focus on endocrine neoplasia rome, july 9-10, 2010 claudio marcocci department of endocrinology and...

Focus on Endocrine NeoplasiaRome, July 9-10, 2010

Claudio MarcocciDepartment of Endocrinology and MetabolismUnit of Endocrinology and Bone Metabolism

University of Pisa, Pisa, Italy

Primary hyperparathyroidism

Calcium Homeostasis

0

20

40

60

80

100

120

0,4 0,7 1 1,3 1,6 2 2,3 2,6Ca2+, mM

PT

H r

ele

ase

, %

of

ma

xim

al

Primary hyperparathyroidism (PHPT)

• PHPT is a hypercalcemic state resulting from excessive secretion of PTH from one or more of the four parathyroid glands

• Together with malignancy, PHPT is the most common cause of hypercalcemia

• Prevalence: 1-2/1000

: = 2-3 : 1

• Incidence: 30:100000/yr

Primary hyperparathyroidism (PHPT)

•85-90% single adenoma

•10-15% hyperplasia

•1-2% double adenoma

•<1% carcinoma

Pathology

Incidence of Definite or Possible Primary PHPT among Residents of Rochester, Minnesota, 1965 to 2001

Wermers, R. A. et. al. JBMR 2006

Primary Hyperparathyroidism (PHPT)

FIHP

Carcinoma

<1%

Adenoma

Sporadic

90%

Hyperplasia

MEN1 MEN2A HPT-JTFHH

Familial

10%

Multiple Endocrine Neoplasia Type 1 (MEN1)menin

Multiple Endocrine Neoplasia Type 2 (MEN2) ret

Familial Hypocalciuric Hypercalcemia (FHH) CaSR

Familial Isolated Hyperparathyroidism associated with Jaw tumor (HPT-JT syndrome) parafibromin

Familial Isolated Hyperparathyroidism (FIHP) menin, parafibromin, CaSR, other genes (?)

Genetics of familial forms of PHPT

Molecular pathogenesis of sporadic PHPT

Adenoma

menin

parafibromin

PRAD1

Carcinoma

parafibromin

Clinical forms of PHPT

Nephrocalcinos

lesioni cistiche+riassorbimento sottoperiosteo

Osteite Fibrosa Cystica

Severe PHPT

Kidney stones AsymptomaticOvert bone disease

0

20

40

60

80

Cope(1930 - 1965)

Heath(1965 - 1974)

Mallette(1965 - 1972)

Silverberg(1986 - 1993)

% o

f pat

ient

s

Changing pattern of clinical presentation of PHPT

Bone mineral density in PHPT

70

80

90

100

Lumbar

spine

Distalradius

% c

on

tro

ls

Bilezikian, Rev Endocr Metab Disord, 2000

Lumbar spine

Femoral Neck

Distal radius

PHPT Controls

• Asymptomatic hypercalcemia with serum calcium levels within 1 mg/dl above the upper limits of normals

• Most patients do not have specific complaints and do not show evidence for any target organ complains

PHPT Today

Differential diagnosis of hypercalcemia

Less common causes (5-10%)Drugs – vitamin D, lithium, thiazide diureticsSarcoidosisTireotoxicosis

Rare causes (1-2%)Familial Hypocalciuric HypercalcemiaGranulamatous diseaseasNo-Hodkin lymphoma, leukemia

Common causes(> 90%)

Primary hyperparathyroidismMalignancy

PTHrp, TNF, PGE2 (lung, kidney and ovary cancer)

Bone metastases (breast cancer)

Multiple Myeloma

Evaluation of hypercalcemia

• Albunin-corrected total serum calcium

An increase of albumin-corrected serum calcium associated with increased or inappropriately normal intact PTH is virtually diagnostic of PHPT

Corrected total calcium = measured total calcium + 0.8x(4-serum albumin)

• Intact PTH

• (Ionized calcium)

Diagnosis of PHPT: Images studies

• Should not be used to make, confirm or exclude the diagnosis

• Controversy on its utility at first surgery• Recommended in patients with

previous failed neck surgery• Prerequisite for minimally invasive

video-assisted parathyroidectomy

Clinical features of parathyroid carcinoma

Female to male ratio 1:1

Age at diagnosis 10 yrs earlier than benign PHPT (40 vs 50 yrs)

Markes increase od serum calcium and PTH

Palpable mas in the neck (up to 75%)

Renal (60 %) and bone (73%) involvement

• High mortality

• Local recurrences

• Distant metastases

Marcocci et al. JBMR 2008

Aim of treatment• To normalize serum calcium and PTH levels and improve

other manifestations of the disease

• Appropriate to consider in all patients • Recommended in all symptomatic patients (symptoms of

hypercalcemia, kidney stones, overt bone disease)

Current treatment options

• Parathyroidectomy (PTx) is the only definitive therapy of PHPT

• Should patients with asymptomatic PHPT be treated by PTx?

• What do we know about the natural history of asymptomatic PHPT followed without surgery?

• Do patients with mild asymptomatic PHPT benefit from PTx?

How should patients with asymptomatic PHPT be managed?


• What do we know about the natural history of asymptomatic PHPT followed without surgery



Measurement 1990 2002 2008

Serum calcium(above upper limit of

normal)

1 - 1.6 mg/dl 1.0 mg/dl 1.0 mg/dl

24 hr urinary calcium

> 400 mg/day > 400 mg/day Not indicated **

Creatinine clearance(calculated)

Reduced by > 30% Reduced by > 30% Reduced to < 60 ml/min

Bone mineral density

Z score < -2.0 in forearm

T score < -2.5 at any site §

T score < -2.5 at any site§ and/or

previous fragility fracture

Age < 50 < 50 < 50

* Surgery is also indicated in patients for whom medical surveillance is neither desired, nor possible** Some physicians still regard urine calcium > 400 mg/24 hr as a surgical indication§ Lumbar spine, hip or forearm (1/3 site)

Comparison of new and old guidelines for parathyroid surgery in asymptomatic PHPT*


• What do we know about the natural history of asymptomatic PHPT followed without surgery?


Measurement Patients Basal End of follow-up

Serum Ca (mmol/L) 80 2.77 ± 0.09 2.77 ± 0.11

Serum creatinine (µmol/L) 80 87.5 ± 17.7 87.5 ± 20.3

Serum PTH (C-term; ng/L) 49 1110 ± 640 1040 ± 570

Serum PTH (mid-region; ng/L) 13 2360 ± 1090 2160 ± 1170

Urinary Ca (mmol/day) 42 6.5 ± 3.3 6.1 ± 3.3

Creatinine clearance (mL/min) 42 82 ± 26 85 ± 27

Proximal forearm BMD (g/cm2) 80 0.657 ± 0.107 0.631 ± 0.112*

Distal forearm BMD (g/cm2) 80 0.466 ± 0.079 0.464 ± 0.083**

*P < 0.001 vs baseline; **P < 0.05 vs baseline

80 patients with asymptomatic PHPT followed for up to 11 yr (median 3.2 yr)

Biochemical and BMD changes in patients with asymptomatic PHPT followed without surgery

Rao et al. JCEM 1988

Rubin et al. JCEM 2008

• Eleven patients died [cardiovascular diseases (n = 5), complications of diabetes mellitus (n = 2), gallbladder cancer (n = 1), unknown (n = 3)]

• Similar baseline serum calcium to those who did not die (10.3 ± 0.1 mg/dl)• Higher baseline PTH (161 ± 25 vs 107 ± 8 pg/ml, P < 0.05)


*

* Development of new surgical criteria

20 patients initially followed up without PTx ultimately underwent PTx



• What do we know about the natural history of asymptomatic PHPT followed without surgery



50 patients (January 2002-September 2005) who did not met the 1990 surgical guidelines for PTx

Lumbar spine

Total hip

Distal third of radiusP = 0.0002

Months

Months

Months

Mea

n B

MD

cha

nge

(%)

Mea

n B

MD

cha

nge

(%)

Mea

n B

MD

cha

nge

(%)

PTxNo PTx

PTx

No PTx

PTx

No PTx

P = 0.0002

BMD changes in mild PHPT

Author Patients Follow-up(months)

Observation Group(OG)

Surgery Group(SG)

Rao et al.JCEM 2004

53 42 LS: +0.5%/yrTotal Hip: -0.6%/yrForearm: +0.4%/yr

LS: +1.2%/yrTotal Hip: +0.3%/yr (P = 0.01 vs OG)Forearm: +0.4%/yr

Bollerslev et al.JCEM 2007

99 24 LS: unchangedFN: unchangedForearm: unchanged

LS: increased (P < 0.01 vs OG)FN: unchangedForearm: unchanged

Ambrogini et al. JCEM 2007

50 12 LS: -1.12% Total Hip: -1.88 %Forearm: -0.55%

LS: +4.6 % (P = 0.0002 vs OG)Total Hip: +2.6 % (P = 0.0001 vs OG)Forearm: - 0.34%

Aim of treatment

• Parathyroidectomy (PTx) is the only definitive therapy of PHPT• Appropriate to consider in all patients • Recommended in all symptomatic patients (symptoms of


• Follow up • Asymptomatic patients who do not met the NIH surgical criteria

• Medical management• Vitamin D supplementation• Estrogens, SERMS


• To normalize serum calcium and PTH levels and improve other manifestations of the disease

Measurement 1990 2002 2008

Serum calcium Biannually Biannually Annually

24-h urinary calcium

Annually Not recommended Not recommended

Creatinine clearance

Annually Not recommended Not recommended

Serum creatinine Annually Annually Annually

Bone density Annually Annually (3 sites) Every 1-2 yr (3 sites)

Abdominal X-ray Annually Not recommended Not recommended

Comparison of new and old guidelines for patients with asymptomatic PHPT who do not undergo PTx

Aim of treatment

• Parathyroidectomy (PTx) is the only definitive therapy of PHPT• Appropriate to consider in all patients • Recommended in all symptomatic patients (symptoms of


• Follow up • Asymptomatic patients who do not met the NIH surgical criteria

• Medical management• Vitamin D supplementation• Estrogens, SERMS• Bisphosphonates• Calcimimetics


• To normalize serum calcium and PTH levels and improve other manifestations of the disease

50,000 U/week for 1 month and then monthly

2-year extension of a 2-year RCT in 42 PM women with mild PHPT assigned to either conjugated estrogen (0.625 mg/d) + MPA (5 mg/d) or placebo

Total body

Lumbar spine

Femoral neck

Trochanter

Khan et al. JCEM 2004

Alendronate in mild primary PHPTForty-four patients randomized to alendronate (10 mg daily or to placebo)Two-year studyAfter one year the placebo group was crossed to active

treatment

Total calcium

Ionized calcium

Urinary calcium

PTH

Placebo

Placebo

Placebo

Placebo

Alendronate

Alendronate

Alendronate

Alendronate

Alendronate 24 months Alendronate 24 months

Alendronate 24 monthsAlendronate 24 months

U-NTX

B-ALP

Placebo 12 months Alendronate 12 months

Placebo 12 months Alendronate 12 months

Alendronate 24 months

Alendronate 24 months

Khan et al. JCEM 2004

Alendronate in mild primary PHPT

Total hip

Forty-four patients randomized to alendronate (10 mg daily) or placebo

Two-year studyAfter one year the placebo group was crossed to active treatment

Distal radius

Femoral neck

Total hip

Lumbar spine

Mean (SE) change in total femur aBMD Mean (SE) change in lumbar spine aBMD

Mean (SE) change in femoral neck aBMD Mean (SE) change in distal 1/3 radiud aBMD

• Cinacalcet (Mimpara®) is approved in Europe for:– “Reduction of hypercalcemia in patients with primary HPT for

whom parathyroidectomy would be indicated on the basis of serum calcium levels (as defined by relevant treatment guidelines), but in whom parathyroidectomy is not clinically appropriate or is contraindicated”

Mimpara® (Cinacalcet), Summary of Products Characteristics (SmPC), Amgen, http://www.emea.europa.eu/

http://www.emea.europa.eu/

Targeted medical management in PHPT

Potential candidates:•Patients with contraindication to surgery•Patients with complications of previous neck surgery•Patients unwilling to have surgery•Failed parathyroidectomy •Relapse (multi-glandular disease)•Selected asymptomatic patients who met surgical criteria for PTX

Treatment options• Antiresorptive therapy• Cinacalcet• Combined antiresorptive therapy and cinacalcet

Therapy of PHPT: Summary and Conclusions

• Parathyroidectomy (PTx) is the only definitive therapy of PHPT

• PTx should be considered in all patients with PHPT in the absence of severe comorbidities or contraindication to surgery

• Caution to operate on patients with previous failed PTx or with complication of previous neck surgery

• Targeted medical therapy• Surveillance may be an option in mild,

asymptomatic cases

PARATHYROIDS 2010From Pathophysiology to the

Clinical Use of PTH

PISA, Italy, February 11-13, 2010

www.parathyroids2010.com

www.parathyroids2010.com

focus on endocrine neoplasia rome, july 9-10, 2010 claudio marcocci department of endocrinology and...

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