Keywords
osteoporosis - apical periodontitis - corticosteroids - bisphosphonates - bone resorption
- calcitonin - raloxifene - alendronate - zoledronate
Osteoporosis
Osteoporosis is a disease characterized by reduced bone mass and disruption of bone
microarchitecture. Bone strength is compromised and the risk of fractures is increased.
Osteoporosis is the most common bone disease in humans and represents a significant
public health problem. Although it affects a large number of patients of both sexes
and all races, it is more common among Caucasians, women, and the elderly. It is a
silent disease until fractures occur.[1]
When examining the bone density of patients aged 50 and over, the incidence of osteoporosis
increases with age: from 3 to 4% to 30% in 80-year-old patients.[2]
[3] In a 2021 study, about 18% of the world's population is reported to be affected
by this disease (23% women and 12% men).[4]
The main indicator of the presence of osteoporosis accepted by the World Health Organization
is BMD (bone mineral density). It is measured using X-rays by determining the amount
of mineral structures absorbing the X-rays. Values equal to or above −1 are considered
normal. With values from −1 to −2.5, the patient has reduced bone density, and below
−2.5 a diagnosis of osteoporosis is made.[5]
Thinned bone trabeculae with defects and wide intertrabecular spaces are seen in patients
with osteoporosis ([Fig. 1]). Osteoporosis is classified as primary and secondary. Primary osteoporosis is type
1 and type 2. Type 1 is known as postmenstrual osteoporosis, caused by estrogen deficiency,
mainly affecting trabecular bone. This is the reason why women are more often affected
than men. Type 2 is senile osteoporosis. In it, the loss of bone mass is due to the
aging of the cortical and trabecular bone structures. Secondary osteoporosis is the
result of diseases, medication or sudden lifestyle changes.[6]
[7]
[8]
Fig. 1 Difference in cancellous bone: in the first photo (left)—Thinned bone trabeculae
with defects and wide intertrabecular spaces are seen in patients with osteoporosis.
In the second photo (on the right)—normal cancellous bone (courtesy of the BMJ Publishing
Group Ltd).[6]
Osteoporosis demonstrates several stages: 1. Osteopenia (decreased bone density);
2. Incipient osteoporosis with risk of fractures; 3. Pronounced osteoporosis with
occurring fractures (most often at the femoral neck, vertebrae, and wrists).
A family history of such a fracture is considered a risk factor for osteoporosis.
Fractures of the hip, wrists, and spine can also be included here.[9] Fractures can also be due to other risk factors, even with normal levels of bone
density, most notably the age of the patient.[10]
The dentist may detect reduced bone density during an X-ray examination and this may
be a reason to refer the patient for a consultation regarding suspected osteoporosis.
This is usually done during orthopantomographic imaging. In the reading, attention
is directed to the intensity of the shadow of the mandibular cortex relative to that
of the trabecular bone. The area below the foramen mentalae is most suitable, due
to the lack of muscles or muscle connections, and the fact that the distance between
the foramen and the lower edge of the cortex remains constant, regardless of life
expectancy and resorption of alveolar bone.[11]
The loss of BMD in various sites of the body, including the mandible, is the main
sign of osteoporosis. Thus, the computer-aided diagnosis system is developed for bone
density assessment and patients were classified into normal, osteopenia, and osteoporosis
groups using a digital panoramic radiograph. A computer-aided system can be used for
osteoporosis and osteopenia assessment by measuring the mandibular cortical width
and texture on dental panoramic radiographs with the average system accuracy of 89.52%.[12]
Osteoporosis can be associated with diseases of the oral cavity. Most often, the dentist
encounters patients who report the presence of primary osteoporosis, especially when
treating postmenopausal women.
Apical Periodontitis
Apical periodontitis is a common inflammatory disease of the periodontium that affects
a wide range of population all over the world. It is known that periodontitis is a
host-mediated process, which includes both periodontal tissue destruction and bone
resorption.
In periodontitis, the pathogen releases chemicals that activate the white cells of
the innate immune system to produce proinflammatory cytokines that play a vital role
in the progression process of periodontitis. Moreover, these pathogens can activate
the acquired immune system that in turn contributes to more and more progression of
the inflammatory condition. As the immune response continues, released cytokines and
chemokines can cause severe damage to the gingiva, periodontal ligaments, and alveolar
bone. This causes permanent alveolar bone damage. Cytokines play a vital role in the
inflammatory process of periodontitis such as interleukin-1β (IL-1β), IL-6, tumor
necrosis factor-α (TNF-α), and receptor activator of nuclear factor kappa-Β ligand
(RANKL).[13]
Apical Periodontitis and Osteoporosis Pathology
Apical Periodontitis and Osteoporosis Pathology
Low Estrogen Levels
Osteoblasts, osteoclasts, and osteocytes have estrogen receptors (ERs). When binding
to them, the production of proteins is regulated. On the other hand, estrogen and
steroid hormones affect the body's immune response.
Brasil et al investigated the influence of estrogen on the development of periodontitis
in experimental mice over a long period. The mice were initially ovariectomized and
allowed 120 days to reach low estrogen levels. This is followed by pulp exposure of
first molars to induce periodontitis. The results showed significantly larger periapical
lesions compared to the control group. Serum calcium concentration was similar in
both groups. Alkaline phosphatase was higher compared to the control group, but without
statistically significant differences.[14]
Receptor Activator of Nuclear Factor Kappa-Β Ligand
Estrogen decreases receptor activator of nuclear factor-κβ ligand (RANKL) levels and
increases osteoprotegerin, thereby decreasing osteoclast activity. Furthermore, estrogen
reduces osteoclast differentiation and facilitates osteoclast apoptosis via transforming
growth factor-beta. The hormone also affects osteocytes. Without it, they cannot respond
normally to mechanical pressure from periodontal inflammation. Osteocytes can also
synthesize RANKL. At low estrogen levels, IL-7, T-cells, and B-cells of the immune
system are also activated, which help bone resorption.[15]
Zhang et al investigated how osteoprotegerin levels affect periapical lesions. Mice
with low estrogen levels and artificially induced periodontitis were used. The authors
found that more significant bone involvement was observed with increased RANKL expression
as a consequence of estrogen deficiency. In parallel, an increase in osteoprotegerin
was also observed, as a counter-protective reaction.[16]
[17]
[18]
Similar were the results of Ikeda et al: Anti-RANKL antibody reduced the number of
osteoclasts in periapical tissues.[19] A lack of estrogen receptor alpha (ERα)-mediated suppression of RANKL expression
was observed in increased bone resorption.[20]
RANKL levels also depend on the patient's psychological state. This should also be
taken into account in patients with osteoporosis.[21]
NLRP3/Caspase-1/IL-1β Cascade
Levels of substances involved in the NLRP3/Caspase-1/IL-1β cascade are increased in
affected tissues of patients with reduced estrogen levels, in contrast to patients
with normal levels. Similar data have been obtained in animal studies. Nod-like receptors
(NLR) play an important role in autoimmune and inflammatory diseases. There are 22
types, 14 of which are NLRP (nucleotide-binding domain and leucine-rich rep protein).
Of these, 5 subtypes (NLRP1, NLRP3, NLRP6, NLRP7, and NLRC4) are involved in the formation
of IL-1β, with NLRP3 being the most important.[22] It can be activated by various stimuli, such as bacterial peptidoglycans, lipopolysaccharides,
endogenous proteins of damaged cells, and others.
Upon activation, it forms an oligoprotein with apoptosis-associated proteins and procaspase-1,
which in turn activates the caspase-1 cascade. As a result, the inflammatory cytokines
(interleukins), IL-18 and IL-1β, are formed.
Various factors can affect IL-1β levels: genetics, systemic diseases, intake of herbal
extracts. IL-1β +3954 gene polymorphism is associated with periodontitis and is expected
to be among the several causes of respective pathology.[23]
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can trigger
a profound cytokine response in the host, often referred to as a “cytokine storm”
that is exhibited as elevated serum levels of TNF-α and IL-1β with higher levels in
those who are critically ill.[24] Centella asiatica is one of the plants that is widely known as medicinal herb. The
extract of it has the effect of reducing the proinflammatory cytokine IL-1β via inhibiting
NF-κB.[25]
TNF and IL-1β levels are the two main indicators by which inflammation can be determined
in apical periodontitis.[26] The levels of IL-1β in the unstimulated saliva are also higher in patients with
periodontitis compared with the healthy control and gingivitis group.[27] This indicates that this IL-1β is an important element of the inflammatory process
in apical periodontitis.
Cascade of reactions leads to bone resorption as a consequence of the inflammation
caused by apical periodontitis.[28]
[29] When studying estrogen-deficient rats, it was found that this cascade of reactions
was activated to a greater extent.[30]
In support of this theory is a study on 50 experimental mice, the ovaries of half
of them were removed, and the pulp of their first molar was exposed. As early as the
first week, serum estrogen levels drop significantly, and osteoclast levels in the
bones increase. NLRP3/Caspase-1/IL-1β levels were also increased in the low estrogen
mice. The authors believe that pharmacological suppression of NLR signaling may be
beneficial in the treatment of inflammatory diseases in menopausal women.[31]
Matrix Metalloproteinases and Cathepsin K
Romualdo et al investigated the levels of proinflammatory cytokines MMPs (matrix metalloproteinases)
and cathepsin K in periodontitis of ovariectomized mice. The results showed increased
levels of IL-1β, TNF-α IL-6, MMP-8 and MMP-13 compared to the control group.[32] Bahuguna et al also noted a role for cathepsin K in osteoclastic bone resorption.
It is inhibited by odanacatib, a drug used to treat osteoporosis. In patients on such
therapy, endodontic treatment can be performed with normal bone regeneration around
the apex.[27]
[33]
Certain molecules like cathepsin, found at a high level in periodontal tissues, particularly
in patients with periodontitis, are involved in the mechanism of entry of SARS-CoV-2
into cells. Periodontopathic bacteria could also play a direct role in the mechanism
of entry of SARS-CoV-2 by cleaving the S-protein, and the cytokines produced during
periodontitis could add to the cytokine storm found in the severe forms of coronavirus
disease 2019.[34] In this way, ARS-CoV-2 can affect patients with osteoporosis and apical periodontitis.
Age and Postmenopausal Period
Age and Postmenopausal Period
Guan et al investigated the mechanism of estrogen action on periapical changes. They
observed the periapical tissues after extraction of teeth with periodontitis in 30
women, half under 35 years of age, and the other half over 58 years of age. Women
with immune diseases, diabetes, and other endocrine diseases were not included. After
extraction, the tissues were processed and subjected to immuno-histo-chemical analysis.
The levels of NLRP3, caspase-1, and IL-1β of postmenopausal women were significantly
higher than those of other women. The levels of the precursor proCaspase-1 were also
increased, and the authors believe that its conversion to caspase-1 is regulated by
estrogen.[31]
Lucisano et al note that in patients with reduced estrogen levels, the microbiota
also changes, leading to a more significant progression of periapical lesions.[35] Therefore, in patients with osteoporosis as a result of the onset of menopause and
the need for the treatment of periapical lesions, the change in the composition and
quantity of microorganisms in the lesions should be taken into account.
Rossetti et al analyzed the publications related to periapical changes in postmenstrual
osteoporosis and how it affects the development of periapical lesions. All 12 studies
that the authors analyzed confirm the fact that low estrogen levels favor the development
of periodontitis. More than half of them is based on histomorphological analysis of
bone loss in the studied area. In five of them, the radiographic image was analyzed.
Microcomputed tomography was used in three patients, fluorescence microscopy in two,
and radiographic density assessment in one patient. Every single study emphasizes
that at low levels of estrogen, bone resorption increases compared to the control
group. The explanation is related to various proinflammatory cytokines, such as IL-1,
IL-6 and TNF-α.[36]
[37]
In a study by López-López et al, it was found that 25% of postmenopausal women with
osteoporosis had at least one periapical lesion, compared to 7.4% in the nonosteoporotic
group. A statistically significant relationship was found between bone density and
the frequency of periapical lesions.[38]
In a study by Duncea et al, 97 postmenopausal women were included, dividing them into
two groups: with and without osteoporosis, focusing on bone density of L1-L4 vertebrae,
femur, and mandible. The results demonstrate that in patients with osteoporosis, the
risk of periapical lesions is six times greater. Its size increases as the patient's
bone density decreases.[39]
Medication
Taking various medications in connection with osteoporosis can have an impact on the
development of periapical processes.
Corticosteroids
Corticosteroids can suppress osteoblast functions. However, there is still uncertainty
about the exact mechanism of action. They affect calcium absorption, inhibit osteoblast
protein production, osteoblast apoptosis, and prolong the life of osteocytes. They
also affect the expression of RANK and osteoprotegerin and IL-6, as well as other
cytokines leading to bone resorption. Glucocorticosteroid-induced osteoporosis is
thought to occur in 0.5 to 1% of the general population, depending on the doses that
are used. The most significant bone loss was observed after the sixth month of admission.[15]
Bisphosphonates
Means of choice for prevention and treatment are bisphosphonates—alendronate, zolendronate
(ZOA), risedronate, and ibandronate. A study by Hsiao et al confirmed that bisphosphonates
can affect healing of the periapical lesion, both in primary endodontic treatment
and in retreatment.[40] Sampaio et al consider that their action supports the healing process during endodontic
treatment.[41]
Bisphosphonate intake was associated with significantly fewer periapical lesions among
patients with osteoporosis. Bisphosphonates suppress bone resorption by interfering
with the internal cellular enzyme system of osteoclasts.[42] In a study by Katz and Rotstein of 42,292 patients with osteoporosis, 754 were found
to have periapical lesions (1.78%). The percentage of patients with periapical changes
averaged 0.52% and was more than three times lower. The data also showed statistically
significant differences between patients with and without osteoporosis. When osteoporosis
is also associated with bisphosphonate intake, the percentage of patients with periapical
lesions is lower. The type of medication is also important. Treatment with alendronate
and risedronate resulted in statistically significant differences compared to other
patients with osteoporosis.[43]
Cadoni et al found that osteoporosis could not be associated with the appearance of
periapical lesions, although they were more common in these patients. Their increased
frequency during root canal treatment highlights the possible connection between the
dynamics of the healing process and osteoporosis. The beneficial influence of bisphosphonates
is emphasized and further research in this direction is recommended.[44]
The intake of bisphosphonates has such a strong influence on the bone structure that
it is part of the criteria for excluding patients in the study of the postextraction
alveolus.[45] This is of particular importance in surgical manipulations and placement of implants.
People with osteoporosis belong to the group of medically compromised patients. With
them, it is necessary to provide appropriate consultation and premedication in order
for the treatment to be successful.[46] In cases of primary osteoporosis, implant treatment is not contraindicated, despite
the changes in the bone structure.[47]
Yarbasi and Bozdemir recommended that before starting treatment with bisphosphonates
in patients with osteoporosis, the oral health should be assessed and the patient's
teeth should be treated. It is important that they are trained to practice proper
oral hygiene and perform preventive examinations. In addition to the standard tests,
they should also be monitored for signs of osteonecrosis. This type of patient should
be treated jointly by dentists and general practitioners.[48]
The dental treatment of patients taking bisphosphonates has some peculiarities. However,
the knowledge of dentists is dentists is unsatisfactory.[49]
Bisphosphonates—Alendronate
Xiong et al investigated the effect of alendronate on periapical lesions and osteoporosis
due to reduced estrogen levels. This study was conducted on experimental mice, and
the medication was placed subcutaneously every day. This resulted in a decrease in
bone loss and a decrease in the number of osteoclasts.[50] Alendronate affects osteocyte apoptosis and IL-6-related inflammatory response mechanisms.[51]
Lilakhunakon et al find that alendronate reduced cell adhesion and viability of preosteoblasts
on Ti surfaces. Alendronate treatment seemed to exert higher inhibitory effects on
nuclear shape and size as well as cell viability in lower cell passage. This led to
the reduction in cell to implant surface interaction after encountering bisphosphonate
treatment.[52]
Bisphosphonates—Zoledronate
Wayama et al investigated the effects of another bisphosphonate, ZOA, in mice. He
uses microcomputed tomography in his research. Several groups are studied: a control
group receiving a placebo, ovariectomy group receiving placebo, a control group receiving
ZOA, and an ovariectomized group receiving ZOA. The results show that taking ZOA can
reduce bone destruction in patients with low estrogen levels.[53] The results of Ikeda et al confirm that zoledronic acid suppresses periapical bone
resorption with maintained osteoclast numbers.[19] Maia et al also proved the potential of zoledronic acid in patients with osteoporosis,
noting its anti-inflammatory and antiresorptive effect on bone.[54]
Marques-Ferreira et al found that in patients without osteoporosis and the presence
of zoledronate therapy, periapical lesions had lower bone resorption compared to the
control group.[55]
Calcitonin
In these patients, the hormone calcitonin can be administered. It inhibits bone resorption,
but has a weaker effect than bisphosphonates and is therefore rarely used in the treatment
of osteoporosis.[56]
Raloxifene
Another medicinal product that is used for osteoporosis is raloxifene. Gomes-Filho
et al investigated the mechanisms of osteoclast formation and angiogenesis in periapical
lesions of mice with reduced estrogen levels. In their study, they used two groups
of animals, one receiving raloxifene and the other a placebo. The results showed higher
levels of alkaline phosphatase, calcium, and phosphates in the group of mice that
received raloxifene compared to the control group. This gives the authors reason to
suggest this medication as part of the treatment for patients with reduced estrogen
levels.[57]
Follicle-Stimulating Hormone and Leuprorelin
Liu et al investigated the effect of follicle-stimulating hormone and its inhibitor
leuprorelin on mice with periapical lesions. The results showed that leuprorelin significantly
reduced bone loss and the number of osteoclasts compared to the control group.[58] There are similar results in the study by Qian et al: Increased expression of follicle-stimulating
hormone and secretion of proinflammatory cytokines, such as IL-1β, IL-6, and TNF-α,
affect periodontal ligament cells; increased production of pro-inflammatory cytokines
induced by Porphyromonas gingivalis lipopolysaccharide. High levels of follicle-stimulating hormone may regulate the
immune status of postmenopausal periodontal tissues.[59]
Strontium
Strontium compounds (strontium ranelate) are also used to treat osteoporosis. The
mechanism of action is not fully understood, but it is assumed that calcium receptors
are activated, cyclooxygenase-2 and prostaglandin E2 are induced. Adverse reactions
are associated with diarrhea and headache.[60]
Although there are no data on the effect of strontium preparations against osteoporosis
on periapical lesions, Oztekin et al found that strontium nanoparticles could significantly
reduce bone resorption and promote new bone formation with a higher frequency of osteoblasts.
The authors note the potential of strontium compounds in the treatment of periapical
lesions.[61]
Denosumab
Another medication to treat osteoporosis is the monoclonal antibody denosumab. It
reduces the risk of fractures. It acts as an inhibitor of RANKL expression. It is
effective against bone loss by increasing bone density. However, there is evidence
that it leads to an increased risk of infections and endocarditis and skin disease.[62] With tooth extractions, there is a serious risk of denosumab-associated necrosis
of the jaw when the drug is used to treat cancer.[63]
Parathyroid Hormone
Parathyroid hormone may also be administered during treatment. Because of its high
cost, it is used only in severe cases.[6] This hormone protects the periapical tissues and the periapical area when it is
used.[64]
Combined Therapy
In some cases, patients with osteoporosis take both corticosteroids and bisphosphonates.
They can also be successfully treated with endodontics. In Lajla's clinical case,
the patient was taking corticosteroids (Medrol 4 mg) and bisphosphonates (ibandronic
acid). Besides osteoporosis, he has other common diseases: Sjogren's syndrome and
hypothyroidism. Additionally, he suffers from temporomandibular joint movement disorders.
The diagnosis was periapical abscess with fistula. In the treatment, temporary medication
with calcium hydroxide and chlorhexidine (gel) is applied three times a month, after
which the root canals are definitively obturated.[65]
This clinical case, as well as the mentioned studies, shows the relationship between
apical periodontitis and osteoporosis. This is one of the examples where common chronic
diseases influence the course of apical periodontitis.[66]
Conclusion
A review of the specialized literature shows that current research confirms the relationship
between chronic diseases and periapical lesions. It is well manifested and documented
in patients with osteoporosis. When treating patients with periapical lesions, the
dentist must take a proper medical history and general medical history. It is good
to keep in mind the reduced bone density when reading the patient's X-rays.
On the other hand, an X-ray examination in connection with dental treatment may be
the reason for the detection of osteoporosis in patients. In cases of osteoporosis
or taking bisphosphonates and other medications, consideration should be given to
whether consultation with a specialist is necessary, what treatment approach would
be most appropriate, and what the prognosis will be.
