Pagets disease of the spine

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The second part of this paper looks at Paget's disease, another osteometabolic disorder that can affect the aging spine. It describes the spinal involvement of Paget's disease in bone and outlines best treatment options.

Etiology

The original disease was described by Sir John Paget [100] in 1877, and despite recent intensive studies, its etiology remains obscure. Paget's disease of bone (PD), a mono-ostotic or polyostotic non-hormonal osteometabolic disorder, is postulated to be caused by a viral infection [10, 49, 127]. This claim is supported by circumstantial evidence garnered from electron microscopic, immuno-logic, and epidemiologic studies [56].

PD is found more commonly in populations of AngloSaxon origin, and is rarely encountered in Asia, Scandinavia, or the Middle East [9]. A survey of PD in South Africa revealed a prevalence of 1.3% among the black population and 2.4% among the white population [44], suggesting that PD may not be uncommon in Africans, as was previously believed [128]. Autopsy and radiographic studies indicate that the overall prevalence of PD is 3-3.7% [23, 104, 123], with a tendency to increase with age. At the age of 90, the expected prevalence is about 10% [123]. A very recent report on radiographic examination of the pelvis [5] revealed an estimated overall prevalence in the US of 1-2%, with near equal distribution between whites and blacks and between sexes.

Genetic factors also play a role in the pathogenesis of PD [62, 65, 129]. A positive family history in patients of siblings was reported in 12.3% of cases, as compared to 2.1% of controls. In another study, the prevalence of PD was found to be approximately seven times higher in relatives of cases than controls.

Viral infection may also help explain the genetic predisposition, by gene mutation, of PD [93]. Circumstantial evidence thus supports the plausible hypothesis that viral infection may trigger the onset of PD as well stimulate inheritable gene mutation. Future research hopefully will cast light on these issues [56].

Histopathology

The histopathology of PD is characterized by two entities: osseous lesions and bone marrow fibrosis. The former is characterized by its so-called mosaic appearance, which is the hallmark of the pagetic lesion. The pagetic cellularity consists of variable sizes of osteoblasts and large osteo-clasts with multiple nuclei (up to 100) [106].

Prevalence of back pain and spinal stenosis

The spine is the second most commonly affected site in PD [2, 30, 95], predisposing patients to low back pain and

Fig. 12 Bone modeling of vertebra depicted diagrammatically to demonstrate tendency of bone expansion in all directions, leading to hypertrophic facet osteoarthropathy and spinal stenosis. [Reprinted, with permission, from Hadjipavlou A, Lander P (1995) Paget's disease. In: White AH, Schofferman JA (eds) Spinal care. Mosby, St Louis, pp 1720-1737]

Fig. 12 Bone modeling of vertebra depicted diagrammatically to demonstrate tendency of bone expansion in all directions, leading to hypertrophic facet osteoarthropathy and spinal stenosis. [Reprinted, with permission, from Hadjipavlou A, Lander P (1995) Paget's disease. In: White AH, Schofferman JA (eds) Spinal care. Mosby, St Louis, pp 1720-1737]

Fig. 13 a Plain radiography demonstrating pagetic involvement of L4 vertebra with typical expansion in the mixed-blastic phase. b Axial computed tomography scan of the third lumbar vertebra, demonstrating circumferential expansion of a mixed-blastic-phase lesion of Paget's disease (PD) causing severe spinal stenosis. [Reprinted, with permission, from Hadjipavlou A, Gaitanis I, Katonis P, Lander P (2001) Paget's disease of the spine and its management. Eur Spine J 10:370-384]

Mitch Fracture
Fig. 14 Tl-weighted magnetic resonance image showing posterior expansion of the vertebral body. [Reprinted, with permission, from Hadjipavlou A, Gaitanis I, Katonis P, Lander P (2001) Paget's disease of the spine and its management. Eur Spine J 10:370-384]

spinal stenosis [4, 52, 64, 137]. Hartman and Dohn have shown that 15.2% of patients with PD had involvement of the vertebrae, and 26% of these patients had symptoms of spinal stenosis [59]. The reported incidence of back pain in PD ranges from 11% [40] to 34% [2] and as high as 43% [113]. The causal relationship between vertebral PD and back pain has been disputed [2], with low back pain in PD being attributed to coexisting osteoarthritis of the spine in 88% of patients and to PD alone in only 12%. Others consider PD to cause back pain even more rarely

[45]. However, in our population, 33% of patients with PD demonstrated pagetic involvement of the spine; 30% had clinical symptoms of spinal stenosis and 54% of these patients suffered back pain (24% attributed clearly to PD alone, 50% to degenerative changes and 26% to a combination of PD and degenerative changes) [46].

Spinal pain (back pain and neck pain)

PD can be defined as an abnormal disturbance of bone remodeling, giving rise to the four phases of the disease observed radiologically: the osteolytic, mixed, osteoblastic, and osteosclerotic phases [79]. This leads to abnormal modeling, which determines the shape and geometry of the bone [43] (Fig. 12) leading, in turn, to spinal stenosis [79] (Fig. 13, Fig. 14) and facet arthropathy [50, 57].

Pagetic facet arthropathy is a major contributing factor to both back pain and spinal stenosis, and the more advanced the facet joint arthropathy, the greater the likelihood that patients will suffer clinical spinal stenosis and/or back pain [46]. However, this does not necessarily preclude that, though present, severe facet arthropathy may remain asymptomatic [46]. Back pain in PD may also be attributed to blood engorgement of the vertebral body caused by vascular and disorganized, hyperactive remodeling processes.

Other factors implicated in spinal pain may include invasion of the vertebral disc space by the pagetic process (Fig. 15) [80], and spinal stenosis [137]. The authors hypothesize that microfractures of pagetic vertebral bodies, especially in the osteolytic or mixed phase, can also lead to back pain [46].

Spinal stenosis

Involvement of the cervical and thoracic spine tends very often to predispose to clinical spinal stenosis with my-

Fig. 15 a Lateral radiograph of the lumbosacral junction demonstrating mixed phase Paget's disease of the first sacral segment with moderate narrowing of the L5-S1 disc space. b Pagetic bone extension across the disc space with adjacent anterior bridging with sclerotic bone noted 3 years after the initial radiograph. c The corresponding axial CT scan of the L5-S1 disc demonstrates pagetic bone within the disc. d Lateral tomogram demonstrating the intradiscal bone extension from the adjacent S1 vertebra resulting in complete bony ankylosis 4 years after the initial radiograph. [Reprinted, with permission, from Lander P, Hadjipavlou A (1991) Intradiscal invasion of Paget's disease of the spine. Spine 16: 46-51]

Paget Disease Mechanism

elopathy [46]. Ten distinct mechanisms have been implicated in the development of neural element dysfunction in patients affected by PD:

Compression of the neural elements by pagetic bone overgrowth [31, 46, 76]

Compression by pagetic intraspinal soft tissue [46, 51] (Fig. 16)

Ossification of the epidural fat similar to ankylosing spondylitis [20]

Neural ischemia produced by blood diversion, causing the so-called "arterial steal phenomenon" [16, 59, 64, 103] (Fig. 17)

Interference with blood supply to the cord due to arterial compression by the expanding pagetic bone [123] or other factors not well defined [91] Vertebral fracture or atlantoaxial subluxation [124, 135] Platybasia with impingement on the medulla [28] Spinal cord compression by epidural hematoma from spontaneous bleeding [81, 110] Formation of syringomyelia as a complication of PD of the spine, especially after cranial settling (basilar invagination) [35, 110], and

10. Rarely, neurocompression can be caused by pagetic sarcomatous degeneration [67].

Bone compression by the expanding pagetic vertebrae is by far the most common cause of neural dysfunction [46]; it was first reported by Wyllie in 1923 [136]. However, severe stenosis, as seen on computed tomographic (CT) scan, may remain asymptomatic, suggesting adaptability of the thecal sac and its neural elements to severe spinal stenosis without significant loss of function [124].

The mechanism of neural ischemia is, however, still hypothetical, and supported only by circumstantial evidence. For example, patients with spinal cord symptomatology respond to calcitonin treatment better than patients with spinal nerve root lesions [28]; some patients experience progressive deterioration of neural function without evidence of myelographic block, which is not easily explained by mechanical effect alone [117]; neurologic signs do not always correlate with the site of skeletal involvement; and rapid clinical improvement occurs in some patients with medical antipagetic treatment alone. These observations suggest that neural dysfunction in PD may also result from mechanisms other than simple bone encroach

Fig. 16 A 63-year-old male patient with pagetic soft tissue expansion originating from the dens and compressing the medulla as seen on: a lateral tomogram of dens (bony element), and b MRI scan of soft tissue (see arrow). The patient was treated successfully with surgical decompression

Fig. 16 A 63-year-old male patient with pagetic soft tissue expansion originating from the dens and compressing the medulla as seen on: a lateral tomogram of dens (bony element), and b MRI scan of soft tissue (see arrow). The patient was treated successfully with surgical decompression

ment on the neural element [32, 47, 64, 74, 103, 134, 136], such as deprivation of blood supply to the neural elements by the rapidly remodeling hypervascular pagetic bone, which produces "arterial steal phenomenon".

Other associated conditions

Malignant transformation

Malignant transformation is the most dreaded complication of PD of bone. Fortunately, this complication is relatively rare, occurring in about 0.7% [52] of cases. In our series of PD patients [52, 53] we have not seen any cases with sarcomatous degeneration in the spine. In Schajow-icz et al. [120], of 62 patients with sarcomatous transformation, five of the sarcomas occurred in the spine. Surgical decompression offers little, if any, true relief of pain, with the longest survival reported at just over 5 months [67].

One should be aware of the appearance of "pseudosar-coma" or "pumice bone," which is a localized extracortical periosteal pagetic bone expansion or a bulky juxtacor-tical soft tissue mass, giving the erroneous appearance of sarcomatous transformation [62, 78] (Fig. 18).

Rheumatic and arthritic conditions

Forestier's disease, or disseminated idiopathic hyperostosis (DISH), can frequently affect patients with PD. However, care should be taken not to confuse DISH with Paget's extraosseous bone formation [15]. The incidence of DISH in PD was reported to range from 14% [48] to 30% [5]. Pagetic tissue may invade the hyperostotic lesions produced by DISH and transform them into pagetic exostosis [46], which may progress to vertebral ankylosis [89].

PD has also been noted to be associated with an increased incidence of gout [40] and pseudogout [105]. These

Fig. 17 A 78-year-old male patient presented himself with unsteady gait and confusion. a Bone scan (99Tc MDP) revealed increased uptake in the skull, and bone blood flow revealed increased engorgement of the skull. b After treatment with i.v. mithramycin, bone scan activity improved somewhat, while bone blood flow was restored to normal. This coincided with improvement of the patients gait and mental status, suggesting that the brain had most likely been deprived of its blood supply (steal syndrome by the skull hypervascularity)

Fig. 17 A 78-year-old male patient presented himself with unsteady gait and confusion. a Bone scan (99Tc MDP) revealed increased uptake in the skull, and bone blood flow revealed increased engorgement of the skull. b After treatment with i.v. mithramycin, bone scan activity improved somewhat, while bone blood flow was restored to normal. This coincided with improvement of the patients gait and mental status, suggesting that the brain had most likely been deprived of its blood supply (steal syndrome by the skull hypervascularity)

conditions, however, are not clearly implicated in the production of back pain. One has to keep in mind that treatment with sodium etidronate may be responsible for the accumulation of pyrophosphate crystals in the synovial joint, producing pseudogout [41].

Fig. 18 Anteroposterior radiograph of the lumbar spine showing a localized bulky juxtacortical bone expansion of the lateral aspect of L4-L5 vertebrae resulting in bone union. The appearance of the lesion may be misconstrued as sarcomatous degeneration (pseu-dosarcoma or pumice bone). The cortical margins are well defined in contrast to the usual appearance of sarcomatous transformation, which remains poorly delineated. [Reprinted, with permission, from Hadjipavlou A, Gaitanis I, Katonis P, Lander P (2001) Paget's disease of the spine and its management. Eur Spine J 10:370-384]

Fig. 18 Anteroposterior radiograph of the lumbar spine showing a localized bulky juxtacortical bone expansion of the lateral aspect of L4-L5 vertebrae resulting in bone union. The appearance of the lesion may be misconstrued as sarcomatous degeneration (pseu-dosarcoma or pumice bone). The cortical margins are well defined in contrast to the usual appearance of sarcomatous transformation, which remains poorly delineated. [Reprinted, with permission, from Hadjipavlou A, Gaitanis I, Katonis P, Lander P (2001) Paget's disease of the spine and its management. Eur Spine J 10:370-384]

Treatment

Treatment of back pain

One must be certain before attributing back pain to PD, otherwise the results of antipagetic treatment may not be rewarding [3]. For patients with low back pain and PD, suppressive therapy with EHDP (disodium etidronate) was beneficial to 36% of patients in one report [4]. This suggests that unless a well-defined lesion is related to low back pain, antipagetic therapy is not expected to be effective. If antipagetic medical therapy is ineffective within 3 months, a concomitant nonsteroidal anti-inflammatory drug and other treatment methods (physical therapy, corsets, etc) for back pain should be prescribed, especially when the presenting back pain is mechanical or arthritic in nature [50, 130].

Treatment of spinal stenosis

Because antipagetic medical therapy is rewarding in the treatment of pagetic spinal stenosis syndrome, one should start with antipagetic drug treatment. Calcitonin, mithra-mycin, sodium etidronate, pamidronate disodium, and clo-dronate have been reported to either improve or to completely reverse the clinical symptoms of spinal stenosis [1, 16, 36, 107]; however, relapse of spinal stenosis symptomatology after medical antipagetic treatment is not uncommon [32, 33]. Therefore, patients should be closely monitored and cyclical therapy should be continued if necessary until biochemical bone indices normalize.

Severe spinal stenosis of lytic type has been shown to respond successfully to antipagetic treatment with clo-dronate [36]. It has been suggested that, for pagetic spinal stenosis in the lytic phase of the disease, administration of vitamin D and calcium supplements to improve mineralization of lytic pagetic spinal lesion causing canal block can enhance the effectiveness of bisphosphonate therapy [36].

If the symptoms persist, in spite of bone remodeling markers normalization, surgery is an alternative treatment. Decompression of spinal stenosis should be implemented promptly after failure of antipagetic therapy. In these circumstances, delaying decompression may result in irreversible myelopathy or radiculopathy [80]. On the other hand, the results of surgery have shown variable improvement in 85% of patients [117], with frequent relapses or failures, which may improve with subsequent medical antipagetic therapy [1, 16, 107]. In our series, patients who demonstrated either partial or temporary improvement after laminectomy and were treated with further antipagetic medical treatment exhibited marked improvement of their symptomatology with sustained relief [50]. From our experience and from other reports, spinal surgery for pagetic spinal stenosis may fail to reverse the neurological deficit completely [15], and may be associated with serious complications such as a mortality rate of 11% [117] and dangerously profuse, if not torrential, bleeding [116]. To avoid such catastrophes, we recommend the preoperative assessment of bone vascularity by means of radionuclide bone blood flow in the affected spinal region. We have found this test reliable, simple and reproducible [11]. To decrease potential bleeding during surgery, if there is increased vascularity in the affected region, we strongly recommend a course of medical an-tipagetic treatment until the bone blood flow normalizes [50]. This may take 2-3 months with calcitonin therapy, or 2-3 weeks with mithramycin treatment [56, 57, 114]. The new generation of IV bisphosphonates can also be used effectively in this situation. In emergency situations, embolization of the region may be indicated. Because of the anticipated massive bleeding during laminectomy, the use of a cell saver is strongly recommended [115].

Surgery for spinal stenosis, when indicated, should be tailored to the pathology responsible for neural compres sion. If neural compression is caused by the posterior expansion of vertebral bodies, an anterior approach with corpectomy and fusion is indicated. If neural compression is caused by posterior vertebral elements, then posterior decompression should be the approach of choice [50]. An acute onset of spinal compression seems to bear a graver prognosis than the more gradual development of symptoms; the former tends to respond better to surgical decompression [126]. Surgery is also indicated as a primary treatment when neural compression is secondary to pathological fracture, dislocation, epidural hematoma, syringo-myelia, platybasia, or sarcomatous transformation.

Pharmacologic treatment

A pressing issue regarding treatment is whether physicians should treat asymptomatic patients. The progressive nature of PD, the severity of its associated complications, the potential negative impact on patients' quality of life, and the availability of effective and relatively safe new antipagetic drugs have led many experts to recommend treatment for asymptomatic patients who have active disease [50, 93, 133]. According to Meunier et al., in a long-term follow up study of 41 cases of PD, antipagetic therapy that did not normalize biochemical markers in 71% of patients did not prevent new complications in 62% of patients [95], suggesting that antipagetic therapy should continue until normalization of biochemical markers is achieved. However, there are no conclusive data to support the theory that complications are preventable by controlling bone-remodeling with drug therapy [133]. Patients who are asymptomatic and inactive by biochemical and imaging parameters do not require treatment. However, patients who are clinically asymptomatic but demonstrate increased disease activity as shown by biochemical markers, bone scan uptake activity, or increased engorgement by radionuclide investigation should be treated repeatedly until a normalization of these indices is accomplished [95, 130].

Five classes of drugs are available for the treatment of PD: bisphosphonates, calcitonin, mithramycin (plicamycin), gallium nitrate, and ipriflavone. Bisphosphonates appear more effective than calcitonin in suppressing the histolog-ical and biochemical activity of PD. Therefore, calcitonin is no longer considered the treatment of choice for this condition. Some of these drugs are still experimental and can be obtained only through clinical trials. A major advantage of the use of bisphosphonates over calcitonin in PD is that biochemical and histological suppression of disease activity may persist for many years after the cessation of treatment [108].

Bisphosphonates. The mechanism of action of bisphos-phonates on bone was originally ascribed to their physi-cochemical effect on hydroxyapatite crystals [38]. They bind strongly to hydroxyapatite crystals and inhibit both their formation and dissolution in vitro. Although such an effect is characteristic of their overall action, their influence on cells is probably of greater importance. The mechanism of action appears to be complex [39], involving several components:

1. A direct effect on osteoclastic activity

2. A direct effect on osteoclast recruitment

3. An indirect effect on osteoclast recruitment mediated by cells of osteoclastic lineage that are capable of stimulating or inhibiting osteoclastic recruitment (macrophages are osteoclast precursors), and

4. A shorter osteoclast life-span due to apoptosis

Bisphosphonates can be classified into nitrogen and non-nitrogen containing groups; two pharmacologic classes with distinct molecular mechanisms. Several bisphospho-nates have been investigated [56, 57], but only the following bisphosphonates have been approved for clinical use: disodium etidronate, clodronate, pamidronate, alendronate, risedronate, neridronate, tiludronate, ibadronate, amino-hydroxybutilene bisphosphonates (ABDP), olpadronate, and zoledronate.

Oral administration of alendronate at a dose of 40 mg per day for 6 months has demonstrated efficacy in normalization of serum alkaline phosphatase [56, 109]. The present authors assessed the effects of an unpublished study of a higher dose (60 mg per day) of oral alendronate (Fosa-max, Merck and Co., inc) on PD over a shorter period (3 months) in 28 patients, 18 male and 10 female with a mean age of 68 years. Ten patients had never been treated before, and 18 had previously received drug therapy. The mean period without treatment prior to alendronate was 14 months. Sites of Paget's were visually scored from +1 to +4 for radiological assessment. Quantitative uptake by region of interest (ratio of Paget's to normal bone) was also determined for scintigraphic examination.

As a result of treatment, alkaline phosphatase levels fell from 266.6 to 82.2 IU/l (mean difference 183.8IU/l, P=0.000). Osteocalcin levels fell from 5.1 to 8.7pmol/l (mean difference 3.6pmol/l, P=0.0002). All patients normalized their alkaline phosphatase levels. Follow-up was carried out on all 28 patients 2 years after the 3-month treatment. All but three were in remission, giving a rate of 89.2%. No side effects were noted in any of the patients treated. The response to therapy was similar between patients who had previously received antipagetic therapy and those who had not. Similarly, there was a marked radiological (Fig. 19) and scintigraphic improvement (Fig. 20).

A major advantage of the bisphosphonates over calci-tonin is that biochemical and histological suppression of the disease activity may persist for many years after the cessation of treatment [108].

Fig. 19 Radiographic effects of alendronate treatment. Patients in group I had never been treated before alendronate treatment. Group II patients had previously received drug therapy

Fig. 20 Scintigraphic evaluation of alendronate treatment. Patients in group I had never been treated before alendronate treatment. Group II patients had previously received drug therapy

Laboratory methods for clinical assessment and monitoring antipagetic drug treatment

Imaging resources

The effects of treatment are monitored by the patient's clinical response, imaging modalities, and bone remodeling markers [56, 57].

Radionuclide bone blood flow can be used to monitor vascularity. Therefore, it can be used:

1. To assess a relevant pagetic region for potential profuse bleeding before proceeding with surgery, and

2. To monitor the effectiveness of an emergency intravenous administration of antipagetic agents

Conventional bone scan is recommended before and 6 months after treatment, and 12 months thereafter depending on the behavior of the pagetic lesion. Twenty-four hour retention scan, a more quantitative radionuclide assessment, can be used as an adjunct to bone scan [11]. Quantitative bone scan scintigraphy allows early and objective assessment of PD when evaluating the effects of therapy. Radiographic images should be obtained before treatment and every 1 to 2 years thereafter, to monitor the modeling (bone expansion) and remodeling changes (phase of the disease activity). Although PD can be diagnosed cost effectively with conventional radiography, magnetic resonance (MR) imaging is well suited for demonstrating specific characteristics of certain complications, including basilar invaginations, spinal stenosis, and secondary neoplasm [12].

Biomechanical bone markers

Recently, the assessment and effectiveness of treatment of patients with Paget's disease have been improved by new emerging biochemical markers for bone remodeling, promptly applied.

Common bone markers used for the evaluation of bone turnover in PD are:

- In serum: total alkaline phosphatase (tAP) and bone alkaline phosphatase (PAP), procollagen type 1 N-termi-nal polypeptide (PINP), beta-carboxyterminal telopep-tide of type 1 collagen (SCTx); osteocalcin and serum bone sialoprotein

- In urine: hydroxyproline (Hyp), amino (NTX) and beta-carboxyterminal (CTX) telopeptides of collagen type I, total pyridinoline (PYD) and deoxypyridinoline (DPD)

Markers of bone resorption representing degradation of type I collagen are: N-telopeptides, C-telopeptides, hydroxy-proline and collagen crosslinks-pyridinoline and dexopy-ridinoline, and urinary calcium.

Serum tartrated-resistant acid phosphatase is a marker for osteoclastic activity. Bone formation markers include bone-specific alkaline phosphatase and N terminal and C terminal extension peptides of procollagen and osteocalcin.

Resorption markers respond approximately 1-3 months after treatment intervention, whereas markers of formation respond much later, usually after 6-9 months [19].

The serum markers of bone turnover show lower biological variability than urinary markers, and are therefore more sensitive indices of disease activity.

Paget's Disease: conclusions

The natural history of PD affecting the spine is therefore progressive, characterized by bone proliferation, vertebral expansion, and structural changes, leading to spinal stenosis and facet arthropathy, clinical entities that are not always symptomatic. Pagetic facet arthropathy is a major contributing factor to both back pain and spinal stenosis, and the more advanced the facet joint arthropathy, the greater the likelihood that patients will suffer clinical spinal stenosis and/or back pain. In the majority of cases the clinical picture of pagetic spinal stenosis and facet os-teoarthropathy is not expected to differ from that of degenerative spondylosis. A minority of patients (13%), however, exhibits constant spinal pain attributed to the pagetic pathologic remodeling process. Treatment of pagetic spinal stenosis symptoms should start with medical anti-pagetic therapy, with surgery being the alternative choice only if the symptoms persist in spite of normalization of bone remodeling markers.

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