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THE ROLE OF HORMONAL BACKGROUND IN THE DEVELOPMENT OF
OSTEOPOROSIS
Assistant M.A. Rixsiyeva
Department of Histology and Medical Biology, Tashkent State Medical University
Abstract:
Osteoporosis is a chronic systemic metabolic disease of the skeleton, which is
characterized by a progressive decrease in bone mass. The predominance of resorption
processes and a decrease in bone formation it lead to a violation of bone microarchitecture
and its shrinkage. Currently, osteoporosis and associated bone fractures are one of the main
causes of disability and premature death in the elderly [1]. One of the main causes of
osteoporosis is a violation of the hormonal background, which has been studied by many
scientists. In particular, impaired activity of testosterone, estrogen, melatonin affects osteons.
Keywords:
osteoporosis, testosterone, estrogen, melatonin, menopause
Quality Maria, Paula A. Melatonin effects on bone: potential use for the prevention and
treatment for osteopenia, osteoporosis, and periodontal disease and for use in bone-grafting
procedures It is reported that 8.9 million osteoporosis-related fractures occur worldwide
each year, which is approximately one osteoporosis-related fracture every 3 seconds.
According to the International Osteoporosis Foundation, more than 200 million women
worldwide have osteoporosis, most of whom are 60 or older; the female-to-male ratio for
fractures is 16:1. In the European Union, it is estimated that approximately 22 million
women and 5.5 million men (aged 50 to 84) have osteoporosis; this number will increase by
23% by 2025. In the United States, approximately 57 million adults over the age of 50 suffer
from bone disease, with 48 million adults having osteopenia and 9 million adults having
osteoporosis, putting them at risk for fracture. If current trends continue, the prevalence of
osteoporosis is projected to increase to 11.9 million and 64.3 million with osteopenia by
2030. [18].
Microstructural abnormalities in osteoporosis affect the trabecular and cortical layers.
A decrease in the thickness and number of trabeculae is characteristic of the pathogenesis of
osteoporosis.
In the pathogenesis of osteoporosis, the cortical layer thins and becomes more porous,
leading to a decrease in bone strength and the development of micro- and macro-fractures.
[2].
In girls, changes in estrogen and testosterone activity begin after the onset of menstruation
during puberty. This is because testosterone increases periosteal thickness, bone growth, and
estrogens, through osteoclasts, affect the thickness of the cortical layer, restoring it on the
endosteal surface of the bone. Thus, the increase in bone thickness occurs due to the
predominance of periosteal synthesis processes over endosteal resorption processes.
During this period, the risk of fractures associated with growth is particularly high in the
distal forearm, since bone volume increases more rapidly in this area. The effect of estrogen
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in this process is realized by inducing apoptosis of chondrocytes and osteoclasts of the
tubular bone in the growth line of the bone.
The hormone melatonin is synthesized from the amino acid tryptophan in the pineal gland.
Its main function is to act as a humoral messenger, transmitting information from the
suprachiasmatic nuclei of the hypothalamus to the div's cells. Many structures in the div
produce melatonin. These include, for example, the retina, bone marrow, platelets, skin,
lymphocytes, the nictitating gland (Harder's gland), the cerebellum, and the gastrointestinal
tract [12, 13]. However, this production is not cyclical and provides melatonin as an
"internal" antioxidant agent. Melatonin performs many physiological functions in the div.
These include:
1. Regulation of circadian rhythms (including the daily sleep-wake rhythm) [14].
2. Regulation of div temperature [15].
3. Reduction of age-related weight gain [15].
4. Pro-inflammatory (production of IL-2, IL-6, IL-12), strengthening the immune system
(production of T-helpers).
The role of melatonin in the regulation of immunity has been proven,
Melatonin has a direct immunostimulating effect in animals and humans [16]. At the same
time, the effect of melatonin on reparative osteogenesis of jaw bones
in bone fractures has been widely discussed, although the increasing possibilities of modern
surgery are of great importance in dentistry and especially implantology.
The aim of the study was to study the effect of melatonin on the processes of
osseointegration of jaw bones
in experimental conditions
Materials and methods. The changes in osteocytes stained with Hematoxylin-eosin by the
method of Van Gison, Mallory, Masson were studied [19]. The effect of melatonin on bone
turnover was studied in 7-8-month-old guinea pigs. The guinea pigs were anesthetized and
injected with Zoletil 50. A 5-mm sample was taken from the lower jaw of the animals.
For 14 days before surgery, a group of guinea pigs (24 animals) were given insulin orally
using a laboratory pipette into an insulin syringe from 4:00 PM to 5:00 AM. The second
control group (24 animals) was given melatonin (in the form of Melaksen®, Unipharm) in a
physiological solution of sodium chloride at a dose of 5 mg / kg div weight of the animals.
Melatonin was removed from the water and food of the animals. [6].
Experimental and control guinea pigs were examined on days 14, 30, 60 and 120 after
surgery. The lower jaw was examined radiographically, fixed with 10% neutral formalin and
stained with Hematoxylin-Eosin, and a preparation was prepared using the Van Gison,
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Mallory, and Masson methods. When examining the guinea pigs in the control group at 60
days, it was found that the structural structure of the lower jaw bone was preserved. During
the same period, when melatonin was administered, histologically dense fibrous tissue was
detected. Histological examination of the preparations obtained up to the 120th day of the
experiment showed that only the use of melatonin provided secondary restructuring of
regeneration in the peripheral area.
Histochemical analysis showed that the speed and duration of changes in the redistribution
of acidic mucopolysaccharides in the tissues increased.
On the 30th day of the experiment, the same dynamics of changes in the composition of
neutral mucopolysaccharides was observed when melatonin was used for 28 days. Together
However, their concentration, unlike acidic mucopolysaccharides, remained high in the
experimental and control groups from the moment of stabilization on the 30th day after
surgery to the 60th day of the experiment.
When studying the activity of cells under an electron microscope, significant changes were
detected in the cytoplasm of osteoblast cells 2 weeks after surgery. Indicative changes were
detected in the endoplasmic reticulum, Golgi complex, and ribonucleotide granules (7)
Histological examination of preparations obtained up to the 120th day of the experiment
showed that
only the use of melatonin provided secondary restructuring of regeneration at the periphery
of the defect, with the development of bone tissue.
Histochemical analysis showed significant differences in the quantitative redistribution of
mucopolysaccharides in the regeneration tissues, including the speed and duration of such
changes. In particular, while the amount of acidic mucopolysaccharides in intact bone callus
cells increased on day 30 of the experiment, melatonin administration for 28 days provided
such a restructuring by day 14 of the experiment. Thus, according to the data of visualization
research methods, chronic intake of melatonin alone within 14 days after surgery ensures the
formation of bone structures, and not dense fibrous tissue, as in the control group of animals.
It is noteworthy that throughout the entire experiment, the process of bone tissue
regeneration with melatonin administration was 14–30 days ahead compared to those who
did not receive it. Changes in regenerative activity are mainly associated with the activation
of cellular metabolic functions, particularly those of osteoblasts, and their structural
reorganization under the influence of melatonin pre-administration. This is evidenced by the
early and quantitatively expressed manifestation of mucopolysaccharides in the regeneration
of animals in the main group.
In scientific articles by Brailova N.B., Kuznetsova V.A., Dudinskaya E.N., and Tkacheva
N.E., the aging process is examined in relation to collagen and gene cells. In 1961, Hayflick
determined the division limit of somatic cells due to the onset of critical telomere length,
after which all signs of cell aging appeared and apoptosis occurred. As in any tissue, aging
in bone — which includes extracellular matrix components such as non-cellular proteins,
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calcium phosphate, and hydroxyapatite-mineralized collagen fibers — leads to a decrease in
the number of osteoblasts and osteocytes due to apoptosis and an increase in adipose tissue
volume. Qualitative changes also occur in bone cells. For example, in aging osteoblasts, the
production of type I collagen (the organic matrix of bone) gradually declines, and aged cells
exhibit irregular morphology, flattening, and accumulation of cellular debris.
Interestingly, in experiments involving prolonged administration of troglitazone (a low-
affinity thiazolidinedione) to mice, an increase in the number of adipocytes was observed
without affecting bone mass. In contrast, injections of rosiglitazone (a high-affinity
thiazolidinedione) were associated with decreased joint mineral density. This, as well as the
stimulation of osteoblast and osteocyte apoptosis, explains the increased incidence of
fractures in individuals treated with thiazolidinediones for diabetes mellitus. Two isoforms
have been identified in mice — PPARγ1 and PPARγ2. PPARγ2 is expressed only in adipose
tissue, whereas the other isoform is expressed in various other tissues.
Studies have shown that PPARγ promotes adipogenesis, and its absence in mice leads to a
lack of terminally differentiated adipose tissue, fatty liver dystrophy, and lipodystrophy. In
humans, somatic mutations of the
PPARG
gene that activate aging contribute to metabolic
disorders, including insulin resistance and the development of arterial hypertension.
Selective PPARγ ligands, particularly thiazolidinedione drugs, are used to treat type 2
diabetes by suppressing insulin resistance.
Adipocytes secrete several proteins (adipokines) that function as hormones via endocrine
pathways, such as leptin. In studies on mice, bone strength loss with age was accompanied
by a decrease in serum leptin levels. Leptin-deficient mice had shortened femurs, reduced
mineral content, and lower mineral density in the femur, while the mineral content of the
lumbar vertebrae was increased.
Leptin is believed to differentially regulate chondrogenic proliferation and differentiation in
appendicular and axial skeletal regions. Thus, primary tibial epiphyseal chondrocytes
cultured in mice proliferated faster than vertebral epiphyseal chondrocytes. Leptin inhibits
apoptosis in tibial epiphyseal plate chondrocytes but promotes apoptosis in vertebral
epiphyseal plate chondrocytes. It regulates osteoclast development by reducing the
production of RANK and RANK ligands. Research results indicate that the level of BMP-7
in tibial epiphyseal chondrocytes is significantly higher than in vertebral epiphyseal
chondrocytes.
In scientific articles by Sifat Maria and Paula A., one of the mechanisms underlying
melatonin’s bone-strengthening effect is its stimulatory action on osteoblasts. Numerous
studies have shown that melatonin promotes the differentiation of hMSCs and preosteoblasts
into mature osteoblasts via multiple signaling pathways involving ERK1/2 and Wnt/β-
catenin. As shown in Figure 2, activation of melatonin receptors by melatonin leads to
increased MAPK activity (ERK1/2, p38, or JNK); for MEK1/2/ERK1/2, this activation is
associated with MT2 melatonin receptors and MT2R/Gi/β-arrestin/MEK/ERK1/2 pathways,
which in turn lead to ALP activation in the cytoplasm and the induction of osteogenic gene
expression involving Runx2, followed by bone morphogenetic protein 2 (Bmp2), osterix,
and osteocalcin (OCN).
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Bone morphogenetic proteins (BMPs) play a crucial role in osteoblastogenesis and are
currently used clinically (INFUSE™) in bone grafting procedures.
As shown in the figure, BMPs bind to bone morphogenetic receptors (BMPRs), which are
membrane-bound and located in osteoblasts and phosphorylated Smad proteins. This leads
to their interaction with common-partner Smads (Co-Smads), resulting in nuclear
translocation and activation of osteogenic genes such as
Runx2
,
Bmp2
, and
osterix
.
Melatonin can also activate
Wnt/β-catenin
in osteoblasts, which enhances
Runx2
expression. The Wnt/β-catenin pathway is a well-known signaling route involved in
osteogenesis. Many other signaling mechanisms also participate in osteogenesis (e.g.,
fibroblast growth factors); it would be interesting to explore how melatonin interacts with
these pathways to stimulate osteoblastogenesis.
Overall, these studies confirm the claims that melatonin accelerates the synthesis and
mineralization of new bone. Indeed, the influence of melatonin on bones supports its use as
an adjunct therapy in osteoporosis populations, alongside other systemic hormones such as
PTH
,
estrogen
, and
calcitonin
, to improve or maintain bone health. (18)
Scientific research also shows that
epigenetic factors
in elderly women are directly related
to
physical activity
. For example, regular physical activity is positively associated with
enhanced bone formation and bone strength, and it positively affects bone metabolism and
remodeling. (10)
During menopause, the rapid decline in estrogen is associated with decreased bone density.
Paradoxically, an increase in bone volume is observed due to an increase in periosteal
diameter, which partially maintains bone strength. Bone resorption and bone formation
processes continue, but resorption predominates, which is linked to increased osteoclast
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activity in trabecular bone. Trabeculae begin to thin, lose their layered structure, become
cylindrical, and are destroyed if mechanical load persists.
Research data suggest that changes in estrogen levels are associated with the secretion of
immune factors by mononuclear cells, and alterations in the local production of bone-
forming cytokines may underlie changes in bone metabolism.
Conclusion.
Melatonin has an optimizing effect on the renewal of jaw bone tissue.
Continuous administration of the drug stimulates osteogenesis and enhances the functional
and morphological reorganization of cells in the early stages of reparative regeneration. (8)
Regarding the treatment of osteoporosis
, currently, there is no medication that completely
cures the disease. The treatment of senile osteoporosis mainly involves managing low-
energy fractures in patients with limited mobility, which slows down the bone regeneration
process. However,
bisphosphonates
can be used as drug therapy, providing
anti-apoptotic
effects
on osteoblasts through mechanisms involving
extracellular signal-regulated
kinases (ERKs)
and
connexin 43 channels
. (11)
Scientific findings have confirmed that
melatonin levels decrease with age
, particularly
during
menopause
. Therefore, restoring nighttime melatonin levels can positively affect
bone health in menopausal women, as shown in studies. Melatonin increases bone density
and accelerates new bone growth, targeting multiple stages of bone regeneration.
Moreover, melatonin improves sleep quality and psychological condition in middle-aged
and elderly individuals. These attributes of melatonin may enhance the patient's overall
condition, ultimately contributing to better health, as sleep disorders and increased
depression are common symptoms reported by older and menopausal women, the
populations most affected by
osteopenia
and
osteoporosis
.
In addition, melatonin's
availability over the counter
and its
low cost
make it especially
beneficial from an economic perspective in promoting health.
Our objective
is to study the effect of melatonin on
osteocytes
when sleep activity is
disrupted and melatonin levels are reduced.
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