Paget’s disease is a localized bone-remodeling disorder that affects widespread, noncontiguous areas of the skeleton. The pathologic process is initiated by overactive osteoclastic bone resorption followed by a compensatory increase in osteoblastic new bone formation, resulting in a structurally disorganized mosaic of woven and lamellar bone. Pagetic bone is expanded, less compact, and more vascular; thus, it is more susceptible to deformities and fractures. Although most patients are asymptomatic, symptoms resulting directly from bony involvement (bone pain, secondary arthritis, fractures) or secondarily from the expansion of bone causing compression of surrounding neural tissue are not uncommon.
There is a marked geographic variation in the frequency of Paget’s disease, with high prevalence in Western Europe (Great Britain, France, and Germany, but not Switzerland or Scandinavia) and among those who have immigrated to Australia, New Zealand, South Africa, and North and South America. The disease is rare in native populations of the Americas, Africa, Asia, and the Middle East; when it does occur, the affected subjects usually have evidence of European ancestry, supporting the migration theory. For unclear reasons, the prevalence and severity of Paget’s disease are decreasing, and the age of diagnosis is increasing.
The prevalence is greater in males and increases with age. Autopsy series reveal Paget’s disease in about 3% of those over age 40. Prevalence of positive skeletal radiographs in patients aged >55 years is 2.5% for men and 1.6% for women. Elevated alkaline phosphatase (ALP) levels in asymptomatic patients have an age-adjusted incidence of 12.7 and 7 per 100,000 person-years in men and women, respectively.
The etiology of Paget’s disease of bone remains unknown, but evidence supports both genetic and viral etiologies. A positive family history is found in 15–25% of patients and, when present, raises the prevalence of the disease seven- to tenfold among first-degree relatives.
A clear genetic basis has been established for several rare familial bone disorders that clinically and radiographically resemble Paget’s disease but have more severe presentation and earlier onset. A homozygous deletion of the TNFRSF11B gene, which encodes osteoprotegrin (Fig. 405-1), causes juvenile Paget’s disease, also known as familial idiopathic hyperphosphatasia, a disorder characterized by uncontrolled osteoclastic differentiation and resorption. Familial patterns of disease in several large kindred are consistent with an autosomal dominant pattern of inheritance with variable penetrance. Familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset Paget’s disease are associated with mutations in TNFRSF11A gene, which encodes RANK (receptor activator of nuclear factor-κB), a member of the tumor necrosis factor superfamily critical for osteoclast differentiation (Fig. 405-1). Finally, mutations in the gene for valosin-containing protein cause a rare syndrome with autosomal dominant inheritance and variable penetrance known as inclusion body myopathy with Paget’s disease and frontotemporal dementia (IBMPFD). The role of genetic factors is less clear in the more common form of late-onset Paget’s disease. The most common mutations identified in familial and sporadic cases of Paget’s disease have been in the SQSTM1 gene (sequestasome-1 or p62 protein) in the C-terminal ubiquitin-binding domain. The other candidate genes include: CSF1 (1p13), which encodes macrophage colony stimulating factor (M-CSF), a cytokine that is required for osteoclast differentiation; RIN3 (14q32), which encodes a guanine exchange factor called Rab and Ras interactor 3; OPTN (10p13), which is involved in regulating NFκB, TNFRSF11A (18q21) which encodes Receptor Activator of Nuclear Factor-κB (RANK), a receptor that is essential for osteoclast differentiation; and TM7SF4, which encodes Dendritic Cell-Specific Transmembrane Protein (DC-STAMP), a molecule that is essential for fusion of osteoclast. The phenotypic variability in patients with SQSTM1 mutations suggests that additional factors, such as other genetic influences or viral infection, may influence clinical expression of the disease.
Diagram illustrating factors that promote differentiation and function of osteoclasts and osteoblasts and the role of the RANK pathway. Stromal bone marrow (mesenchymal) cells and differentiated osteoblasts produce multiple growth factors and cytokines, including macrophage colony-stimulating factor (M-CSF), to modulate osteoclastogenesis. RANKL (receptor activator of nuclear factor-κB ligand) is produced by osteoblast progenitors and mature osteoblasts and can bind to a soluble decoy receptor known as osteoprotegerin (OPG) to inhibit RANKL action. Alternatively, a cell-cell interaction between osteoblast and osteoclast progenitors allows RANKL to bind to its membrane-bound receptor, RANK, thereby stimulating osteoclast differentiation and function. RANK binds intracellular proteins called tumor necrosis factor receptor–associated factors (TRAFs) that mediate receptor signaling through transcription factors such as NF-κB. M-CSF binds to its receptor, c-fms, which is the cellular homologue of the fms oncogene. See text for the potential role of these pathways in disorders of osteoclast function such as Paget’s disease and osteopetrosis. IL, interleukin; IGF, insulin-like growth factor.
Several lines of evidence suggest that a viral infection may contribute to the clinical manifestations of Paget’s disease, including (1) the presence of cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles and respiratory syncytial virus) in pagetic osteoclasts and (2) viral mRNA in precursor and mature osteoclasts. The viral etiology is further supported by conversion of osteoclast precursors to pagetic-like osteoclasts by vectors containing the measles virus nucleocapsid or matrix genes. The decline in the incidence of Paget’s disease coincides with the widespread vaccination against measles, also consistent with the potential role of virus in the development of the disease. However, the viral etiology has been questioned by the inability to culture a live virus from pagetic bone and by failure to clone the full-length viral genes from material obtained from patients with Paget’s disease.
The principal abnormality in Paget’s disease is the increased number and activity of osteoclasts. Pagetic osteoclasts are large, increased 10- to 100-fold in number, and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal osteoclast). The overactive osteoclasts may create a sevenfold increase in resorptive surfaces and an erosion rate of 9 μg/d (normal is 1 μg/d). Several causes for the increased number and activity of pagetic osteoclasts have been identified: (1) osteoclastic precursors are hypersensitive to 1,25(OH)2D3; (2) osteoclasts are hyperresponsive to RANK ligand (RANKL), the osteoclast stimulatory factor that mediates the effects of most osteotropic factors on osteoclast formation; (3) marrow stromal cells from pagetic lesions have increased RANKL expression; (4) osteoclast precursor recruitment is increased by interleukin (IL) 6, which is increased in the blood of patients with active Paget’s disease and is overexpressed in pagetic osteoclasts; (5) expression of the protooncogene c-fos, which increases osteoclastic activity, is increased; and (6) the antiapoptotic oncogene Bcl-2 in pagetic bone is overexpressed. Numerous osteoblasts are recruited to active resorption sites and produce large amounts of new bone matrix. As a result, bone turnover is high, and bone mass is normal or increased, not reduced, unless there is concomitant deficiency of calcium and/or vitamin D.
The characteristic feature of Paget’s disease is increased bone resorption accompanied by accelerated bone formation. An initial osteolytic phase involves prominent bone resorption and marked hypervascularization. Radiographically, this manifests as an advancing lytic wedge, or “blade of grass” lesion. The second phase is a period of very active bone formation and resorption that replaces normal lamellar bone with haphazard (woven) bone. Fibrous connective tissue may replace normal bone marrow. In the final sclerotic phase, bone resorption declines progressively and leads to a hard, dense, less vascular pagetic or mosaic bone, which represents the so-called burned-out phase of Paget’s disease. All three phases may be present at the same time at different skeletal sites.
Diagnosis is often made in asymptomatic patients because they have elevated ALP levels on routine blood chemistry testing or an abnormality on a skeletal radiograph obtained for another indication. The skeletal sites most commonly involved are the pelvis, vertebral bodies, skull, femur, and tibia. Familial cases with an early presentation often have numerous active sites of skeletal involvement.
The most common presenting symptom is pain, which may result from increased bony vascularity, expanding lytic lesions, fractures, bowing, or other deformities. Bowing of the femur or tibia causes gait abnormalities and abnormal mechanical stresses with secondary osteoarthritis of the hip or knee joints. Long bone bowing also causes extremity pain by stretching the muscles attached to the bone softened by the pagetic process. Back pain results from enlarged pagetic vertebrae, vertebral compression fractures, spinal stenosis, degenerative changes of the joints, and altered body mechanics with kyphosis and forward tilt of the upper back. Rarely, spinal cord compression may result from bone enlargement or from the vascular steal syndrome. Skull involvement may cause headaches, symmetric or asymmetric enlargement of the parietal or frontal bones (frontal bossing), and increased head size. Cranial expansion may narrow cranial foramens and cause neurologic complications including hearing loss from cochlear nerve damage from temporal bone involvement, cranial nerve palsies, and softening of the base of the skull (platybasia) with the risk of brainstem compression. Pagetic involvement of the facial bones may cause facial deformity; loss of teeth and other dental conditions; and, rarely, airway compression.
Fractures are serious complications of Paget’s disease and usually occur in long bones at areas of active or advancing lytic lesions. Common fracture sites are the femoral shaft and subtrochanteric regions. Neoplasms arising from pagetic bone are rare (<0.5%). The incidence of sarcoma appears to be decreasing, possibly because of earlier, more effective treatment with potent antiresorptive agents. The majority of tumors are osteosarcomas, which usually present with new pain in a long-standing pagetic lesion. Osteoclast-rich benign giant cell tumors may arise in areas adjacent to pagetic bone, and they respond to glucocorticoid therapy.
Cardiovascular complications may occur in patients with involvement of large (15–35%) portions of the skeleton and a high degree of disease activity (ALP four times above normal). The extensive arteriovenous shunting and marked increases in blood flow through the vascular pagetic bone lead to a high-output state and cardiac enlargement. However, high-output heart failure is relatively rare and usually develops in patients with concomitant cardiac pathology. In addition, calcific aortic stenosis and diffuse vascular calcifications have been associated with Paget’s disease.
The diagnosis may be suggested on clinical examination by the presence of an enlarged skull with frontal bossing, bowing of an extremity, or short stature with simian posturing. An extremity with an area of warmth and tenderness to palpation may suggest an underlying pagetic lesion. Other findings include bony deformity of the pelvis, skull, spine, and extremities; arthritic involvement of the joints adjacent to lesions; and leg-length discrepancy resulting from deformities of the long bones.
Paget’s disease is usually diagnosed from radiologic and biochemical abnormalities. Radiographic findings typical of Paget’s disease include enlargement or expansion of an entire bone or area of a long bone, cortical thickening, coarsening of trabecular markings, and typical lytic and sclerotic changes. Skull radiographs (Fig. 405-2) reveal regions of “cotton wool,” or osteoporosis circumscripta, thickening of diploic areas, and enlargement and sclerosis of a portion or all of one or more skull bones. Vertebral cortical thickening of the superior and inferior end plates creates a “picture frame” vertebra. Diffuse radiodense enlargement of a vertebra is referred to as “ivory vertebra.” Pelvic radiographs may demonstrate disruption or fusion of the sacroiliac joints; porotic and radiodense lesions of the ilium with whorls of coarse trabeculation; thickened and sclerotic iliopectineal line (brim sign); and softening with protrusio acetabuli, with axial migration of the hips and functional flexion contracture. Radiographs of long bones reveal bowing deformity and typical pagetic changes of cortical thickening and expansion and areas of lucency and sclerosis (Fig. 405-3). Radionuclide 99mTc bone scans are less specific but are more sensitive than standard radiographs for identifying sites of active skeletal lesions. Although computed tomography (CT) and magnetic resonance imaging (MRI) studies are not necessary in most cases, CT may be useful for the assessment of possible fracture, and MRI is necessary to assess the possibility of sarcoma, giant cell tumor, or metastatic disease in pagetic bone. Definitive diagnosis of malignancy often requires bone biopsy.
A 48-year-old woman with Paget’s disease of the skull. Left. Lateral radiograph showing areas of both bone resorption and sclerosis. Right. 99mTc HDP bone scan with anterior, posterior, and lateral views of the skull showing diffuse isotope uptake by the frontal, parietal, occipital, and petrous bones.
Radiograph of a 73-year-old man with Paget’s disease of the right proximal femur. Note the coarsening of the trabecular pattern with marked cortical thickening and narrowing of the joint space consistent with osteoarthritis secondary to pagetic deformity of the right femur.
Biochemical evaluation is useful in the diagnosis and management of Paget’s disease. The marked increase in bone turnover can be monitored using biochemical markers of bone formation and resorption. The parallel rise in markers of bone formation and resorption confirms the coupling of bone formation and resorption in Paget’s disease. The degree of bone marker elevation reflects the extent and severity of the disease. For most patients, serum total ALP remains the test of choice both for diagnosis and assessing response to therapy. Occasionally, a symptomatic patient with evidence of progression at a single site may have a normal total ALP level but increased bone-specific ALP. For unclear reasons, serum osteocalcin, another marker of bone formation, is not always elevated and is not recommended for use in diagnosis or management of Paget’s disease. In contrast, bone formation marker P1NP does reflect the activity of the disease and can be used instead of total ALP. Bone resorption markers (serum or urine N-telopeptide or C-telopeptide measured in the blood or urine) are also elevated in active Paget’s disease and decrease more rapidly in response to therapy than does ALP.
Serum calcium and phosphate levels are normal in Paget’s disease. Immobilization of a patient with active Paget’s disease may rarely cause hypercalcemia and hypercalciuria and increase the risk for nephrolithiasis. However, the discovery of hypercalcemia, even in the presence of immobilization, should prompt a search for another cause of hypercalcemia. In contrast, hypocalcemia or mild secondary hyperparathyroidism may develop in Paget’s patients with very active bone formation and insufficient calcium and vitamin D intake, particularly during bisphosphonate therapy when bone resorption is rapidly suppressed and active bone formation continues. Therefore, adequate calcium and vitamin D intake should be instituted prior to administration of bisphosphonates.
TREATMENT Paget’s Disease of Bone
The development of effective and potent pharmacologic agents (Table 405-1) has changed the treatment philosophy from treating only symptomatic patients to treating asymptomatic patients who are at risk for complications. According to the Endocrine Society Clinical Practice Guidelines published in 2014, pharmacologic therapy is indicated for most patients with active Paget’s disease who are at risk of complications. Treatment may be initiated to control symptoms caused by metabolically active Paget’s disease such as bone pain, fracture, headache, pain from pagetic radiculopathy or arthropathy, or neurologic complications; to decrease local blood flow and minimize operative blood loss in patients who need surgery at an active pagetic site; to reduce hypercalciuria that may occur during immobilization; and to decrease the risk of complications when disease activity is high (elevated ALP) and when the site of involvement involves weight-bearing bones, areas adjacent to major joints, vertebral bodies, and the skull. Whether or not early therapy prevents late complications remains to be determined. A randomized study of over 1200 patients from the United Kingdom showed no difference in bone pain, fracture rates, quality of life, and hearing loss between patients who received pharmacologic therapy to control symptoms (bone pain) and those receiving bisphosphonates to normalize serum ALP. However, the conclusions of that study are debatable since the most potent agent (zoledronic acid, the current drug of choice) was not used/available. It seems likely that the restoration of normal bone architecture following suppression of pagetic activity will prevent further deformities and complications.
Agents approved for treatment of Paget’s disease suppress the very high rates of bone resorption and secondarily decrease the high rates of bone formation (Table 405-1). As a result of decreasing bone turnover, pagetic structural patterns, including areas of poorly mineralized woven bone, are replaced by more normal cancellous or lamellar bone. Reduced bone turnover can be documented by a decline in serum formation markers (ALP and P1NP) and urine or serum resorption markers (N-telopeptide, C-telopeptide).
Bisphosphonates are the mainstay of pharmacologic therapy of Paget’s disease. Among them, zoledronic acid is currently recommended as the first choice, particularly for those who have severe disease or need rapid normalization of bone turnover (neurologic symptoms, severe bone pain due to a lytic lesion, risk of an impending fracture, or pretreatment prior to elective surgery in an area of active disease). Zoledronic acid normalized bone turnover faster and in a high proportion of patients (over 90%) than oral bisphosphonates with the therapeutic effect persisting for months or even years. It is given at a dose of 5 mg as an intravenous infusion over 20 min although slower rates of infusion are recommended for elderly or those with mild impairment of renal function. More significant renal impairment (GFR <35 mL/min) is a contraindication for use of zoledronic acid due to higher risk of further deterioration of renal function. About 20–25% of patients experience a flu-like syndrome after the first infusion, which can be partly ameliorated by pretreatment with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). Oral bisphosphonates, alendronate and risedronate, can be used in subjects who have mild disease or some degree of renal impairment. Oral bisphosphonates should be taken first thing in the morning on an empty stomach, followed by maintenance of upright posture with no food, drink, or other medications for 30–60 min. The first clinically useful agent, etidronate, is no longer used due to its low potency and higher risk of inducing osteomalacia. The efficacy of different agents, based on their ability to normalize or decrease ALP levels, is summarized in Table 405-1, although the response rates are not comparable because they are obtained from different studies.
The subcutaneous injectable form of salmon calcitonin is approved for the treatment of Paget’s disease but is rarely used due to its low potency and should be reserved for patients who either do not tolerate bisphosphonates or have a contraindication to their use. For patients with contraindication to bisphosphonates, another alternative is denosumab, an antibody to RANKL, which has been reported to result in reduction in ALP. However, it has not been approved for this indication and has less complete and less durable effect than bisphosphonates.
TABLE 405-1Pharmacologic Agents Approved for Treatment of Paget’s Disease ||Download (.pdf) TABLE 405-1 Pharmacologic Agents Approved for Treatment of Paget’s Disease
|Name ||Dose and Mode of Delivery ||Normalization of alkaline phosphatase (ALP) |
|Zoledronic acid ||5 mg IV over 15 min ||90% of patients at 6 mo |
|Pamidronate ||30 mg IV/d over 4 h on 3 days ||~50% of patients |
|Risedronate ||30 mg PO/d for 2 mo ||73% of patients |
|Alendronate ||40 mg PO/d for 6 mo ||63% of patients |
|Tiludronate ||800 mg PO daily for 3 mo ||35% of patients |
|Etidronate ||200–400 mg PO/d × 6 mo ||15% of patients |
|Calcitonin (Miacalcin) ||100 U SC daily for 6–18 mo (may reduce to 50 U 3 × per wk) ||(Reduction of ALP by up to 50%) |