Early Effects of Parathyroid Hormone (PTH) on the Proximal Femur

Osteoporosis with consequent hip fractures causes substantial disability, morbidity and
mortality. Teriparatide (TPTD), the aminoterminal fragment of parathyroid hormone (PTH),
increases bone mineral density (BMD) and bone strength and reduces fracture incidence
throughout the skeleton, but data confirming specific efficacy against hip fracture will
never be available. Histomorphometric studies after 18-36 months of TPTD treatment show
improvements in bone volume and structure in the iliac crest. Both biochemical and
histomorphometric investigations of the iliac crest at very early time points (within 4-6
weeks of administration) show that bone formation is dramatically stimulated. Apart from the
beneficial effect of TPTD on bone density and bone strength by finite element analysis at the
hip, nothing is known about the mechanism of the effect of TPTD on the proximal femur. While
BMD changes are smaller and slower in the hip in response to TPTD than in the spine, it is
possible that stimulation of bone formation on the periosteal bone surface could result in
expansion of bone size, obscuring the increase in non-invasively measured BMD. The current
study will provide evidence for or against this possible TPTD-induced periosteal expansion.
From a clinical perspective, it is unclear whether TPTD would be preferable to other
osteoporosis medications, such as zoledronic acid, in patients at high risk for hip fracture.
TPTD induced bone formation in the femur would be expected to improve bone strength and would
provide a mechanistic basis for the use of TPTD in patients at high risk of hip fracture. The
proposed project is the only practical and ethical way to obtain information on the effects
of TPTD on bone formation in the proximal femur in humans. In patients undergoing total hip
arthroplasty (THA) for degenerative joint disease, the hip samples of greatest interest are
extracted routinely during the procedure. At the same time, an iliac crest biopsy can be
taken with minimal added time and risk. The protocol has the following Specific Aims:

In patients undergoing elective, noncemented total hip arthroplasty (THA): 1. To determine
the early effects of 1-34hPTH (teriparatide; TPTD 20 mcg) vs placebo, administered
subcutaneously daily for 6 weeks, on histomorphometric indices of bone formation in
cancellous and cortical bone of the proximal femur (femoral neck and intertrochanteric bone)
and iliac crest. 2. To evaluate the association between changes in biochemical indices of
bone turnover and histomorphometric indices of bone formation in the proximal femur (femoral
neck and intertrochanteric bone) and iliac crest over 6 weeks of treatment with TPTD vs.
placebo. 3. To determine if circulating osteoblast precursor cells increase over 6 weeks of
treatment with TPTD vs Placebo and to compare the change in size of this osteoblast precursor
pool with the change in a biochemical marker of bone formation and indices of bone formation
in the femur and iliac crest.

Inclusion Criteria:

- Age 50-90 years old.

- Male or postmenopausal (women who have had no menses for one year)

- Degenerative joint disease of the hip (osteoarthritis) requiring total hip
arthroplasty, based on radiologic and clinical impression.

Exclusion Criteria:

- Any contraindications to use of TPTD.

- Age younger than 50, greater than 90 years old.

- Metabolic bone disease other than osteoporosis.

- History of hyperparathyroidism without surgical correction.

- Unexplained hypercalcemia.

- Paget's disease (or unexplained elevated bone alkaline phosphatase level).

- History of any metastatic cancer or osteosarcoma.

- Prior radiation treatment.

- Secondary hyperparathyroidism due to vitamin D deficiency or renal disease. Active
hyperthyroidism or excessive thyroid hormone replacement (with TSH below normal
range).