Efficacy of Cinacalcet in the Control of Primary Hyperparathyroidism
Condition: Hyperparathyroidism, Primary; Osteoporosis
MeSH terms: Osteoporosis; Hyperparathyroidism; Hyperparathyroidism, Primary
Study type: Interventional
Phase: Phase 4

Summary: 
      To assess the efficacy and safety of treatment with cinacalcet and with cinacalcet plus
      alendronate in controlling bone loss induced by primary hyperparathyroidism.
    

Detailed description: 
      The project was conducted at the Istituto Auxologico Italiano, IRCCS, Milano (Italy).

      Principal Investigator: Maria Luisa Bianchi, M.D., Nephrologist, Bone Metabolism Unit,
      Istituto Auxologico Italiano IRCCS, Milan, Italy

      Other investigators:

      Silvia Vai, M.D., endocrinologist, Bone Metabolism Unit, Istituto Auxologico Italiano IRCCS,
      Milan, Italy Francesca Broggi, Dr., biologist, Bone Metabolism Unit, Istituto Auxologico
      Italiano IRCCS, Milan, Italy Luca Persani, M.D., Endocrinologist, University of Milan &
      Division of Endocrine and Metabolic Diseases, Istituto Auxologico Italiano IRCCS, Milan,
      Italy

      Introduction Cinacalcet is an orally active second-generation calcimimetic drug. Cinacalcet
      increases the sensitivity of calcium receptors located on the surface of parathyroid cells,
      thus inhibiting parathyroid hormone (PTH) secretion (which is increased in
      hyperparathyroidism). Cinacalcet has been approved by FDA and EMEA for the use in dialyzed
      patients affected by chronic renal failure with uncontrolled secondary hyperparathyroidism,
      on the basis of three 6-month double-blind placebo-controlled studies on more than 1,100
      patients.

      PTH secretion and parathyroid cell proliferation are regulated by the serum levels of ionized
      calcium (Ca++). The mechanism is based on the binding of the Ca++ ion to a G-protein coupled
      membrane receptor (GPCR), called Calcium Sensing Receptor (CaR). With low circulating levels
      of Ca++ or with an alteration of the calcium-receptor binding, higher amounts of PTH are
      secreted, hyperparathyroidism develops, and in the long term systemic alterations (bone
      mineral density (BMD) reduction, increased fracture risk, hypercalciuria, renal stones,
      hypertension, etc.) appear.

      Substances with calcimimetic action, such as Cinacalcet, have been recently developed. Until
      now, Cinacalcet has been mainly used in hyperparathyroidism secondary to renal insufficiency.

      In this condition, Cinacalcet has been proven effective in reducing the circulating PTH to
      acceptable levels, obtaining the normalization of serum Ca++ and phosphate levels in about
      50% of cases. Moreover, the drug is usually well tolerated. Side effects (essentially nausea
      and vomiting) are reported in about 30% of cases.

      Pilot studies have confirmed the efficacy of Cinacalcet in maintaining a normal calcemia in
      the long term also in patients with primary hyperparathyroidism (PHP) due to adenoma or
      carcinoma of one parathyroid gland.

      For this reason, the investigators proposed to use of Cinacalcet in cases of PHP, in which
      surgical intervention was not possible, and its use in combination with oral alendronate in
      the presence of osteopenia/osteoporosis.

      Study objectives

        -  To assess the efficacy and safety of long-term Cinacalcet treatment in patients with
           PHP, who are not operable, or in whom the localization of the parathyroid adenoma has
           not been possible.

        -  To assess the efficacy of a combined therapy with Cinacalcet and alendronate in
           controlling the bone loss induced by PHP.

      Study design: prospective, single-arm, 24-month study, organized in two phases. During Phase
      1, all patients were treated with Cinacalcet alone for 12 months. During Phase 2, all
      patients were treated with Cinacalcet (as before) plus oral alendronate (70 mg once weekly)
      for another 12 months.

      The study was conducted in accordance with the Good Clinical Practice (GCP) rules, and was
      approved by the Ethical Committee of the Istituto Auxologico Italiano, IRCCS.

      Timelines

      The study was organized as follows:

        -  10 months for patient enrolment

        -  24 months for the study (Phase 1 plus Phase 2)

        -  6 months for the analysis of results

      The enrolment was started after the approval of the protocol and the commitment of the
      manufacturing Company to supply the Cinacalcet.

      Study population 22 patients with PHP, who are not operable, or in whom the localization of
      the parathyroid adenoma has not been possible, and with reduced bone density (T-score ≤ -2 at
      spine or hip) were included in the study. All patients were post-menopausal women.

      Patients were included in the study, according to the pre-defined inclusion criteria (all 5
      criteria must be met) and exclusion criteria (none of these criteria must be met).

      Definition of PHP: serum intact PTH level higher than 65 ng/ml on at least two determinations
      during the 12 months before the start of the study (after exclusion of severe hypovitaminosis
      D), and serum calcium higher than 10.4 mg/dl.

      All patients were studied in advance with parathyroid ecography or neck CT, and scintigraphy
      with Sestamibi.

      At the time of enrolment, the following exams were done:

        1. evaluation of phosphate and calcium metabolism (blood: intact parathyroid hormone, total
           calcium, ionized calcium, phosphate, creatinine, 25-hydroxy-vitamin D
           1,25-dihydroxy-vitamin D, bone-specific alkaline phosphatase, C-terminal telopeptide;
           urine: calciuria 24-hours, phosphaturia 24-hours, N-terminal telopeptide, creatinine
           clearance)

        2. bone density evaluation (DXA scan: radius, lumbar spine, proximal femur, and total body)

        3. general evaluation (liver function, blood cell count, renal function (serum creatinine
           and creatinine clearance)

      Treatment and follow-up The initial treatment regimen was 30 mg of Cinacalcet twice a day, at
      12-hour intervals.

      The follow-up was done as follows:

        -  2 weeks after starting Cinacalcet, the plasma levels of total calcium and intact PTH
           were measured. If the calcemia was still above 10.6 mg/dl, the Cinacalcet dose was
           doubled (60 mg twice a day).

        -  4 weeks after starting Cinacalcet, the following biochemical parameters were measured:
           blood: PTH, total calcium, ionized calcium, phosphate, creatinine, liver function, blood
           cell count; urine: calciuria 24-hours, phosphaturia 24-hours, N-terminal telopeptide,
           creatinine clearance. If calcemia was still above 10.6 mg/dl, the Cinacalcet dose was
           increased 90 mg twice a day.

        -  every 8 weeks, the following biochemical parameters were measured: blood: PTH, calcium,
           ionized calcium, phosphate, creatinine, liver function, blood cell count; urine:
           calciuria 24-hours, phosphaturia 24-hours, N-terminal telopeptide, creatinine clearance.

        -  after 12 months of Cinacalcet therapy, the DXA scan was repeated, and oral alendronate
           at the dose of 70 mg weekly will be added

        -  at the end of the 24th month of therapy, all the exams done at the time of enrolment
           were repeated During the study, if serum total calcium levels decreased below 8.4 mg/dl,
           the Cinacalcet daily dose was halved. If serum total calcium levels were still below 8.4
           mg/dl with the minimum dose of Cinacalcet (30 mg once a day), Cinacalcet was stopped.

      In these cases, serum calcemia was measured again at 1-week intervals, and the Cinacalcet
      treatment was resumed accordingly.

      All the patients' data were collected in a specially designed CRF (case report form).

      Side effects and adverse reactions were appropriately recorded in the CRF. The severity of
      the side effects or adverse reactions were evaluated in order to decide whether the involved
      drug(s) should be stopped.

      Adverse events (AE) were recorded in a dedicated section of the CRF, in accordance with the
      standard rules of clinical trials. The adverse events were classified, as usual, as serious
      AE (SAE) or non-serious AE (AE). For each AE severity and causality were recorded. SAEs were
      immediately reported to the drug manufacturer (Amgen). Appropriate clinical decisions
      (immediate and follow-up) were made.

      According to the available literature, side effects of Cinacalcet were generally mild.

      In case of severe side effects or SAE, treatment was to be stopped.

      Methods All DXA scans and laboratory tests were performed at the Istituto Auxologico Italiano
      IRCCS.

      Bone mass was measured with a dual X-ray (DXA) Hologic Discovery densitometer at distal
      radius, lumbar spine, hip and on total body.

      Serum and urinary calcium and phosphorus were measured with standard methods. Serum bone
      alkaline phosphatase (BSAP) were measured by EIA (enzyme-linked immunosorbent assay; Quidel,
      San Diego, USA); serum C-terminal telopeptide (CTx) by immunoluminescent method (Roche
      Diagnostic, Monza, Italy); urinary N-terminal telopeptide of procollagen type I (NTx) by EIA
      (enzyme-linked immunosorbent assay; Ostex Intern. Inc., Seattle, USA). Serum intact
      parathyroid hormone (PTH) was measured by immunoluminescent method (Roche Diagnostic, Monza,
      Italy); 25-hydroxyvitamin D (25-OH D) by RIA (radioimmunological assay, DiaSorin Inc,
      Stillwater, USA); 1,25-dihydroxyvitamin D (1,25(OH)2 D) by radio receptor assay (Nichols
      Institute Diagnostics, San Juan Capistrano, USA).

      Statistical methods

      To evaluate the sample size, the following points were considered:

        1. The study was focused on a well-characterized, homogeneous group of patients affected by
           PHP without the possibility of surgical removal of the adenoma, and also affected by
           osteopenia/osteoporosis.

        2. These patients had already been followed at our Center for several years, so the risk of
           drop-out re was very low (estimated 10%).

        3. Considering the characteristics of the study (single-arm), a confidence level of 95%, a
           5% significance, a drop-out rate of 10%, the 2.5% change in BMD, a sample size of 16
           patients was calculated.

      On the basis of the patients coming to our attention, the investigators estimated to be able
      to enroll 20 patients meeting the inclusion criteria.

      Data were expressed as the mean plus or minus SD. All the variables were analyzed to evaluate
      their normality (Shapiro-Wilk test), in order to choose the appropriate statistical tests.

      To estimate the comparison of the means, after evaluating the validity assumptions, the
      Student's t test and one-way ANOVA were used.

      Statistical significance was defined as p<0.05, two-sided. At the end of the study, the
      occurrence of adverse events was analyzed with descriptive statistics.
    

Intervention name(s): cinacalcet; Alendronate
Intervention type(s): Drug; Drug
Intervention description(s): During Phase 1 (months 1-12): oral administration; 30 mg twice/day (dose to be increased if needed).; During Phase 2 (months 13-24): oral administration; 70 mg once/week (in addition to cinacalcet 30 mg twice/day as during Phase 1).
Other intervention name(s): Mimpara; Alendronic acid; Fosamax
Intervention MeSH terms: Alendronate; Cinacalcet
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: primary hyperparathyroidism; hypercalcemia; osteoporosis; bone turnover; bone mineral density; fractures