Treatment of Hypoparathyroidism

Treatment of
Hypoparathyroidism
Tamara Vokes, MD
University of Chicago
Section of Endocrinology
Disclosure
• NPS pharmaceutical – consultant and
investigator
• Discussing unapproved indications
Hypopara – definition and
prevalence
• Rare endocrine disorder characterized by
low serum calcium and high phosphate
due to absent or inappropriately low PTH
• Prevalence – not known
• Estimate – 78-80,000 in the US
Etiology – inadequate PTH
secretion
• Post-surgical (78%)
– Thyroid surgery: total thyroidectomy (38%),
partial (9%)
– Parathyroid surgery (21%)
– Head and neck cancer (5%)
• Autoimmune
– Isolated
– Polyglandular failure
– Activating antibodies against calcium sensing
receptors
Etiology – rare causes
• Genetic (7%)
– Familial hypocalcemic hypercalciuria (gain of
function mutation in CaSR)
– Polyglandular autoimmune syndrome (mutation in
autoimmune regulation gene – AIRE)
– DiGeorge, PTH gene mutation etc
• Infiltrative disease (thalassemia,
hemochromatosis, Wilson’s disease)
• Irradiation (131I therapy)
Etiology – not due to deficient
PTH secretion
• Resistance to PTH action (pseudohypoparathyroidism)
• Hypomagensemia (Functional hypopara –
deficient PTH secretion and action)
PTH controls mineral homeostasis
PTH deficiency:
• Decreased intestinal calcium absorption
(low 1,25 Vitamin D)
• Increased urinary calcium and magnesium
excretion (decreased phosphate excretion)
• Decreased bone resorption
Consequences of PTH deficincy
• Low serum calcium and
magnesium, high serum
phosphate - symptoms
• Hypercalciuria (kidney
stones, nephrocalcinosis,
CKD)
• High calcium*phosphate
product = soft tissue
calcifications (cataracts,
basal ganglia)
Clinical manifestations are due
to hypocalcemia
• Treatment to normalize serum calcium
– Calcium supplements (carbonate or citrate)
– Vitamin D
• calcitriol - onset 1-2 days, offset 2-3 days
• ergocalciferol (less desirable) – onset 10-14 days,
offset 14-75 days
– Thiazide diuretics
Goal of treatment of hypopara
– Low normal serum calcium (8-8.5mg/dl)
– 24 hour urine calcium<300 mg/24 hrs
– Calcium*phosphate product <55
Parathyroidectomy patient story
Two days after surgery I experienced tetney, followed by a pth
test less than 3. I felt awful, tingled, ached and couldn't
concentrate. After my second ER trip for tetney I was placed on
calcium, magnesium, and calcitriol while being assured that my
para would wake up and I would feel normal again. Nearly five
months later I have a pth of 9.6 and am still struggling to
manage my calcium keeping it in the low 8's. Since that day I
have experienced many symptoms and struggled to regain my
previous energy and health. Trying to explain my condition to
friends and family is daunting and confusing. Even medical
doctors are unfamiliar with my "rare disorder" and I am still
trying to make sense of it all. Some days I feel great while other
days I struggle to just go to work. There are muscle aches,
twitches, tingling and mood swings.
Therapeutic challenges
• Hypo- and hypercalcemia
• Poor quality of life – brain fog, tingling,
cramping (claw, perching), numbness,
twitching, poor exercise tolerance,
headaches, insomnia, needing to carry
calcium tablets
• Long term complications
Hypopara is the only endocrine deficiency
for which there is no FDA approved
replacement therapy
Use of PTH for hypopara
NOT FDA APPROVED
• Prevent hypo and hypercalcemia
• Improve QOL (Prevent wide fluctuations in
serum calcium)
• Decrease the amount of supplements
• Minimize hypercalciuria
PTH replacement therapy
• PTH(1-34) approved for osteoporosis in
the US and elsewhere
• PTH(1-84) approved for osteoporosis in
Europe
PTH(1-34) for hypoparathyroidism
20 subjects treated with PTH vs. calcitriol in cross-over design
Winer et al JAMA 276:631, 1996
Winer et al JAMA 276:631, 1996
PTH 1,34: 1 vs 2
daily injections
17 subjects
treated for 28
weeks in crossover design
Twice daily
PTH produced
less variability
in calcium
levels
Winer et al JCEM 88:4214, 1998
PTH 1-34: twice daily injection vs. pump
8 patients: cross-over
Mean daily PTH dose was
65% lower during pump Tx
Winer et al JCEM 97:391, 2012
PTH (1-34) for hypopara
• May be helpful in reducing fluctuations in
serum calcium
• Needs to be dosed twice a day
• Not approved for hypopara but available
for treatment of osteoporosis (teriparatide)
Use of PTH (1-84) for hypopara
• 62 subjects in a randomized placebo
controlled trial given 100mcg of PTH
• Calcium dose reduced by 75%, calcitriol
dose by 73%: 15 subjects stopped
calcium completely
• 11 subjects developed hypercalcemia
(Supplement dose was not titrated unless
subjects developed hypercalcemia)
Sikjaer et al JBMR 26:23581, 2011
------PTH (1-84)
Placebo
Sikjaer et al JBMR 26:23581, 2011
30 subjects given 100mcg of PTH(1-84) every
other day in open label study over 24 months
Reduction in
supplement doses
Serum calcium
improved, low risk
of hypercalcemia
Rubin et al Osteo Int 21:1927, 2010
Randomized double blind placebo
control trial of rhPTH(1,84)
134 subjects randomized (2:1) to escalating
doses of PTH or placebo for 24 weeks
Inclusion criteria
• Age 1885 y
• HypoPARA for ≥18 mo
• calcitriol ≥0.25 µg/d and
oral Ca ≥1 g/d over diet
• Normal TFT or stable
thyroid replacement
Exclusion criteria
• activating CaSR mutation
or ↓ responsiveness to PTH
• thyroid cancer within 5 y
• GI disease
• Serum 25D levels <1.5ULN
• Pregnant or lactating
Randomized double blind placebo
control trial of rhPTH(1,84)
• Primary endpoint
50% in
calcium
+
50% in
active VitD
While maintaining normal
serum calcium
Bilezikian et al, 2012 Endocrine Soc S18-3
Randomized double blind placebo
control trial of rhPTH(1,84)
Secondary endpoints
− Percent change in oral Ca supplement at
Week 24
− Percent who achieve supplement
independence
− Frequency of clinical symptoms of
hypocalcemia Weeks 16 - 24
Bilezikian et al, 2012 Endocrine Soc S18-3
Study Design
100µg
75µg
50µg
Optimization
2-16 weeks
Titration 12 weeks
PTH or placebo
injection daily
Maintenance 12 weeks
Adjust active vitamin D and then calcium
Randomization
End of study
During titration phase weekly visit with progressive
increase in PTH dose until calcitriol eliminated and
oral calcium <500mg/day
Guideline used for reducing
supplements
• Start PTH 50µg; reduce calcitriol by 50%
• Test serum calcium 1-2 days later and if
– Ca <8mg% - resume calcitriol
– Ca 8-9mg% - no change
– Ca 9.1-10.5 stop calcitriol, retest next day
– Ca 10.6-11.9 stop calcitriol, reduce calcium by
50%, retest next day
Adjustment at the discretion of physician
Patient in
PTH (1-84)
study
Patient Demographics
rhPTH(1-84)
(n=90)
Placebo
(n=44)
Total
(n=134)
Mean age, year
47.0
48.5
47.5
Women, n (%)
69 (77)
36 (82)
105 (78)
Caucasian, n (%)
85 (94)
43 (98)
128 (96)
Mean BMI, kg/m2
29.3
29.2
29.2
Geographic area, n (%)
North America
Europe
49 (54)
41 (46)
25 (57)
19 (43)
74 (55)
60 (45)
Hypoparathyroidism etiology, n (%)
Postsurgical
Idiopathic
Autoimmune disease
Other (genetic, radiation)
68 (76)
14 (16)
5 (6)
3 (3)
31 (71)
8 (18)
4 (9)
1 (2)
99 (74)
22 (16)
9 (7)
4 (3)
Variable
Mannstadt et al. Endo Soc 2012, SUN-34130
Primary Endpoint:
Responder Rate at Week 24
rhPTH(1-84) n=90
Placebo n=44
70
Primary Endpoint*
48/90
Responders Rate, %
60
50
40
30
20
10
1/44
0
1
2
3
4
5
6
8
12
16
20
24
Week
 53% rhPTH(1-84) vs 2% placebo (P<0.001*)
Bilezikian et al, 2012 Endocrine Soc S18-3
31
Secondary Endpoint:
Active Vitamin D Independence and Oral Ca Dose ≤500 mg/day
rhPTH(1-84) n=90
Placebo n=44
Patients Who Met the Criteria, %
70
60
Secondary Endpoint*
36/84
50
40
30
20
10
0
1
2
3
4
5
6
8
12
16
20
24
Week
 43% rhPTH(1-84) vs 5% PBO (P<0.001*)
Bilezikian et al, 2012 Endocrine Soc S18-3
32
Secondary Endpoint:
Clinical Symptoms of Hypocalcemia During Weeks 16-24
Clinical Symptoms of
Hypocalcemia
Overall (P=0.392)
rhPTH(1-84)
n=90
Placebo
n=44
n
%
n
%
30
33
18
41
Includes paresthesia (include oral), muscle spasms, hypoesthesia
(include oral and facial), tetany, back pain, myalgia, muscle twitching,
throat tightness, musculoskeletal pain, anxiety
Bilezikian et al, 2012 Endocrine Soc S18-333
Albumin-corrected Serum Ca Levels
rhPTH(1-84) n=90
Placebo n=44
Mean (SD) Albumin Corrected Total
Serum Ca Concentration, mg/dL
11
Serum Ca
laboratory
normal range of
8.4 to 10.6 mg/dL
10
9
Serum Ca
target range
of 8.0 to
9.0 mg/dL
8
7
7
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Week
 Albumin-corrected total serum Ca levels remained at or above baseline
level in the rhPTH(1-84)-treated patients despite large reductions in
active vitamin D and oral Ca doses
Bilezikian et al, 2012 Endocrine Soc S18-334
Placebo
Serum and Urine Ca Levels
Serum Ca target range of 8.0 to 9.0 mg/dL
Normal urine Ca excretion 50-300 mg/24 hr
700
600
10
500
400
9
300
200
8
100
Mean (SD) 24-Hour Urinary
Ca Excretion, mg/24 h
Mean (SD) Albumin Corrected Total
Serum Ca Concentration, mg/dL
Placebo
Urine
Serum
11
0
7
7
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Week
 In the placebo group, urine Ca excretion is directly related to
serum Ca levels
Bilezikian et al, 2012 Endocrine Soc S18-335
rhPTH(1-84)
Serum and Urine Ca Levels
Serum Ca target range of 8.0 to 9.0 mg/dL
Normal urine Ca excretion 50-300 mg/24 hr
700
600
10
500
400
9
300
200
8
100
Mean (SD) 24-Hour Urinary
Ca Excretion, mg/24 h
Mean (SD) Albumin Corrected Total
Serum Ca Concentration, mg/dL
rhPTH(1-84) n=90
Urine
Serum
11
0
7
7
0
0
1
2
3
4
5
6
7
8
9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24
Week
 Albumin-corrected total serum Ca levels remained at or above baseline
level in the rhPTH(1-84)-treated patients with a small decrease in mean
24-hour urinary Ca excretion
Bilezikian et al, 2012 Endocrine Soc S18-336
Summary of AEs and SAEs
During Treatment Period (Weeks 1-24)
Patients, n (%)
rhPTH(1-84)
n=90
Placebo
n=44
n
%
n
%
AEs
81
90
42
96
Serious AE
5*
6
2
5
AE leading to discontinuation
3†
3
0
0
Deaths
0
0
0
0
*Treatment-related hypercalcemia requiring brief hospitalization (n=1)
†Hypertension (n=1); stroke (n=1); multiple events (n=1)
Bilezikian et al, 2012 Endocrine Soc S18-3
37
Incidence of Hypocalcemia and
Hypercalcemia During Study Period
rhPTH(1-84)
n=90
Placebo
n=44
n
%
n
%
Optimization (~2–16 wks)
7
8
2
5
Treatment, Titration (Week 0 - 12)
9
10
7
16
Treatment, Stable (Weeks 16 – 24)
30
33
18
41
Post-treatment (4 wks)
28
31
4
9
Optimization (~2–16 wks)
3
3
0
0
Treatment, Titration (Week 0-12)
12
13
1
2
Treatment, Stable (Weeks 16 – 24)
8
9
0
0
Post-treatment (4 wks)
2
2
3
7
Hypocalcemia
Hypercalcemia
38
Shoback et al. Endocrine Soc 2012, SUN-325
Response to PTH is similar in
surgical and non-surgical
• Among the 99 postsurgical patients, 57%
were responders in the rhPTH(1-84) group
vs 3% in the placebo group (P<0.001).
• Among the 35 nonsurgical patients, 41%
were responders in the rhPTH(1-84) group,
compared with 0% in the placebo group
(P=0.013).
Schoback et al, 2012 ATA annual meeting
Vokes et al, 2013 Endo Surgeons meeting
Lower doses of PTH may be
effective in some patients
• 46 hypopara patients randomized to either
25µg (22 subjects) or 50µg (24 subjects)
of PTH(1-84) by daily injection for 8 weeks
• Reduction in supplements to <500mg of
calcium and <0.25µg of calcitriol (with
serum calcium >7.5mg/dl):
– 18% of 25µg group
– 25% of 50µg group
Vokes et al, 2012 ASBMR 2012
PTH (1-84) Tx of hypoparathyroidism
• Allows reduction or even elimination of oral
calcium and calcitriol
• Decreased fluctuations in serum calcium
• Overall higher calcium levels without
hypercalciuria
• Patients report improved quality of life and
improved exercise tolerance
• Flexible dosing is important due to interindividual variability in the response to PTH
• Normal levels of 25(OH) Vitamin D
Effect of PTH Tx on bone
• Hypopara patients have low bone turnover
and high BMD
• PTH (1-84) Tx restores bone turnover
Patient with recent parathyroid
surgery
52Y/O woman who is s/p 3.5 gland excision
for PHPT from 4-gland hyperplasia. She has
had continued symptoms of
numbness/tingling in her toes and fingertips
that has not subsided since her surgery. She
states that once these symptoms start she
gets anxious which usually exacerbates her
symptoms.
Findings during surgery
Left side exploration
Right side
exploration
time -22
-7
8
15
-15
5
10
PTH
83
67
51
52
13
6
70
½ parathyroid left lower parathyroid
gland left in place
Patient was initially on calcium and
calcitriol but since calcium was 9.2
2 weeks post op calcitriol was stopped
1 month postop
•
•
•
•
Calcium 8.1 mg/dl (8.4-10.2)
Albumin 4.4 mg/dl (3.5 – 5.0)
Ionized calcium 4.2 mg/dl (4.6 – 5.4)
Phosphate 5.1 (2.5 – 4.2 mg/dl)
Hungry Bone?
More labs
•
•
•
•
•
•
•
Calcium 8.1 mg/dl (8.4-10.2)
Albumin 4.4 mg/dl (3.5 – 5.0)
Ionized calcium 4.2 mg/dl (4.6 – 5.4)
Phosphate 5.1 (2.5 – 4.2 mg/dl)
PTH 29 pg/ml (15-75)
25(OH) vitamin D 43 ng/ml (10-52)
1,25 (OH) Vitamin D 29 pg/ml (15-75)
Partial hypopara?
Thank
You!
???