Patient Management 

The most widely used biochemical marker to aid diagnosis of PDB is serum total alkaline phosphatase (ALP), which is typically elevated in active PDB. It should be noted that Paget's disease can be active and yet the alkaline phosphatase (ALP) may remain within the normal range, particularly if the area involved is small.

The condition has characteristic features on x-ray (summarised in Box 1). Individually, these features are not specific, but when they occur in combination, they are usually diagnostic. 

Radionuclide bone scintigraphy is widely considered to be a valuable technique for the diagnosis of PDB and to assess the extent of the disease

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Decisions to treat Paget’s disease should be made by a specialist, on an individual basis. 

Paget’s Association Centres of Excellence
Most UK hospitals have a specialist (usually a metabolic bone clinic or rheumatologist) who can deal with the condition. If there is no one locally, then referral to one of the Paget’s Association Centres of Excellence might be beneficial. The Centre of Excellence Award recognises hospital (NHS) and university departments, within the UK, which demonstrates excellence, in both the care of patients and research into Paget’s disease. NHS Centres of Excellence can be found by following this link

When Paget's disease is diagnosed, referral to a specialist for assessment is recommended.

Specific anti-pagetic treatment involves the use of osteoclast inhibitors to reduce the elevation in bone turnover that is characteristic of active disease. In addition, analgesics, non-steroidal anti-inflammatory drugs, and anti-neuropathic pain agents can be used for symptom control.

When treatment is required, Bisphosphonates are used and Zoledronate is often the drug of choice as it acts quickly and can be effective for many years.

The main reason for treatment is if the affected bones are painful. If the pain is directly from Paget’s disease, it often improves with treatment. Pain, however, can arise from complications. The clinical benefit of giving bisphosphonates to patients who have a raised level of alkaline phosphatase in their blood, but do not have symptoms, is unknown. It can take several months for bisphosphonates to have their full effect and for the individual to feel the maximum benefit.

Alkaline Phosphatase (ALP) is an indicator of disease activity and should be measured prior to starting treatment and repeated about 3 months later when it should have decreased. It should be noted that Paget's disease can be active and yet the alkaline phosphatase (ALP) may remain within the normal range, particularly if the area involved is small.

Zoledronate

For those with Paget's disease who require treatment, the current first-line bisphosphonate, due to its potency and prolonged duration of action, is zoledronate (zoledronic acid). It is the bisphosphonate most likely to relieve pain from active Paget’s disease. A single infusion of 5mg is given and over the following months, often normalises the abnormal bone remodelling. This single dose can be effective for many years. 

• 5 mg of Zoledronic acid intravenously over 15-30 minutes 

• One dose may be effective for many years

Paget's Clinical Guideline

You can download a PDF of the full Guideline here: *Diagnosis and Management of Paget’s Disease of Bone in Adults - A Clinical Guideline 2019 Alternatively, download a summary of the Guideline - Paget's Guideline Summary 2019

Pamidronate

Pamidronate is an effective treatment but has largely been superseded by zoledronate (zoledronic acid) which lasts longer and is easier to administer.

Pamidronate is given in several doses, intravenously and repeated when necessary, depending on symptoms. Doses can vary, but commonly 60mg is given by an infusion and this is repeated on 3 consecutive days.

Pamidronate: given intravenously over 2-4 hours.  Dosage (60 – 90 mg) and frequency will depend on the severity of symptoms.

Risedronate

• Intravenous treatment with zoledronic acid is usually the first consideration, as it acts quicker and lasts longer, however, treatment can be given orally using Risedronate.

• The most commonly used oral treatment is 30mg of risedronate sodium, daily, for two months.

• If necessary, the course can be repeated. 

• Risedronate helps relieve pain from active Paget’s disease with effects that can last for 2 years or more. The duration of effect is not as long as that of zoledronic acid.
  
  Risedronate: 30mg daily for 2 months.

In cases where bisphosphonates are not recommended, calcitonin injections may be considered to treat bone pain in Paget’s disease.

An assessment of the response to treatment for Paget's disease should take place between 3 and 6 months after treatment has been completed. 

An annual ALP can help monitor the condition.

Paget's Guideline

A clinical Guideline, for the Diagnosis and Management of Paget’s Disease of Bone in Adults, was commissioned by the Paget's Association and published in 2019, in the Journal of Bone and Mineral Research. It has been endorsed by the European Calcified Tissues Society, the International Osteoporosis Foundation, the American Society of Bone and Mineral Research, the Bone Research Society (UK), and the British Geriatric Society. 

You can download a summary of the Guideline here.  Alternatively, download the full document here. 

The overall frequency with which complications occur in PDB is unknown but when they occur, surgical treatment is often required. Medical treatment with bisphosphonates is seldom effective at treating complications of Paget’s disease when they are established. 

Bone Deformity
Paget’s disease can cause bone to become enlarged and misshapen. Long-standing disease may cause the weight-bearing bones of the leg to bow.
Osteoarthritis
Paget’s disease can predispose to the development of osteoarthritis at adjacent joints. Joint replacement is common in those with Paget’s disease (Figure 2). The changes of Paget’s disease usually affect only one side of a joint and are not present in both bones that make up the joint. 
Fracture
There is an increased risk of fracture, particularly in the weight-bearing bones of the legs. Fractures may initially be incomplete, (stress fractures or fissure fractures), which are at high risk of complete fracture. Fissure fractures predominantly, but not exclusively, affect weight-bearing bones, such as the thigh bone (femur).
Hearing Loss
If the skull is involved, hearing loss can occur. 
Nerve Entrapment
Enlarged bones may cause nerve compression. Complications can therefore include basilar invagination of the skull, obstructive hydrocephalus, spinal canal stenosis, and paraplegia. It has been suggested that, in some cases, paraplegia may be due to a vascular “steal” phenomenon, rather than direct compression of the spinal cord. 
Excessive Blood Loss During Surgery
Owing to the increased blood flow to areas of active PDB, were the bone to fracture or surgery be undertaken, active disease would have the potential to result in excessive blood loss in patients undergoing surgery.
Cardiac Failure
In severe cases, high-output cardiac failure, due to increased bone blood flow, has been reported but is extremely rare, especially as Paget’s disease is decreasing in severity.
Paget’s Associated Osteosarcoma 
Osteosarcoma associated with Paget’s disease is a rare primary bone cancer. It should be suspected in any patient with Paget’s disease, where there is a sudden increase in bone pain, or there is enlargement of the affected bone. Patients suspected to have osteosarcoma should undergo urgent imaging with a CT scan or MRI and be referred for a surgical opinion.

Osteosarcoma associated with Paget’s disease is a rare primary bone cancer. It should be suspected in any patient with Paget’s disease, where there is a sudden increase in bone pain, or there is enlargement of the affected bone. Patients suspected to have osteosarcoma should undergo urgent imaging with a CT scan or MRI and be referred for a surgical opinion.

When and Why GPs should Refer to a Specialist

This article in the British Journal of General Practice discussed when and why to refer to a consultant. The authors explain that the most common presentation of Paget’s disease is with bone pain, deafness, or fractures caused by the disease. In about one-fifth of patients, however, it is an incidental finding when a blood test or x-ray is carried out for another reason. They advise that when there is pain or deformity due to Paget’s disease, a referral to a specialist should be considered to enable further assessment to be carried out and treatment to be offered if appropriate. They point out that referral may not be required in those who do not have symptoms because there is no evidence yet to suggest that treatment with bisphosphonates is of benefit when there are no symptoms present, however, research is currently in progress to investigate this further. Read the full article here (external link). 
Reference - Nairn, C and Ralston, S.H., ‘Paget’s disease of bone: when and why to refer to specialist care’, British Journal of General Practice; 2020, 70: 561-562.

Diagnosis and Management

The diagnosis and management of Paget’s disease were discussed in an article published in The Practitioner. The authors point out that the three main risk factors for Paget’s disease are age, male gender and family history. They provide a suggested pathway for referral to a consultant and comment on the three currently licensed (in the UK) bisphosphonates for the treatment: zoledronate (generally considered first choice and most likely to give a favourable pain response), risedronate and pamidronate. They also comment that following successful treatment, pain may recur even if the alkaline phosphatase level is not elevated, therefore the patient should be referred back to the consultant for evaluation. Download the PDF here.
Reference -  Nairn, C and Ralston, S.H., Diagnosis and Management of Paget’s Disease of Bone. The Practitioner, 2020, Nov 2020;264(1842):11-15.

Paget’s Disease: Commonly Missed and Poorly Understood

Providing an overview of the condition, the article, ‘Adult Paget’s Disease of Bone’, was published in ‘Clinical Medicine’. It provided an overview of Paget’s disease, including diagnosis, treatment, complications, and monitoring. The authors explain that when zoledronate is given, it can be effective for years, however, an annual follow-up appointment is required to assess for relapse and potential complications. They conclude that Paget’s is, “commonly missed and, even when identified, it is poorly understood and inadequately treated, despite the efficacy of bisphosphonates.” Read the full article here (external link). 
Reference - Tuck, S.P., Walker, J., ‘Adult Paget’s Disease of Bone’, Clinical Medicine, 2020, vol 20, no 6: 1-4.

Treatment for Paget’s Disease

In the journal ‘Bone’, Professor Stuart Ralston looked in detail at bisphosphonates, explaining that bisphosphonates are the treatment of choice for Paget’s disease, with zoledronate the bisphosphonate most likely to ease pain. Looking towards the future he discussed how many people who have Paget’s disease do not have pain, even when there is increased bone turnover, therefore, more research is needed to find out why this is the case. Research is also needed into the effects of bisphosphonates on complications such as deformity, fractures and deafness. Research studies, known as PRISM and PRISM-EZ, investigated the long-term effects of bisphosphonates in those with established Paget’s disease. They showed that intensive bisphosphonate therapy aimed at normalising the level of alkaline phosphatase in the blood was no more effective for preventing complications than treatment given to those who had symptoms. The Zoledronate in the Prevention of Paget's Disease (ZiPP) trial, which is currently in progress, seeks to determine whether early intervention with zoledronate might be effective in preventing disease progression. If the study shows beneficial effects, genetic testing, together with early bisphosphonate therapy, might be used in the future. Read the full article here (external link). 
Reference - Ralston S.H., ‘Bisphosphonates in the management of Paget's disease’, Bone, 2020, Sep;138:115465.

Clinical Guideline

A clinical Guideline, for the Diagnosis and Management of Paget’s Disease of Bone in Adults, can be found by following this link.

Case 1

A 67-year-old man with pain in his right hip

Presenting Complaint
A 67-year-old man attended his GP complaining of pain in his right hip. It was present at rest and became slightly worse on walking. His general health was good. He was taking lisinopril 10mg daily for hypertension; atorvastatin 10mg daily for high cholesterol; and paracetamol 1-2g daily for pain.
Investigations
Routine bloods showed normal renal function, normal calcium biochemistry and normal LFT, apart from a raised serum total alkaline phosphatase at 350 U/L (reference range 40-125). Serum 25(OH) vitamin D was low at 24nmol/L (reference range 25-160).  
An x-ray of the pelvis showed changes typical of Paget’s disease in the right upper femur (Figure 1). 
Management
The patient was referred to secondary care. 
A radionuclide bone scan showed Paget’s disease in the right upper femur with a stress fracture on the lateral femoral cortex, but no other affected sites.
Following discussion of treatment options, he was given vitamin D supplements and went on to have a single infusion of zoledronic acid 5mg, as a day case in his local hospital.
Outcome
On review 4 months later, the pain had improved, and repeat bloods showed that the ALP had fallen to 76 U/L. 
On follow up 2 years later, his pain had remained well controlled with intermittent paracetamol and his ALP remained within the normal range.

Figure 1. X-ray showing bone expansion, accompanied by osteosclerosis and osteolysis in the upper right femur. The stress fracture is indicated by the white arrow.
Comment
The patient had pain localised to an affected site and biochemical evidence of increased metabolic activity of Paget’s disease, on biochemistry and bone scan. His symptoms responded well to zoledronic acid, which is considered the treatment of first choice in Paget’s disease because of its beneficial effects on pain and long duration of action, which in many cases can extend for up to 5 years or more

Case 2

A 72-year-old man with back and leg pain

Presenting Complaint
A 72-year-old man attended his GP complaining of pain in the lower back region with radiation to both legs, which had been gradually worsening over the previous 
2-3 years. He had a history of ischaemic heart disease.
He was being treated with atorvastatin 10mg daily, bisoprolol 10mg daily, vitamin D 800 units daily and co-codamol up to 
8 tablets daily.
Investigations
Routine bloods showed normal renal function, and normal calcium biochemistry. Liver function tests showed a raised serum total alkaline phosphatase at 245 U/L 
(reference range 40-125). Serum 25(OH) vitamin D was 55nmol/L (reference range 25-160).  
An x-ray of the pelvis showed evidence of Paget’s disease and osteoarthritis in the lumbar spine (Figure 2).
Management
The patient was referred to secondary care for further evaluation. 
A radionuclide bone scan showed Paget’s disease of L1-L3 with widespread OA change and MRI scan showed evidence of lumbar stenosis at L2-L3.
Following discussion of treatment options, he was offered a therapeutic trial of zoledronic acid, but the possible need for spinal surgery was also discussed.
Outcome
He had a severe reaction to zoledronic acid with fever, bone pain and gastrointestinal upset for a week after the infusion. 
On subsequent review 6 months later, his ALP had fallen to 56 U/L, but his pain had not improved. He was referred for spinal decompression surgery which markedly improved his symptoms. 
He remained well on follow up 3 years later with some back pain, which is well controlled with co-codamol.

Figure 2. X-ray showing osteosclerosis and osteolysis of L1, L2 and L3 with superadded OA change and osteophyte formation in the posterior vertebral elements (arrows).
Comment
The patient had pain localised to an affected site, but the lack of response to zoledronic acid indicated that this was most likely due to spinal stenosis and osteoarthritis, both of which can complicate Paget’s disease. Imaging with MRI is not generally required to make a diagnosis of Paget’s disease, but as this case illustrates, it can help assess the presence of complications such as spinal stenosis.

Case 3

A 62-year-old man with right hip and knee pain on walking

Presenting Complaint
A 62-year-old man attended his GP complaining of pain in the right hip and right knee on walking, which had been gradually worsening over the previous 2-3 years. He was previously well with no significant past medical history and was taking diclofenac 50mg three times daily for the pain and co-codamol up to 8 tablets daily.
Investigations
An x-ray of the pelvis showed Paget’s disease in the upper femur, but OA change in the right hip joint (Figure 3). 
Routine bloods showed normal renal function, and normal calcium biochemistry. Liver function tests showed a raised serum total alkaline phosphatase (ALP) at 175 U/L 
(reference range 40-125). Serum 25(OH) vitamin D was 75nmol/L (reference range 25-160).
Management
The patient was referred to the department of orthopaedic surgery for further evaluation, considering that the pain was most likely due to OA and he was listed for a hip replacement. He underwent a right total hip replacement and was then referred to the metabolic bone clinic for follow up of the Paget’s disease. Treatment options were discussed, but he declined to have bisphosphonate therapy as his pain had disappeared.
Outcome
He remained well about 12 months after the right hip arthroplasty, with no pain and serum ALP remained elevated at 168 U/L. 
He is being kept under annual review to monitor his symptoms.

Figure 3. X-ray showing trabecular coarsening and bone expansion of the upper right femur, consistent with Paget’s disease (white arrows), and loss of joint space in the right hip joint, consistent with advanced osteoarthritis (blue arrows).​
Comment
The patient had pain localised to the right hip, but the radiation to the knee is characteristic of osteoarthritis. Although there is Paget’s of the right upper femur, the pain responded fully to arthroplasty indicating that OA was the likely cause. Clinical experience indicates that the outcome of arthroplasty in patients with Paget’s is excellent. There isn’t any evidence so far to suggest that normalization of ALP in patients with PDB is of clinical benefit, but this is an area of ongoing research.

Case 4

Long-standing, undiagnosed PDB with subsequent osteosarcoma

Presenting Complaint
A 90-year-old man was referred for treatment of presumed osteoarthritis, which had reached the point that he could no longer cope. 
For 30 years he had had a painful lower left leg and had been forced to retire at the age of 60 due to the pain. His tibia was bowed with consequent leg shortening.
Investigations
Isolated raised alkaline phosphatase.
X-rays revealed Paget’s disease (Figure 4), with some secondary osteoarthritis in the knee.
Isotope bone scan showed Paget’s in the tibia. No other areas involved.
Management
He was treated with risedronate, 30mg daily for 2 months and provided with a raised shoe.
Outcome
There was considerable improvement in his pain. On subsequent review, he developed worsening pain in his tibia and he was found to have osteosarcoma. This was confirmed after referral to the specialist sarcoma service and he sadly passed away a few months later.

Figure 4.
Comment
This is a rare case of malignant transformation in bone affected by Paget’s. New symptoms arising from involved bones need investigation as to the cause, especially when the disease has previously been asymptomatic or well treated and brought under biochemical control. Possible explanations include fissure fractures, secondary osteoarthritis in adjacent joints and nerve entrapment. 
Osteosarcoma is a rare cause, but one not to miss as it requires urgent referral to centres specialising in this type of tumour for investigation and treatment. As an aside, risedronate was used in this individual because the case predated the availability of zoledronate.
 

Images copyright of the Paget's Association