Annals of the Rheumatic Diseases 1993; 52: 582-585

Methotrexate osteopathy in rheumatic disease

Sally J Preston, Terence Diamond, Andrew Scott, M Rodger Laurent

AbstractObjective-To determine whether twoadults with stress fractures receiving lowweekly doses of methotrexate had metho-trexate osteopathy.Case reports-Two adult patientsdeveloped features consistent with metho-trexate osteopathy while receiving lowweekly doses ofmethotrexate.Methods-Iliac crest biopsy samples weretaken and bone histomorphometrycarried out.Results-Symptoms resolved when themethotrexate was discontinued. Bonehistology showed changes consistent withosteoblast inhibition by methotrexate.Conclusions-When given in low doses forprolonged periods, methotrexate mayhave adverse effects on bone, particularlyin post-menopausal women.

(Ann Rheum Dis 1993; 52: 582-585)

Department ofRheumatology,Royal North ShoreHospital,St Leonards 2065,AustraliaS J PrestonM R Laurent

Department ofEndocrinology,Royal North ShoreHospital,St Leonards 2065,AustraliaT DiamondDepartaent ofNuclearMedicine,Royal North ShoreHospital,St Leonards 2065,AustraliaA ScottCorrespondence to:Dr M R Laurent,Department ofRheumatology,Royal North Shore Hospital,St Leonards 2065, Australia.

Accepted for publication29 April 1993

Methotrexate, a competitive inhibitor of folicacid metabolism, is widely used in thetreatment of rheumatic disease, particularlypsoriatic and rheumatoid arthritis.' The majorside effects on the liver and gastrointestinaltract are well recognised.2 Methotrexateosteopathy has been reported in children inassociation with high doses used for thetreatment of malignancies in childhood.3-7 It ischaracterised by a triad of bone pain, osteo-porosis, and fractures.7 We report the cases oftwo adults who developed methotrexateosteopathy who, to our knowledge, are the firstto be described with the disorder during longterm treatment with low doses of methotrexateused in the treatment of rheumatic disease.

Case reportsCASE 1

A 58 year old white woman presented withbilateral ankle pain of several months' durationassociated with swelling of the right leg andankle. There was no history of trauma. She hadbeen taking methotrexate for skin psoriasis forfive years and, after the death of herdermatologist, began to treat herself with dosesas high as 25 mg methotrexate weekly. Shesmoked 20 cigarettes each day, did not drinkalcohol, was post-menopausal, and had never

taken corticosteroids.On examination there was extreme

tenderness to palpation along both distal tibiae.The range of movement of her ankle and kneejoints was normal, and there was no evidenceof synovitis. She had thin hair, mucositis of the

mouth, but no psoriatic skin rash. Initial radio-graphs of her ankles showed a poorly definedarea of sclerosis at the distal left tibialmetaphysis (figs 1A and B). A bone scanshowed increased blood pool activity anddelayed technetium uptake in the metaphysealregions of the proximal and distal tibiae,suggestive of stress fractures (fig 1 C).

Radiographs performed six months latershowed bilateral distal tibial fractures and aproximal left tibial fracture, but no abnor-malities in the hands, feet, or sacroiliac joints.A complete blood count was normal. Serum

B-12, folate and red cell folate, and serumbiochemistry were normal. Serum alkalinephosphatase was 100 U/1 (normal range20-95 U/1), but other liver function testswere normal. Serum calcium (2.35 mmol/l),phosphate (1.05 mmolIl), and thyroid func-tion tests were normal. Serum parathyroidhormone was 0-26 ng/ml (normal <0 4 ng/ml),25 hydroxyvitamin D 38 nmol/l (18-128 nmolIl),and 1,25-dihydroxyvitamin D 70 pmol/l(46-207 pmolIl). The bone mineral density ofthe lumbar spine was reduced (table) and iliaccrest bone histomorphometry (table) showedreduced osteoid surfaces and osteoid thicknessand low bone formation rates (fig 2). Therewas no evidence of osteomalacia or hyperpara-thyroidism.

Methotrexate was stopped with a gradualresolution of bone pain, but the tendernessover the distal tibiae and the proximal left tibiapersisted for several months. Twelve monthslater the patient reported weightbearing pain inthe right forefoot. A technetium bone scanshowed features compatible with a metatarsalfracture of the right foot. In addition thereappeared to be a reduction in isotope uptakein the proximal and distal tibiae compared withprevious scans.

CASE 2A 75 year old white woman with a 15 yearhistory of seropositive, erosive, nodularrheumatoid arthritis had been treated withmethotrexate, 10 mg/week, for six years. Shepresented with a history of several months ofleft leg and ankle pain, which on examinationshowed marked swelling and tendernesspredominantly over the distal left tibia.Examination showed evidence of a cliniciallyinactive chronic deforming arthritis. She hadnever received corticosteroids by mouth. Herpast history included a total thyroidectomywhich required thyroxine replacement of 50,ug/day to maintain a euthyroid biochemicalstatus. She had smoked 10-15 cigarettes a dayin the past, but did not drink alcohol. She was

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Methotrexate osteopathy in rheumatic disease

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-IFigure 1 (A, B) Radiographs of the left ankle showing a poorly defined area ofsclerosis in the distal tibial metaphysis. (C) Bone scan showing bilateralincreased uptake in the metaphysial regions of the proximal and distal tibiae.

Figure 2 Bone biopsy sample showing normal osteoid thickness (left) and reduced osteoid thickness (right) (arrowed).

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54Preston, Diamond, Scott, Laurent

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Figure 3 (A, B) Anteroposterior and lateral radiographs of the left ankle showing osteopenia but no evidence offracture. (C) Bone scan showing increaseduptake consistent with a fracture in the distal left tibia.

post-menopausal and had never receivedhormone replacement therapy.

Radiographs of the left ankle showedosteoporosis but no evidence of stress fractures(figs 3A and B). Radiographs taken twomonths later did not show callus formation.Radiographs of her hands and feet showederosive changes of rheumatoid arthritis. Abone scan showed increased blood poolactivity and delayed technetium uptake in thedistal left tibia, suggestive of stress fracture(fig 3C). Increased technetium uptake wasalso seen in her knees, wrists, the small jointsof her hands and feet, and in the right anklejoint, in a pattern consistent with rheumatoidarthritis.

Bone mineral estimations and iliac crest histomorphometry in patients with methotrexateosteopathy

Patient 1 Patient 2 Normal range

OsteodensitometryDistal radius (units)* 38-5 9-6 16-42-8Lumbar spine (g/cm')f 0 91 1-3 0-9-1-4

HistomorphometrytCancellous bone area (%) 19-4 16-8 18-6-25-4Osteoidarea (%) 1-1 0-5 1-2-3-0Total osteoid surface (/) 6-5 4-2 9-13 9Osteoid thickness (,jm) 7-8 6-5 94-12-0Osteoblast surface (%) 3-2 1-8 56-10-8Osteoclast surface (/) 0-4 1-2 0-6-2-2Mineral appositional rate (,m/day) 0.0 0-48 0-60-0-80Mineralising surface (%/o) 15§ 5-6 6-0-11-2Bone formation rate (jimY/pm2/day) 0 0 0-02 0 04-009Aluminium stain Negative NegativeIron stain Negative Negative

*Forearm osteodensitometry was measured by single photon absorptiometry using a Noroosteodensitometer.tSpinal osteodensitometry was measured by dual photon absorptiometry using a Norland 2600dichromatric base osteodensitometer.tMethod of Diamond et al."§Only single tetracycline labels.

Haemoglobin was 127 g/l, white blood cellcount 8*7X iO/1, platelets 284X iO0/1, anderythrocyte sedimentation rate 25 mm/h. Serumbiochemistry was normal. Serum alkalinephosphatase was 160 U/1 (normal range 20-95U/1), but other liver function tests were normal.Serum calcium was 2-38 mmol/l, phosphate0-98 mmol/l, osteocalcin 3-1 mg/ml (normalrange 2 1-8-1 mg/ml), 25-hydroxyvitamin D37 nmol/l (normal range 18-128 nmol/l),1,25-dihydroxyvitamin D 74 pmolll (normalrange 46-207 pmol/l), and parathyroidhormone 0 16 ng/ml (normal <0 4 ng/ml).Forearm bone mineral density was signifi-

cantly reduced, whereas the lumbar spine bonemineral density was pseudoelevated owing tothe presence of radiologically documentedfacet joint osteoarthritis (table). Iliac crest bonehistomorphometry showed reduced osteoidsurfaces and osteoid thickness, and a low boneformation rate (table). There were no featuresof osteomalacia or hyperparathyroidism.

Methotrexate was stopped with theresolution of symptoms after two months.Within weeks the patient had a flare of herrheumatoid arthritis which did not respond tosulphasalazine or prednisone by mouth. Thepatient asked to begin taking methotrexateagain as this was the only drug which had anyeffect on her arthritis. A dose of methotrexate15 mg/week was required to control herrheumatoid arthritis. After three months oftreatment pain, swelling, and bone tendernessrecurred in her legs, once again requiringmethotrexate to be stopped before thesymptoms resolved.

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Methotrexate osteopathy in rheumatic disease

DiscussionMethotrexate osteopathy is a recogniseddisorder with characteristic clinical and radio-graphic features.7 Our two patients whopresented with bone pain, swelling, and meta-physeal fractures are, to our knowledge, thefirst reported patients with rheumatic diseasewith methotrexate osteopathy.

Methotrexate has a reversible effect on bonewhen used in the treatment of malignancy inchildhood.7 In children long term metho-trexate treatment by mouth for acutelymphocytic leukaemia has been shown tocause bone pain and fractures, usually in thelegs but occasionally in the arms and spine.3-7Radiographs have shown osteoporosis,fractures, and multiple transverse bands in themetaphysis. The bone pain usually improvesthree to four weeks after discontinuing themethotrexate, though the radiographic changestake about four months to resolve.3 Delayedhealing of fractures has also been reported,with bone union not occurring until the metho-trexate has been discontinued.6 Abnormalitiesin the bone scans may precede radiographicchanges.

In our patients the symptoms of bone pain,tenderness, and swelling occurred after longterm treatment with low doses of metho-trexate. The pain was sufficiently severe tointerfere with walking and resolved over two tothree months, slower than that previouslydescribed in childen,3 presumably owing to thedecreased regenerative capacity of aging bone.Fractures were evident on bone scans beforeany radiographic changes were seen.A dose dependent effect of methotrexate on

bone mineral density has been shown in adultstreated for osteosarcoma and has beenattributed to the inhibtion of osteogenesis.' Itwas concluded that high doses of methotrexatemay result in a higher incidence of spontaneousfractures in elderly subjects in whom senileosteoporosis is also present.8

In our patients bone mineral densitymeasurements were reduced and bone histo-morphometry showed a low bone turnoverstate with reduced osteoid matrix formation.The reduction in osteoblast surfaces, osteoidmatrix parameters, and tetracycline labelling issimilar to the findings in animals where areduction in bone formation rates, osteoidvolume, and osteoid thickness is apparent.9Our patients were all active, did not consumealcohol, and did not have a history of long termtreatment with corticosteroids by mouth.Moreover, iron and aluminium stains were alsonegative in the bone biopsy specimens, thereby

excluding other potential factors which couldhave inhibited osteoblast function.There are two theories about the toxic effects

of methotrexate on bone. Increased osteo-clastic bone resorption based on the finding ofincreased urinary and faecal calcium excretionhas been proposed in patients taking metho-trexate, but there have been no studies showinghistomorphometric evidence of boneresorption.9 On the other hand, short termadministration of methotrexate in the ratproduced a 60% reduction in bone formationrates, with a toxic effect on osteoblasts beingreflected by reduced osteoid volume andthickness,'0 findings similar to those seen in ourpatients. This suggests that methotrexate, aninhibitor of protein synthesis, may be toxic toosteoblasts by inhibiting the recruitment ofosteoblasts from the progenitor osteoblaststage and function. Furthermore, the reducedbone turnover state may also be detrimentaland predispose to delayed microfracturerepair.

In conclusion, we have described two adultpatients who had features consistent withmethotrexate osteopathy. Bone biopsy sampleswere consistent with osteoblast inhibition as aconsequence of methotrexate action on thebone cells. When given in low doses forprolonged periods, methotrexate may be anadditional risk factor for osteoporosis,especially in post-menopausal women, whoalready have multiple risk factors for thisdisorder.

1 Christophidis N. Methotrexate. Clin Rheum Dis 1984; 10:401-15.

2 Kremer J. Methotrexate therapy in the treatment ofrheumatoid arthritis. Rheum Dis Clin North Am 1989; 15:533-56.

3 Ragab A H, Frech R S, Vietti T J. Osteoporosis fracturessecondary to methotrexate therapy of acute leukaemia inremission. Cancer 1970; 25: 580-5.

4 O'Regan S, Melhorn D K, Newman A J. Methotrexate-induced bone pain in childhood leukaemia. Am J DisChild 1973; 126: 489-90.

5 Nesbit M, Krivit W, Heyn R, Sharp H. Acute and chroniceffects of methotrexate on hepatic, pulmonary andskeletal systems. Cancer 1976; 37: 1048-54.

6 Stanisavljevic S, Babcock A L. Fractures in children treatedwith methotrexate for leukaemia. Clin Orthop Rel Res1977; 125: 139-44.

7 Schwartz A M, Leonidas J C. Methotrexate osteopathy.Skeletal Radiol 1984; 11: 13-6.

8 Gnudi S, Butturini L, Ripamonti C, Avella M, Baci G. Theeffects of methotrexate on bone. A densitometric studyconducted on 59 patients with methotrexate administeredat different doses. ItalJ Orthop Traumatol 1988; 14: 231.

9 Nevinny H B, Krent M J, Moore E W. Metabolic studieson the effects of methotrexate. Metabolism 1965; 14:133-9.

10 Friedlander G E, Tross R B, Doganis A C, Kirkwood J M,Baron R. Effects of chemotherapeutic agents on bone.J Bone J7oint Surg [Am] 1984; 60: 602-7.

11 Diamond T, Stiel D, Posen S. Osteoporosis in haema-chromatosis: iron excess, gonadal deficiency, or otherfactors? Ann Intern Med 1989; 110: 430-6.

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