Clinical manifestations

Presentation and course

Paget disease of bone is a focal disorder where the normal relationship between the continuous remodeling of bone by resorption and reformation is disrupted. Increased bone resorption with increased but abnormal bone reformation results in a disorganized mechanical structure and formation of thickened and structurally weakened bone (“mosaic” pattern of lamellar bone). The most common sites of involvement are the pelvis, lumbar spine, and femur, which are involved in more than 75% of cases; polyostotic disease is a more common occurrence than monostotic. The predilection for involvement of the vertebrae and the skull (skull involvement has a lower prevalence in men) is reflected by the potential for neurologic complications involving the spinal cord, cauda equina or spinal nerves, cranial nerves, and brain (33; 64; 56; 21; 02; 07).

Paget disease of bone is asymptomatic in over 70% of affected patients. Major clinical features include bone pain, deformity, pathological fracture, secondary osteoarthritis, and deafness. Less common are spinal stenosis and nerve compression syndromes, and rarely encountered are hypercalcemia, hydrocephalus, paraplegia, cardiac failure, and osteosarcoma (57; 56). The neurologic syndromes of Paget disease of bone result from the close relationship between the skeletal and nervous system. They can be classified as those originating from involvement of the skull or the spine (64; 21). Direct compression of nervous tissue explains most observed syndromes, but vascular steal phenomena as blood flow is rediverted to the highly vascular bone of skull or spine and may play a role (41).

The diagnosis of Paget disease of bone begins with a careful history and examination, supported by laboratory studies (elevated total alkaline phosphatase), with subsequent x-ray and bone scintigraphy establishing the diagnosis. Further radiological evaluation may be necessary with CT or MRI but is dictated by history and examination and not routinely performed.

In the setting of known Paget disease of bone, no neurologic syndromes are specific for the disorder. However, the presence of hearing loss or clinical features that suggest basilar impression, atlantoaxial instability, or spinal cord or nerve root syndromes suggest a possible relationship. Otherwise, it is best to consider Paget disease of bone as only one possible etiology for neurologic symptoms, and it is prudent to develop a complete differential diagnosis in each particular case.

Involvement of the skull leads to deformities of the skull base, narrowing of cranial nerve foramina, involvement of the cochlear capsule, and hypemia of the skull (41). Reported symptoms include headache, cranial neuropathies, dementia, parkinsonism (29), seizures, hydrocephalus, and a brainstem syndrome (06; 54), but the casual relationships are not always clear. The headache is often occipital, severe, and aggravated by coughing, sneezing, or straining (18) and may be secondary to basilar impression or a vascular steal phenomenon (41).

Paget disease of bone involvement of the base of the skull can affect the craniovertebral junction, which comprises the occiput, atlas, axis articulations, and ligaments; these structures enclose the cervicomedullary junction and lower four cranial nerves. Symptoms develop when the vertebral column becomes situated at an abnormally high level with respect to the skull base or basilar impression (or acquired basilar invagination). Symptoms and signs appear as neural structures are compromised, usually slowly and insidiously, manifested as dysfunction of brainstem, cerebellum, lower cranial nerves, cervical spinal cord, or upper cervical roots. Clinical findings include occipital headache, myelopathic motor and sensory deficits, brainstem or cerebellar signs, lower cranial nerve dysfunction, and at times evidence of vascular compromise (41). Hydrocephalus can develop as a result of basilar impression, presenting with clinical features of normal pressure hydrocephalus and responding to ventriculoperitoneal shunting (63). These skeletal changes of Paget disease of bone require careful consideration prior to surgery in regard to intubation, head positioning, and potential for excessive bleeding from hypervascularity of bone.

Hearing loss is a frequent feature of Paget disease of bone with skull involvement, prominent in 54.7% (control 20%), but likely underreported (05;40:189-93." data-code="PMID 16962839" data-url="https://www.ncbi.nlm.nih.gov/pubmed/16962839">84). Tinnitus is more frequent and obvious with increasing hearing impairment (38). The majority of patients demonstrate a high-frequency sensorineural hearing loss with low frequency air-bone gap. A continuous loss of bone mineral density of the cochlear capsule in Paget disease of bone explains both of those observations, possibly through disruption between mechanical and electrical sensory transduction; neither involvement of the ossicular chain nor compression of the acoustic nerve has been consistently demonstrated (44).

Other than hearing loss, cranial nerve deficits are uncommon and are frequently anecdotal in their reporting, with a crude relative risk of 1.2 with a 95% CL of 0.7 to 2.1 (05). Blindness is rare, but narrowing of the optic foramina can lead to optic atrophy (06), and papilledema may be evident if there is associated hydrocephalus. Anosmia can develop from involvement of the cribriform plate and ophthalmoplegia from nerve compression at the supraorbital fissure or petrous apex (52). Proptosis and enophthalmos may result from a disproportionate increase in the cranium compared to the ocular bones (26). Trigeminal neuralgia with hemifacial spasm (19), facial paralysis, bulbar palsy with dysphagia, and weakness of the sternocleidomastoid, trapezius, and tongue have been reported (41).

The possible causes of an acute cranial epidural hematoma, rare in the elderly, in the pagetoid skull following minimal head trauma include: (1) pathologic fracture due to pagetic changes of the skull, (2) hypervascularity of pagetic bone, (3) loosened dural adhesion to the internal table of the skull, and (4) a decreased tamponading effect to the developing epidural hematoma due to age-related atrophy of the brain (30). Epidural hematoma has been described in the spine with resulting cauda equina syndrome (62).

The spine is the second most common site of involvement, leading to an increased incidence of back pain, with the reported incidence ranging from 11% to 43% (24). Care must be exercised in attributing back pain to Paget disease alone because back pain solely attributed to Paget disease occurs in only 12% to 24% of cases with spine involvement. In the remainder of cases, arthritic or coexisting arthritic processes are responsible (22). The pain associated with Paget disease of bone is different than mechanical or arthritic pain and reflects different or multiple etiologies. It tends to be described as a deep, dull ache, unrelated to activity and not relieved by rest, sleep, or non-steroidal medications.

Paget disease of bone spine involvement is present at one or more sites in the majority of patients. Lumbar (54%) or thoracic (44%) sites are more frequently involved than cervical (15%) (33). Neurologic compromise remains uncommon but occurs more frequently with involvement of the thoracic or cervical spine. Perhaps the relatively larger lumbar central canal is responsible for this selectivity (22). Vertebral body compression fracture is the most common complication involving the spine and presents with the sudden onset of back pain, frequently at the lumbar site.

In one third of patients with spine involvement, symptoms of spinal stenosis may develop (24). The presentation of spinal stenosis with neurologic manifestations shows no pattern specific for Paget disease of bone. Lateral spinal stenosis could result in a radicular syndrome with the accompanying clinical features. Central stenosis may present as cauda equina, conus medullaris, or as a syndrome of neurogenic claudication while at the thoracic or cervical spine level, a myelopathic presentation may be seen. At times, a slowly progressive myelopathic presentation may not correspond to a demonstrable compressive lesion but may respond to medical treatment, suggesting either a decrease in soft-tissue swelling or reversal of a redistribution of blood flow from a “vascular steal” (41). Atlantoaxial instability from an underlying odontoid fracture is an uncommon but serious presentation (66).

Although a rare occurrence, the development of a sarcoma should be considered in the setting of a progressive deficit, increasing pain, or swelling. In such settings, further neurologic evaluation is necessary and by necessity may include MRI or CT imaging of the involved site.

Prognosis and complications

The prognosis of Paget disease of bone has markedly improved with the institution of bisphosphonate therapy, and neurologic complications may stabilize with medical therapy, but long-term prognosis remains unclear (07; 42). Rare complications such as hydrocephalus may improve with shunting, and advances in the surgical management of spine and atlantoaxial instability have also benefited Paget disease of bone patients. Non-skeletal neurologic complications from Paget disease of bone remain infrequent and population-based estimates suggest involvement of cranial nerves (0.4%), peripheral nerves (1.7%), nerve roots (3.8%), and basilar invagination (2.1%). Hearing loss was noted in 61% of patients (80), and although bisphosphonate therapy leads to a reduction in total alkaline phosphatase and might lessen tinnitus and vertigo, hearing loss may not improve (16).

Sarcomatous transformation of a pagetic bone (type of secondary osteosarcoma) is a rare occurrence that more often affects men, has a mean age at diagnosis of 66 years, and predominantly involves the axial skeleton (especially the pelvis); 88% of these were high grade osteosarcomas (15). Paget disease sarcomas were once believed to arise more often in polyostotic (78%) versus monostotic disease, but 42% to 47% of cases are now monostotic and may represent the initial manifestation of Paget disease of bone (15; 39). The current incidence of pagetic sarcoma in most series remains less than 1%, but despite advances in the treatment of primary osteosarcomas in children, there has been no similar significant improvement in outcome over the last several decades in Paget disease of bone, with a median survival of 0.67 years (39; 65).

A registry review of Paget sarcoma identified 13 patients with involvement of the spine (14.6%), 10 of whom were male with a median age of 66.9 years and with sacral and lumbar spine predominantly involved, but it remains a rare occurrence (69). As expected, their presentation was with increasing back and radicular pain accompanied by lower extremity weakness and autonomic dysfunction. Decompressive laminectomy (three patients) or radiotherapy (eight patients) treatments were instituted, but median survival was 4.2 months (0 to 13 months), and the predominant tumor was osteosarcoma.

Explanations for poor outcomes of sarcomas include limitation in chemotherapy administration by comorbidities within elderly patients, difficulty in its radiologic distinction from Paget disease of bone changes, and pre-existing pain or disability making malignant transformation less symptomatically obvious (39). Each of these contributes to the fact that at the time of diagnosis most tumors are at an advanced stage.

Clinical vignette

An 80-year-old, right-handed man presented with a brief episode of vertigo, which occurred as he rolled onto his right side when going to sleep and lasted seconds. His medical history included coronary artery disease (s/p CABG), hypertension, hyperlipidemia, and Paget disease of bone, which had been diagnosed earlier when he presented with bone pain and an elevated total alkaline phosphatase. Physical examination demonstrated only his hearing loss. Dix-Hallpike maneuver was negative. Laboratory evaluations included a normal CBC, ESR, and chemistry survey. Brain MRI described moderate chronic small vessel ischemic change in the deep white matter of either hemisphere; on MR angiography only mild to moderate mild basilar artery narrowing was seen. His audiogram demonstrated high-frequency sensorineural hearing loss bilaterally, worse on the right, but no low frequency air-bone gap. A diagnosis of benign positional vertigo was made, and his medical treatment for hypertension was further optimized while aspirin therapy was maintained.

This man’s hearing loss may have been secondary to his Paget disease of bone, but in light of the otherwise asymptomatic nature of his Paget disease, the lack of more prominent changes on radiological imaging, and normal total alkaline phosphatase level, no further interventions were undertaken (56; 68).

Biological basis

Etiology and pathogenesis

Although the etiology of Paget disease of bone is unknown, there is evidence for both genetic and environmental factors. Familial and sporadic subtypes are described. There are geographic differences in prevalence and an increasing prevalence with age but the overall prevalence and severity have decreased over the last 25 years (10). A positive family history is elicited in at least 15% of cases (36), and the risk of developing the disease in a relative of an affected person is 7 to 10 times greater than in the general population. In familial forms of Paget disease of bone, at least seven chromosomal regions or loci (PDB1 to PDB7) are described as containing a potential candidate gene, but only PDB-3 codes for a gene on chromosome 5q35, sequestosome 1 (SQSTM1). Mutations within SQSTM1 are identified in up to 40% of hereditary autosomal dominant Paget disease of bone cases and 10% of sporadic cases; the mutations may, however, predict individuals at risk of more severe disease (78; 58). Additional candidate genes that increase the risk of Paget disease of bone are being identified (01).

The primary cellular abnormality in Paget disease of bone is considered to arise from the osteoclast or its precursor, but abnormalities of the osteoblast and bone microenvironment suggest a more complicated pathogenesis (57). However, the osteoclast signaling pathway and in particular the receptor RANK (Receptor Activator of NF-Kappa B) on osteoclast precursors and its activating ligand, RANKL (secreted by stromal cells and osteoblasts), has the greatest relevance to Paget disease of bone and several related disorders. RANK/RANKL interaction leads to osteoclast activation and inhibition of osteoclastic apoptosis. The SQSTM1 gene encodes p62, a scaffolding protein that forms a complex with RANK and other proteins that after RANKL binding are important for the eventual downstream activation of several transcription factors including NF-κB. Mutations in the SQSTM1 gene affect its ubiquitin binding and through unclear mechanisms affect osteoclastic function (59).

Several rare genetic disorders share characteristics with Paget disease of bone: increased bone turnover, expansion, and deformity as well as alkaline phosphatase elevations (08). The allelic autosomal dominant disorder that affects the RANK protein (TNFRSF11A gene) by activating it is familial expansive osteolysis (expansile skeletal hyperphosphatasia or early-onset familial Paget disease). Onset is in childhood or early adulthood, tends to symmetrically involve the appendicular skeleton, and is associated with early deafness. An autosomal recessive disorder, juvenile Paget disease of bone (familial hyperphosphatasemia or idiopathic hyperphosphatasia) affects the protein osteoprotegerin (TNFRSF11B), a decoy receptor for RANKL. Onset is in infancy or early childhood; the whole skeleton is involved symmetrically; and deafness as well as retinal changes may occur. An autosomal disorder, IBMPFD (inclusion body myopathy, Paget disease of bone, and frontotemporal dementia) affects the VCP gene encoding the valosin-containing protein. Although it is involved in various cellular processes, one process is of relevance, ubiquitin-dependent protein degradation affecting NF-κB signaling through regulation of an associated protein, 1κB-alpha. The most typical presentation for IBMPFD is at a mean age of onset of 44 years and with a proximal myopathy. Muscle biopsy shows nonspecific myopathic changes with or without rimmed vacuoles consistent with inclusion bodies (77; 28). Patients may have typical features of Paget disease of bone (seen in 57%) and an elevated alkaline phosphatase, but the mean age of onset of these symptoms is earlier, at 40 years of age (34). A frontotemporal dementia with a mean age of onset of 57 years “completes” the triad, but the triad is found in only 27% of individuals. A report noted Paget disease in association with spastic paraparesis in a patient with a VCP mutation (47).

A viral etiology was suggested in Paget disease of bone after the identification of nucleocapsid-like structures within the nuclei and cytoplasm of osteoclasts; paramyxoviruses were suggested as the etiology (60). Because SQSTM1 and VCP genes play a role in the process of autophagy, these same inclusions may only represent abnormal degradation products or aggregates of cellular proteins (32; 56).

Three main phases of Paget disease of bone correspond to the “prominence” of either osteoclastic or osteoblastic activity: (1) the osteolytic phase where osteoclastic activity predominates and bone resorption (or absorption) occurs, (2) the mixed phase with a combination of osteoblastic and osteoclastic activity, and (3) the osteoblastic phase where new bone formation (apposition) occurs. The high bone turnover characteristic of Paget disease of bone is manifested as increased trabecular number (rather than thickness), resulting in an increase in cancellous bone volume and prominent fibrosis seen at the trabecular bone surface. The contributory role of osteoblast involvement is further highlighted within a quantitative histomorphometric review of biopsied cases. Using specific indices, the prominence of the resulting osteoid formation reflects increased osteoblast function rather than a mineralization defect (67). One other phase, inactive sclerotic phase where new osteoclastic and osteoblastic formation ceases, but the bone retains a sclerotic architecture, may represent “the” final stage (13).

Recognition of the initial lytic phase is dependent on the ratio between trabecular and cortical bone. When the ratio is low (skull, femur, and humerus) a clear lytic radiographic leading edge at the interface with normal bone is seen.

When the ratio is high (vertebra, sacrum, and pelvis) the lytic phase is not detected (13). All phases can otherwise be identified in the same patient and in different bones. An interesting observation is that while progression of disease occurs, new bone involvement, crossing of Paget disease of bone to adjacent bone or across joints, or “metastasis” to new sites is uncommon (33).

Neurologic complications can occur during any phase of the disease (54; McKloskey and Kanis 2002; 64). The mechanisms of neurologic compromise include: (1) direct compression of neurologic structures from expansion of bone (79), (2) ossification of adjacent structures (25; 27; 48), (3) pathologic fracture or subluxation, (4) epidural hematoma (17; 30; 62), (5) sarcomatous change (40), and (6) ischemia due to vascular steal (55; 85), or compression of the vascular supply to neurologic tissues.

Involvement of the spine in Paget disease of bone results in vertebral body expansion in the anterior-posterior and lateral dimensions, usually through periosteal apposition and endosteal absorption. Vertebral height remains unchanged as the vertebral endplates are subchondral condensations of trabecular bone, not true bony cortex, so they lack a periosteum or endosteum interface (13). This combination of apposition and absorption at the periosteal/endosteal surfaces of the anterior and posterior border results in trabecular bone hypertrophy and thickening of the end-plates of the vertebrae that results in a radiographic image referred to as “picture-frame” sign; progression to the sclerotic phase with an increased density of the vertebra body leads to a radiographic image of an “ivory vertebrae.” Involvement of the posterior neural arch elements causes further narrowing of the spinal canal through periosteal apposition and either endosteal apposition or absorption. Involvement of the adjacent soft tissue, cartilage, ligaments, and intervertebral disc (24) as well as extra-osseous extension can occur. Secondary bone marrow changes develop, but their variable expression on MRI may necessitate comparison to standard radiographs or CT images to exclude suspected Paget disease of bone.

The symptoms that result from spine involvement are attributable to vertebral expansion, facet joint arthritis, ligament ossification, spondylolisthesis, fracture, extra-osseous involvement, or an arterial steal syndrome (13). However, involvement of the spine in Paget disease of bone may be asymptomatic or the etiology of such symptoms unrelated. Rare causes of compression of the cord or cauda equina by ossification of the epidural fat and ligamentum flavum (25; 23; 27; 48) have been reported. Myelopathy has been described in Paget disease without evidence of compression (85) and with or without compression may respond completely to calcitonin or bisphosphonate therapy. Vascular steal may account for neurologic compromise in these patients. Blood flow in pagetic bone using 18F clearance in 14 patients ranged from 4.4% to 18.9% blood volume/min in patients with Paget disease compared to 4.4% to 5.9% in those without Paget disease of bone. The increase in skeletal blood flow correlated with increased levels of total alkaline phosphatase. Both fell towards normal after treatment with calcitonin (83).

Epidemiology

There are substantial differences in the prevalence of Paget disease of bone with distinct regional clusters of high prevalence, but the highest rates occur in Britain, Australia, and New Zealand. It is rare in Scandinavia, the Indian subcontinent, and Southeast Asia (57). It is rarely diagnosed under the age of 50 years, but by the age of 85 years, 7% of men and 6% of women in Britain are affected. Within the United States, a similar tendency for prevalence to increase with age has been noted, but the overall prevalence is estimated as 1% (03). The prevalence of clinically diagnosed Paget disease of bone in Britain compared to radiographic prevalence suggests that approximately 7% of radiographic disease comes to clinical diagnosis (76).

What has been evident is that the prevalence, severity, sarcomatous transformation, age at onset, and extent of Paget disease of bone have continued to decrease whereas monostotic disease has become more frequently recognized (03; 11). These changes have been most marked in areas with the highest prevalence and suggest an unclear interaction between environmental and genetic factors (04; 10).

Some form of neurologic involvement has been reported in up to 76% of patients with Paget disease of bone (64).

Prevention

Treatment of Paget disease of bone with antiresorptive therapy has led to an improvement in symptoms, normalization of total alkaline phosphatase, radiographic improvement on scintigraphy, and resolution of lytic changes on x-ray (56; 68). Although more effective metabolic control of the disease is possible with the newer bisphosphonates, it is not known whether these treatments reduce or prevent long-term complications, as disease progression has occurred in earlier trials and with different agents (61). Another uncertain question is the benefit of treatment in asymptomatic individuals. With respect to this question the Zoledronate in the Prevention of Paget’s disease (ZiPP) study is evaluating the risks and benefits of prophylactic zoledronic acid therapy versus placebo in asymptomatic patients who have SQSTM1 mutations but have not yet been diagnosed with Paget disease of bone.

Differential diagnosis

The diagnosis of Paget disease of bone begins with a careful history and examination, supported by laboratory studies (elevated total alkaline phosphatase), with subsequent x-ray and bone scintigraphy establishing the diagnosis. Further radiological evaluation may be necessary with CT or MRI but is dictated by history and examination and not routinely performed.

In the setting of known Paget disease of bone, no neurologic syndromes are specific for the disorder. However, the presence of hearing loss or clinical features that suggest basilar impression, atlantoaxial instability, or spinal cord or nerve root syndromes suggest a possible relationship. Otherwise, it is best to consider Paget disease of bone as only one possible etiology for neurologic symptoms, and it is prudent to develop a complete differential diagnosis in each particular case.

Although a rare occurrence, the development of a sarcoma should be considered in the setting of a progressive deficit, increasing pain, or swelling. In such settings, further neurologic evaluation is necessary and by necessity may include MRI or CT imaging of the involved site.

Diagnostic workup

The serendipitous discovery of an elevated total alkaline phosphatase with normal liver function was often the manner that Paget disease of bone was first identified. Total alkaline phosphatase testing remains a useful marker of disease activity and effectiveness of treatment whereas other markers are not as useful or necessary (12). However, the observation of a decreasing prevalence, increasing age of presentation, and tendency for monostotic disease may now limit its “diagnostic” usefulness (56).

Bone imaging is necessary for the confirmation of Paget disease of bone as well as in the differential diagnosis. Bone scintigraphy and x-ray are the primary methods of imaging employed. Neither can detect all legions in Paget disease of bone, but bone scintigraphy detects lesions that are metabolically active and complimentary to biochemical markers, whereas those that are inactive can only be detected by x-ray. Quantitative bone scintigraphy can be used to access the effectiveness of therapies and interpretation of new symptoms that occur at sites distant from those identified. The uses of CT and MRI are not as clearly delineated, but high-resolution CT is effective in defining skull base and bony spine abnormalities, whereas MRI is useful in identifying sarcomatous degeneration and further clarifying spine and skull base changes (74). MRI has become the investigative modality of choice in patients with back pain and neurologic compromise. MRI findings in Paget disease of bone, however, are subtle and nonspecific (35).

Management

Asymptomatic Paget disease of bone identified by radiographs or an elevated serum alkaline phosphatase currently does not require treatment but follow-up is advised. Treatment in Paget disease of bone has the short-term goal of reducing bone turnover and alleviation or prevention of symptoms from neurologic and skeletal complications, whereas the long-term goals are to prevent osteoarthritis and progression of the disease (70). Symptoms that require treatment include bone pain, back pain, pain from arthropathy, or neurologic symptoms such as headache, hearing loss, radiculopathy, spinal cord syndromes, or symptomatic basilar impression. Possible indications for medical intervention in asymptomatic individuals include hypercalcemia, age of onset less than 50 years of age, lesions in high-risk areas such as the cervical or thoracic spine, or elevated total alkaline phosphatase. Treatment may also be instituted prior to a planned orthopedic procedure to reduce hypervascularity to a pagetic site (14).

The general management of pain is with nonsteroidal anti-inflammatories and additional treatment regimens. Mechanical assistance such as canes and heel lifts may be used as needed.

The PRISM (Randomized trial of Intensive versus Symptomatic Management of Paget disease) treatment trial compared symptomatic treatment (administered to patients experiencing pain) to intensive treatment (administered to patients with or without pain) in regard to the beneficial effects of lowering the serum alkaline phosphatase as a marker of disease activity (75). Serum alkaline phosphatase levels were significantly lower in the intensive treatment group within 4 months of beginning treatment, but there was no difference in quality-of-life assessments, overall bodily pain, or in pagetic bone pain (37). The PRISM-EZ study was an extension of the PRISM study and investigated the long-term effects of a treatment strategy that aimed to normalize bone turnover with that of symptomatic treatment (72). It showed that long-term intensive bisphosphonate therapy did not provide clinical benefit over symptomatic therapy and was associated with a nonsignificant increase in the risk of fractures, orthopedic events, and serious adverse events. Based on these studies it has been suggested that bisphosphonate therapy in Paget disease of bone should focus on symptom control rather than suppression of bone turnover.

The primary modality of treatment of Paget disease of bone is with antiresorptive therapies and any of the FDA-approved treatments can be used. Bisphosphonates are now considered drugs of first choice although their ability to prevent long-term complications is currently unknown (20). Pamidronate, zoledronic acid, and risedronate are favored because of their greater effectiveness in reducing bone turnover, but although randomized trials are not yet available in regards to comparative effectiveness (57), zoledronate is becoming the treatment of first choice. Pamidronate and zoledronate can be administered intravenously but are associated with a flu-like reaction in 10% to 25% of patients. Risedronate may be associated with gastrointestinal side effects and requires fasting before its administration. A single infusion may have a long-term effect (61). Intramuscular neridronate may be an alternative to those unwilling to undergo intravenous therapy or intolerant of oral bisphosphonates (43). Bisphosphonate therapy should be avoided in renal impairment and limited safety data suggest it should also be avoided in pregnancy and lactation. Although bisphosphonate therapies are increasingly used, postmarketing surveillance has suggested different safety issues summarized in a review (71): 1) although the absolute risk of atypical femoral fracture is increased with long-term use, that risk is small; 2) osteonecrosis of the jaw is rare and more common in high-dose therapy used in oncology (82), but jaw pain can occur in Paget disease of bone; 3) risk of atrial fibrillation is negligible; and 4) a definite link to an increased risk of esophageal cancer is not established. Although not a formal recommendation, after 5 years consideration should be made to a drug holiday for those patients at low risk of fracture (71).

“Resistance” (biochemical or total alkaline phosphatase normalization) to one bisphosphonate does not indicate resistance to the class of drugs, and total alkaline phosphatase response may occur with another (31). Acquired resistance to the effectiveness of bisphosphonates has also been observed with pamidronate and with clodronate and may be related to vitamin D receptor gene polymorphisms (45), but this type of resistance has not yet been evident with zoledronate.

Dietary calcium and vitamin D deficiencies must be corrected prior to the use of any bisphosphonates to prevent hypocalcemia or focal osteomalacia.

The cost-effective way to evaluate the success of bisphosphonate therapy is with total alkaline phosphatase measured 3 months after therapy and a decision to retreat by a total alkaline phosphatase level at 6 months. Recurrence or persistence of symptoms, elevation of total alkaline phosphatase to 25% above normal, or the lowest nadir and reappearance of lytic lesions support consideration of retreatment (14). The newer intravenous bisphosphonates may allow the total alkaline phosphatase to be followed less often, every 6 to 12 months, due to their longer skeletal half-life. Pain may have alternate etiologies, and it alone may not necessarily support a therapeutic intervention, prior to investigation for other potential non-Paget disease of bone etiologies.

The most common indication for surgical treatment of Paget disease of bone is joint replacement for osteoarthritis, but other surgical procedures include fixation of a fracture or osteotomy. Paget disease of bone involvement of spine or skull may necessitate surgical intervention, but medical management may still be effective and an initial consideration. Therefore, aggressiveness of initial interventions needs to be tempered by severity and acuteness of the neurologic deficit. In select cases, spinal decompression to relieve compression of neural elements may be indicated (02).

CSF diversionary procedures for Paget disease related hydrocephalus may result in significant neurologic recovery (49).

Surgery or spinal complications are difficult due to involvement at multiple levels, vascular bone with problematic bleeding, and the older age group. A review of 62 published cases showed some degree of benefit in 82% but an 11% mortality rate and reoperation required in 9% (79). Medical management is still the preferred initial intervention, but there are benefits of newer techniques such as vertebroplasty (73). Careful preoperative assessment and attention to perioperative bleeding risks remains critical (53).

Special considerations

Pregnancy

The lack of safety data suggests that bisphosphonate therapy should be avoided in pregnancy and lactation.

Anesthesia

There is no increased risk from anesthesia in these patients. However, increased bone vascularity can place the patient at risk for perioperative increase in bleeding, and pagetic involvement of the skull base or cervical spine may restrict mobility, so surgical positioning as well as intubation may be more problematic. Regional spinal anesthesia can also become difficult if pagetic involvement of bone results in compression fractures and ossification of ligaments (46).