Treatment of Hypoparathyroidism

Treatment of Hypoparathyroidism

Tamara Vokes, MDUniversity 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 (pseudo-hypoparathyroidism)

• 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 storyTwo 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

Winer et al JAMA 276:631, 1996

20 subjects treated with PTH vs. calcitriol in cross-over design

Winer et al JAMA 276:631, 1996

PTH 1,34: 1 vs 2 daily injections17 subjects treated for 28 weeks in cross-over design

Twice daily PTH produced less variability in calcium levels

Winer et al JCEM 88:4214, 1998

PTH 1-34: twice daily injection vs. pump8 patients: cross-over

Winer et al JCEM 97:391, 2012

Mean daily PTH dose was 65% lower during pump Tx

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

Sikjaer et al JBMR 26:23581, 2011

------PTH (1-84) Placebo

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)

Inclusion criteria

• Age 1885 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

134 subjects randomized (2:1) to escalating doses of PTH or placebo for 24 weeks


• Primary endpoint

50% in calcium

50% in active VitD+

While maintaining normal serum calcium

Bilezikian et al, 2012 Endocrine Soc S18-3


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


Study Design

50µg75µg

100µg

Optimization2-16 weeks

Titration 12 weeks Maintenance 12 weeks

PTH or placebo injection daily

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

30

VariablerhPTH(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 AmericaEurope

49 (54)41 (46)

25 (57)19 (43)

74 (55)60 (45)

Hypoparathyroidism etiology, n (%)PostsurgicalIdiopathicAutoimmune diseaseOther (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)

Patient Demographics

Mannstadt et al. Endo Soc 2012, SUN-341

31

Primary Endpoint:Responder Rate at Week 24

1/44

53% rhPTH(1-84) vs 2% placebo (P<0.001*)

Primary Endpoint*48/90

Res

pond

ers

Rat

e, %

0

40

50

70rhPTH(1-84) n=90Placebo n=44

60

10

20

30

Week1 2 3 4 5 6 8 12 16 2420


32

Secondary Endpoint: Active Vitamin D Independence and Oral Ca Dose ≤500 mg/day

43% rhPTH(1-84) vs 5% PBO (P<0.001*)

Secondary Endpoint*36/84

Patie

nts

Who

Met

the

Crit

eria

, %

0

40

50


60

10

20

30

Week1 2 3 4 5 6 8 12 16 2420


33

Secondary Endpoint: Clinical Symptoms of Hypocalcemia During Weeks 16-24

Clinical Symptoms of Hypocalcemia

rhPTH(1-84)n=90

Placebo n=44

n % n %

Overall (P=0.392) 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


34

Serum Ca laboratory

normal range of 8.4 to 10.6 mg/dL

Albumin-corrected Serum Ca Levels

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

Week

Mea

n (S

D) A

lbum

inC

orre

cted

Tot

alSe

rum

Ca

Con

cent

ratio

n, m

g/dL

0 1 2 3 4 5 6 8 18077

8

9


7 9 10 11 12 13 14 15 1716 2419 20 21 2322

Serum Ca target range

of 8.0 to 9.0 mg/dL

10


35

PlaceboSerum and Urine Ca Levels

Week0 1 2 3 4 5 6 8 18

077

8

9

11UrineSerum

7 9 10 11 12 13 14 15 1716 2419 20 21 2322

10

Mean (SD

) 24-Hour U

rinaryC

a Excretion, mg/24 h

0

100

300

500

700

200

400

600

Serum Ca target range of 8.0 to 9.0 mg/dLNormal urine Ca excretion 50-300 mg/24 hr

Placebo

In the placebo group, urine Ca excretion is directly related to serum Ca levels

Mea

n (S

D) A

lbum

inC

orre

cted

Tot

alSe

rum

Ca

Con

cent

ratio

n, m

g/dL


36

rhPTH(1-84) Serum and Urine Ca Levels

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

Week0 1 2 3 4 5 6 8 18

077

8

9

11UrineSerum

7 9 10 11 12 13 14 15 1716 2419 20 21 2322

10

Mean (SD

) 24-Hour U

rinaryC

a Excretion, mg/24 h

0

100

300

500

700

200

400

600

rhPTH(1-84) n=90

Mea

n (S

D) A

lbum

inC

orre

cted

Tot

alSe

rum

Ca

Con

cent

ratio

n, m

g/dL

Serum Ca target range of 8.0 to 9.0 mg/dLNormal urine Ca excretion 50-300 mg/24 hr


37

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)


38

Incidence of Hypocalcemia and Hypercalcemia During Study Period

Shoback et al. Endocrine Soc 2012, SUN-325

rhPTH(1-84)n=90

Placebo n=44

n % n %HypocalcemiaOptimization (~2–16 wks) 7 8 2 5

Treatment, Titration (Week 0 - 12) 9 10 7 16

Treatment, Stable (Weeks 16 – 24) 30 33 18 41Post-treatment (4 wks) 28 31 4 9

Hypercalcemia

Optimization (~2–16 wks) 3 3 0 0

Treatment, Titration (Week 0-12) 12 13 1 2Treatment, Stable (Weeks 16 – 24) 8 9 0 0

Post-treatment (4 wks) 2 2 3 7

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 meetingVokes 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 inter-

individual 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.

Left side exploration Right side exploration

time -22 -7 8 15 -15 5 10

PTH 70 83 67 51 52 13 6

Findings during surgery

½ parathyroid left lower parathyroid gland left in place

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?

Patient was initially on calcium and calcitriol but since calcium was 9.2

2 weeks post op calcitriol was stopped

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!???

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Treatment of Hypoparathyroidism