INTRODUCTION:

In 1877, Sir James Paget identified a pathological condition that he designated as osteitis deformans, which he subsequently referred to as Paget's disease of bone (PDB) in his original publication.¹ PDB is a chronic ailment characterized by localized or multifocal bone remodeling and disrupted bone architecture. This disorder manifests through alterations in bone metabolism and turnover, resulting in changes to the composition and structure of the bone matrix.²PDB represents the second most prevalent metabolic bone disorder after osteoporosis.³

The occurrence of PDB leads to Elevated Bone production due to the Increased bone resorption process. Consequently, this gives rise to the formation of disorganized, excessively vascularized woven bone, resulting in the characteristic signs of an expanding, painful, and inflamed bone lesion. PDB is a chronic condition that affects one or multiple sites within the skeletal system, exhibiting either a monostotic or polyostotic pattern.^4-5PDB is typically asymptomatic, But It can Elevate bone deformity, risk of fractures, discomfort, and other complexities such as osteosarcoma and deafness.⁶ Pain, deformity, and skeletal fragility are caused by the ensuing abnormal bone structure.^7-8

PDB is uncommon in those below the age of 40, and its predominance rises with increasing age.⁹ PDB is more common in males with a ratio of 1.8:1 and is uncommon in adults under the age of 50, but affects about 2-4% of people above the age of 50.10 PDB’s cause is unknown, and first-degree relatives are significantly more likely to get the condition.¹⁰Bone turnover biomarkers are frequently used to evaluate disease function and check the effectiveness of Bisphosphonate therapy

SIGNS AND SYMPTOMS:

PDB is usually asymptomatic or has mild symptoms, but early warning signs may include joint and bone discomfort, specifically in the hips, knees, and back. Bone pain may be severe and excruciating, and it may intensify at night.¹¹ Compression of brain tissues and nerves can cause headaches and hearing loss.¹²PDB may cause discomfort that worsens with weight-bearing and may lead to gradual swelling or deformity of the affected area. Bone weakening and thickening can result in malformations such as the bowing of weight-bearing long bones. As the disease progresses, other symptoms may appear such as limb bending, a waddling stride, joint pain and inflammation, fractures, and sensory problems.

CAUSES:

PDB has an elusive cause. Researchers hypothesize that the condition may have a complex origin, such as being the report of the interplay of a few hereditary and environmental elements

ENVIRONMENTAL FACTORS:

Several studies conducted in Italy and Spain have established a positive correlation between environmental factors, namely rural living arrangements and regular contact with animals, and elevated susceptibility to Paget's disease of bone.^13-14 Additionally, emerging evidence suggests the potential involvement of viral infections in the development of this condition.¹⁵ Notably, investigations utilizing in situ hybridization techniques.¹⁶and reverse transcription-polymerase chain reaction (RT-PCR) methods.^17-18 have successfully identified the presence of Measles virus and Canine distemper virus RNA within pagetic bone cells.

GENETIC FACTORS:

Most people with PDB have first-degree relatives who have the illness in their family history. It is important to look at the OPG system/RANK/RANK ligand.¹⁹which regulates osteoclast activity.²⁰before examining the genetics of PDB and related disorders. Osteoclast progenitors contain the NF-kB receptor stimulator RANK, while osteoblasts and the marrow stroma contain the RANKL ligand. Osteoclast progenitors are stimulated to proliferate and differentiate when RANKL binds to RANK. Osteoclast development is prevented by the decoy receptor OPG because it stops RANKL from binding to RANK. OPG therefore, prevents osteoclast differentiation.

In PDB, genetic factors are important, and 10–20% of patients have a family history.^21-23The SQSTM1 gene, which codes for the sequestosome-1 protein (SQSTM1/p62), has defects that account for up to 50% of familial instances of PDB.^21,22The SQSTM1/p62 protein is a crucial regulator of the NF-kappa B signaling pathway that is activated by mutations in osteoclasts, which is likely related to the pathogenesis of the illness.²³Alterations in valosin-containing protein (VCP) have been identified as the cause of PDB But they do not appear to be a frequent cause of familial or sporadic PDB.²⁴

AFFECTED POPULATION:

PDB is uncommon in people Below the age of 40 and can affect people of all racial and ethnic backgrounds. Both men and women are susceptible, with a slight masculine predominance. 1-3% of adults over the age of 40 are affected by PDB, and the prevalence rises to 10% in those over the age of 80.²⁵ PDB can damage one or more bones, depending on whether it is polyostotic or monostotic. It mostly affects people over the age of 40, with 1–3% of those in this age range suffering from it. For those over the age of 80, the frequency rises to 10%. Additionally, according to.^26-2740% of individuals with PDB have a favourable family history. First-degree relatives of PDB patients have an almost 7-fold increased risk of developing PDB.²⁷PDB is the second most common disorder of bone metabolism (after osteoporosis) and may affect up to 5% of women and 8% of men over the age of 80.²The disease worsened in both sexes.

DIAGNOSIS:

· A Proper clinical evaluation, the patient's medical history in detail, and several specialized tests can all support the diagnosis of PDB. The Detection of an elevated level of the ALP enzyme is one of the typical procedures used to identify the condition.²⁸

· The presence of elevated levels of certain bone turnover markers, such as urinary N-terminal telopeptide (NTX), procollagen type-1 amino-terminal propeptide (P1NP), bone-specific alkaline phosphatase, and serum C-terminal telopeptide (CTX), can also be used to establish the diagnosis of PDB.²⁹

· plain radiography - Criteria for diagnosis as its features are easily identifiable. To identify sarcomatous degeneration, positron emission tomography, magnetic resonance imaging, and computerized tomography are all helpful.³⁰

· Tc-99 Bone scan – provides pictures of elevated uptake in regions of osteoblastic activity and elevated vascularity.³¹

· Bone biopsy- Helpful for tumor differential diagnosis.³²

HISTOPATHOLOGY:

The histological traits of PDB that affect bone construction are the mixed, osteosclerotic, and osteolytic phases, which can happen concurrently or one after the other. A noticeable increase in the quantity of aberrant, multinucleated osteoclasts causes areas of resorption during the osteolytic phase. The ensuing disorderly osteoblastic phase is what leads to the formation of broken and asymmetrical bones. PDB is characterized by bone fragments with uneven forms and a resemblance to jigsaw puzzle pieces. During the osteoblastic stage, the vascularized fibrous tissue that closes the marrow gap produces a persistent fever and warmth that promote the growth of fibrous, coarse bone.

The newly generated bone following the osteoblastic phase in PDB is weakly mineralized and lacks structural integrity. There are also no centralized blood vessels or Haversian networks in the bone.^33-35A mosaic-like pattern of disorganized cement lines and woven bone are signs of severe bone resorption.³² as have a large number of osteoclasts with many nuclei per cell.³⁶

Osteoclasts' bone absorption and osteoblasts' bone synthesis are both necessary for maintaining bone homeostasis. Diseases like osteoporosis and other bone abnormalities can result from an imbalance in this closely related mechanism.^37-38 Osteoblasts: are cells that synthesize new bone, whereas osteoclasts: are specialized cells that resorb bone. Through its interaction with the receptor activator of nuclear factor-kappa-b" (RANK) on the osteoclast, the osteoblast-expressed protein receptor activator of nuclear factor-kappa-b ligand (RANK-L) plays a significant role in the formation, function, and survival of osteoclasts.^38-40

STANDARD THERAPY:

PDB can be treated using non-pharmacological therapies such as physical therapy, which can improve muscle strength. Pharmacological therapies such as bisphosphonates or calcitonin can also be used. Pain can be managed through the use of analgesics or surgical intervention.

Pain in the damaged bone is a crucial absolute use for treatment when there is a definite clinical proof of PDB.³¹The most key element of PDB treatment is antiresorptive therapy, which is used primarily to alleviate symptoms. Since it may lessen vascularization before surgery, treatment is utilized to treat immobilization-associated hypercalcemia as well as in advance of surgical procedures.^41-43

BISPHOSPHONATES:

Bisphosphonates are powerful antiresorptive substances that can be used to lower metabolic activity and treat PDB symptoms as a result.^43-44

S. No	Drugs	Frequency	Route
1	Zoledronic Acid⁴⁵	OD	IV
2	PAMIDRONATE⁴⁶	OD	IV
3	RISEDRONATE⁴⁷	OD	ORAL
4	ALENDRONATE⁴⁸	OD	ORAL
5	TILUDRONATE⁴⁹	OD	ORAL
6	ETIDRONATE	OD	ORAL
7	DISODIUM ETIDRONATE	OD	ORAL

CALCITONINS:

Salmon calcitonin, also known as Miacalcin, is a therapy for PDB that can be given through subcutaneous injection at a dosage of 50-100U per day or 3 times per week for 6-18 months.⁵⁰

OTHER DRUGS:

Denosumab is a promising alternative antiresorptive agent for Paget’s disease of bone. especially in individuals with renal impairment where bisphosphonate use is limited. NSAIDs and Calcitonin may provide symptomatic relief in cases where bisphosphonates cannot be used. However, metabolic control with calcitonin is poor.⁷

COMPLICATIONS:

cranial nerve or spinal cord compression, hydrocephalus (or) deafness.^51-52PDB can have rare complexations such as sarcomatous modification of the pagetic lesion and high output CHF.⁸ An uncommon complication of Paget’s disease is hypercalcemia, which may occur in individuals who are immobilized for a long period, such as during crack recovery. Sarcomatous alteration of pagetic bone is one of the most serious complications.^53-55Osteoarthritis, deformity, fractures, Neurological complexations such as headache and spinal stenosis, hearing loss, nerve compression syndromes.^56-57

CONCLUSION:

PDB of bone is a localized ailment of the aging skeletal system which manifests as either a sporadic or familial condition and can affect one or multiple bones within an individual. The occurrence of geographic and familial clusters of the disease has facilitated the identification of environmental and genetic factors associated with PDB. Unfortunately, no definitive cure exists for this condition. Nonetheless, effective treatment modalities are available to alleviate the pain and nerve compression syndromes associated with pagetic bone. Additionally, these treatments can normalize serum alkaline phosphatase ranges in many patients and, hopefully, impede the development of early PDB.

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Received on 16.07.2023 Modified on 22.09.2023

Res. J. Pharmacology and Pharmacodynamics.2023;15(4):186-190.

DOI: 10.52711/2321-5836.2023.00033