Paget’s Disease of Bone

Description of the pathology 

Paget's disease is a disorder that is characterized by areas of more than normal and disordered bone remodeling. The condition usually affects either one bone or more than one bone but not all bones at the same time. The Paget's disease commonly targets the axial skeleton (Ralston, 2013). The usual age of onset of this disease is usually 55 years, and it has a genetic basis for a high number of cases within specific regions (Ralston, 2013). Some patients with the disease, especially those with a family history, have been found to have mutations in the SQSTM1 gene, which codes for p62, a protein responsible for osteoclast regulation (Shaker, 2009). Paget's disease could be asymptomatic or could present with bone pain, bone deformity, arthritis, and neurological problems. This disease can be debilitating for some patients. 

Normal Anatomy of major body system affected 

The gross anatomy of bone is made up of two different parts: the diaphysis and the epiphysis. The diaphysis extends from two ends of a long bone such as the femur. Within the diaphysis is a hollow part of the bone is the medullary cavity, and the bone marrow occupies this space. The endosteum is also found in the medullary cavity and is where growth and remodeling of bone occurs. Compact bone, a strong type of bone, is contained in the walls of the epiphysis. The epiphysis is the broader part of the bone at the end of long bone and is made up of spongy bone. The junction between the epiphysis and the diaphysis is the metaphysic, which has the growth plate. In adults, however, the growth plate is replaced by an epiphyseal line. 

Healthy bone is usually made up of cells found within a collagen surface on which inorganic salt crystals adhere. Mineral salts such as calcium phosphate, calcium carbonate combine with hydroxyapatite and crystallize on collagen fibers within the anatomy of bone (Solomon et al., 2010). The cells found within bone include the following: osteoblasts, osteoclasts, osteocytes, and osteogenic cells. These cells are usually trapped within the calcified collagen. Bone cells are essential in bone remodeling, and aid in maintaining healthy bone physiology. The collagen fibers found in bone helps in providing the flexibility of bone, while bone mineral serve to provide strength to bones. Hence the bone becomes strong yet flexible. 

Normal Physiology of body system affected 

Normal bone remodeling takes place through resorption of old bone and formation of new bone. Throughout the lifetime of the bone, bone continuously undergoes this process to maintain shape and other properties. New bone takes the place of old bone to ensure that bone can support weight and prevent bone's failure to support weight. Refashioning of trabeculae is based on the amount of stress subjected to the bone. Trabeculae that are stronger are found in places of more significant pressure, while finer trabeculae are located in more tensile stress areas Solomon et al., 2010). 

Bone remodeling is usually orderly. It starts with osteoblasts prompting osteoclasts to move towards a surface of the bone and begin evacuating bone from that surface—this process of excavation proceeds for about two to four weeks. After the process ends, osteoclasts responsible go through apoptosis and are taken up by phagocytes. The excavated bone stays untouched for a while before osteoblasts move in to replace the bone that was removed (Solomon et al., 2010). Osteoblasts lay down new bone called osteoid, which is later mineralized by calcium carbonate and calcium phosphate to form an osteon. This process takes place over about three months. Osteoblasts and osteoclasts work together seamlessly, with several million of these cells working together at any one time in the bone. Resorption is automatically followed by formation. 

While these processes appear automatic, they are under the influence of vitamin D and parathyroid hormone. These two hormones ensure that the process of bone remodeling is always balanced. Coordination between osteoclasts and osteoblasts is linked to a cytokine called OPG and a cytokine named RANK, both of which are expressed by osteoblasts (Solomon et al., 2010). OPG is responsible for stopping bone resorption through binging to RANKL, which causes a decrease in osteoclast differentiation (Solomon et al., 2010). This way, bone resorption stops and paves the way for formation by osteoblasts. Hence, bone remodeling is under the influence of cytokines, hormones, diet, medication, and stress impacted on bone. All these factors maintain bone normalcy and one of these regulators could be altered in the event of Paget’s disease. 

Mechanism of Pathophysiology 

Paget’s disease occurs due to a modification in bone remodeling. The condition usually starts at one end in bones that are tubular and progress towards the diaphyses of these bones. As the disease progresses, it leaves behind bone whose architecture has been grossly altered (Ralston et al., 2008). Under a microscope, there is an expanded action of osteoclasts and osteoblasts. Due to the rise in the operation of osteoblasts, there is an increase in blood alkaline phosphatase. Also, due to an increase in osteoclast activity, there is a high level of urinary hydroxyproline (Solomon et al., 2010). The normal osteoclast-osteoblast coordination is altered in this condition. Some schools of thought also suggest that Paget’s disease occurs due to abnormal osteoclasts. The precursors of osteoclasts show an increase in sensitivity to elements such as 1, 25 dihydroxy vitamin D, and the cytokine RANKL, factors known to increase osteoclastic activity (Shaker, 2009). Pathological destruction therefore occurs as a result of a high level of the activity of osteoclasts. This destruction of bone is followed by osteoblasts depositing lamellar bone in a disorganized manner. Spaces between the new bones are filled with connective tissue, which has a high number of blood vessels. 

Treatment 

Treatment of Paget's disease requires intervention using pharmacological and non-pharmacological methods. Antiresorptive therapy is indicated for use in the condition during specific indications. Bone pain is a strong indication for the use of antiresorptive therapy (Ralston, 2013). Patients should be well examined to exclude other sources of bone pain before administering antiresorptive medication. Another indication for the use of drugs is the presence of pseudofractures in bone (Ralston, 2013). Asymptomatic patients, however, have not been shown to benefit from antiresorptive medication. The use of bisphosphonates reduce bone turnover without alleviating symptoms. Another drug commonly used is calcitonin, which has been shown to decrease bone turnover. However, its use is not recommended unless in cases where bisphosphonates are contraindicated. 

Non-pharmacological approaches to management include acupuncture, physiotherapy and hydrotherapy. Also, the use of aids, such as canes, has been shown to improve complications such as limb deformities (Solomon et al., 2010). Orthopedic surgery is essential, not for treatment of the disease but for managing complications arising from it. Fractures, pseudofractures, and arthritis can be managed by orthopedic surgery. Osteotomies to remove pieces of bone help correct deformities resulting from the disease. Internal fixation is also recommended for the management of long bone fractures. Surgery for management of the disease can be complicated because of the weak nature of bone and its increased vascularity (Ralston, 2013). As a result, bisphosphonates are recommended for use before surgical interventions are carried out. 

Prevention 

Paget’s disease of bone has no preventive measure documented yet. Most patients who have the disease could not avoid it in any way. Treatment also does not cure the disease but instead helps slow down the progression and reduce complications arising from it. Hence, patient education is vital so that they follow up treatment for symptomatic relief and slowing down of the disease progress. 

References 

Ralston, S. H. (2013). Paget's disease of bone. New England Journal of Medicine , 368 (7), 644-650. 

Ralston, S. H., Langston, A. L., & Reid, I. R. (2008). Pathogenesis and management of Paget's disease of bone. The Lancet , 372 (9633), 155-163. 

Shaker J. L. (2009). Paget's Disease of Bone: A Review of Epidemiology, Pathophysiology and Management. Therapeutic advances in musculoskeletal disease , 1 (2), 107–125. https://doi.org/10.1177/1759720X09351779