Tumor-induced osteomalacia—a diagnostic dilemma for an orthopedic surgeon

1 23

������� ���������������������������������� ����������� ������������������������������������������������������� ������������ �!""��#$%&�'(%)�� ����������� ���*�!�#+,#++&-�#.(&+�+#/�+./'��

�������� ������������ ���������� ��������������������� ������

�������� ����������� ������������ �����������������������

1 23

Your article is protected by copyright and allrights are held exclusively by EFORT. This e-offprint is for personal use only and shall notbe self-archived in electronic repositories. Ifyou wish to self-archive your article, pleaseuse the accepted manuscript version forposting on your own website. You mayfurther deposit the accepted manuscriptversion in any repository, provided it is onlymade publicly available 12 months afterofficial publication or later and providedacknowledgement is given to the originalsource of publication and a link is insertedto the published article on Springer'swebsite. The link must be accompanied bythe following text: "The final publication isavailable at link.springer.com”.

REVIEWARTICLE

Tumor-induced osteomalacia—a diagnostic dilemmafor an orthopedic surgeon

Deep Sharma & D. K. Patro & Murali Poduval &M. Karthikeyan & Pooja Dhiman

Received: 10 October 2013 /Accepted: 19 November 2013# EFORT 2013

Abstract Tumor-induced osteomalacia is a rare conditioncaused by excess production of phosphatonins most notablyfibroblast growth factor−23 (FGF-23), by the tumor cells, lead-ing to phosphate wasting and consecutive severehypophosphatemia. This results in patient developing graduallyprogressive muscle weakness and bone loss resulting in severeosteomalacia, making the patient bedbound. These tumors aremostly benign mesenchymal tumors, which remain hidden insoft tissues or bone and thus are difficult to diagnose. And in thepresence of normal serum calcium and parathyroid levels withonly mild alteration of vitamin D levels, the diagnosis getsfurther delayed causing a lot of apathy to the patient.We herebypresent a thorough review of this condition along with ourexperience in diagnosing and treating this patient. This under-lines the fact that a high index of suspicion is required fordiagnosing this condition in a patient with persistent complainsof fatigue and bone pains. Appropriate investigations done at anearly stage can help one in identifying and excising thesetumors, bringing about a rapid relief of symptoms and savingthe patient from a lot of distress.

Keywords Phosphate . Tumour . Osteomalacia . FGF23

Introduction

Tumor-induced osteomalacia (TIO) is a rare paraneoplasticsyndrome associated with benign mesenchymal tumors, whichis characterized by phosphaturia, hypophosphatemia and lowserum levels of 1,25 vitamin D3 in the presence ofnormocalcemia. It is a disease entity known now for manyyears. The first case with symptoms similar to TIOwas reportedby McCance in the year 1947 [1], but the true etiopathogenesisof the disease was not known for many years, till Andrea Prader[2] in a case report in 1959 postulated the presence of arachitogenic substance being produced by some tumors, whichcan lead to the development of clinical features of severeosteomalacia with near normal levels of calcitriol and calcium.In further experiments, it was found out that this substance leadsto phosphate wasting by the body by causing phosphaturia andthus hypophosphetemia and so it was labeled as phosphatonin.Since phosphate is vital for important physiological functionssuch as intracellular signaling, membrane function, energymetabolism and bone metabolism, the lack of phosphate inthe body leads to severe fatigue, muscle and bone pains andpathological fractures [3, 4]. Patients of TIO generally presentwith diffuse pain and weakness, which can progress to thembeing completely bedridden. Most of the times the early symp-toms are puzzling, and thus, the diagnosis gets delayed.However, the removal of the causative tumor completely curesthese symptoms and biochemical abnormalities. Therefore, theidentification of the tumor responsible for TIO is clinicallyimportant. It is not uncommon for tumor that causes TIO tobe small and exist within bone, thus making them difficult todetect. Several techniques have been used to identify the tumorsresponsible for TIO, including computed tomography (CT),skeletal survey by magnetic resonance imaging (MRI),octreotide scintigraphy and positron emission tomography(PET), indicating that there is no standardized method for thispurpose [2, 5, 6]. In addition, even if tumors are found by these

D. Sharma (*) :D. K. Patro :M. Poduval :M. KarthikeyanDepartment of Orthopaedics, JIPMER, Pondicherry, Indiae-mail: [email protected]

D. K. Patroe-mail: [email protected]

M. Poduvale-mail: [email protected]

M. Karthikeyane-mail: [email protected]

P. DhimanDepartment of Biochemistry, JIPMER, Pondicherry, Indiae-mail: [email protected]

Eur Orthop TraumatolDOI 10.1007/s12570-013-0234-y

Author's personal copy

methods, none is able to establish that the detected tumor isindeed the cause of TIO.

In this review, we aim to explain the pathophysiology ofthis rare disorder of phosphate metabolism and elaborate uponthe various ways in which the patients can present clinically.We would also discuss the important biochemical markers andthe radiological studies, which can lead us to the correctdiagnosis of this condition. This should prove useful for anearly diagnosis and management of these patients.

Phosphate homeostasis

Dietary phosphate, which is present abundantly in cereals,meat and milk, is mainly absorbed in the duodenum andjejunum [7]. Bones are the main storehouses of phosphate inour body comprising 85 % the total body phosphorus, while14 % of phosphate is intracellular forming an important com-ponent of lipids, proteins, nucleic acids and small molecules

of metabolic and signaling pathways. Only 1 % is present inthe serum and extracellular fluid. This phosphate present inthe extracellular fluid is filtered into the renal tubules; how-ever, normally, almost 90 % of this is reabsorbed back by theproximal renal tubular cells, by the aid of sodium-dependentphosphate cotransporter (NaPi-2a and Na Pi-2c), so as tomaintain an optimum serum phosphorus level of 2.5–3.6 mg/dl. Any change in these levels leads to significantdisruption in normal functioning, with higher levels associatedwith soft tissue calcification and nephrolithiasis, whereashypophosphatemia causing muscle fatigue and severe osteo-malacia of bones. Thus, phosphate homeostasis is under astrict humeral control exerted via an exquisite interplay ofvarious factors including Vitamin D, parathyroid hormone(PTH) and Phosphatonins. However, the true nature ofphosphatonins was not known till 2001, when White et.al[8, 9] identified this phosphatonin substance as fibroblastgrowth factor−23 (FGF-23). Since then, a few otherphosphatonins have also been identified such as frizzled re-lated protein-4, matrix extracellular phophoglycoprotein andFGF-7 [10, 11]; however, FGF-23 remains as the most impor-tant and clinically relevant one till date. FGF-23 is normallysecreted by the bone cells and is an important regulator ofphosphate levels in the body [12–14]. It acts on the proximalrenal tubular cells in the kidney, which are the sites of maxi-mum phosphate reabsorbption. FGF-23 causes a decrease inthe expression of sodium-dependent phosphate transporter(NaPi-2a) on the surface of the basal cells in the proximalrenal tubule, and this leads to decrease in the reabsorption ofphosphate by the kidney. In addition, FGF-23 also causesdownregulation of 1-alpha hydroxylase enzyme and upregu-lation of 25-Hydroxylase enzyme, thus leading to decreasedlevels of 1,25, dihydroxyvitamin D3 [13]. In patients sufferingfrom phosphate-wasting conditions such as autosomal-

Fig. 1 X-Ray pelvis of the patient—showing severe osteomalacia withpseudo fractures involving bilateral neck of femur

Fig. 2 CT Scan—showing the presence of loosers zones in bilateral femoral necks

Eur Orthop Traumatol

Author's personal copy

dominant hypophosphatemic rickets (ADHR), X-linkedhypophosphatemic rickets (XLH) and TIO, the levels ofFGF-23 are markedly raised in the serum [15–18], due towhich these patients present with severe phophaturia produc-ing hypophosphatemia and osteomalacia-like picture. A sim-ilar type of picture is also seen in conditions such aspolyostotic fibrous dysplasia, hematological malignancies,prostate cancer and oat cell cancer [12, 19–22], but when theprimary disease is obvious, it is referred to as a secondary TIO.In primary TIO, the tumor is not obvious.

Clinical presentation

What makes TIO a diagnostic dilemma for the treating sur-geon is the fact that the patients of TIO can present with a widevariety of symptoms, which are mostly nonspecific and ill-defined. These may range from generalized fatigue and mus-cle weakness to backache, muscle cramps, joint pains, loss ofheight, bone pain, leg pain and abnormal gait [23]. Thesepatients are often misdiagnosed with a variety of musculo-skeletal ailments, rheumatologic diseases and sometimes evenpsychiatric disorders [24, 25]. Children can develop ricketsand growth retardation [26, 27]. The vague nature of thecomplaints and the absence of any objective clinical signs inthe early stages of the disease make the diagnosis exceedinglydifficult; compounded on it is the fact that the tumor causingTIO is very inconspicuous and remains hidden clinically. Allthese factors lead to a significant delay in the diagnosis lead-ing to increased morbidity.

In our tertiary care hospital, we were consulted by a 25-year-old male patient who presented with complaints of low

back ache for several months, which was insidious in onsetand progressively increasing in severity. This was associatedwith left thigh pain and bilateral knee pain. Since the past fewmonths, the patient had started to limp, with difficulty ingetting up from sitting and squatting position and had alsodeveloped bilateral hip pain, due to which the patient wasreferred by the primary care physician to a rheumatologist, butin the absence of any rheumatic disorder and due to presenceof proximal muscle weakness, the patient was asked to consulta neurologist. Neurologic workup was also normal, but by thetime the patient had become bedridden and thepseudofractures started becoming evident on the X-ray(Figs. 1 and 2), which brought the patient to us, and a diag-nosis of osteomalcia was made. Following a complete bio-chemical workup, the patient was found to havehypophosphatemia with phophaturia, with near normal levelsof calcium, PTH and Vitamin D3. FGF-23 levels were foundto be elevated in serum, so after excluding the other

Fig. 3 FDG-PET Scan image showing the presence of FDG avid soft tissue tumor present near the cortex of the fibula

Fig. 4 1×1 cm Mesenchymal tumor exiced with wide margins

Eur Orthop Traumatol

Author's personal copy

phosphate-wasting disorders, the diagnosis of oncogenic os-teomalacia was contemplated, and further localization studiesconfirmed the presence of an FDG avid tumor near the prox-imal fibula on FDG-PET Scan (Fig. 3). Following the surgicalexcision of the tumor, the patient improved remarkably within2 weeks and in 4 months time, the radiological and biochem-ical abnormalities also disappeared (Figs. 4 and 5).

Similarly, another patient, a 42-year-old male factory work-er, presented to us with a history of pain in both the knees andlegs since past 6 months, followed by appearance of pain inboth ankles and also recently in both hips and thighs. Before

coming to us, the patient had consulted numerous doctors andin the absence of any clear objective signs was being treatedsymptomatically; however, the symptoms were progressivelyworsening and now, the patient even had difficulty walkingunaided. Again, a thorough evaluation showed the presence ofpseudofractures in both femoral necks (Fig. 6), and aphosphate-wasting disorder with raised levels of FGF-23and normal levels of calcium, PTH and Vitamin D3. FDG-PET Scan was able to pick up a small soft tissue tumor in theproximal leg (Fig. 7), and upon its removal, the patient’ssymptoms improved dramatically, and so did his radiologicaland biochemical abnormalities.

Our experience matches the experience of other authors[23], who also found that the diagnosis of this rare disorder isexceedingly difficult; yet, it is easily curable and gives verygratifying results with excision of the tumor.

Diagnosis

Most of the time, the tumor is a benign mesenchymal tumor(Fig. 4), which may be present in the soft tissue or the bone.Though more common site for these tumors is the head andneck region [26], however, as in our cases, the tumors may bepresent in the limbs as well. They usually remain undetectablebecause of their small size and benign nature. The biochemical

Fig. 5 Four-month post operative pelvis X-ray of case 2 shows completehealing of the pseudo fractures

Fig. 6 MRI Scan showing the presence of pseudo fractures in the femoral necks

Eur Orthop Traumatol

Author's personal copy

workup mostly shows normal or mild decrease in the levels ofserum calcium and calcitriol, and PTH may remain normal ormildly elevated. However, the ALP is elevated, with a markeddecrease in the levels of serum phosphorus and an increasedphosphorus loss in the urine. The radiological picture is ofsevere osteomalacia with pseudofractures (Fig. 1). The diag-nosis at this stage rests on eliminating other causes of phos-phate wasting such as ADHR, ARHR and XLH from TIO, allof which are associated with raised FGF-23 levels. ADHR,ARHR and XLH are caused by genetic mutations and thusmostly present early in life, but TIO is an acquired disorderand mostly present after 30 years of age. Also a negativefamily history and previous normal reports of serum phospho-rus levels prove helpful in ruling out these inherited causes ofphosphate wasting. Also, some of the genetic conditions such

as XLH can present with associated dental abnormalities inthe form of enamel hypoplasia, dental abscess or caries [28],whereas muscle fatigue and pain points towards the diagnosisof TIO. Once the diagnosis of TIO is established, a systematicapproach as described by Chong et al. [29] should be adoptedto identify this FGF-23 producing tumor. This includes firstperforming the functional imaging studies to localize the siteof the tumor, the most sensi t ive being the F18Flourodeoxyglucose Positron Emission Tomography withCT Scan (FDG-PET/CT), but it has a low specificity.Indium-111 octreotide scintigraphy along with SPECT/CTcan be very specific in tumor localization as most of thesetumors have somatostatin receptors. The Ga-68 DOTANOC-PET/CT, which uses modified octretide molecule instead ofFDG, has the advantage of having both high sensitivity andspecificity. Once a tumor is localized, the exact location of the

Fig. 7 FDG—PET Scan showing the presence of an FDG avid soft tissue tumor in the proximal leg

Fig. 8 Tumor showing classical hemangiopericytoma appearance withspindle shaped cells embedded in abundant matrix Fig. 9 Immunohistochemistry showing vimentin positivity of the tumor

Eur Orthop Traumatol

Author's personal copy

tumor can be determined by performing a local part CT or anMRI. Most of the time, the tumors can be localized by theabove method; however, if the tumor still remains hidden,then it is warranted to perform anatomical imaging of thebrain and the abdomen as tumors in these locations havea propensity to be missed by functional imaging. Someauthors have also proposed to perform selective venoussampling for tumor localization [30], but presently, the onlyindication to perform such a test is when the tumor is at alocation, which is associated with high postoperative mor-bidity, or if there are multiple tumors detected on functionalimaging. In such cases, if possible, one can also do anaspiration of the tumor and examine it for the cell type andlevels of FDG-23 in the aspirate. If the tumor still cannotbe identified, then it is recommended to continue with themedical management and repeat the localizing imagingstudies after 1–2 years [29].

Management

The ideal treatment for TIO is to excise the tumor completelywith a wide surgical margin as these tumors are locally infil-trative and have a high chance of local recurrence. Followingthe excision as was also seen in our cases, the patient’ssymptoms and biochemical parameters show a marked im-provement within a fortnight.

If the tumor excision is not possible, then the patient can becontinued on medical management in the form of phosphatesupplements 15–60 mg/kg per day, which comes to about 1–3 g daily in 4–6 divided doses, along with calcitriol oralphacalcidol (15–60 ng/kg per day), typically 1.5 mg perday in an adult. However, the patient has to be closely mon-itored for the side effects, which can be in the form of GIdisturbance, hypercalcemia, nephrocalcinosis andnephrolithiasis.

Histopathology

The most common histological type that is seen is aphosphaturic mesenchymal tumor (mixed connective tissuevariant) (PMTMCT), which contains neoplastic cells that arespindled to stellate in shape, normochromatic with smallnuclei and indistinct nucleoli (Fig. 8). They are low gradewith very little mitotic activity. The cells are usually embed-ded within a myxoid or myxochondroid matrix with ‘grungy’calcification that can resemble chondroid orosteoid. An im-portant feature of these tumors is an elaborate intrinsic micro-vasculature with an admixture of vessel size and vascularpattern classically referred to as a hemangiopericytoma [6,31, 32]. Immunohistochemical staining is positive for FGF-23 in 70 % of cases [6], and in some cases, these also stainpositively for vimentin [33] (Fig. 9).

Conclusion

TIO is a well-established disease entity; however, because ofthe rarity of its occurrence and inconspicuous symptoms earlyin the course of the disease, it remains undiagnosed for a longtime causing a lot of distress to the patient. However, a highindex of suspicion for this condition and getting serum andurinary phosphorus levels done in patients who present withpersistent complains of fatigue and generalized bone andmuscle pain can help in early and timely identification andmanagement of such cases.

Conflict of interest Nil.

References

1. McCance R (1947) Osteomalacia with Looser’s nodes (Milkman’ssyndrome) due to a raised resistance to vitamin D acquired about theage of 15 years. Q J Med 16:33–46

2. Prader V, Illig R, Vehlinger E, Stalder G (1959) Rachitis, infolge,Knochen tumors. Helv Paediatr Acta 14:554–565

3. Sommer S, Berndt T, Craig T, Kumar R (2007) The phosphatoninsand the regulation of phosphate transport and vitamin D metabolism.J Steroid Biochem Mol Biol 103:497–503

4. Renkema KY, Alexander RT, Bindels RJ, Hoenderop JG (2008)Calcium and phosphate homeostasis: concerted interplay of newregulators. Ann Med 40:82–91

5. Edmister KA, Sundaram M (2002) Oncogenic osteomalacia. SeminMusculoskelet Radiol 6:191–196

6. Folpe A, Fanburg Smith J, Billings S et al (2004) Most osteomalaciaassociated mesenchymal tumors are a single histopathological entity.Am J Surg Pathol 28:1–30

7. Mount D, Yu A (2008) Phosphate transport. In: Brenner B (ed)Brenner & Rectors: The kidney, 8th edn. Saunders Elsevier,Philadelphia, pp 196–204

8. White K, Evans W, O’Riordan JL, Speer M, Econs MJ, Lorenz-Depiereux B, GrabowskiM,Meitinger T, Strom T (2000) Autosomaldominant hypophosphataemic rickets is associated with mutations inFGF23. Nat Genet 26:345–348

9. White KE, Jonsson KB, Carn G, Hampson G, Spector TD, MannstadtM, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O et al(2001) The autosomal dominant hypophosphatemic rickets (ADHR)gene is a secreted polypeptide overexpressed by tumors that causephosphate wasting. J Clin Endocrinol Metab 86:497–500

10. White KE, Larsson TE, Econs MJ (2006) The roles of specific genesimplicated as circulating factors involved in normal and disorderedphosphate homeostasis: frizzled related protein-4, matrix extracellu-lar phosphoglycoprotein, and fibroblast growth factor 23. EndocrRev 27(3):221–241

11. De Beur SM, Finnegan RB, Vassiliadis J, Cook B, Barberio D, EstesS, Manavalan P, Petroziello J, Madden SL, Cho JY et al (2002)Tumors associated with oncogenic osteomalacia express genes im-portant in bone and mineral metabolism. J Bone Miner Res 17:1102–1110

12. Riminucci M, Collins MT, Fedarko NS, Cherman N, Corsi A, WhiteKE,Waguespack S, Gupta A, Hannon T, EconsMJ et al (2003) FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphatewasting. J Clin Investig 112:683–692

Eur Orthop Traumatol

Author's personal copy

13. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y,Fujita T, Nakahara K, Fukumoto S, Yamashita T (2004) FGF-23 is apotent regulator of vitamin D metabolism and phosphate homeosta-sis. J Bone Miner Res 19:429–435

14. Berndt TJ et al (2005) ’Phosphatonins’ and the regulation of phos-phorus homeostasis. Am J Physiol Renal Physiol 289:F1170–F1182

15. ADHR Consortium (2000) Autosomal dominant hypophos-phataemic rickets is associated with mutations in FGF23. TheADHR Consortium. Nat Genet 26:345–348

16. Imel EA, Peacock M, Pitukcheewanont P, Heller HJ, Ward LM,Shulman D, Kassem M, Rackoff P, Zimering M, Dalkin A et al(2006) Sensitivity of fibroblast growth factor 23 measurements intumor-induced osteomalacia. J Clin Endocrinol Metab 91:2055–2061

17. Imel EA, Hui SL, Econs MJ (2007) FGF23 concentrations vary withdisease status in autosomal dominant hypophosphatemic rickets. JBone Miner Res 22:520–526

18. Jonsson KB, Zahradnik R, Larsson T, White KE, Sugimoto T,Imanishi Y, Yamamoto T, Hampson G, Koshiyama H, Ljunggren Oet al (2003) Fibroblast growth factor 23 in oncogenic osteomalaciaand X-linked hypophosphatemia. N Engl J Med 348:1656–1663

19. Dent CE, Gertner JM (1976) Hypophosphataemic osteomalacia infibrous dysplasia. Q J Med 45:411–420

20. Taylor HC, Fallon MD, Velasco ME (1984) Oncogenic osteomalaciaand inappropriate antidiuretic hormone secretion due to oat-cellcarcinoma. Ann Intern Med 101:786–788

21. NakahamaH, Nakanishi T, UnoH, Takaoka T, Taji N, UyamaO, KitadaO, Sugita M, Miyauchi A, Sugishita T et al (1995) Prostate cancer-induced oncogenic hypophosphatemic osteomalacia. Urol Int 55:38–40

22. Reese DM, Rosen PJ (1997) Oncogenic osteomalacia associated withprostate cancer. J Urol 158:887

23. Linovitz RJ, Resnick D, Keissling P, Kondon JJ, Sehlar B, Nejdl RJet al (1976) Tumour induced osteomalcia and Rickets: a surgicallycurable syndrome. J Bone Joint Surg 58(A):419–423

24. Teasell RW, ShapiroAP (2002)Misdiagnosis of conversiondisorders.Am J Phys Med Rehabil 81:236–240

25. Lewiecki EM, Urig EJ Jr, Williams RC Jr (2008) Tumor inducedosteomalacia: lessons learned. Arthritis Rheum 58:773–777

26. Jan de Beur SM (2005) Tumor-induced osteomalacia. J Am MedAssoc 294:1260–1267

27. Haeusler G, Freilinger M, Dominkus M, Egerbacher M, Amann G,Kolb A, Schlegel W, Raimann A, Staudenherz A (2010) Tumor-induced hypophosphatemic rickets in an adolescent boy – clinicalpresentation, diagnosis, and histological findings in growth plate andmuscle tissue. J Clin Endocrinol Metab 95:4511–4517

28. Baroncelli GI, Angiolini M, Ninni E, Galli V, Saggese R, Giuca MR(2006) Prevalence and pathogenesis of dental and periodontal lesionsin children with X-linked hypophosphatemic rickets. Eur J PaediatrDent 7:61–66

29. ChongW,Molinolo A, Chen CC, CollinsMT (2011) Tumor-inducedosteomalacia Endocrine-Related. Cancer 18:R53–R77

30. Andreopoulou P, Dumitrescu CE, Kelly MH, Brillante B, Cutler CM,Wodajo FM, Chang R, Collins MT (2011) Selective venous cathe-terization for the localization of phosphaturic mesenchymal tumors. JBone Miner Res 26(6):1295–1302

31. Weidner N (1991) Review and update: oncogenic osteoma-laciarickets. Ultrastruct Pathol 15:317–333

32. Drezner MK (2001) Tumor-induced osteomalacia. Rev EndocrMetab Disord 2:175–186

33. Weidner N, Bar RS, Weiss D, Strottmann MP (1985) Neoplasticpathology of oncogenic osteomalacia/rickets. Cancer 55:1691–1705

Eur Orthop Traumatol

Author's personal copy