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

Early Phase 1

Completed

Conditions: Osteoporosis
Hyperparathyroidism
Humoral Hypercalcemia of Malignancy

Brief Summary: 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.

Detailed Description: 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.

Recruitment & Eligibility

Inclusion Criteria

Healthy caucasian subjects of both sexes between the ages of 24-35 years, who are able to spend one week on the Clinical & Translational Research Center at the University of Pittsburgh Medical Center (UPMC) Montefiore

Exclusion Criteria

Pregnancy
Any cardiac, renal, pulmonary, endocrine, musculoskeletal, hepatic, hematological, malignant or rheumatologic diseases
Body mass index great than 30
Anemia
Significant alcohol or drug abuse
Baseline hypotension or hypertension
Abnormal screening labs
Use of certain chronic medications excluding oral contraceptives
Receiving an investigational drug in the last 90 days
Previously receiving PTH or PTHrP
African-American race

Arm && Interventions

Group	Intervention	Description
PTHrP(1-36) 5 pmol/kg/hr	PTHrP (1-36)	PTHrP(1-36) at 5 picomoles/kg/hr for one week.
PTHrP(1-36) 6 pmol/kg/hr	PTHrP (1-36)	PTHrP(1-36) at 6 picomoles/kg/hr for one week.
PTHrP(1-36) 2 pmol/kg/hr	PTHrP (1-36)	PTHrP(1-36) at 2 picomoles/kg/hr for one week.
PTHrP (1-36) 4 pmol/kg/hr	PTHrP (1-36)	PTHrP(1-36) at 4 picomoles/kg/hr for one week.

Primary Outcome Measures

Name	Time	Method
Dose Limiting Toxicity (DLT)	12 hours after the infusion was started then q 8 hours for 7 days	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.
Total Serum Calcium	12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete	mg/dl
Ionized Serum Calcium	12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete	mg/dl
Serum Phosphorous	12 hours after the infusion was started then q 8 hours for 7 days, Follow-up 1 week after infusion complete	mg/dl

Secondary Outcome Measures

Name	Time	Method
1,25 Vitamin D	Baseline and Daily through day 8 then at follow-up visit	pg/ml
24 Hour Urine Calcium	24 hours	mg/gm creatinine collected on day 7 of PTHrP infusion
Tubular Maximum of Phosphorous (TmP/GFR)	daily	mg/dl calculated from daily second morning void
Serum Amino-terminal Telopeptide of Collagen -1 (sNTX)	Baseline, Daily, and 1 week follow-up	% change from baseline
Serum Carboxy-terminal Telopeptide of Collagen -1 (sCTX)	Baseline, Daily, and 1 week follow-up	% change from baseline
Amino-terminal Peptides of Procollagen 1 (P1NP)	Baseline, Daily, and 1 week follow-up	% change from baseline
Bone Specific Alkaline Phosphatase (BSAP)	Baseline, Daily, and 1 week follow-up	% change from baseline
Parathyroid Hormone (1-84)	Baseline and Daily	pg/ml
Fractional Excretion of Calcium	daily	% calculated from daily second morning void

Locations (1): University of Pittsburgh Medical Center
🇺🇸
Pittsburgh, Pennsylvania, United States