1. Focus on Endocrine Neoplasia Rome, July 9-10, 2010
Primary hyperparathyroidism
Claudio Marcocci
Department of Endocrinology and Metabolism
Unit of Endocrinology and Bone Metabolism
University of Pisa, Pisa, Italy

2. Calcium Homeostasis 20 40 60 80
100
120
0,4
0,7 1
1,3
1,6 2
2,3
2,6
Ca2+, mM
PTH release, % of maximal

3. 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

4. Primary hyperparathyroidism (PHPT)
Prevalence: 1-2/1000
: = 2-3 : 1
Incidence: 30:100000/yr
85-90% single adenoma
10-15% hyperplasia
1-2% double adenoma
<1% carcinoma
Pathology

5. Incidence of Definite or Possible Primary PHPT among Residents of Rochester, Minnesota, 1965 to 2001
Wermers, R. A. et. al. JBMR 2006

6. Primary Hyperparathyroidism (PHPT)
Adenoma
Sporadic
90%
Hyperplasia
MEN1
MEN2A
HPT-JT
FHH
Familial
10%
Carcinoma
<1%
FIHP

7. Genetics of familial forms of PHPT
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 (?)

8. Molecular pathogenesis of sporadic PHPT
Adenoma
Carcinoma
parafibromin
menin
parafibromin
PRAD1

9. Clinical forms of PHPT

10. Severe PHPT Osteite Fibrosa Cystica lesioni cistiche
+riassorbimento sottoperiosteo
Osteite Fibrosa Cystica
Nephrocalcinos

11. Changing pattern of clinical presentation of PHPT
Kidney stones
Asymptomatic
Overt bone disease 20 40 60 80
Cope
( )
Heath
( )
Mallette
( )
Silverberg
( )
% of patients

12. Bone mineral density in PHPT
Controls
% controls
Lumbar spine
Femoral Neck
Distal radius
Bilezikian, Rev Endocr Metab Disord, 2000

13. PHPT Today
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

14. Differential diagnosis of hypercalcemia
Common causes(> 90%)
Primary hyperparathyroidism
Malignancy
PTHrp, TNF, PGE2 (lung, kidney and ovary cancer)
Bone metastases (breast cancer)
Multiple Myeloma
Less common causes (5-10%)
Drugs – vitamin D, lithium, thiazide diuretics
Sarcoidosis
Tireotoxicosis
Rare causes (1-2%)
Familial Hypocalciuric Hypercalcemia
Granulamatous diseaseas
No-Hodkin lymphoma, leukemia

15. Evaluation of hypercalcemia
Albunin-corrected total serum calcium
Corrected total calcium = measured total calcium
+ 0.8x(4-serum albumin)
(Ionized calcium)
Intact PTH
An increase of albumin-corrected serum calcium associated with increased or inappropriately normal intact PTH is virtually diagnostic of PHPT

16. 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

17. 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
CARCINOMA
High mortality
Local recurrences
Distant metastases
Marcocci et al. JBMR 2008 17

18. Aim of treatment Current treatment options
To normalize serum calcium and PTH levels and improve other manifestations of the disease
Current treatment options
Parathyroidectomy (PTx) is the only definitive therapy of PHPT
Appropriate to consider in all patients
Recommended in all symptomatic patients (symptoms of hypercalcemia, kidney stones, overt bone disease)

19. How should patients with asymptomatic PHPT be managed?
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?

20. How should patients with asymptomatic PHPT be managed?
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?

21. Comparison of new and old guidelines for parathyroid surgery in asymptomatic PHPT*
Measurement
1990
2002
2008
Serum calcium
(above upper limit of normal)
mg/dl
1.0 mg/dl
24 hr urinary calcium
> 400 mg/day
Not indicated **
Creatinine clearance
(calculated)
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
* 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)

22. How should patients with asymptomatic PHPT be managed?
Should patients with asymptomatic PHPT be treated by PTx?
What do we know about the natural history of asymptomatic PHPT followed without surgery?

23. Biochemical and BMD changes in patients with asymptomatic PHPT followed without surgery
80 patients with asymptomatic PHPT followed for up to 11 yr (median 3.2 yr)
Measurement
Patients
Basal
End of follow-up
Serum Ca (mmol/L) 80
2.77 ± 0.09
2.77 ± 0.11
Serum creatinine (µmol/L)
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)
82 ± 26
85 ± 27
Proximal forearm BMD (g/cm2)
0.657 ± 0.107
0.631 ± 0.112*
Distal forearm BMD (g/cm2)
0.466 ± 0.079
0.464 ± 0.083**
*P < vs baseline; **P < 0.05 vs baseline
Rao et al. JCEM 1988

24. Rubin et al. JCEM 2008

25. Higher baseline PTH (161 ± 25 vs 107 ± 8 pg/ml, P < 0.05)
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)
Rubin et al. JCEM 2008

26. Rubin et al. JCEM 2008

27. 20 patients initially followed up without PTx ultimately underwent PTx*
20 patients initially followed up without PTx ultimately underwent PTx
* Development of new surgical criteria
Rubin et al. JCEM 2008

28. How should patients with asymptomatic PHPT be managed?
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?

29. 50 patients (January 2002-September 2005) who did not met the 1990 surgical guidelines for PTx

30. Lumbar spine Distal third of radius Total hip P = 0.0002 P = 0.0002
PTx
Mean BMD change (%)
No PTx
PTx
Mean BMD change (%)
No PTx
Months
Total hip
Months
P =
PTx
Mean BMD change (%)
No PTx
Months

31. BMD changes in mild PHPT
Author
Patients
Follow-up
(months)
Observation Group
(OG)
Surgery Group
(SG)
Rao et al.
JCEM 2004 53 42
LS: %/yr
Total Hip: %/yr
Forearm: %/yr
LS: %/yr
Total Hip: %/yr (P = 0.01 vs OG)
Forearm: %/yr
Bollerslev et al.
JCEM 2007 99 24
LS: unchanged
FN: unchanged
Forearm: unchanged
LS: increased (P < 0.01 vs OG)
FN: unchanged
Forearm: unchanged
Ambrogini et al. JCEM 2007 50 12
LS: %
Total Hip: %
Forearm: %
LS: % (P = vs OG)
Total Hip: % (P = vs OG)
Forearm: %

32. Current treatment options
Aim of treatment
To normalize serum calcium and PTH levels and improve other manifestations of the disease
Current treatment options
Parathyroidectomy (PTx) is the only definitive therapy of PHPT
Appropriate to consider in all patients
Recommended in all symptomatic patients (symptoms of hypercalcemia, kidney stones, overt bone disease)
Follow up
Asymptomatic patients who do not met the NIH surgical criteria
Medical management
Vitamin D supplementation
Estrogens, SERMS

33. Comparison of new and old guidelines for patients with asymptomatic PHPT who do not undergo PTx
Measurement
1990
2002
2008
Serum calcium
Biannually
Annually
24-h urinary calcium
Not recommended
Creatinine clearance
Serum creatinine
Bone density
Annually (3 sites)
Every 1-2 yr (3 sites)
Abdominal X-ray

34. Aim of treatment Current treatment options
To normalize serum calcium and PTH levels and improve other manifestations of the disease
Current treatment options
Parathyroidectomy (PTx) is the only definitive therapy of PHPT
Appropriate to consider in all patients
Recommended in all symptomatic patients (symptoms of hypercalcemia, kidney stones, overt bone disease)
Follow up
Asymptomatic patients who do not met the NIH surgical criteria
Medical management
Vitamin D supplementation
Estrogens, SERMS
Bisphosphonates
Calcimimetics

35. 50,000 U/week for 1 month and then monthly

36. 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

37. Total body
Femoral neck
Lumbar spine
Trochanter

38. Alendronate in mild primary PHPT
Forty-four patients randomized to alendronate (10 mg daily or to placebo)
Two-year study
After one year the placebo group was crossed to active treatment
U-NTX
B-ALP
Placebo 12 months
Alendronate 12 months
Alendronate 24 months
Total calcium
Ionized calcium
Urinary calcium
PTH
Placebo
Alendronate
Alendronate 24 months
Khan et al. JCEM 2004

39. Alendronate in mild primary PHPT
Forty-four patients randomized to alendronate (10 mg daily) or placebo
Two-year study
After one year the placebo group was crossed to active treatment
Lumbar spine
Femoral neck
Total hip
Total hip
Distal radius
Khan et al. JCEM 2004

41. 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

42. 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,

43. 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

44. 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

45. From Pathophysiology to the Clinical Use of PTH
Parathyroids 2010
From Pathophysiology to the Clinical Use of PTH
PISA, Italy, February 11-13, 2010

46. Thanks for your attention