MILD FORMS OF HYPERPARATHYROIDISM.pptx

HYPERPARATHYROIDISM WITH
CLINICIAN’S PERSPECTIVE
Dr. Rishi Shukla
M.D , D.M (Endo)
H.O.D Regency Hospital Ltd.
Founder of Center for Diabetes and Endocrine Diseases.

Key points
• Are most patients with primary hyperparathyroidism asymptomatic?
• How do you evaluate normocalcemic primary hyperparathyroidism?
• What medical management can we offer?
• Who should we refer for parathyroid surgery?

Outline
• Introduction
• Clinical presentation
• Guidelines
• Diagnosis and indications for genetic testing
• Screening and management
• Bones
• Kidney
• Normocalcemic primary hyperparathyroidism
• Medical therapy
• Surgery

History of the parathyroid glands
The parathyroid glands were first
discovered by Richard Owen in
1852 when he performed an
autopsy on the Great Indian
Rhinoceros kept by the Zoological
Society of London
McAneny DB, Beazley RM. Endocr Pract 2010; 16:1078-9; Dubose J, et al. Curr Surg 2005; 62:91-5

Primary hyperparathyroidism is relatively common
• Parathyroid hormone (PTH) is made by the (usually) four
parathyroid glands that sit posterior to the thyroid
• Primary hyperparathyroidism (PHPT) is a disorder traditionally
characterized by elevated levels of PTH and hypercalcemia
• PHPT is one of the most common endocrine disorders
Estimated prevalence 0.1-1% in postmenopausal women
Prevalence is about 3 times greater in women than men
More common with increasing age
PHPT is a common secondary cause of osteoporosis

The prevalence of PHPT in the US has tripled
Yeh MW, et al. J Clin Endocrinol Metab 2013;98:1122-28
233 per 100,000 85 per 100,000
76 per 100,000 30 per 100,000

Phenotypes of PHPT
Before 1970:
A disease of bones, stones, groans, and moans

The early clinical picture of PHPT
1918 1926
Zarnegar R and Clark OH. Clin Rev Bone Miner Metab 2007;5:81-88

Symptomatic PHPT
• Nephrolithiasis
• Remains the most common complication of PHPT
• Osteitis fibrosa cystica
• Manifest clinically by bone pain and radiographically by “salt
and pepper” appearance of the skull (A), tapering of the distal
clavicles (B), subperiosteal bone resorption of the phalanges
(C), and cysts and brown tumors of the long bones (D)
https://clinicalgate.com/primary-hyperparathyroidism

Symptomatic PHPT remains common in certain regions
Lo CY, et al. Arch Surg 2004
Zhao L, et al. J Clin Endocrinol Metab 2013
Liu J, et al. Bone Res 2013
Hamidi S, et al. Med Sci Monit 2006
Malabu UH and Founda MA. Med J Malaysia 2007
Pradeep PV, et al. Int J Endocrinol 2011
Shah VN, et al. Indian J Med Res 2014
Prasarttong-Osoth P,et al. Int J Endocrinol 2012
Paruk IM, et al. Postgrad Med J 2013
Oliveira U, et al., Braz J Med Biol Res 2007
Eufrasino C, et al. Endocr Rev 2012
Bandeira F, et al., Curr Rhematol Rep 2015
Spivacow F, et al., Medicina (B Aires) 2010

Phenotypes of PHPT
Before 1970:
After 1970:
A disease with primarily biochemical and densitometric signatures

The modern clinical profile of PHPT
Cope1
1930-1965
Mallette2
1965-1974
Silverberg3
1984-1999
Walker4
2000-2014
Nephrolithiasis 57% 37% 17% 19%
Hypercalciuria NR 40% 39% 17%
Overt skeletal disease 23% 14% 1.4% 0%
Asymptomatic 0.6% 22% 82% 81%
1Cope O. N Engl J Med 1966;274:1174-82
2Mallette LE, et al. Medicine (Baltimore) 1974;53:127-46
3Silverberg SJ, et al. N Engl J Med 1999;341:1249-55
4Walker MD, et al. Osteoporos Int 2015; 26:2837-43

Prevalence of kidney stones in “asymptomatic” patients with
PHPT
36.4
Noted on history Detected by imaging
60
50
40
30
20
10
0
n=140
Cipriani C, et al. J Clin Endocrinol Metab 2015, 100:1309-15

Prevalence of kidney stones in “asymptomatic” patients with
PHPT
Noted on history Detected by imaging
0
20 36.4
10
40
30
55.0
17 of 76 (22.4%) patients classified as “asymptomatic” at baseline
were found to have kidney stones or vertebral fractures on imaging
Another study in 96 patients with PHPT without known history of
nephrolithiasis found occult kidney stones in 21% of patients
60
50
n=140
Cipriani C, et al. J Clin Endocrinol Metab 2015, 100:1309-15; Tay YD, et al.Endocr Res 2018 May;43:106-115

Cope1
1930-1965
Mallette2
1965-1974
Silverberg3
1984-1999
Walker4
2000-2014
Nephrolithiasis 57% 37% 17% 19%*
1Cope O. N Engl J Med 1966;274:1174-82; 2Mallette LE, et al. Medicine (Baltimore) 1974;53:127-46; 3Silverberg SJ, et al. N Engl J Med 1999;341:1249-
55; 4Walker MD, et al. Osteoporos Int 2015; 26:2837-43
*More common if imaging performed for screening

Cope1
1930-1965
Mallette2
1965-1974
Silverberg3
1984-1999
Walker4
2000-2014
Nephrolithiasis 57% 37% 17% 19%
1Cope O. N Engl J Med 1966;274:1174-82; 2Mallette LE, et al. Medicine (Baltimore) 1974;53:127-46; 3Silverberg SJ, et al. N Engl J Med 1999;341:1249-
55; 4Walker MD, et al. Osteoporos Int 2015; 26:2837-43

The biochemical signature of PHPT in the modern era
Index
1984-1991
N=121
2000-2014
N=100
p value
Normal
range
Calcium (mg/dL) 10.6 ± 0.6 10.7 ± 0.6 0.14 8.4-10.2
PTH (pg/mL) 127 ± 69 85 ± 48 <0.0001 10-65
25-hydroxyvitamin D (ng/mL) 23 ± 10 29 ± 10 <0.0001 30-100
1,25-dihydroxyvitamin D (pg/mL) 57 ± 20 69 ± 24 0.002 15-60
Urinary calcium excretion (mg) 229 ± 119 250 ± 144 0.28 100-300
Silverberg SJ et al. N Engl J Med 1999; 341:1249-55
Walker MD et al. Osteoporos Int 2015; 26:2837-43

The biochemical signature of PHPT in the modern era
Index
1984-1991
N=121
2000-2014
N=100
p value
Normal
range
Calcium (mg/dL) 10.6 ± 0.6 10.7 ± 0.6 0.14 8.4-10.2
PTH (pg/mL) 127 ± 69 85 ± 48 <0.0001 10-65
25-hydroxyvitamin D (ng/mL) 23 ± 10 29 ± 10 <0.0001 30-100
1,25-dihydroxyvitamin D (pg/mL) 57 ± 20 69 ± 24 0.002 15-60
Urinary calcium excretion (mg) 229 ± 119 250 ± 144 0.28 100-300
Silverberg SJ et al. N Engl J Med 1999; 341:1249-55
None of the patients in the prior cohort were taking vitamin D supplements compared to
64% in the new cohort (median 800 IU daily)

The densitometric signature of PHPT in the modern era
Bone
density
(%
of
expected)
Lumbar spine Femoral neck Radius
70
80
90
100
*
*
*Differs from radius, p<0.05
Silverberg SJ, et al. J Bone Miner Res 1989;4:283-91

The densitometric signature of PHPT in the modern era -2-

Management of asymptomatic PHPT
• Who needs surgery?
• Who doesn’t need surgery?
Even though patients may not meet any specific criteria for surgery,
parathyroidectomy is not inappropriate, as long as there are no medical
contraindications

Management of asymptomatic PHPT
• Who needs surgery?
• Who doesn’t need surgery?
 First International Workshop,1990
 Second International Workshop, 2002
 Third International Workshop, 2008
 Fourth International Workshop, 2013
 Fifth International Workshop, ongoing
American Association of Endocrine Surgeons,
2016

Guidelines overview
• Biochemical presentation
• Diagnostics
• Clinical presentations
• Natural history
• Densitometric features
• Other skeletal features
• Non-traditional features
• Pharmacological approaches
• Localization and surgical approaches
Bilezikian JP, et al. J Clin Endocrinol Metab 2014;3561-9
Eastell R, et al, J Clin Endocrinol Metab 2014;99:3570-9
Silverberg SJ, et al. J Clin Endocrinol Metab 2014;99:3580-94
Udelsman R, et al. J Clin Endocrinol Metab 2014;99:3595-606
Marcocci C, et al. J Clin Endocrinol Metab 2014;99:3607-18
Wilhelm SM, et al. JAMA Surg 2016;151:959-68

Differential diagnosis
Patient with hypercalcemia and normal or high PTH;
not taking drugs (i.e. thiazide, lithium, vitamin D preparations)
Eastell R et al, J Clin Endocrinol Metab 2014;99:3570-9
Wangrey A, et al. Endocr Pract 2013;19:451-5
If low PTH, exclude biotin supplements

Proceed to genetic testing
(next figure)
YES
Assess for family history of PHPT
and for syndromic forms of PHPT

Measure:
Urinary calcium:creatinine
Serum 25-hydroxyvitamin D
Estimated GFR
NO
UCCR=[24-hour urine Ca x serum Cr]÷[Serum Ca x 24-hour urine Cr]

Measure:
Serum 25-hydroxyvitamin D
Estimated GFR
UCCR >0.02
Sporadic PHPT >90% likelihood

Measure:
25(OH)D >30 ng/mL
eGFR >60 cc/min
UCCR >0.02
UCCR = 0.01 to 0.02
Not able to distinguish PHPT and
FHH
Genetic testing for CASR, GNA11 and
AP2S1 to confirm FHH1, FHH2 and
FHH3, respectively

Measure:
25(OH)D >30 ng/mL
eGFR >60 cc/min
UCCR > 0.02
UCCR = 0.01 to 0.02
Not able to distinguish PHPT and
FHH
UCCR <0.01
FHH >95% likelihood
Consider genetic testing to facilitate
screening of relatives

Approach to suspected genetic etiology
Patient with PHPT
Young age, multigland disease, parathyroid carcinoma, atypical adenoma, family history
Young age = Age <45 years
Multigland disease = ≥2 glands
Atypical adenoma = Cysts, fibrous bands

Patient with PHPT
Young age, multigland disease, parathyroid carcinoma, atypical adenoma, family history
Mutational analysis (in order of
likely frequency):
1. MEN1
2. CASR, AP2S1, GNA11
3. HRPT2 (CDC73)
4. CDKN-1A, -B, -2B, -2C
5. RET
6. PTH
o PRAD1
YES
Mutation detected.
1. Follow-up with regular screening for other
tumors in MEN syndrome or HPT-JT
2. Screen 1st degree relatives
Mutation not detected.
Likelihood of MEN, HPT-JT or FHH low

Recommendation 1-6: Genetic counseling should be performed
for patients younger than 40 years with PHPT and multigland
disease and considered for those with a family history or syndromic
manifestations (strong recommendation; low-quality evidence)

Surgical guidelines for asymptomatic PHPT
Index Third workshop (2008) Fourth workshop (2013)
Age <50 years <50 years
Serum calcium >1.0 mg/dL above normal >1.0 mg/dL above normal
Recommendation 3-2: Parathyroidectomy is indicated when the serum calcium
level is greater than 1 mg/dL above normal, regardless of whether objective
symptoms are present or absent (strong recommendation; low-quality evidence)
Recommendation 3-5: Parathyroidectomy is indicated when PHPT is diagnosed at
50 years or younger regardless of whether objective or subjective features are
present or absent (strong recommendation; moderate-quality evidence)

Fracture risk in PHPT
• Bone density and bone biopsy data show
decreased cortical bone but preservation of the
trabecular skeleton1-3
• Fracture risk may be expected to be
 at vertebral sites
 at nonvertebral sites
1Silverberg SJ et al. J Bone Miner Res 1989;4:283-91
2Parisien M, et al. J Clin Endocrinol Metab 1990;70:930-8
3Dempster DW, et al. Bone 2007;41:19-24

Fracture risk in PHPT -2-
Khosla S et al, J Bone Miner Res 1999;14:1700-7
All fractures
Years following diagnosis

Khosla S et al, J Bone Miner Res 1999;14:1700-7
All fractures
Years following diagnosis Years following diagnosis
Vertebral

40
35
30
25
20
15
10
5
0
Vertebral
fracture
cases
(%)
Controls
(n=300)
Vignali E, et al. J Clin Endocrinol Metab 2009;94:2306-12

35
30
25
20
15
10
5
0
40
Vertebral
fracture
cases
(%)
Symptomatic
(n=41)
Controls
(n=300)
P<0.0001

20
15
10
5
0
25
30
35
40
Vertebral
fracture
cases
(%)
Symptomatic Asymptomatic
(n=41) (n=109)
Controls
(n=300)
P<0.0001
P=0.15
P<0.0001

20
15
10
5
0
40
Vertebral
fracture
(%)
Symptomatic Asymptomatic
(n=41) (n=109)
Controls
(n=300)
P<0.0001
P=0.15
35
cases
30
25
P<0.0001
Most studies of fracture risk in PHPT
demonstrate an increase in both vertebral and
nonvertebral fractures

Trabecular bone is also affected in asymptomatic PHPT
• High-resolution peripheral quantitative computed
tomography (HRpQCT) is a non-invasive
methodology to determine bone quality
• Using HRpQCT, two groups have demonstrated
abnormalities in both cortical and trabecular bone in
women with PHPT
Normal Osteoporotic
Hansen S, et al. J Bone Miner Res 2010;25:1941-7
Stein EM, Silva BC, Cusano NE, et al. J Bone Miner Res 2013;28:1029-40

Microstructure is abnormal in asymptomatic PHPT
Matched control
PHPT
Stein EM, Silva BC, et al. J Bone Miner Res 2013;28:1029-40

-20% 0% 20% 40% 60% 80%
Percentage Difference in the PHPT Group Relative to Controls
-40%
Total vBMD
Tb.vBMD
Tb.N
Tb.Th
Tb.Sp
Tb.Sp.SD
HRpQCT Parameters
Total Area
*
*
Distal Radius
Ct.vBMD *
Distal Tibia
*
Ct.Th *
*
*
*
*
*
*
*
*
Microstructure is abnormal in asymptomatic PHPT
Stein
EM,
Silva
BC,
et
al.
J
Bone
Miner
Res
2013;28:1029-40
Cortical and trabecular indices are reduced at
the radius and tibia in asymptomatic PHPT

Percentage
change
from
baseline
Tb.BMD Ct.Th Dmeta Dinn Dmeta/inn BV/TV Stiffness Failure
load
2.0%
8.0%
10.0%
0.0%
-2.0%
-4.0%
-6.0%
Radius Tibia
‡
‡
*
†
‡
‡
‡
*
6.0% ‡
‡
‡ ‡ ‡ ‡
4.0%
‡
‡ ‡ ‡
‡
†
†
Ct.Ar Tb.Ar Tt.BMD Ct.BMD
Cusano NE, et al. J Clin Endocrinol Metab 2018 103:196-205
Changes in skeletal microstructure by HRpQCT 24 months after
parathyroidectomy
Volumetric BMD, cortical parameters, trabecular BMD, stiffness
and failure load improve after successful parathyroidectomy

Skeletal  T-score <-2.5 at any site
 Clinical fragility fracture
 T-score <-2.5 at any site
 Vertebral fracture by vertebral
fracture assessment (VFA), X-ray, CT
or MRI
Recommendation 3-4: Parathyroidectomy is indicated in patients with PHPT and
osteoporosis, fragility fracture, or evidence of vertebral compression fracture on spine
imaging (strong recommendation; high-quality evidence)

Renal data in PHPT
• Kidney stones are still the most common complication of PHPT
• Kidney stones can be detected by non-invasive imaging (e.g. X-ray,
ultrasound, CT)

Renal data in PHPT
• Kidney stones are still the most common complication of PHPT
• Kidney stones can be detected by non-invasive imaging (e.g. X-ray,
ultrasound, CT)
• Following successful parathyroid surgery, the probability of
developing new stones decreases markedly (although a small risk
remains likely due to coexisting idiopathic hypercalciuria)
• Skeletal involvement more evident in PHPT when the eGFR<60
cc/min

Skeletal  T-score <-2.5 at any site
 T-score <-2.5 at any site
 Vertebral fracture by VFA, X-ray, CT
or MRI
Renal Creatinine clearance <60 cc/min
[24-hour urine not recommended]
 eGFR <60 cc/min
 Kidney stone by X-ray, CT, or US
 Urinary calcium >400 mg + other
urinary indices of increased stone risk
Recommendation 3-3: Parathyroidectomy is indicated for objective evidence of renal involvement,
including silent nephrolithiasis on renal imaging, nephrocalcinosis, hypercalciuria (24-hour urine calcium
level >400 mg/dL) with increased stone risk, or impaired renal function (glomerular filtration rate <60
mL/min) (weak recommendation; low-quality evidence)

Other aspects of PHPT
• Neurocognitive
• Cardiovascular
• Calcium and vitamin D

Putative neurocognitive and constitutional manifestations
of asymptomatic PHPT
Frequent complaints
• Weakness
• Easy fatigability
• Depression
• Intellectual weariness • Difficult to quantitate
• Increased sleep • Adequately controlled
requirements studies are a challenge
Issues in attribution
• Present in many chronic
conditions
• Lack specificity
Inconsistent data from 3 randomized controlled trials of the effect of
parathyroidectomy on psychiatric/cognitive symptoms and quality of
life, despite similar design and assessment tools:
 One suggested parathyroidectomy prevents worsening of quality of life and
improves psychiatric symptoms
 Another demonstrated improvement in quality of life
 The third indicated no benefit

Putative cardiovascular manifestations of mild,
asymptomatic PHPT
• Subtle abnormalities have been noted in:
• Blood pressure
• Vascular reactivity
• Left ventricular hypertrophy/function
• Carotid intimal thickness
• The functional significance is unknown and uncertain
• Reversibility after successful parathyroid surgery is not clear
• A meta-analysis of 15 studies found a decrease in left ventricular mass by 12% following
parathyroidectomy
• No consistent improvement in other parameters
Silverberg SJ, et al. J Clin Endocrinol Metab 2014;99:3580-94; McMahon DJ, et al. J Clin Endocrinol Metab 2015;100:4399-407

Recommendations: Neurocognitive and cardiovascular
Neurocognitive and Cardiovascular complications:
Still not enough data for decisions on surgical management
Recommendation 3-8: Parathyroidectomy is recommended for patients
with neurocognitive and/or neuropsychiatric symptoms that are
attributable to PHPT (strong recommendation; low-quality evidence)
Recommendation 3-9: Parathyroidectomy may be offered to surgical
candidates with cardiovascular disease who might benefit from
mitigation of potential cardiovascular sequelae other than
hypertension (weak recommendation; low-quality evidence)
*

Recommendations: Neurocognitive and cardiovascular
Recommendation 3-10a: The nontraditional symptoms of muscle
weakness, functional capacity, and abnormal sleep patterns should be
considered in the decision for parathyroidectomy (weak
recommendation; moderate-quality evidence)
Recommendation 3-10b: The nontraditional features of gastro-
esophageal reflux and fibromyalgia symptoms may be considered in
the decision for parathyroidectomy (insufficient evidence)

Calcium intake and PHPT
• No data to support dietary restriction of calcium in patients with PHPT
• Patients with PHPT are often erroneously advised to restrict calcium
intake
• Low dietary calcium intake has been shown to stimulate PTH secretion
• In a prospective trial, asymptomatic PHPT patients with daily calcium
intake <450 mg were supplemented with 500 mg daily
• No significant increase in serum calcium level after 4 and 12 weeks
• ↓
in serum PTH after 4 weeks
• ↑
in femoral neck BMD after 52 weeks
Locker FG, et al. Am J Med 1997;102:543-50
Jorde R, et al. Eur J Nutr 2002;41:258-63

Vitamin D deficiency in PHPT
• A meta-analysis and literature review of 10 studies (340 patients)
showed preoperative vitamin D repletion in patients with PHPT and
vitamin D deficiency produced no significant change in serum calcium
levels despite a significant increase in 25-hydoxyvitamin D1
• 5 patients developed worsening hypercalcemia, requiring cessation of vitamin D
• No patient developed hypercalcemic crisis
• A double-blind randomized control trial showed cholecalciferol 2800 IU
daily vs. placebo significantly ↓PTH(↓17%), ↑BMD(↑2.5% at the lumbar
spine) and decreased bone turnover markers2
• No difference in adverse events between groups
• No difference in any time point in serum or urinary calcium levels between groups
1Shah VN, et al. Clin Endocrinol (Oxf) 2014;80:797-803
2Rolighed L, et al. J Clin Endocrinol Metab 2014;99:1072-80

Recommendations: Calcium and vitamin D intake
Recommendation 5-1: Most patients with PHPT should follow Institute
of Medicine guidelines for calcium intake (strong recommendation;
moderate quality evidence
Nutritional elements
 Calcium intake should follow national guidelines
 25-hydroxyvitamin D levels >20 ng/mL (>50 nmol/L) using initial
doses of 600-1000 IU daily
 Monitor serum and urine calcium with vitamin D repletion
Recommendation 5-2: Prior to parathyroidectomy, patients with PHPT
who are vitamin D deficient can safely begin vitamin D
supplementation (weak recommendation; low quality evidence)

Phenotypes of PHPT
Before 1970:
After 1970:
After 2000:
A disease that may present at first with a more subtle biochemical
signature – elevated PTH levels with normal serum calcium

Normocalcemic PHPT
• Recognized at the time of the Third International Workshop
• Diagnostic criteria and management recommendations
made at the time of the Fourth International Workshop
• There is still no evidence to guide physicians regarding
management decisions

Diagnostic features of normocalcemic PHPT
• Elevated PTH
• Normal albumin-adjusted serum calcium
• Normal ionized calcium
 4-64% of patients with a diagnosis of normocalcemic PHPT
reclassified as having traditional hypercalcemic disease with
measurement of ionized calcium
Nordenström E, et al. Clin Biochem. 2011;44:849-52; Ong GS, et al. J Clin Endocrinol Metab 2012;97:3138-45; Gómez-Ramírez J, et al. Am J Surg
2020;219:150-153.

Diagnostic features of normocalcemic PHPT
• Elevated PTH
• Normal albumin-adjusted serum calcium
• Normal ionized calcium
• Corrected and ionized calcium ALWAYS NORMAL
Cusano NE, et al. J Clin Densitom 2013;16:33-9

Exclude secondary hyperparathyroidism
• Vitamin D deficiency
• Minimal goal level should be 20 ng/mL (50 nmol/L) but desirable >30
ng/mL (>75 nmol/L)
• Renal insufficiency
• eGFR <60 cc/min
• Medications
• Thiazide or loop diuretics, lithium, bisphosphonates, denosumab
• Hypercalciuria
• Malabsorption

Study Monitoring Surgical Management
Tordjman et al.(2004)
32 patients
20 patients followed for 4.1 ± 3
years without developing
hypercalcemia
12 patients with positive
localization underwent PTX; single
adenoma or hyperplasia
Lowe et al.(2007)
37 patients
40% of patients developed other
signs of PHPT (3.1 ± 2 years), 19%
with hypercalcemia
3 hypercalcemic and 4
normocalcemic patients
underwent PTX; single adenoma
or hyperplasia
Šiprová et al.(2016)
187 patients
111patients followed for at least 4
years with 19% becoming
hypercalcemic (67% within 2 years)
9 hypercalcemic patients
underwent PTX, 8 with adenoma
were cured
Garcia-Martin et al.(2012)
6 patients
None developed symptoms or
hypercalcemia (1 year)
N/A
Natural history of normocalcemic PHPT

Study Monitoring Surgical Management
Tordjman et al.(2004)
32 patients
20 patients followed for 4.1 ± 3
years without developing
hypercalcemia
12 patients with positive
localization underwent PTX; single
adenoma or hyperplasia
Lowe et al.(2007)
37 patients
40% of patients developed other
signs of PHPT (3.1 ± 2 years), 19%
with hypercalcemia
3 hypercalcemic and 4
normocalcemic patients
underwent PTX; single adenoma
or hyperplasia
Šiprová et al.(2016)
187 patients
111patients followed for at least 4
years with 19% becoming
hypercalcemic (67% within 2 years)
9 hypercalcemic patients
underwent PTX, 8 with adenoma
were cured
Garcia-Martin et al.(2012)
6 patients
None developed symptoms or
hypercalcemia (1 year)
N/A
Population-based study identifying subjects with hypercalcemic PHPT
Rejnmark et al.(2012) 44 patients without hypercalcemic PHPT at inclusion; 13 (30%) had
117 patients normocalcemic PHPT at inclusion
Natural history of normocalcemic PHPT

1Cesareo R, et al. Osteoporos Int 2015;26:1295-1302; 2Brardi C, et al. Arch Ital Urol Androl 2015;87:66-71
Medical management of normocalcemic PHPT
• Increased bone density in patients with normocalcemic PHPT treated
with alendronate (n=15) vs cholecalciferol alone (n=15)1
• +4.7% with alendronate at the lumbar spine vs -1.6%
• +4.0% increase at the total hip vs -1.4%
• Small unblinded pilot study of 6 patients with normocalcemic PHPT
using cinacalcet at a dose sufficient to decrease PTH levels2
↓
the number and diameter of kidney stones

Surgical management of normocalcemic PHPT
• Imaging studies less likely to localize a parathyroid lesion
• ↓sensitivity: 4D CT performed best for normocalcemic PHPT (56% vs. 75% in
normocalcemic versus hypercalcemic)→ultrasound (22% vs. 58%)→scintigraphy
(11% vs. 75%)
• ~ ↑2-3-fold multiglandular disease in normocalcemic vs hypercalcemic PHPT
• ~↓50%adenoma size in normocalcemic vs hypercalcemic PHPT
• Four-gland exploration, a more challenging approach with higher
surgical risk, is required if multiglandular disease or nonlocalization
Šiprová H, et al. Endocr Pract. 2016;22:294-301; Traini E, et al. Langenbecks Arch Surg 2018;403:317-323; Pandian TK, et al. Surgery 2020;167:168-
172; Lim JY, et al. Surgery 2017;161:70-77; Trinh G, et al. Otolaryngol Head Neck Surg 2018;159:630-637; Cunha-Bezerra P,et al. J Med Imaging
Radiat Oncol 2018 Apr 15

Surgical management of normocalcemic PHPT
• Increased need for conversion from minimally invasive approach to
bilateral neck exploration in patients with normocalcemic versus
hypercalcemic PHPT (13% versus 4%; p<0.001)1
• Limited data show normocalcemic patients after surgery have
improvement in bone density, nephrolithiasis, cardiovascular
parameters, and quality of life2-5
1Trinh G, et al. Otolaryngol Head Neck Surg 2018;159:630-637; 2Koumakis E, et al. J Clin Endocrinol Metab 2013;98:3213-20; 3Sho S, et al. Ann Surg
Oncol 2019;26:539-546; 4Beysel S, et al. BMC Cardiovasc Disord. 2019;19:106; 5Bannani S, et al. Br J Surg 2018;105:223-229

Bilezikian JP, et al.J Clin Endocrinol Metab 2014;99:3561-9
Calcium and PTH annually
DXA every 1-2 years
Progression to
hypercalcemic PHPT
Follow guidelines
Management of asymptomatic normocalcemic PHPT

Bilezikian JP, et al.J Clin Endocrinol Metab 2014;99:3561-9
Calcium and PTH annually
DXA every 1-2 years
Progression to
hypercalcemic PHPT
Progression of disease
 Worsening bone density or fracture
 Kidney stone or nephrocalcinosis
Follow guidelines
Surgery
Management of asymptomatic normocalcemic PHPT

Phenotypes of PHPT
Before 1970:
After 1970:
After 2000:
A disease that may present at first with a more subtle biochemical
signature – elevated PTH levels with normal serum calcium
The present:
The parathyroid incidentaloma

Parathyroid incidentaloma
• Incidental parathyroid nodules noted at the time of an imaging
study or during neck surgery
• Less than 50 cases reported in the literature
• The majority of reported cases are biochemically silent
• Monitoring and other management?
Pesenti M, et al. J Endocrinol Invest 1999;22:796-9
Ozdemir D, et al. Endocrine. 2012;42:616-21
Ghervan C, et al. Med Ultrason. 2012;14:187-91
Hussain RAH, et al. Indian J Nucl Med 2017;32:235-236

Medical management of PHPT
• Observation
• Pharmacological approaches
Marcocci C, et al. J Clin Endocrinol Metab 2014;99:3607-18

15-year natural history without surgery
Index Baseline 5 years 10 years 13 years 15 years
Calcium 10.5 ± 0.1 10.7 ± 0.1 10.8 ± 0.2 11.0 ± 0.2 11.1 ± 0.2
PTH 122 ± 10 119 ± 12 123 ± 14 124 ± 16 121 ± 18
25-hydroxyvitamin D 21 ± 1 22 ± 2 22 ± 3 21 ± 3 20 ± 4
1,25-dihydroxyvitamin D 50 ± 2 58 ± 3 54 ± 6 40 ± 5 48 ± 7
Urine calcium 238 ± 19 215 ± 23 185 ± 32 247 ± 36 202 ± 36
Rubin MR, et al. J Clin Endocrinol Metab 2008;93:3462-70

15-year natural history without surgery -2-
Rubin
MR,
et
al.
J
Clin
Endocrinol
Metab
2008;93:3462-70
v

37% of patient developed one or more
indications for surgery during 15 years of
monitoring (nephrolithiasis, hypercalcemia,
or reduced bone mineral density)
Rubin MR, et al. J Clin Endocrinol Metab 2008;93:3462-70

63% of patients did not develop an indication
for surgery during 15 years of monitoring
(nephrolithiasis, hypercalcemia, or reduced
bone mineral density)

Pharmacologic approaches to PHPT
• When?
• Surgery is indicated but medically contraindicated or
patient declines
• Which agent?
• The surgical indication can be ameliorated by the drug
(e.g., severe hypercalcemia, reduced bone density)
• Cinacalcet is the only approved agent for therapy of
hypercalcemia in the US and EU
• Other agents that have been studied include: estrogen,
raloxifene, alendronate

Pharmacologic approaches to PHPT
Agent Serum calcium PTH
Bone
density
Estrogen1
Raloxifene2
Alendronate3
Cinacalcet*4
Cinacalcet +
Alendronate5
1Grey et al., 1996; 2Rubin et al., 2005; 3Khan et al., 2004; 4Peacock et al., 2005, 2009; 5Faggiano et al., 2011
*The only agent approved for PHPT in the US and EU
Fracture
data lacking

Recommendations: Pharmacologic management
Recommendation 3-12: Operative management is more effective and
cost-effective than either long-term observation or pharmacologic
therapy (strong recommendation; moderate quality evidence)
 For the control of hypercalcemia, cinacalcet is the treatment of
choice
 To improve BMD, bisphosphonate therapy is recommended
 The best evidence is for the use of alendronate
 To reduce the serum calcium and improve BMD, combination
therapy with both agents is reasonable, but strong evidence for
efficacy is lacking
*

Surgical management of PHPT
• Surgical approaches include minimally invasive parathyroidectomy
with intraoperative PTH and full exploration
In the modern era, MIP with IPTH has helped achieve cure rates of 97-99%
• Preoperative localization is necessary (ultrasound, 99mTc sestamibi,
MIBI SPECT/CT, 18F-fluorocholine PET/CT, MRI)
• The ideal localization study depends on local availability and
expertise, the preference of the surgeon, need for reoperation
Udelsman R, et al. J Clin Endocrinol Metab 2014;99:3595-606
“The most important preoperative localization challenge in PHPT
is to locate the parathyroid surgeon!” – John Doppman, 1975

Surgical management of PHPT
Recommendation 4-1: Patients who are candidates for
parathyroidectomy should be referred to an expert clinician to decide
which imaging studies to perform based on their knowledge of regional
imaging capabilities (strong recommendation; low-quality evidence)
Recommendation 4-3: Cervical ultrasonography is recommended to
localize parathyroid disease and assess for concomitant thyroid
disease (strong recommendation; low-quality evidence)

Following successful parathyroid surgery…
• Serum calcium
• PTH
• 25-hydroxy- and 1,25-dihydroxyvitamin D
• Urine calcium
• Risk of nephrolithiasis
• Bone markers (resorption and formation)
• Bone density
• Bone microarchitecture
→Normalize or return towards normal

Monitoring guidelines for asymptomatic PHPT
Serum
calcium
Annually Annually
Skeletal DXA: Every 1-2 years  DXA: Every 1-2 years
 Imaging if clinically indicated
Renal Annual monitoring of
creatinine clearance
 Annual monitoring of eGFR
 Stone risk profile or abdominal
imaging if clinically indicated

Indications for surgery during monitoring
Index Fourth workshop (2013)
Serum calcium >1 mg/dL above the normal limit
Skeletal  T-score <-2.5 at lumbar spine, total hip, femoral neck, or
distal 1/3 radius; or a significant reduction in BMD*
 Vertebral fracture by X-ray, CT, MRI or VFA
Renal • eGFR <60 cc/min
 Clinical development of a kidney stone or by imaging (X-ray,
ultrasound, or CT)
*A significant change is defined by a reduction that is greater than the least significant change (LSC) as defined by the
International Society for Clinical Densitometry. If the reduction is > LSC of the measurement to a T-score that is <-2.5 then,
surgery is recommended. If the patient demonstrates a progressive reduction in BMD that exceeds the LSC at any site and is
between -2.0 and -2.5, the physician may opt to recommend surgery even though guidelines have not been strictly met.

Are the scales tipping toward surgery?
Both options are important to consider in each patient
• 15-year natural history
• Vitamin D deficiency
• Neurocognitive data?
• Cardiovascular data?
• Cortical and trabecular abnormalities
and improvement following surgery
• Better imaging techniques
• Improvements in surgical technique
• Patient preference
Surgery Medical management
• 15-year natural history
• Use of vitamin D
• Medical alternatives
• Patient preference
Would a noninvasive method of “parathyroidectomy”
(ultrasound guided microwave ablation) further tip the scale?

Key points
Yes, but we should screen for kidney stones and vertebral fractures in
“asymptomatic” patients

Key points
Monitor serum total and ionized calcium and exclude secondary causes of
hyperparathyroidism (vitamin D deficiency, renal failure, drugs,
malabsorption, hypercalciuria)

Summary
• Primary hyperparathyroidism is a common endocrine disorder
• Non-surgical management may be appropriate for individuals
who do not meet surgical criteria or if there are
contraindications to surgery
• Surgery may also be appropriate for individuals who do not
meet surgical criteria, if there are no medical contraindications

Key points
Cinacalcet for hypercalcemia and antiresorptive therapy for osteoporosis

Key points
Cinacalcet for hypercalcemia and antiresorptive therapy for osteoporosis
• Who should we refer for parathyroid surgery?
Symptomatic patients, “asymptomatic patients” with kidney stones and
osteoporosis, age <50 years, serum calcium >1 mg/dL above normal

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