Comparison Study of PTHrP and PTH to Treat Osteoporosis

Study Overview
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Brief Summary
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This is a three month comparison trial of standard dose parathyroid hormone (PTH) (1-34) and two different doses of Parathyroid Hormone-related Protein (PTHrP) (1-36). The investigators want to to demonstrate that daily subcutaneous injection of PTHrP (1-36) in postmenopausal women with osteoporosis stimulates bone formation to the same or greater degree than PTH (1-34) but with less bone resorption.

Detailed Description
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Osteoporosis is a metabolic bone disease characterized by low bone mass and structural deterioration of bone tissue. It results from failure of osteoblasts to form sufficient new bone, from an excessive rate of osteoclastic bone resorption, or from the combination of both processes. The resultant bone fragility leads to an increased susceptibility to fractures, especially of the hip, spine and wrist. There is an increased mortality rate following both hip and vertebral fractures, and the presence of one fracture is a potent risk factor for future fractures. This leads to a decline in the quality of life and an associated loss of independence among the millions of individuals in the United States and worldwide afflicted with the disease. There is an additional population at an increased risk for fractures due to a less severe loss of bone mass, known as osteopenia (1). Already ten million individuals in the United States are estimated to have the disease and thirty four million more are at increased risk due to low bone mass (1). Approved pharmacological treatments for postmenopausal osteoporosis include two classes of drugs: the antiresorptive and the anabolics (2). The antiresorptive include estrogen, calcitonin, selective estrogen receptor modulators, and bisphosphonates. The antiresorptive medications prevent bone loss by inhibiting both osteoclastic bone resorption and formation, by slowing bone turnover, and by allowing for increased mineralization of osteoid (2). The increase in bone mineral density from the antiresorptive agents is generally reported to be in the range of 2-8% over 1-7 years (3-7). There is only one anabolic agent that is presently approved by the FDA for treatment for osteoporosis: parathyroid hormone, PTH (1-34), or teriparatide. PTH(1-34) was approved by the FDA in 2002 and it acts by increasing bone density by stimulating the PTH-1 receptor. This induces an increase in osteoblast mediated bone formation and osteoclast mediated bone resorption. Daily subcutaneous PTH is anabolic as there is stimulation of bone formation to a greater extent than bone resorption. The overall net result of biosynthetic PTH (1-34) is an increase in bone mineral density and a decrease in fractures (8). Daily PTH(1-34) treatment has been shown to effectively reduce the risk of both vertebral and nonvertebral fractures. Measurements of bone mineral density (BMD) of the lumbar spine (LS) resulted in an increase in bone density of 9 percent when compared to placebo (9). A daily 20 microgram dose of subcutaneous PTH(1-34) reduced the risk of getting two or more vertebral fractures by 77%, and the risk of at least one moderate or severe fracture was reduced by 90 and 78% respectively (9). Additionally, one vertebral fracture was prevented for every 12 patient years of treatment, and women were 35% less likely to have one or more new nonvertebral fragility fractures (9). Parathyroid hormone-related protein or PTHrP is a protein peptide that was first isolated in 1987 as the factor responsible for the syndrome of humoral hypercalcemia of malignancy (HHM) (10-14). PTHrP is found in almost every tissue and cell type in the body, and appears to regulate cellular proliferation, survival, and differentiation in normal tissue as well as in malignancies (15-16). As the name implies, PTHrP is similar to PTH. Both peptides bind to the same receptor, PTH-1 R, and activate downstream signaling pathways causing similar post receptor effects (17). Since PTH is a potent anabolic agent, we hypothesize that PTHrP may act in an anabolic fashion as well. We are seeking to demonstrate in this study that PTHrP acts as an anabolic agent in the treatment of osteoporosis with similar or better efficacy than PTH in respect to bone formation but with less bone resorption and fewer side effects, such as hypercalcemia. The current studies are a sequel to initial phase 1 trials assessing the efficacy and safety of daily subcutaneous injection of PTHrP on the human skeleton. Previous studies have demonstrated that a single daily injection of   400 mcg/day of PTHrP (1-36) in postmenopausal women on estrogen with osteoporosis led to a 4.7% increase in lumbar spine bone mineral density (BMD) after three months and all subjects were free of hypercalcemia or other adverse effects (18). In contrast with PTH, the doses of PTHrP are much larger, yet well-tolerated, and the increments in spine BMD are large and rapid with some subjects showing increases in spine BMD of 6-8% in as soon as three months in studies done thus far (18). PTHrP appears to selectively stimulate bone formation without stimulating bone resorption (18). This exciting observation may point towards PTHrP being a pure skeletal anabolic agent (21). Preliminary data analysis from a more recent three week dose escalation trial indicates demonstrates that the dose of 500 mcg/day of PTHrP causes 38% increase in P1NP and a 20% decrease in CTX indicating far greater bone formation than bone resorption with no hypercalcemia. At 625 mcg/day there were similar increases in P1NP with hypercalcemia in only 10% of subjects and hypercalcuria in 20%. In contrast in subjects receiving 750 mcg/day 50% developed hypercalcemia requiring early termination. The P1NP and CTX data from the three week dose escalation trial was used for both determining dose and sample size calculations for this study.

Official Title
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Comparison of 3 Month PTHrP(1-36) and PTH(1-34) on Post-Menopausal Osteoporosis

Conditions
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Osteoporosis

Intervention / Treatment
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* Drug: Parathyroid hormone related protein (1-36)
* Drug: Parathyroid hormone related protein(1-36)
* Drug: Parathyroid hormone (1-34)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 45 - 75 year old Caucasian, Hispanic or Asian women one year post-menopausal if older than 50 years three years post-menopausal if between the ages of 45 - 50 years body mass index less than or equal to 30 T-scores on screening Dual X-Ray Absorbiometry (DXA) scan between - 2.0 to - 4.5 of lumbar spine or hip have at lease two spinal vertebrae evaluable by DXA analysis Exclusion Criteria: bisphosphonate therapy within the last two years estrogen replacement hormones or SERMS within last one year no more than one week of PTHrP, PTH, or an analog of PTH within the last year an atraumatic bone fracture within the last 6 months significant or active diseases of any organ system history of malignancy anemia with a hematocrit less than 34% significant drug or alcohol abuse having received any investigational drug within the last 90 days taking any medication that may interfere with skeletal metabolism, such as phenobarbital, dilantin, glucocorticoids, and hydrochlorathiazide abnormal screening labs including serum Ca greater than 10.5 g/dl, 25 hydroxy vitamin D less than 20 ng/ml or PTH greater than 65 pg/ml African-Americans for this particular study - although future studies are planned

Ages Eligible for Study
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Minimum Age: 45 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PTHrP 400 mcg/day<br>Post-menopausal women with osteoporosis will subcutaneously administer PTHrP 400 micrograms daily for three months. | Drug: Parathyroid hormone related protein (1-36)<br>* PTHrP (1-36) 400 micrograms / day administered subcutaneously for 3 months<br>* Other names: PTHrP;|
| Experimental: PTHrP 600 mcg/day<br>Post-menopausal women with osteoporosis will subcutaneously administer PTHrP 600 micrograms daily for three months. | Drug: Parathyroid hormone related protein(1-36)<br>* PTHrP(1-36)600 micrograms subcutaneously administered daily for 3 months<br>* Other names: PTHrP;|
| Active Comparator: PTH 20 mcg/day<br>Post-menopausal women with osteoporosis will subcutaneously administer the FDA approved dose of PTH 20 micrograms daily for three months. | Drug: Parathyroid hormone (1-34)<br>* PTH(1-34)20 micrograms subcutaneously administered daily for 3 months<br>* Other names: Teriparatide (brand name: Forteo);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Procallagen-1 Amino-terminal Peptide (P1NP) |  | Baseline, Day 15, Day 30, Day 60, Day 90 | 
| Carboxy-terminal Telopeptides of Collagen-1 (CTX) |  | Baseline, Day 15, Day 30, Day 60, Day 90 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Bone Mineral Density of the Lumbar Spine. |  | 90 days | 
| Changes in Bone Mineral Density of the Total Hip. |  | 90 days | 
| Changes in Bone Mineral Density of the Femoral Neck. |  | 90 days | 
| Changes in Bone Mineral Density of the Forearm. |  | 90 days | 
| Changes in Bone Mineral Density of the Distal 1/3 Radius. |  | 90 days | 
| Total Serum Calcium (mg/dl) |  | Baseline, Day 15, Day 30, Day 60, Day 90 | 
| Serum Phosphorous |  | Baseline, Day 15, Day 30, Day 60, Day 90 | 
| 24 Hour Urine Calcium |  | 90 days | 
| 1,25 Vitamin D |  | Baseline, Day 15, Day 30, Day 60, Day 90 | 
| Fractional Excretion of Calcium | (Serum Creatinine X Urine Calcium)/(Serum Calcium X Urine Creatinine) | Baseline, Day 15, Day 30, Day 60, Day 90 | 
| Tubular Maximum for Phosphorous/Glomerular Filtration Rate (TMP/GFR) | Fractional tubular reabsorption of phosphate (TRP) = 1-{(U phos/P phos) x ( P creat/U creat)} if TRP < or = 0.86 then TMP/GFR = TRP x P phos if TRP > 0.86 then TMP/GFR = 0.3 x TRP/{1-(0.8 x TRP)} x P phos U= urine, P = plasma | Baseline, Day 15, Day 30, Day 60, Day 90 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteoporosis, post-menopausal, bone anabolic agents