Differential effects of teriparatide on regional bone formation using 18F-fluoride positron emission tomography

Abstract

Teriparatide increases skeletal mass, bone turnover markers, and bone strength, but local effects on bone tissue may vary between skeletal sites. We used positron emission tomography (PET) to study 18 F-fluoride plasma clearance (K i ) at the spine and standardized uptake values (SUVs) at the spine, pelvis, total hip, and femoral shaft in 18 postmenopausal women with osteoporosis. Subjects underwent a 1-hour dynamic scan of the lumbar spine and a 10-minute static scan of the pelvis and femurs at baseline and after 6 months of treatment with 20 mg/day teriparatide. Blood samples were taken to derive the arterial input function and lumbar spine K i values evaluated using a three-compartment model. SUVs were calculated for the spine, pelvis, total hip, and femoral shaft. After 6 months treatment with teriparatide, spine K i values increased by 24% (p ¼ .0003), while other model parameters were unchanged except for the fraction of tracer going to bone mineral (k 3 /[k 2 þ k 3 ]), which increased by 23% (p ¼ .0006). In contrast to K i , spine SUVs increased by only 3% (p ¼ .84). The discrepancy between changes in K i and SUVs was explained by a 20% decrease in 18 F À plasma concentration. SUVs increased by 37% at the femoral shaft (p ¼ .0019), 20% at the total hip (p ¼ .032), and 11% at the pelvis (p ¼ .070). Changes in bone turnover markers and BMD were consistent with previous trials. We conclude that the changes in bone formation rate during teriparatide treatment as measured by 18 F À PET differ at different skeletal sites, with larger increases in cortical bone than at trabecular sites. ß

18F-fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: A prospective, randomized, controlled clinical study

“…In agreement with a previous single-arm study of postmenopausal women with osteoporosis treated with TPT for 6 months by the same authors, (23) percentage changes in K i were greatest at the hip (Table 2, Fig. 3).…”

“…The early timing of the DXA scan limits any useful comparison with other studies, but results from the pivotal fracture trials of TPT showed that changes in areal BMD are greatest at the lumbar spine, with only relatively modest gains or even loss in BMD being seen at the hip. (35)(36)(37)(38) As observed in an earlier 6-month study of the effect of TPT treatment at the lumbar spine, (23) there was a disparity between the changes in regional bone formation and results from studies of the effects of teriparatide on BMD at the spine and hip. (35)(36)(37)(38)(39) The increases in BMD at the hip are relatively modest compared with those observed at the lumbar spine.…”

“…(24) Increases in K i in response to the anabolic treatment TPT have been observed in the current randomized, controlled 12-week study and an earlier single-arm study of the long-term (6 months) effect of TPT treatment at the lumbar spine. (23) It must also be demonstrated that the measurement parameter K i is measuring a clinically relevant biological process and that measurement precision is acceptable. 18 F-fluoride PET has been validated by direct comparison with bone biopsy in one animal study (9) and one clinical study.…”

“…For each subject in the present study, the population residual curve was scaled for injected activity and, after adjusting the time of peak count rate to the time determined from an ROI drawn on the dynamic scan over the femoral artery, the scaled and time-adjusted population residual was added to the individual's terminal exponential curve to obtain the 0-to 60-minute arterial plasma input function used for kinetic analysis. (23,27) The data from the PET dynamic scan were processed using Patlak graphical analysis to estimate regional bone plasma clearance of 18 F-fluoride to bone tissue (K i ) at different sites at the hip and pelvis. The Patlak plot, described in full elsewhere, (12,19,28) is a graphical analysis technique that assumes that 18 F -is taken up by two compartments, a central compartment that is in rapid equilibrium with plasma and a peripheral bone mineral compartment that tracer enters without ever leaving during the time of the measurements.…”

“…(18)(19)(20)(21) The most important role of 18 F-PET is likely to be in clinical drug development, and a number of studies have demonstrated that it is possible to quantify the direct effects of long-term pharmacological treatments for osteoporosis and other metabolic bone diseases on bone formation rate at the spine and hip. (15,(22)(23)(24) The primary objective of this study was to determine if 18 F-PET can be used as an early noninvasive biomarker of treatment efficacy at the hip by examining changes in regional bone formation rate at the proximal femur in a prospective, randomized, and controlled study of postmenopausal women with osteopenia treated with the anabolic agent teriparatide for 12 weeks.…”