Brandi ML (ed): Parathyroid Disorders. Focusing on Unmet Needs.

Front Horm Res. Basel, Karger, 2019, vol 51, pp 165–171 (DOI: 10.1159/000491047)

A New Era for Chronic Management

of Hypoparathyroidism: Parathyroid
Hormone Peptides
Gemma Marcucci · Maria Luisa Brandi
Bone Metabolic Diseases Unit, Department of Surgery and Translational Medicine, University of Florence,
Florence, Italy

Abstract
Several studies have investigated replacement therapy with recombinant human parathyroid hor-
mone [rhPTH(1-84)] for patients affected by chronic hypoparathyroidism who are not adequately
controlled with standard treatment. In 2015, the Food and Drug Administration (FDA) in the USA
approved rhPTH(1–84), named Natpara®, for the pharmacological management of hypoparathy-
roidism. In Europe, in February 2017, the European Medicines Agency (EMA) recommended granting
a conditional marketing authorization in the European Union for rhPTH(1–84). Here we review the
studies conducted with rhPTH(1–84) and PTH(1–34) in patients with chronic hypoparathyroidism.
The research done in this field has shown that replacement treatment with rhPTH(1–84) is an impor-
tant therapeutic option for subjects with chronic hypoparathyroidism who are not well controlled
with conventional treatment. However, further long-term investigations are needed.
© 2019 S. Karger AG, Basel

Despite the use of standard treatment with calcium and active vitamin D, some pa-
tients affected by hypoparathyroidism are not well controlled and require high doses
of these supplementations with an associated risk of long-term complications, such as
hypercalciuria, renal stones or calcinosis, renal function impairment, and extraskel-
etal calcifications [1, 2]. Moreover, in some cases treated with conventional therapy,
wide swings of serum calcium concentration with associated symptomatology have
been described. Standard pharmacological management does not provide a physio-
logical replacement remedy for the lack of PTH in these patients [3], and it is not able
to normalize the typical bone structure abnormalities [4]. Finally, conventional ther-
apy does not alleviate quality of life complaints [1, 5].
Over the past two decades, several studies have investigated replacement therapy
with recombinant human PTH [PTH(1-84)], the full-length peptide missing in this
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disease, and with the N-terminal PTH fragment, teriparatide [PTH(1-34)] in chronic
hypoparathyroidism. In the USA, the Food and Drug Administration (FDA) ap-
proved rhPTH(1–84) in 2015 as a hormone replacement therapy for the management
of patients affected by chronic hypoparathyroidism, with a “black box” warning be-
cause of the potential risk of osteosarcoma, but with no limit on the duration of use
[6]. The FDA indication is for patients with hypoparathyroidism of any etiology, ex-
cept autosomal dominant hypocalcemia (ADH), who cannot be controlled well with
calcium and active vitamin D [6]. In Europe, in February 2017, the European Medi-
cines Agency (EMA) recommended granting a conditional marketing authorization
in the European Union for rhPTH(1–84).
The recent guidelines recommend the use of rhPTH(1–84) therapy in any pa-
tient affected by chronic hypoparathyroidism (except for ADH) in case of the fol-
lowing situations: variable and inconstant control of the serum calcium and epi-
sodes of hypo- and hypercalcemia frequently reported; renal complications, such
as renal stones, nephrocalcinosis, or reduced creatinine clearance or estimated glo-
merular filtration rate to <60 mL/min; hypercalciuria and/or other biochemical in-
dices of renal stone risk; persistently high serum phosphate concentrations and/or
calcium-phosphate product (>55 mg2/dL2 or 4.4 mmol2/L2); the need for large
amounts of oral supplementations, >2.5 g of calcium or >1.5 μg of active vitamin
D, or both; and a gastrointestinal disease causing variable calcium and vitamin D
absorption [1].

Parathyroid Hormone (1–34)

Winer and colleagues [3, 7–12] have conducted a series of investigations with PTH(1–
34), the biologically active amino-terminal fragment, in hypoparathyroid patients
(small groups), establishing the experimental basis for the use of PTH in this disorder.
These studies analyzed varying dose regimens of PTH(1–34) (once-daily and twice-
daily injections, or the use of a pump delivery system, in adults and children with
various types of hypoparathyroidism).
The first study described that the use of PTH(1–34), with once-daily injections, was
associated with better results by maintaining normal serum calcium and urinary cal-
cium excretion concentrations if compared to standard treatment [7]. Another study
conducted in adult patients comparing daily with twice daily injections of PTH(1–34)
showed that twice-daily injections resulted in significantly higher serum calcium con-
centrations with less fluctuation throughout the day, and a better control of urine cal-
cium levels [8]. In addition, the total daily PTH dose was markedly reduced with the
twice-daily regimen [8].
Other studies by Winer et al. [9, 10], conducted for 3 years, showed that PTH(1–34)
was superior to active vitamin D by maintaining urinary calcium excretion in the nor-
mal range along with stable bone density Z-scores in adults and children. Pediatric
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patients treated with PTH(1–34) showed stable renal function and normal linear
growth and bone accrual [10].
Subsequently, Winer et al. [11, 12] adapted a pump delivery system by which
PTH(1–34) could be administered continuously. Overall, in these studies, urinary cal-
cium excretion fell, and markers of bone turnover normalized, and a smaller daily
dose was required with pump delivery compared to multiple daily dosing regimens.
Of note, in a 6-month study, pump delivery showed normal, steady-state serum cal-
cium concentrations, except minimal fluctuation, and avoided the rise in serum and
urine calcium levels, evident soon after PTH(1–34) injection. In addition, pump de-
livery of PTH(1–34) also normalized markers of bone turnover levels, serum calcium
concentration, and urine calcium excretion [11].
Regarding the potential effect on quality of life, a 2-year prospective, open-label
study described a significant improvement in the mean scores of all 8 domains of the
Rand 36-Item Short Form Health Survey (SF-36) in 42 patients with chronic hypo-
parathyroidism due to neck surgery, treated with PTH(1–34) 20 μg twice daily [13].
The main limit of this study was the absence of a control group, and therefore the re-
sults should be confirmed. Up to date, no registration trails have been conducted with
PTH(1-34) on hypoparathyroid patients.

rhPTH(1–84): Hormone Replacement Therapy

Unlike PTH(1–34), rhPTH(1–84) is the native hormone and, thus, would replace
what is missing in chronic hypoparathyroidism. In addition, the half-life of
rhPTH(1–84) is longer than PTH(1–34); therefore, once-daily dosing is usually used
and sufficient [3, 14].
Sikjaer et al. [15] conducted a randomized double-blind study in which pa-
tients with chronic hypoparathyroidism were treated with a fixed dose of rhPTH(1–84)
100 μg daily or similar placebo for 24 weeks as add-on therapy to conventional treat-
ment. Compared with the placebo group, patients treated with rhPTH(1–84) reduced
their daily dose of calcium and active vitamin D supplementations significantly by
75 and 73%, respectively, and plasma calcium and phosphate levels were maintained
within the physiologic range. However, during the down-titration of calcium and ac-
tive vitamin D, hypercalcemia frequently occurred. rhPTH(1–84) decreased the bone
mineral density (BMD) at the hip, lumbar spine, and whole body, but not at the fore-
arm, most likely due to the marked increased bone turnover [15]. Indeed, rhPTH
treatment tends to reverse the state of overmineralized bone and, over time, may cause
a more physiologic bone metabolism [15].
Cusano et al. [16] studied the effect of rhPTH(1–84) treatment, administered at a
starting subcutaneous dose of 100 μg every other day, in adult patients with chronic hy-
poparathyroidism, through an open label study (without a control group) for 4 years. In
this study, reductions in oral calcium and vitamin D requirements were significant and
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maintained over a 4-year period, maintaining normal serum calcium levels. Reductions
in urinary calcium excretion were more variable and not constant over time, and fell
significantly below baseline during years 1, 2, and 3. BMD values of the lumbar spine,
measured by dual-energy X-ray absorptiometry, increased, whereas the hip and the dis-
tal radius were stable. Bone turnover markers increased significantly from baseline val-
ues at 6–12 months, subsequently declining to steady-state levels at 30 months. During
the study period, 11 episodes of mild hypercalcemia in 8 subjects (1.9% of all values) were
reported; most were resolved with adjustment of calcium and vitamin D dosages [16].
The pivotal phase III trial of rhPTH(1–84) in hypoparathyroidism was reported by
Mannstadt et al. [17]. This study was a multicenter, double-blind, placebo-controlled,
randomized study, named “REPLACE,” in which patients with chronic hypoparathy-
roidism were randomly assigned to rhPTH(1–84) or placebo [17]. This trial was con-
ducted for 26 weeks, involving over 134 subjects with a randomization scheme of 2:1
(drug:placebo). The dose of rhPTH(1–84) could be titrated up from 50 to 75 μg and
then 100 μg, and most subjects (52%) needed the highest dose. The trial’s triple pri-
mary endpoint included: (1) reduction of calcium supplementation by 50% or more;
(2) reduction of active vitamin D supplementation by 50% or more, and (3) mainte-
nance of stable serum calcium levels within the normal range. The results of the study
showed that 53% of study subjects receiving rhPTH(1–84) met this triple primary
endpoint, whereas only 2% of study subjects receiving placebo did so (p < 0.001).
Compliance with injection was excellent for both patient groups. An important dif-
ference between subjects receiving rhPTH(1–84) and the placebo group was also in
the percentage of subjects who could eliminate active vitamin D while taking no more
than 500 mg of oral daily calcium (43 and 5%, respectively; p < 0.001). Adverse events
were similar, with the most common reports related to signs of hypocalcemia, name-
ly muscle spasms, paresthesias, headache, and nausea [17].
A 24-week, open-label, flexible-dose extension study of REPLACE, named
“REPEAT” was conducted in adults with hypoparathyroidism [18]. Patients who pre-
viously completed or were enrolled in REPLACE received rhPTH(1–84) (50 μg/day,
escalated to 75 and then to 100 μg/day, if necessary). The primary endpoint was ≥50%
reduction in oral calcium (or ≤500 mg/day) and active vitamin D (or calcitriol ≤0.25
μg/day, or alfacalcidol ≤0.50 μg/day), maintaining normal calcium levels. At the study
end, 75% of patients achieved the study endpoint, and 58% eliminated oral calcium
and active vitamin D. Urinary calcium excretion, serum phosphate levels, and calci-
um-phosphate product decreased by the study end, and mean serum bone turnover
markers increased with rhPTH(1–84). No serious adverse events were reported [18].
A short, 8-week, double-blinded, multinational, randomized trial, named “RELAY,”
evaluated whether doses as low as 25 μg/day could be efficacious in chronic hypopara-
thyroidism [19, 20]. Some of the enrolled patients were able to reach the primary end-
point, which included taking oral calcium not more than 500 mg/day and active
vitamin D not more than 0.25 μg/day; however, most patients required more than
50 μg/day rhPTH(1–84), confirming the results of the REPLACE trial [19, 20].
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 An open-label extension of the REPLACE and RELAY trials, named “RACE,” was
conducted in the USA [19–21]. To date, the results at 1 year confirm the evidence of
the primary endpoints of the REPLACE trial [19–21].
Recently, another study evaluated the effect of rhPTH(1–84) (50 μg/day, titrated to
75 and then 100 μg/day), on phosphate and vitamin D metabolite levels in patients
with hypoparathyroidism [22]. In total, 124 adult patients belonging to the REPLACE
study were analyzed [17]. Serum phosphate concentrations decreased rapidly from
the upper normal range and remained lower with rhPTH(1–84). At week 24, the se-
rum calcium-phosphate product was lower with rhPTH(1–84) versus placebo. After
24 weeks, despite significantly greater reductions in active vitamin D dose in the
rhPTH(1–84) group, 1,25-dihydroxyvitamin D levels were unchanged in both treat-
ment groups [22]. In summary, rhPTH(1–84) reduced serum phosphate levels, im-
proved calcium-phosphate product, maintained 1,25-dihydroxyvitamin D and serum
calcium levels in the normal range, in association with significant dose reductions of
active vitamin D and oral calcium supplementations [22].
Regarding the potential effect of rhPTH(1–84) on quality of life, Cusano et al. [23]
evaluated the improvement of this aspect in hypoparathyroid subjects receiving open-
label rhPTH(1–84) over 5 years. Before and during therapy, subjects completed the
SF-36, and rhPTH(1–84) therapy was associated with an improvement in mental and
physical health [23], confirming the results obtained in the previous study conducted
on hypoparathyroid subjects receiving open-label rhPTH(1–84) for 12 months [24].
The main limit of both studies was that they did not have control groups. On the oth-
er hand, a placebo-controlled study conducted on patients affected by chronic hypo-
parathyroidism [randomized to 6 months of treatment with either rhPTH(1–84) 100
μg/day or placebo, given as add-on therapy to conventional treatment] evaluated the
effect on quality of life using SF-36 and the WHO-5 Well-Being Index, but did not
demonstrate an improvement in the rhPTH-treated group [25]. However, relatively
large fluctuations in serum calcium were described, and this could have influenced
the results. Therefore, further studies are necessary.
In conclusion, rhPTH(1–84) appears to be a more attractive replacement hor-
mone compared to PTH(1–34) because it is the full-length peptide missing in this
chronic disorder and, since it has a longer half-life, it can be administered once dai-
ly [1, 14, 26, 27]. To date, the scientific investigations performed have described that
the use of rhPTH(1–84) in these patients induces: a short- and long-term reduction
in the need for conventional supplementations with calcium and active vitamin D
[15, 16, 23]; a reduction in urinary calcium excretion, albeit only transient [15]; an
increase of lumbar spine BMD levels and a tendency of reduction at the distal 1/3
radius [16]; an increase of bone turnover markers in the first years [28], and im-
provement in quality of life as determined by the SF-36 scale studies without large
fluctuations in serum calcium [23, 24]. However, in the future, further studies are
needed to evaluate the long-term effects of chronic therapy with rhPTH(1–84) in
these patients [29, 30].
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Maria Luisa Brandi, MD, PhD
Department of Surgery and Translational Medicine, University of Florence
Largo Palagi 1
IT–50139 Florence (Italy)
E-Mail marialuisa.brandi@unifi.it
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