Comparison Study of PTHrP and PTH to Treat Osteoporosis

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.

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