Sunitinib-induced hyperparathyroidism

Sunitinib-Induced HyperparathyroidismA Possible Mechanism to Altered Bone Homeostasis

Valentina Baldazzi, MD1; Renato Tassi, MD1; Alberto Lapini, MD2; Alice Lunghi, MD1; Eleonora Garofoli, MD1;

Salvatore Caruso, MD1; Marco Carini, MD2; and Roberto Mazzanti, MD1

BACKGROUND: Sunitinib malate is an orally bioavailable tyrosine kinase inhibitor that is active against many tyrosine

kinase receptors involving crucial pathways in both healthy tissues and malignant tissues. Because its use in clinical

practice is quite recent, many of its possible side effects remain unknown. In this report, the authors describe the inci-

dence of new-onset hyperparathyroidism in a cohort of patients with metastatic renal cell carcinoma who received

treatment with sunitinib. METHODS: Twenty-six patients who received first-line sunitinib for metastatic renal cell car-

cinoma were enrolled in this study for a mineral and parathyroid function assessment. Plasma levels of intact parathy-

roid hormone; serum levels of calcium, phosphorus, 25-hydroxyvitamin D3, and 1,25-dihydrovitamin D3; and urinary

24-hour calcium and phosphorus excretion all were measured in each patient. Biochemical evaluations were per-

formed before the beginning of treatment and at the end of each sunitinib treatment period. RESULTS: Eighteen of

26 patients (69.2%) developed hyperparathyroidism with normal serum calcium levels, and 6 of them developed

hypophosphatemia. Patients presented with a mean elevation of parathyroid hormone after 2.2 cycles of sunitinib.

The levels of 25-OH vitamin D3 were stable over the course of treatment, whereas 1,25-OH vitamin D3 levels were

increased in 5 hyperparathyroid patients. Those who presenting with elevated parathyroid hormone levels had low or

undetectable urinary calcium levels. Parathyroid hormone elevation usually persisted but did not progress during

long-term therapy with sunitinib. Permanent treatment interruption resulted in a resolution of hyperparathyroidism.

CONCLUSIONS: Hyperparathyroidism developed in an high percentage of patients on sunitinib. Therefore, the

authors concluded that sunitinib may affect parathyroid function and bone mineral homeostasis, possibly resulting in

abnormal bone remodeling. Cancer 2012;118:3165-72. VC 2011 American Cancer Society.

KEYWORDS: metastatic renal cell carcinoma, sunitinib, hyperparathyroidism, hypophosphatemia, bone.

INTRODUCTIONSunitinib malate (Sutent; Pfizer Inc., New York, NY) is an orally bioavailable, multitargeted tyrosine kinase inhibitor(TKI) currently approved for the treatment of imatinib-intolerant or refractory gastrointestinal stromal tumors and meta-static renal cell carcinoma (mRCC). To date, this molecule has demonstrated the ability to inhibit vascular endothelialgrowth factor (VEGF) receptors (VEGFR-1, VEGFR-2, and VEGFR-3), platelet-derived growth factor (PDGFR) recep-tors (PDGFR-a and PDGFR-b), stem cell growth factor (KIT), FMS-like tyrosine kinase 3 (FLT3), colony-stimulatingfactor 1 receptor (CSF-1R), and glial cell line-derived neurotrophic factor receptor (RET).1

Like other TKIs, sunitinib was modeled specifically to target the activity of only selected enzymes. However, manyoff-target kinases are targets of this drug, resulting in unexpected side effects. Moreover, VEGF, PDGF, and other path-ways that are inhibited selectively by sunitinib are expressed in healthy tissue, in which they play a critical role in cell differ-entiation and survival; their pharmacologic inhibition is related to some sunitinib-induced adverse events. Therefore,considering the extremely wide range of signaling pathways inhibited by sunitinib, widespread toxicities would beexpected during sunitinib administration. Nonetheless, it is usually well tolerated with minor or moderate toxicities.

Several studies have attributed many side effects of sunitinib to the inhibition of its molecular targets in healthy tis-sue, including hypertension, hemorrhages, anemia or other disorders involving blood cells, cardiotoxicity, hand-foot syn-drome, and mucosal inflammation.2,3 To our knowledge, the effects of sunitinib on bones have not been described.

DOI: 10.1002/cncr.26435, Received: March 18, 2011; Revised: June 1, 2011; Accepted: June 20, 2011, Published online September 28, 2011 in Wiley Online

Library (wileyonlinelibrary.com)

Corresponding author: Roberto Mazzanti, MD, Department of Internal Medicine, Second Medical Oncology Unit, A.O.U. Careggi, Istituto Toscano Tumori, Largo

Brambilla 3, Florence, 50134, Italy; Fax: (011) 39-0554271066; [email protected]

1Second Medical Oncology Unit, Careggi University Hospital, Florence University, Florence, Italy; 2First Urology Unit, Careggi University Hospital, Florence Univer-

sity, Florence, Italy

Cancer June 15, 2012 3165

Original Article

However, a reduction in serum phosphate levels wasreported among patients who were receiving sunitinib,suggesting the possible dysregulation of mineral metabo-lism and, more extensively, of bone homeostasis.2,4

Since 2007, we have observed an unexpected eleva-tion of intact plasma parathyroid hormone (PTH) insome patients on sunitinib. All of these patients werereceiving sunitinib for mRCC. These findings promptedus to prospectively evaluate parathyroid and mineral me-tabolism parameters among patients who received first-line sunitinib to assess a possible relation between thedrug and phosphorus and calcium homeostasis. In this ar-ticle, we report the results of our evaluation.

MATERIALS AND METHODSBetween May 2007 and December 2010, 26 patients whowere admitted consecutively to our department, all ofwhom were affected by mRCC with a clear cell histology,were evaluated prospectively and observed. Fifteenpatients were men, and 11 patients were women. The me-dian patient age was 63.9 years (range, 50-85 years; me-dian age: men, 61.9 years; women, 66.6 years [allpostmenopausal]). At the time of diagnosis 22 patientshad undergone nephrectomy or nephron-sparing surgeryfor RCC. The other remaining 4 patients did not undergosurgery because of the extent of malignant tissue and thepresence of contraindications. In these patients, the histo-logic diagnosis of RCC was established by fine-needle bi-opsy of the renal mass or metastases. The characteristics ofall patients are reported in Table 1.

All patients received front-line therapy with suniti-nib 50 mg daily according to a classic 6-week schedule (4weeks of daily 50 mg administration [ON] followed by 2weeks of rest [OFF]). Depending on toxicities, treatmentinterruptions or dose adjustments were performed accord-ing to manufacturer’s recommendations. Patients had nofood or medical restrictions, and medications other thansunitinib were not standardized. When patients werereceiving sunitinib, vitamin D, calcium, and phosphatesupplements were not allowed. Patients who did notreceive sunitinib for at least 12 weeks because of diseaseprogression or toxicity were excluded from the analysis.Four patients presented with bone metastatic disease.Because of the presence of limited bone involvement andcontraindications, 2 of these patients did not receivebisphosphonate therapy. Each of the other 2 patientsunderwent surgical excision of a single bone metastasisbefore starting sunitinib because of the high risk of frac-

ture, and these patients did not receive bisphosphonatetherapy while they were receiving sunitinib.

At baseline, all patients presented with adequate re-nal function, with an average serum creatinine level of1.19 mg/dL (range, 0.59-1.68 mg/dL; 95% confidenceinterval [CI],�0.15 mg/dL). All patients provided fastingserum and plasma samples as well as urine samples from a24-hour collection to perform biochemistry measure-ments; and all patients had an intact PTH plasma assess-ment at baseline and in last week of each sunitinibadministration cycle. Creatinine, 1,25-dihydroxyvitaminD, 25-hydroxyvitamin D, and serum and urinary phos-phate and calcium levels also were measured within 1month before the beginning of treatment. Blood testswere repeated at the end of each sunitinib ON period(between days 22 and 28 of a 6-week cycle). Urinary cal-cium and phosphate levels (expressed as 24-hour excre-tion) were measured for each patient every 3 months or assoon as plasma PTH values increased above the upper lab-oratory range. All patients provided informed writtenconsent before the beginning of the study.

These analysis were performed at our university hos-pital in the same laboratory. Serum and urinary sampleswere collected, handled, and analyzed according to inter-nal standard operating procedures. Measurements wereperformed in accordance with international standardizedmethods. Our laboratory reference ranges are 1.3 to 7.6pmol/mL for PTH, 8.2 to 10.7 mg/dL for serum calcium,2.5 to 5 mg/dL for serum phosphate, 100 to 300 mg/24hours for urinary calcium, 400 to 1000 mg/24 hours for

Table 1. Patients Characteristics

Characteristic No. of Patients (%)

Total no. of patients 26

Men 15 (57.7)

Women 11 (42.3)

Median age [range], y 63.9 [50-85]

Men 61.9 [50-85]

Women 66.6 [54-75]

Previous nephron surgery 22

Site of metastasesLung 12

Lymph node 8

Bone 4

Liver 4

Brain 1

Kidney 2

Soft tissue 3

No. of treatment cycles 7.2

Original Article

3166 Cancer June 15, 2012

urinary phosphate, 19.9 to 67 pgm/mL for 1,25-dihy-droxyvitamin D3, and a 25-OH vitamin D level between30 and 100 ng/mL is considered normal, whereas <10ng/mL is considered a severe impairment.

The primary objective of this study was an assess-ment of parathyroid function and bone mineral metabo-lism abnormalities among patients who were receivingsunitinib for mRCC. The data are summarized descrip-tively as frequency counts, means, and ranges. Both abso-lute and relative changes in biochemical parametersduring treatment and at the end of treatment were ana-lyzed. All statistical tests were 2-sided, and a P value< .05was considered statistically significant.

RESULTSAll 26 patients who received sunitinib were eligible forevaluation. The mean treatment duration was 7.2 six-week cycles and ranged from 2 cycles to 22.5 cycles. Allpatients had adequate renal function at baseline, and cre-

atinine variations during treatment were not significant(P > .05). Plasma PTH levels and urinary and serum cal-cium and phosphorus levels were within normal rangebefore the beginning of sunitinib administration in all en-rolled patients. Baseline biochemical data are summarizedin Table 2.

During sunitinib administration, an increase abovethe upper limit of plasma PTH was observed in 18 of 26patients (69.2%), although serum calcium levels remainedstable during treatment. On average, an increased in PTHdeveloped after 2.2 complete sunitinib administrationcycles (range, 1-6 cycles); whereas, in 9 patients, anincrease in PTH already was observed within the firstcycle of sunitinib. Once the PTH level increased, itresulted stable during treatment. Moreover, we did notobserve a significant reduction in plasma PTH duringsunitinib OFF periods.

In the patients who developed hyperparathyroidism,PTH serum levels also were measured after sunitinib wasdiscontinued because of disease progression or toxicity. Itis noteworthy that PTH levels progressively returned tothe normal range within 2 to 4 months after sunitinibinterruption (Fig. 1). This was observed in all 18 patientswho developed hyperparathyroidism during sunitinibadministration.

While patients were receiving sunitinib, PTH levelswere elevated compared with baseline. The mean PTHlevel was 5.91 pmol/L at baseline (95% CI, �13.3 pmol/L), 105.5 pmol/L in the first cycle (95% CI,�15.6 pmol/L; change from baseline, þ78.36%; P ¼ .005); 113.6pmol/L in the third cycle (95% CI, �3.9 pmol/L; changefrom baseline,þ92.15%; P¼ .0008); and 142 pmol/L in

Table 2. Baseline Biochemical Characteristics of the StudyPatients

Variable Mean(Range)

NormalRange

Serum creatinine, mg/dL 1.19 (0.59-1.30) 0.6-1.33

Plasma PTH, pmol/L 5.91 (3.9-7.4) 1.3-7.6

Serum calcium, mg/dL 9.4 (8.2-10.6) 8.2-10.7

Serum phosphate, mg/dL 2.8 (2.7-3.7) 2.5-5

Urinary calcium, mg/24 h 173 (119-264) 100-300

Urinary phosphate, mg/24 h 779 (502-886) 400-1000

Serum 25-OH vitamin D3, ng/mL 15.25 (10.5-19.9) 30-100

Serum 1,25-OH vitamin D3, pg/mL 46.16 (19.1-60) 19.9-67

Abbreviations: PTH, parathyroid hormone.

Figure 1. This is a logarithmic scale illustrating parathyroid hormone (PTH) levels (in pg/mL), serum calcium levels (in mg/dL),phosphate levels (in mg/dL), and urine calcium levels (in mg/24 hours) from the beginning of sunitinib treatment until 3 monthsafter its interruption in a study patient. Note that the increase in PTH is followed by a marked reduction in 24-hour urinary excre-tion. Three months after sunitinib discontinuation, the PTH level returned to within the laboratory range.

Sunitinib-Induced Hyperparathyroidism/Baldazzi et al


the sixth cycle (95% CI, �19.9 pmol/L; change frombaseline, þ140.06%; P ¼ .004) (Fig. 2). We observed amean PTHmaximal increase of 152% compared with thebaseline level (P< .001).

Unexpectedly, serum calcium levels were within thelaboratory range, as mentioned above; whereas serumphosphate levels were slightly reduced (mean serum cal-cium, 9.48 mg/dL at baseline; mean serum phosphate,2.88 mg/dL at baseline; mean serum calcium range, 9.12-9.53 mg/dL during sunitinib administration; mean serumphosphate range, 2.15-3.25 mg/dL during sunitinibadministration) (Fig. 2). In particular, hypophosphatemiawas observed in 6 patients, including 3 who did not de-velop a hyperparathyroid state. To assess a possible eleva-tion of serum ionized calcium, this was measuredrandomly in some hyperparathyroid patients and wasalways within the reference range.

At baseline, in accordance with observations reportedfrom the general population,5 25-hydroxyvitamin D3 lev-els were in the range of inadequacy (mean, 15.25 ng/mL)and major variations during sunitinib administration werenot reported. Conversely, we observed an increase frombaseline 1,25-dihydroxyvitamin D3 levels in some patientswho developed a hyperparathyroid state (mean 1,25-dihy-droxyvitamin D3 at baseline, 46.16 pg/mL; mean 1,25-dihydroxyvitamin D3 on sunitinib, 60.3 pg/mL; P> .05).In particular, 5 of 18 patients (27.7%) developed anincrease in serum 1,25-dihydroxyvitamin D3 above thelaboratory reference range, which was an expected conse-quence of increased PTH.

Each patient had urinary calcium excretion moni-tored while they were receiving sunitinib, and the levels

were lower compared with baseline. In particular, low oreven undetectable urinary 24-hour calcium excretion wasobserved in patients who developed increased plasmaPTH levels (mean urinary calcium, 20.3 mg/24 hourswhile receiving sunitinib among hyperparathyroidpatients) with an average decrease from baseline of94.14% (P < .001) (Fig. 2). Twenty-four-hour urinaryphosphate excretion remained within the laboratory refer-ence range without a significant change from baseline(mean urinary phosphate, 779 mg/24 hours at baseline;624 mg/24 hours on sunitinib; P > .05). The results ofbiochemical evaluations are summarized in Table 3 and inFigures 2 and 3.

A correlation analysis was performed in patientswith hyperparathyroidism in which PTH was comparedwith serum and urinary phosphate and calcium and vita-min D. Although the patient numbers were smallpatients, the development of hyperparathyroidism wasassociated with low or undetectable urinary calcium(Pearson correlation index,�0.6).

To asses the relation between these laboratoryabnormalities and bone homeostasis, collagen degrada-tion products, bone alkaline phosphatase, and osteocalcinwere measured in a subgroup of 6 patients who presentedwith hyperparathyroidism during sunitinib administra-tion. Three of these patients presented with reduced levelsof osteocalcin, and the others presented values within thelaboratory range. With regard to bone resorption bio-markers, bone alkaline phosphatase levels were within thelaboratory range during sunitinib administration, whereascollagen n-telopeptide levels were increased only in 1patient.

Figure 2. This chart illustrates mean parathyroid hormone (PTH) levels (in pmol/L), serum calcium levels (in mg/dl), and phos-phorus levels (in mg/dl) for the entire study cohort of 26 patients. The PTH level rapidly increases above the laboratory referencerange then remains stable over time. It is noteworthy that the serum calcium level remains stable within the laboratory referencerange despite PTH elevation. Also note that, during the period analyzed, the number of patients on sunitinib decreased, and themean values reported here are related to a smaller sample of patients.

Original Article


DISCUSSIONPTH is the most important regulator of body calcium andphosphorus levels within bone and blood through a regu-latory effect on 3 mechanisms: resorption of phosphateand calcium by the kidneys, absorption by the gut, anddissolution from bone. This hormone acts on bone-resorbing osteoclasts in the bone to increase the dissolu-tion of calcium and phosphate, increase the renal resorp-tion of calcium and excretion of phosphate, and stimulatethe production of 1,25-dihydroxyvitamin D3, whichstimulates phosphate and calcium resorption by the gutand kidneys. Hyperparathyroidism is a condition charac-terized by increased plasma levels of PTH and may be the

result of an autonomous hyperproduction of PTH byparathyroid glands, usually resulting in a hypercalcemicstate; or, conversely, it may be a physiologic consequenceof hypocalcemia from attempting to correct serum cal-cium levels.6

In the current study, we demonstrate that nearly70% of patients on sunitinib develop hyperparathyroid-ism with a series of changes in bone-related mineral me-tabolism. Because serum calcium levels were stable overtime, it is possible that there is a secondary pathogenesisof this hyperparathyroid state. Furthermore, increasedPTH levels were strictly associated with a marked reduc-tion in 24-hour calcium urinary excretion, as

Figure 3. Mean plasma parathyroid hormone (PTH) levels (in pg/mL) and 24-hour urinary excretion (in mg/24 hours) are illus-trated from baseline and through 6 cycles of sunitinib treatment. Only hyperparathyroid patients are represented. The develop-ment of hyperparathyroidism is accompanied by a marked reduction in urinary calcium excretion.

Table 3. Results of Biochemical Evaluations During Sunitinib Treatmenta

Mean (Range)

Variable Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6 Cycle 7

Serum creatinine, mg/dL 1.19 1.25 1.14 1.19 1.16 1.15 1.29

Plasma PTH, pmol/L 10.55 (3.1-18.6) 12.23 (5.9-25) 11.36 (6.1-16.9) 14.16 (2.6-29) 13.10 (6.5-30.4) 14.20 (10-20) 14.10 (9.8-18.4)

Serum calcium, mg/Dl 9.42 (9.1-10) 9.25 (8.4-10.4) 9.43 (8.6-10) 9.20 (8.5-10) 9.40 (8.9-9.8) 9.12 (8.7-9.8) 9.53 (8.9-10.2)

Serum phosphate, mg/dL 2.8 (2.3-3.9) 2.9 (2.1-3.5) 3.1 (3.9-2.5) 3 (2.3-3.4) 2.7 (2.1-3.2) 3.2 (3-3.6) 2.1 (2-2.8)

Urinary calcium, mg/24 h 275.4 14.7 29 24.25 23.7 22 68

Urinary phosphate, mg/24 h 904.4 450.9 572 718.6 580 680 540

Serum 25-OH vitamin D3, ng/mL 16.9 17.7 24.6 21.2 23.5 13.5 24.2

Serum 1,25-OH vitamin D3, pg/mL 36.7 30.2 67 83.5 56.9 — 76.2

Abbreviations: PTH, parathyroid hormone.aMeasurements were performed during the last week of treatment (ON period). Creatinine, PTH, serum calcium, and phosphate levels were measured at each

cycle. Urinary calcium and phosphate were levels measured in all patients every 3 months or as soon as plasma PTH levels increased over the upper labora-

tory range. Mean values of urinary calcium, phosphate, and vitamin D are related only to patients who had hyperparathyroidism.



demonstrated by urinary calcium measurements and ele-vation in some patients of 1,25-dihydroxyvitamin D3 lev-els, possibly resulting in increased calcium absorption bythe gut and kidneys. Perhaps, in patients on sunitinib, asobserved among those with end-stage chronic kidney dis-ease, a progressive slight reduction in the serum calciumlevel could generate a hyperparathyroid state followed byan increase in urinary calcium retention and gut absorp-tion that, finally, would result in a normalization of serumcalcium. It is noteworthy that these biochemical changespersisted, but did not progress, during long-term therapy.Moreover, once treatment was interrupted definitively,PTH plasma levels returned to within the laboratoryrange in a few months, confirming the hypothesis thatthese alterations in mineral homeostasis are a consequenceof sunitinib administration.

Similar events have been described among patientswho received imatinib.7-13 Since 2006, different groupshave reported on the incidence of altered phosphate levelsand hyperparathyroidism in at least 50% of patients whoreceive imatinib therapy.7-10 Different mechanisms havebeen proposed as the cause of these abnormalities. Amongthem, reduced efflux of calcium and phosphate from boneto extracellular space because of decreased bone resorptionnot corrected by a reduction in osteoblast activity; or, con-versely, an increase in osteoblast activity not balanced byan increased osteoclast function; or both at the same time,seem to be the most likely mechanisms.14 Thus, as a con-sequence of these early events, a decreased serum ionizedcalcium level would stimulate PTH secretion, promotingcalcium and phosphate dissolution from bone and cal-cium resorption from kidneys, resulting in a normaliza-tion of serum calcium levels. This hypothesis is supportedby data indicating that changes in bone density parame-ters, as well as hyperparathyroidism and serum mineralabnormalities, may occur in patients who are receivingimatinib.11,12,15 Some evidence about the effects of imati-nib on the proliferation and activity of cells involved inbone homeostasis (both osteoclasts and osteoblasts) sup-ports this theory14; however, the exact pathogenic mecha-nism (or mechanisms) of this alteration remain to be fullyelucidated.

Several known imatinib targets may contribute to itsantiosteoclastogenic and osteoblastic activity. PDGFR-aand PDGFR-b represent the best candidates to explainthe mechanism whereby imatinib affects bone. In particu-lar, imatinib administration is supposed to interfere invivo with osteoclast function directly by inhibitingPDGFR-b on osteoclasts or indirectly by inhibiting

PDGFR-a on osteoblasts tightly coupled with osteoclaststhrough the nuclear factor-kappa B pathway.16-21

Imatinib inhibits tyrosine kinases commonly tar-geted by sunitinib, resulting in common side effects, withcommon pathogenic mechanisms. Therefore, a possiblerole of sunitinib in altering bone and mineral homeostasiscould be expected.

In our experience, we observed a new-onset, second-ary, normocalcemic hyperparathyroid state in a major per-centage of patients on sunitinib, supporting thehypothesis that sunitinib may affect bone-related mineralmetabolism and, more extensively, bone remodeling.Commonly described biochemical effects of hyperpara-thyroidism, such as reductions in calcium excretion andserum phosphate and an increase in 1,25-dihydroxyvita-min D3, also were observed in some of our patients.Therefore, we hypothesize that sunitinib may alter bonehomeostasis, possibly through the inhibition of PDGFRon both osteoclasts and osteoblasts, as suggested withregard to imatinib.14 This may induce a decreased effluxof calcium and phosphate from bone matrix to extracellu-lar space because of decreased bone resorption and forma-tion. We suppose that, as a possible consequence of atransient hypocalcaemia, a secondary hyperparathyroidstate would occur, promoting calcium mobilization frombone and its resorption from kidney (as demonstrated bylow urinary calcium levels), both directly by PTH actionand indirectly by an increase of active 1,25-dihydroxyvita-min D3, finally resulting in a normalization of calcemia.During long-term therapy, this may result in profoundbone alterations, causing unexpected consequences forbone health by an excessive resorption of matrix and min-erals or abnormal formation.

Although bone turnover biomarkers were not ana-lyzed prospectively in all patients enrolled in this prelimi-nary study, we report some unexpected observations insome patients that support our hypothesis. In particular,levels of osteocalcin, a noncollagenous bone protein usedas marker of bone formation, commonly increased inpatients who present in a hyperparathyroid state, were lowor normal; whereas bone resorption biomarkers, such asbone alkaline phosphatase, were within the laboratory ref-erence range. It is noteworthy that these results are not inaccordance with the presence of a hyperparathyroid state,because increased osteocalcin and bone resorption bio-markers would have been expected but were not observed.However, considering some alteration in bone homeosta-sis as the primary cause of sunitinib-induced hyperpara-thyroidism, especially reduced bone resorption and

Original Article


formation or, more extensively, an ‘‘adynamic bone’’ state,these data could be explained more easily. Despite this, weare aware of the limitations of our results related to oursmall sample size, different timing of sampling duringtreatment, and absence of baseline control parameters.

It is interesting to note a recent observation thatsunitinib was able to interfere with a myeloid cell bloodprofile and circulating monocytes, a known source ofbone osteoclasts, confirming a possible role for this drugin bone homeostasis. In particular, an increase in bloodmonocytes was reported among patients who were receiv-ing sunitinib, and this was related to tumor response,22,23

Therefore, it appears that an alteration in bone metabo-lism is the most appropriate explanation for the alteredmineral metabolism and parathyroid function we describein this preliminary work.

Recently, an increased incidence of joint osteonecro-sis was reported among patients who were receivingVEGF and VEGFR inhibitors, especially when associatedwith the administration of diphosphonates.24-26 This ob-servation supports a possible interaction of drugs that tar-get the VEGF pathway and bone homeostasis.

Like in patients who are receiving imatinib,throughout an inhibition of PDGFR, sunitinib couldaffect bone formation and resorption, a feature commonto TKIs that are active on the PDGFR itself. It might beof interest to define whether bone alterations appear onlyin patients who develop hyperparathyroidism or are com-mon to all patients undergoing sunitinib.

It is noteworthy that, among patients who are receiv-ing sunitinib, an association has been described betweenthe occurrence of toxicities as hypothyroidism and betteroutcomes.27,28 Similarly, the occurrence of hypophospha-temia during imatinib therapy has been related toimproved response rates in patients with chronic myeloidleukemia.13 In our cohort of patients, we analyzed theprogression-free survival rate of patients according toparathyroid function state; however, possibly because ofthe small sample of patients, we did not identify any sig-nificant difference in survival (9.1 months vs 10.6 monthsprogression free for hyperparathyroid patients; P > .05).Moreover we did not observe a significant relationbetween the occurrence of thyroid dysfunction and hyper-parathyroidism, because we observed it both in hypothy-roid patients and in euthyroid patients.

In summary, although sunitinib inhibits tyrosine ki-nases associated with specific disease, in vivo inhibition ofmolecular targets in healthy tissue may occur with unex-pected clinical consequences. It is reassuring that we did

not observe an increase in calcium levels above the normalrange, even during long-term therapy with its potentiallylife-threatening consequences. In our experience, theoccurrence of hyperparathyroidism is not followed byhypercalcemia; therefore, no patient in the current cohortrequired a specific treatment for hyperparathyroidism.These data, with evident limitations based on a small sam-ple of patients, suggest that sunitinib affects phosphorusand calcium homeostasis. However, the exact incidenceand possible consequences of this side effect have to beconfirmed in larger analysis, possibly including bone turn-over biomarkers. If this is confirmed, then routine moni-toring of serum calcium, phosphate, and vitamin D levelsas well as controls on bone mass density, would be advisa-ble to prompt an adequate treatment especially forpatients who are receiving long-time therapy.

FUNDING SOURCESNo specific funding was disclosed.

CONFLICT OF INTEREST DISCLOSURESThe authors made no disclosures.

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Sunitinib-induced hyperparathyroidism