosphonates for
Box 2 American Association of Oral and Maxillofacial Surgeons staging and treatment strategies for manage-ment of osteonecrosis of the jaw
BRONJ* Staging Treatment strategies�
At-risk category: No apparent necrotic bone in patients
who have been treated with either oral or intravenous
bisphosphonates
• No treatment indicated
• Patient education
Stage 0: No clinical evidence of necrotic bone, but
nonspecific clinical findings and symptoms
• Systemic management, including the use of pain
medication and antibiotics
Stage 1: Exposed and necrotic bone in patients who are
asymptomatic and have no evidence of infection• Antibacterial mouth rinse
• Clinical follow-up on a quarterly basis
• Patient education and review of indications for
continued bisphosphonate therapy
Stage 2: Exposed and necrotic bone associated with infection
as evidenced by pain and erythema in the region of the ex-
posed bone with or without purulent drainage
• Symptomatic treatment with oral antibiotics
• Oral antibacterial mouth rinse
• Pain control
• Superficial debridement to relieve soft tissue irrita-
tion
Stage 3: Exposed and necrotic bone in patients with pain,
infection and one or more of the following: exposed and
necrotic bone extending beyond the region of alveolar bone
(i.e. inferior border and ramus in the mandible, maxillary
sinus and zygoma in the maxilla) resulting in pathologic
fracture, extra-oral fistula, oral antral ⁄ oral nasal communi-
cation, or osteolysis extending to the inferior border of the
mandible or sinus floor
• Antibacterial mouth rinse
• Antibiotic therapy and pain control
• Surgical debridement ⁄ resection for longer term
palliation of infection and pain
*Exposed bone in the maxillofacial region without resolution in 8–12 weeks in persons treated with a bisphosphonate who have not received radiationtherapy to the jaws.�Regardless of the disease stage, mobile segments of bony sequestrum should be removed without exposing uninvolved bone. The extraction of symp-tomatic teeth within exposed, necrotic bone should be considered because it is unlikely that the extraction will exacerbate the established necrotic process.Discontinuation of the intravenous bisphosphonates shows no short-term benefit. However, if systemic conditions permit, long-term discontinuation maybe beneficial in stabilizing established sites of bisphosphonate-related osteonecrosis of the jaw, reducing the risk of new site development and reducingclinical symptoms. The risks and benefits of continuing bisphosphonate therapy should be made only by the treating oncologist in consultation with theOral Maxillofacial surgeon and the patient. Discontinuation of oral bisphosphonate therapy in patients with bisphosphonate-related osteonecrosis of thejaw has been associated with gradual improvement in clinical disease. Discontinuation of oral bisphosphonates for 6–12 months may result in eitherspontaneous sequestration or resolution following debridement surgery. If systemic conditions permit, modification or cessation of oral bisphosphonatetherapy should be performed in consultation with the treating physician and the patient.
128
Otomo-Corgel
2–3 years or longer with concomitant use of steroids
(138). In one study, patients on oral bisphosphonates
had increased complications and incidence if they
were taking them for longer than 3 years (139). A
recent study indicated risk within 2 years of bis-
phosphonate initiation that increased four-fold after
2 years (19). This study also found that suppuration,
dental extractions, steroid use and head ⁄ neck radi-
ation significantly increased the risk for osteonecrosis
of the jaw. Patients with periodontal disease and
dental abscesses are also at higher risk. Migliorati�sstudy indicated that 84% of patients with osteone-
crosis of the jaw also had periodontal disease
(151). Marx proposed the potential of an indicator of
bone turnover, C-terminal cross-linking telopeptide,
to measure higher risk after 3 years on oral
bisphosphonates; however, the American Dental
Association Report of the Council on Scientific Affairs
concluded �the current screening and diagnostic tests
are unreliable for predicting a patient�s risk of
developing osteonecrosis of the jaw� (63).
Owing to the aforementioned risk factors, the
clinician should work closely with their medical
colleagues before prescribing oral bisphosphonates.
Ideally, optimal periodontal ⁄ dental health state
should be established before the patient com-
mences bisphosphonate therapy. This involves clo-
sely evaluating radiographs, extracting teeth with a
hopeless prognosis, removal of multilocular tori,
appropriate periodontal therapy, root canal therapy
and provision of necessary restorative treatment.
Also, the patient should be informed of the risks
associated with 2–3 years or longer of continuous
oral bisphosphonate therapy. Finally, the treating
physician should be updated regarding the patient�soral status.
If the patient has already been on an oral bis-
phosphonate, there is minimal risk of osteonecrosis
of the jaw if they have been taking the medication
for less than 2–3 years, there are no medical risk
factors and they have no dental problems. One
source has stated that it is safe to proceed with
periodontal and oral surgical procedures as needed
(138). The latter did not, however, differentiate be-
tween length of time of treatment with the oral
bisphosphonates. It has also been recommended
that patients with active periodontitis should receive
�appropriate forms of non-surgical therapy which
should be combined with a prolonged phase of
initial therapy for observation… if the disease does
not resolve, surgical treatment should be aimed
primarily at obtaining access to root surfaces with
modest bone recontouring being considered and
necessary� (63). There are no data on the risk of
osteonecrosis of the jaw with periodontal regenera-
tive therapy. With regard to implants, there is con-
sensus that the recommendations are to obtain
documented consent from the patient after review-
ing the risks, benefits and treatment alternatives.
There are no clear data to guide the clinician
Box 3. Guidance documents andweb resources for clinicians toseek information relating tomanagement of dental patientswho are taking bisphosphonates
• American Academy of Endodontists Position
Statement �Endodontic Implications of
Bisphosphonate-Associated Osteonecrosis of
the Jaws� 2006 http://www.aae.org/dentalpro/
guidelines.htm (10)
• Ruggiero et al. (206), Practical Guidelines for the
Prevention, Diagnosis, and Treatment of
Osteonecrosis of the Jaw in Patients with
Cancer, 2006.
• American Society of Clinical Oncologists (13).
Updated Recommendations for the Prevention,
Diagnosis, and Treatment of Osteonecrosis of
the Jaw in Cancer Patients, 2006.
• Migliorati et al. (151), Managing the care of pa-
tients with bisphosphonate-associated osteone-
crosis. An Academy of Oral Medicine position
paper, 2005.
• American Academy of Periodontology State-
ment on Bisphosphonates http://www.perio.
org/resources-products/bisphosphonates.htm
(11)
• American Dental Association Report of the
Council on Scientific Affairs – Expert Panel
Recommendations: Dental Management of Pa-
tients on Oral Bisphosphonate Therapy, 2008
(63)
• American Association of Oral and Maxillofacial
Surgeons – Position Paper on Bisphosphonate-
Related Osteonecrosis of the Jaws – 2009 Update
(12)
• Canadian Consensus Practice Guidelines for
Bisphosphonate Associated Necrosis of the Jaw,
2008 (102).
• National Institutes of Health Consensus Devel-
opment Panel on Osteoporosis Prevention,
Diagnosis, and Therapy, 2001 (165).
129
Osteoporosis and osteopenia: implications for periodontal and implant therapy
regarding the impact of oral bisphosphonate therapy
on implant placement and occurrence of osteone-
crosis of the jaw. Two recent studies found that oral
bisphosphonate therapy did not alter implant out-
comes and there were no reported cases of osteo-
necrosis of the jaw (82, 133). The American Dental
Association states that the risk for osteonecrosis of
the jaw increases when augmentation of atrophic
ridges or extensive implant placements are per-
formed (63). Patients with implants and receiving
therapy with oral bisphosphonates should be mon-
itored and maintained closely.
If the patient has been taking oral bisphosphonates
for longer than 3 years, the treating physician should
be contacted. The physician needs to be informed of
the patient�s periodontal ⁄ dental status and of the
dental treatment plan. If a surgical procedure is war-
ranted, current American Association of Oral and
Maxillofacial Surgeons recommendations are that the
patient discontinues the oral bisphosphonates for
3 months before the procedure. However, this is
controversial and the American Dental Association,
states �discontinuing bisphosphonate therapy may
not eliminate any risk for developing osteonecrosis of
the jaw� (63). �Drug holidays� have been recommended
following a 10-year alendronate study, indicating that
stopping the medication after 3 years diminished
bone mineral density minimally, had no increase in
fractures, and improved bone remodeling (30). Bio-
chemical markers of bone turnover may be used to
complement measurement of bone mineral density;
however, their clinical utility is limited. Current
markers of bone resorption include serum collagen
type 1 cross-linked telopeptide, cross-linked N-
telopeptides of type I collagen, and pyridinoline
cross-linked carboxy-terminal telopeptide of type I
collagen. There are also biochemical markers of bone
formation, such as specific-alkaline phosphatase,
osteocalcin and procollagen type I N- and C-pro-
peptides (227). Urinary cross-linked N-telopeptides of
type I collagen and serum pyridinoline cross-linked
carboxy-terminal telopeptide of type I collagen cor-
relate with risk for skeletal complications, disease
progression and overall survival. Rosen et al. identi-
fied serum CTX as a marker of bone resorption that
was useful specifically to assess the efficacy of anti-
resorptive treatments (203). Marx recommended that
a test for collagen type 1 cross-linked telopeptide
should be performed at the initial consultation and
immediately before performing a procedure (138).
Therefore, serum collagen type 1 cross-linked
telopeptide might provide the clinician with infor-
mation regarding bone suppression and risk of
osteonecrosis of the jaw (Table 7). His recommenda-
tion is therefore:
• Take a baseline initial serum measurement of
collagen type 1 cross-linked telopeptide.
If it is less than 150 pg ⁄ ml, consult with the
medical doctor.
Recommend to discontinue the oral bisphospho-
nate for 3 months with the consent of the pre-
scribing physician.
If the patient has severe osteoporosis, the physician
may elect to prescribe an alternative drug (see
Table 4).
• Repeat the measurement of serum collagen type 1
cross-linked telopeptide in 3 months.
If the level of serum collagen type 1 cross-linked
telopeptide is ‡150 pg ⁄ ml, it is permissible to
proceed with dental procedures.
• Restart the oral bisphosphonate 3 months after the
procedures.
For each month in which the patient is not taking the
oral bisphosphonate, the collagen type 1 cross-linked
telopeptide value will increase by approximately
25 pg ⁄ ml.
The American Dental Association and others,
however, indicate that the collagen type 1 cross-
linked telopeptide may be of questionable value and
is not based on strong clinical evidence (63, 113).
If a patient has established oral bisphosphonate-
induced osteonecrosis of the jaw, the treating physi-
cian should be contacted. The medication should be
discontinued and it is recommended that the pre-
scribing physician should provide an alternative
medication. There is also an opinion that discon-
tinuing the bisphosphonate should not be recom-
mended once necrosis of the jaws has occurred (122);
however, this was based on four case reports. If the
physician elects to not prescribe a substitute drug,
stringent periodontal maintenance and monitoring is
necessary. Oral bisphosphonate-induced osteone-
crosis of the jaw has been reported to be less exten-
sive and more responsive to discontinuation of the
medication without debridement. Marx states that
Table 7. Laboratory risk assessment for patients takingoral bisphosphonates
Telopeptide CTX
(pg ⁄ ml)
Risk for osteonecrosis
of the jaw
300–600 None
150–299 None or minimal
101–149 Moderate
<100 High
130
Otomo-Corgel
approximately 60% of patients will have recovering
osteoclasts that will resorb bone around the necrotic
area in order to sequestrate it from adjacent viable
bone within 6 months to 1 year. The 40% that do
not sequestrate will require surgical debridement,
including extraction of teeth in necrotic sites with
alveolar resection and primary closure (138). He also
states that the remaining bone should be viable and
restored with nonimplant-supported appliances;
however, if an alternative osteoporosis drug is pre-
scribed, bone augmentation and implants are viable.
It is imperative that dental clinicians treat these
patients in partnership with medical professionals.
Patients need to be aware of the risks vs. benefits of
the procedures. Recently, case reports indicate heal-
ing of osteonecrosis of the jaw after therapy with
teriparatide after other treatments have failed (118,
162). Clinical trials are urgently needed to evaluate
the most effective treatment protocols for patients
with different stages of osteonecrosis of the jaw.
Cases of oral bisphosphonate-induced osteonecro-
sis of the jaw are seldom reported, so it may appear to
be a rare occurrence. A randomized clinical trial may
not have adequate numbers of cases of osteonecrosis
of the jaw or the drug may have been taken for too short
a duration to present adverse effects. A database
should be developed for clinicians to easily report
cases, citing the type of bisphosphonate, duration of
use, compliance, medical history and nature of the
reported osteonecrosis of the jaw. Currently, it is
imperative that clinicians report cases of osteonecrosis
of the jaw to the US Food and Drug Administration at
http://www.fda.gov/MedwWatch/report.htm.
Conclusion
Clinical periodontal and implant therapy in the
osteoporotic ⁄ osteopenic patient provide new chal-
lenges. The numbers of patients with low bone
mineral density and the numbers of patients who are
taking bisphosphonates for long periods of time are
rising dramatically. As the treatment of osteoporosis
evolves, we need to present options to our patients
and to recognize the impact of osteoporosis ⁄ oste-
openia on our clinical therapy. Decisions regarding
periodontal treatment and implant placement in
patients taking bisphosphonates depend on a host of
variables: length of time on the drug, patient age, type
of drug, dosage, dosing (continuous or intermittent),
compliance, oral vs. intravenous delivery, dental ⁄periodontal status and overall systemic health. With
the development of alternative medications to oral
bisphosphonates, we must monitor other potential
oral side effects. We must stay current with medical
technologies that enhance earlier diagnostics to
prevent or treat complications. The clinician needs to
understand the mechanisms of actions of the various
therapies. Periodontal therapy, augmentation and
placement of dental implants are still viable options
for the clinician predicated on best clinical judg-
ment for that individual patient. Preventive care,
especially oral hygiene reinforcement, monitoring
and periodontal maintenance therapy, is of para-
mount importance.
Periodontal professionals can potentially play a
pivotal role in the early detection of osteoporosis via
diagnostic tests (e.g. radiographs), clinical monitor-
ing and continual updating of patient risk. With the
advent of genomic, experimental, mechanistic and
clinical trials we must continually interpret the data
in the context of the healthcare needs of our patients
at a given time. There is no single therapy that is safe
and effective for all people and therefore it is vital
that data from population-based studies do not get
�lost in translation� when applied to individuals (121).
Because osteoporotic patients are at higher risk for
periodontal disease and patients with periodontitis
are at higher risk for osteonecrosis of the jaw, peri-
odontal intervention and disease prevention are
imperative. Close periodontal maintenance, meticu-
lous monitoring, understanding of periodontal and
implant therapy for the individual patient at a given
time and collaboration with medical professionals
will provide patients with the highest level of care.
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