Calcimimetic Therapy for Severe Secondary Hyperparathyroidism Refractory to Vitamin D Repletion after Duodenal Switch Surgery

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Calcimimetic Therapy for Severe Secondary
Hyperparathyroidism Refractory to Vitamin D
Repletion after Duodenal Switch Surgery
DEEPIKA NALLALA, MD, CHAITANYA MAMILLAPALLI, MD,
MICHAEL JAKOBY, MD/MA
1Fellow, 2Faculty member, and 3Chief, Division of Endocrinology, Southern Illinois University School of Medicine
2 Carle Foundation Hospital, Urbana, Illinois
This case was presented in the guided
poster tour at the American Associa-
tion of Clinical Endocrinologists 21st
Annual Scientic Meeting and Congress,
Philadelphia, PA, May 25, 2012.
ABSTRACT
Duodenal switch surgery achieves weight loss through
both restrictive and malabsorptive changes to the ali-
mentary tract. Hypovitaminosis D and hypocalcemia
may result and lead to secondary hyperparathyroidism
(SHPT). Little is published regarding refractory SHPT
in obese patients managed by bariatric surgery. We pres-
ent a case of severe SHPT that persisted after vitamin
D repletion but responded well to calcimimetic therapy.
A 49-year-old woman who underwent duodenal switch
surgery six years before referral was seen for manage-
ment of vitamin D deciency, SHPT, and osteoporosis.
Hypovitaminosis D was treated with high-dose ergocal-
ciferol (50,000 IU three times daily), and 25-OH D recov-
ered to 41 ng/mL. However, after nine months of high
dose vitamin D, intact PTH (iPTH) remained markedly
elevated (1337 pg/mL). The calcimimetic agent cina-
calcet was started at 30 mg daily and increased at two
to three week intervals to a maximum dose of 120 mg
daily. Calcium carbonate was advanced to 3000 mg three
times daily, and high dose calcitriol (2 mg twice daily)
was also added to the patient’s regimen. Intact PTH fell
nearly four-fold to < 400 pg/mL, and bone density at the
hips and lumbar spine increased signicantly after one
year of treatment.
Though cinacalcet is used to manage SHPT due to
chronic kidney disease, we are unaware of any reports
documenting cinacalcet as therapy for SHPT caused by
bariatric surgery. This case demonstrates that calcimi-
metic agents can be used to safely and eectively lower
PTH levels in vitamin D replete patients with refrac-
tory SHPT after biliopancreatic diversion with duodenal
switch.
INTRODUCTION
Bariatric surgery is now an established treatment op-
tion for patients with Class III obesity (body mass index
[BMI] ≥ 40 kg/m2) and Class II obesity (BMI ≥ 35.0–
39.9) with major obesity-related co-morbidities (eg, Type
2 diabetes mellitus). The number of bariatric surgeries
performed in the US increased from slightly more than
13,000 in 1998 to over 200,000 in 2008.1 Roux-en-Y gas-
tric bypass (49.6%) and biliopancreatic diversion (2.0%)
account for slightly more than half of bariatric proce-
dures.2 Both surgeries limit nutrient consumption and
absorption. Bariatric surgery leads to signicant im-
provement or resolution of important complications of
obesity such as Type 2 diabetes mellitus, hypertension,
dyslipidemia, and obstructive sleep apnea and reduces
obesity-related mortality.3
Unfortunately, patients who undergo malabsorptive
surgeries are at risk for signicant metabolic and nu-
tritional derangements related to poor absorption of
key nutrients such as iron, calcium, vitamin B12, fo-
late, thiamine, and fat-soluble vitamins. In particular,
poor absorption of calcium due to duodenal bypass and
poor absorption and suboptimal consumption of vita-
min D predispose bariatric surgery patients to second-
ary hyperparathyroidism (SHPT). Patients undergoing
biliopancreatic diversion with duodenal switch have a
40–50% risk of secondary hyperparathyroidism depend-
ing on common channel length.4 We present a case of
severe SHPT after biliopancreatic diversion with duode-
nal switch that was refractory to vitamin D repletion but
responded well to a novel attempt at management with
the calcimimetic agent cinacalcet (Sensipar®).
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CASE REPORTS
Calcimimetics for Secondary Hyperparathyroidism after Bariatric Surgery
CASE PRESENTATION
A 49-year-old postmenopausal woman was referred to
the Southern Illinois University Division of Endocrinol-
ogy six years after duodenal switch surgery for manage-
ment of persistent vitamin D deciency and low bone
density. This prior surgery was also complicated by
renal tubular acidosis, recurrent nephrolithiasis, and
persistent hypokalemia. The patient denied use of to-
bacco or consumption of alcohol, and she was unaware
of a family history of osteoporosis. There was no his-
tory of fractures, and the patient denied musculoskeletal
discomfort or muscle weakness. Physical examination
was unremarkable. Initial laboratories were notable for
25-hydroxyvitamin D level (25-OH D) 4 ng/mL, intact
parathyroid hormone (iPTH) 826 pg/mL (10–65), se-
rum calcium 8.4 mg/dL (8.6–10.2), phosphorus 3.5 mg/
dL (2.5–4.9), albumin 3.7 g/dL (3.4–5.0) and creatinine
0.9 mg/dL (0.6–1.0). Dual-energy x-ray absorptiometry
(DXA) scan showed severe osteoporosis (Table 1) with
left hip T-score -4.1, right hip T-score -5.0, and total lum-
bar spine T-score -3.4. Total hip and lumbar spine bone
mineral densities were decreased by 26% and 16%, re-
spectively, compared to measurements three years ear-
lier.
Ergocalciferol 50,000 IU three days/wk was prescribed
to treat hypovitaminosis D, and the patient’s 25-OH
D level increased to 41 ng/mL (vitamin D replete sta-
tus > 30). Serum calcium consistently ranged from
8.5–9.0 mg/dL, and phosphorus level ranged from
3.5–4.0 mg/dL. Despite dramatic improvement in vi-
tamin D level, SHPT persisted as indicated by refrac-
tory and markedly elevated iPTH level (1337 pg/mL).
The patient declined parathyroid exploration and partial
parathyroidectomy, so treatment with the calcimimetic
drug cinacalcet was attempted. After initial favorable re-
sponse to 30 mg daily, cinacalcet was titrated at two to
three week intervals to a maximum dose of 120 mg. (Fig-
ure 1) Supplemental calcium carbonate was advanced to
3000 mg with meals to treat mild hypocalcemia, with
total serum calcium maintained in the range of 7.5–8.0
mg/dL. After iPTH level reached a plateau, high-dose
calcitriol (2 mg twice daily) was added to the regimen,
and iPTH improved by an additional 65%. Overall, the
combination of cinacalcet, calcitriol, and calcium car-
bonate improved iPTH level by nearly four-fold. Repeat
bone densitometry after one year of calcimimetic ther-
apy demonstrated signicant improvements in lumbar
spine and total hipbone density measurements. (Table
1, Figure 2)
DISCUSSION
To the best of our knowledge, this is the rst case report
of calcimimetic therapy for management of refractory
SHPT after malabsorptive bariatric surgery. Cinacalcet
is an oral agent that reduces PTH levels by allosterically
enhancing the sensitivity of calcium sensing receptors
(CaSR) in parathyroid glands to calcium. It is approved
as adjunct therapy to vitamin D and vitamin D analogs
for management of secondary hyperparathyroidism in
patients with chronic renal insuciency requiring di-
alysis. In phase 3 clinical trials,5 patients receiving cina-
calcet were much more likely than patients receiving
placebo to achieve the endpoint of iPTH < 300 pg/mL or
the combined endpoint of iPTH < 300 pg/mL and Ca x P
product < 55 mg2/dL2. Combined analysis of phase 3 tri-
als and a phase 2 trial found that patients randomized to
cinacalcet had signicantly lower risks of parathyroidec-
tomy, fracture, and cardiovascular hospitalization than
patients randomized to receive placebo.6 A prospective
observational study with over 19,000 patients found that
patients managed with cinacalcet had a 25% lower mor-
tality rate than patients managed without the drug.7
Table 1. Lumbar spine (L2-L4) and total hip bone mineral density measurements.
Region 2008† 2011§ 2012¶
BMD(gm/cm2) T-score BMD(gm/cm2) T- score BMD(gm/cm2) T- score
L2-L4 0.919 -2.2 0.768 -3.4 0.912 -2.4
Left total hip 0.609 -3.2 0.491 -4.1 0.596 -3.4
Right total hip 0.572 -3.5 0.377 -5.0 0.488 -4.3
† Three years after surgery; § At consultation and before treatment; ¶ After one year of treatment

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Risk of developing nutritional deciencies and metabol-
ic disorders after bariatric surgery is highest in patients
undergoing biliopancreatic diversion with duodenal
switch. The distance from the entero-enteric anastamo-
sis to the ileocecal valve is called the “common chan-
nel,” and risk of SHPT increases with shorter common
channel length. In a study of 165 consecutive patients
undergoing duodenal switch, patients with shorter com-
mon channel (75 cm) were over three-fold more likely
to develop new onset secondary hyperparathyroidism
than patients with a longer common channel (100 cm).4
However, secondary hyperparathyroidism is a risk of all
malabsorptive bariatric surgeries, with incidence rang-
ing from 29–53%.8,9 Johnson et al documented a linear
decrease in vitamin D level coupled with linear increas-
es in iPTH and alkaline phosphatase levels over a period
of 5–8 years after surgery.10 Despite normal calcium and
vitamin D levels, up to 30% of bariatric surgery patients
experience persistent iPTH elevations and SHPT indic-
ative of PTH resistance or persistent autonomous para-
thyroid gland function.11
Secondary hyperparathyroidism after malabsorptive
bariatric surgery is mostly a consequence of chronic cal-
cium malabsorption. Calcium absorption from the gas-
trointestinal tract is signicantly decreased after bypass
of the duodenum and proximal jejunum, the sites in the
small intestine where calcium absorption is maximal.
Also, dietary calcium absorption may be impaired by
concurrent vitamin D deciency, which is present in as
many as 50% of bariatric patients within two years of
surgery.12 Signicant reduction in dietary
Figure 1. Panel A: Improvement in intact parathyroid
hormone (iPTH) level over twelve months of
treatment with cinacalcet with or without calcitriol.
Panel B: Changes in calcium (left vertical axis) and
phosphorus (right vertical axis) during treatment.
Figure 2. Panel A: Dual-energy x-ray absorptiometry
(DXA) scan of lumbar spine at time of consultation
(2011); Panel B: DXA scan of lumbar spine after
one year of treatment (2012); Panel C: DXA scan of
both hips 2011; Panel D: DXA scan of hips 2012. All
images were obtained using the same GE Healthcare
Hologic densitometer. Note the improvement in
lumbar spine and hip mineralization from 2011 to
2012 that is quantified in Table 1.
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calcium absorption is a potent stimulus for increased
PTH secretion, resulting in accelerated mobilization of
calcium from bone and eucalcemia at the expense of
skeletal mineralization. Over a sustained period, SHPT
predisposes patients to loss of bone density. This is an
especially signicant concern in middle-aged women
such as our patient who may already suer low bone
density prior to surgery due to chronic vitamin D de-
ciency or as a consequence of low estradiol resulting
from obesity-induced disruption of normal menses or
menopause.
CONCLUSION
Our patient’s experience demonstrates that, in a single
case, calcimimetic based therapy signicantly improved
SHPT induced by bariatric surgery that is refractory to
successful vitamin D repletion. Lowering PTH level
also partially reversed skeletal demineralization that
was likely a consequence of SHPT. Mild hypocalcemia
occurred as cinacalcet was advanced, eventually limit-
ing further improvement in iPTH. Aggressive calcium
supplementation and calcitriol dosing prevented further
decline in serum calcium, and this facilitated additional
improvement in PTH. Treatment with cinacalcet was
successful in this single case. It might have potential
to be an option for patients who decline or are not good
candidates for partial parathyroidectomy to manage
refractory SHPT following bariatric surgery, though
more experience with this approach together with well-
designed research are both needed before it can become
a generally recommended alternative to surgical man-
agement.
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CORRESPONDING AUTHOR:
Michael Jakoby, MD/MA
SIU School of Medicine
701 North First Street
Suite D405
PO Box 19636
Springeld, IL 62794
Phone: (217) 545-0166
Fax: (217) 545-1229
mjakoby@siumed.edu
CASE REPORTS
Calcimimetics for Secondary Hyperparathyroidism after Bariatric Surgery