Chow, WS

Kung, AWC

Lam, JKY

Lam, KSL

Tan, KCB

Tso, AWK

HKU Scholars Hub

Title A woman with raised alkaline phosphatase and forearmdeformityAuthor(s) Lam, JKY; Lam, KSL; Kung, AWC; Tan, KCB; Chow, WS; Tso,AWKCitation Bmj, 2011, v. 342 n. 7811Issued Date 2011URL http://hdl.handle.net/10722/135201Rights BMJ. Copyright © BMJ Group.PICTURE QUIZAwomanwith raised alkaline phosphatase and forearmdeformityJoanne K Y Lam resident , Karen S L Lam professor , Annie W C Kung professor , Kathryn C BTan professor , Wing-Sun Chow associate consultant , Annette W K Tso assistant professorQueen Mary Hospital, Pokfulam Road, Hong KongA 71 year old Chinese woman was referred from the generaloutpatient clinic to our endocrine clinic for evaluation of raisedserum alkaline phosphatase (ALP), which had been measuredas part of a routine check-up. Apart from a history ofhypertension and gout, she was well. For the past two years herblood tests had shown a raised ALP (183-277 U/L; referencerange 47-124). Liver enzymes, renal function tests, thyroidfunction tests, and adjusted calcium and phosphateconcentrations were all within normal ranges.Examinations of the abdomen, cardiovascular system, andrespiratory system were normal. She was noted to have adeformity of the right forearm (fig 1). She denied a history oftrauma or fracture. The deformity had been present for threeyears, but she had not sought medical advice because it did notaffect her hand function and was not painful. A radiograph ofthe right forearm was taken (fig 2).Fig 1 Deformity of the right forearmFig 2 Radiograph of the right forearmQuestions1 What is the diagnosis?2 Describe the radiological abnormalities that confirm thediagnosis3 How would you treat this condition?Answers1 What is the diagnosis?Short answerThe diagnosis is Paget’s disease of bone.Long answerPaget’s disease of bone was first described by James Paget, whonamed this skeletal condition “osteitis deformans” in 1877.1 Itis a disease of bone remodelling and is characterised byexcessive bone resorption at affected skeletal sites, followed bydisorganised bone formation. The overproduced bone is scleroticand of poor quality, and it is susceptible to deformity andfracture.2 Paget’s disease of bone is the second most commonmetabolic bone disease in European countries. The prevalenceof Paget’s disease in the United Kingdom has been estimatedat 5% in people over 55 years of age.3 Paget’s disease, however,is rare in Chinese people. The prevalence of Paget’s disease innon-white populations is not known because few case reportsand case series are found in the literature.4 5 Pagetic lesions areusually found in the pelvis, spine, skull, and long bones of thelower extremities. Paget’s disease of the radius is rarelyreported.6Most patients with Paget’s disease are asymptomatic.Around 5% of patients have symptoms including bone pain,bowing of long bones, skull deformities, fractures, and nerveentrapment syndromes.7The diagnosis is usually made using plain radiographs (seebelow). Plain radiographs are also useful in the diagnosis ofCorrespondence to: J K Y Lam kyjoanne414@yahoo.com.hkReprints: http://journals.bmj.com/cgi/reprintform Subscribe: http://resources.bmj.com/bmj/subscribers/how-to-subscribeBMJ 2011;342:d3435 doi: 10.1136/bmj.d3435 Page 1 of 5EndgamesENDGAMESsecondary complications such as contiguous arthritis andfractures. Radionuclide bone scan using a radiolabelledbisphosphonate is highly sensitive in assessing the extent ofskeletal involvement.8 However, it is not specific to Paget’sdisease—focal uptake or “hot spots” can also be seen infractures, infections, and evenmetastases. Any increased uptakein bone scan should be followed by targeted radiographs.Serum alkaline phosphatase is a sensitive marker of boneformation, and concentrations are increased in 85% of patientswith Paget’s disease of bone.9 In patients with monostoticdisease (only one bone affected; about 15% of cases) orunderlying liver derangement, bone specific alkalinephosphatase may be more useful.10 Bone formation markers,such as procollagen type 1 N-terminal propeptide (P1NP), andbone resorption markers, such as urinary pyridinoline, areusually raised, but they are not widely available and are seldomused for diagnosis or monitoring of disease activity.11Bone biopsy is rarely needed for the diagnosis, but it might helpexclude osteosarcoma or bone metastases. Histological analysistypically shows an increase in bone resorption, with largemultinucleated osteoclasts and increased bone marrow fibrosissurrounding bone trabeculae.2 Describe the radiological abnormalities thatconfirm the diagnosisShort answerThis radiograph shows cortical thickening of the radius andulnar with a coarse trabecular pattern and bowing of the radius.Sclerosis of the distal radius is also seen, as well as lytic lesionsin the shaft of the radius (fig 3).Fig 3 Radiograph of the right forearm showing sclerosisof the distal radius and lytic lesions in the shaft of the radiusLong answerPaget’s disease is usually diagnosed with the use of plainradiographs. The characteristic radiological findings are mostprominent in the skull and long bones. Initially, osteolysis ofthe skull causes “osteoporosis circumscripta,” which is seen asradiolucent areas on radiographs. This is followed by excessiveformation of new bone, which leads to cortical thickening,“cotton wool” appearance as a result of localised sclerosis, andskull enlargement. The long bones typically show corticalthickening and enlargement, mixed areas of sclerotic and lyticlesions, and bowing deformities. If the vertebral body is affecteda characteristic “picture frame” appearance is seen, as a resultof enlargement of the vertebral body.103 How would you treat this condition?Short answerBisphosphonates are the gold standard treatment. The aim is todecrease the abnormal bone turnover caused by osteoclasticbone resorption.Long answerTreatment is not warranted in asymptomatic patients who havenormal serum alkaline phosphatase or a normal bone scan.Indications for treatment include symptoms that are caused bymetabolically active Paget’s disease, such as bone pain, jointpain, headache (when the skull is affected), or neurologicalsymptoms; planned surgery at a metabolically active pageticsite (treatment can decrease intraoperative bleeding); thepresence of immobilisation hypercalcaemia; serum alkalinephosphatase concentration more than 1.5 times the upper limitof normal; and prevention of disease progression or futurecomplications.12Around 5% of patients with Paget’s disease of bone experiencebone pain.7 They may benefit from simple analgesics, low dosetricyclic antidepressants, and physical methods, includingtranscutaneous electric nerve stimulation.13 Surgery may bewarranted if pain is caused by osteoarthritis or nervecompression.13Bisphosphonates are the mainstay of medical treatment inPaget’s disease of bone, which aims to suppress the abnormalbone turnover.13 Five bisphosphonates are currently indicatedfor the treatment of Paget’s disease of bone:• Zoledronic acid (5 mg infusion)14 15• Pamidronate (30 mg or 60 mg infusion every threemonths)16• Risedronate (30 mg daily for two months)15 17• Etidronate (5 mg/kg daily for six months, or 10mg/kg dailyfor three months)18• Tiludronic acid (400 mg daily for three months).19The first two come as intravenous preparations, whereas thelast three are oral preparations. They are associated with a50-80% reduction in plasma concentrations of alkalinephosphatase, and an improvement in bone pain and appearanceon radionuclide scanning.Serum creatinine, calcium, and vitamin D concentrations shouldbemeasured before using intravenous bisphosphonates, becausesevere hypocalcaemia can occur with pre-existing vitamin Ddeficiency. Consider reducing the dosage and infusion rate inpatients with mild renal impairment. Intravenousbisphosphonates are generally well tolerated, although somepatients may experience febrile reactions, especially after thefirst infusion. Febrile reactions are self limiting and easilymanaged with paracetamol.Oral bisphosphonates, on the other hand, are poorly absorbedfrom the gastrointestinal tract and associated withgastrointestinal side effects. It is recommended that oralbisphosphonates are taken with a full glass of water on an emptystomach and that patients wait for at least half an hour beforeeating or drinking. Adequate intake of calcium (1000-1500 mgdaily) and vitamin D (800-1000 IU daily) is recommendedbefore and after treatment with bisphosphonates. Ocular sideeffects including conjunctivitis and uveitis have been reportedwith bisphosphonates, but these complications are rare.Serum alkaline phosphatase concentrations usually fall within7-10 days of starting bisphosphonates, but the nadir occurs threeto six months later. Pain relief and normalisation of serumalkaline phosphatase are the goals of treatment. Serum alkalinephosphatase should be monitored every three months for thefirst six months of treatment, and at six monthly intervals monthsthereafter. Retreatment with bisphosphonates may be consideredin patients with recurrence of bone pain or biochemical relapse,Reprints: http://journals.bmj.com/cgi/reprintform Subscribe: http://resources.bmj.com/bmj/subscribers/how-to-subscribeBMJ 2011;342:d3435 doi: 10.1136/bmj.d3435 Page 2 of 5ENDGAMESdefined as an increase in alkaline phosphatase of 25% abovethe nadir.13Patient outcomeA radionuclide bone scan showed intense tracer uptake over L3and the right radius, with a patchy increase in uptake over theskull (fig 4). Radiography of the lumbar spine showed aheterogeneous increase in density of the L3 vertebral body, withbony expansion (fig 5). She was treated with a single infusionof 60 mg pamidronate and had a mild febrile illness for a fewdays after treatment. Her ALP fell from 277 U/L to 110 U/L inthree months.Reprints: http://journals.bmj.com/cgi/reprintform Subscribe: http://resources.bmj.com/bmj/subscribers/how-to-subscribeBMJ 2011;342:d3435 doi: 10.1136/bmj.d3435 Page 3 of 5ENDGAMESFig 4 Radionuclide bone scan showing intense traceruptake over L3 and the right radius, with a patchy increasein uptake over the skullFig 5 Radiography of the lumbar spine showing aheterogeneous increase in density of the L3 vertebral bodyand bony expansionCompeting interests: All authors have completed the ICMJE uniformdisclosure form at www.icmje.org/coi_disclosure.pdf (available onrequest from the corresponding author) and declare: no support fromany organisation for the submitted work; no financial relationships withany organisations that might have an interest in the submitted work inthe previous three years; no other relationships or activities that couldappear to have influenced the submitted work.Provenance and peer review: Not commissioned; externally peerreviewed.Patient consent obtained.1 Paget J. On a form of chronic inflammation of bones (osteitis deformans). Trans Med ChirSoc 1877;60:235-56.2 Whyte MP. Clinical practice. Paget’s disease of bone. N Engl J Med 2006;355:593-600.3 Barker DJ. The epidemiology of Paget’s disease of bone. Br Med Bull 1984;40:396-400.4 Irving K, Jawad ASM. Paget’s disease of bone in non-Caucasians in East London: a reportof eight cases and a review of the literature. Grand Rounds 2005;5:23-5.5 Hsu LF, Rajasoorya C. A case series of Paget’s disease of bone: diagnosing a ratheruncommon condition in Singapore. Ann Acad Med Singapore 1998;27:289-93.6 Urai J, Csink L. A case of Paget’s disease limited to the radius [in German]. Z Orthop IhreGrenzgeb 1962;95:362-5.7 Kanis JA. Clinical features and complications. In: Pathophysiology and treatment of Paget’sdisease of bone. 2nd ed. Martin Dunitz, 1998:110-38.Reprints: http://journals.bmj.com/cgi/reprintform Subscribe: http://resources.bmj.com/bmj/subscribers/how-to-subscribeBMJ 2011;342:d3435 doi: 10.1136/bmj.d3435 Page 4 of 5ENDGAMES8 Wellman HN, Schauwecker D, Robb JA, Khairi MR, Johnson CC. Skeletal schintimagingand radiography in the diagnosis and management of Paget’s disease. Clin Orthop RelRes 1977;127:55-62.9 Eastell R. Biochemical markers of bone turnover in Paget’s disease of bone. Bone1999;24:49S-50S.10 Steinbach HL. Some roentgen features of Paget’s disease. Am J Radiol 1961;86:950-64.11 Shankar S, Hosking DJ. Biochemical assessment of Paget’s disease of bone. J BoneMiner Res 2006;21(suppl 2):P22-7.12 Josse RG, Hanley DA, Kendler D, Ste Marie LG, Adachi JD, Brown J. Diagnosis andtreatment of Paget’s disease of bone. Clin Invest Med 2007;30:E210-23.13 Selby PL, Davie MW, Ralston SH, Stone MD; Bone and Tooth Society of Great Britain;National Association for the Relief of Paget’s Disease. Guidelines on the managementof Paget’s disease of bone. Bone 2002;31:366-73.14 Reid IR, Miller P, Lyles K, Fraser W, Brown JP, Saidi Y, et al. Comparison of a singleinfusion of zoledronic acid with risedronate for Paget’s disease. N Engl J Med2005;353:898-908.15 Hosking D, Lyles K, Brown JP, Fraser WD, Miller P, Curiel MD, et al. Long-term controlof bone turnover in Paget’s disease with zoledronic acid and risedronate. J Bone MinerRes 2007;22:142-8.16 Siris ES. Perspectives: a practical guide to the use of pamidronate in the treatment ofPaget’s disease. J Bone Miner Res 1994;9:303-4.17 Siris ES, Chines AA, Altman RD, Brown JP, Johnston CC, Lang R, et al. Risedronate inthe treatment of Paget’s disease of bone: an open label, multicenter study. J Bone MinerRes 1998;13:1032-8.18 Altman RD, Johnston CC, Khairi MR, Wellman H, Serafini AN, Sankey RR. Influence ofdisodium etidronate on clinical and laboratory manifestations of Paget’s disease of bone(osteitis deformans). N Engl J Med 1973;289:1379-84.19 Roux C, Gennari C, Farrerons J, Devogelaer JP, Mulder H, Kruse HP, et al. Comparativeprospective, double-blind, multicenter study of the efficacy of tiludronate and etidronatein the treatment of Paget’s disease of bone. Arthritis Rheum 1995;38:851-8.Cite this as: BMJ 2011;342:d3435Reprints: http://journals.bmj.com/cgi/reprintform Subscribe: http://resources.bmj.com/bmj/subscribers/how-to-subscribeBMJ 2011;342:d3435 doi: 10.1136/bmj.d3435 Page 5 of 5ENDGAMES

A woman with raised alkaline phosphatase and forearm deformity

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