A 76-year-old widow presented to the Emergency Department with a mid-shaft right femoral fracture after a low-impact fall outside a supermarket. She had a past history of ischaemic heart disease, peripheral vascular disease, intermittent claudication, and mechanical right knee pain. She had been reviewed in rheumatology outpatients 3 months prior to admission for investigation of a painful swollen right elbow. She lived alone and had moved from County Durham where her husband had been a coal miner. Her usual medication included aspirin, bendroflumethiazide, and simvastatin.
On examination, in addition to the fractured femur she had a warm swollen R distal upper arm. She was haemodynamically stable, normotensive, and in sinus rhythm. Her distal pedal pulses were all impalpable.
Her initial blood results showed the following:
◆ Hb 10.5 g/dL (MCV 88 fL); WCC 6.8 × 109/L; platelets 468 × 109/L
◆ Creatinine 138 µmol/L; asparatate transaminase (AST) 48 IU/L; gamma glutamyl transferase (GGT) 52 IU/L; ALP 785 IU/L
◆ Corrected calcium 2.23 mmol/L; phosphate 1.2 mmol/L
◆ C-reactive protein (CRP) 8 mg/L.
Her femoral fracture was successfully pinned and plated, and she made a good postoperative recovery. Prior to discharge she was given an intravenous infusion. One week after discharge she was re-admitted profoundly unwell with nausea, vomiting, and tingling in her hands and feet.
Second admission bloods were as follows.
◆ Hb 11.5 g/dL (MCV 88 fL); WCC 7.9 × 109/L; platelets 488 × 109/L
◆ Creatinine 144 µmol/L; asparatate transaminase (AST) 55 IU/L; gamma glutamyl transferase (GGT) 30 IU/L; ALP189 IU/L
◆ CRP 10 mg/L
◆ Corrected calcium 1.87 mmol/L; phosphate 0.8 mmol/L
◆ Vitamin D level 7 nmol/L (threshold 20).
2. Describe the clinical features, natural history, and potential complications of this condition.
3. What is the likely infusion she was given?
4. What complication of treatment did she develop and why?
1. What is the underlying bony diagnosis? What is the differential diagnosis?
The diagnosis is Paget’s disease of bone.
The differential diagnosis of a low-impact fracture in an elderly woman includes osteoporosis, osteomalacia, pathological fracture through a malignant focus, and Paget’s disease. This patient’s calcium was low normal on admission. Her phosphate was also low normal and her alkaline phosphate was very high. The rise in ALP could have been due to Paget’s disease, osteomalacia, malignancy, or her recent fracture.
The plain radiographic features in the humerus (Fig. 1.1), and below the femoral fracture site (Fig. 1.3) in this case are typical of Paget’s disease (Fig. 1.5). The bones are expanded with coarse trabeculation, cortical thickening, a mixture of lytic and sclerotic areas with intra-cortical resorption, loss of cortico-medullary junction, and early secondary osteoarthritis changes in the knee. Radiographic features are pathognomonic in established disease, but early or isolated lesions might be confused with malignancy and severe osteomalacia.
The technetium-99m isotope bone scan (Fig. 1.2) shows increased uptake in the right humerus right distal femur, right hemi-pelvis, and thoracic spine.
Isotope bone scans are the current standard method of establishing the pattern of skeletal site involvement. Typical abnormalities are easily recognized. However, if abnormalities are detected, further clinical and radiographic assessment is necessary. There is a move towards limited skeletal survey, imaging the clinically significant sites of skull, long bones, and spine as first-line investigation.
In this patient's technetium scan the characteristic V-shaped advancing front of Paget’s disease is seen in the femur and humerus. This represents marked osteolysis without accompanying sclerosis. Other affected areas include the sacrum and the T9 vertebral body.
CT imaging may be useful to delineate difficult fractures and MRI should be used to characterize spinal Paget’s disease which may cause nerve root compression and spinal canal stenosis (Fig. 1.6).
2. Describe the clinical features, natural history, and potential complications of this condition
Paget’s disease of bone occurs in up to 10% of the population aged over 80 years and can affect any bone. The most common bones affected are pelvis (75%), lumbar spine (50%), femur (35%), sacrum (35%), skull (35%), tibia (30%) radius (15%). Patients often present with pain or deformity. The pain is of a deep bony, boring quality, and is present at rest. If the pagetic lesions involve subchondral bone they may result in secondary osteoarthritic changes and additional mechanical pain.
Pagetic bone is often increased in size, bowed, and mechanically weak. The bones are hypervascular, warm, and prone to fracture. Bony enlargement in the spine may cause mechanical compression of the nerve roots or spinal canal, leading to radicular pain or spinal claudication. Microfracture and vertebral collapse may lead to pain and kyphosis.
The cause of pain may be difficult to determine and requires careful history and examination.
This patient’s fracture is just above her pagetic bone and a typical site for pathological fracture. Prior to the fracture, her most troublesome symptom was her knee pain, attributed to associated osteoarthritis. As with many elderly patients, she has a number of comorbidities, including vascular claudication, which may have complicated the clinical picture.
Pagetic bone is hypervascular, and this has important consequences in relation to joint replacement surgery or surgery after fracture. The bleeding from hypervascular pagetic bone needs to be anticipated and is often difficult to control. Pretreatment with bisphosphonates may help prevent perioperative blood loss (see below). High-output cardiac failure, although often cited, is rarely seen in practice.
Deformity and associated symptoms are site-specific. Skull involvement can cause deafness from cranial nerve VIII compression, change in head shape, deep-seated headache, toothache (mandible involvement); blindness from optic nerve compression, and change in voice from nasal bone and airway narrowing. Long bones such as the tibia (‘sabre tibia’) and femur may be bowed, warm, and painful. Associated leg-length inequalities can lead to mechanical low back pain. Spinal involvement may lead to pain, spinal claudication; radicular symptoms from nerve root entrapment, or vertebral collapse and kyphosis.
Many patients are asymptomatic and Paget’s disease is an incidental finding on X-ray or from a raised alkaline phosphatase (ALP) as part of a routine blood screen for liver function. The natural history is unknown. Patients may be asymptomatic for many years, and it is not yet known whether treatment of asymptomatic patients increases longevity or prevents future problems. However, treatment is generally given for lower-limb long-bone, spinal, skull, and painful pagetic lesions.
3. What is the likely infusion she was given?
This patient was treated with a potent intravenous bisphosphonate, either pamidronate or zoledronate.
The treatment of symptomatic Paget’s disease of bone has been improved by the introduction of bisphosphonates which are potent inhibitors of bone turnover. The current regimes include 2 months oral risedronate 35 mg daily or 6 months oral alendronate 40 mg, quarterly intravenous pamidronate 30–90 mg over 2 h, or annual zolendronate 5 mg over 30 min. The aim of bisphosphonate therapy is to decrease pain, prevent further fracture, and normalize the alkaline phophatase. This is particularly effective prior to orthopaedic operations. Although there is a theoretical risk of impeding bone healing and remodelling by preventing osteoclast function, it is acceptable practice to use bisphosphonate therapy to try to prevent disease complications such as long-bone fracture.
ALP is the most commonly used marker of bisphosphonate activity. Bone resorption markers such as urinary cross-linked N-telopeptides of type 1 collagen (NTX) and serum carboxy-terminal collagen crosslinks (CTX) are raised, but are rarely helpful in clinical decision-making.
An ALP within the normal range may still be abnormally high for an individual patient, and comparison with premorbid ALP levels, if available, will help inform treatment decisions. In general, high ALP levels are associated with high disease activity.
Oral bisphosphonate normalizes ALP in 60% of patients at 18 months, IV pamidronate normalizes ALP in 50% at 6 months, and IV zoledronate normalizes ALP in 80% of patients at 6 months.
There is no benefit in terms of subsequent fracture rate or quality of life in treating Paget’s disease to maintain normal ALP levels. Treatments are repeated according to patient symptoms. As yet there are no data about the safety and efficacy of long-term bisphosphonate use.
Patients who are intolerant of bisphosphonates may respond to calcitonin given by subcutaneous injection—100 units daily for 3–6 months. This treatment should reduce pain and ALP in up to 50% of patients at 6 months. Side effects, including flushing, nausea, and headache, are common and may limit therapy.
4. What complication of treatment did she develop and why?
This patient developed profound hypocalcaemia in the presence of previously undiagnosed hypovitaminosis D. Hypovitaminosis D is very common and underdiagnosed in the elderly, particularly from northern latitudes. Low vitamin D levels can lead to myalgia, bone pain, weakness, and even falls. Borderline vitamin D levels in this woman prior to bisphosphonate infusion exaggerated the hypocalcaemic effect and led to dangerously low serum calcium levels.
All bisphosphonates can cause hypocalcaemia. The effect is greater with the more powerful longer-acting preparations and in patients with low vitamin D levels. Ideally, all patients should have their serum calcium and vitamin D levels checked before administration of parenteral bisphosphonate. As vitamin D levels are not always readily available, it is recommended that all patients receiving bisphosphonate treatment should receive calcium and vitamin D supplementation unless there are specific contraindications.
Oral bisphosphonate preparations need to be taken on an empty stomach with a large glass of water, and the patient should remain upright for at least 30 minutes before eating. Gastritis and indigestion are common. Many centres are moving towards using the more powerful longer-acting intra-venous preparations because of poor compliance and gastrointestinal side effects with the oral preparations. This general move is mirrored in the treatment of osteoporosis, where there is widespread use of bisphosphonates. Therefore this case serves to illustrate a potential problem that could occur with increasing use of powerful long-acting bisphosphonates.
Paget’s disease of bone commonly occurs in families with an autosomal dominant but incompletely penetrant pattern of inheritance. As a first-degree relative, this woman’s daughter has a seven times increased risk of developing the condition.
There is ethnic and geographic clustering around cooler latitudes, particularly Europe, North America, and Australasia. The highest prevalence is in populations from northern Britain and where they have subsequently migrated into the former British colonies.
Recent genetic studies from familial Paget’s disease of bone have linked a number of genetic loci and mutations have been identified in four genes, the most important of which is sequestosome 1 (SQSTM1). This is a scaffold protein in the nuclear factor kappa B (NFkappaB) signalling pathway. Patients with SQSTM1 mutations have severe Paget’s disease with a high degree of penetrance with increasing age. Environmental factors, such as deficiency in dietary calcium, and repeated mechanical loading have recently been linked to Paget’s disease of bone. Other possible environmental triggers include paramyxoviral infection, measles, canine distemper, and respiratory syncytial virus. Given the ubiquitous nature of many of these viruses, interplay of genetic and environmental factors must occur to explain the geographical distribution as well as the focal and heterogenous nature of the condition.
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