Abstract and Introduction

Abstract

Adult PD of bone is the second commonest metabolic bone condition after osteoporosis. The condition is characterized by increased bone cell activity, with bone-resorbing osteoclasts often larger and containing more nuclei than normal, and osteoblasts producing increased amounts of disorganized bone. This leads to expanded bone of poor quality possessing both sclerotic and lytic areas. PD of bone has a strong genetic element, with a family history being noted in 10–20% of cases. A number of genetic defects have been found to be associated with the condition. The most common disease-associated variants identified affect the SQSTM1 gene, providing insights into disease aetiology, with the clinical value of knowledge of SQSTM1mutation status currently under active investigation. The diagnosis may be suggested by an isolated raised total ALP without other identifiable causes. This can be confirmed on plain X-rays and the extent determined by isotope bone scan. The mainstays of treatment are the bisphosphonates, especially i.v. zoledronate, which results in long-term suppression of bone turnover. ALP is the usual means of monitoring the condition, although more specific bone turnover markers can be helpful, especially in coincident liver disease. Patients should be followed up to monitor for biochemical relapse or development of complications, which may require medical or surgical intervention.

Introduction

Adult PD of bone (PDB) was first described by Sir James Paget in 1877, a condition he referred to as osteitis deformans.^[1] It is characterized by increased bone cell activity that results in expanded bone possessing both sclerotic and lytic areas. It is initiated by enhanced resorption by abnormal multinucleated osteoclasts followed by disorganized bone formation by osteoblasts.^[2] There is a high rate of bone remodelling at affected sites in the skeleton, and the bone is highly metabolically active and has a high blood flow, which can make the overlying skin feel warm to the touch.^[3] PDB is the second most common metabolic bone disorder after osteoporosis. Despite this, it is both underdiagnosed and undertreated, with many patients never coming to medical attention.^[4] The condition tends to affect an older population, being unusual in individuals under 40 years of age. It can affect anything from a single bone (monostotic) to many bones (polyostotic).^[2,3]The condition is often asymmetric with, for example, only one femur involved. PDB does not generally spread from bone to bone, and it is unusual for new bones to become involved.^[5]

Epidemiology

PDB is more common in males than females; for example, in a study published in 2002, the incidence was reported as 5.4 cases/10 000 person-years in women of ⩾85 years, compared with 7.6 cases/10 000 person-years in men of the same age.^[4] UK and other populations of British descent have the highest prevalence of PDB, with up to 2% in those over 55 years estimated to be affected (based on analyses of radiographic records over the period 1993–95). In contrast, PDB is rare in Scandinavia, the Indian subcontinent and the Far East.^[6] Curiously in some countries, including the UK, the incidence and severity of PDB has declined rapidly in recent years;^[7]in certain populations, incidence rates may only be 10–20% of those seen 20–30 years ago.

Pathogenesis

In PDB there is loss of the normal regulation of bone resorption and formation, with the process biased towards one or the other depending on the phase of the disorder.^[8] There are three phases. The first is a lytic phase in which normal bone is resorbed by numerous, enlarged and more nucleated than normal osteoclasts and bone turnover is markedly increased. Secondly, a mixed phase of lytic and blastic activity characterised by rapid increases in bone formation from numerous osteoblasts. The newly synhesised bone is abnormal with collagen fibres deposited in a haphazard way. There is both osteobalstic and osteoclastic activity, but formation becomes dominant. Finally, there is sclerotic phase in which bone formation predominates, but the formed bone is disorganised (woven bone) and is weaker. The resultant bone has altered and often abnormal architecture. While PDB has previously been regarded as primarily a disease of osteoclasts, there is evidence that the functioning of stromal cells and osteoblasts is also abnormal, and there is loss of the usual tight regulation of the process of bone resorption and formation, for example, mediated via TGF-β.^[9,10]

In the early phase of PDB, microscopic assessment can show a combination of bone resorption, endosteal fibrosis and prominent vascular sinusoids (Figure 1). There are increased numbers of enlarged osteoclasts with more nuclei than normal and increased bone resorption. Subsequently, there is increased formation of new bone when the characteristic microscopic features of PDB occur. The irregular and variably sized resorption bays (Howship lacunae) left by the excess osteoclast activity become filled in with bone newly synthesized by osteoblasts. As bone remodelling is not properly regulated, new bone is present in variably sized patches separated by prominent, irregular, scalloped cement lines, and referred to as a mosaic. Characteristically, a high proportion of the initial new bone formed is actually of lamellar type, but it is irregularly and randomly organized, therefore decreasing strength and load-bearing capacity.^[11] In the later stages of PDB, the histology is that of thickly reconstructed bone with increased numbers of prominent and irregular cement lines that are prone to fracture. In the final sclerotic phase in which bone formation predominates, the collagen fibres are deposited in a haphazard way, the bone is disorganized (appearing woven) and is weaker. There is a modest increase in the incidence of osteosarcoma,^[12,13] which should be distinguished from the periosteal (juxtacortical) bone masses that can be seen in PDB.

Figure 1.

Typical histology of adult PD of bone
An H and E image viewed down a microscope of a thin section of involved bone. It shows in more detail that, as the phases of resorption and formation progress, the trabeculae become abnormally shaped. There are numerous reversal lines, which make the trabeculae appear to be composed of several pieces fitted together—the so-called mosaic pattern.

Genetic factors play an important role in PDB, with 10–20% of patients having a family history of the disorder. Susceptibility probably arises from a combination of relatively rare pathogenic mutations and more common small-effect variants (that predispose to disease) at several loci within or close to genes relevant to osteoclast function.^[14] The most well-characterized genetic links are mutations affecting the SQSTM1 gene, which encodes the SQSTM1/p62 protein (Sequestosome-1) and is found in up to 50% of familial and some sporadic cases of PDB.^[15,16] Patients with SQSTM1mutations often have severe PDB, are diagnosed earlier and have a high degree of penetrance with increasing age.^[17] The SQSTM1/p62 protein is an important regulator of osteoclast RANK-mediated NF−κB signalling, with mutation-associated activation of this pathway likely linked to disease aetiology.^[18] Indeed, SQSTM1 mutation status plays a major role in determining the disease phenotype in patients, with other risk alleles associating in an additive manner.^[19] Interestingly, SQSTM1 mutations are also linked to neurodegenerative disorders such as the amyotrophic lateral sclerosis and frontotemporal lobar degeneration spectrum, which exceptionally rarely can also coexist with PDB,^[20] and PDB can also occur as part of the multisystem disorder inclusion body myopathy with PDB and frontotemporal dementia,^[21] caused by mutations affecting the VCP gene. It is important to note that any rare neurodegenerative phenotypes are distinct from neurological symptoms that may result from neurological complications in PDB cases in which there is involvement of the spine or cranium. Severe PDB associated with giant cell tumour has also recently been linked to mutations affecting the gene encoding the zinc finger protein 687 (ZNF687), which like SQSTM1/p62 plays a role in NF−κB signalling.^[22] Finally, variants in the OPTN gene are associated with PDB and in mouse models these result in increases in RANK ligand (RANKL)-dependent NF-κB activation.^[23]

The declining incidence,^[7] coupled with the fact that not everyone with gene defects develops PD, suggests that environmental factors must also play a role influencing development and severity of the disease. Viruses such as the measles virus have been proposed as an aetiologic factor, although involvement has not been confirmed in all studies.^[24] There are probably other unknown environmental triggers.^[25]

Clinical Features, Complications and Presentation

The clinical presentation and complications of PDB are a result of the increased bone cell activity in affected bone, bone expansion, deformity and poor bone quality (Table 1). In order of frequency, PDB affects the femur, spine, skull, sternum and pelvis, but can be found in any bone in the body.^[26] Many patients are asymptomatic, and the diagnosis is often incidental as a result of blood tests revealing an isolated raised ALP, or imaging undertaken for other reasons. The serum calcium and phosphate are usually normal, although it is possible, albeit very rarely, for hypercalcaemia to occur during immobilization or should concomitant hyperparathyroidism develop. Subsequent X-rays and an isotope bone scan may then confirm the diagnosis and extent of the disease.

Bone pain occurs in ~50% of cases presenting clinically.^[27] The pain may arise from the affected bone itself, when it is often described as lancinating^[27,28] (occurring throughout the day, worse at night and on standing) in weight-bearing limbs.^[26] Alternatively, it can arise from the altered biomechanics of limb deformity; for example, bowed tibia or femur, which alters gait and puts stress on joints and soft tissues and causes secondary OA.^[2,29] Approximately 10–30% of PDB patients sustain fractures.^[2] These may initially be incomplete, traversing the cortex (especially the outer borders) of bowed bones (fissure fractures). Fissure fractures predominantly, but not exclusively, affect weight-bearing bones, which are at high risk of complete fracture. Complete fractures are often transverse when they are referred to as chalk stick or banana. Bone healing seems to take place normally.^[2] The development of osteosarcomas within the affected bone, or more rarely chondro- or fibrosarcomas, can also cause pain, a soft tissue mass and a rise in ALP level.^[2,4]

Neurological complications occur generally as a result of bony overgrowth leading to compression, and the commonest is hearing loss, probably due to cochlear damage,^[30] most famously in the composer Ludwig van Beethoven.^[31] Compression at the base of the skull may lead to basilar invagination, cerebellar dysfunction and even obstructive hydrocephalus, resulting in nausea, ataxia, incontinence, altered gait and dementia. Thoracic and lumbar spine involvement may cause nerve entrapment and even spinal canal stenosis, but sometimes this is the result of the increased vascularity causing vascular steal phenomena. If this presents with paraparesis or paraplegia then this should be managed as an emergency (see below).

The increased vascularity can result in excessive blood loss should the bone fracture or any surgery be undertaken upon it unless the PDB has been brought under control beforehand. It could also potentially cause increased cardiac output and high-output cardiac failure should the disease be extensive and uncontrolled. Hultgren reported that there was an association between PDB and aortic stenosis, arteriosclerosis and intracardiac calcification.^[32]

Diagnosis

The possibility of PDB is often first raised by an isolated raised ALP, which isoenzymes reveal to be largely of bone origin. Other possible causes of this need to be excluded, including vitamin D deficiency, hyperparathyroidism, hyperthyroidism, renal osteodystrophy and malignancy. Bone metastases, including prostate cancer and myeloma, can usually be differentiated by blood tests, plain X-rays and other imaging. Very occasionally it is necessary to resort to bone biopsy to be certain, especially if PDB and malignancy are found to be coexistent.

Bone turnover markers (BTMs) are not specific, and the diagnosis is best established by imaging. Isotope bone scans are very sensitive for detecting areas of increased bone cell activity—allowing the extent of disease to be determined—but are not specific. X-rays of affected bone will usually be diagnostic and show the characteristic features of the illness (Figure 2 and Figure 3). The three phases of PDB are evident on X-rays:^[2,33] an early lytic phase giving the characteristic blade-of-grass appearance, progressing through the bone at about 8 mm/year;^[34] a mixed picture of osteolysis and osteosclerosis; and finally a phase in which sclerosis is the main appearance.

Figure 2.

Gentleman found on routine blood tests to have an isolated raised ALP
X-rays confirmed the presence of PD of bone affecting the right hemipelvis, where there is sclerosis. A subsequent isotope bone scan confirmed the disease to be confined to the pelvis.

Figure 3.

Isotope bone scan of man with PD of bone affecting his left tibia
It is worth noting that the bowing has resulted in him standing on tiptoe. He had leg length discrepancy, with pain from the Pagetic bone, altered biomechanics and secondary OA.

The changes can also be detected with CT scans, MRI and PET CT, which can be useful in distinguishing from other potential causes and to assess complications.^[3]

Treatment

The pharmacological treatment of PDB is targeted at reducing osteoclast function (Table 2). Other treatment is aimed at relieving symptoms and complications of the illness. Pain from PDB itself will improve with treatment, but often arises from complications, for example, secondary OA. Analgesia may start with paracetamol and escalate to more powerful agents; it may respond well to NSAIDs. Pain from nerve compression may be helped by medications such as amitriptyline, gabapentin or pregabalin. It is important to ensure that patients are vitamin D replete (⩾50 nmol/l), have good calcium intake and normal calcium levels prior to specific therapy, otherwise hypocalcaemia can be induced.

Bisphosphonates

The advent of potent bisphosphonates has revolutionized treatment. The current first-line treatment for active disease or in those at risk of complications is i.v. 5 mg zoledronate because of its potency and prolonged duration of action. Zoledronate brings about rapid normalization of BTMs and maintains this for many years.^[2,26,35] It is also hoped, although the evidence is lacking, that treatment might prevent the development of complications.

Zoledronate has been studied in a randomized clinical trial comparing a single i.v infusion of 5 mg with risedronate.^[36] After 6 months, 96% of patients receiving zoledronate had a therapeutic response compared with just 74% of those randomized to risedronate (P < 0.001), with ALP levels normalizing in 89 and 58% of patients, respectively (P < 0.001). At 2 years the response was 98% vs 57%,^[37] and by 6 years this was 87 and 38%, respectively.^[38] The zoledronate group showed a more rapid response and superior effects on quality of life, including pain. Zoledronate is well tolerated, although there is a 20–25% risk of flu-like reactions, which can be reduced by the use of paracetamol or NSAIDs. The acute-phase response can include uveitis in ~1% of patients, which requires prompt treatment and resolves quickly with topical steroids. Zoledronate is also potentially nephrotoxic and should not be given if the estimated glomerular filtration rate is <35 ml/min.

Both alendronate and risedronate have been studied in clinical trials. Alendronate normalized ALP in 60–70% of cases and was associated with healing of lytic lesions and restoration of normal lamellar bone histology.^[39,40] Oral risedronate shows evidence of pain relief and normalization of ALP in 73% of patients.^[41–44] Intravenous pamidronate has largely been replaced by the more effective bisphosphonates, but it is capable of normalizing ALP levels and sustaining the response for ⩾12 months.^[45,46]

Alternatives

As a potent inhibitor of osteoclasts, Denosumab would seem to be an attractive alternative medication in those unable to have bisphosphonates. Unfortunately, experience is anecdotal at present, with only a handful of case reports and no evidence on the optimum dose, frequency and duration of affect..^[47,48] Schwarze et al. used it in a case in which renal failure precluded the use of bisphosphonates.^[47] Reid et al.^[48] used Denosumab when an individual had severe musculoskeletal pain with alendronate. They found a good response, but ALP rose gradually after the first dose and symptoms reoccurred, necessitating a second dose 15 months after the first. They felt it to be less effective than i.v. bisphopshonates and suggested that the osteoclastic overactivity in PDB was not wholly mediated by RANKL.^[48]We have found 60 mg s.c. Denosumab given every 6 months to work well at keeping the ALP suppressed when oral or i.v. bisphosphonates could not be used.