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Brittle bone disease

Osteogenesis imperfecta (OI), commonly known as brittle bone disease, is a group of genetic bone disorders. People with OI either have less collagen than normal or the quality is poorer than normal. As collagen is an important protein in bone structure this impairment causes those with the condition to have weak or fragile bones. more...

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As a genetic disorder, OI is a autosomal dominant defect. Most people with OI receive it from a parent but it can also be an individual (de novo or "sporadic") mutation.

Types

There are four types of OI, though the symptoms range from person to person. Type I is the most common and mildest form, followed by Type IV, Type III and Type II. A Type V has been proposed based on studies of Type IV.

Type I

  • OMIM 166200 - Type I
  • OMIM 166240 - Type IA

Collagen is normal but not of a high enough quantity:

  • Bones fracture easily, especially before puberty
  • Slight spinal curvature
  • Loose joints
  • Poor muscle tone
  • Discolouration of the sclera (whites of the eyes)
  • Early loss of hearing

Type II

  • OMIM 166210 - Type II

Collagen is not of a sufficient quality or quantity

  • Most cases die before adulthood
  • Severe respiratory problems due to underdeveloped lungs
  • Severe bone deformity and small stature

Type III

  • OMIM 259420 - Type III

Collagen quantity is sufficient but is not of a high enough quality

  • Bones fracture easily, sometimes even before birth
  • Bone deformity, often severe
  • Respiratory problems possible
  • Short stature, spinal curvature and barrel-shaped rib cage
  • Loose joints
  • Poor muscle tone in arms and legs
  • Discolouration of the sclera (whites of the eyes)
  • Early loss of hearing

Type IV

  • OMIM 166220 - Type IV

Collagen quantity is sufficient but is not of a high enough quality

  • Bones fracture easily, especially before puberty
  • Short stature, spinal curvature and barrel-shaped rib cage
  • Bone deformity is mild to moderate
  • Discolouration of the sclera (whites of the eyes)
  • Early loss of hearing

Treatment

At present there is no cure for OI so treatment is aimed at maintaining mobility and strengthening bones as much as possible.

Physiotherapy is used to strengthen muscles and improve motility in a gentle manner which minimises bone breakages. This often involves hydrotherapy and the use of support cushions to improve posture. Individuals are encouraged to change positions regularly throughout the day in order to balance the muscles which are being used and the bones which are under pressure. One of the biggest problems is that children often develop a fear of trying new ways of moving due to movement being associated with pain. This can make physiotherapy difficult to administer to young children.

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Paget's disease of the bone and its management
From Journal of Bone and Joint Surgery, 3/1/02 by Hadjipavlou, Alexander G

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.

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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.

Copyright British Editorial Society of Bone & Joint Surgery Mar 2002
Provided by ProQuest Information and Learning Company. All rights Reserved

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