3-Week Parathyroid Hormone-related Protein (PTHrP) Dose Escalation Study in Post-Menopausal Women
Condition: Osteoporosis; Osteoporosis, Postmenopausal
MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal
Study type: Interventional
Phase: Phase 1

Summary: 
      The main purpose of this study is to determine the safety and effectiveness of three week
      daily subcutaneous injections of Parathyroid Hormone-related Protein (1-36). Previous studies
      indicated that PTHrP has a skeletal 'anabolic' or bone-building effect, and has shown to
      increase bone mineral density in postmenopausal women with osteoporosis. Safety of PTHrP will
      be determined by measurements of blood pressure and pulse, serum blood calcium levels and
      subjective symptoms. Effectiveness will be measured by changes in measurements of blood and
      urine markers of bone turnover.
    

Detailed description: 
      Parathyroid Hormone-related Protein (1-36) or PTHrP is a neuroendocrine peptide which shares
      significant homology with the only currently FDA approved anabolic agent for the treatment of
      osteoporosis: parathyroid hormone(1-34) or PTH. PTH, when given alone, has shown to increase
      lumbar spine bone mass by 12-15% over a 2-3 year period.

      Previous studies indicate PTHrP may have a pure anabolic effect on bone. Postmenopausal women
      taking estrogen with osteoporosis who received daily subcutaneous PTHrP for 3 months
      exhibited a 4.7% increase in bone mineral density compared to those taking placebo. There
      were no side effects associated with PTHrP, despite the fact that the doses given were 20
      times the usual doses of PTH. In another study, young healthy volunteers received a single,
      one-time subcutaneous doses of PTHrP in amounts up to 2 mg without any dose limiting
      toxicities.

      This study will directly compare the effect of placebo and escalating doses of PTHrP given
      subcutaneously to postmenopausal women for three weeks. Each subject will have four
      outpatient visits and one inpatient 24-hour visit on the last day. 20 women in phase I will
      receive either placebo or 500 micrograms/day of PTHrP. 500 micrograms/day was selected as the
      lowest dose because it is similar to the dose used in our previous 3 month placebo controlled
      study. In Phase II, the doses of PTHrP will be increased in increments of approximately 30%
      for each successive group, i.e., 750, 1000, 1250, and 1500 micrograms. After the first group
      of 10 successfully receives 500 micrograms/day for 21 days, increased doses will be given to
      groups of three subjects until evidence of dose limiting toxicity (DLT) occurs, or a maximum
      dose of 1,500 micrograms is reached. Dose limiting toxicities are specified in the protocol
      and comprise either one major criteria: hypotension, orthostatic hypotension, tachycardia,
      hypertension, hypercalcemia or hypophosphatemia; or two minor criteria: flushing,
      nausea/vomiting, abdominal or muscle cramps, dizziness/lightheadedness, palpitations, or any
      other unpleasant subjective symptom.

      If a particular dose of PTHrP causes a dose-limiting toxicity, the immediately preceding
      lower dose will be defined as the maximum safely tolerated dose. Once the maximum safely
      tolerated dose is determined, it will be given to a total of ten healthy subjects to ensure
      that is is safe and well tolerated.

      Study methods include outpatient visits on days 1, 5, 10, 15, and an in-patient visit on day
      21 for lab collection and patient examination. Blood and urine safety labs consist of serum
      ionized calcium, total calcium, creatinine, phosphorus and albumin. Efficacy labs consist of
      urine and blood measurements of 25-hydroxy vitamin D, 1,25 vitamin D, PTH, osteocalcin, bone
      specific alkaline phosphatase, procollagen peptide-1, C-telopeptide (CTx), N-telopeptide
      (NTx), Insulin-like growth factors (IgF) and serum free deoxypyridinoline (DPD).

      Subject population includes up to 48 healthy 50-75 year old postmenopausal women who are
      Caucasian, Asian, and Hispanic. African-Americans are excluded from the study since it is
      well documented that African-Americans have clear quantitative differences in bone density
      and sensitivity to parathyroid hormone. No bone densitometry scans are done during this
      study.
    

Intervention name(s): Parathyroid Hormone-related Protein; Placebo
Intervention type(s): Drug; Drug
Intervention description(s): PTHrP(1-36) starting at 500 micrograms, then increasing by 125 micrograms up to a maximum of 1,500 micrograms.; Placebo drug via subcutaneous injection in single blinded fashion daily for 3 weeks
Other intervention name(s): study drug; Placebo group
Intervention MeSH terms: Hormones; Parathyroid Hormone; Parathyroid Hormone-Related Protein
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Participant)
Primary purpose: Treatment
Keywords: Endocrine System Diseases; MusculoSkeletal System Diseases; Hormone; Postmenopausal Women