The Effects of Alendronate After Cure of Primary Hyperparathyroidism

Study Purpose:

Hypothesis: After successful surgical cure of primary hyperparathyroidism alendronate provides even greater beneficial skeletal effects than parathyroidectomy alone.

Primary hyperparathyroidism (PHPT) is typically a disorder of mild hypercalcemia. Skeletal involvement can be demonstrated when bone densitometry is performed. Effects of excess PTH on bone include preferential involvement of cortical bone (e.g. forearm) and relative sparing of cancellous bone (e.g. vertebral spine). Bone properties, such as bone turnover, size and geometry, are also altered in PHPT. The only cure for PHPT is removal of abnormal parathyroid tissue. In the absence of medical intervention, bone mass increases briskly after successful surgical treatment of PHPT. Parathyroid surgery also promptly reduces bone remodeling, typically increased in PHPT, to normal values. Bone resorption markers fall first, followed by bone formation markers. The difference in time course between the rapid fall in resorption markers and the more gradual fall in formation markers provides a window of time when bone mass increases rapidly. The post-surgical increase in BMD is attributed to a filling-in, or mineralization, of the enlarged, PTH-driven, remodeling space. Whether further gains in bone density could be achieved with more prompt and greater suppression of bone resorption in the postoperative period is unknown. The potent bisphosphonate, alendronate (Fosamax), reduces bone remodeling and enhances secondary mineralization. It has been shown to increase bone density in subjects with PHPT who do not undergo parathyroid surgery. The goal of this project is to test the hypothesis that after successful surgical cure of PHPT, alendronate provides even greater beneficial skeletal effects than parathyroidectomy alone.

Study Design and Statistical Analysis:

The clinical investigation will have as its primary outcome variable an increase in lumbar spine density (DXA) when alendronate is used during the first year after surgery. The patients will be stratified by BMD upon presentation, because we have shown a variable response to parathyroidectomy depending on initial spine BMD. The study design is a randomized, double-blind, placebo, 1-year, controlled clinical trial, in which patients will receive alendronate 70 mg weekly or a placebo tablet identical in appearance. As a secondary endpoint, we also plan to examine the effects of alendronate after parathyroidectomy on bone structure and skeletal dynamics using sensitive, state-of-the-art, non-invasive quantitative tools. With central and peripheral quantitative computed tomography, we will investigate changes in bone size, geometry and cortical porosity in cancellous and cortical bone. With serum and urinary markers of bone turnover, we will determine whether alendronate hastens control of bone resorption, thus enhancing the discordance between bone formation and resorption and leading to even greater improvements in bone mineral density.