Gland and Hormone Related Diseases

All Conditions

Musculoskeletal Diseases

Nutritional and Metabolic Diseases

Hyperparathyroidism

Osteoporosis

Bone Diseases

Endocrine System Diseases

Hypercalcemia

Bone Diseases, Endocrine

Bone Diseases, Metabolic

Metabolic Diseases

Parathyroid Diseases

Calcium Metabolism Disorders

Water-Electrolyte Imbalance

All Drugs and Chemicals

Bone Density Conservation Agents

Micronutrients

Vitamins

Hormones

Vitamin D

Cholecalciferol

Calcium

Calcium, Dietary

Parathyroid Hormone

Parathyroid Hormone-Related Protein

Anabolic Androgenic Steroids

Anabolic Agents

Testosterone

Testosterone Congeners

Hormone Antagonists

Performance-Enhancing Substances

Vitamin D3

Calciferol

Subjects receive PTHrP(1-36) starting with doses of 2 picomoles (pmols)/kg/hr for one week. Subsequent dosing groups are determined by the response to PTHrP doses.

Subjects receive PTH(1-34) starting with doses of 2 picomoles (pmols)/kg/hr for one week. Subsequent dosing groups are determined by the response to PTH doses.

PTHrP (1-36) intravenously at 2 picomoles (pmols)/kg/hr for one week; doses will be increased by 2 picomoles (pmols)/kg/hr in subsequent subjects.

Parathyroid Hormone-related Protein (1-36)

PTH (1-34) intravenously at 2 picomoles (pmols)/kg/hr for one week; doses will be increased by 2 picomoles (pmols)/kg/hr in subsequent subjects.

parathyroid hormone (1-34)

This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, or Parathyroid Hormone, PTH, that can be given safely over one week in healthy African-American volunteers. The investigators plan to infuse low doses of intravenous PTHrP or PTH to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrP and PTH on vitamin D metabolism, markers of bone turnover, and fractional excretion of calcium.

PTH (1-34) and PTHrP (1-36)

Mara J. Horwitz, MD

This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, or Parathyroid Hormone, PTH, that can be given safely over one week in healthy African-American volunteers. The investigators plan to infuse low doses of intravenous PTHrP or PTH to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrP and PTH on vitamin D metabolism, markers of bone turnover, and fractional excretion of calcium. These results will be compared to previous studies of Caucasian volunteers.

This study will expand upon earlier infusion studies in healthy Caucasian and Asian volunteers in which continuous infusions of PTH and PTHrP were given for six-, 12-, and 48 hours. These studies demonstrated: 1) There is a dose-related increase in 1,25 (OH)2 vitamin D in response to PTHrP and PTH over multiple days. 2) There is a markedly attenuated vitamin D response to PTHrP compared to PTH, particularly during the second 24 hours. 3) The increase in 1,25 (OH)2 vitamin D is almost certainly responsible for the greater calcemic effect of PTH compared to PTHrP. 4) PTHrP is obviously a weaker agonist of 1,25 (OH)2 vitamin D but does not result in its suppression as is seen in Humoral Hypercalcemia of Malignancy (HHM). Thus, the suppression of 1,25 (OH)2 vitamin D seen in HHM remains unexplained. In addition to assessing the effects of an infusion of PTHrP and PTH on calcium handling and 1,25 (OH)2 vitamin D, we also measured their effects on markers of bone turnover. Given the clinical observations seen in primary hyperparathyroidism (HPT) and HHM, we anticipated that PTH would stimulate both bone resorption and formation, while PTHrP would stimulate bone resorption but inhibit formation. However, we observed that infusions of PTHrP and PTH resulted in an equivalent, rapid increase in bone resorption as measured by N-telopeptide (NTx) and C-telopeptide (CTx), as well as a progressive decline in bone formation. There was no difference between PTH and PTHrP. Because of these findings, it was surmised that infusions of a longer duration would lead to an increase in bone formation and 1,25 (OH)2D production with both peptides, as is seen in HPT. Very recently, we have completed a seven-day infusion model in healthy Caucasian and Asian volunteers to test this hypothesis (J. Bone Min. Res., 2011). A total of 22 individuals were given either seven-day infusions of PTH or PTHrP, and maximal safe doses were found to be 2 and 4 picomoles (pmol)/kg/hour, respectively, lower than the doses used in previous, briefer infusion studies. All patients developed sustained but very mild hypercalcemia (mean = 10.3 mg/dL) and hypercalciuria with rapid increase in bone resorption. Surprisingly, bone formation again was suppressed for the entire seven days with a robust rebound in bone formation on cessation of the respective peptide. This is consistent with what may occur during lactation and HHM, but again contrary to what occurs in HPT.

The previous infusion studies were done only in Caucasian and Asian volunteers as there are extensively documented physiologic differences in bone metabolism between African-Americans and Caucasians. Much of the racial differences noted in bone metabolism come from the osteoporosis literature. African-Americans are known to have higher bone mineral densities (BMD) and to be at lower risk of developing fragility fractures. There are many factors which may explain these racial differences in bone metabolism, including altered calcium economy, vitamin D differences, peak attained bone mass, muscle mass and obesity, mechanism of falls, remodeling rates, bone micro-architecture, hip axis geometry, and other unknown hereditary differences. It is also well established that African-Americans on average, have lower 25-OH vitamin D concentrations and thus higher PTH levels. Despite elevations in PTH, there is paradoxically no increase in bone loss indicating that a relative skeletal resistance to PTH may exist. We hope that by performing this seven-day infusion protocol in healthy African-American volunteers we can learn more about racial differences in bone turnover, renal calcium, PTH concentrations, vitamin D metabolism, and skeletal responses to lactation in this under-studied population.

Ninety healthy African-American men and women will be screened for an eight-day inpatient admission to the Clinical \& Translational Research Center (CTRC). Sixty evaluable research participants will receive a seven day infusion of a predetermined dose of either PTHrP or PTH. Vital signs and blood and urine tests will be monitored frequently as per the study flow sheet. The starting dose of either peptide, 2 picomoles (pmols)/kg, will be given to three normal healthy subjects. Via a dose escalation protocol, the dose will be escalated in increments with successive groups of three subjects each, until early adverse effects (mild hypercalcemia, postural hypotension, tachycardia) are seen. This determined safe dose will then be given to 10 subjects. This dose escalation study design has been used in several prior studies at this institution in order to achieve a sustained mild serum hypercalcemia in the 10.5-11 mg/dL range in research studies. The investigators with this study are trying to determine a safe dose of PTHrP and PTH in African-American volunteers and determining if this population has the same physiologic response as Caucasians.

Subject population will consist of healthy young African-American adults, ages 24-35. It is anticipated that we will need to screen 90 patients in order to obtain 60 evaluable subjects.

One Week Comparison Study of PTH and PTHrP Infusions

Comparison of Skeletal and Mineral Metabolism Responses in Healthy African-Americans and Caucasians Using a Continuous Seven-Day Parathyroid Hormone (PTH) or Parathyroid Hormone-related Protein (PTHrP) Infusion

University of Pittsburgh

Associate Professor, University of Pittsburgh School of Medicine

PTHrP(1-36) at 2 picomoles/kg/hr for one week.

PTHrP(1-36) at 4 picomoles/kg/hr for one week.

PTHrP(1-36) at 5 picomoles/kg/hr for one week.

PTHrP(1-36) at 6 picomoles/kg/hr for one week.

PTHrP (1-36)

Mara J Horwitz, MD

This is a dose escalation study to determine the maximum tolerable dose of Parathyroid Hormone-related Protein, PTHrP, that can be given safely over one week. The investigators plan to infuse low doses of intravenous PTHrP to determine if it leads to a sustained and progressive suppression of bone formation as occurs in humoral hypercalcemia of malignancy (HHM) or an increase in bone formation as occurs in hyperparathyroidism (HPT). Additionally, the investigators will assess the direct influence of PTHrp on markers of bone turnover, and plasma 1,25 (OH)2 vitamin D regulation in healthy human volunteers.

During this research the investigators administer PTHrP to healthy young volunteers in a controlled, continuous intravenous manner. As research subjects complete the week-long study without adverse effects, the dose of PThrP will be increased in later subjects. In the event of a significant adverse effect, immediate action will be taken to reverse it. The investigators want to estimate the effect of a sustainable level of mild hypercalcemia achieved by a week-long intravenous infusion of PTHrP has on vitamin D metabolism, markers of bone turnover and fractional excretion of calcium.

One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study

Determining the Maximal Safe Dose of a Continuous Infusion of Parathyroid Hormone-related Protein(1-36): Effects on Bone Formation

DLT was defined as achieving one major criterion or two minor criteria rated at ≥ 2 on a scale of 0-5. The major criteria were defined as symptomatic orthostatic hypotension (systolic BP fall \>30 mm/hg), tachycardia (pulse \> 120), hypertension (systolic BP \>160 mm/hg on 2 occasions), hypercalcemia (serum calcium ≥ 12 mg/dl), and hypophosphatemia (serum phosphorous \< 1.5 mg/dl). Minor criteria included symptoms such as flushing, nausea, abdominal or muscle cramps, dizziness, lightheadedness, palpitations, etc.

mg/gm creatinine collected on day 7 of PTHrP infusion

mg/dl calculated from daily second morning void

% calculated from daily second morning void

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Associate Professor of Medicne

PTHrP(1-36) 2 picomoles/kg/hr for one week.

Group 1

PTHrP(1-36) 4 picomoles/kg/hr for one week.

Group 2

PTHrP(1-36) 5 picomoles/kg/hr for one week.

Group 3

PTHrP(1-36) 6 picomoles/kg/hr for one week.

Group 4

Total

Age, Categorical

Sex: Female, Male

United States

Region of Enrollment

Small number of subjects in each group Study limited to Caucasians Only one timepoint for follow-up was measure Study did not include saline infused controls

PTHrP(1-36) 4 picomoles/kg/hr for one week

PTHrP(1-36) 5 picomoles/kg/hr for one week

PTHrP(1-36) 6 picomoles/kg/hr for one week

Dose Limiting Toxicity (DLT)

baseline

Day 2

Day 3

Day 4

Day 5

Day 6

Day 7

Day 8

follow-up

1,25 Vitamin D

24 Hour Urine Calcium

Baseline

Tubular Maximum of Phosphorous (TmP/GFR)

11P DAY 1

7A DAY 2

3P DAY 2

11P DAY 2

7A DAY 3

3P DAY 3

11P DAY 3

7A DAY 4

3P DAY 4

11P DAY 4

7A DAY 5

3P DAY 5

11P DAY 5

7A DAY 6

3P DAY 6

11P DAY 6

7A DAY 7

3P DAY 7

11P DAY 7

7A DAY 8

FOLLOW-UP

Total Serum Calcium

Ionized Serum Calcium

Serum Phosphorous

Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)

Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)

Amino-terminal Peptides of Procollagen 1 (P1NP)

Bone Specific Alkaline Phosphatase (BSAP)

Parathyroid Hormone (1-84)

Fractional Excretion of Calcium

Overall Study

Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

Symptoms and General Pathology

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Pain

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Anti-Inflammatory Agents

Antineoplastic Agents

Antiemetics

Gastrointestinal Agents

Dexamethasone

Bortezomib

Dexamethasone acetate

Zoledronic Acid

Glucocorticoids

Antineoplastic Agents, Hormonal

For this study, Velcade will be administered at the standard dose of 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle.

Dexamethasone will be administered at a dose of 12 mg/m2 p.o., on days 1-2, 4-5, 8-9 and 11-12 of the same cycle.

Zoledronic acid will be administered at a dose of 4 mg, iv (15-minute infusion), every 28 days for up to 8 cycles, and then every 28 days for the next 18 months

1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles

4 mg, iv, at a 15 min infusion, Day 1 of every cycle for up to 8 cycles, and then every 28 days for the next 18 months

12 mg/m2 p.o. on days 1-2, 4-5, 8-9 and 11-12 of a 21-day cycle for up to 8 chemotherapy cycles

Meletios- Athanasios Dimopoulos, Professor

The aim of this study is to evaluate the effect of bortezomib in combination with dexamethasone and zoledronic acid on bone mineral density (BMD) and skeletal related events (SREs) in Patients with Multiple Myeloma who Have Relapsed after 1-3 Prior Lines of Therapy

Multiple Myeloma represents a malignant proliferation of plasma cells derived from a single clone. The most common symptom in myeloma, affecting more than 70% of patients at diagnosis, is bone pain. The pain usually involves the back and ribs, and is precipitated by movement. Bone fractures are commonly seen in myeloma patients and may present with persistent localized pain.

VELCADE (bortezomib) is a proteasome inhibitor used for the treatment of multiple myeloma.

VELCADE seems to be the first agent to combine significant anti-myeloma activity and beneficial effects on bone remodeling. Thus, it appears to be a very promising tool for the treatment of myeloma patients.

In this study, a regimen consisting of bortezomib/dexamethasone/zoledronic acid will be used. The rationale for using this regimen is that:

* VELCADE (bortezomib) is indicated for the treatment of relapsed myeloma patients participating in the study and it has also a beneficial effect on biochemical markers of bone formation.
* In phase II studies, the addition of dexamethasone in patients with a suboptimal response to bortezomib alone improved efficacy in relapsed or refractory multiple myeloma patients, without increasing adverse events. Therefore, in this study, the addition of dexamethasone aims at providing the optimal therapy for participating myeloma patients.
* Zoledronic acid, the most potent i.v. bisphosphonate, is used because of its established effect on reducing skeletal related events in patients with multiple myeloma due to its inhibitory effect on osteoclastic bone resorption.

Dosages and timing of dosages are based on current recommendations and guidelines for the treatment of myeloma patients who Have Relapsed after 1-3 Prior Lines of Therapy.

Effect of Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Disease in Patients With Multiple Myeloma Relapsed After 1-3 Prior Lines of Therapy

A Prospective, Multicenter, Non-comparative, Open-label, Phase II Study to Evaluate the Effects of the Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Mineral Density, Bone Metabolism, Radiographically-detected Osteolytic Bone Lesions, Skeletal-related Events and Bone Pain in Patients With Multiple Myeloma Who Have Relapsed After 1-3 Prior Lines of Therapy

BMD of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) using a Hologic QDR-1000 scanner on day 21 of cycle 4 (day 84)

BMD of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by Dual Energy X-Absorptiometry scan (DEXA-scan) using a Hologic QDR-1000 scanner on day 21 of cycle 8 (day 168)

Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation markers \[osteocalcin (OC)\].

Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 8 (day 168) using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation marker \[osteocalcin (OC)\].

Bone pain was measured with the use of the Visual Analogue Scale on day 21 of cycle 4 (day 84).

Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured.

The VAS for Bone Pain was constructed as follows:

None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome.

Bone pain was measured with the use of the Visual Analogue Scale on day 21 of cycle 8 (day 168).

Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured.

The VAS for Bone Pain was constructed as follows:

None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome.

Skeletal survey was measured using conventional radiography \[imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)\] on day 21 of cycle 8 (day 168)

Skeletal survey was measured using conventional radiography \[imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)\] every 6 months for up to 18 months

New Skeletal-related events (SRE: pathologic fractures, need for bone radiation therapy or surgery) following 8 cycles (day 168) of therapy

New Skeletal-related Events (SRE: Pathologic Fractures, Need for Bone Radiation Therapy or Surgery) after 18 months post VD

Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA) bone formation marker \[bone-specific alkaline phosphatase (bALP)\].

Bone remodelling was studied by the measurement of the following serum indices on day 21 of cycle 4 (day 84) using an enzyme-linked immunosorbent assay (ELISA): bone formation marker \[bone-specific alkaline phosphatase (bALP) \].

University of Athens

Director of the clinic

For this study, Velcade will be administered at the standard dose of 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle.

Dexamethasone will be administered at a dose of 12 mg/m2 p.o., on days 1-2, 4-5, 8-9 and 11-12 of the same cycle.

Zoledronic acid will be administered at a dose of 4 mg, iv (15-minute infusion), every 28 days for up to 8 cycles, and then every 28 days for the next 18 months

Bortezomib: 1.3 mg/m2, iv, bolus, on days 1, 4, 8 and 11 of a 21-day cycle for up to 8 chemotherapy cycles

Zoledronic Acid: 4 mg, iv, at a 15 min infusion, Day 1 of every cycle for up to 8 cycles, and then every 28 days for the next 18 months

Dexamethasone: 12 mg/m2 p.o. on days 1-2, 4-5, 8-9 and 11-12 of a 21-day cycle for up to 8 chemotherapy cycles

Bortezomib/Dexamethasone/Zoledronic Acid

Greece

Lumbar spine (L1-L4)

Femoral neck (FN)

Bone Mineral Density of the lumbar spine (L1-L4, anteroposterior view) and femoral neck (FN) was measured by Dual Energy X-Absorptiometry scan (DEXA-scan) using a Hologic QDR-1000 scanner

Bone remodelling was studied by the measurement of the following serum bone metabolism parameters indices using an enzyme-linked immunosorbent assay (ELISA): i) bone resorption marker C-terminal cross-linking telopeptide of collagen type I (CTX) and ii) bone formation marker \[osteocalcin (OC)\].

Bone remodelling

Skeletal survey was measured using conventional radiography \[imaging of the whole skeleton (skull, cervical spine, thoracic spine, lumbar spine, pelvis, humeri, femoral bones)\].

Skeletal survey for osteolytic lesions/fractures

Bone pain was measured with the use of the Visual Analogue Scale. The visual analogue scale or visual analog scale (VAS) is a psychometric response scale which can be used in questionnaires. It is a measurement instrument for subjective characteristics or attitudes that cannot be directly measured.

The VAS for Bone Pain was constructed as follows:

None Mild Moderate Severe Worst possible 1,2 3,4 5,6 7,8 9,10 Lower values are considered to be of a better outcome, higher values are considered to be of a worst outcome.

Bone pain

Bone remodelling was studied by the measurement of the following serum bone metabolism parameters indices using an enzyme-linked immunosorbent assay (ELISA) bone formation marker \[bone-specific alkaline phosphatase (bALP)\].

Prof. M. A. Dimopoulos

Out of the 17 patients enrolled 12 patients completed the 8 VD cycles, 2 patients 6 VD cycles (due to peripheral neuropathy), 1 patient 5 VD cycles (and then progressed) and 2 patients died after receiving 1 and 2 VD cycles (respectively)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
One Week Comparison Study of PTH and PTHrP Infusions	NCT01333267	Osteoporosis Hypercalcemia o... Hyperparathyroi... Bone Diseases, ...	Parathyroid Hor... parathyroid hor... PTH (1-34) and ...	24 Years - 35 Years	University of Pittsburgh
One Week Parathyroid Hormone-related Protein (PTHrP) IV Dose Escalation Study	NCT00580788	Osteoporosis Humoral Hyperca... Hyperparathyroi...	PTHrP (1-36)	24 Years - 35 Years	University of Pittsburgh
One Week Comparison Study of PTH and PTHrP Infusions	NCT01333267	Osteoporosis Hypercalcemia o... Hyperparathyroi... Bone Diseases, ...	Parathyroid Hor... parathyroid hor... PTH (1-34) and ...	24 Years - 35 Years	University of Pittsburgh
Effect of Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Disease in Patients With Multiple Myeloma Relapsed After 1-3 Prior Lines of Therapy	NCT00972959	Multiple Myelom...	Bortezomib Zoledronic Acid Dexamethasone	18 Years -	University of Athens
One Week Comparison Study of PTH and PTHrP Infusions	NCT01333267	Osteoporosis Hypercalcemia o... Hyperparathyroi... Bone Diseases, ...	Parathyroid Hor... parathyroid hor... PTH (1-34) and ...	24 Years - 35 Years	University of Pittsburgh
Effect of Combination of Bortezomib/Dexamethasone/Zoledronic Acid on Bone Disease in Patients With Multiple Myeloma Relapsed After 1-3 Prior Lines of Therapy	NCT00972959	Multiple Myelom...	Bortezomib Zoledronic Acid Dexamethasone	18 Years -	University of Athens

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