Brittle bone disease

Paget's disease of bone (PD) is a monostotic or polyostotic non-hormonal osteometabolic disorder. Over a century after the original disease was described by Sir John Paget1 in 1877, and despite recent intensive studies and widespread interest, its aetiology remains obscure. This review describes the pathomechanism of the structural changes which occur in bone affected with PD, induced by the different dynamic patterns of activity of the disease, and outlines the current methods of treatment.

Aetiology

The tendency for sarcomatous transformation, the variability of the appearance of the osteoblasts as regards size, shape and staining, the peculiarity of the osteoclasts with differences in size and up to 100 nuclei, as seen also in giant-cell tumours, and control of the disease by antimitotic agents such as plicamycin, also known as mithramycin, suggest that PD may be a benign neoplasm of the mesenchymal osteoprogenitor cell, as was suggested by Rasmussen and Bordier in 1973.2

It has been postulated that it may be the result of a viral infection.3-6 Electron microscopy of osteoclasts has shown the presence of viral intranuclear inclusion structures resembling those of an RNA-type virus related to measles or subacute sclerosing panencephalitis. Immunological studies have indicated the presence of specific viral antigens in osteoclasts and cells grown from Paget's bone.7 A characteristic feature of paramyxoviruses is their ability to persist at very low levels, and to invade the host immune system. Factors which can be activated by the ROS virus, for example, IL-6, C-fos and Bcl-2, are all strongly elevated in PD suggesting that it may be a viral infection.

It has been noted that PD is associated with the ownership of birds, dogs, cats or cattle. 8,9 Investigations have shown that canine distemper, a paramyxovirus closely related to measles, can contaminate human osteoclast cells, which may contribute to the development of PD.lo,u Other studies,12 however, have found no risk factors associated with dogs or cats.

Prevalence, distribution and genetic factors

PD is found more commonly in people of Anglo-Saxon origin and is rarely encountered in China, Japan, Iran, India, Scandinavia, Africa or the Middle East. 13 A survey in Johannesburg, South Africa, revealed a prevalence of 1.3% among the black population and 2.4% among the white,14 but a recent report on radiological examination of the pelvis 15 showed an estimated overall prevalence in the USA of 1% to 2% with nearly equal distribution between whites and blacks and between sexes. Post-mortem16,17 and radiological studies18 indicate that the overall prevalence of PD is 3% to 3.7%, increasing with age. By the age of 90 years, the expected prevalence is about 10%.17

Genetic factors play a role in the pathogenesis of PD, which is inherited as an autosomal dominant trait with high penetrance.19,20 It may be seen in more than one member of a family with a prevalence of approximately seven times more in relatives or patients than in control subjects.21

Studies in families with PD have shown linkage to a region of chromosome 18q near the polymorphic locus D18S42, most likely as a result of gene mutation.19,22,23 Genetic heterogeneity is almost certainly present; data from some families with PD suggest the presence of at least one additional locus, which remains to be identified. 19

Histopathology

Histopathological examination shows changes in the structure of bone and fibrosis of the marrow. The bone has a socalled mosaic appearance, the hallmark of a Pagetic lesion, and a peculiar cellularity consisting of variable sizes of osteoblast and large osteoclasts with up to 100 nuclei.2 Bone-marrow fibrosis is not associated with anaemia because the haemopoietic activity can expand to the appendicular skeleton;24 extramedullary haemopoiesis may occasionally be seen in the thorax.25

Pathomechanics of bone deformity

There is a disturbance of bone remodelling. Frost 26 has defined remodelling as a constant bone renewal or turnover without changes in the size and shape of bone. In PD, changes in this process give rise to the four phases of the disease observed radiologically: the osteolytic, mixed and osteoblastic phases, and the inactive osteosclerotic phase characterised by normal or decreased activity as seen on bone scanning. 27

The process of modelling determines the shape and geometry of the bone 28 and in PD may lead to expansion or contraction by centrifugal or centripetal drift of cortical bone. Bone expansion with a wide cortex is due to apposition of bone on the periosteal and endosteal envelopes. An increase in the external diameter with a thin cortex is caused by periosteal apposition with concomitant absorption in the endosteal envelope, leading to enlargement of the marrow cavity. Bone contraction, or centripetal cortical bone drift, is produced by apposition on the endosteal and absorption on the periosteal surface (Figs I and 2).

Complications include pathological fractures, delayed union, progressive skeletal deformities, chronic bone pain, neurological compromise of the peripheral and central nervous systems with facial or ocular nerve compression and spinal stenosis etc, Pagetic arthritis, malignant transformation, loss of hearing, Peyronie's disease and highoutput heart failure.

Pathological fractures

Pathological fractures are a frequent complication and may be the presenting feature, with a reported incidence of between 10% and 30%. Fractures of the long bones occur in all phases of remodelling, but are more common in the mixed and osteoblastic stages. Those in the osteolytic phase usually occur at the junction of normal bone density and the radiolucent front.31

Union tends to be delayed in the osteoblastic and sclerotic phases, whereas fractures in the osteolytic stage usually heal in the expected time.31-33 The incidence of nonunion also increases in patients being treated with disodium etidronate 34 which should not be used in the presence of fractures.31

Predisposing factors to complete fractures are partial stress fractures, stress rises at bone-plate interfaces and prolonged therapy with etidronate disodium. 34,35 Partial or incomplete stress fractures arise mostly on the tension side of long bones where they partially involve the cortex, either from the endosteal or the periosteal surface, and occur mostly in the blastic and sclerotic phases. Circumstantial evidence suggests that sclerotic bone is brittle 36,37 and therefore may predispose to fracture.

Pain and local tenderness at the site of a partial stress fracture suggest impending progression to a complete lesion. Treatment then depends on the stage of remodelling. In the mixed phase, walking on crutches with or without bracing may suffice. In the osteoblastic or sclerotic phases, especially with associated deformity, prophylactic realignment osteotomy and intramedullary stabilisation are the appropriate treatment which avoid stress rises associated with fixation by a plate. The mean time for union of femoral fractures treated by an intramedullary nail is approximately 32 weeks.38

Fractures which occur in the presence of pronounced bony deformity are best treated surgically, allowing correction of the malformation, a major factor contributing to fracture, and improvement of the alignment of the adjacent joint. Patients treated by electrical stimulation and bone grafting usually show exuberant formation of callus and therefore this procedure is recommended for fractures occurring in the Mastic or sclerotic phase.31

Rheumatic and arthritic conditions

Forestier's disease, or disseminated idiopathic hyperostosis (DISH), may affect patients with PD, and should not be confused with focal Pagetic bone formation. 27 The incidence of DISH in PD has been reported to range from 14% 39 to 30%.4 Pagetic tissue may invade the hyperostotic lesions produced by DISH and transform them into Pagetic exostoses39 which may then progress to vertebral ankylosis.41 Other rheumatic and arthritic conditions such as psoriatic or ankylosing spondylitis may coexist and be responsible for the clinical presentation. PD has also been noted to be associated with an increased incidence of gout 43 and pseudogout.44 Treatment with sodium etidronate may be responsible for the accumulation of crystals of pyrophosphate in the synovial joint, producing pseudogout.45

Osteoarthritic change in PD has been considered to be either a non-specific arthropathy, a coincidental finding,46 or a specific entity.17 Several distinct pathological processes contribute to the degeneration and destruction of articular cartilage. Erosion of the subchondral bone may lead to collapse of the articular cartilage 47 which can also be eroded by accelerated endochondral ossification of the subchondral bone 48 or by the invasion of aggressive Pagetic change.35,49 Bone expansion and bone deformity may also produce incongruity of the articular cartilage, contributing to arthritic change.

Pain which originates in an arthritic Paget joint may be attributed to the occurrence of microfractures or to increased vascularity of the bone.47 Normalisation of blood flow in the bone with antiPagetic therapy may influence pain relief.50,51 Such treatment may also produce improvement in the appearance of bone scans and in the level of activity markers of bone remodelling, but if pain persists, conservative therapy has then failed.

In the presence of bone deformity with joint malalignment, and a relatively good preservation of the articular cartilage, osteotomy can correct the deformity and restore joint mechanics. The osteotomy can be stabilised successfully by either intramedullary nailing or Ilizarov external fixation. 52 Total joint arthroplasty is indicated for patients with advanced destruction of cartilage.

When osteoarthritis of the hip is associated with varus deformity of the femur, this can be managed by single or multiple osteotomies, followed by implantation of a longstemmed, fully-coated, porous ingrowth hip system. 53,54 Another option is to use a two-stage procedure in which the varus deformity is first treated by a conventional osteotomy and fixation with an intramedullary nail followed by removal of the nail and a total joint replacement.

The survivorship to revision for total hip arthroplasty has been reported to be 98% at ten years and 91% at 15 years for the acetabular component, and 93% at ten years and 89% at 15 years for the femoral stem.55 The only increased risks identified were nonunion of the trochanteric osteotomy (13%) and the occurrence of heterotopic ossification in 29% of cases. The results for cemented arthroplasty appear to have been slightly worse than those for uncemented components but the long-term results for the latter remain to be established.56 Patients with a sclerotic acetabulum may be at risk of perioperative fracture when an underreaming technique is used.57

Malignant transformation

This is relatively rare, occurring in about 0.7%58 to 0.9%59 of patients with PD, although a higher incidence of between 5% and 5.5% has been reported.33,60 Since the condition was first noted by Sir John Paget in 1889,61 numerous reviews have described malignant transformation and defined its clinical and radiological presentation. 62-68

The tumours noted to arise from Pagetic bone have been, in decreasing order of frequency, osteosarcoma (22% to 90%), 58,59,64,65,68,69 fibrous histioytoma (7% to 26%), 58,63,69, fibrosarcoma (3% to 25%), 59,62,64,68,69, chondrosarcoma (1% to 5%), 62-64 giant-cell sarcoma (3% to 10%), 62,66 unspecific malignant neoplasm (9%), 66 lymphosarcoma (12%), 58 and rarely haemangiosarcoma70 and lymphoma.71 Pagetic sarcomatous transformation constitutes between 3.3% and 14% of all osteogenic sarcomata of bone.63,72

An acute onset of pain or an increase in the intensity of chronic pain is usually the presenting complaint. 58,62,71 Confusion as to the radiological appearance of the primary Pagetic lesion and malignant transformation may overlap, leading to a delay in diagnosis.73,74 Swelling or associated soft-tissue masses are present in 48% to 75% of cases,58,62 but swelling in Paget's disease is not always due to malignant transformation. Benign focal modelling lesions can result in a localised periosteal expansion, a so-called `pumice-stone appearance.27 This lesion is characterised radiographically by a smooth uninterrupted margin. In lesion are irregular and interrupted. Similar juxtacortical soft-tissue formation called 'pseudosarcoma' may mimic a juxtacortical sarcima.75

CT67 and MRI can delineate the cortical penetration and associated soft-tissue mass invariably seen with a sarcomatous lesion. Biopsy is neccessary to establish a definite diagnosis. The differential radiological appearance of malignant transformation must be distinguished from pseudosarcomatous ostelysis secondary to medication,76 cystic degeneration of Pagetic lesions causing pseudoneoplastic lesions with central necrosis,74 and active PD with variable abnormalities of remodelling. 27,62

Some reviews have identified the pelvis as the most common site of sarcomatous transformation, 63,65,69 whereas others 58,67 have found an equal incidence in the humerus, femur and skull. Most lesions in the appendicular skeleton are found in the metaphyseal-diaphyseal region.58,62 There is no consensus in the literature regarding the most common phase of remodelling at which sarcomatous transformation occurs, but a high frequency of osteolysis has been described at the site of the sarcoma.58,62-65,67

Pathological fractures may present as the inital clinical manifestation with a reported incidence ranging from 10% to 50%.58,62,64-68 Sarcomatous transformation of Pagetic bone at the site of a previous fracture has been observed58,64-67 and fractures have even been implicated as a possible causative factor.65-67

The prognosis for sarcomatous transformation in PD is dismal. In spite if regimes of management incorporating amputation, chemotherapy, and radiation, the five-year survival rates from 0% to 15% (0% 58,65 2%. 64 5%, 62,63 8%, 59,68 15% 72,77), but in most series reported most patients have died from their malignant neoplasms within a few months.69 The poorer outcome of these patients compared with those with de novo sarcomatous lesions has been attributed to the increasing vascularity of the Pagetic bone allowing unimpeded haematogenous spread of the tumor.59 espically in older patients who may have less resistance to malignant neoplasm. Lymphoma-lymphosarcoma associated with PD has a better prognosis.58,66,71,78

Giant-cell tumors complicating PD have a very good prognosis and have been described as responding very well to steroid therapy.79

Spinal involvement

The spine is the second most commonly affected site in PD, 24,34 predisposing patients to low back pain and spinal stenosis.80,81 Hartman and Dohn82 have shown that 15.2% of patients with PD had involvement of the vertebrae, and 26% of these patients had symptoms of spinal stenosis. The reported incidence of back pain in PD ranges from 11% 28 to 34%34 and 43%.83 The causal relationship between vertebral PD and back pain has been disputed because of the high incidence of coexisting osteoarthritis.34,84 In one study,39 of 33% of patients who demostrated Pagetic involvement of the spine, 30% had clinical symptoms of spinal stenosis and 54% suffered back pain,39 24% of which was attributed mainly to PD alone, 50% to degenerative changes and 26% to a combination of PD and degenerative changes.

Spinal stenosis. About one-third of patients with spinal involvement have symptoms of clinical spinal stenosis.40 Involvement of the cervical and thoracic spine may predispose to myelopathy. 39,82,85 Different factors have been implicated in producing dysfunction of the neural lelments. The most common is neurocompression by overgrowth of bone due to abnormal modelling39,85,86 (Figs 3 and 4). This Pagetic spinal stenosis is characterised by exuberant bone formation and is reminiscent of exaggerated degenerative spondylotic disease. However, severe spinal stenosis may remain asymptomatic, suggesting adaptability of the thecal sac and its neural elements without significant loss of function. 39,85 Other distinct factors contributing to neural dysfunction are ischaemia produced by blood diversion, causing the so-called 'arterial steal phenomenon',80,82,87,88 neurocompression by Pagetic intraspinal soft tissue39,89 or ossification of the epidural fat similar to ankylosing spondylitis90 and interference with the blood supply to the cord due to arterial compression by the expanding bone or other factors.85,91 Platybasia or cranial settling (basilar invagination) may cause either impingement of the medulla92 or the formation of syringomyelia.93 Rarely, neurocompression can be produced by an epidural haematoma from spontaneous bleeding 94 or Pagetic sarcomatous degeneration.95 Spinal pain. Pagetic facet arthropathy is a major contributing factor to both back pain and spinal stenosis, and the more advanced the arthropathy, the greater is the likelihood that patients will suffer clinical spinal stenosis and/or back pain. However, severe facet arthropathy may remain asymptomatic.39 Back pain may also be attributed to engorgement of the vertebral body caused by vascular processes and by disorganised hyperactive remodelling.96 Other factors implicated in spinal pain may include invasion of the vertebral disc space by the Pagetic process which results in vertebral ankylosis.

Treatment

Treatment of back pain. Care must be taken before attributing back pain to PD, otherwise the results of antiPagetic treatment may be disappointing. 97 Suppressive therapy with disodium etidronate is beneficial in about one-third of cases in patients with back pain and PD of the spine. 41 This suggests that unless a well-defined focus of PD is related to low back pain, antiPagetic therapy is not expected to be rewarding. If such therapy is ineffective within three months, a concomitant non-steroidal anti-inflammatory drug and other methods of treatment for back pain should be prescribed, especially when the pain is mechanical or arthritic in nature. 31,98

Treatment of spinal stenosis. Treatment of the symptoms of spinal stenosis in Paget's disease should begin with medical therapy. 86 Calcitonin, mithramycin, sodium etidronate, pamidronate disodium, and clodronate have been reported to either improve or completely reverse the clinical SYMPtOMS,87,99-103 but subsequent relapse is not uncommon. 101.104.105 Patients should be closely monitored and cyclical therapy should be continued if necessary until the biochemical bone indices are normal.106,107 If symptoms still persist operation should be considered.

Decompression of spinal stenosis should be implemented promptly after failure of antiPagetic therapy. Delay in decompression may result in irreversible myelopathy or radiculopathy. 39.101 The results of surgery have shown variable improvement in 85% of patients, 108 with frequent relapses which may improve with subsequent medical treatment. 87,99,101,102 Surgery ma fail to reverse the neurological deficit completely""' 109 and may be associated with serious complications such as dangerously profuse, if not massive, bleeding 110 and a mortality rate of 11%.'0" Preoperative assessment of bone vascularity by means of radionucleide studies of bone blood flow in the affected spinal region is a reliable, simple and reproducible teSt.50 In order to decrease potential bleeding during surgery, when there is an increased vascularity in the affected region, a course of medical treatment should be given until the blood flow in the bone is normal. 51 This may take two to three months with treatment with calcitonin or two to three weeks with mithramycin.51 The new generation of intravenous bisphosphonates can also be used effectively in this situation. In an emergency embolisation of the region may be indicated. Because of the expected torrential bleeding during laminectomy, the use of a cell saver is also suggested. 101

Surgery for spinal stenosis, when indicated, should be tailored to the abnormality responsible for neural compression. If this is caused by the posterior vertebral elements posterior decompression should be undertaken. 31,51 If compression is caused by the posterior expansion of the vertebral body, especially when the cervical or thoracic spine is involved, an anterior approach with corpectomy and fusion should be carried out. An acute onset of spinal compression has a more grave prognosis than the gradual development of symptoms. III Surgery is also indicated as a primary treatment when neural compression is secondary to pathological fracture, dislocation, epidural haematoma, synngomyelia, platybasia, or sarcomatous transformation. Pharmacological treatment. The progressive nature of Paget's disease, the severity of its associated complications, the potential negative impact on quality of life and the availability of effective and relatively safe new drugs have led many experts to recommend treatment for asymptomatic patients who have active disease. 31,112,113 However, there is no conclusive evidence to suggest that complications can be prevented by controlling bone remodelling by drug therapy. 113 Patients who are clinically asymptomatic, but show increased activity of the disease as indicated by abnormal biochemical markers, bone-scan activity or increased engorgement on radionucleide investigation, should be treated repeatedly until these indices return to normal values.107,112 Patients who are asymptomatic and inactive when assessed by biochemical investigation and imaging do not require treatment.

Five classes of drugs are available: bisphosphonates, calcitonin, mithramycin (plicamycin), gallium nitrate and ipriflavone. Some of these are still under development and can be obtained only for use in clinical trials. A major advantage of the bisphosphonates over calcitonin is that biochemical and histological suppression of the disease may persist for many years after the cessation of treatment. 14

Bisphosphonates. The mechanism of action of bisphosphonates on bone can be ascribed to their physicochemical effect on hydroxyapatite crystals 115 and to their influence on bone cells,' 16,117 which is probably of greater importance. Interference with the growth of calcium phosphate crystals inhibits normal calcification. The bisphosphonates also inhibit bone resorption at the cellular level, and eventually bone formation also decreases, probably because of the coupling effect between formation and resorption. The mechanism of action appears to be complex,"16,117 involving several functions including a direct effect on osteoclastic activity, a direct effect on recruitment of osteoclasts, an indirect effect on the latter mediated by cells of osteoclastic lineage which are capable of stimulating or inhibiting osteoclastic recruitment and shortening of the life-span of osteoclasts because of apoptosis.

Bisphosphonates can be grouped into two pharmacological classes with distinct molecular mechanisms of action. Nitrogen-containing bisphosphonates are the most potent and act by inhibiting the mevalonate pathway in osteoclasts, thereby preventing prenylation of small GTPase-signalling proteins required for osteoclast function. Bisphosphonates which lack nitrogen in their chemical structure do not inhibit prenylation of protein and have a different mode of action which may involve the formation of cytotoxic metabolities in osteoclasts or the inhibition of protein tyrosine phosphatase.16

Other cellular effects of bisphosphonates have been described such as an increase in the production of alkaline phosphatase, an increase or decrease in the synthesis of proteoglycans, inhibition of the synthesis of prostaglandins which are powerful bone-resorbers and a decrease in the production of lactic acid, which plays an important role in crystal dissolution. They can also directly induce apoptosis and disruption of actin rings in osteoclasts. In general, these effects are not uniform but vary from bisphosphonate to bisphosphonate.

The quality of the newly-formed bone is lamellar in appearance without significant defects in mineralisation, Giving large amounts of bisphosphonates such as disodium etidronate, however, can inhibit mineralisation by a physicochemical inhibition of crystal growth" 9 and result in osteomalacia.

Bisphosphonates appear to be more effective than calcitonin in suppressing the histological and biochemical activity in Paget's disease. Calcitonin is no longer considered to be the treatment of choice for this condition. Several bisphosphonates have been investigated, but only those shown in Table 181.120 have been approved for clinical use. Other antiPagetic drugs are shown in Table 11. 81,120

Methods for clinical assessment and monitoring of antiPagetic drug treatment

Imaging. The effects of treatment are monitored by the clinical response, imaging modalities and bone-remodelling markers. 101,107

Determination of radionucleide blood flow can be used to assess a relevant Pagetic region for potential profuse bleeding before proceeding with surgery, and to monitor the effectiveness of emergency intravenous administration of antiPagetic agents. A conventional bone scan is recommended before and six months after treatment, and every 12 months thereafter depending on the behaviour of the Pagetic lesion. A 24-hour retention scan, a more quantitative radionucleide assessment, can be used as an adjunct to a bone scan.50 Quantitative scintigraphy allows early and objective assessment of PD when evaluating the effects of treatment. 121.

Radiographs should be obtained before treatment and every one to two years thereafter to monitor changes in modelling and remodelling. MRI is suitable for demonstrating specific characteristics of certain complications, including basilar invagination, spinal stenosis and secondary neoplasms. 122

Biochemical bone markers. Recently, the assessment and effectiveness of treatment of patients with Paget's disease have been greatly enhanced by evaluating biochemical markers for bone remodelling.

Common markers in the serum used for the evaluation of bone turnover in PD are the total alkaline phosphatase (tAP), bone alkaline phosphatase (BAP), tartrated-resistant acid phosphatase, procollagen type-I N-terminal polypeptide (PINP), 0-carboxyterminal telopeptide of type-I collagen (SCTX), osteocalcin and serum bone sialoprotein.

Biochemical markers for clinical assessment in the urine are hydroxyproline (Hyp), amino (NTX) andBeta-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, hydroxyproline and collagen crosslinks - pyridinoline and dexopyridinoline. The urinary calcium is an indicator of bone resorption. The serum tartrated-resistant acid phosphatase is a marker for osteoclastic activity. Markers of bone formation include bone-specific alkaline phosphatase and N-terminal and C-terminal extension peptides of procollagen. Osteocalcin, produced by osteoblasts or released during degradation of bone matrix by osteoclasts, may indicate either formation when resorption and formation are coupled or turnover when they are uncoupled. Therefore this is not a practical bone marker.

Markers of bone resorption respond approximately one to three months after treatment begins, whereas those of bone formation respond much later, usually at six to nine months. 123

The serum markers of bone turnover show lower biological variability than urinary markers and are therefore more sensitive indices of the activity of the disease. Bone alkaline hhosphatase and PINP seem to reflect Pagetic activity best. 124,125 The total alkaline phosphatase can also be considered to be a sensitive and inexpensive marker for therapeutic monitoring of Paget's disease. However, more specific markers may improve the usefulness of the biochemical assessment in certain situations.126 Urinary Ntelopeptide (NTX) has emerged as a sensitive marker for bone resorption in the management of Pagetic patients, 121,127

Serum levels of pyridinium cross-links correlate well with its urinary excreation (a sensitive index of bone resorption).124 in patients with PD. Therefore the determination of serum levels of pyridinium cross-links avoids the usual problems related to the collection of urinary specimens.128 Urinary excreation of Beta-isomers of type-I collagen (CTX) reflects lamellar bone turnover which is impaired in PD, whereas alpha-CTX is an index of the woven bone structure present in active PD. An abnormal alphs/beta-CTX ratio, which becomes normal after therapy, probably indicated the formation of lamellar structures in the newly-formed bone.127,129

Patients should be followed by measuring bone markers every three to six months depending on the activity of the Pagetic lesions and the drug used.42 Treatment should be recommended when remodelling indices rise above the upper limits of normal or by 25% above the previous lowest point.117

Other tests. The haematological profile, the level of serum electrolytes, and tests of kidney and liver function are helpful in assessing the side-effect of the drugs, or the overall medical condition in elderly patients.39 They may help to detect potential side-effects especially when drugs such as mithramycin or the latest generation of bisphosphonates are being given.

References

1. Paget J. On a form of chronic inflammation of bone (osteitis deformans). Trans R Med Chir Soc Land 1877;60:36-9.

2. Rasmussen H, Bordier P. The physiological cellular basis of metabolic bone disease. N Engl Med 1973;184:25-32.

3. Basle MF, Rebel A, Fournier JG, Russell WC, Malkani K. On the trail of paramyxoviruses in Paget's disease of bone. Clin Orthop 1987;217:9-15.

4. Hadjipavlou A, Begin LR, Abitbol JJ. Observations morfologiques, histochimiques et ultrastructulares de culture cellulaires in vitro d'os pagetique et normal. Union Med Can 1986;115:746-50.

5. Mee AP. Paramyxoviruses and Paget's disease: the affirmative view. Bone 1999:24, Suppl 5:19-21.

6. Singer RF, Millis BG. The etiology of Paget's disease of bone. Clin Orthop 1977;127:37-41.

7. Mills BG, Singer FR. Critical evaluation of viral antigen data in Paget's disease of bone. Clin Orthop 1987;217:16-25.

8. Khan SA, Brennan P, Newman J, et al. Paget's disease of bone and unvaccinated dogs. Bone 1996;19:47-50.

9. Lopez-Abente G, Morales-Piga A, Elena-Ibanez A, Rey-Rey JS, Comes-Gonzalez J. Cattle, pets, and Paget's disease of bone. Epidemiology 1997;8:247-5 1.

10. Holloway IM, Ibberston HK, Wattie D, et al. Previous pet ownership and Paget's disease. Bone Miner 1990:8:53-8.

11. O'Driscoll JB, Buckler HM, Jeakock J, Anderson DC. Dogs, distemper, and osteitis deformans: a further epidemiological study. Bone Miner 1990;11:209-16.

12. Siris ES, Kelsey JL, Flasher E, Parker S. Paget's disease of bone and previous pet ownership in the United States: dogs exonerated. Int J Epidemol 1990;19:455-8.

13. Barry HC. Paget's disease of bone. Edinburgh: Churchill Livingstone, 1969.

14. Guyer PB, Chamberlain AT. Paget's disease of bone in South Africa. Clin Radiol 1988;39:51-2.

15. Altman RD, Bloch DA, Hochberg MC, Murphy WA. Prevalence of pelvic Paget's disease of bone in the United States. J Bone Miner Res 2000;15:461-5.

16. Collins DH. Paget's disease of bone: incidence and subclinical forms. Lancet 1956;2:51-6.

17. Schmorl G. Uber osteitis deformans Paget. Virch Arch Anat Physiol 1932:183:694-701.

18. Pygott F. Paget's disease of bone: the radiological incidence. Lancet 1957:1:1170-9.

19. Haslam SI, Van Hul W, Morales-Piga A, et al. Paget's disease of bone: evidence for a susceptibility locus on chromosome 18q and for genetic heterogeneity. J Bone Miner Res 1998;13:911-7.

20. Hocking L, Slee F, Haslam SI, et al. Familial Paget's disease of bone: patterns of inheritance and frequency of linkage to chromosome 18q. Bone 2000;26:577-80.

21. Siris ES, Kelsey JL, Flasher E, Parker S. Familial aggregation of Paget's disease of bone. J Bone Miner Res 1991 ;6:495-500.

22. Cody JD, Singer FR, Roodman GD, et al. Genetic linkage of Paget disease of the bone to chromosome 18q. Am J Hum Genet 1997;61:1117-22.

23. Nellissery MJ, Padalecki SS, Brkanac Z, et al. Evidence for a novel osteosarcoma tumor-suppressor gene in the chromosome 18 region genetically linked with Paget disease of bone. Am J Hum Genet 1998;63:817-24.

24. Danais S, Hadjipavlou A. Etude scintigraphique comparative des lesions osseuses et de la modelle osseuse dans la maladie de Paget. Union Med Can 1977;106:1100-9.

25. Relea A, Garcia-Urbon MV, Arboleya L, Zamora T. Extramedullary hematopoiesis related to Paget's disease. Eur Radiol 1999;9:205-7.

26. Frost HM. Bone remodelling and its relationship to metabolic bone diseases. In: Orthopedic lectures. Vol. 3. Springfield, 11: Charles C. Thomas, 1973:65-75.

27. Lander PH, Hadjipavlou AC. A dynamic classification in Paget's disease. J Bone Joint Surg [Br] 1986;68-B:431-8.

28. Frost HM. Bone modelling and skeletal modeling errors. In: Orthopedic lectures. Vol. 4. Springfield, II: Charles C. Thomas, 1973;3-35.

29. Grundy M. Fractures of the femur in Paget's disease of bone: their etiology and treatment. J Bone Joint Surg [BrI 1970;52-B:252-63.

30. Merkow RL, Lane JM. Current concepts of Paget's disease of bone. Orthop Clin North Ariz 1984;15:747.

31. Hadjipavlou AG, Lander PH, Enker P. Paget's disease of bone: orthopedic management in arthritis pathology and management. In: Uttof, ed. Current concepts of bone fragility. Berlin, etc: SpringerVerlag, 1986.

32. Lake M. The pathology of fractures in Paget's disease. Aust NZ J Surg 1957:27:307-15.

33. Lake M. Studies of Paget's disease (osteitis deformans). J Bone Joint Surg [Br] 1951;33-B:323-5.

34. Krane SM. Etidronate disodium in the treatment of Paget's disease of bone. Ann Intern Med 1982;96:619-25.

35. MacGowan JR, Pringle J, Morris VH, Stamp TC. Gross vertebral collapse associated with long-term disodium etidronate treatment for pelvic Paget's disease. Skeletal Radiol 2000;29:279-82.

36. Lowry AM, Rutherford JL. Osteitis deformans (Paget's disease) fissure fractures: their etiology and clinical significance. Am J Radiol 1937;38:109-14.

37. Redden JF, Dixon J, Vennart W, Hoskins DJ. Management of fissure fracture in Paget's disease. Int Orthop 1981:5:103-6.

38. Shardlow DL, Giannoudis PV, Matthews SJ, Smith RM. Stabilisation of acute femoral fractures in Paget's disease. Int Orthop 1999;23:283-5.

39. Hadjipavlou A, Lander P. Paget's disease of the spine. J Bone Joint Surg [Am] 1991;73-A:1376-81.

40. Altman RD, Brown M, Gargano F. Low back pain in Paget's disease of bone. Clin Orthop 1987:217:152-61.

41. Marcelli C, Yates AJ, Barjon MC, et al. Pagetic vertebral ankylosis and diffuse idiopathic skeletal hyperostosis. Spine 1995;20:454-9. 42. Altman RD. Musculoskeletal manifestations of Paget's disease of the bone. Clin Orthop 1987;217:152-61.

43. Franck WA, Bress NM, Singer FR, et al. Rheumatic manifestations of Paget's disease of bone. Am J Med 1974;56:592-603.

44. Radi I, Epiney J, Reiner M. Chondrocalcinose et maladie osseuse de Paget. Rev Rheum 1970;37:385-8.

45. Gallagher SJ, Boyle IT, Capell HA. Pseudogout associated with the use of cyclical etidronate therapy. Scott Med J 1991;36:49.

46. Guyer PB, Dewbury KC. The hip joint in Paget's disease (Paget's coxopathy). Br J Radio( 1978;52:574.

47. Hadjipavlou A, Lander P, Srolovitz H. Pagetic arthritis: pathophysiology and management. Clin Orthop 1986;208:15-9.

48. Goldman AB, Bullough P, Kammeron S, Ambos M. Osteitis deformans of the hip joint. Am J Radiol 1977:128:601-6.

49. Resnick D, Niwayama G. Diagnostic of bone and joint disorders with emphasis on articular abnormalities. Philadelphia: W. B. Saunders, 1981:1738.

50. Boudreau RJ, Lisbona R, Hadjipavlou A. Observations on serial radionuclide blood-flow studies in Paget's disease. J Nucl Med 1983;24:880-5.

51. Hadjipavlou AG, Tsoukas GM, Siller TN, et al. Combination drug therapy in treatment of Paget's disease of bone: clinical and metabolic response. J Bone Joint Surg [Am] 1977;59-A: 1045-51.

52. Louette L, Lammens J. Fabry G. The Ilizarov external fixation for treatment of deformities in Paget's disease. Clin Orthop 1996;323:298-303.

53. Alexakis PG, Brown BA, Hohl WM. Porous hip replacement in Paget's disease: an 8-2/3-year follow-up. Clin Orthop 1983;50: 138-42.

54. Namba RS, Brick GW, Murray WR. Revision total hip arthroplasty with correctional femoral osteotomy in Paget's disease. J Arthroplasty 1997;12:591-5.

55. Sochart DH, Porter ML. Charnley low-friction arthroplasty for Paget's disease of the hip. J Arthroplastv 2000;15:210-9.

56. Lewallen DG. Hip arthroplasty in patients with Paget's disease. Clin Orthop 1999.369:243-50.

57. McGrory BJ. Periprosthetic fracture of the acetabulum during total hip arthroplasty in a patient with Paget's disease. Am J Orthop 1999;28:248-50.

58. Hadjipavlou A, Lander P. Srolovitz H, Enker P. Malignant transformation in Paget's disease of bone. Cancer 1992;70: 802-8.

59. Greditzer HG, McLeod RA, Unni KK, Beabout JW. Bone sarcomas in Paget's disease. Radiology 1983: 146:327-33.

60. Freydinger JE, Duhig JT, McDonald LW. Sarcoma complicating Paget's disease of bone: a study of 7 cases with report of one long survival after surgery. Arch Pathol 1963;75:496-500.

61. Paget J. Remarks on osteitis deformans. Illus Med News 1889; 2:181-5.

62. Halbach H, Farrell C, Dittrich FJ. Neoplasm arising in Paget's disease of bone: a study of 89 cases. Am J Clin Pathol 1985;83:594-600.

63. Huvos AG, Butler A, Bretsky SS. Osteogenic sarcoma associated with Paget's disease of bone: a clinicopathologic study of 65 patients. Cancer 1983;52:1489-95.

64. McKenna RJ, Schwinn CP, Soongy KY, Higinbotham NL. Osteogenic sarcoma arising in Paget's disease. Cancer 1964;17:42-66. 65. Porretta CA, Dahlin DC, Jones JM. Sarcoma in Paget's disease of bone. J Bone Joint Surg [Am] 1957;39-A:1314-29.

66. Price CHG, Goldie W. Paget's sarcoma of bone: a study of eighty cases from the Bristol and the Leeds Bone Tumour Register. J Bone Joint Surg [Br] 1969;51-B:205-24.

67. Smith J, Botet J, Yeh SDJ. Bone sarcoma in Paget's disease: a study of 85 patients. Radiology 1984;152:583-90.

68. Wick MR, Siegal UP, Unni KK, McLeod RA, Greditzer HG III. Sarcomas of bone complicating osteitis deformans (Paget's disease): fifty years' experience. Am J Surg Pathol 1981;5:47-59.

69. Jattiot F, Goupille P. Azais I, et al. Fourteen cases of sarcomatous degeneration in Paget's disease. J Rheumatol 1999,261:150-5.

70. Chen KTK. Hemangiosarcoma complicating Paget's disease of the bone. J Surg Oncol 1985;28:187-9.

71. Molle D, Bard H, Kuntz D, et al. Osteolyse relatrice d'un lymphome developpe sur un os pagetique. Rev Rhum Mal Osteartic 1983;50:217-21.

72. Dahlin HC, Coventry MB. Osteogenic sarcoma. J Bone Joint Surg [Am] 1967;49-A:101-10.

73. Anderson JT, Dehner LP. Osteolytic form of Paget's disease: differential diagnosis and pathogenesis. J Bone Joint Surg [Am] 1976;58-A:994-9.

74. Bawerman LW, Altman J, Hughes JL, Zadek RE. Pseudo-malignant lesion in Paget's disease of bone. Am J Roentgenol Radium Ther Nucl Med 1975: 124:57-61.

75. Lamovec J, Rener M, Spiler M. Pseudosarcoma in Paget's disease of bone. Ann Diagn Pathol 1999;3:99-103.

76. Rondier J, Huchet B, Calya J. Osteolyse pseudo-sarcomateuse chez un Pagetique traite par letidronate disodique (EHDP). Rev Rhum Mal Osteoartic 1984;51:49-54.

77. Schatzki SC, Dudley HR. Bone sarcoma complicating Paget's disease: a report of 3 cases with long survival. Cancer 1961;14:518-23.

78. Lauchlan SC, Walsh MJ. Reticulum cell carcinoma complicating Paget's disease. Can Med Assoc J 1963;88:891-92.

79. De Chiara A, Apice U, Fazioli F, et at. Muticentric giant cell tumour with viral-like inclusions associated with Paget's disease of bone: a case treated by steroid therapy. Oncol Rep 1998:5:317-20.

80. Herzberg L, Bayllis E. Spinal cord syndrome due to compressive Paget's disease of bone: a spinal artery steal phenomena reversible with calcitonin. Lancet 1980;2:13-5.

81. Zlatkin MB, Lander PH, Hadjipavlou A, Levine JS. Paget's disease of the spine: CT with clinical correlation. Radiology 1986;160: 155-9.

82. Hartman JT, Dohn DF. Paget's disease of the spine with cord or nerve-root compression: report of six cases. J Bone Joint Surg [Am] 1966;48-A: 1079-84.

83. Rosenkrantz JA, Wolf J, Kaicher JJ. Paget's disease (osteitis deformans). Arch Intern Med 1952;90:610-5.

84. Guyer PB, Shepherd DFC. Paget's disease of lumbar spine. Br J Radio( 1980;53:286-8.

85. Schwarz GA, Reback S. Compression of the spinal cord in osteitis deformans (Paget's disease of the vertebrae). Am Roentgenol Rad Ther 1939;42:345-7.

86. Hadjipavlou A, Gaitanis I, Katonis P. Lander P. Paget disease of the spine and its management. Eur Spine J 2001;10:370-89.

87. Chen IR, Richard SCR, Wallach S, Avramides A, Flores A. Neurologic disturbances in Paget's disease of bone: response to calcitonin. Neurology 1979;29:448-57.

88. Porrini AA, Maldonado-Cocco JA, Morteo GO. Spinal artery steal syndrome in Paget's disease of bone. Clin Exp Rheumatol 1987,5:377-8.

89. Hadjipavlou A, Shaffer N, Lander P. Srolovitz H. Pagetic spinalstenosis with extradural pagetoid ossification: a case report. Spine 1988:13: 128-30.

90. Clarke PR, Williams HI. Ossification in extradural fat in Paget's disease of the spine. Br J Surg 1975;62:571-2.

91. Mathe IF, Delobel R, Resche F, Cler JM. Feve JR. Syndromes medullaire au cours de la maladie de Paget: role du facteur vasculaire. Nouv Presse Med 1976;5:2619-21.

92. Curran JE. Neurological sequelae of Paget's disease of the vertebral column and skull bone. Austral Radio[ 1975;19:15-9.

93. Elisevich K, Fontaine 5, Bertrand C. Syringomyelia as a complication of Paget's disease. J Neurosurg 1987;67:611-3.

94. Richter RL, Semble EL, Tbrner RA, Challen VR. An unusual manifestation of Paget's disease of bone: spinal epidural hematoma presenting as acute cauda equina syndrome. J Rheumatol 1990; 17:975-8.

95. Huang TL, Cohen NJ, Sahgal S, Tseng CH. Osteosarcoma complicating Paget's disease of the spine with neurologic complication. Clin Orthop 1979;141:260-5.

96. Lander P, Hadjivpavlou A. Intradiscal invasion of Paget's disease of the spine. Spine 1991; 16:46-51.

97. Altman RD. Paget's disease of bone: rheumatologic complications. Bone 1999;24,Suppl 5:47-8.

98. Stewart GO, Gutteridge DH, Price RI, et al. Prevention of appendicular bone loss of Paget's disease following treatment with intravenous pamidronate disodium. Bone 1999;24:139-44.

99.Alexandre C, Trillet M, Meunier P. Fischer C. Traitement desparaplegics pagetiques par les disphosphonates. Rev Neurol (Paris) 1979;135:625-32.

100. Eulry F, Poirer JM, Perard D, et al. Cauda equina syndrome with pagetic vertebral fusion: clinical recovery under calcium-vitamin D supplementation plus clodronate after apparent failure of pamidronate and acquired resistance to etidronate. Rev Rhum (Engl Ed) 1997:64:495-9.

101. Hadjipavlou AG, Lander PH. Paget's disease. In: White AH, Schofferman JA, eds. Spinal care. Mosby, 1995:1720-37.

102. Ravichandran G. Neurologic recovery of paraplegia following use of salmon calcitonin in a patient with Paget's disease of the spine. Spine 1979;4:37-40.

103. Whalley N. Paget's disease of the atlas and axis. J Neurol Neurosurg PsYchiat 1946:9:84-51.

104. Douglas DL, Duckworth T, Kanis JA, et al. Biochemical and clinical responses to dichloromethylene disphosphonate (CI2MDP) in Paget's disease of bone. Arthritis Rheum 1980;23:1185-92.

105. Douglas DL, Duckworth T, Kanis JA, et al. Spinal cord dysfunction in Paget's disease of bone: has medical treatment a vascular basis? J Bone Joint Surg [BrJ 1981;63-B:495-503.

106. Hadjipavlou A. Paget's disease of bone: comments by eight specialists. In: Excerpta Medica. Princeton, NJ, 1988:5.

107. Smidt WR, Hadjipavlou AG, Lander P, Dzioba RB. An algorithmic approach to the treatment of Paget's disease of the spine. Orthop Rev 1994;23:715-24.

108. Sadar SE, Walton RI, Grossman HH. Neurological dysfunction in Paget's disease of the vertebral column. J Neurosurg 1972;37:661-5.

109. Cantrill JA, Buckler HM, Anderson DC. Low dose intravenous 3-amino-hydroxy-prohlidene-1, bisphosphonate (APD) for the treatment of Paget's disease of bone. Ann Rheum Dis 1986;45:1012-8.

110. Ryan MD, Taylor TKF. Spinal manifestations of Paget's disease. Aust NZ J Surg 1992;62:33-8.

111. Siegelman SS, Levine SA, Walpin L. Paget's disease with spinal cord compression. Clin Radiol 1968;19:421-5.

112. Meunier PJ, Vignot E. Therapeutic strategy in Paget's disease of bone. Bone 1995;17, Suppl 5:489-91.

113. Tiegs RD. Paget's disease of bone: indications for treatment and goals of therapy. Clin Ther 1997;19:1309-29.

114. Reginster JY. Lecart MP. Efficacy and safety of drugs for Paget's disease of bone. Bone 1995;17, Suppl 5:485-8.

115. Fleisch H. Experimental basis for the use of bisphosphonates in Paget's disease of bone. Clin Orthop 1987;217:72-8.

116. Rogers MJ, Gordon 5, Benford HL, et al. Cellular and molecular mechanisms of action of bisphosphonates. Cancer 2000:88, Suppl 12:2961-78.

117. Russell RG, Rogers MJ, Frith JC, et al. The pharmacology of bisphosphonates and new insights into their mechanisms of action. J Bone Miner Res 1999;14, Suppl 2:53-65.

118. Hiroi-Furuya E, Kameda T, Hiura K, et al. Etidronate (EHDP) inhibits osteoclastic-bone resorption, promotes apoptosis and disrupts actin rings in isolate-mature osteoclasts. Cak-if Tissue Int 1999;64:2;19-23.

119. Fleish H. Mechanism of action of the bisphosphonates in Paget's disease of bone. Medicina (B Aires) 1997;57, Suppl 1:65-75.

120. Gaitanis I, Hadjipavlou A. Paget's disease of the bone and its management. In: Thorngren KU, Soucacos PN, Horan F, Scott J, eds. European Instructional Course Lectures 2001:5:110-23.

121. Pons F, Alvarez L, Peris P, et al. Quantitative evaluation of bone scintigraphy in the assessment of Paget's disease activity. Nucl Med Common 1999;20:525-8.

122. Boutin RD, Spitz DJ, Newman JS, Lenchik L, Steinbach LS. Complications in Paget disease at MR imaging. Radiology 1998;209:641-51.

123. Christenson RH. Biochemical markers of bone metabolism: an overview. Clin Biochem 1997;30:573-93.

124. Alvarez L, Ricos C, Peris P, et al. Components of biological variation of biochemical markers of bone turnover in Paget's bone disease. Bone 2000;26:571-6.

125. Bonnin MR, Moragues C, Nolla JM, et al. Evaluation of circulating type I procollagen propeptides in patients with Paget's disease of bone. Clin Chem Lab Med 1998;36:53-5.

126. Wallace E, Wong J, Reid JR. Pamidronate treatment of the neurologic sequelae of pagetic spinal stenosis. Arch Intern Med 1995;155:1813-15.

127. Delmas PD. Biochemical markers of bone turnover in Paget's disease of bone. J Bone Miner Res 1999;14, Suppl 2:66-9.

128. Sinigaglia L, Varenna M, Binelli L, et al. Serum levels of pyridinium crosslinks in postmenopausal women and in Paget's disease of bone. Calcif Tissue Tnt 1997;61:279-84.

129. Garnero P, Fledelius C, Gineyts E, et al. Decreased beta-isomerisation of the C-terminal telopeptide of type I collagen alpha I chain in Paget's disease of bone. J Bone Miner Res 1997;12:1407-15.

Alexander G. Hadjipavlou, Ioannis N. Gaitanis, George M. Kontakis

From the University of Crete Medical School, Heraklion, Crete

A. G. Hadjipavlou, MD, FRCS C, FACS. Professor and Chairman of Ortho

paedic Surgery

1. N. Gaitanis, MD, Senior Resident

Department of Orthopaedic Surgery and Traumatology

University of Crete. Medical School, Heraklion, Crete 71110, Greece.

G. M. Kontakis, MD, Assistant Professor

Department of Orthopaedic Surgery and Traumatology, University of Thraki at

Alexandroupoli, Thraki, Greece.

Correspondence should be sent to Professor A. G. Hadjipavlou.

Printed with permission of EFORT. The original version of this article appears

in European Instructional Course Lectures Vol. 5. 2001.

(C)2002 British Editorial Society of Bone and Joint Surgery

0301-620X/02/213047 $2.00

J Bone Joint Surg [Br] 2002;84-B:160-9.

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