Are You Sure the Patient Has Paget's Disease?
Paget Disease of bone is a disorder of localized bone remodeling caused by abnormal osteoclasts with increased activity (1). These abnormal osteoclasts cause excessive bone resorption which is followed by increased rates of bone formation creating disordered bone matrix, which when mineralized leads to enlarged, weakened bones. The disorder may be confined to one bone (monostotic, 40%) or multiple bones (polyostotic, 60%) of patients.
Although this is a chronic skeletal disease, 60-70% of affected individuals have the diagnosis made because of an elevated serum alkaline phosphatase level, or a radiograph done for another reason that shows a bone involved with Paget Disease, causing no symptoms. Because of the wide variety of bones that can be involved, the symptoms caused by the disorder vary widely (2).
Although any bone in the skeleton can be involved, it has a predilection for the axial skeleton. The most commonly involved bones are the pelvis, lumbar spine, proximal femur, tibia and skull. The most common symptom is bone pain, typically an aching, low-grade, deep pain that can be worse at night and may be related to activity. Other causes of the bone pain can be from the increased vascularity in affected bones as well as from the stretching of the periosteum from the new amounts of bone formed by the increased remodeling.
Osteoarthritis occurs in 50% of affected patients because the abnormal bone remodeling can destroy the joint or the affected bones enlarge or bow so the cartilage and joint are damaged. Weight bearing bones can bow from the reduced strength of the abnormally remodelled bones. These bones can also fracture with minimal trauma. Such fractures are called “chalk stick” or “banana” fractures because of the poor quality of the skeletal tissue. Bone sites with normal skeletal fractures have more jagged pieces (2, 3).
Pseudofractures are thin, radiolucent bands across the lateral cortex of affected weight-bearing bones. Such fractures may resolve or become painful. When this occurs, surgical stabilization should be considered.
Neurological complications occur from Paget Disease when it involves the vertebrae or skull. Spinal stenosis can occur with one or multiple vertebrae involved. Rarely do patients develop para-/quadriplegia, and when it occurs, it is usually due to a vascular steal syndrome rather than neurologic compromise, and is reversible if treated promptly with an antiresorptive agent. Skull involvement can cause headaches, hearing loss, tinnitus, and vertigo. Most hearing loss is from damage to the cochlea, probably from elevated bone turnover. The skull can become enlarged. When this occurs in the maxilla or mandible, malocclusion of teeth results (2, 3).
When some patients with polyostotic disease become bed ridden, they can become hypercalcemic. More commonly, when hypercalcemia occurs in these patients, it is from hyperparathyroidism. With high rates of bone turnover, some patients develop nephrolithiasis. Although hyperuricemia and gout are reported to occur in patients with Paget Disease, it is unclear whether these are just two common diseases occurring together or whether the elevated bone remodeling rates in some fashion cause it (2, 3).
Because of the accelerated bone remodeling and its attendant increase in blood flow the tibia or fibula may become warm to the touch. High output cardiac failure is rare, and such patients generally have 35% of their skeleton involved. There are some additional aortic stenosis, generalized atherosclerosis, endocardial calcifications, increased cerebrospinal fluid pressure, and fibrosing conditions: Peyronie Disease, Dupuytren contractures, and Hashimoto thyroiditis (2, 3, 4).
A rare complication of Paget Disease (<1%) is osteosarcoma. Usually occurring in patients with polyostotic disease, this neoplasm is aggressive and unless it can be completely removed is rapidly fatal. Osteosarcoma is the most common cancer, arising most frequently in the femur, humerus, or pelvis. Other associated cancers occurring with the disease are chondrosarcoma, fibrosarcoma, benign giant cell tumors and occasionally metastases from other primary cancers to areas of Paget Disease. There are no data to suggest that treatment of Paget Disease reduces the incidence of these malignancies. Suspicion that malignant transformation has occurred when there is a rapid rise in serum alkaline phosphatase levels, a fracture or an increase in pain in an area of diseased bone (3).
Paget Disease was first described by Sir James Paget in 1877. From examination of mummies we know the disease has been present for thousands of years. The disease is most common in Western Europe, North America, Australia and New Zealand, with incidence rates as low as 0.7% to a high of 4.6%. Men and women are almost equally affected, with the disease rarely presenting before 40 years of age, increasing in frequency as people age. It is now clear that the incidence of Paget Disease is declining and when patients present with the disease, it is less severe. First recognized by investigators in New Zealand, similar declines are reported in Spain and the United Kingdom. Some experts believe that the decline can be attributed to measles vaccination while others feel that there is currently no valid explanation for the decline (2, 6).
What Else Could the Patient Have?
Since 70% of patients with Paget Disease are asymptomatic, many are diagnosed because of an elevation of serum alkaline phosphatase levels or an abnormal radiograph or bone scan done for another reason.
Elevated alkaline phosphatase level.The concern is whether the elevated level is from bone or liver. Check to see if other liver enzymes and chemistries on a multiphasic screening chemistry panel are normal: aspartate aminotransferase, alanine aminotransferase, total bilirubin and albumin (7). This will help differentiate between bone and liver disease. Although some experts believe that it is not necessary to obtain a bone specific alkaline phosphatase level, I order one in most of my patients because the cases I am seeing have less severe disease and I follow it as I treat them. Another option is to fractionate the alkaline phosphatase.
Other skeletal diseases can cause elevation of serum bone alkaline phosphatase levels (modified from Table 112-5, ref 3):
Malignant neoplasms in skeleton, primary or metastatic – bone biopsy may be necessary.
Osteomalacia – serum phosphorus and 25 hydroxy-vitamin D levels may be low.
Hyperparathyroidism with osteitis fibrosa cystica – serum parathyroid and calcium levels elevated. Hand radiographs will show subperiosteal resorption in the phalanges.
Idiopathic hyperphosphatasia – Normal bone scan and radiographs will aid in this diagnosis.
Abnormal bone on radiograph. When radiographs show a bone that is abnormal (sclerotic, enlarged, lytic areas or increased trabeculae) frequently the radiologist will suggest Paget Disease of bone and recommend a total body bone scan to determine the extent of disease. The radiologist may not be comfortable making this diagnosis with images and request a bone biopsy. This is rare and occurs in less than 5% of patients (7).
Causes of skeletal lesions with similar radiographic appearance (modified from Table 112-5, ref 3):
Metaphyseal dysplasia (Englmann Disease)
Familial expansile osteolysis
Sternocostal clavicular hyperosteosis
Diagnosing these disorders generally requires additional imaging studies and the help of a skeletal radiologist. Rarely a bone biopsy is required to make the diagnosis.
Abnormal uptake on bone scan. This occurs when patients with cancer have bone scans to determine if their malignancy has metastasized to the skeleton. Generally the bone lesions in Paget Disease show intense uptake of the scanning agent, whereas skeletal metastases have more a patchy uptake. Most oncologists the author has worked with want to confirm with a tissue diagnosis for the first skeletal metastasis, unless the radiologist is certain that the increased uptake is from Paget Disease (7). Very rarely a patient with Paget Disease will develop a cancer than metastasizes to the area of pagetic bone. Sorting out this diagnosis usually requires CT scans and a biopsy.
Joint or back pain thought to be arthritis. The most common symptom of Paget Disease of bone is skeletal pain. Radiographs can show Paget Disease. The lesions of Paget Disease can cause pain by themselves, usually a dull aching pain, sometime worse at night. Because Paget Disease causes bone deformities with abnormal stress on joints, the Paget lesion may cause pain and the attendant osteoarthritis may cause pain and disability also. Deciding which lesion/abnormality causes the pain is difficult and therapy may need to be directed at both entities.
Key Laboratory and Imaging Tests
Most patients with Paget Disease of bone have their diagnosis made by an elevated serum alkaline phosphatase level. When the diagnosis is being made all patients should have a total body bone scan to identify areas of update of the imaging isotope indicating sites of symptomatic and asymptomatic disease. Areas where these is osteoarthritis can usually be easily distinguished from areas of Paget Disease because of the intensity of the uptake of the isotope. It is recommended that areas suspected of having disease have conventional radiographs that will confirm the diagnosis and such studies in weight bearing bones can identify lytic lesions and pseudofractures that may later go on to fracture (7).
All patients suspected of having Paget Disease of bone should have a serum alkaline phosphatase level measured. If radiographs show disease and the level is normal a bone specific alkaline phosphatase level should be performed, since it is a more sensitive measure of disease activity.
Other Tests That May Prove Helpful Diagnostically
Besides using serum alkaline phosphatase levels, a serum bone specific alkaline phosphatase level is useful in patients who have radiographic evidence of Paget Disease and a normal serum alkaline phosphatase level. If both levels are normal, the patient can have the disease, and it is referred to as quiescent or burned out disease. Some experts occasionally use other markers for bone formation: serum procollagen 1 intact N-terminal level (PINP) and for bone resorption: serum Beta C-terminal propeptide of type 1 collagen (Beta CTx) or Serum N-terminal propeptide of type 1 Collagen (NTx) (7).
Additional radiographic studies may be necessary to diagnose Paget Disease or to assess some of its complications. Such studies include CT scans and MRIs. When such studies are contemplated, it is advisable to consult with the radiologist to make sure the chosen study will answer the clinical question.
Management and Treatment of the Disease
Since Paget Disease is a chronic disorder, patient education about the disease and its treatment with expected outcomes is critical.
Treatment of the disease is not indicated in all patients, specifically those who are not symptomatic and are at low risk for developing complications. Treatment is recommended for the following patients with these indications:
Active disease at risk for future complications (e.g., impending fracture, worsening hearing, paraplegia, etc)
Prior to elective surgery at or near a pagetic site (e.g., total joint replacement, osteotomy to correct deformity, surgical excision of skeletal malignancy, etc)
Symptoms (e.g., bone pain, headache from skull involvement, neurologic symptoms including paraplegia, congestive heart failure, etc)
Hypercalcemia in the setting of immobilization (8)
Many of the complications (bone enlargement, bowing of limbs, arthritis, hearing loss) of Paget Disease take years to develop. Drug treatment studies of Paget Disease are of relatively short duration so there is a lack of data on whether arresting the elevated bone remodeling rate will reduce the long-term complications. Clinical trials using bisphosphonates to treat Paget Disease have demonstrated that these agents can lower alkaline phosphatase levels to the normal range, improve bone pain, heal the osteolytic lesions seen radiographically, improve quality of life measures and result in normal lamellar bone histology on biopsy in areas of pagetic bone. This has led to the practice by many specialists who treat Paget Disease to attempt to lower elevated serum alkaline phosphatase levels into the mid-normal range (7, 8). Not all experts who care for patients with Paget Disease believe that patients who are risk of long-term complications should be treated with bisphosphonates to prevent these, because they argue that there are no clinical trials to show that they can be prevented (2, 9). Because the disease is slowly disappearing, it may never be possible to obtain such data.
Patients with Paget Disease should use vitamin D3 supplements to maintain their 25-hydroxy-vitamin D levels between 20 -30 ng/ml. To prevent secondary hyperparathyroidism, especially when using bisphosphonates, patients’ total daily calcium intake should be 1200 to 1500 mg.
Bisphosphonates: This class of drugs are the treatment of choice for Paget Disease of bone. Because bisphosphonates have a P-C-P structure, similar to the P-O-P structure in pyrophosphate, they avidly bind to the calcium in hydroxyappetite in bone. They are preferentially taken up by active areas of bone turnover in pagetic lesions. Once there the nitrogen containing bisphosphonates (alendronate, risedronate, and zoledronate) inhibit one of the final enzyme steps in protein prenylation, farnesyl pyrophosphate synthase, inhibiting the production of intracellular signaling models. This action causes apoptosis in the osteoclasts, reducing and ultimately normalizing the increased bone remodeling occurring in pagetic lesions (3, 7, 8).
Zoledronate (5 mg given intravenously over 15-30 minutes) is the preferred treatment and the first line of therapy. Studies have shown that serum alkaline phosphatase levels decline within 10 days of administration, continuing to fall over the next 3-6 months. In a clinical trial 88.6% of patients receiving zoledronate had normalization of alkaline phosphatase levels while treatment with a comparable course of risedronate resulted in 57.9% of affected patients normalizing their levels (9). More importantly most patients receiving zoledronate had suppression of their alkaline phosphatase levels for six years (10).
Zoledronate does have side effects, the most common is an acute phase response with malaise, fever, myalgias and bone pain at sites of pagetic lesions occurring in 25-40% of patients. Generally the reaction is over in 3-4 days and responds to analgesics (acetaminophen, aspirin or NSAIDs). As with all bisphosphonates there is the rare risk of osteonecrosis of the jaw (1 in 10,000 to 100,000 patients treated) and atypical femur fractures (1 in 10,000 to 100,000 patients treated). Before receiving this agent the patient should have a calculated creatinine clearance of >35cc/min and a 25-hydroxy vitamin D level of 25 ng/ml.
Alendronate (40 mg orally daily for 6 months) and Risedronate (30 mg orally daily for 2 months) are both FDA-approved therapies for Paget Disease of bone. While they are less likely to cause an acute phase response, they are associated with esophagitis. They also should be used in patients with a calculated creatinine clearance of >35cc/min. These bisphosphonates have the same risk, as does zoledronate, of causing osteonecrosis of the jaw and atypical femur fractures. As a general caveat, patients who are hypoparathyroid or at risk for having this condition such as previous thyroid or head and neck surgery should not receive bisphosphonates. Hypoparathyroid patients who receive these agents can become profoundly hypocalcemic. If there is a question about potential hypoparathyroidism, checking a parathyroid hormone level is advised (3, 7).
There several other uses for bisphosphonates for complications arising in patients with Paget Disease. Many orthopedic and neurosurgeons want patients treated with a bisphosphonate 2-3 months before they perform an operation on a site with pagetic bone to reduce the blood loss. Bisphosphonates should be considered when a patient has ischemia-induced paraplegia resulting from disease in the vertebrae. Improvement can be seen with these agents in 2 weeks, but if paraplegia is from pagetic skeletal deformity, surgery should be considered sooner.
Calcitonin was one of the first antiresorptive agents used to treat Paget Disease. Injectable salmon calcitonin can still be used for patients who are allergic to bisphosphonates. It can relieve bone pain and can partially lower alkaline phosphatase levels. In doses used to treat Paget Disease the drug can cause nausea and flushing. With reports that is carcinogenic, it has been removed from the market in Europe and is infrequently used in the United States (3).
Denosumab is another potent antiresorptive agent, which directly acts to reduce osteoclast activity. It has not been formally tested as a treatment for Paget Disease. Its use for this disease has not been approved by the FDA. Denosumab with dexamethasone are used to reduce the size of giant cell tumors or bone which are associated with Paget Disease.
Analgesics: Skeletal pain occurs in 70% of affected patients. Some of the pain can be controlled with antiresorptive treatment of the disease. Many patients have osteoarthritis from disease close to or involving joints. Acetaminophen, aspirin and NSAIDs can bring relief of pain. When limb deformities are severe, patients can get relief from osteotomies, but there is an increased risk of non-union. Many times the osteoarthritis is so severe that total joint replacement is the only way to control the pain and improve function. For joint replacement it is important to refer to orthopedic surgeon with experience in operating on such patients with significant deformity. Despite lack of evidence from controlled trials acupuncture, hydrotherapy, physiotherapy, and transcutaneous electrical nerve stimulation have been reported to bring patients relief (3, 7).
Monitoring response to therapy: Patients who receive bisphosphonates for their disease usually report that their pagetic pain begins to improve in 2-3 months. Although bone turnover markers begin to decrease within 10 days of treatment, it is generally accepted that alkaline phosphate levels should be checked 3-6 months after completing therapy. It may take 6 months for the levels to reach a nadir. Most patients should be followed at yearly intervals, checking serum alkaline phosphatase levels and assessing symptoms. If pagetic pain reoccurs before the alkaline phosphatase levels rise, a serum beta CTX or an NTX level may indicate that the remodeling activity has increased. Another way of following these patients is to establish a value for the nadir of their serum alkaline phosphatase response and then retreat when the alkaline phosphatase level rises by 25% over the nadir value (7).
Additional measures to offer patients: Some patients with long-standing Paget Disease develop leg length discrepancies with attendant gait impairment and muscle weakness. They should be referred to a physical therapy for limb strengthening exercises. They should be encouraged to use lift applied to their shoes to correct the discrepancies. Improvement in these discrepancies can have a significant effect on attendant knee, hip and back pain. Canes or walkers should also be encouraged if there are significant gait impairments since falls with fractures can worsen their gait impairments and pain (3).
What’s the Evidence?/References
Paget, J.. “On a form of chronic inflammation of bones (osteitis deformans).”. Med. Chir. Trans.. vol. 1877. pp. 37-64. (Classic clinical description of the disease.)
Ralston, SH, Langston, A, Reid, IR. “Pathogenesis and management of Paget’s disease of bone.”. Lancet.. vol. 372:. 2008:. pp. 155-63. (Excellent review of pathogenesis and treatment.)
Swanson, CM, Lyles, KW, Orwoll, ES. “Hyperparathyroidism and Paget’s Disease of Bone. Hazzard’s Geriatric Medicine and Gerontology.”. McGraw-Hill Inc. New York, NY.. 2016:. pp. 1695-1713. (Excellent review of the disease and how to manage it.)
Altman, RD. “Musculoskeletal manifestations of Paget’s Disease of bone.”. Arthritis Rheum.. vol. 23:. 1980. pp. 1121-1127. (Classic description of clinical manifestations.)
Cundy, T, Gamble, G, Wattie, D. “Paget’s Disease of bone in New Zealand: Continued Decline in disease severity. Calcified Tissue International.”. vol. 75:. pp. 358-364. (Description showing that the disease is declining in incidence and severity.)
Singer, FR. “Paget’s Disease of bone-genetic and environmental factors.”. Nat. Rev. Endocrinol.. vol. 11:. 2015:. pp. 662-671. (Excellent review of pathophysiology and factors causing the disease.)
Singer, FR, Bone, HG, Hosking, DJ. “Paget’s Disease of Bone: An Endocrine Society Clinical Practice Guideline.”. J. Clin. Endocrinol. Metab.. vol. 99:. 2014:. pp. 4408-4422. (The Endocrine Society’s clinical guideline for diagnosis and treating the disease.)
Siris, ES, Lyles, KW, Singer, FR, Meunier, PH. “Current Recommendations for Medical management of Paget’s Disease of Bone: US Perspective. J.”. Bone Mineral Res.. 2006:. pp. P94-P98.. (Review and rationale for US guideline for disease treatment.)
Langston, AL, Campbell, MK, Fraser, WD. “Randomized Trial of Intensive Bisphosphonate Treatment Versus Symptomatic Management in Paget’s Disease of Bone. J. Bone Mineral Res.”. vol. 1. 2010:. pp. 20-31. (Clinical trial done in the United Kingdom showing that in patients with established disease intensive treatment of the disease has no advantage over symptom-driven management.)
Reid, IR, Miller P., Lyles KW. “A single infusion of Zoldedronic Acid Improves Remission Rates in Paget’s Disease: A Randomized Controlled Comparison with Risedronate.”. New Engl. J. Med.. vol. 353:. 2006:. pp. 898-908. (Trial to show zoledronic acid is superior to risedronate in producing a response in Paget’s Disease and shows improvement in quality of life measures.)
Reid, IR, Lyles, KW, Su, G. “A Single Infusion of Zoledronic Acid Produces Sustained Remissions in Paget’s Disease. J.”. Bone Mineral Res.. 2011:. pp. 2261-2270. (Study shows the ability of Zoledronic Acid to produce sustained remissions in Paget Disease.)
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